Podcast

INTERVIEW TRANSCRIPT

Ingrid Kohlstadt, MD, MPH

Integrative Medicine Physician Specialist

www.ingridients.com

Those of you who have been long-term supporters of Functional Medicine Update recognize that we have done the remarkable. We’ve just transitioned from our 33 years of monthly editions into a new format, which is a format that is taking it live to the world through a non-subscription-based service that we’re quite excited about that allows this extraordinary resource that we’ve developed of speaking to so many remarkable leaders in the field of biomedicine and healthcare for their contributions historically to be better well-known and to be more accessible. There was no one that I really thought could better exemplify what we’re trying to do in this new format than our clinician and leader for this first edition, Dr.  Ingrid Kohlstadt.   Let me tell you a little bit about Ingrid. She and I have had a collegial friendship now for the better part of 20-plus years. She is an MD and an MPH graduate of Johns Hopkins School of Medicine, and faculty associated with Johns Hopkins at the Bloomberg School of Public Health, and as you probably know if you follow this field her voice is widely circulated, her opinions are sought after as her double board both in preventive medicine and nutrition. She earned a Master’s degree in public health and epidemiology, an undergraduate degree in biochemistry, and is a Fellow of the American College of Nutrition and the American College of Preventive Medicine. She has recently completed a two-year appointment in the US Food and Drug Administration (the Office of the Commissioner in the Office of Pediatric Therapeutics), and her goal is to transform the health of children and their families through nutrition and it’s profoundly shaped by her clinical public health research and regulatory activity. And she just recently got back—if it was not enough, what I’ve already said—from a stint in Antarctica, and that’s probably a whole other chapter of her life that would be interesting to explore. She’s been a world leader in all things that relate to lifestyle management, weight management, nutrition, and in particular her strong support and education as it relates to problems with children in their developing years.   Dr. Kohlstadt, it’s just such a pleasure to have you as our lead off in our new Functional Medicine Update format, and I think probably—as would be logical—the first question I might ask you is just by going over your truncated biography you clearly have traveled an interesting road less traveled in your medical experience. How did you get into this area of this wide, diverse series of opportunities, and foci, and what does that mean in terms of your passion and the way that you’re taking your career and really making it work for people in improving their health?   Early Research Focus on Trans Fats IK:           Wow, Jeff, thank you for that introduction. Kind and generous as always. Let me just point out that the opportunity that you’ve given me to talk with you and be the first, as I understand, on your new format for the Functional Medicine Update—and congratulations on those 33 years and counting, by the way; it’s certainly been an influence in my career—I wanted to make it clear that what I’m sharing are my own opinions right now—that I’m not representing my previous work at the Food and Drug Administration or my role as an Associate at Johns Hopkins Bloomberg School of Public Health, or the NutriBee nonprofit organization that I founded based on my work at the School of Public Health.   I am appreciative of my mentors and also the opportunities early in my career. I think that when you pose the question the sentinel event, if you will, that caused my interest in metabolism and looking at the metabolic underpinnings of disease started in 1989. I was studying biochemistry at the University of Maryland and had received from the Rotary Club an international scholarship—an exchange year—at the University of Tubingen in what was then West Germany. That’s also co-located with the Max Planck Institute, and it was there at that institute, they were looking at trans fat and the effect of trans fat from the diet on human health. And this fascinated me, that if someone ate butter or margarine virtually inconsequential that after two or three months you could actually measure changes in that person’s biochemistry. You had biomarkers to hang your lab coat on based on those dietary changes, and that fascinated me. But was more intriguing—in fact, I paid so much attention to it—was because later that year in 1989 I went back across the pond back to the US to start medical school, and in the biochemistry class there we were reminded about the overconsumption of saturated animal fats (also true) and that therefore margarine was better than butter.   But as it played out we know a lot more about trans fats today. Other than the naturally occurring ones, which are the much lower concentration than those consumed in our diets from processed food today, they really don’t have a place in the diet. And today you can see the effects of that early research from 1989 when you look at the diets in Europe and you look at the diets in the US, to the connection between the basic science and clinical research and public policy, it’s a very interesting forum for me. I saw ready application between the science that I was learning and being able to improve the health of the entire public. So that excited me.   JB:          That is a fantastic example. You know, you have a quote in your writing that I think really exemplifies. It’s like a Rorschach test of your diverse and—I think—very impactful opinion and background. I’m going to quote it and this is from you: “Nutrition is much broader than health. It is an expression of the interconnectedness with the earth and future generations with each other and those who have gone before us.” Now that is a very interesting definition of food, nutrition, and dietary relationships not only to physiology but to the experience that we call life, both as the individual and as a community. Just through that quote we understand so much about you and your perspective. How does that translate over? That’s a very expansive view and for some people it might be, “Oh, my word, that sounds like philosophically so broad. How do you ever make sense of that?” How does that translate over into the way you communicate with patients, the way you do your work, how you see your mission?   Nutrition: From Clinic to Classroom IK:           That’s a poignant question when you go about your everyday doings and your research you don’t necessarily stop and think about that. Certainly placing a value on the health of our children, the health of our future every day is really important. It’s also important for young people to see. It’s the “show them” rather than the “teach them” approach. I think when you look at nutrition and metabolism in clinical practice, one of the things we could be doing more and something that I’m really striving to do, and have taken some risks in my career in a hope to achieve them or have an impact on them, is the ability to reach across the aisles. I’m not talking Democrat/Republican. I’m talking about reaching across from the clinic to the classroom. Where clinicians work with families, teachers are working with classrooms. There’s very little cross-talk. In fact I know of no forums that bring school teachers and doctors together on a regular basis. So I’m striving for more communication between doctors and teachers.   One thing that influenced me greatly is the Institute of Medicine’s report from 2012. It was the findings of the committee tasked with researching childhood obesity. The report was called Solving the Weight of the Nation.[1] They said that with a 20-hour hands-on classroom learning in the areas of nutrition and physical activity each year, they measured two effects: they found that this 20-hour intervention improved standardized test scores and they also found that it reduced absenteeism. I thought, well this is just music to the ears of any elementary school principal, so I was excited about working with the National Association of Elementary School Principals. I rented a booth at their national convention in Baltimore a few years ago, only to find that…the only shortcoming with it was that the Institute of Medicine report wasn’t known to the school principals. It was only on the medical side, it wasn’t on the teaching education side of things. So that’s when I formed the NutriBee program. I developed it and researched it at Johns Hopkins. I was inspired by a quote by Yogi Berra, the late Baseball Hall of Fame catcher. He had some great quips and one of them is, “When you come to a fork in the road, take it.” I kept saying, “This is the fork!” I mean what you put on your kids’ plate and what they fill their fork with—what they put in their mouth—can change their health, so take the fork! And that has been my motto, in a way: Take the fork!   Studying the Use—and Consequences—of Obesogenic Medications in Children JB:          That is a great metaphor. And, you know, your probing mind has taken that into a very interesting place—a place that I had never thought about that was a real ah-ha for me and I’m sure for tens of thousands of other people, and that is your advocacy in the area of medications that children are on, and how that influences their metabolism and their weight, and this concept that 31 percent of 385 products that are drug products can influence a child’s weight. You’ve got a couple of extraordinary publications in this area. One is titled “Clinician Uptake of Obesity-Related Drug Information: A Qualitative Assessment Using Continuing Medical Education Activities.”[2] That’s in Nutrition Journal. And the other is in the Jacobs Journal of Neurology and Neuroscience titled “Systematic Review of Drug Labeling Changes That Inform Pediatric Weight Gain.”[3] Can you tell us a little about this? This is, I think, for a lot of people real new news.   IK:           This is an area where we as medical doctors can really have a voice, and I think the work that you have done in functional medicine provides us with very useful and important tools for helping kids reclaim their health following the side effects of medications. What may have influenced me most on this was it was in the mid 90s. I was serving as an itinerant physician, doing locum tenens work in the outer reaches of rural America, including on some American Indian reservations, where the Native American communities have been especially affected by diabetes. I diagnosed two girls in their teens with type 2 diabetes, which at the time was almost unheard of. We thought for sure that there was some type 1 component to it, but in fact it was really genetic, environmental, and epigenetic factors all converging on these kids and it was type 2 diabetes. We didn’t know how to treat it. In addition to making the recommendations about healthful lifestyle physical activity, many people advised us to begin teenagers on insulin. While I was at the FDA I had a little more insight into the decision-making process on that and there really were few alternatives to medications for these teenagers. You know the challenge with teenagers and giving them insulin for type 2 diabetes is that insulin promotes appetite, it promotes weight gain, so we were making their appetite less easy to control at the same time we were encouraging them to eat less and exercise more. It was really doing them a disservice. We’ve come a long way in 20 years. There are so many more ways that we can treat teenagers pharmacologically who have type 2 diabetes. But we also can see the diabetes developing. We can see it coming more like a slow moving train. And one of the more difficult things for medical doctors, in my opinion, has been a blank prescription pad. When we see a child who is struggling with the need for taking obesogenic medications like corticosteroids to manage their asthma and then they gain weight, and then of course the weight gain adds to their obesity, then the obesity in turn adds to the asthma, and the asthma makes it more difficult for them to exercise and then they gain more weight and they need more steroids. This is a vicious cycle that is very difficult to intercept. I think there are non-pharmacologic therapies that can be used in conjunction with pharmacology to have a big impact. That’s one of the ways our NutriBee program is working. It’s a 20-hour intervention much like those recommended by the Institute of Medicine that can be used in conjunction with medications known to be obesogenic.   Special Concerns about Autism and Atypical Antipsychotics The articles that you mentioned reference some of my publications on the atypical anti-psychotic medications in kids. These are used for managing symptoms associated with autism. One of the first challenges with the psychotropic medications, and particularly the atypical antipsychotics is that they affect the liver, the ability to take triglycerides from the bloodstream and use them as energy. They essentially interfere with the body’s natural metabolism. And if you use these in kids with autism, they’re already not able to communicate some of their symptoms—if they have discomfort or they have a craving for a certain food—so they’re limited in their ability to say something is going on, something’s not right with me. So the medication may be interfering with diagnosing the underlying problem, and it may also accelerate the weight gain and influence what foods and how much food the child takes in.   Sometimes people confuse the symptoms with autism and say, “Oh this is a treatment for autism.” It’s not a treatment for the underlying problems with autism. It’s a way to manage the aggression and some of the other symptoms associated with autism. So I think that’s an important distinction. The other concern with autism and the atypical antipsychotics is that clinicians are largely unaware of the metabolic side effects of these medications and aren’t screening for them early enough and when they start to see changes in liver function tests, even if they are screening early enough, then they need to back off on the amount of the atypical antipsychotic medications and it may be too low to be within the therapeutic range. In other words, the metabolic side effects may actually prevent the use of the medication or the safe use of the medication going forward, and that can happen within a year or so of the use, or within many years. That depends on multiple factors: the epigenetic factors and different aspects of that individual’s metabolism.   I had worked with the Office of Pediatric Therapeutics, which cross centers with the FDA on this issue, and then also the NIH. It was very interesting to look at the challenge from a clinician’s perspective, from a parent or care provider’s perspective, and also the patient’s perspective—to put on those different hats, and what should a regulator do? We soon realized there’s not any easy answer for that.   Another group of medications that are increasingly in use now and can influence a weight gain in kids is…there are several but the antihypertensive medications as a whole can do that, and it may be interesting for clinicians to know that the more centrally acting medications tend to be the ones that can alter satiety and hunger centers in the brain. So the more it acts in the central nervous system, the more likely it is to interfere with some of the very many centers in the brain for food preferences as well as satiety.   JB:          Well I know one of the things you’re a master at is helping children—people, in general—to modify some of their eating habits, and with kids you’ve particularly done some remarkable things in using the sense of smell and taste of food to guide nutrition and food decisions. Can you tell us a little bit? Because maybe that’s some of the antidotes to these other problems we’re having the medications, is to get kids to eat right.   Food Preferences, Hunger Cues, and the Developing Brain IK:           Oh, you know, that’s an excellent point. That’s certainly true of the atypical antipsychotic medications. That if you’re able to make someone aware that just because your sense of hunger is a sign that you are to eat: you eat when you are hungry and you choose the foods that taste good. But when you receive this medication, you can’t rely on those cues anymore. Your body will be hungry even when it does not need food. Your body will wish for foods that it does not need. And if you tell the parents or care providers that, and you tell the patients (not necessarily patients with autism; some of them aren’t aware enough of that effect), this is a general rule for many medications that you can instruct people. It’s especially important to instruct kids because when we say that the brain is developing until age 18, we probably ask what parts of the brain are developing? It appears that the centers for taste and satiety—for food preferences—are some of the last to develop. The developing brain—the teenage brain—is definitely learning, laying down, those lifetime food selection habits, and that makes it an especially vulnerable time. I focused on the ages of 10 to 12, partly because of a conversation years ago with Robert Wood Johnson Foundation when they said that was the area where there were the fewest resources for helping kids make healthful choices, and also because of the Institute of Medicine’s concern that the advertising for foods that aren’t in the kids’ best interest is drifting down beyond the age of 12. (So lower than the age of 12, which had been the agreed upon age for limiting commercials.) I mean, we’re affected by commercials in adulthood. We like to think we know better, but advertising is becoming more and more persuasive.   One of the ways I developed successful non-pharmacologic interventions for youth—specifically the NutriBee program—is to draw from the resources of these advertisers. Their research is state-of-the art for behavioral medicine, it’s just that people haven’t taken that research and applied it to nutrition very often. Some of that research is around the smell and taste, or chemosenses. I wrote an article in Time magazine, partly because I felt compelled to as a physician/scientist, and it was called “Coming to Our Senses.”[4] I think we really need to aptly do that: come to our senses and recognize that our chemosenses (smell and taste) are underutilized in our society. It may seem obvious when you look at it, but they’re really rather subtle changes. Our instruction has become more online instruction, and when we teach using the computer—I’m a big fan of incorporating computer technology, virtual classrooms, webinars—we don’t have a way to engage the sense of smell and the sense of taste. So as more curriculum and more instruction is in this visual/auditory realm, we need to consciously promote smell and taste in the classroom when we are in person with people. The other aspect about food is that it is very social, and we take our cues not only from smell and taste but how other people model their interaction with the smells and tastes of food.   One thing we do in the NutriBee program in our very first module on the very first day is we tell the kids, “Thank you for being McCormick Company’s taste testers.” They’re not—this isn’t affiliated with McCormick; only that McCormick is a company in Baltimore and I’m born and bred from Baltimore so I incorporated that bit of local history into the curriculum. They taste hot chocolate. They taste hot cocoa. And they learn the difference between cocoa and chocolate. Cocoa (cacao) is the product that comes from the trees before it meets sugar. Once it meets sugar it’s chocolate. They get to taste different spices added to their hot cocoa, different sweeteners added to their hot cocoa. And some people think peppermint is the best, others vanilla sugar—oh, a little bit of vanilla sugar is great. Or cardamom—they’ve never had cardamom before and now they get to add it to their hot cocoa and see how it tastes.   So we enlist them as taste testers, and by doing that they hear each other’s reactions, so this becomes social eating. One of the first things they say is “Yuck” and “You like that? Eww!” And then we remind them, “Don’t yuck my yum.” That’s one of the rules: don’t yuck my yum. Why would McCormick Company or any other food companies or spice companies need taste testers if everybody liked the same thing? The employees could just taste it and they’d be done with it and say, “Okay, this one tastes the best.” The point of tasting is that it is an individual response. So when food is healthful as in the case of NutriBee—we serve only nourishing foods—then the rule becomes don’t yuck someone else’s yum. That engenders a discussion that gets a lot of good results among the kids.   I think there’s another aspect of smell and taste that really intersects with functional medicine that I’d like to address, and that’s the aspect of metals—that minerals are bioactive in the brain. They cross the blood-brain barrier and influence our senses of smell and taste. Could I elaborate on that?   JB:          Yes, I wish you would. I think that’s very important.   How Metals in Minerals Influence Smell and Taste Senses IK:           Good. My interest in this was piqued by Richard Anderson. He is an excellent scientist/researcher at the USDA Agricultural Research Service in Beltsville, and he researched chromium. Now chromium is taken up by the same transport molecule as iron, and what interests me about iron deficiency was that it causes people to eat unusual foods. They actually crave ice and dirt, and I witnessed this firsthand, especially in my clinical work in developing countries. It’s given a name; it’s called pica. There are several problems with pica—the dirt can then cause kids to develop worms and other illness, so it’s complicated from a medical side. But just that iron can interact with something in the brain and we still don’t know what that something is. Now PET scans are giving us a clue. You do the spec, the MRIs that can help you locate active parts of the brain, and you get a little more idea of what’s going on. But chromium influences food choices also and most of that literature comes from livestock, so agricultural research, and it does apply to people as well. The problem with looking at blood and serum levels of chromium is that you’re trying to identify a penny in a million dollars worth of pennies. It’s a picagram level, so we can’t really measure it. If we can’t measure it we tend to put less emphasis on it.   But what about other metals in minerals? What about zinc? Oral rehydration salts contain zinc. Pedialyte, the most commonly prescribed one, does. I’ve seen people go from yum to yuck within a day with Pedialyte. First they drink it and if they really need the zinc particularly: “Oh, you gave me some water and it tastes a little different and it tastes good” to “Oh my goodness, what did you give me?!” They spit it out and if you spit it out your body doesn’t need it. So we’re not really assessing zinc and chromium or using smell and taste to measure minerals, but if you think about smell and taste as being mass spectrometers that are within our body—our own personal individualized mass spectrometers—I think you start paying more attention to smell and taste.   JB:          Yes, I think that that is a hugely interesting topic. I recall many years ago—in fact, in Functional Medicine Update back in the 1980s—we interviewed Dr. K. Michael Hambidge, a pediatrician/researcher at the University of Colorado, who was studying Hispanic children who were short in stature for age. What he did is he was assessing the threshold of the taste of sweet and salt and found out there was a functional zinc insufficiency, and when these children were repleted with zinc that suddenly they started tasting sweet and sugar much more effectively at much lower concentrations. Their diet improved and they grew in stature. I mean, these kids were actually in a functional nutritional deprived state, and as their appetite and chemosensory perception improved so did their growth and their development. So I think what you’re saying is extraordinarily important.   It also reminds me—as you were talking about the taste and the variety of things that come through spices—if we look back historically at what drove Europeans to travel over the oceans and put their lives in jeopardy and put their lives in jeopardy in sailing ships, a lot of that was really created by the desire for spices and the exploration of the Spice Islands. Magellan, actually for his three ships it was their objective to go out and to fill the ships with spices—the cinnamon, the cardamom, the cloves, black pepper. This was more than worth its weight in gold at the time. Clearly this is a big driver for us to find these tastes, or the economics of food would be entirely different without the exploring new territories in the world.   I think that there are a lot of extraordinary compelling reasons, sociologically, to get in touch with our senses, and how that then influences our eating habit which then influences our whole body’s physiology, so I think you’ve really done a fantastic job of weaving that together for us.   Let me, if I can, just close with a last question, and that is you have referred on a number of occasions to this extraordinary program, NutriBee, that you put together. Can you give us a summary? It sounds like something that people should know more about and come to the website to learn about.   NutriBee: A Program to Engage Children in Healthful Nutrition IK:           Oh great. I’d like to see us, as doctors, equipped with more non-pharmacologic therapies, even ones that we can use with pharmacologic therapies, so a program that I developed was the heartbeat, the vision, of the Institute of Medicine. It’s a 20-hour program to engage 10-to-12 year olds in healthful nutrition, and it takes some unique approaches to engage them. First of all, in model, it brings teachers and physicians together; they co-instruct this program. And for most participating instructors, the teachers and the doctors haven’t had an opportunity to bridge the classroom and the clinic in this way. We implement it in clubs (after school clubs) and summer camps, so that the 10-to-12 year olds who have asthma or have a food allergy or some chronic condition associated with hypertension or weight gain isn’t saying, “I’m tired of going to the clinic. I want to be a ‘normal’ kid.” What we tried to do is move it from a “have-to” (the clinic and the classroom feel like have-tos most of the time, those settings do to 10-to-12 years olds). So we tried to move it into a “get to,” like at camp: “Oh, I get to go kayaking and learn something about nutrition. I get to hang out at Girl Scouts [one of our partners]. We get to work together and play together, and oh, I’m going to learn about nutrition.” So moving it into the space from “have to” to “get to” is really vital because we’re trying to communicate and educate the kids on life-long skills, but 80 percent of memory is volitional. So if kids are sitting there—“I don’t want to be here. This isn’t interesting. This isn’t relevant to my life at this time.”—they’re only going to remember 20 percent of it because 80 percent of memory is what we decide we want to learn. We do several things to move the kids along into wanting to do this, and one of them is having their teacher role model learning from the clinician about nutrition, so you have their teachers modeling learning also. We have high school students who participate in developing online resources. They actually help make the curriculum and they link diverse interests, from making pottery and berry bowls to sports broadcasting to musical instruments to geocaching—interests you would not think at all related to nutrition on the surface, they explain how they’re excited about that and how knowing something about nutrition helps them better with their game. So peers—especially cross-age peers—can advance younger peers interests in a way that no one else can. That’s been a very popular and effective component of our NutriBee program.   I used the “Bee” because—like the spelling bee or the geography bee—we would like to be able to engage youth. But we had a dilemma in doing that because both the geography bee and the spelling bee, which are widely publicized and widely known here, are also very competitive, and the media is the message. If we tell people to relax and enjoy your food, don’t stress, and we’re providing a venue that is stressful, then that’s a problem. So we compete with teams, and we do this from a behavioral health perspective, too. Sometimes it surprises the teachers that our summary activity, the 20 hours of learning) is not didactic. They don’t take any tests. What they do, in fact, is have a game show, and the game show is the summary learning. So we had several teachers say, “Well it’s not complete; you don’t have some kind of record.” I said, “I have the scores to the game. I know what questions they answered and which ones they didn’t answer. I can tell a lot from that and mostly I can tell that they wanted to learn what they learned and they’re excited about it and now they’re going to remember it.”   Behavioral Science and Outcome Measures So that’s the difference between education and behavioral science. I partnered with a team at Hopkins whose been working in behavioral science for decades. I think that influenced me greatly to look at the outcome measures and make sure they are behavioral outcome measures. So our behavioral outcomes are: does this change what they eat? And it does; it changes the diet. And does this change psychosocial parameters, like their interest in nutrition—how relevant they think it is? They feel that they can make a difference and they can make a difference and they can make these changes? Do they feel empowered? And the answer to all of those questions was yes, which is very exciting to me. So right now we’ve transitioned our research findings into a nonprofit organization, which is focused on disseminating the NutriBee program nationwide. It was very important to us that we encourage kids to aspire to something that they could achieve, so we didn’t only want to engage their interest in nutrition, we wanted to say that there is a national program where you compete—in a good way, not like a stressful competitive environment; you work together in teams—to show that you are national leaders in nutrition and that the solution to our nutrition challenges of the future rests on you, the youth. We’re going to empower you, because we’re not going to be able to solve this challenge with nutrition and all that’s gone wrong in metabolism associated with the changes in nutrition over our lifetime. I think we can empower our youth to do that, and that’s what I like to see—the sense of empowerment. So we are committed to making sure that kids of all ethnic backgrounds and lower socioeconomic status also feel included in the program and have a way to participate even on the national level—that what they can aspire to they can also achieve.   JB:          That is exciting. So where do people find, then, information about NutriBee? Can they go to your website?   IK:           NutriBee.org is the program’s website and we definitely invite the dialog and the discussion right now, and we’re at the early stages of disseminating it nationally and this is great time to partner school teachers and medical doctors and other healthcare providers. People can say they would like a NutriBee program in their area and we will train them and help them launch a program in their community.   JB:          This is very exciting. This is really great news to use. Once again I just want to thank you for all your years of service, for the friendship and the scholarship, the leadership, and your commitment to really making a difference. This, I think, left us all with some really great takeaways as to how we’re going to be a little bit better as our advocacy in this new health continuum. Thank you so much, Dr. Kohlstadt, and we wish you the very, very best.   IK:           Thank you!   Biolography [1] Institute of Medicine. Accelerating Progress in Obesity Prevention: Solving the Weight of the Nation. Washington D.C., National Academies Press, 2012. Web. 26 February 2016.   [2] Kohlstadt I, Wharton G. Clinician uptake of obesity-related drug information: a qualitative assessment using continuing medical education activities. Nutr J. 2013 Apr 10;12:44.   [3] Kohlstadt I, Murphy MD. Systematic review of drug labeling changes that inform pediatric weight gain. J J Neur Neurosci. 2014;1(2):013.   [4] Kohlstadt, Ingrid. “Coming to Our Senses on Education and Nutrition.” Time. 2014 November 12. Web. 26 February 2016.

INTERVIEW TRANSCRIPT

  Interview: Gerry Curatola, DDS Rejuvenation Dentistry New York, NY http://www.rejuvdentist.com/   Here we are back at the microphone with Functional Medicine Update and, boy, we’re having fun with this new format in 2016 and our chance to spread our wings and flap globally here and hopefully touch on interests that people have as it relates to this emerging revolution that we’re seeing in healthcare. We’re really excited to revisit a topic that we’ve only really done in the 33 years of Functional Medicine Update, as I recall, twice before. It’s an emerging very important area in healthcare and that’s oral health and the oral microbiome and how that is in a relationship with systemic inflammatory disorders. We could not find a better person to represent this than Dr. Gerry Curatola. Let me give you a little background if you’re not familiar with Dr. Curatola. He majored in neurosciences at Colgate University and after graduation he attended dental school at the NYU College of Dentistry. In 1984, the Upper East Side dentist returned to the faculty as an Associate Clinical Professor in the Department of Cariology and Comprehensive Care and continued his postgraduate studies at the Pratt Institute at Harvard Medical School’s program in complementary and alternative medicine, as well as numerous programs in natural health, and he’s a leader, really, in where the tire meets the road: how appropriate dental care, the technology of the emerging understanding of oral biology, can translate into improved comprehensive care, not just for dental health but for systemic health.   Link Between Oral Biology and Systemic Health: Numerous Examples in the Medical Literature If you’re not familiar with what I’m saying, let me just give you a couple of thoughts, quickly, about what the medical literature is saying about this important topic in 2016. I’m picking at random a few of the more recent peer-reviewed published articles: “Periodontitis and Cognitive Decline in Alzheimer’s Disease,” so here we have the first connection.[1]“Periodontal Disease and Systemic Diseases: An Update for the Clinician,” focused on the diabolical diabetes mellitus and periodontitis.[2] Next, “Saliva as a Diagnostic Tool for Oral and Systemic Diseases,” looking at systemic inflammation where the origin is in the oral cavity.[3] “Obesity and Its Relationship to the Oral Microbiome.”[4] “Periodontics and Oral-Systeric Relationships,” with a focus on both obesity and diabetes, a review paper.[5] “Liver Cirrhosis and Chronic Periodontal Disease,” again showing the liver cirrhosis connection to this inflammatory condition.[6] “Chronic Kidney Disease Exacerbation with Periodontitis,” another review paper.[7] “Comparison and Prevalence of Periodontal Disease in Women with Polycystic Ovarian Syndrome versus Healthy Controls,” again showing a correlation because of the systemic inflammatory connection that influences ovarian function.[8] And the list goes on. I think you can get the drift that we’re seeing and witnessing a virtual revolution in the understanding of how important oral health is in systemic health. This has been obviously a topic of my interest for now going on 40 years, since I first met Dr. William Fisher when I was a professor in the 70s and he was a preventive dentist and doing all sorts of work in systemic health from an oral health perspective and it really introduced me to this topic. So it is with this kind of broad range introduction that I am thankful that we have Dr. Gerry Curatola to be our representative in this important area.   Dr. Curatola, thanks so much for joining us on Functional Medicine Update.   Dr. Weston Price: Oral Health Research Pioneer GC:         Thank you. Thank you, Dr. Bland. It’s exciting to be on the show and it was really a pleasure to be with you at the Functional Forum recently. You know, for me oral health is the 800-pound gorilla in the room in the wellness movement. I was listening to what you were sharing and in 2016 alone there have been five major studies. I got one just this past weekend—another study recently published linking, basically, oral pathogens to everything from Alzheimer’s to colon cancer. So we have one end to the other and you’re saying, well, the problem is is that the oral systemic link has been well established now. In 1916, Dr. Weston R. Price, who everyone in the functional medicine community is probably familiar with—in 1939 he wrote a seminal book called Nutrition and Physical Degeneration—but in 1917 this man made a major presentation to the St. Louis Dental Society, then a fledgling part of the American Dental Association, on “The Present Status of Our Knowledge of the Relationship of Mouth Infections to Systemic  Disease.”[9],[10] And he went on to say in a subsequent paper, “Dental Infections and Related Degenerative Diseases,” that the relationship between dental infection and degenerative diseases needs to be looked at as focal infections having effects far beyond the body.[11] This was unheard of, and really not accepted, and discredited completely back in the early 1900s, and here we are today with study after study emerging linking gum disease to a 700 percent higher incidence of preterm birth, a ten times greater chance of heart attack and stroke, a seven times greater chance of adult type 2 diabetes, which is also even in type 3 diabetes—what we look at with Alzheimer’s and neurodegenerative diseases as almost a type 3 diabetes. It’s extraordinary, this avalanche of research. What the problem is with physicians, dentists, and healthcare professionals alike is that most don’t really know what to do with it and they know about the oral microbiome, but their solution is brush and floss, see your dentist twice a year, don’t smoke, and a lot of dentists still support fluoridation and other things as preventative dental initiatives, which is as archaic as saying the world is square.   Cause or Effect? Exploring the Connection Between Periodontal Health and Systemic Disease JB:          Well, I think that’s an incredible intro into this very, very important topic, so let me be a little bit, if I can, a naysayer just to get the spirited conversation going. I’ve heard some people ask the question as it relates to the connection between oral health and systemic disease as to whether it is a cause or an effect, and I’ve heard people say, “Oh yeah, your oral health is poor because your health is poor, and so when your health is poor, it causes, then, your oral health to be poor.” Versus the other side of which is to say you oral health, when it’s poor, then creates poor systemic health. How would you respond to that?   GC:         Well, I think there is definitely a bidirectional component, especially in neurodegenerative diseases and in diabetes. So for example, people with diabetes tend to get more periodontal problems, they tend to get more dental infections and decay. Primarily in an unstable diabetic condition that’s the case. However, what we’ve seen is—in the other direction—when you have periodontal disease it’s more difficult to regulate blood sugar. So you do have this bidirectional thing going on, but we are now looking and finding periodontal pathogens in the lining of a woman’s placenta. We’re finding Fusobacterium nucleatum—it’s a commensal bacteria, but in an unstable state becomes a very nasty, thuggish, gram negative anaerobic bacteria that actually carries even other bacteria past the blood-brain barrier. And you see all kind of, you know, Porphyromonas gingivalis, a very nasty periodontal bug (pathogen) that has been found to be related to a 67 percent higher incidence of pancreatic cancer in men. We see there are really three routes that periodontal pathogens to systemic disease, and I’m not discrediting the fact that certain systemic diseases cause difficulty in maintaining good oral health. So that does happen. I mean, I’ve seen HIV virus ravage someone’s mouth, and not that their dental infection obviously related to HIV. As a matter of fact, in the 1980s when there was a case of a patient infected by HIV and they think it happened at the dentist, it was actually the dentist was an oral surgeon who deliberately infected the patient—essentially murder—with his own blood. But we find that saliva is amazing. It is incredibly protective. It actually brings nutrients to and from the oral microbiome and things like that. But again getting back to your question, there are three routes of access of dental infections to causing systemic illness. One is that bacteria in diseased gums actually permeate into the bloodstream, so in bleeding gums you have periodontal pathogens getting into the bloodstream, which triggers the liver to release C-reactive proteins that has inflammatory effects. So that’s one route, is this CRP as an inflammatory response. Then we see the direct invasion of these pathogens causing havoc in all kinds of different organ systems. And the third route is we’re really looking at the interleukin genes, and we’re looking at how it affects the immune response and causes immunosuppression. So there are three different routes that dental infections cause terrible problems in systemic wellness.   JB:          I think that’s a really superb overview of a tremendous amount of literature and very, very well stated. You know, it’s interesting. As I’m listening to you I’m thinking we have a lot of concentration on the gut and the microbiome now on what’s called “leaky gut”—kind of euphemistically this break down of the paracellular junctions. And yet we also recognize that that there are leaky membranes at every cellular level of the body, so you could have leaky gingival tissues, you can have leaky gums, and you can have leaky synovia, and you can have leaky brain, so all of these tend to conjoin themselves together. When you treat a patient, I guess the first question is how do you know what patients to treat when you have them sitting there in your chair, and secondly, once you identify the need to treat, what do you do?   Evaluating Dental Patients as a Physician of the Mouth GC:         Those are great questions. I have a protocol. I set up a very interesting new model for dentistry called rejuvenation dentistry. What you didn’t say in my background is I was an art minor. When I was in college I actually was a sculptor and still am a sculptor, and so the thing that I gravitated to dentistry about, it wasn’t just science, it was also art. I enjoy doing reconstructing smiles and things like that, but at the same time, when I graduated dental school I didn’t want to be a drill ‘em, fill ‘em, and bill ‘em dentist. I was really interested in being a physician of the mouth and I saw myself as part of a team, and I consider myself a vital part of the team now. I actually consult and work with a lot of functional medicine physicians: “Gerry, I’m sending a patient over. I don’t know what’s going on. Their blood sugar is this. There’s that, but the mouth is a mess.” So the first thing I do when I bring in a patient is I do a thorough intake on everything: diet, lifestyle, medications, medical history, dental history, including what their past dental experience is and dentistry has been like. Dentists tend to be extremely myopic. It’s part of being in a profession, working in a 2” by 2” cube that’s called the mouth. You know, we’re really doing microsurgery every day and a lot of dentists tend to focus on the hard tissues, meaning teeth and bone and things like that. But really with periodontal tissue the tone of the tissue, the tone of the tongue, what’s going on on the palate, and soft tissues of the mouth can show everything from leukemia to lymphoma to diabetes to candida infections. All kinds of things show up in the mouth, and I have a book that’s coming out later this year called The Mouth-Body Connection. It’s being finished right now. This mouth-body connection really looks at how people can self-assess and look in the mirror. Even Chinese medicine looked at the tongue as being a very vital diagnostic tool.   So the first thing we do is we do a thorough intake, thorough oral examination, intraoral/extraoral diagnostic photos, and then we get what is a footprint, periodontally, to check periodontal pockets, and there are nine different specific barometers we use when evaluating the gums. And then from that, you know, I have all kinds of transelimination. We try to limit exposure to patients of dental radiographs, although dental radiographs show a vital amount of information. We use digital radiography, but I’m using more transelimination, which eliminates the hard tissues (teeth in the mouth), and we can actually see a cavity without even to take an X-ray. So the diagnostic tools we have are absolutely spectacular. The cameras we use and everything else. Just even doing an upper GI or a lower GI, gastrointestinal guys will always tell you how we have diagnostic abilities that are far beyond what we could even do five years ago with the resolution of cameras and things like that. But from that—from this thorough intake and this thorough examination—we can then put together a treatment plan, and what I look at—foundational—is diet. So the first thing I look at. This is why, for example, fluoridation, which to me was an absolute disaster (public health disaster). We know it does nothing to remineralize teeth, drinking fluoridated water. It’s a poison, and it is something which is now responsible for major systemic issues, including skeletal fluorosis and dental fluorosis being widespread and epidemic, especially children and adolescent children now have 41 percent (over 4 out of 10) have teeth damaged by fluoride, making them more prone to decay. So fluoridation was never the answer to dental decay. To me the answer to dental decay is what Weston Price wrote back in the book on nutrition and physical degeneration. We have to look at diet and the amount of refined carbohydrates and sugars that people take in. It’s not that sugar goes on the teeth and causes a cavity, it’s the imbalance in the oral microbiome, and that is really the essence. So we have equally been focused on nuking—you know, the scorched earth policy—in the mouth. Products that kill germs on contact. Products that even put pesticides in them. The number one leading toothpaste in America has triclosan, a polymer, a known toxic, non-biodegradable substance which has done nothing to reduce the epidemic incidence of gum disease in this country.   So I don’t know if I went too far for you, Jeff…   JB:          No, I think that’s the story we’re really looking for because it’s a landscape, it’s a…   GC:         Terrain.   JB:          Yes, thank you. That’s a great word. It reminds me when you’re talking about the mouth, at the Institute for Functional Medicine, Michael Stone and his colleagues there have put together a nutritional assessment program so that the phenotypic signs of nutritional inadequacy can be better identified. This is kind of a lost art in clinical diagnosis, and one of the major portions that they teach is the mouth—the tongue, the soft tissue, the hard tissue, the gingiva. So I think what you’re talking about is right in the core of what a well-trained functional medicine provider would start to understand.   American Dental Association Recognized Periodontitis as a Microbiome-Mediated Disease GC:         Sure, and the sad part about this is that I’m trying to…you know, I lectured to 500 dentists just a couple of months ago. These, by the way, are biologic dentists, holistic dentists. Unfortunately an accurate understanding of the microbiome is just starting to take root in the dental profession. It is still very far off. I spent 17 years researching the oral microbiome, and I came up with a rational application to the epidemic incidence of gum disease as far back as 2003, I believe. The Journal of the American Dental Association stated periodontitis (gum disease) is a classic example of a microbiome-mediated disease (a biofilm-mediated disease). You know, the term microbiome was just coined in 2002 by Josh Lederberg, but prior to that we used to call it biofilm. These ecological communities were biofilms: skin, respiratory, gut, etc. The American Dental Association has finally recognized that periodontitis is a microbiome-mediated disease. In other words, it’s a community or a terrain, it’s not one bug. So more rational therapies got thought of, but even calling it that, many dentists still think…I lecture to dentists and I said, “What do you guys think of dental plaque as a biofilm?” They said, “Plaque is a biofilm of many different bacteria.” I said, “Well how should we manage it?” And they were all like, “Kill it. Kill plaque. Eliminate plaque.” You know, they were parroting what they hear from the major consumer products companies. Two major consumer products companies really sort of run the ADA and the messaging is still archaic, even though they funded a lot of the microbiome research in the mouth.   JB:          I think isn’t there a connection, also, I notice fairly heavy use of antimicrobials in dentistry to manage what is the presumed cause rather than looking systemically.   GC:         Yes, that’s my point. It is that the dentists still are in this kill plaque mentality when I try and teach them that plaque—dental plaque—is really an unhealthy expression of the oral microbiome. So in other words, that thick, smelly film that you wake up in the morning and it’s on your teeth is really an unhealthy expression of the oral microbiome. What we find now is that the terrain that is healthy—a healthy oral microbiome—is a thin, odorless film on all of the teeth and soft tissue and mucosal tissues in the mouth, and it plays a vital role in three things. It aids in digestion and is a very close cousin to the gut microbiome. As a matter of fact, bacteria are shared, and oral bacteria are constantly swallowed, going down. There are bacteria in the mouth called persistors that actually secrete a protein shell and make it through the hydrochloric acid in the stomach. There are an amazing variety of 600 different species of bacteria that we know of, and there could be 6 to 10 billion at one time in the mouth, but there is a broad diversity. I compare it to when I was a boy and I used to watch Jacques Cousteau’s underwater adventures. Jacques Cousteau invented the sport of scuba diving, but once we could stay underwater and look at the biodiversity that exists in our oceans it’s amazing. That biodiversity exists in our bodies, and so we’re on this Jacques Cousteau journey right now because we have some really great new tools that have enabled us to study the oral microbiome in its natural habitat, and these are confocal laser microscopy, metomic microscopy, which gives us a great 3D map, and even fluorescent probes. These types of tools enable us to study the microbiome and what we found is that, oh my goodness, you don’t want to kill it. You want to rebalance it. You want to promote microbial homeostasis. Because nuking it is actually not only ineffectual but harmful.   JB:          I think that is an incredible message because I believe that often we jump to simple-minded conclusions. We see something associated with something else and we assume the way to manage it, then, it to get rid of it, right? And then you get resolution. Interesting you had cited earlier in your discussion the arthritis-periodontal connection and I note reading recently a paper out of the New York State Dental Association Journal—I think this was last summer actually, in 2015—of rheumatoid arthritis and periodontal disease in which the authors suggested oral health parameters should be more closely monitored in patients with rheumatoid arthritis and the suggestion is that intervention in perio will improve joint health.[12]   GC:         Absolutely. As a matter of fact, the study that came out this weekend found that—and you were talking about this bi-directional thing, too and we’re looking at the bi-directional effect of the oral microbiome with the other communities. You know, you have the gut microbiome, you have the respiratory microbiome, genitourinary microbiome, skin…We’re looking at this bi-directional effect, but a paper just published—February 2016—on the relationship of periodontal bacterial in synovitis and juvenile idiopathic arthritis.[13] I continuously get updates on new studies that are emerging, but it’s fascinating. This is juvenile idiopathic rheumatoid arthritis.   Documented Link Between Periodontal Disease and Risk of Pancreatic Cancer JB:          I think that that again mirrors the systemic effect that we’re talking about, and you had also mentioned pancreatic cancer, and I think there was just recently, in January 2016, a very interesting epidemiological study in a journal called Pancreas titled “Investigating the Association Between Periodontal Disease and the Risk of Pancreatic Cancer” showing a significantly positive association between periodontal disease and the risk of pancreatic cancer.[14]   GC:         Absolutely.   JB:          I think we’re still searching.   GC:         Yes, it was actually Harvard University in 2006, the first to show the correlation between chronic periodontitis, chronic gum disease, and a 67 percent higher incidence of pancreatic cancer in men.   JB:          Yes, and I find this paper very interesting because they did quite a bit of work to remove other independent risk, such as diabetes, hyperlipidemia, allergies, hepatitis, peptic ulcer, pancreatitis, obstructive pulmonary disease for cigarette smoking, and alcohol-related conditions as a proxy for alcohol drinking. Independent of all of those was this fairly strong association. Again, I think we need to be cautious not to jump to a conclusion of cause and effect, but…   Prebiotics May Be the Future of Oral Care GC:         No, no, no. Exactly, you hit the nail on the head. These studies emerge and you see correlations, but definitely the mechanism is one of which…and I’ve described three different mechanisms in the mouth with direct infiltration or various inflammatory routes and responses caused by periodontal pathogens. But we really need good science continuing to explore this. But the one thing that I do know is that our approach and the types of oral care products that are being used right now drove me to develop a prebiotic formulation which I’m about to introduce next month. I received three patents for the work on this. It is called Revitin and revitin.com. If you go to the website you’ll see the whole microbial science. We have a slogan, “Make peace with your microbes.”   JB:          That’s good.   GC:         The most effective way to promote oral microbiome homeostasis, or the most effective way to get your mouth healthy again, is to take…what we found in our research is that taking a prebiotic approach, not a probiotic approach, because I started to say that the oral microbiome does three very, very important things. One, it protects you from deadly viruses and bacteria in the environment around us. So we know that there are a lot of bad bugs out there. What we have is a community of organisms. Our resident bacteria protect us in the mouth, especially because it’s a front line of defense. And I always say if your oral microbiome is healthy, you have a good chance of your sister microbiome, the nasal, the respiratory microbiome, also being healthier, and the gut microbiome, which the oral microbiome is connected to, having a more synergistic relationship. So the oral microbiome makes it very inhospitable for other bacteria from the outside to set up shop. I kind of get a chuckle out of seeing the attempt to drop in S saliveras and Lactobacillus in the mouth and thinking that probiotics, well if we drop in more good guys, you know, they’ll outnumber the bad guys, and it was like this good guy/bad guy thing. And I try to help people understand that the same bacteria, like a Fusobacterium nucleatum, in a balanced oral microbiome these are commensal bugs, they live there. They live there, they didn’t invade your mouth, set up shop, and go and attack the rest of your body. They live in the mouth. My research started in 1997, and I really was taking a nutritional approach. For me, toothpaste and most oral care products were invented by soap makers. A hundred years ago we had tooth powders and then we had basically flavored soap for the mouth. You know, you use soap on your skin. We put soap that was palatable in the mouth with strong mint oils, which by the way—peppermint oil and many other essential oils have strong antimicrobial effects that are disturbing to the oral microbiome. So I said to myself, “Gee, we’ve got to get out of the soap business and start promoting organic gardening in the mouth.” I was on Martha Stewart’s show about eight years ago and I said, “We need to start doing organic gardening not just outside our bodies, but in and on our bodies as well, because have this wonderful community of organisms we live with called the microbiome.” Like Rodney King said after the LA riots, “Can’t we all just get along?”   JB:          I think that’s a really great metaphor: organic gardening in the microbiome. It’s interesting because Dr. Marcel Roberfroid from Catholic University Louvain in Belgium was the gentleman who actually coined the term “synbiotics” and he had worked extensively on probiotics over the last 35 years and his group included Patrice Cani and Nathalie Delzenne, who are really carrying forward this whole concept of the microbiome as it relates to diabetes and obesity. His comment was that if you really want to establish the appropriate community you need prebiotics as your principal approach because that’s where they’re going to take their message, from the food that their eating. It’s interesting how history reinforces itself in different disciplines.   I really want to thank you. I think what you’re doing is absolutely at the cutting edge of whole-body health. I know you’ve got some things you’re going to be doing in the media here soon to help broadcast this better. Tell us a little bit about that.   GC:         That started awhile back. I had an opportunity over the past 15 years to be an oral health expert to various networks and shows, and made three or four appearance on Dr. Oz. The producers were like, “There is such a need for the information that you’re speaking about to get out there. We really want to talk about doing a show.” And that started this PBS program that is going to be airing later in May of 2016 called The Dr. Gerry Show. They couldn’t come up with a name so I go by “Dr. Gerry” so they came up with The Dr. Gerry Show, which my wife then said, “It’s been the Dr. Gerry show for all the years of our marriage.” I guess there’s Dr. Phil, Dr. Oz, Dr. Laura, and now there’s Dr. Gerry. The Dr. Gerry Show is focused on the latest science and has a science component on technology, but takes a unique look at the oral systemic link as well. We’re very, very excited to bring a lot of the microbiome research forward with some great people on the show. We’ve got Marty Blaser from NYU who has done an exhaustive amount of work on the human microbiome.   JB:          Yes, we had the chance to interview Dr. Blaser about his book and he did a fantastic job in giving us our first primer in the microbiome.   GC:         We love that. We’re looking at toxicity, we’re looking antiaging. I guess if you could sum it up we’re really solidly planted in the middle of the functional medicine world and I’m looking at the show as a means of bringing all of us together in a way to communicate effectively to everyone around. So whether it is Mark Hyman or yourself who has been father of functional medicine for so many years. You know, Jeff, I have to tell you one of the things I really enjoyed hearing you say is you actually had a little background in dental research yourself.   JB:          Yes, that’s actually how I got started in this whole area with Dr. Fisher back in the 1970s. He was a prominent dentist at the time in the Seattle community. Well, Dr. Curatola I want to tell you how much we appreciate this. This is a great step off for us in 2016 with Functional Medicine Update. It opens the field of discussion to a greater extent to where we want to be. We wish you the very best and we’ll keep in touch with you. It sounds like your advocacy is really going to create some great positive change in the field.   GC:         Well, thank you so much and I really appreciate the invitation to be on. I enjoy doing these so much and it’s really a pleasure and honor to be with you as well.   JB:          Likewise and we’ll talk soon. Be well.  

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Bibliography

[1] Ide M, Harris M, Stevens A, Sussams R, Hopkins V, et al. Periodontitis and Cognitive Decline in Alzheimer’s Disease. PLoS One. 2016 Mar 10;11(3):e0151081.   [2] John V, Alqallaf H, De Bedout T. Periodontal Disease and Systemic Diseases: An Update for the Clinician. J Indiana Dent Assoc. 2016 Winter;95(1):16-23.   [3] Javaid MA, Ahmed AS, Durand R, Tran SD. Saliva as a diagnostic tool for oral and systemic diseases. J Oral Biol Craniofac Res. 2016 Jan-Apr;6(1):66-75.   [4] Atabay VE, Lutfioglu M, Avci B, Sakallioglu EE, Aydogdu A. Obesity and oxidative stress in patients with different periodontal status: a case-control study. J Periodontal Res. 2016 Mar 2.   [5] Glascoe A, Brown R, Robinson G, Hailu K. Periodontics and Oral-Systeric Relationships: Diabetes. J Calif Dent Assoc. 2016 Jan;44(1):29-34.   [6] Gronkjaer LL. Periodontal disease and liver cirrhosis: A systematic review. SAGE Open Med. 2015 Sep 0;3:2050312115601122.   [7] Sharma P, Dietrich T, Ferro CJ, Cockwell P, Chapple IL. Association between periodontitis and mortality in stages 3-5 chronic kidney disease: NHANES III and linked mortality study. J Clin Periodontol. 2016 Feb;43(2):104-13.   [8] Rahiminejad ME, Moaddab A, Zaryoun H, Rabiee S, Moaddab A, Khodadoustan A. Comparison of prevalence of periodontal disease in women with polycystic ovary syndrome and healthy controls. Dent Res J (Isfahan). 2015 Nov-Dec;12(6):507-12.   [9] Price, Weston A. Nutrition and Physical Degeneration 8th Edition. Lemon Grove, CA: Price-Pottenger Nutrition, 2009.   [10] Price, Weston. “The Present Status of Our Knowledge of the Relationship of Mouth Infections to Systemic  Disease.” 1917 Apr. Coletrex.com. Web. http://coletrex.com/resources/abstracts/present-status-our-knowledge-relation-mouth-infection-systemic-disease   [11] Price, Weston A. Dental Infections and Related Degenerative Diseases Some Structural and Biochemical Factors. JAMA. 1925;84(4):254-261.   [12] Venkataraman A, Almas K. Rheumatoid Arthritis and Periodontal Disease. An Update. N Y State Dent J. 2015 Aug-Sep;81(5):30-6.   [13] Pugliese C, van der Vinne RT, Campos LM, Guardieiro PR, Saviolli C, et al. Juvenile idiopathic arthritis activity and function ability: deleterious effects in periodontal disease? Clin Rheumatol. 2016 Jan;35(1):81-91.   [14] Chang JS, Tsai CR, Chen LT, Shan YS. Investigating the Association Between Periodontal Disease and Risk of Pancreatic Cancer. Pancreas. 2016 Jan;45(1):134-41.

THE INTERVIEW

Rob Knight, PhD Professor, Department of Pediatrics Additional Appointment, Department of Computer Science University of California, San Diego https://knightlab.ucsd.edu/   So here we are in our 2016 podcast version of Functional Medicine Update and really I think we’re out of the blocks with a bang, so to speak. We’re very fortunate to have, in this edition, Dr. Rob Knight. I think that name probably goes without me giving a lot of description because he’s in the news, he’s on the marquee, and his work is really at the primacy of where the frontier of this whole field of functional health is going. But just for those of you who might not fully know of Rob’s background, let me just quickly give you some of the high points. He’s presently a professor at the University of California, San Diego, and he’s the co-founder of the American Gut Project, which has received a tremendous amount of attention. He was educated in New Zealand, and his lab’s research presently is involved with the development and computational techniques that are related to characterization of the microbes of humans, animals, and in the interrelationship with the environment. He has a background in biochemistry from a university in New Zealand and his PhD at Princeton, and I found his PhD focus to be really interesting. Only at Princeton, probably, could you have such a wonderful title: The Origin and Evolution of the Genetic Code.[1] He completed his PhD in 2001. Until 2014 he was a professor at the University of Colorado in Boulder, and now has moved over to UCSD. Having read his recent book, which is titled Follow Your Gut: The Enormous Impact of the Tiny Microbes, I can say that’s the starting point for any of you that are wanting to get into more understanding about implications and concepts related to health and disease associated with the microbiome.[2] This is the expert, this is the man, this is one of the people that are leading the charge in really explicating this very complicated story about these thousands of species that reside either as symbionts, commensals, or parasites within the human gut microbiome. Rob, it’s wonderful to have you as our leader of this edition of Functional Medicine Update. Thank you so much. RK: Well, thank you so much, Jeff, for that overly kind introduction. It’s truly an honor to be part of this. Thanks again for the invitation to connect with this community. I think being able to exploit the microbiome for functional medicine is something that is just emerging, but something that holds so much potential and I’m really glad that your listeners are excited about the topic. JB: Rob, a question that I commonly ask individuals who are leaders in the field is what led you into this area where you’re now investing so much of your time, energy, emotion, and your psyche into this field? What drew you into it? It’s a very interesting path from biochemistry ultimately into the microbiome. Early Research Using RNA Molecules to Study Environmental Conditions RK: Yes, well, you mentioned my PhD thesis on the origin and evolution of the genetic code, and what I was doing there was looking at RNA molecules from the basis of life that might have led to the origination of life in what’s called an RNA world billions of years ago before the evolution of DNA and proteins. And so it was really basic studies of RNA that led me to look at how RNA is put together, how it changes in composition and how the sequences change. And one RNA that there was a whole lot of in the sequence databases that I was using was the ribosomal RNA that makes up the ribosome, the factory in our cells that makes proteins. I was curious about why people were gathering so many of these sequences, and actually Norm Pace, who is a National Academy member, a recipient of one of the MacArthur Genius Awards and so forth, was a professor at Boulder at the time I was there, and he was one of people who had collected a lot of these sequences and put them in the database. So I went to his office and asked him why and started coming to his lab meetings. And the reason why is that they weren’t so much interested in the structure of that molecule, but in using it as a tool to readout where organisms fall on the tree of life, and place and categorize biological knowledge. So I realized that we could take that tool a step further, where if you were looking at the whole community based on its RNA, instead of using a single RNA molecule as the tool to find out about where the organisms are phylogenetically (in other words, in terms of where they are on the tree of life), what you could do is you could use the whole community of organisms as a tool to find out about the environmental conditions where that community was, whether you’re talking about the oceans or the soil or even our own bodies. And so that’s what led me to getting interested in this, in a very indirect path. Now, more directly the events surrounding the birth of my own child a little over four years ago got me thinking about how we could really apply these tools much more directly to health, and so in large part that’s what prompted my move from Boulder to UC San Diego, where I’m now in the Departments of Pediatrics and Science and Engineering. Pioneering a Cross-Disciplinary Collaborative Approach to Research JB: That in itself is a title that is really a 21st century academic title, isn’t it? Because you’re crossing disciplines and that would be almost considered breaking the trust or the guild maybe 20 years ago, to have just a person covering that swath of different disciplines. RK: That’s absolutely right. A lot of people think that pediatrics and computer science and engineering is one department rather than two. Often I joke right now that we’re working on a robot that goes “Mom!” Yes, there’s a lot of stuff in the works. JB: I know that Craig Venter and his group have been very interested in charting phylogeny from the oceans and the environment. Is there any kind of interrelationship between what you’re doing and the Venter group? RK: Yes, absolutely. As you know, Craig is really a pioneer in metagenomics, both with the global ocean survey, the expedition of the Sorcerer II mapping oceans around the planet in terms of their microbiology, as well as the Human Microbiome Project with the JCVI. The J. Craig Venter Institute played a very early and leading role. So I worked with a large consortium including the JCVI in the Human Microbiome Project, which was this huge, 172 million dollar project funded by NIH that really provided the overall map and framework for understanding the human microbiome. One thing that’s really nice about the density of research institutes here in La Jolla is the JCVI San Diego site is only a couple of miles from my lab, so you can literally just walk there from my lab. We have done it on occasion, and we frequently have people from the JCVI at our lab meetings and that kind of thing, and there are a number of collaborative projects. Not only are we building on techniques that Craig pioneered, but on top of that there’s a lot very interesting opportunities for collaboration, both in the environmental space and in the health space. JB: One of the other interesting people in this field that we’ve had the privilege of speaking to on Functional Medicine Update is Eric Schadt, and I’m sure you know him and his work. I wonder, has there been any collaboration with what is going on with the Schadt group in translational genomics? RK: Yes, there have been some interactions there, too. In fact, Jose Clemente, who was a very talented post-doc out of my lab was hired by Eric at Mount Sinai a couple of years ago to add a microbiome dimension to their research programs there, and they have been very successfully working together in that regard. One thing that has been very exciting is seeing how systems have been starting to evolve to embrace the microbiome, and in a lot of ways that makes a lot of sense. Your own metaphor that food is really something that speaks to our genes and it does so in a language of color, and when it speaks to our genes our genes do different things. I always think it’s important to remember that although we have a lot of human genes—the human genome has about 20,000 human genes depending upon what exactly you count—that’s only a tiny fraction of the genes associated with our bodies. And given that the size of the microbial gene catalog is two to twenty million genes, 99 percent of the genes that you have aren’t even in your human genome. It’s always important to remember that your food speaks to all those genes as well. JB: That’s a powerful concept. That’s a great segue, then. Could you let us know, for those not familiar, you’re one of the founders and directors of the American Gut Project. Tell us a little bit about the project, if you would. The American Gut Project and Citizen Science RK: Well, the American Gut Project really built on the success of projects like the Human Microbiome Project and other traditionally governmental foundation-funded projects, where what you do is you come up with a design for a study, you write a grant to support the study, you battle for a couple of years to get that grant funded, then you go through your institutional review board, it takes a year to get approval, you then start to recruit people, and then maybe five years later you have enough data, and maybe five years after that you can write up and publish a paper about the results. And while that’s very important and you need those kinds of cohorts to really draw valid scientific conclusions, it leaves a lot of people out in the cold. You know, a lot of your listeners are probably thinking, “Hey, wait, what about my microbiome? How can I get involved in this? Because, you know, I poop, too. Why can’t I find out what’s in that poop?” And the answer is that the traditional model is not very participatory. So what American Gut is is an effort to bring these technologies that we developed for the Human Microbiome Project and other projects to everybody and make it possible for you to find out what’s in your own microbiome in the context of citizen science and open science, which is really a radically new way of conducting scientific research. Effectively what we do is we make it possible for anyone who is interested to basically sign informed consent, participate in the research project, send us their sample, and then we’ll tell them how their microbiome looks compared to a huge number of other people. At this point we’ve had over 8000 people sign up for it. We’ve released the data—de-identified, obviously, so you can’t tell whose sample goes with which, although you can see which is your sample. We’ve released thousands of samples so that you can see how your data look like in comparison to other people. What’s really exciting about this is it builds on the map that the Human Microbiome Project provides us, to tell us where in that space of possible microbiome configurations different groups of people are. So, for example, we’re right in the process of looking at some of the healthiest people at UC San Diego, so the student athletes, for example, the people in the healthy aging cohort. And then some of the sickest people, so people in the cardiac ward, people in the oncology ward, people in the IBD clinic, so that we can get a full understanding of where the good places and bad places are on that map, and things that you have control over can move you into a good place or move you into a bad place, so that we can give people guidance about what you should do to optimize your microbiome for health over your lifetime. The Future of Microbiome Treatments JB: That is unbelievably exciting, both from a scientific question-and-answer perspective, but also from a methodological perspective. I think that you are pioneering on several levels, there. And by the way, for those that have not followed your publications, you know in the academic world the measure of productivity of researcher is through their publication record and yours is just stellar, both in the quality of the journals you’re publishing in and the number of publications you’ve amassed that are really, I think, of high scientific impact over the last, really, not that many years. One of those—of the many—is a very interesting paper that I really enjoyed in which the title was “Why Microbiome Treatments Could Payoff Soon.”[3] That was in Nature, which is obviously a very high profile journal, in 2015. Could you tell us a little bit about what led you into both that title and that article, because I think it says it all. It’s a very interesting and provocative article. RK: Yes, absolutely, and thanks for your kind comments on the publication record. One thing I’ll note is that in science, although there’s this myth of the lone scientist working away, actually what matters most is teamwork and having great collaborators and great students working with you on these things, and so a lot of what you’re seeing is much more being part of a number of really great teams than something that is considered individual accomplishment. I think teamwork is an incredible part of this. In that particular article, what I think is so exciting about the microbiome is both its capacity to diagnose and its capacity for change. It’s important to remember that microbiome therapies aren’t just something in the future; they are happening right now. For example, there are many people walking around alive now who would be dead had they not received fecal microbiota transplants for Clostridium difficile-associated disease, or C diff as it is commonly called. But that’s a pretty extreme intervention, and in terms of being able to find out what the microbiome means for us in terms of our capacity to respond to drugs, our capacity to respond to diet, and so forth, and if you are doing a diagnostic that can change your behavior or the behavior of your prescribing physician, you can potentially use that information a lot faster than you can use information about a therapeutic, which has to go through a much more rigorous FDA approval process than a diagnostic. And so given that we now know that the microbiome is linked not just to things like obesity, but also to things like our ability to metabolize drugs, ranging from Cyclophosphamide to even acetaminophen, so everything from cancer drugs to pain killers. This has tremendously exciting potential to exploit that knowledge about the microbiome to figure out the best treatment plan. Now one thing that wasn’t even on the radar when I wrote that article is the possibility that the microbiome can tell you what specific you should eat, and two very talented Israelis, Eran Segal and Eran Elinav, had a great paper that came out in Cell right at the end of last year, where what they did is they hooked up continuous glucose monitors to a cohort of 800 people and fed them standardized diets so that they could tell what was the effect of each dietary item for each person on their blood sugar.[4] And what was amazing about that was in terms of blood sugar control, for some people it is actually worse to eat a bowl of white rice than it is to eat a bowl of ice cream. You know, that’s the sort of thing where you might really want to know which category you were in, right? Should I forsake the ice cream and focus on the rice, or should I do exactly the opposite? Being able to extend that to the attraction between all kinds of other components of our diet and all kinds of other component systems of our health, that’s exactly the kind of thing that we’re seeing techniques today that are ideally suited to. JB: Thank you for bringing up that paper. I think that for those of us that follow Cell on a regular basis—or just follow the field—that was one of those ah-ha papers. When it was published we immediately did a little blogosphere broadcast to our user group about it because I thought it was one of those paradigm-shifting studies, both in terms of the methodology but also in terms of how they were looking, in a systems biology way, at personal differences (individual differences) as we move towards a more precision-based form of healthcare. I think that your work is a linchpin in really adding a huge part to this story. You mentioned drugs. One of them that we know is being used with greater and greater frequency that is influenced significantly by the microbiome is metformin in the management of blood sugar in type 2 diabetics. I think that this cuts across the full spectrum—everything from prevention to tertiary treatment as it pertains to what you are learning. RK: That’s right, and metformin is a fascinating case because it really illustrates the difficulty of getting at causality in these microbiome studies. You might have been following—published in Nature—where a Chinese group essentially reported one set of microbes associated with type 2 diabetes and then a Scandinavian group reported a completely separate set of biomarkers, and a lot of what they were picking up was actually the result of metformin treatment, which was different in the disease between those two populations, and so this is really why we need to do prospective longitudinal studies with a lot of people to figure out what’s cause and what’s effect in the microbiome, as well as using various preclinical models.[5] If you’ve been following this stuff, you’re probably aware of the work of Jeff Gordon at Washington University and his colleagues, including some of the work my lab participated in where it’s possible to transmit phenotypes like obesity or malnutrition from one mouse to another by transferring the microbes, and even more excitingly, transferring from individual people into mice by transferring the microbes.[6] There’s a lot of work in the field at the moment basically aimed at asking what other diseases can we do those kinds of transfers from, where it’s almost like you can infect a mouse with obesity. Really, based on the human microbiome, could you infect a mouse with Alzheimer’s or with Parkinson’s, for example, by transferring the microbes from someone who was sick with those diseases? We don’t know the answer to that yet, but we will very shortly. Examining the Mechanisms of Action Within the Microbiome JB: So obviously this is right at the frontier of such a dramatic change that if Metchnikoff was alive today he would probably be saying, “I told you that this was important!” It’s really, really unbelievably interesting. It bears a question, which I’m not sure if this is a fair question to ask but I’m going to ask it anyway. There are multiple putative mechanisms of action as to how these microbes in the microbiome could influence systemic health. I would say that there are two, maybe, general—and maybe I’m being too limited, but two general ways that I would think about this from a mechanistic perspective. One is that the microbes that represent the gut microbiome have differing cell wall chemistries and they have different lipopolysaccharides, and different types of marker compounds on their surface that interact with different receptors, maybe of the G-protein coupled receptor family or other receptors on the gut epithelia, than then signal through those interactions, or the release of things like LPS of different types through different receptors like the toll-like receptors. I guess I’m going back to Metchnikoff, here, with innate immunity when I talk about that. That’s one possible mechanism. Another mechanism is that the gut bacteria—and I know you’ve explored, by the way, both of these, so I know I’m not asking this question without your knowledge being greater than. The second is that the microbes have differing physiologies and therefore they produce secondary metabolites that are different, and so you get the effect of their metabolism not directly through receptor binding of their cell wall constituents but through their release of different waste products or secondary metabolic byproducts that then are absorbed and have influence systemically through their influence as signaling substances or metabolic substances on cell-specific activity within the host. Are either or those mechanisms or both of those mechanisms operative, or what’s your thought right now? RK: Yes, absolutely. So we know a lot more about mice than we do in humans in this respect, especially because we can dissect the mice afterwards and really find out what’s going on, which is a little bit more difficult to get approval to do with humans, right? And there’s also a third mechanism, which is direct neural signaling between the gut and the brain, so for example through the vagus nerve, which can affect a whole range of physiological responses. So in mouse models, it’s certain that both of those mechanisms are operating as well as the third one I mentioned. So for example, in terms of secondary metabolites, there’s a very nice story from Stan Hazen’s lab on TMAO (Trimethylamine N-oxide), where essentially microbes produce TMAO from choline, which is a product of digesting meat and eggs and cheese and so forth, and then that gets processed into TMAO, which can then cause cardiovascular disease if you have particular kinds of bacteria, but not if you lack those bacteria.[7] And then there’s another very nice story related to autism with maternal immune activation leading to pups that have an altered microbial community with a lot of the chemical called 4EPS, where that chemical, if you deliver it by itself, can induce a lot of symptoms similar to autism in that mouse model—and remember this is only to the extent…you know, you can’t really call it autism, but a lot of the symptoms in the mouse are reminiscent of symptoms in humans.[8] So we know the metabolite mechanism definitely operates. We know for sure the immune mechanism operates. I don’t really need to go into detail for this audience, I think. I think a lot of people are familiar with leaky gut and the role of gut barrier dysfunction in causing systemic inflammation, and that leads to all kinds of downstream influences on diabetes and a range of other conditions with an autoimmune component. And then, intensive gut-brain connections, there has been some very interesting work looking at Lactobacillus probiotics and their effects on anxiety, where basically you can make a timid mouse braver by giving it the right probiotic, but it only works if the vagus nerve is intact, so this nerve that carries signals directly from the gut to the brain.[9] If you stunt that nerve, you don’t see any fate of the probiotic anymore. So there is a lot of fascinating work demonstrating that these pathways exist, and what we don’t know right now is which of those pathways are really important in human disease and which of those pathways are not important. We also don’t yet know which are the right control levers, so which pathways you want to target primarily in order to modify human disease and whether you want to target the bacteria directly, or you want to target the diet, or you want to target a modifiable lifestyle factor, or you want introduce drugs and target the host, or maybe the interaction between some of those variables, and that’s all work in progress at the moment. JB: Wow, exciting, exciting stuff. So one of the many papers that you’ve authored and had published recently is in Cell Metabolism around microbiome metabolites in health and disease.[10] The reason I’m bringing that back to discussion for a half a second is there are a number of clinicians who use different types of urinary metabolite analyses to do a surrogate analysis of microbial activity in the gut. So this would be like urinary organic acids and certain members of that family. Is there some support, based on what you’re finding, for that type if surrogate analysis? Surrogate Analysis of Microbiome Metabolites RK: Yes, I think we’re going to see a much richer use of metabolomics, not just from urine but from plasma and perhaps directly from stool as well, which is something that we’re working on with Peter Dorrestein. He’s another member of the leadership team of the Center for Microbiome Innovation that I run here at UC San Diego. We’ve also been reaching out to Joe Wang, who’s a faculty member and director of the Center for Wearable Sensors here at UC San Diego. One thing that’s a really exciting prospect is being able to figure out which of the right metabolites you would want to track in the blood on a continuous basis, where basically you can get readouts every minute and deliver them to the subject’s smartphone, so you can get them and then upload them to the cloud for analysis. So you can really get into the situation where you have a very rich datastream coming in from continuous monitoring of metabolites. This is analogous to what’s being done for glucose already. One thing I’m hoping is to have a more detailed conversation with you later on to try to figure out which of the metabolites we should be most focused on. At this point I’m starting to get the impression, though, that maybe nobody knows, and a lot of what we’re going to have to do is basic discovery science to figure out which metabolites and which body products are the best proxy for what’s going on, either with our physiology or with our microbiome or with the interactions between them. JB: Fantastic. As I again just look at kind of a Rorschach evaluation—just a quick snapshot—of your publication record recently: Journal of Neurosciences in 2014, “The Microbiome and the Nervous System”; in 2015, “The Microbiome Influence on the Endocrine System”; Trends in Endocrinology and Metabolism in 2015, “Microbiome and Obesity”; and then that leads us up into these kind of threshold papers that you’ve authored with your collaborators on things like “Prebiotics and the Microbiome,” and “The Microbiome and Diet,” and how quickly does the microbiome change—if at all—with dietary change, and can you use probiotics and/or probiotics to actually modulate or modify the human microbiome?[11],[12],[13],[14],[15] I’m asking a big question here, but is there kind of a sound bite summary that can help directionally point us as to what you’re finding in this extraordinary area? Current Types of Microbiome Interventions: Probiotics, Prebiotics, Symbiotics RK: Yes, sure. Just in case your listeners don’t know this already, the three types of intervention that there is a lot of interest in at the moment are probiotics, where you add some good bacteria directly as live bacteria; there’s prebiotics, where you feed them some fertilizer that will help the right bacteria grow; and then there’s symbiotics, which is basically putting in bacteria and the right fertilizer. So for example, breast milk is a great example of a symbiotic, because in addition to delivering all the beneficial oligosaccharides and other compounds in the breast milk, the breast milk itself helps promote the growth of the right bacteria, and the breast milk also delivers a lot of bacteria that are beneficial to the baby. So to summarize a large and complex field, basically what we’re finding is that all of these strategies, as well as many others like phage therapies, immunotherapies, and so forth—all of these things can alter the microbiome. And there’s a lot of research right now showing that you can have a statistically significant effect on the microbiome with those interventions, as well as all kinds of other interventions, like altering exercise, altering sleep patterns, altering diet, obviously, which has a huge effect, especially with respect to the plant component of the diet and all of these different things. Most of the science so far has focused on: you have a control group, you have a group that you put through one of these interventions, and do you see a statistically significant difference? What research hasn’t really focused on yet is what is the relative effect size of those differences, and which of those differences promote a healthy versus a disease state? That’s what we’re really trying to put together with American Gut and with other projects that we can feed into the same framework with the laboratory methods and the data analysis, where what we want to be able to do is to define the regions of the map that are healthy versus not so healthy, and then ask, for all of these interventions, which interventions are saving you and helping you stay in a healthy region versus an unhealthy region? Was that at about the right level of detail you were interested in or were you looking for something more specific? JB: No, I think that’s extraordinarily helpful, because I believe that as with any new exciting area, people get very interested in it, and because obviously most of us don’t have even superficially as much knowledge in this topic as an expert such as yourself, sometimes there’s an over-reading or an over-interpretation or there is a quick-to-act without really understanding there’s a lot more complication below the surface. I’m just trying to put some context to the excitement that people have clinically about this as to what level of knowledge we still have yet to go before we’ve got the size of the playing field all described. RK: Right, absolutely. And one thing that’s a big issue that probiotics in the United States are regulated as food supplements. As a result, if you are able to demonstrate a clinical endpoint it actually harms rather than helps your product because then you’re re-regulated as a drug and you have to go through a very cumbersome approval process. So most of the clinical trials that have been done demonstrating probiotics that actually work have been done in Europe or Australia or other countries outside the United States. But one huge issue at the moment is that the public enthusiasm for probiotics is greatly outstripping the actual evidence. Although there are some probiotics that have been very carefully validated in clinical trials—so things like post-antibiotic diarrhea or for irritable bowel syndrome or inflammatory bowel disease. Those are typically different probiotics for different conditions. The state at the moment is kind of along the lines of someone telling you, “Well, you know, I felt sick, so I took a chemical and then I felt better. So obviously what I think is that chemicals are great and everyone should take a lot of chemicals every day to promote their health.” You probably have a lot of follow-up questions about that, right? Like, what were you sick with? And, what chemical did you take and has it actually been clinically validated as a drug or did you just get it from some guy off the street? And you should really have equivalent questions about probiotics, because you can think of the genome as being an insanely complex and precise chemical, but it consists of millions of different substances you put together in a very precise arrangement. It’s not just a chemical itself, but a factory for producing thousands to millions of other chemicals. And when you think of it that way, it just makes a lot of sense that different probiotics would do different things. And remember that they’re living organisms as well, so it’s almost analogous to the promotion of a plant-based diet, right? There’s a lot of evidence coming in from different groups, including your own, that a diverse, plant-based diet is really beneficial for health, but at the same time you don’t recommend to people that they should eat any plant that comes their way, right? You want to be a bit smart about which plants, for example a tomato rather than a deadly nightshade. Use of Fecal Microbiome Analysis in Clinical Decision-Making JB: Thank you. I think that was a very eloquent summary of a whole variety of deep-level information that helps guide our thinking. A lot of clinicians who are getting fecal microbiome analyses done are looking at the Firmicutes and Bacteroidetes families of bacteria and making clinical decisions about the health or the status of that individual’s microbiome. Could you just give us a quick comment about those two as markers? RK: Yes, so remember that Firmicutes and Bacteroidetes are bacterial phyla and to give you an idea of phyla in the animal world, the arthropod phylum includes everything from wasps to lobsters, right? The mollusk phylum includes everything from like a clam to an octopus. So you’re talking about very broad groupings of organisms, where within those groupings they do different things. What we’re seeing, and this has been seen in many different projects including the Human Microbiome Project, is that there is tremendous variation in most phyla and the relative abundance, even within healthy people. So although if you have a large population you can get statistically significant differences between groups based on those phylum-level classifications, the variation within each of those groups is much larger than the variation between groups, so that’s not necessarily going to be a healthy diagnostic. Now at the same time, if you take the data and you feed it into a machine learning classifier, what you can do frequently is you can classify someone as, say, lean or obese with 90 percent accuracy based on their microbial profile, using a machine learning algorithm called Random Forest, but you can’t do it by eye. And 90 percent accuracy for obesity, although it’s an impressive technical trick that we can do for the microbiome, because remember you can only do that task with 58 percent accuracy from the human genome versus 90 percent accuracy based on the microbiome. You’d have to have a computer algorithm to do it. You can’t do it by eye and you can’t do it just from one number. What is going to develop is as we get better information in a consistent way about different diseases, what you’ll probably move away from is looking at the raw taxonomic output, and what you’ll move towards is having an indicator that tells you directly what is your progression towards a particular disease and what is your risk of developing it in the future. So, for example, we’re starting to get engaged in a project where we’re looking at thousands of stool samples that we collected 15 years ago from people with complete medical records, where we’re going to be able to predict what are the bad things that happened to them based on the stool sample from before the disease developed. In many ways this is really helpful, right? Because the last thing, as a clinician, you want is for someone to come into your office with a list of a thousand species, or even worse, a list of a million genes, and, you know, you’ve got 15 minutes with them and what do you get to tell them about that list? I guess at the moment the best thing you can do is refer them to a psychiatrist for being crazy enough to think that they could get out of that information in its present form. But I mean it’s just very difficult to grapple with. So in terms of what you can get out of those phyla right now, you can probably tell them a fair bit about their diet, which is always an interesting party trick, I guess. And if you have enough data—like if you have enough people—you can tell systematic differences that, taken as an aggregate, reveal a lot of things about their lifestyle and about their health. But you can’t do it just from one number, and you can’t do it just from those phylum-level representations, and ideally you want to look at how the person changes over time. So Larry Smarr, who is the director of CAL ITT, which is one of the major research institutes here at UC San Diego, and he was the founding director of NCSA, in charge of the team that developed Mosaic, which intended to navigate and founded the whole graphical web browser idea and so forth. He’s now been very interested in his own gut microbial ecology. He’d been staring at those kinds of pictures for years, of how much different phyla you have in the gut, and it was only when we got samples over time and used some of the techniques that we used in American Gut at the whole profile level that we finally understood what was going on, which is we can see very clearly in his data that he switches between two different microbial states, and one of those states is correlated with feeling really bad with IBD symptoms, and the other state is correlated with feeling fine, gaining weight rather than losing it, and having very few IBD symptoms. So moving away from those kinds of taxonomic readouts towards a readout that is more directly connected to function is going to be really important. Now, the basis for that is going to be the kind of sequencing you’re doing right now, where you get the taxonomy, but you don’t want to look at the taxonomic data any more than you want to look at 1s and 0s that make up a picture on your smartphone, right? You’d much rather see it as a picture than try to decipher it from the binary. JB: That was an extraordinarily helpful explanation for the clinicians listening. Thank you very much. How much of this changing composition of the microbiome is an effect of changing metabolism and how much is the cause of a changing metabolism? So you get this interesting diet, don’t you, as it relates to these approaches that you’re questioning? RK: Absolutely. Well, with causality you can get at when you can do interventions and that’s something that I think as a clinician you have a remarkable to do on a therapeutic basis because you’re recommending that you patient does something, then if they do it and you see a change you can reasonably attribute it to the intervention, especially if it’s repeatable and you can see them switching back and forth as they go on and off the intervention. One thing that is developing from our forensics project is that we do a fair amount of forensics work funded by the National Institutes of Justice, is we can find out a remarkable amount about someone from their microbiome and from their metabolites. One thing that’s very interesting in terms of the things that are shaping up for the future is you might be able to tell whether your patients are compliant with what you’re prescribing, either in terms of taking drugs, or for example, in wildlife applications there has been a lot of work doing things like trying to figure out what does a seal or a penguin eat? It’s very difficult to strap a camera on them—is it going to stay on underwater or not, or have enough drag to slow them down? So what you can actually do is you can use the DNA of the organisms they ate to readout their diet directly, and so we may be able to this with humans as well. Of course, this is only going to work if they’re eating real food, because if you’re eating mostly highly refined foods there’s not going to be any DNA left in it, but that in itself may be really useful for figuring out are your patients eating real food and thus has the full spectrum of secondary metabolites that we probably have evolved with and eat as humans, or are they very eating highly processed and refined diets where there’s not enough DNA left to detect? Studying the Microbiome and the Health of Infants JB: That’s fascinating. One last question. I want to come full circle, back to where you started. You gave us a teaser early on saying that one of the reasons that you left Colorado and joined the faculty at UCSD, and I’m sure there are many reasons but one of them that you teased us with was that you became a father. You and your wife had your child and this whole concept of the importance of the microbiome and the health of infants. And I noticed that in 2016 you have a very, very interesting paper in Nature Medicine, another high-tier scientific publication, on vaginal transfer and influence on neonates. Tell us a little bit about that, maybe in close, as we come full circle.[16] RK: Sure, absolutely. So when we had our child towards the end of 2011, being in Boulder and exposed to that kind of environment, we had a very detailed birth plan. We were hoping things were going to go naturally, so we were planning for vaginal delivery, minimal use of drugs, breastfeeding, all of those kinds of things. We had worked all this out with our care team. And, as anyone who has kids knows, things don’t necessarily go according to plan once you have kids on the scene. That was true with us as well, so we wound up having to have an unplanned C-section. Then, for various reasons, breastfeeding didn’t work out either despite going through the whole parade of medical professionals, so everyone from lactation consultants to psychiatrists to figure out why. So that really got me digging into the evidence for a lot of the ideas that we have about what’s healthy and unhealthy in the birth and neonatal context, especially with respect to things like breastfeeding, for example. If breastfeeding doesn’t work out, should you bottle feed with a specific formula, should you use other milk, does it matter if that other milk is pasteurized, which is going to kill the bacteria and potentially denature some of the proteins? What are the cost benefit trade-offs and so on? If you’re thinking about finite resources, should you put your resources primarily into your kids’ diet or should you be looking at other things, like for example hiring additional care so that the mother can get some sleep and be better rested, which is one of those things that there’s excellent evidence for, especially when there are other issues. And so what was fascinating to me was how little we know about a lot of those processes. In some sense, it’s being able to bring microbiome science right to the beginning of life and being able to help address a lot of those questions, but also being able to intercept people early on, as young children, and being able to take what we’re learning about the microbiome and how it intersects with diet and so forth and using that in a way that can promote health over someone’s lifetime. That was a very compelling motivation to move to a medical school and to really be in a position where I could work closely with clinicians on clinical problems and figure out how we can use the best technology to make progress in those areas. JB: I just want to close by acknowledging something that I think is quite remarkable beyond the scope and depth of what you shared with us, which is really quite remarkable, what you’re accomplishing as a scientist. But I want to talk about methodology. What is a scientist? What is translational research? What are high impact projects? And what is leadership in a field all about? My feeling, having had the privilege of speaking to and knowing many pace-leading scientists over the years is that what you’re doing and how you’re doing it fulfills all those criteria of a true scientist of distinction. You’re obviously crossing barriers, you’re crossing various levels of specialization, you’re venturing into new areas. There’s always risk in being first to prospect in a new area for fear of all sorts of things. And yet you’re being guided by not only the keenness of your mind but by a spirit of inquiry that is coupled together with this ability to make sense out of this work and make it translatable into improving the health and function of people. It’s quite remarkable. I feel actually very privileged to know that there are people like you coming up that are doing this kind of work and approaching it in the way that you’re doing it. It’s the kind of work that really makes a difference in our society. Rob, thanks so much. I think both as an admirer of your work and also as a person who is really very much a student of the history of science I think that you are really doing some extraordinary work with you and your team and this collaborative model you’ve talked about—this distributive model, this translational model—this is the science of the 21st century and I really appreciate both the way both you are doing it and how you communicate it. RK: Thanks so much for those kind comments. I don’t really know how to response to that other than to say that it certainly means a lot to hear those kinds of things from a leader in the field and in this community such as yourself. I guess the way I think about it is a lot of the things that we’re doing in terms of trying to explore completely new areas are very risky and—coming from an evolutionary biology background—I always worry a little bit about whether, when you’re taking strategies that are increasing the variability of your outcome, you know, if it works then it can be really spectacular, but of course there’s the other tail of the distribution that you could equally probably have been at, and keeping that in mind when evaluating people who are interested in joining the lab and taking those risks, it’s always important to try to ensure that they have good career outcomes themselves. I think actually so much of it is about being open to new ideas, being open to teamwork, and being open to learning from other communities that you might not have considered before, and being able to apply techniques from other fields. And one thing I’m really excited about is a lot of these issues were grappling with in the microbiome, you’ve already faced in the natural products community and in the nutrition community. One thing that inspires me is that there is still a tremendous amount that we don’t understand about nutrition, but at the same time if you look at the chronic diseases of a century ago, like scurvy, pellagra, beri beri, and so forth, those diseases that sickened millions and incapacitated or even killed very large numbers of people are just gone now, right? You won’t meet anyone who’s met anyone who’s met anyone who has goiter probably, which used to be a very prevalent condition. The idea that we could do the same sort of thing in the microbiome, where even before we fully understand something and the full complexity of the community we may be able to come up with simple, safe, and effective interventions that we can apply either at the precision level to individuals or at the whole population level and have that kind of impact. That’s what I think is really inspiring and what I think is really worth doing as vigorously as we can. JB: Well, thank you. I think that’s a wonderful way, I think, to bring this discussion to a close. We wish you, obviously, great success and we’ll be following you and your group’s work very closely. Thanks so much for spending so much time with us. This message will resonate around the world I’m sure and be transferred from person to person. It’s really a lot of news to use. RK: Thanks again, Jeff. Thank you for what you’re doing. You’re such an eloquent spokesman for the role of diet in promoting and maintaining our health and figuring out how to add the microbiome into that I think is spectacular, so thanks again for your interest. JB: Thank you. Best to you. Bye. RK: Thanks. You, too.

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Bibliography

[1] Knight, Robin Douglas. The Origin and Evolution of the Genetic Code: Statistical and Experimental Investigations. Diss. Princeton University, 2001. Web. 27 May 2016. Retrieved from: http://www.ece.iit.edu/~biitcomm/research/Genetic{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Code/The{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Origin{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20and{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Evolution{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20of{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20the{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Genetic{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Code{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Statistical{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20and{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Experimental{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Investigations{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20-{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}202001.pdf [2] Knight, Rob and Brendan Buhler. Follow Your Gut: The Enormous Impact of Tiny Microbes (TED Books). New York: Simon & Schuster/TED, 2015. [3] Knight R. Why microbiome treatments could pay off soon. Nature. 2015 Feb 26;518(7540):S5. [4] Zeevi D, Korem T, Zmora N, Israeli D, Rothschild D, et al. Personalized Nutrition by Prediction of Glycemic Responses. Cell. 2015 Nov 19;163(5):1079-94. [5] Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015 Dec 10;528(7581):262-6. [6] Ussar S, Griffin NW, Bezy O, Fujisaka S, Vienberg S, et al. Interactions between Gut Microbiota, Host Genetics and Diet Modulate the Predisposition to Obesity and Metabolic Syndrome. Cell Metab. 2015 Sep 1;223):516-30. [7] Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016 Mar 24;165(1):111-24. [8] Hsaio EY, McBride SW, Hsien S, Sharon G, Hyde ER, et al. The microbiota modulates gut physiology and behavioral abnormalities associated with autism. Cell. 2013 Dec 19;155(7):1451-1463. [9] Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, et al. Ingestion pf Lactobacillus strain regulates emotional behavioral and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16050-5. [10] Sharon G, Garg N, Debelius J, Knight R, Dorrestein PC, Mazmanian SK. Specialized metabolites from the microbiome in health and disease. Cell Metab. 2014 Nov 4;20(5):719-30. [11] Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014 Nov 12;34(46):15490-6. [12] Neuman H, Debelius JW, Knight R, Koren O. Microbial endocrinology: the interplay between the microbiota and the endocrine system. FEMS Microbiol Rev. 2015 Jul;39(4):509-21. [13] Rosenbaum M, Knight R, Leibel RL. The gut microbiota in human energy homeostasis and obesity. Trends Endocrinol Metab. 2015 Sep;26(9):493-501. [14] Eilam O, Zarecki R, Oberhardt M, Ursell LK, Kupiec M, et al. Glycan degradation (GlyDeR) analysis predicts mammalian gut microbiota abundance and host diet-specific adaptations. MBio. 2014 Aug 12;5(4). pii:e01526-14. [15] Org E, Parks BW, Joo JW, Schwartzman W, Kang EY, et al. Genetic and environmental control of host-gut microbiota interactions. Genome Res. 2015 Oct;25(10):1558-69. [16] Dominquez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016 Mar;22(3):250-3.  

Welcome to Functional Medicine Update for January 2015, and oh my word, what a next three months we have in store for you with our mini-course in functional neurology. You are going to be informed, excited, emotionally moved, and, I think, get news to use that is going to make a real difference not only in your patients but in the world at large as you hear from our key opinion leaders.   We’re starting this month as a wonderful lead in with Dr. David Perlmutter and you should probably know that Dr. Perlmutter comes with no small reputation and is a leader in the field of functional neurology. I want to just say a couple of things about the nature of this three-part series that I think you’ll find will be the deliverables that we hope to be able to accomplish over the course of the months of January, February, and March.   Functional Neurology: New Technologies Have Lead to New Approaches As you probably recognize, functional neurology is gaining a reputation in the traditional medical quarter, probably out of the constructs of functional MRI and functional radiology, using things like CT scans and PET scans and the ability to do brain mapping. So we’re starting to actually look at function at a different level in terms of neurology than in the past, and I think this is opening up a whole approach towards systems biology that is very, very different than what we have had in looking at individual piece parts of the neurological system in isolation or in a reductionistic model. This really can apply to things as far ranging as seizure disorders and epilepsy and motor neuron diseases like Parkinson’s and ALS, or cognitive dysfunctions and memory deficits in things like Alzheimer’s disease, and even cognitive behavioral issues related to things like ADHD (attention deficit hyperactivity disorder) and autism.   I think that this model that you’re going to be hearing developed of functional neurology over the next three months is a model that has applications across these many, many different DSMs, or diagnostic indicators. It also relates to what we see happening as it pertains to genetic evaluation, the so-called GWAS (genome-wide association studies) that have been done with diseases like Alzheimer’s, trying to define specific families of genes that may be tied to risks to these neurological disorders. I think what we’ve seen is that the genetic risks are, at most, weak—that the more significant contributors to these disorders are things that relate to how our genes are exposed to various agents, either positive and/or negative agents that relate to the dysfunctions that we ultimately see downstream as the pathologies associated with these neurological diseases. The good news part of the story is as we can identify the factors that are associated with individual gene expression patterns in the person, we can modify those factors because they’re not hard wired; they are built into lifestyle and environmental considerations. And that’s going to be a theme that you’ll find weaves together our three key opinion leaders over the months of January, February, and March.   You’re also going to hear some very interesting things that will trace back to discussions that we’ve had in the past with people like Abram Hoffer and his colleague, Humphry Osmond, who looked at dementia from the perspective of nutrient therapies and talked about things like orthomolecular medicine, which Dr. Linus Pauling and his colleague, Dr. Hawkins, wrote about in the 1970s and 80s. I think actually the first paper that appeared with that title in a large, well-recognized, peer-reviewed journal was the paper “Orthomolecular Psychiatry” in Science magazine in 1968 authored by Dr. Pauling.[1] And you recall that it was Dr. Hoffer, who was an MD/PhD, who had made observations as a farm boy from Saskatchewan that these nutrient deficiencies that were being discovered at that early part of the 20th century with names like pellagra had presentations of the three Ds: dermatitis, diarrhea, and dementia. And so he started wondering whether there was a relationship between some schizophreniform disorders in humans and various nutrients that could be tied together with things like pre-pellagrous dementia. And that led him into the whole discovery of the connections between things like tryptophan, and neurotransmitters of serotonin, and phenylalanine and tyrosine and the relationship to the dopaminergic neurons and ultimately to nutrients like B6, B12, vitamin C, niacin, vitamin B3, and how they related to neurological function. So it’s a very interesting chapter in the development of this topic.   And then that takes us into things that we’ll be talking about as it pertains to mitochondrial bioenergetics and neuronal function and how that interrelates with insulin and what’s been called “type 3” diabetes, and how toxins like bisphenol A and other neuroendocrine disruptors play roles in these neurological disorders, and how chronic metabolic inflammation that might be tied together with what’s called metabolic endotoxemia, the interrelationship between the gut microbiome and diets that are high in fat and sugar that can induce the release into the blood of these proinflammatory mediators like lipopolysaccharides and proinflammatory cytokines like TNF-alpha and IL-6. And how that then also relates to things like epigenetic modeling—things that we’ve discussed in the past like methylation of promoter regions of genes that you see with PTSD (post-traumatic stress syndrome). You’ll recall the interview I had with Moshe Szyf at the McGill University stress research laboratories, in which he talked about PTSD and war and violence and how that triggers, in children, certain kinds of neurological, cognitive, and behavioral function throughout their lives. So all of these are really extraordinarily new concepts in the field of functional neurology that are opening up a very, very different epic period of discovery in intervention potential, and it’s that that we’ll be focusing on in this three-part series starting with an extraordinary introduction by Dr. Perlmutter.

INTERVIEW TRANSCRIPT

Clinician of the Month David Perlmutter, MD, FACN, ABIHM Perlmutter Health Center 800 Goodlette Road North #270 Naples, FL 34102 www.drperlmutter.com What better person to have as a lead off person for our mini-course in functional neurology than Dr. David Perlmutter? It was actually so recent ago, but also so long ago, that Dr. Perlmutter was a key contributor to Functional Medicine Update. When I went back I couldn’t believe that it was August of 2005 that we had a chance to visit with David. So much has happened in those subsequent nine years, both in the field and his career, and there would be no better person to lead off the important topic of functional neurology than Dr. Perlmutter. Grain Brain Has Become an International Bestseller Let me just, for those of you not familiar with him, bring you up to speed. I’m sure if you’re a reader at all you’re familiar with the fact that his book, Grain Brain: The Surprising Truth About Wheat, Carbohydrates, and Sugar, has been on the best-seller NY Times list as number one for 55 consecutive weeks.[2] That’s a pretty auspicious accomplishment. I think it is so because it’s such an important book in terms of news to use. Dr. Perlmutter is a board-certified neurologist and a fellow of the American College of Nutrition. He’s a clinical associate professor of medicine at the University of Miami School of Medicine, where he was awarded the Leonard Rowntree Research Award as a medical student for the best medical project when he was at the University of Miami School of Medicine. He has contributed extensively to the world of clinical development of functional neurology and publications and research. His paper that I think was a landmark paper for those of us who have followed the field for so many years, which appeared in Movement Disorders in 2009, was titled “Randomized Double-Blind Pilot Evaluation of Intravenous Glutathione in Parkinson’s Disease.”[3] We’ll have a chance to talk a little bit about that with Dr. Perlmutter. There are so many things that we could say about his background, his experience, and his contribution that it would take up the whole of the time, so rather than that let’s jump right in. David, thanks so much for leading this opening opportunity to discuss the history and development of functional neurology. The concept functional neurology…I was just on PubMed and I typed in “functional neurology” and asked how many citations have been published that have that descriptor somehow embedded within the manuscript, and according to this morning, it is 24,280 publications that have somehow talked functional neurology, and of those, 61 of them have talked about functional neurology and systems biology—areas that you are really a pioneer and a leader in. Let’s start down the Dr. Perlmutter path. How would you contrast your life as a leader in functional neurology to that of, say, a more garden variety, typical neurologist? What are the points of differentiation? How does your life vary? What is your perspective and how does it differ from that of maybe the training that you had as kind of a down-the-middle-of-the-road neurologist? Considering Lifestyle Influences is New to Neurology DP: Well, thank you, Jeff, for that retrospective. When I hear you say those words, you take a moment and think back about not only where we have been but where I have been with reference to neurology and then embracing the notion that there is a moniker that can characterize the way that we practice, and that is functional medicine as it applies to neurology. And I would indicate that as a mainstream neurologist, my life was characterized, I think, by one word and that is “frustration,” because I realized we were really only treating symptoms and doing not a very good job at that. You know, as a neurologist, I think the main thing was determining where is the lesion, and then naming it, and if you did that that was a good day’s work and the patient was pretty much just the byproduct of how you arrived at that situation and we’re going to feel good about that. You know, the medicines that were designed and are still used are basically an attempt to treat the smoke and not the fire—looking at the end results of a panorama of multiple events that ultimately conspire to give clinical outcome, each of which is fundamentally important if you’re going to really have leverage in terms of dealing with the disease itself and not simply remain focused on the symptoms, whether it is a tremor, Parkinson’s, headache, dementia, other cognitive issues. I really felt frustrated in accepting the notion that somewhere in the Physician’s Desk Reference would be a magic bullet—a reflexive, Newtonian response to an array of clinical manifestations—and realize that beyond my frustration those answers were not there. Lo’ and behold, I began exploring the notion that, oddly enough, lifestyle factors may in fact be playing a role in the pathogenesis of neurological conditions at a time in medicine when we were just beginning to understand the notion that there were influences with respect to lifestyle choices as they related to heart disease, diabetes, and perhaps even cancer that were just beginning to enter the spotlight in terms of some powerful traction in terms of making lifestyle modification. And, you know, those were the years where—talk about being the odd man out—as a neurologist, this was anathema; no one would talk about these issues. I recall that several years ago I became friends with a doctor, Amar Bose, and you may in fact be wearing his headphones right now, I don’t know, but an amazing physicist, a real pioneer. He proudly took me to his research facility in Massachusetts. What was most compelling for me and impressive was not his latest technology—and believe me, there were things that were 10, 20 years down the pipeline that were very exciting—but a quote that was on, actually, the glass door entering into his private office that said something like this: “On the pathway that leads to the future, each progressive soul is confronted by a thousand mediocre minds appointed to defend the past.” (A quote by Maeterlinck.) And when I saw that I realized first what he had gone through in his career and how he had to be iconoclastic, and how there is really nothing wrong with being that. I mean, we measure our progress in a salutatory way and I felt like it was time, at least in the area of neurology, to make quantum changes. And, as you well know, it’s bearing fruit. We’re seeing some very dramatic shifts now in our perception, with national and global recognition in work done by people who are embracing the notion that to consider neurologic disease from a Newtonian billiard ball—one illness, one name, one remedy—perspective is, to be nice we call that myopic, but the upside is to light the candle and not curse the darkness and embrace the notion that the pathogenesis of these diseases are multifactorial and therefore dealing with them requires an aggressive approach that embraces a multitude of issues that will slowly but gently offload the camel’s back, as opposed to trying to monetize a patentable one remedy approach. We know that isn’t going to work—it hasn’t worked—and yet, now for the first time in history, Dr. Bredesen has actually published results reversing symptoms of Alzheimer’s disease, something that others of us who are using these types of approaches have now embraced and have also had the opportunity to experience. [4] So Many Interview Topics: Oxidative Stress, Inflammation, the Microbiome, and More! JB: That’s a fantastic introduction not only to your work, but also to the whole nature of this mini-series on functional neurology. We are very fortunate that Dr. Bredesen will be your follow on in the second chapter of this three-part series. I’d like to have you take us through those areas that you have really been a pioneer in each of these areas in functional neurology over the last 20 years. I’ll list them just for the sake of putting them out there for the listener, but then give you an opportunity if you would take us through how this evolved and how these are applied within your practice. These include oxidative stress and free radical pathology-related issues in neurological disorders, and of course you’ll tell us about your glutathione work and your hyperbaric work, which is pioneering. Second—and these are all interrelated so I don’t want to sound like they are siloed, but one might think of them as being differentiated although they are interconnected—the second is inflammation, chronic inflammatory disorders and how that relates to neurological function. The third is insulin resistance, which you’ve been a big pioneer in and obviously Grain Brain deals with that whole topic very eloquently and brings it to the reader in a sensible way that they don’t have to be a neurologist to understand. The next is that of the microbiome—this gut/brain connection—and you recently became the author of a new journal, Gut Brain, which obviously is a very important medical topic that is emerging at the frontier that you have been a pioneer in. The next is what Abram Hoffer maybe would have talked about years ago as nutritional imbalances, and how do nutrition imbalances—it could be vitamins or minerals or other co-factors—interrelate with neurological disorders? Next is allergy and intolerance. We’ve had the privilege of interviewing Alessio Fasano in Functional Medicine Update, but I know you’re taking that to the next level as it relates to some of these neurological sequelae. And then methylation as it relates to epigenetics; how does that whole methylome interrelate with neurological disorders? I’m almost done…Toxicity and endocrine disruptors and how does neurotoxicity and environmental disruptors interrelate with neurological disease? And then lastly, these genetic risk factors that some people are so worried about—things like apo E double 4 polymorphisms and how does that play a role in what you might see as the future of functional neurology. So with that as an overview, let’s start with the oxidative stress. Tell us how you got down the glutathione pathway and what you’ve helped pioneer and helped us to learn. DP: First, let me just say that as you were listing all of those topics and to some degree they are a bit chronological, at least in my life, what’s always been so incredible to me is that the margin between them is never distinct. It’s always been blurred and they always circle back around and how fascinating it is to recognize the empowering role of the human microbiome in terms of regulating inflammation, inflammatory mediators. How those inflammatory mediators ultimately influence mitochondrial energetics and how the role of mitochondrial energetics is so profound as it relates to signaling for apoptotic pathways, for example, through the caspase system. And mentioning the work of Dr. Fasano in terms of gut permeability, I recently interviewed him actually for our new journal and his comment was that the most important factor related to the microbiome was the very food that we eat, so how validating it is that the at the end of the day we keep coming back to the food that we eat. These days people say maybe it wasn’t Hippocrates who said “Let food be thy medicine and medicine be thy food,” but nonetheless the quote still stands. I don’t care who said it, I think it’s very important. Mitochondrial Energetics and Brain Health With that said, let’s start off moving back to the work of Dr. M. Flint Beal, whose really pioneering work in dealing with the fundamental role of mitochondrial energetics in brain health I think really was an eye-opener for me because it became something applicable in the clinical arena that upregulating of mitochondrial energetics and protecting mitochondrial function through nutritional intervention and a reduction of entities that we know present as mitochondrial stressors really might have some important role in enhancing brain health and function and making the brain perhaps more resistant to disease, with the understanding that yes, the brain is a very energy-hungry organ, and you mentioned Mark Mattson earlier. Mark Mattson’s work indicating that this thought that we need to power the brain with glucose—and he’s really, with his work on caloric restriction and more of a ketogenic diet—I think has really opened the door for us to understand that a far more efficient and less radical producing approach to fueling mitochondria really has to do with allowing mitochondria the opportunity to metabolize ketones in terms of creating ATP with less cost in terms of radical production, and ultimately from that work has been the production of an FDA-approved medical food that we can write prescriptions for the actual treatment of Alzheimer’s disease. So that said, what did Dr. Mark Mattson say? He said that calorie restriction—a mild state of stress for mitochondria—is actually a powerful hormetic approach to enhancing viability and enhancing function. And when you recognize that really as the cornerstone, the final common pathway, of neurodegeneration in general is mitochondrial dysfunction, then concepts like dietary intervention to reduce calories and allow the availability of ketone fuel sources, really get your attention. What I’ve done is kind of embrace the publications that have been supportive, and then put them into implementation protocols in the clinical arena in a very nonacademic way, I’m happy to say, because I’ve not been constrained. That said, we’ve had great results in applying these ideas not only to neurodegenerative conditions but to issues as disparate as epilepsy and glioblastoma. We fully understand that a ketogenic approach, for example, to treating epilepsy, which has been popularized at least in children since 1928, a direct intervention focused on mitochondrial upregulation and salvaging mitochondrial function, it has now been validated as a profound intervention in adults, as was published just two weeks ago in the journal Neurology.[5] So anything, then, that leads to upregulation of the inflammatory cascade enhances risk for brain degeneration when we recognize that while we know multiple sclerosis, for example, is a prototypic neurodegenerative condition focused on inflammation, so is Parkinson’s, so is Alzheimer’s disease. As you well know, we can image activated microglia in the Alzheimer’s brain, and we can see that they are upregulated. Measuring interleukin-6 tumor necrosis factor alpha—a variety of markers of inflammation—clearly points a finger at the role of inflammation in these degenerative conditions. Understanding the Role of Gluten in Inflammation So to flash forward a little bit, my interest has been: where does it begin? And that took me to understanding the role of gluten in terms of inflammation, and the work, as you mentioned, of Dr. Fasano indicating that gluten sensitivity is something that needs to be considered not in ten percent of humans or even the 1.8 percent who may have an autoimmune condition called celiac disease, but he believes that through the mechanism of zonulin activation that there is some increased gut permeability induced in all humans when exposed to this protein—gluten—found in wheat and other grains (barley and rye). And that is a very profound notion that here is a gastroenterologist at Harvard talking about gut permeability, or leaky gut, that you and your team have been talking about for a long…I don’t want to say how long, but for a long time. And you know what, Jeff? You think back over the years when we’ve talked about leaky gut, that didn’t come into the mainstream nomenclature until very, very recently, yet we’ve been talking about it for a long time. And now a leaky brain, that Dr. Fasano has demonstrated similar changes in the blood-brain barrier permeability brought on by similar changes in the blood-barrier permeability brought on by similar influences. So it takes us to a situation that all disease begins in the gut, and here you are having a conversation with a neurologist and what this neurologist is telling you is that that’s where our focus needs to be; it needs to be on the gut. And I have a tough time convincing my neurology colleagues that there really are important issues below…south of the foramen magnum—that the gut has a very, very powerful role. The Role of the Microbiome in Brain Health May Be Powerful We’re just beginning to scratch the surface in understanding this powerful role of the microbiome—the trillions of living organisms that reside mostly within the gut—in terms of their influence on seemingly distant parts of the body, my interest of course being the brain. We now know that there is this intimate and beautiful dance that occurs with respect to those organisms living within the gut and the health and vitality and resistance to disease in the human brain. Interesting work that was published in the Proceedings of the National Academy of Science in June of 2010, for example, looked at stool analysis of children in Burkina Fosa, a western African nation, and compared the stool specimens to similar age-matched children living in Europe, and did 16S rDNA analysis of the various organisms, and in addition looked at what are called short-chain fatty acid analyses of these individuals and found really remarkable differences based upon a rural environment and foods that were consumed versus children eating a more westernized diet.[6] And it was really quite interesting when you looked at the short-chain fatty acid array that overall the kids in Africa had much higher levels of short-chain fatty acids, but the array was different. The African children had much lower levels of propionic acids and higher levels of butyric and acidic acid. So the arrays are very important because we now recognize, for example, that this notion of elevated propionic acid that we see in the European groups and we’re seeing in other Western groups may have a huge role to play in brain function. We now recognize, for example, that propionic acid level is higher, and produced in higher quantity, in those individuals whose gut arrays are higher in the clostridial species, and where are we finding that? We’re finding higher levels of clostridial species when we fingerprint the gut microbiome in autistic children. Dr. Derrik MacFabe at the University of Ontario has done some incredible work in looking at what happens when you inject, interventricularly, in the laboratory model, propionic acid? And creates a laboratory rodent that looks all the word like an autistic child: stays in the corner, will not socialize with others of his companions. So the idea that changing the milieu of the gut bacteria will have a powerful effect on the brain and that there may be clinical application of this science in moving forward, I think to me is super exciting because we now understand there have been some dramatic changes that have happened to the human microbiome in very, very recent years, and that—as Dr. Fasano would agree—much of this has happened as a consequence of our dietary changes: favoring higher carbohydrate, less available good fat, and other changes to the human diet that change the ratio on a phylum level of the make up of the gut bacteria. Now how do we know that? One report in PLoS Biology published in December 2012, a really interesting study, looked at the coprolites—fossilized stool and gut contents from individuals who had died years ago, some of whom were frozen, like Oxy the Iceman, and lived 5500 years ago (or before current times, years ago), and what they found was that their array of microbial organisms was pretty similar to non-urbanized humans living today.[7] The point is that this has been the type of bacterial array that we’ve had for a long, long time, and that the bacteria haven’t changed over time, but little has our DNA or our genome changed significantly, so we co-evolved with this group of organisms for a couple of million years and suddenly we’ve turned the table on what represents 99 percent of the genetic material in your body. That’s a pretty sobering number when you consider that we’ve been so excited with our 23,000 genes, thinking “Gee whiz, that’s an awful lot that can make you who you are, Jeff Bland versus David Perlmutter.” You know, when a rice plant has 50,000 genes, that’s a sobering notion. I like to think that we have become efficient in off-loading or up-loading parts of our genome—most of our genome—to the cloud, so we don’t have to walk around with it at all time. That cloud is the microbiome that we carry around as a reference source for powerful genetic information. It takes us, then to the glutathione story. I’m going to try to get these in the order that you mentioned them. Really that was an attempt by me to directly intervene in terms of mitochondrial function, but beyond that, understanding that glutathione plays a pivotal role in detoxification at multiple levels, we began a protocol using intravenous glutathione with great success in treating Parkinson’s and then published the article to which you referred, again demonstrating significant moment-to-moment improvement, as well as long-term reduction in the rate of decline in Parkinson’s patients. Then as things moved on, we began recognizing that there were epigenetic pathways that are available to us to also enhance availability of reduced glutathione in human physiology and other forms of glutathione in terms of its detoxification of glutathione, peroxidase activity, glutathione-S-transferase activity, as well as—again, as you mentioned—inflammation, reducing the power of inflammation in human physiology by reducing what is called NFkappaB, and also enhancing other parts of antioxidant function and reducing even apoptosis by activating pathways like the NRF2 pathway, and began understanding why it is that things like turmeric, caloric restriction, aerobic exercise, DHA, resveratrol really have wonderful science behind them and allow us to pursue various dietary changes with the idea that we can enhance through epigenetics, taking advantage of our new knowledge that the notion of our genome being fixed is really something that is quite passé at this point, and really are beginning to see as our major research centers that the gatekeeper of longevity, NRF2 pathway, really may offer up some powerful leverage points in terms of dealing with neurodegenerative diseases that are predicated on upregulation of radical activity, oxidative stress, and inflammation. And basically, as I like to say, that’s every neurodegenerative condition that has a vowel in its name, so the list is fairly long. That said, beyond the notion of specific food choices and supplement choices, it really also brings to mind the idea of simple calorie restriction again and aerobic exercise as epigenetic factors. We’ve now seen some exciting work that demonstrates that the simple notion of engaging in aerobic exercise is a powerful epigenetic modulator of brain drive neurotrophic factor, as is turmeric, for example. But that the simple act of getting aerobic exercise actually enhances neurogenesis, allows the hippocampal neurons to replicate and become function, and is associated with improvement in memory, and that is a claim that cannot be made by any pharmaceutical available as you and I have this conversation. Simple aerobic exercise that no one can own, it cannot be proprietary, all you need to do is buy a pair of sneakers and have some motivation. So how many points have we covered thus far? Glutathione Treatment Produced Remarkable—But Not Sustainable—Results JB: I think you’ve been doing a fantastic job. Let me trace back just briefly to the glutathione story because you talked about remarkable moments. I would say from my perspective and literally tens of thousands of my colleagues, your sharing your clinical videos of the response the Parkinson’s patients to glutathione was more than an ah-ha experience; it was a remarkable, miraculous experience, and I’m sure it was even more so for you, living through that personally with your patients. But I’m sure there was also some disappointment that somehow you couldn’t sustain those extraordinary benefits that you saw, post-infusion. Do you have any sense as to what’s going on that leads to the decline of functions after the infusion of glutathione? DP: Well, I think ultimately in Parkinson’s we are dealing with a situation of increased oxidative stress, and I think basically the patient is shifting the ratio of glutathione from reduced to oxidized, and in terms of sustaining the benefit, that has required that these infusions be done about every three days or so, but I will say that in terms of the longevity of the benefit, my goodness, we have patients now 14 years using glutathione getting wonderful results from it, but it doesn’t last more than a couple of days. My dream would be to somehow create technology that would allow a constant infusion, and even more than just a simple intravenous pump (the technology exists for that), even an intrathecal, or administering it into the spinal fluid, and that technology already exists for delivering antispasmodic medications, or analgesics. The problem, as we explored that, is glutathione is a very heat sensitive tripeptide, and as such exposing it to 98.6 in the reservoir became a conflict for us and we’re still looking at how we can get around that, creating a product that could be more heat stable. But that’s where we’re going in the future. I will say that I have been offered a research opportunity moving forward into 2015, and that’s going to be one of the players on the top of the list. But it’s been a big circle to come back through the years to the importance of diet—fundamental diet—and as of now we understand it relates to the microbiome, even as it relates to Alzheimer’s disease. That may seem like a stretch, but we now understand there are clear indications that our obsession with hygiene and our lack of judicious use of antibiotics and the effects that that is having on the human microbiome may in fact extend in some correlative way to risk for Alzheimer’s disease. In a study in Evolution Medicine and Public Health in August of 2013, British researchers showed that when you mapped out diversity of the microbiome in well over a hundred different countries globally, it lined up perfectly with the prevalence of Alzheimer’s disease.[8] Those countries that had high levels of diversity and high levels of parasitic stress, for example, had the lowest prevalence of Alzheimer’s disease. Microbial Diversity is Key in Avoiding Gut Inflammation Now again, some may say, “Well, correlation doesn’t indicate causation,” and the hair on the back of my neck when people make that argument because I think the argument is that we should ignore this data and absolutely not. The point is that with microbial diversity we maintain gut wall integrity, and gut wall integrity is seen to be breached in Alzheimer’s. We are now able to measure lipopolysaccharide (LPS), the bacteria membrane coating found on Gram negatives, which, interestingly enough, getting back to the Burkina Fosa stool analysis, we see much higher levels of Gram negatives in European western microbiome compared to rural Africans, but that said, lipopolysaccharide is a powerful marker of gut permeability. Lipopolysaccharide is used in the experimental laboratory to create inflammation in experimental protocols. So when you measure either LPS itself or antibodies against LPS, this is a powerful indicator of gut permeability. We see direct correlation between higher levels of LPS in Alzheimer’s with amyotrophic lateral sclerosis, and it predicts the level of neurologic impairment. It’s seen in major depressive disorder, and is dramatically associated with autism. So again, these are the powerful indications that something has gone awry with the gut that ultimately is paving the way for inflammation, a cornerstone of everything I’ve mentioned and then some. So, it takes us back to then what do we do before we become interventional? What do we do from a preventive perspective in terms of preserving the bacterial array of the gut, and therefore preserving gut wall integrity? And, you know, from day one…let’s go before day one. Let’s go to when a baby is born. Clearly, we see very powerful data that is indicative of method of delivery playing a significant role in how that microbiome is created. When we see that the risk of autism is now 1 in 50 male births in America, and that risk is doubled if a child was born by Caesarian section, that’s important information. Risk of ADHD is increased three-fold. Risk of type 1 diabetes, an autoimmune condition, is increased 75 to 80 percent. These are important statistics that need to be shared with mother, rather than just focusing on the length of the scar that she will have if she chooses to have a Caesarian section. I’ve got to qualify this statement by saying this is not mommy bashing. This is not telling mothers that they should feel guilty that they delivered by C-section. I want to be proactive. I want to just say that moving forward these are important life-changing decisions to make and weigh this information prior to Caesarian section. That’s a procedure that saves lives, but the notion that that is what has to happen in one of three American births today I think is clearly stretching a point. Breastfeeding cultivates a wonderful microbiome, but by far and away I think we’re focusing these days, as is so wonderfully described in the book, Missing Microbes, that antibiotic over usage is having a devastating effect on the human microbiome, both in terms of in the clinical arena and also in terms of the foods that we’re eating—the antibiotics, 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of which in America are used in cultivating our livestock.[9] So I think we’ve really got to understand that threats to the human microbiome are real and present danger, and that there are things that we can do if we focus on therapeutic techniques at the level of the microbiome that can have powerful outcomes in terms of any degenerative condition that you can name, so clearly this is the future. I had the opportunity several months ago to lecture at Harvard on the microbiome as it relates to neurologic conditions. The following day, as fate would have it, in the exact same lecture hall at the exact same podium was another series of lectures for a different conference focused on probiotics. There was a lecturer named Dr. Nieuwdorp, from Amsterdam, who demonstrated that in his series of over 250 patients with type 2 diabetes, he was able to almost normalize their insulin sensitivity by reestablishing a healthy gut microbiome by doing—dare I say—fecal transplantation. Fecal transplantation for individuals with type 2 diabetes by reprogramming their gut bacteria. Wow. I mean, it literally took my breath away to see that, because we—“we” parenthetically—are focused on the development of drugs to influence the insulin receptor, to influence pancreatic output of insulin, PPAR-gamma activators that can affect insulin levels, metformin, and so narrowly focused on lifestyle factors that when we see that there is a role for the gut bacteria, which are influenced by diet, which may yet be another place that diet induces diabetes, it’s really very interesting. If I may say, of all the factors that increase permeability like antibiotics, xenobiotics, gluten, one factor that we’re now understanding also leads to breakdown of the tight junction is glycation of proteins—that these very advanced glycosylated end products that we use as markers (hemoglobin A1c) for glucose control in diabetes, aside from upregulating radical production and turning on inflammation dramatically in and of themselves because they are quaternary and tertiary characteristics have been changed, actually destabilize, deconstruct the tight junction and lead to gut permeability, so yet another way that diets higher in carbs and sugar can enhance the risk for diabetes by enhancing inflammation. JB: I’d like to pick up on this—you’ve left us so many pearls, there, we could obviously…hey, I just thought about it: pearls from Dr. Perlmutter; it sounds like a pretty good aphorism… DP: I’d better get the URL before you do… JB: Let’s talk about this fecal transplantation for a second. I know that you’ve had some observed clinical influence on some of your patients with that technology. Tell us a little bit about it because it sounds, in the minds of some, to maybe be way out, and in the minds of others who have been in this field, maybe a logical extension of what we’ve learned in terms of the clinical application. Making a Case for Fecal Transplantation DP: And it is the latter, clearly. It’s clearly a logical extension, and let me just build the case for you if I may. So many have heard of fecal transplantation, or fecal microbial transplantation in America, because that has now assumed the number one position in terms of treating a specific bowel condition called Clostridium difficile infection. C. diff is potentially life-threatening; about twenty thousand Americans die annually from this gut overgrowth of bacteria, and I don’t necessarily call it an infection because that connotes an invasion by a species that is foreign and overrides the system. In fact, nothing is further from the truth. Many of us are carrying C. diff. At nursing homes, 50 percent of the elderly individuals have levels of C. diff. And, in fact, newborns have high levels of C. diff as well. The problem arises when the balance of bacteria is disturbed and then C. diff is allowed proliferate, especially when individuals are exposed to a class of antibiotics called fluoroquinolones. With that said, the treatment for C. diff has been, historically, the use of a specific antibiotic called vancomycin, which is about 28 to 30 percent effective in eradicating C. diff on a permanent basis, and that’s a pretty crummy metric. We now understand that using fecal microbial transplant, and to be very specific that is to say, taking fecal material from a healthy individual who has been screened for communicable diseases like HIV, hepatitis, etc. That stool specimen has been screened for pathogenic parasites. And transplanting that material into the colon of the C. diff sufferer has been demonstrated to be between 92 to 96 percent effective in total eradication of the illness called C. diff. By far and away, the most effective treatment for C. diff in the world. Dr. Feingold published a report several years ago in which he used vancomycin to treat autistic children. Now, why would he do that? He did that because new research is demonstrating higher levels of clostridial species (Clostridium histoliticum, for example), to be found to be quite prevalent across the board in many autistic children. Dr. Feingold recognized this and began an open-label trial and demonstrated significant improvement in the autistic children, as well as fielded reports from his colleagues, who were doing the same thing—using the best treatment at the time, vancomycin, to reduce C. diff population, and therefore seeing clinical results. So, the natural extension that you referred to stems, number one, from that work, and also from the work of Dr. Derrek MacFabe at the University of Ontario that I alluded to earlier, demonstrating that perhaps the player is this abnormal ratio of short-chain fatty acid with higher levels of propionic acid. Dr. MacFabe has brought to our attention the notion that propionic acid is a mitochondrial toxin, which takes us back to our origins—a mitochondrial toxin that has a role to play in changing omega-6 to omega-3 ratios, increasing inflammation by increasing omega-6 availability by altering neurotransmitters, by enhancing glutamate influx into the mitochondria and thus serving as a mitochondrial toxin, and that, as mentioned, there are higher levels of propionic acid in those people whose gut microbial array has higher levels of clostridia. So then, looking at Dr. Feingold’s work, he’s eradicating clostridia and finding results. I feel it is a natural extension, then, for me to have had discussions with parents of children devastated with autism, and parents devastated by the fact that their children have autism, to be a little bit outside the box and outside the envelope. I’m hopeful that your listeners will understand that this is natural extension and that there is perfect rationale. You know, Louis Pasteur said that chance favors the prepared mind, so we do the homework and then we move ahead for discovery. We’ve been, now, working with families to perform fecal microbial transplants on autistic children. To be clear, I’m not doing that procedure in my office, but parents are learning how to do the procedure, and we are seeing results that are profound. So, it’s a new day. I have to say I was lecturing recently in Frankfurt, Germany, and during the break I received a text message from a mother of a child who underwent this procedure. The mother actually found a donor—a 14-year-old healthy girl—who wanted to help this kid and donated her stool. The mother figured out how to do a fecal microbial transplant, and the child began speaking. This is a kid who couldn’t be moved and the video she sent me was of this child jumping up and down on a trampoline, and she indicated to me in a phone conversation that after his sixth transplant she took him to the beauty parlor one day, he sat in his chair next to her having her hair done, and they had a 40-minute conversation. Now, this is in a day and age where there is no treatment for these kids whatsoever. That mainstream medicine is absolutely scratching their head because they are focused on the brain, and we’ve got to take a broader view. It is a holistic perspective that recognizes that we are a composite of multiple systems, and that when we embrace the notion the multiple systems come to bear, to manifest, as either health and disease, this is when we’re going to have the best results and we’re going to be able to push the reset button and give people another chance. JB: What a message of optimism for many of our clinicians that are looking for solutions to these very complex problems. One of the other areas of the many that you have been a pioneer in maybe seems paradoxical to people, again, not familiar with this field, and that is hyperbaric oxygen. People might say, “Well, hold it. Aren’t we exposing people now to an oxidant stimulus, and aren’t we just promoting oxidative stress by giving them oxygen?” But we get into hypoxic-induced factors, and gene regulation, and so tell us a little bit about the hyperbaric oxygen approach towards normalizing mitochondrial bioenergetics. Using Hyperbaric Oxygen to Normalize Mitochondrial Bioenergetics DP: I will. Let me just take you back for just one moment. You know, you’re bringing up mitochondria again. I think there’s actually a very nice segue from our previous conversation about the microbiome when we recognize, in 1968, the work of Lynn Margulis, talking about this endosymbiotic relationship that we have—that these were once free-living bacteria with their own circular DNA. They took up residence within us and have given us the gift of energetics, as well as regulating life or death wielding the sword of Damocles, as we talked about earlier. So there is this kind of intriguing segue to consider mitochondria as yet another part of the microbiome—that they are bacteria-like organisms and we need to embrace them as such and stop fighting these wars. You know, many pesticides that are used are ultimately mitochondrial toxins, and I think when you recognize that mitochondrial toxicity is at the root of neurodegenerative conditions, it makes you want to, again, take pause to understand that we’re exposing ourselves to mitochondrial toxins. In the Journal Archives of Neurology last year was a wonderful report that showed increased risk of Parkinson’s in individuals exposed to various things like pesticides, etc., and there was one chemical called mancozeb that I was unfamiliar with.[10] I went on Wikipedia and learned about it, and it is a mitochondrial toxin that’s used in the experimental rodent and primate model to create Parkinson’s in the experimental laboratory. When you look further you see you can buy the stuff at the garden store to put on your vegetables. So something is very wrong. As Gregory Bateson said, “Man is the only animal who will befoul his own nest, a sure sign of madness.” So that said, we look at, what does a mitochondria need to be happy? It needs to have the right fuel. It needs to not have exposure to these toxins. And it needs a place to transfer that electron at the end of the day. And where that electron goes in the process of creating ATP is, of course, oxygen. So if we can enhance that activity of oxidative phosphorylation with hyperbarics, it seemed reasonable that this was the explanation as to why hyperbarics has proven so helpful in wound healing, in reversing the changes of osteoradionecrosis. Does the application of an increased oxidative state run the risk of those things that you mentioned, and I would say absolutely there is that consideration, but again we take a step back and look at risk/benefit ratios. Many of the mainstream therapeutics have, in fact, the notion of one-step-back/two-steps-forward, and what we understand happens when we increase oxidative stress is that we induce the upregulation of protective antioxidant systems, of detoxification systems, of inflammation-reducing activity as well. As a matter of fact, oxidative stress is a very powerful upregulator of the NRF-2 pathway. Oxidative stress is a homeostatic mechanism that allows us, when we’re suddenly involved in a situation of increased oxidative stress demand, to enhance our production of protective species, protective chemicals, antioxidants. So at the end of the day, we are putting our patients into a lower level of oxidative stress, while at the same time recruiting macrophages, enhancing phagocytosis, increasing detoxification, and reducing inflammation by this very, very powerful approach by putting people in a chamber pressurized with oxygen, to the extent that Israeli study that was published about 12 months ago—published in PLoS One—looked at actually functional MRI scans in individuals pre- and post-hyperbarics who had sustained a cerebrovascular event, showing that those areas of functional-but-not-functioning tissue came back online when they were treated in this way.[11] So I think we’re going to see a lot more to come from the value of hyperbarics, especially in conjunction with the notion of reprogramming the gut bacteria. Knowing Your apoE4 Status Does Not Mean Knowing Your Future JB: Well, we just have a few minutes left. Obviously we could continue this discussion and we’d all be enlightened for going on for hours, but we’re begging on your indulgence of time. Let’s finish up talking about the concern a lot of people have with neurodegenerative disease—that it was passed on as a legacy that they didn’t fill out an application card for, which is called their genes. I find it very interesting, both sociologically as well as medically that many people are very resisting in knowing about their apoE genotype because they are fearful that this would be a death sentence if they understood something like the Huntington’s disease gene, if they knew their apoE4 that would be kind of an end-of-life experience for them. Tell us a little bit, David, how you see genetic testing weaving itself into functional neurology, and maybe specifically related to the apoE4 double allele. DP: Well, I think that first of all, this notion that carrying the apoE4 allele is a sentence for Alzheimer’s is silly. I mean, the apoE4 allele is something that has evolved in recent times from our primate ancestors, and for a genotype like that to have persisted, I think it’s not unreasonable to ask what there may be in terms of some advantage that has allowed it to persist. Why has it become prevalent? Why is it found in up to 20 percent of humans? There must perhaps be some advantage, and I think that you’re about to learn about that with your next interview, and I’m not going to spill the beans on that (with Dr. Bredesen). New insights into possibly some other attributes that the apoE4 genotype and the phenotype that is a manifestation therefrom. But that said, I am not usually involved in that screen for my patients. The reason being is that it is not a sentence. It is a risk marker to some degree, but by no means is it a determinant. I feel that there is a fair chance I may carry the apoE4 allele in light of my father’s Alzheimer’s disease, and that said, I don’t know whether I do or I don’t, because I know that the notion of epigenetics, to me, carries a far more attraction in the idea that there are powerful things that I can do and that I am doing that will, I believe, clearly offset the notion that I carry or don’t carry the apoE4 allele. Now that is not to say that there are other aspects of looking at single nucleotide polymorphisms that aren’t really important to know, as they may relate to an individual’s choice of medication and his or her detoxification abilities. I think that’s valuable information. Is the apoE genotype information that’s important? To some degree. But with my patients, I pull out all the stops without regard to that metric, so therefore, they’re getting soup-to-nuts the whole program because by and large these are people who I’m seeing because either they are beginning to have some issues with cognitive impairment, which we now understand are, in fact, reversible. That these mild issues, and even moderate issues, of cognitive impairment that go by the name Alzheimer’s disease are, in fact, reversible, and the answer isn’t on the prescription pad. There’s no one approach that makes that happen. It is not definable, nor is it proprietary. The point is that, again, multiple lifestyle factors can undo this genetic predisposition, and we are just, just now beginning to embrace what Dr. Jeffrey Bland taught us many, many years ago, and that is we’ve got to pay attention to the web—the web of interacting, interrelating factors that can either conspire to manifest disease, or can be looked upon as powerful allies in creating health, wellness, and longevity. JB: Well, Dr. Perlmutter, to say thanks to you would be a great understatement of our appreciation for your 20-plus years of work. You’re pioneering, against a lot of conventional old thinking, a new model that is, I think, much more optimistic in terms of plasticity and opportunity for self-improvement and giving new tools to clinicians that have been probably frustrated they didn’t have the tools they needed to their patients’ problems. It’s not an easy job. It’s one that requires courage, and high intellect, and high communication skills. Fortunately you were gifted with all those from your parents and you’ve developed them very, very well. There would be no better person I could think of starting off this three-part mini-series on functional neurology than the person who has really birthed what I consider truly functional neurology. So thank you for your tireless work and contributions to the patients and the field at large. DP: Well, I sure do appreciate those kind words, Jeff. And your work has had a very, very powerful influence on me in terms of allowing me to stay the course, and encouraging me, you know, at times when we’ve all had our moments of doubt—being the odd man out, that’s for sure. But people have always said, “Gee, you know, all the stuff that you’re doing is really…it’s so outside the box and you’re a really outside the box thinker, and I always like to come back and tell them that that’s not the goal. The goal is to make the box bigger, so that we embrace these ideas because these are natural extensions from current science, and they work. Maybe ten years from now we’re going to have another conversation. I can’t imagine what we’ll be talking about, but I’m looking forward to that day. JB: Well, so am I, and I think of your book, Grain Brain and the millions of people that have been impacted by it. I think of other neurology journal articles that have been considered pioneer journal articles that have transformed neurology—how many of them have been read by millions of people? The impact of your book is a great social agent of change. DP: Twenty-seven languages, and I have no way of reading those and knowing if they are giving the right message, but I’ve finished writing a new book called Brain Maker, and what’s that about is dealing specifically with what we’ve talked about a lot: not just the role of the microbiome, but I think more importantly for clinicians and non-clinicians alike, what can we do about it, both in a preventive way and also in an interventional way? JB: Well, you can be assured we’ll be coming back to visit with you before ten years. Thanks a million, Dr. Perlmutter. We can’t appreciate enough all of your contributions. And be well and best to you and your family. Thank you. DP: Thank you, my friend. Bye-bye.  

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Welcome to February 2015 Functional Medicine Update. This is the second of our series—our mini-course—on functional neurology. And those of you that had the chance to review chapter one of our series, you had to be as enthralled as I was in hearing Dr. Perlmutter lay the landscape out. I would call it fertilize the field of discovery and opportunity for progress to be made in these intractable neurological diseases using a new model. And you’re not going to be disappointed this month. This is an extraordinary next step in our evolving model. We’re going to be moving from what I think is a landscape discussion and particularly focusing on things that may appear so remotely removed from the traditional field of neurology, like the gut-brain connection. Over many years we’ve seen the evolution of this model, and now Dr. Perlmutter talking about fecal transplants and how that can influence neurological function. So we’re seeing the interweaving—the interpolation of these various perspectives in developing the new model, the new medicine, the functional systems biology-based medicine that is going to define 21st century medicine.   Are We Entering an Era of Treatable Alzheimer’s Disease? And we are very privileged in the February issue of 2015 to have the second step in our journey in functional neurology with Dr. Dale Bredesen. Dale will open up for us clinical news to use as it relates to what, for many people, is considered an irreversible, downslide-sloping concern called Alzheimer’s disease. His work as an extraordinary research neurologist now moving into clinical applications at the UCLA Alzheimer’s Research Center has really opened up many of the areas that we feel are going to pioneer new discoveries, new opportunities, and better outcomes for the Alzheimer’s patient. I think it will cut across many other areas, as you’ll see, in how you approach complexity in science. It will open up our minds to new experimental models to discover how we explore networks and systems rather than just look at particular binary relationships between A goes to B, a ligand binding to a receptor producing an outcome. And it’s that kind of new model—that systems thinking model—that is going to really help us to transform the way that we will personalize treatments for individuals with complex chronic illness and improve clinical outcome. The old models of medicine of the average are dying. The new models of medicine for the individual are emerging. And you’re going to hear that beautifully stated, using the example of Alzheimer’s disease, from Dr. Bredesen in his presentation.   And Dr. Bredesen comes with no small reputation or background. A person who has authored over two hundred scientific papers in the peer-reviewed literature, who has worked for a Nobel Prize-winning laureate in the area of neurological disease discovery. A person who has pioneered pathways of understanding about neurogenesis and plastogenic effects that relate to nervous system function, to cell signaling, to the relationship of neurological development, and ultimately the interrelationship of these two general pathways and processes that, under the concepts of functional medicine, we call seven core physiological processes is really what I would call the premier functional medicine neuroscientist. So you’re going to have the opportunity to not only be titillated by the process of discovery and how one lays the bricks down in the road to move from hypothesis to proof, but also how one then moves to employ and deploy these concepts into clinical management programs, not waiting for 50 years for all the answers to be in before we actually start doing something to reduce the burden of this reducible disease that we call Alzheimer’s disease.   So with that in mind, let’s move into our discussion with our second key opinion leader on our journey in functional neurology, Dr. Dale Bredesen.  

INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Dale Bredesen, MD Augustus Rose Professor of Neurology Director, Mary S. Easton Center for Alzheimer’s Disease Research at UCLA Director, Alzheimer’s Disease Program Director, Neurodegenerative Disease Research David Geffen School of Medicine at UCLA We are so fortunate to have, following Dr. David Perlmutter, our lead interviewee, Dr. Dale Bredesen, who is an extraordinary contributor to the development of this field. Our longstanding FMU subscribers are aware of Dr. Bredesen’s work because we’ve had the pleasure of interviewing him in the past. Those of you who have not heard him or about his work are in for an extraordinary treat because the progress he is making in the area of neurodegenerative diseases and its relationship to functional neurology is nothing short of miraculous. Let me give a quick biography for Dr. Bredesen. He’s the Augustus Rose Professor of Neurology, Director of the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA. You probably are aware of his work if you’re involved at all in this field in that not only does he have a very prestigious background—an undergraduate degree from Cal Tech, his MD at Duke, and he completed his neurology residency at UCSF—but he was also an NIH Fellow in the laboratory of Nobel Laureate Stanley Prusiner, who was awarded the Nobel Prize for his discovery of prions. In 1989 he joined the faculty at UCLA, where he was awarded the Elizabeth R. and Thomas E. Plott Chair. He then was recruited to Burnham Institute to direct the program on aging, and in 1998 became the founding president and CEO of the Buck Institute for Research on Aging, which is the nation’s only independent institute devoted to research on aging and age-associated diseases. So he has held faculty positions at UCSF, at UCLA, and at the University of California at San Diego. His work spans an extraordinary array of contributions in the field. I went back and looked at his more than 160 publications, and if you go back to the early days of Dale Bredesen you find that some of his early papers back in the 1980s were involved with the development of understanding of cell signaling, and neuronal pathways, and apoptosis, and neuronal cell death, looking at whole mechanisms of disease, platform technologies, understanding the complexity of synaptic plasticity and synaptic signaling, really being, I think, one of the fundamental pioneers in the understanding of the complexity of brain and brain function and how, in fact, the brain is connected to the overall scheme of the network of physiology of the body and things like brain-derived neurotrophic factors, and various kinase-signaling pathways that relate to gene expressions that are triggered by inflammatory mediators and neuronal oxidative stress. He was an early pioneer really looking at mitochondrial neuronal function and how that relates to the presence and absence of various redox-active substances and the establishment of proper neuronal bioenergetics. So his footprint in the field has been nothing short of remarkable, and there could be no one I could think of that would be more suitable to help us to understand what is really happening on the cutting edge of 21st century functional neurology than Dr. Bredesen. And on this day that we’re having this interview, we’re very privileged to see a CNN health article that has been published titled “We May be Able to Reverse Signs of Early Alzheimer’s Disease.”[1] That’s by Stephanie Smith and it’s talking about none other than Dr. Bredesen and the work that he is doing at UCLA and the results that were encoded within a paper that was recently authored by Dr. Bredesen that is titled “Reversal of Cognitive Decline: A Novel Therapeutic Program.”[2] This appeared in the journal Aging in the fall of 2014. So with that and much more that I could say, Dale, thanks so much for being available to talk with us about what’s happening in your laboratory and in the field in general in this extraordinary age of functional neurology. DB: Thanks very much, Jeffrey. I have never been, in my entire career, more excited and more enthusiastic than I am right now because I think we are now at what I would say is the dawn of the era of treatable Alzheimer’s disease. JB: Well, there’s a great way to start the discussion! I could tell you, there’s probably no better way to get us off the launching pad than that statement. Before we jump out and talk about the most recent extraordinary experiences that you’re having clinically, let’s go back and talk about this thing that Dr. Perlmutter actually brought up, which was a quote from Louis Pasteur, which is chance favors a prepared mind. You’ve been preparing your mind professionally for many decades to be able to make these observations and these understandings and the association. Maybe you could take us back a little bit in your career—I don’t want a complete biography—but if you could take us through kind of how you see the topography of your professional career as an experimental neurologist and primary research investigator leading you up to this opportunity to have this ah-ha experience, it might be very helpful for all of us to see the evolution of ideas through the life of Dale Bredesen. Investigating the Science of Cell Death DB: Thank you, Jeffrey. So we started with the very simple question and have asked a couple of very simple questions through the research over the last 25 years, and the initial one was: What is it that drives neurons to die? Why do you have neurodegeneration occurring so frequently? As you probably know, just recently it was shown that Alzheimer’s has now become the third leading cause of death, after heart disease and cancer, in the United States. There are about 30 million people globally. So a huge problem and so we wanted to know, what are the molecular mechanistics that go into loss of neurons, loss of synapses, loss of neurites, etc., as we age, and we started this actually back in 1989, and we identified specific gene products, and we published—in Science, back in 1993—that there are specific receptors that we dubbed dependence receptors, and that these receptors induced a program of cell death when they do not interact with their appropriate trophic ligands.[3] So what was happening there is that these were essentially backwards from what had been described in the immunological literature, where you bind a ligand—for example, fast ligand—and you induce the death of the cells. These were receptors, and we now know of over two dozen of these, where they are literally waiting for a trophic ligand, such as nerve growth factor or brain-derived neurotrophic factor—things like that. And when they bind, then it turns off the cell death and when they then lose those, it turns on the cell death. It was interesting because I had been interested in work from back in the 1930s, as you probably recall, with Dirac, when he pointed out when the electron was first identified he said, “Well maybe there is something where there is something that is like a hole.” He described it as a hole, and of course this turned out to be the positron. And so we thought, “Okay, if you take away neurotrophic factors from these important receptors, is it possible that there is also an anti-trophin out there? And at the time there was no such thing as an anti-trophin, but what we found later is, in fact, that Abeta, the very peptides that are increasing in the brains of Alzheimer’s (and you have about a thousand-fold too much of this Abeta in the brain of an Alzheimer’s patient), they fulfill all the criteria as an anti-trophin. So they block the trophic activity of insulin and insulin signaling, for example. They block the activity of NGF. They block the activity even of acetyl choline at the alpha-7 receptor. So it turns out that in fact there are anti-trophins, and these can also trigger this process. So we began to look at APP (the amyloid precursor protein that interacts with—as we found—netrin), whether or not that actually functioned as one of these dependence receptors. That is to say, does it mediate things like programmed cell death, neurite retractions, synaptic reorganization when you pull back a trophic factor, when you take away the trophic factor? And we found out, in fact, that APP is indeed a dependence receptor. Its trophic ligand is netrin-1, and there are other things that are trophic; for example, it also binds with laminins. And its anti-trophic factor is Abeta; it interferes with that activity and induces neurite retraction, induces programmed cell death. Alzheimer’s Disease is an Imbalance in Brain Plasticity So we thought, okay, this is very interesting because it gives us a handle for the first time on what Alzheimer’s disease may actually be. It actually may be an imbalance in the fundamental nature of plasticity in the brain. So over the last ten years, we’ve made transgenic mice to show that in fact this is exactly the case. So we can engineer these transgenic mice so that their APP—this balance of signaling—is imbalanced toward better, more trophic, signaling. And as you might imagine you get mice that are smarter, that remember more, and that forget over a longer period of time. And on the other hand you can go the other way and engineer ones that are actually worse and in fact will get Alzheimer’s disease. So this told us that in fact APP is an important contributor. People have focused on just one of its derivative peptides, i.e. Abeta, rather than on the entire picture. But if you take a step back what you can see is that APP mediates this synaptic plasticity balance, and that that’s what we’ve after in our treatment for Alzheimer’s disease. JB: Well this is an incredible model. I think for most people, unless they are specialists, they probably can’t understand all the piece parts like you, obviously, as an expert in the field, but I believe that the model that you’re providing is understandable by everyone—this concept of a balance point and equilibrium, because it seems to fit in to the whole model of cellular regulation at many levels that we’ve learned, this almost yin and yang between activators and inhibitors. So this whole concept of synaptogenesis versus synaptolysis, or how we would find these balance points, appears to be a very central theme in establishing proper function of the organism. Can you give us a little bit of a description of the teeter-totter, as you have described it, in terms of neurological function? I believe that’s a wonderful metaphor and learning tool for all of us. DB: Absolutely. And so what we found is that all this complexity really boils down to something that is relatively straightforward, and that is to say if you think about osteoporosis, as you know you—throughout life—have a beautiful balance in osteoblastic signaling, when the osteoblasts are putting down more bone than the osteoclastic activity. And of course your osteoclasts are phagocytosing and pulling up the structure, and so I often tell people, “Imagine that you’ve got two sets of contractors coming to your home for many years. You’ve got the ones that are doing the demolition and you’ve got the ones that are doing the construction. You might want to add a room here or take something off. Well, imagine that for 20 years the ones that are doing the demolition always did more than you asked them to do, and the ones that were doing the construction never showed up.” Your house would dwindle, and that’s exactly what’s happening in the brain in someone with Alzheimer’s disease. So what we’ve found is that synaptoblastic activity has a number of signals that contribute to it. Things like: are you learning new items? Are you exercising regularly? Are you in good health? Is your inflammation at a minimum? All the things, of course, that functional medicine directs and functional medicine studies turn out to impact this critical balance, and so, you know, you’re actively forgetting the seventh song that played on the radio on the way to work yesterday, and that’s very normal. That’s part of the synaptoclastic effects. And there are many things that contribute to this. So, for example, reducing vitamin D, reducing hormones, and things like that all contribute to the synaptoclastic activity. Throughout much of your life you have this beautiful balance—you’re learning new things but you are also forgetting things appropriately and physiologically. Unfortunately, as you age, and depending on your genetics and depending on many lifestyle things, etc., you can have this chronic imbalance in the synaptoblastic versus synaptoclastic. And I should add a new concept. We all think about carcinogens, but we never talk about dementogens. And in fact we are realizing more and more that there are many things out there that are dementogens, and this has to do, in fact, with everything from your diet, to whether you’re drinking from things with plastic, whether you’re eating processed foods—all these things. So we’re very used to hearing about the carcinogen concept but not about dementogens, and yet we’re exposed to them. So when we did the transgenic mouse studies, we were able to make very precise changes genetically. As we then went from the mouse to the human, we realized that with a human you’re not going to be able to do genetic engineering prior to the human being born. You’re presented with someone who’s already early in the course—hopefully very early in the course—of Alzheimer’s disease. So we looked at all of the things that can affect the synaptoblastic-to-synaptoclastic ratio, and fortunately, for many of these things, we can actually measure them. A simple example: homocysteine. Turns out that as you increase your homocysteine, in this beautiful work showing biochemically that it leads to a post-translational modification on one of the subunits of the PP2A phosphatase, and what that does is reduce its effect, and therefore the net effect is to increase phospho-tau. Now, phospho-tau, again, is a physiological signal for pulling back the neurites. Again, if you want to pull back your house, you’ve got to pull out the rivets that are holding the structure together, and that’s exactly what happens; the tau stabilizes the microtubules, stabilizing those interactions. So if you want to pull back on them critically, you phosphorylate the tau, which pops it off of the microtubules and allows you to pull back on the structure. So no big surprise: when you look in an Alzheimer’s patient’s brain, you find a massive increase in phospho-tau. Literally it is telling you there is an ongoing signal for neurite retraction. The Synaptic Symphony Has 36 Players So when we then asked, “Okay, what can we do for humans?” we used the analogy that it’s a little bit like the 36 holes in the roof. If you try to fix just one hole with a drug, you’re not going to get very far because you’ve got 35 other ones. I say 36 because we identified 36 different players in this beautiful network—this synaptic symphony, as it were—and we can now change all of them. So the good news is we can affect all of those parameters. The bad news is that there may be some other ones out there that we don’t know about yet. But what we’re hoping is that now that that you affect these other parameters, if you want to use a drug and certainly that’s going to be appropriate at certain times, now use the drug appropriately. The drug is a little bit like the dessert; instead of starting with the drug, do all the right things first, and then if you need that drug, now you’re doing it in the right background. So we think that this will be a wonderful platform going forward, for testing drugs that have a single mechanism of action or a limited number of mechanisms of action. So we use the analogy with other chronic illnesses—such as osteoporosis—to direct us, to guide us for what we can do with Alzheimer’s disease. And the excitement is that—as you mentioned—we just published the first paper showing that we can reverse cognitive decline. There are lots of open questions. We don’t know yet how late in the process we can reverse this. We don’t yet know whether this is helpful in other disease processes. There are a lot of things we don’t know yet. We don’t know whether you need all 36. But the exciting part is you can see, typically within 3 to 6 months, rather dramatic improvements in these patients, so we’re very enthusiastic about that. JB: So before we go on into the details of your clinical observations and the description in the journal Aging, I’d like to do a weigh station check in with you here for a moment because I think there are so many things that you said that have profound, deep implications. One of those was this concept of post-translational effects. I want to just take a moment to hang out with you on that topic. For many people who think about the way genes regulate function, they may have learned and understand that genes control the production of proteins, and ultimately proteins which can be enzymes (or structural proteins) then control function of cells, which then aggregate to make tissues and organs and so forth. And so we have this kind of fairly linear thought that genes ultimately must control the outcome of function directly. But the word that you use—“post-translational”—is a very interesting term because it implies that there are things that happen after the genes have been transcribed or translated into proteins that can modulate their function, and obviously one of those is work that you did with Dr. Prusiner, which is conformational changes in protein that we call prions. So if you would help people to understand that even structural changes in proteins at the three dimensional level can have profound effects upon outcome and these may not be genetically linked directly, that’s a pretty interesting concept, I think, in terms of a different approach towards the hard-wired, bad gene concept. DB: Yes, this is a really important point. As you know, going forward it’s just been increasing, increasing levels of sophistication that people have understood, now, about your genetics and the gene products. So it’s like multiple checks and balances. As you know, you’re given a specific gene, but then there are somatic mutations that occur. Then of course, as you mentioned, transcriptional—the whole field of epigenomics is just blowing up right now—so many new observations there. So that’s an issue. Then, of course, RNA processing is a huge issue, so there you’ve got all sorts of different possibilities. And then, of course, there are all sorts of microRNA control on whether you’re going to make protein, whether you’re going to have a short-lived mRNA or long. So there are all sorts of microRNA controls. And then as you mentioned, once you finally get to the point of actually exporting, processing, all that sort of stuff, and you now get the ribosome and you now actually make the protein, you’ve also got things like where are you directing the protein? How are you making the protein in terms of its confirmation? There is, of course, beautiful work—as you mentioned—from Stan Prusiner, also from people like Vishu Lingappa, showing that you can actually direct different topologies of the same protein with the same coding sequence by changing the region just upstream from the start site, which is, again, amazing. Then once you make it, as you said, you’ve now got the ability also to change its function through things like protein phosphorylation, methylation, sumoylation, you know, on and on and on—acetylation. And you’ve got things like the sirtuins that are protein deacetylases. So you’ve got beautiful cycles here, where you can change protein function and structure at multiple levels, at multiple times, and at multiple different locations. What I mentioned with respect to homocysteine is there is now identified a specific post-translational modification that changes the function of this protein phosphatase-2A, reducing its overall effectiveness and leading, therefore, to a net increase in the phosphorylation of tau, so that you’re changing the balance toward pulling back of neurites, toward a positive programmed cell death, and toward synaptic reorganization. Similar things, for example, also occur with what’s called WAV1, which is involved with actin depolymerization (so, to pull back neurites). And you’ve got similar kinases involved, similar phosphatases involved. So what it really shows is that in this beautiful dance, you have higher order organization through specific nodes and that there are controlling features. And one of the ones that we identified, for example, is this balance between SirT-1 and NFkappaB. The apoE4 Gene Increases a Proinflammatory State A few years ago we started a new project to ask: why is it that apo E4 is such an important risk factor for Alzheimer’s disease? As you know, apo E4 is present, typically, in 60 percent of all people with Alzheimer’s disease. It is also a big risk factor for cardiovascular disease, and also for chronic traumatic encephalopathy, and actually other neurodegenerative conditions such as Lewy Body disease. It’s been unclear why and the suggestion has been very simple—that it somehow changes the clearance of Abeta, but it turns out to be much, much more interesting than that. Apo E4, by the way, is one of the genes that changed between the Simians and the Hominids, so it has been argued that apo E4 is a critical gene for allowing us to be human. It turned out to increase the proinflammatory state. You’d think that would be a bad thing, and in fact it is as you get older, but when you are young, in fact, the idea of the Simians coming out of the trees and walking in the savanna and doing all the things that the early Hominids did that we were doing 5 to 7 million years ago, it turns out that apo E4 was quite helpful because it allowed us to eat raw meat, with the many microbes that are associated with it. It allowed us to do things like walk with dung in the savanna. It allowed us to fight with each other and get cuts and scrapes and things like that, and to kill animals (again, with the associated cuts and scrapes) that turned out to be much better addressed by a proinflammatory state, but it’s never been clear why this proinflammatory state exists. What we published just recently is, in fact, that apo E4 reduces the levels of SirT1 markedly, and it turns out that it changes the balance.[4] There is this beautiful balance, with mutual antagonism, between SirT1 and NFkappaB, and specifically it turns out that the apo E will interact and operate at the level of the NFkappaB. And so what it really does is to change your cell programming from the SirT1 side, which is the longevity side, the reduced inflammatory side, the oxidative phosphorylation side. It’s a little bit like having a country that’s interested in recycling and research, and it switches it over to the NFkappaB side, which is a little bit like a country that puts a lot of its resources into weapons: very good for the short term, very good for fighting things off, not so good for the long run. Just like Louis the XIV—very powerful guy, put a lot of money into weapons and fighting wars. As you know, that didn’t turn out so great for the Louis the XVI and Marie Antoinette. So it’s the same sort of story: when you have apo E4, you’re putting more of your resources into the proinflammatory NFkappaB side—great for walking in the savanna, great for 5 to 7 million years ago, but not good for being over 50 here. But the good news is we can now look early and we can now make a big impact on the future of these patients, and, in fact, a number of these initial patients were apo E4 positive patients with either mild cognitive impairment (a pre-Alzheimer’s condition) or early Alzheimer’s disease, and they’ve done very, very well on the approach we’ve taken. JB: Again, I want to loop back with you just for a second, because I think you said something very, very important there as it relates to your approach, which we’re going to describe. You know better than I—and you’ve helped educate us—that the approach that the pharmaceutical industry has taken towards remediation and treatment of these neurodegenerative diseases is to find a target and then a high-ligand-binding target to that drug to that target and then trying to block or inhibit it very effectively, assuming that that’s going to be an effective treatment. At present it appears as if that model has not been very successful in bringing safe and effective drugs to treat Alzheimer’s or Parkinson’s. So we get to the question that you just raised: if you have all this complexity out there, is Alzheimer’s one disease, or is it a just a phenotype that happens to have certain presenting characteristics that come from multiple arrays of differing genetic and environmental post-translational influences, for which, then, the solution is—as you said—in treating the nodes of the network rather than treating the individual targets downstream? DB: Well, you bring up a good point, and let me quote from Jeffrey Bland: The Disease Delusion. As with these other chronic illness—obviously you’ve written a whole book about this—and what we’re seeing is that these chronic illnesses tend to be physiological pathway imbalances that are present chronically, and so one needs to identify all of the disparate factors that contribute to this specific network. So we’re actually working with a connectomics expert and looking at all the things that contribute to this network imbalance. This is where, I think, the drug companies are going to play a huge role, as long as you address all of the other features, because, yes, these are powerful drugs, but trying to use them without the arrest of the change in the network is not the best way to go. So as a simple example, in the decade from 2002 to 2012, 244 clinical trials were conducted for Alzheimer’s disease at an aggregate cost of over a billion dollars, and 243 failed outright. The only one that was considered a success was for Namenda, which is memantine, which was such a minimal success that the families could not tell who was on it and who was not on it, so it’s a very modest impact. So the idea here is that if we now use all the appropriate changes in this network, then we should be able to see which drugs are actually having the appropriate impact, are actually targeting the right thing, and are actually making a big impact. Right now I believe we are asking these drugs to do much more than they can do. We’re asking something that’s an excellent patch for one hole to patch 36 holes. It’s just not capable of doing that. Now on the positive side, what we found is that there is a very interesting phenomenon of feedback. You know, in medical school we’re all taught about homeostasis and homeostatic feedback, and this is feedback that is negative feedback that drives you back toward a mean. A simple example is your serum pH is 7.4; you never want it to be 2.4 or 12.4. So if you drink an acidic cola, then in fact you’ll have respiratory and metabolic compensation that will drive you back towards 7.4. On the other hand, what we’re not typically taught in medical school is that there is a very different form of feedback. When you have a multi-goal outcome and you require amplification, you literally have a molecular switch, and a simple example is you want to have blood clotting either activated or not activated. If a cave person cuts their finger off, they’re going to bleed to death if you don’t very quickly amplify that signal and create the clot. And then, of course, over time you can destroy the clot with specific proteases, etc. That system actually is a positive feedback system. And what we’ve come to realize is that that is the origin of what we call prionic loops. Balancing Peptides: Memory versus Forgetting So in this situation, your input is amplified instead of inhibited, and that’s exactly what we see when we look at the amyloid precursor protein—the parent of the Abeta and these other peptides that we’ve studied. When you cleave this APP at three sites (the beta site, the gamma site, and the caspase site), you produce four peptides (SAPP beta; Abeta, that everyone is focused on; J-Casp; and C31) that are all physiological mediators of neurite retraction and synaptic reorganization, caspase activation, just as you might imagine. These are forgetting peptides, literally. On the other hand, if you cleave it at a single different site—the alpha site—this produces two peptides, SAPP-alpha and alpha-CTF (C Terminal Fragment). Both mediate—guess what?—neurite extension, caspase inhibition, synaptic maintenance. So these are literally memory peptides. And no big surprise: when you have Alzheimer’s, you’re on the wrong side of that balance. But it turns out that many things will contribute to that balance, just as we discussed. What’s interesting is these peptides turn out to feedback positively, not negatively. For example, the Abeta peptide inhibits the alpha cleavage, so you don’t go down that side. And on the other hand, the SAPP-alpha will inhibit the beta secretase cleavage and the alpha-CTF inhibits the gamma CFT secretase cleavage. That’s all been published. It’s a beautiful, beautiful system that literally functions as a molecular switch, so it’s a little bit like a snowball rolling downhill. Once it picks up some snow it’s going to tend to go down that same side instead of rolling itself back up and going down the other side of the mountain. So our job in the therapy side, then, is to get that thing to the other side—to reduce the side of the synaptoclastic peptides and to increase the side of the synaptoblastic peptides. So you’re absolutely right. You can look at it as multiple diseases, but they all have in common that they feed into this network. And by the way, getting back to your point of multiple diseases, one of the things that’s become very clear from these patients we’re looking at is that Alzheimer’s can come in different flavors. We call this—as a simple example—hot Alzheimer’s and cold Alzheimer’s. So when you look at the patients with hot Alzheimer’s, they have all their inflammatory markers, for example, the hs-CRP, and IL-6, and IL-8, and things like this. These are all increased. The albumin-to-globulin ratio is decreased. These are inflammatory patients, where that’s an important contributor. And interestingly part of that, of course, is NFkappaB, which—by the way—the many genes that it activates includes—guess what?—beta secretase, gamma secretase. So it’s clearly putting you on the side of these “forgetting” peptides. On the other hand, if you look at the two peptides, then in fact you are supporting the memory. The other patients—the ones who don’t have hot Alzheimer’s, so they don’t have this inflammatory state but nonetheless they are clearly presenting with the same loss of memory, the same imbalance in synaptic plasticity—when you look at them, their hs-CRPs are normal. Their IL-6s are normal. But what they have is a decrease in, for example, hormonal support, so they often will have a very low vitamin D level. Or they will have, for example, a very high homocysteine level. Or they will have a very low testosterone or estradiol level. And so forth and so on. So they are, as we say, cold Alzheimer’s patients. They don’t have this massive inflammatory system activated. Reversal of Cognitive Decline Study at UCLA JB: So with that extraordinary background…I want to again compliment you for the ability that you have, which is very unique among scientists, to take very, very sophisticated information and weave it together into metaphors that—for those of us who are not specialists in the field—are understandable and give us our balance points (our reference points) from which we can draw. I want to go into a discussion now of your article “The Reversal of Cognitive Decline: A Novel Therapeutic Program” in which you describe the clinical outcome of these patients, but before I do that I wanted to return back to this little CNN article that just appeared authored by Stephanie Smith, and I’m going to quote because this will bear on a question I want to ask you about the process of innovation. So she says in this article, and I’m selectively quoting now: “Yet a very small study out of UCLA is offering a glimmer of hope of those with what is often a hopeless diagnosis of Alzheimer’s. Nine out of the 10 patients involved in the study…”—that’s your study—“who were in various stages of dementia, say their symptoms were reversed after they participated in a rigorous program. The program included things like optimizing vitamin D in the blood, using DHA supplements to bridge broken connections in the brain, optimizing gut health, and strategic fasting to normalize insulin levels.” Then—I’m going to segue forward in the article—she says the following: “Hendrix with the Alzheimer’s Association said one sound element of Bredesen’s study, given the complexity of Alzheimer’s disease, is its focus on addressing multiple risk factors. He cites as an example a two-year, 1200-person clinical trial out of Finland, the results of which were presented earlier this year at the Alzheimer’s Association International Conference. Among study participants engaging in nutritional changes, physical activity, brain training, social activities and management of risk factors for heart problems, cognitive performance improved. Bredesen stresses that identifying the culprit for early Alzheimer’s symptoms must be based on a patient’s specific deficits and imbalances.” I’m going to stop there. So clearly, Dale, with any kind of work of your magnitude of paradigm-shifting conceptual framework you’re going to have people who get it and people who don’t get it, people who are supporters and people that are detractors, people who use old metaphors to describe new knowledge which doesn’t really fit and those that have new language to describe new observations that does fit. Can you tell us a little bit about how you’re seeing the landscape of understanding respond to your work? DB: Yes, that’s just a great question, Jeffrey. So the people who are invested in keeping the status quo, whether it’s related to drug development, philanthropy, grant support, long-term laboratories, any of these things, are not surprisingly skeptical and often quite negative. You know, she mentioned something in the article about, you know, not recommending that people go out and do these things. Yes, certainly don’t go out and eat well and improve your health. That’s absolutely right. But it is, in that sense, a little bit silly. As I mention in the paper, one of the side effects of the program is that you improve your BMI, and you improve your health. So there has been skepticism, and the response—and I know this happens often when you are doing something that is a bit disruptive to the system that is in place, and so we need more patients. We need more documentation and we’re in the middle of doing that right now. You mentioned the Finnish study, and the Finnish study actually had little to do with what we’re doing in that we’re taking people who were symptomatic with early Alzheimer’s or it’s precursors, and looking at all their various parameters and then optimizing them. I think it’s important to say not just normalizing them, but optimizing. So as you well know, a homocysteine of 12 is considered normal. It’s certainly sub-optimal and that’s been well studied, published, etc. You know, we look at that with all these parameters because we’re trying to change that threshold. So we want more documentation. We want continued number of patients, etc. And we want to optimize these parameters. Now, what the Finnish study did, was simply to take people who had some cardiovascular risk factors. That was it. So none of them was symptomatic from the standpoint of cognitive decline—nobody had Alzheimer’s—and they simply said, “Okay, you know, you should eat better and exercise.” They used four different parameters. They had four different things on the protocol. They didn’t evaluate all these other things. So a very, very different sort of study. [5] What we’re looking at here is to understand why it is that you are on the wrong side of this synaptoblastic/synaptoclastic balance, and then to change that so that you can literally reverse the cognitive decline. Now obviously when I first talked to some of my colleagues about this a couple of years ago, they said, “Well, that’s impossible because you can’t reverse neurodegeneration. Once the degeneration is there it’s there.” Well, it turns out it’s not quite that simple, as you know. It’s turned out that in fact there’s a lot of chemical abnormality, and there’s also a fair amount of reversible synaptic loss, it appears, so that in fact there is a lot that can be done, at least up to a point. And one of the things we’re most interested in is when you reach that point where you can’t reverse this—wherever that may be and we don’t yet know where it is—then, okay, what do you do next? Is it possible that with the addition of stem cells to critical areas, for example in the hippocampus or potentially in the cortex, is that good enough? Or do you now need to add trophic factors intracerebroventricularly? There are a number of possibilities to take this to the next step. Right now, there’s a lot we can do for people not only at the prevention level but at the reversal level for SCI, as I mention in the paper (subjective cognitive impairment—the earliest stage), then even through mild cognitive impairment (the next stage), and even through early Alzheimer’s, and we’ve seen improvements in all of those. I doubt if we’re going to be able to do anything in the later stages. We only had one patient who was literally end-stage when we started. She was only on this for four or five months. She did not show improvement and we mentioned that in the paper, but that’s an n-of-1. We’ll see going forward. What about when we have the next hundred? I think there are many questions, and as you mentioned, this is something that not just our study, but many, many studies in functional medicine have gone up against. When you’re trying to change the paradigm, there’s going to be a lot of pushback. JB: So let’s now talk a little bit specifically about this extraordinary paper that you’ve recently had published. I want to go to page four of the paper, which is your Table 1 Therapeutic System 1.0, in which you outline some of the multiple indices or contributors (your 36-hole model). So you have—and I’m just going to list the kind of categories so that the listener will understand a little bit as to where these fit into—first we have optimizing diet, minimize simple carbohydrate, and minimize inflammation. Enhance autophagy through ketogenic effects, and that is, I think, a very interesting part of what Dr. Perlmutter was talking about as well. Autophagy is another part of how we modulate mitochondrial bioenergetics. Reducing stress, optimizing sleep, exercise, which you’ve already spoken to and Dr. Perlmutter spoke to as it relates to the impact of aerobic exercise and neurogenesis. Homocysteine (lower than 7), serum B12 (greater than 500 micrograms per mL), CRP (C-reactive protein) that you mentioned, hs-CRP less than 1 milligram per dL. Fasting insulin less than 7. Hemoglobin A1c less than 5.5 percent. These are indications, obviously, of insulin sensitivity. Hormonal balance—you’ve talked about thyroid, and testosterone, progesterone, pregnenolone, cortisol (the stress hormone). GI health—again coming back to some things that Dr. Perlmutter mentioned as it relates to what we call leaky gut. Reduction of Abeta, which you’ve talked about considerably. There are some botanicals seem to have positive impact on reducing Abeta. Cognitive enhancement through training and exercise. There are a variety of tools on the computer now that are available to do that. Vitamin D levels greater than 50 nanograms per mL. Synaptic structural components, optimize antioxidants to reduce oxidative stress, optimize the zinc-to-copper ratio. Ensure nocturnal oxygenation so you don’t have people that have obstructive airway conditions or that are having problems that need to be on the CPAP machine. Optimizing mitochondrial function, improving SirT1 function, as you mentioned, like resveratrol. Exclude heavy metal toxicity (mercury, cadmium, lead), and effects of medium chain triglycerides. So that is your list in Table 1. So when you have a person come in, how do you go about clinically evaluating what holes to start repairing first? Dietary Links to Alzheimer’s Disease DB: Let me just say at the outset that you could spend hours on each one of these things, as you well know. I mean just the diet part alone, we’ve just scratched the surface—you know, the obvious, very critical things, like sugar. Simple carbohydrates—and I realize I’m sure that David Perlmutter has talked a lot about this—this is a huge issue. What’s really intriguing to me is that when you look at the actual function in the brain, and there is some beautiful work that has just come from Ed Goetzl, who studies neural exosomes, so these are these very small, hundred-nanometer fragments that break off from cells and you have 1.2 billion of these per cc of blood. It turns out about 10 to 15 percent of these are derived from the nervous system, so you can look at neural markers and identify these as having come from neurons, which is amazing. So for the first time, then, we really have a window on the mind. You can isolate blood, isolate the exosome, and then isolate from those the neural exosome, and then you can study these, and you find the obvious things, like it increases Abeta peptides, and like an increase in phospho-tau just as you’d expect, but then it allows you to start studying the biochemistry that’s actually going on in the neurons. And one of the things that he found was that all of the patients with Alzheimer’s disease—and this is beginning about 10 years before they had the diagnosis of Alzheimer’s disease—they had insulin resistance. So the classical thing that we think about for type 2 diabetes was part of the picture, and it really supports this notion that signaling is imbalanced in this condition even long before you have the condition itself. So this is a critical piece and we can see that—how people are contributing to their own development of Alzheimer’s disease. And so he actually used a specific approach where he looked at IRS-1, a signaling molecule, and he looked at the ratio of serine-threonine phosphorylation, which is essentially what’s downregulating its activity to the tyrosine phosphorylation, which is the active part, and showed that these people had an increase in the serine-threonine phosphorylation. Literally, so he is looking at insulin resistance.[6] So what we do, then, to get back to your question, is to do a typical evaluation. We want to know what the MRI looks like. We want to know, what about the PET scan? So that you can look at whether there is a change in metabolism that has the typical distribution of Alzheimer’s disease, which is a temporal-parietal decrease in glucose utilization by the brain. And then what we want to do, which isn’t typically done, is we want to look at all these other serum parameters that you just mentioned a minute ago. So we want to know what your copper-to-zinc ratio is, what your free copper-to-zinc ratio is, what your hs-CRP is, and all the things that you just mentioned, because these are all things that we’ve identified as being critical mediators of that balance. Then what we want to do is to optimize all of those parameters and then follow you. And then of course part of this is to iterate. So in other words, you want to continue, instead of giving someone one pill on one day and saying, “Go home and come back in three months,” we want to work with these people to change things a group at a time. You can’t change all 36 things on one day—no one’s been able to do that. The good news is that because of this prionic loop feedback that I mentioned, what happens is that you reach a threshold. For example, one of the patients we worked with started eight things at the beginning. She noticed a little improvement, but it wasn’t spectacular. A few months later we added another several things. Again, she noted additional improvement. And it wasn’t until that third set that now at the third set she said, “Oh my gosh, things are now really back to normal.” And so we got over that threshold, and it really fits exactly, again, with the biochemistry. One of my favorite quotes is from Richard Feynman who said, “Nature uses only the longest threads to weave her patterns, so each small piece of her fabric reveals the organization of the entire tapestry.” This is what we see with the APP cleavage. We see the prionic loops in it. We see that things actually mediate synaptic loss with synaptic reorganization, and other things mediate caspase inhibition. We see the basic biochemistry that forms—it allows you to form the memories—and we see how it is altered in Alzheimer’s disease, and of course we see what we can do about it. JB: Just listening to you is such a treat because you really are speaking—in specific examples—around this general theme (this philosophical theme) of network biology, systems biology in medicine. As I’m hearing you speak about the insulin receptor substrate 1 (IRS-1) and its phosphorylation, I’m reminded that we just completed a mini-course in type 2 diabetes in which one of our three experts was Dr. Ron Kahn who is the head of the Joslin Institute at Harvard Med—a diabetes expert—and he was credited as the discoverer of the phosphorylation of IRS-1 and the kind of initiation of our understanding of insulin signaling some 25 years ago. What we are talking about are interwoven patterns. As you’ve said, it’s almost like holographic. You can pick out any part of the puzzle and you can understand the whole puzzle because they are all interwoven, one with the other. That is a very, very different model, as you spoke to, than the way most of us were trained: differential diagnosis, reducing large to small until we get to knowing everything about nothing. I think that this construct of assembly out of a structural, complex level so that we can then actually see the forest for the trees is a very, very powerful new concept in medicine. This early paper that you’ve now published with these clinical outcome studies of real people I think are the proof of the pudding. This is very difficult work to do. It’s much easier to have one drug for one disease with one outcome. It’s much more complex to deal with the complexity of chronic illness as it really exists in biology and then to design different approaches to prove a hypothesis in knowing that each patient is kind of an n-of-1 in their own discovery of life. I believe all of us who are listening want to compliment you for the courage, and the resourcefulness, and the scholarship, and the extraordinary precision that you’re bringing into really defining a whole new field in medicine. DB: Thanks, Jeffrey. Of course we’re using the functional medicine approach that you’ve pioneered over the last 30 years. You know, we have to quit asking what it is and start asking why it is. I think that’s where the excitement is. When we can understand why it is, we can really do something about it. JB: Dr. Bredesen, I want to—on behalf of all of our listeners—send a large amount of support and encouragement to you. I know it’s not easy getting grants to do this kind of work. I know it’s not easy, sometimes, for your faculty colleagues and peers to understand exactly what’s going on when you’ve taken this different approach. I think that this is the kind of groundbreaking systems approach that will change medicine and allow the move-forward in the management of these—as you said, the third major cause of death now is Alzheimer’s-related illness, which we need a new model to approach. On behalf of all of us we send our strongest support and encouragement for your continued work in this area. DB: Thanks, Jeffrey, and thanks for all the great things you’re doing.  

Bibliography

[1] Smith, Stephanie. “We May Be Able to Reverse Signs of Early Alzheimer’s Disease.” CNN Health, 8 December 2014. Web. 9 December 2014. http://edition.cnn.com/2014/12/08/health/alzheimers-reversal/index.html   [2] Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY). 2014 Sep;6(9):707-17.   [3] Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, et al. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993 Nov 19;262(5137):1274-7.   [4] Theendakara V, Patent A, Peters Libeu CA, Philpot B, Flores S, et al. Neuroprotective Sirtuin ratio reversed by ApoE4. Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18303-8.   [5] Ngandu T, Lehtisalo J, Levälahti E, Laatikainen T, Lindström J, et al. Recruitment and baseline characteristics of participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)—a randomised controlled lifestyle trial. Int J Environ Res Public Health. 2014 Sep 10;11(9):9345-60.   [6] Kapogiannis D, Boxer A, Schwartz JB, Abner EL, Biragyn A, et al. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exomes of preclinical Alzheimer’s disease. FASEB J. 2015 Feb;29(2):589-96.

Welcome to Functional Medicine Update for March 2015 and the third of our three-part series on functional neurology. By the way, we may have a bonus for you, don’t tell anybody, but there may be a fourth component to this series. We’ve gotten such extraordinary response to this particular topic that we feel it might be very valuable to extend out our key opinion leaders into a fourth addendum, so I’m just giving you a little tip off as we move into the month of April.   This month, however, we have an extraordinary opportunity to visit with a clinician/researcher, who is both a PhD neurology researcher and an MD clinical neurologist who has really become an expert in Alzheimer’s management care, both early diagnosis and treatment of various forms of dementia, including Alzheimer’s. His name is Dr. Gregory Jicha, and you’re going to learn much more about him, so let’s turn to our third extraordinary clinical specialist in this area of functional neurology.  

INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Gregory Jicha, MD, PhD Professor, Department of Neurology Sanders-Brown Center on Aging University of Kentucky 1030 S. Broadway Lexington, KY 40536 We are so excited about having our third key opinion leader who is going to help us to understand much better the expanding domain that interfaces function of the nervous system with the environment and some of the remarkable things that are occurring right now in better understanding of early loss of function. That would be things like early diagnosis of conditions like Alzheimer’s disease at a place where possibly we’d be more successful in intervention—the earlier that we can intervene and understand the pathology before it becomes severe. And so our key opinion leader is a neurologist with an extraordinary background, Dr. Gregory Jicha, who is presently at the University of Kentucky. I’m going to give you a little bit of his background and this is only a thumbnail of the extraordinary accomplishments that Dr. Jicha has been involved in: 172 citations in the peer-reviewed published literature. He is a professor in the department of neurology at the Sanders-Brown Center on Aging at the University of Kentucky School of Medicine. He serves on the executive committee and as the director of the clinical core for the University of Kentucky NIA-funded Alzheimer’s Disease Center. He also directs the Telemedicine Cognitive Clinic at the University of Kentucky, which I think is a very interesting theme that’s designed to reach out to rural populations across Kentucky for both clinical and research-related activities. In the area of Alzheimer’s disease and related disorders, Dr. Jicha holds the Robert T. and Niles Y. McCown Endowed Chair in Alzheimer’s Research at the institution and his current interests lie in the areas of mild cognitive impairment, clinical pathological correlations in early pre-clinical disease states, and clinical trials of disease-modifying therapies for Alzheimer’s disease. He is a principal investigator at the University of Kentucky for the National Alzheimer’s Disease Cooperative Study Group, and serves on the clinical task force and steering committee for the National Institutes of Aging Alzheimer’s Disease Center Program. So, extraordinary background and skill level, and if I was just to cite some of the 2014 citations alone from Dr. Jicha’s laboratories and efforts, they include things as far-ranging as assessing discriminate ability and reliability of very short forms of evaluating Alzheimer’s disease early onset, looking at various genome-wide association studies that associate certain genomic profiles with relative incidence and risk to Alzheimer’s disease, to looking at the prevalence and epidemiology of Alzheimer’s disease, to examining the tau-ology (the tau pathology) that relates to beta amyloid accumulation and how that relates to the mechanism of pathophysiology of Alzheimer’s disease, to looking at various new technologies that are involved with early assessment of onset of Alzheimer’s disease before serious terminal pathology exists. So you can see, just from the 2014 publication list alone, which is more than 20 publications, Dr. Jicha is right at the cutting edge of this field. Dr. Jicha, thank you so much for being a guest and a key opinion leader on Functional Medicine Update. As a neurologist, how did you fall into this area of research, which obviously goes back many years of your career, and what is it that draws your total commitment to the field? GJ: Yes, you know that’s always an interesting question because many of us just fumble around in life waiting until we discover our true calling, I guess, so to speak. In the 1980s I started out researching psychopharmacology of Parkinson’s disease in an animal model of that, and I thought that that was fascinating, but at the time—as naïve as I was—I really believed that we had solved the major mysteries of Parkinson’s disease and I still believe that to this day. I think translating them into more effective treatments and cures for Parkinson’s is where we’re still kind of suffering in the field. Given my thought that the field of Parkinson’s was rapidly coming to an end, I was searching for a bigger mystery. I started thinking about this and ran into and began working with patients who had experienced changes in their memory in thinking, changes in behavior that can accompany those changes in memory and thinking, changes in personality—in essence, the loss of the person through a disease process. And I thought, “This is the cruelest of all diseases. This is a disease that robs us, literally, of who we are.” And if there is a great mystery that exists and if there is a great injustice that diseases do, truly working in the field of Alzheimer’s and related dementias fit the bill for both of those, and as I’ve become wrapped in this through my years of PhD training on the laboratory bench to my medical career, caring for thousands of patients, many of whom have been followed from when they were normal through the entire disease process, and—yes—I frequently attend the funerals of my patients as Alzheimer’s and other related dementias are universally fatal. Every year my passion for the work and impetus and drive to continue until we find cures for these diseases is strengthened really overall. So I hope that anybody out there that is looking for their future calling stumbles into it in as an effective a way as I have in my life. JB: Wow, I couldn’t think of a more inspiring way to start this conversation. I felt the goose bumps just listening to you speak. It’s that level of advocacy that can change the world. Thank you for sharing that. I look at your background and you have multiple fellowships in your background, including Mayo Clinic at Rochester and your neurology residency, and I noticed that you’ve also done some training in behavioral neurology, which I find very interesting. Tell us a little bit about how that connects to your PhD lab-bench studies, this behavioral neurology connection? Brain Connectivity to Function is the Focus of Many Translational Scientists and Clinicians GJ: My basic lab bench neurology was in the area of tau biology and tau is one of the proteins that keeps neurons interconnected with one another—in essence, runs the telephone lines between nerve cells that are responsible for the communication in our memory and thinking in day-in-day-out lives and in many degenerative diseases this tau protein is altered, it begins to form insoluble, kind of concrete, inside the nerve cells, which is very deadly to the nerve cells and is part of the degenerative disease process in not just Alzheimer’s disease, but in many of the frontotemporal dementias, in many other age-related diseases—progressive supernuclear palsy, corticobasal degeneration, the lists goes on and on. So obviously a key element. And so from a basic science perspective, looking at the molecular biology of how nerve cells interact with one another, how they communicate and send signals that lead to our higher order thought processes, really resulted in the natural evolution of clinical interest in how the brain puts this all together, and as nerve cells start to become damaged, how do we really change? And so the field of behavioral neurology encompasses higher order thought processes: how we receive sensory input and translate that into thought, convert that to actions that we may want to or not want to engage in, how we generate emotional context for the things we experience in our life, and truly—of all the mysteries of the brain that remain—these are the richest of the mysteries. So brain connectivity to function and I think that’s what all of us, as translational doctors or translational scientists, are really trying to do: bring things together from the molecular and genetic side of things, all the way through to how this really impacts us all in our day-in-day-out lives. So that study of behavioral neurology, again, is the study not just of memory, but of all aspects of our cognitive functioning: how we use language, how we process or are able to multitask, perhaps, how we are able to manage our emotions, how we respond to emotionally or cognitively challenging situations. So, really, the two fit together incredibly perfectly. They are all part of the same continuum, and to really treat—and I think to understand—these diseases and to move the field forward, we really need to be able to grasp that breath from the bench to the molecular all the way to the bedside, to the real world, to the things that matter to real people today. JB: Well, I think you used a number of words there that are really powerful words, and one of them—which I think is a great segue—is the word “continuum.” Because it’s clearly obvious that a condition like Alzheimer’s doesn’t occur as a bump in the night–yesterday you weren’t without Alzheimer’s and today you have it—there’s this continuum of progression of increasing severity and loss of function. I’d like to go to your work as it relates to these early cognitive changes and ask what’s happening on the assessment front. We’ve heard things about measurements of things like balance, or smell acuity, or taste acuity, or recall. What’s happening on the early assessment frontier to better understand what the trajectory might look like before we get to the end pathology? The Challenges of Early Assessment in Degenerative Diseases GJ: Yes, that’s incredibly important, Jeff, because these diseases, unlike acute events that can occur medically—a heart attack that occurs almost instantaneously or a stroke that occurs instantaneously—we understand that these diseases are occurring over perhaps decades—perhaps over an entire lifetime. And in that respect, not so different from stroke or heart attack because the build-up of cholesterol and the like that eventually can lead to a heart attack and stroke through atherosclerosis, is again a lifelong process. These degenerative diseases, however, have really been masked by the simple view that we’ve taken towards degenerative dementias and that is we’ve essentially been waiting over time for one to develop enough cognitive and functional disability—enough struggle with day-in-day-out activities—that essentially a patient’s life falls apart, and that is traditionally where we’ve been diagnosing diseases like Alzheimer’s: life has fallen apart, family is struggling with issues, now’s the time to look at the disease. And we all know the major medical breakthroughs that have come about throughout the years have really been in the recognition of early disease and intervention: an ounce of prevention worth a pound of cure. So going back to what we understand about Alzheimer’s disease, a lot of this has come from autopsy studies and more recently from human biologic studies, but the biology of disease appears to involve both genetic and environmental factors, and they may begin to interplay really very, very early in life, and so some of the pathology may begin to appear as early as our teens or twenties. We clearly know that within ten to twenty years prior to one developing even the earliest of memory problems, that the brain is already filling with amyloid plaques, that the nerve cells are already beginning to die by dysfunction of tau and the build-up of neurofibrillary tangles. And yet we have been traditionally still waiting until—in essence—the brain and the person’s life falls completely apart. So these processes occurring over decades do have biological markers, and so there is a bit that folks have been doing. Number one: You know, in looking at our memory and thinking tests, we’ve been looking at more refined tests—computerized testing that can actually measure response times down to the milliseconds. We’re looking at more challenging paradigms that can detect early change in folks, and that is an entire field of discovery, still, however, looking at a stage of disease when the brain is clearly not functioning well. Other folks have begun looking at other aspects of disease. You know, I always find this and I have to make a small commentary on the smell test because we hear these constant, you know: “You can’t smell peanut butter, you have Alzheimer’s disease.” The problem with smell tests is they’re not specific. Aging, in and of itself, leads to a loss of smell, and here—especially during allergy season—almost nobody in Kentucky can smell anything. And so that type of detection test is plagued by its lack of specificity. It’s not that if you have trouble smelling something you are coming down with Alzheimer’s disease. It’s more likely you have allergies or an upper respiratory infection—a cold of some sort. I don’t hold much stock in those as really being clear cut, definitive ways to diagnose the disease. You know, the Holy Grail is the blood test, and all of us are used to that. We go to the doctor, the doctor takes our blood, and then we ask him, “Doc, do I have diabetes?” And we’re looking for that kind of blood test. There’s a problem in the field of Alzheimer’s with that, and the problem results from something that we call the blood-brain barrier. The brain is privileged in the body. It has evolved to not want all of the toxins and other things that could be running around our bloodstream to be able to readily get into the brain and cause us injury because, of course, you know evolutionarily the brain is our greatest success story. It’s really what makes us what we are. So this blood-brain barrier prevents things that are in the body—infections and toxins—from getting into the brain, but likewise it prevents things that are in the brain—markers of disease, tau and amyloid, other components of the disease process—from making it out into the bloodstream. So we have this limitation on reliable detection of disease. A Spinal Fluid Test is Currently the Best Way to Track the Progression of Alzheimer’s Disease Nonetheless, people are still working on this and every few years we have a huge news release of the new blood marker for Alzheimer’s disease. I’m waiting for it to happen, Jeff. And part of that is that all of these great discoveries that have come out, not a single one has ever been replicated by another researcher or another independent lab in an independent sample, and so they are certainly moving the field forward, but I think we have a ways to go because we don’t understand how the blood-brain barrier is influencing what we’re actually measuring within the body because we’re not measuring the brain. That realization has brought us along to the point where, how can we measure what’s happening biologically in the brain? And there are several ways that we can do this that track the disease process. One is spinal fluid. Many people cringe at that, but actually it’s widespread in most of the major medical centers throughout Europe that, if you have a memory and thinking problem, one of the first things your doc does is draw your spinal fluid to test for these proteins because we’ve eliminated the blood-brain barrier. And that is a very safe procedure that perhaps been de-popularized in the United States through rock movies like Spinal Tap. It really is like a blood draw. I did two of them on two of my patients today in the office. It takes about 10 minutes. They get up and go afterwards; they’re doing just fine. And that can give us some definitive measures of the rate of nerve cell death, the rate at which amyloid is building up in the brain, the rate at which tau is becoming abnormal, the rate at which the brain may be inflamed in any given disease state like Alzheimer’s disease, or other features such as oxidative stress. Functional MRI and New Imaging Techniques are Revolutionizing Diagnosis of Alzheimer’s Disease We can use imaging, and really imaging has advanced over the years—a picture of the brain, an MRI. CAT scans are less than useful. As I always tell people, I think they are like old black-and-white TVs with rabbit-ear antennas. You know, you see a fuzzy picture, and if that’s all you’ve got you’ll sit and watch it for an hour and a half, but when you have digital TV, you will turn right over to that. And that is the state-of-the-art for MRI technology nowadays—not just looking at a picture of the brain structure, where we can see shrinkage and we—and others—have published this over the past decade or more, that we can detect early patterns of shrinkage in the brain five years—maybe even ten years—before one comes down with memory problems that illustrate or are representative of the pattern of nerve cell loss and brain shrinkage or atrophy that we see in Alzheimer’s disease.[1],[2] Newer techniques are able to look at the contributions of vascular disease, perhaps what a common person might refer to as mini strokes or pre-strokes or something of that nature—the wear and tear on the brain from vascular disease that could really be mimicking Alzheimer’s disease. We can look at the white matter—the connections—between nerve cells to make sure that they’re fully healthy and not suffering from a disease process. We can measure blood flow between brain areas. And with functional MRI we can actually look at brain areas that are communicating with one another at any individual instance. So in the MRI machine we can actually give people tests to do—memory and thinking tests—and then look at which brain area is someone using to complete the task at any given moment. I find that data fascinating and we do a lot of functional MRI here. It turns out that as we’re beginning early in life to learn tasks—tasks like reading or solving problems—the brain uses a tremendous amount of its area, and may be reliant on 20, 30, 40 percent of the brain to accomplish an individual task. As we mature and get better at that task, the brain doesn’t learn to use more of itself, it actually learns to use less. So an accomplished violinist uses almost none of his brain to play the most beautiful music, whereas when they were initially training, they used a tremendous amount. We see the opposite occur in degenerative diseases. We see people go from using very little of their brain to complete a simple memory or language task to needing to use larger and larger portions of the brain, so functional MRI. And then the final development, you know, which really we’re right in the midst of right now, is the development of molecular imaging. So these are tracers that are typically injected into the vein and we use either PET or SPEC scan. These are scans that have been used routinely in medicine to detect tumors, to look at bone densities, things of that nature, over the years. We can actually inject medicines or tracers that will bind to amyloid plaque. Twenty years ago the only way to know definitively if someone had amyloid plaques in their brain from Alzheimer’s disease was to either wait until they came to autopsy or to biopsy (take a piece of brain out and have the pathologist look under at it in the microscope), but now we can see this noninvasively in a living patient. New imaging agents have been developed that can look at the tau biology, and so more and more of these compounds are coming out that are enabling us for the first time to peer through that veil, through the blood-brain barrier and actually see what’s occurring in the brain. That has revolutionized the field of diagnosis to the point where we can tell, 10 to 20 years before one is going to develop Alzheimer’s disease, that they indeed are heading down that path. JB: Well this has been the most comprehensive summary review I have ever heard of where we are in the whole assessment area. Thank you. That was brilliantly put together. So that leads obviously into a question that is on every clinician’s (and probably every person’s) mind, and that is, “Okay, what about this connection of genes? Is Alzheimer’s really a genetic disease?” You know, everyone’s heard about the double E4 allele, the so-called “death gene,” and how that interrelates with Alzheimer’s and cardiovascular disease risk. I think there’s a perception that this disease is kind of hard-wired into our genes. Where are we on that whole part of the story? Truly Genetic Alzheimer’s Disease is Very Rare GJ: Yes, you know, that is a great question and something that I’m commonly asked as well, because I think there are a lot of misconceptions out there. I think sometimes we as scientists and clinicians actually create some of that confusion. If you ask a geneticist how much of Alzheimer’s disease is determined by genetics, they may give you numbers as high as 90 percent. If you ask a non-geneticist who studies environmental real-world exposures for Alzheimer’s disease, they may tell you that less than 10 percent of Alzheimer’s is genetic. I think we need to be clear. I usually say—whenever there is a debate like that in the field, with two different parties saying 90/10 and 10/90—chances are it’s more like 50/50, and I think that’s probably about where we are. We do know that there are some forms of Alzheimer’s disease that are truly genetic. These are incredibly rare. There are three genes that we have identified—they’ve been identified, now, for almost 20 years, and those genes are all related to the build up of amyloid plaques in the brain. But there are certain mutations, and if you have that mutation, we know, 100 percent, definitely, you will get Alzheimer’s disease. That is true genetic Alzheimer’s disease. And yet that is extremely rare, probably less than one to two percent of Alzheimer’s patients; it’s only 500 families, by estimate, in the world that carry that gene, and so what we really see in the real world is not genetic Alzheimer’s in that context—not inescapable, autosomal dominant genetics. What we see instead are things like—as you mentioned—the apo E4 allele. And we now know that there are over ten of these risk genes, and they’re risk genes, meaning you can get the gene, and yet you may never get Alzheimer’s disease, but they’re going to increase your risk. As I like to tell people, this is kind of like a gene that may cause family members to carry a little bit of excess weight. And so we may have an overweight family and it runs in the family, but that doesn’t mean that an individual member of that family could not modify their environment, couldn’t change their diet, exercise more, and not carry any extra weight around but be perfectly fit. So these genes are making it harder. Those of us that carry those risk factor genes for Alzheimer’s disease, we have to work harder for our brain health, we have to work harder to avoid Alzheimer’s disease, but if we have those genes, it’s not an absolute sentence that we’re going to come down with Alzheimer’s, so I think that’s important. Medical Organizations Advise Against Genetic Testing for Alzheimer’s Disease That’s one of the reasons why currently the American Academy of Neurology, backed by the American Medical Association, recommends against testing for those genes. If you come from a family where the onset of Alzheimer’s is in the 40s or 50s and one out of every two in every generation of children comes down with Alzheimer’s, then there’s a possibility for true genetic Alzheimer’s and genetic testing may be helpful. The problem with genetic testing with these risk genes is that if you are positive and that goes into your medical record, you could potentially be discriminated against despite the development of things like GINA, the Genetic Information Nondiscrimination Act, which our US government has as one of its key components in health privacy protections. It really doesn’t matter. We really advise not to get these genes. They’re still being used for research purposes and there’s good reason for that. We make discoveries from these genes, and so these genes change how the brain functions, and understanding those changes is leading to new pathways—new ways that we can intervene and potentially prevent disease. We’ve been working here at the Sanders-Brown Center on Aging and the University Alzheimer’s Center on several studies that are looking at manipulating some of these genes in terms of how they express themselves. Whereas those genes want to turn on the Alzheimer’s switch, so to speak, we’re using medicines to turn off those same genetic switches. And so these will become very powerful in the future. We potentially foresee a day when that genetic testing may be needed to decide which medicines a person may benefit most from, but at the present time, I think one should really take resolution in the fact that if you have a family member who suffered from Alzheimer’s—a first degree family member (mom, dad, brother, sister, son, or daughter)—you need to work harder at your brain health and try to fight some of those environmental factors that are changing, because you can’t change your genes. JB: Well, this again is just an extraordinarily uplifting message that you’re providing. It really speaks to these constructs of a constitutive effect, which is kind of hard-wired, versus an inducible or an expressible effect that can be modified through various choices that we can volitionally elect to either be exposed to or not exposed to, so that takes us into the whole discussion of lifestyle and environment as modulators of gene expression. Let’s quickly review, from your observations, things like exercise, which I’ve heard in the news quite a bit related to Alzheimer’s prevention, and also cognitive activities—social interactions and things that stimulate brain function. Where are we on those two as modulators of function? Epigenetic Influences on Alzheimer’s Disease: More Studies are Needed Before Official Consensus Will Be Achieved GJ: Yes, yes, that’s incredibly important. This is really the field that we call epigenetics—how genes interact with the environment to create disease burden. As I said, as of yet, you know, we haven’t been able to change genes, but we can change the environmental factors that may influence whether or not those genes are expressed in a negative way and/or may have independent contributions to whether one comes down with a disease like Alzheimer’s. You know, I’m a little disappointed in the field in some respects because it is in its infancy, but more disappointed, perhaps, by some of the consensus work in the field. So, for instance, the National Institutes of Health held a scientific roundtable several years ago—I believe 2011—when they pulled together experts to really discuss this issue. What can one do? Does exercise help? Does social interaction help? Does diet or other modifiable daily activities—do they influence your risk for Alzheimer’s disease? And unfortunately the consensus from that roundtable was as of yet nothing is proven to be able to prevent your risk for Alzheimer’s disease. I agree with that consensus statement, but it was misrepresented and, I think, mistaken and further propagated by some of the media and other lay folks in the community. What they were really saying is that we need to do more studies, here. The animal data and the human data clearly demonstrate risk association with lower levels of exercise, and protective benefits with higher levels of exercise. This seems to be mediated through what’s called brain-derived neurotrophic factor—MiracleGro for the brain, so to speak. And the more we exercise, and it doesn’t take much—20 minutes a day of getting your heart rate and your breathing up a little bit—to increase circulating levels of BDNF, and, in animals, lead to the birth of new brain cells, especially in memory areas of the brain. The same thing appears to happen in humans. We do not take brain tissue after exercise to look at the birth of new nerve cells, so we have yet to prove that this definitively occurs, but we can clearly see, using functional imaging, glucose metabolism studies with PET in the brain, and even MRI scans, that we can reverse or stop some of the changes associated with Alzheimer’s disease with this kind of an intervention. The same holds true for dietary modulation. There’s a wealth of data on social interactions and daily engagements and it’s really lead us to what we really have known, and our ancestors have known more than likely, for hundreds if not thousands of years, the old adage, “Use it or lose it.” And so the more we engage and strengthen our brain, the more it is going to be able to withstand the ravages of these types of degenerative diseases that are waiting to consume our brains as we age. And so fighting back really requires this kind of a comprehensive program, which unfortunately I don’t really understand why more people aren’t thinking about this in a concrete fashion. We know that if we have a physical ailment—say we have a heart attack and we go to cardiac rehab, and the cardiac rehab doctors put together a comprehensive program for us, they say, “You need these kinds of exercises, this kind of aerobic exercise will build up your heart muscle, your diet needs to be modulated, so on and so forth,”—they work on lifestyle factors, and we know that cardiac outcomes are greatly influenced. And yet, people take for granted. If you ask folks who are having memory and thinking problems, “What do you do for your brain health?” They may say, “Well, you know, every Sunday I do the New York Times crossword,” or “I read the newspaper every morning over coffee,” those are great activities and I don’t want people to give that up. But if you’re going to go to the gym and work out, you get yourself a work out partner. You set a schedule: Monday, Wednesday, Friday, I’m going to the gym from 9 to 10. We don’t do that for our brain, and I propose that folks should do this. There actually is a study that was reported preliminarily from Finland; it’s called the FINGER study (the Finnish Geriatric Intervention Study—I forget what the acronym fully is, Jeff). But basically it is the first study of its kind to come up with a comprehensive program where they’re doing just that for brain health and aging. And the initial results, which were presented last July (2014) at the Alzheimer’s Association International Conference, were incredibly intriguing, suggesting we get more bang for the buck if we don’t focus in any one area, like exercise, social interaction, or diet, but rather develop this kind of comprehensive strategy to really strengthen the brain—make it resistant to disease, make it so the genetic risks are not stronger than the environmental risk pushing us towards brain health.[3] JB: Oh boy, is this an illuminating discussion. This is stimulating my brain just to listen to you speak. I’m already engaged in this exercise. Let’s segue over to one of the areas that I know you have put your thoughts to. It’s not the only area, obviously, but one of the areas. The result of that is a recent review paper that you wrote, which I consider very well written called “Nutrition and Prevention of Alzheimer’s Dementia.”[4] Let’s move over to the nutrition side. You know, I have yet to find someone that hasn’t eaten at some time in their life, so this is shared common human experience, and as we eat, we eat information—we don’t just eat calories—and that information is translated into gene expression patterns and modulates function. And, as you said, although the brain represents a fairly small percentage of overall body weight, it represents a very remarkable portion of calorie consumption, particularly glucose. With all of that in mind, nutrition, we feel, must play a role. Tell us a little bit about how you see the nutrition and Alzheimer prevention dyad fitting together as we evolve the science. The Role of Nutrition in Alzheimer’s Disease Prevention GJ: Yes, this is incredibly important, you know, the aspects of nutrition. Because the brain is an organ in the body, certainly—as you have mentioned— one of the most metabolically active organs in the body, and it has a very unique make up. And so in order to keep the brain healthy, it needs different building blocks. It needs building blocks that may differ somewhat from the building blocks that you need to build up muscle if you’re a body builder, or the building blocks that you may need to work on lung function. And nowadays we know that if you go into the supplement store, there you can pick up vitamins for your eyes, vitamins for your kidneys, vitamins for your heart, and now there is an emerging industry, which is vitamins and supplements for your brain. Truly the vast majority of these are based on very sound, basic science, and based very well on animal data where animals have been supplied these agents, and we can show they have a healthier brain or they are resistant to the modeling of Alzheimer’s-type changes that we see in human beings. And yet we’re lacking in many respects, taking this all the way—taking this into clinical studies where we can actually be clear on the benefit to individual human beings. So while there are a wealth of agents that are out there, the field has really been kind of road-blocked at the very end, and instead we have people making claims about nutritional supplements that may not have the real science to back them. The reason for this, in part, is that it is very difficult to patent what may grow naturally or be part of a natural product, meaning things like fish oils, which may have very potent effects on the brain and brain health from the studies that have been done. If you spent the millions of dollars to do a human clinical trial with one of these, well your competitors would not pay anything and they would be able to jump on board with that. There are not many funding agencies that fund nutritional studies here in the United States at the National Institutes of Health. We have the National Institute of Alternative and Complementary Medicine, and so sometimes in collaboration or independently by the National Institutes on Aging we can get a study funded in this area, but not nearly to the extent that we need to do it. We’ve also been plagued by the fact that many people think that a single nutritional supplement or a single pill that is just going to be the panacea for brain health is the way to go, and it’s unlikely to be the case. The brain is so complex. It requires so many different components as building blocks for healthy nerve cells, that more than likely we’re going to need some combination of nutrients, and they may be in different percentages to one another. So we may need some of the polyunsaturated fatty acids. We may need some of the antioxidant compounds. We may need some of the other energy substrates for the brain, and we may need them in a specific combination. The field is really just starting to explore these nutritional combinations. Again, I think we have a long way to go. I do advise to everyone out there, if you’re interested in nutrition and prevention of Alzheimer’s or maintenance of brain health, to always please check up on whatever agent that you’re thinking about taking. I think it’s really important to discuss with your doctor. I had a patient come in and ask me about a particular product just a little over a week ago, and it was one that I was not familiar with and I’m familiar with most of them, and so I went and looked it up. And I always go directly to the FDA website first because I want to see if there is any danger or what’s really been done clinically, and there actually were two warning letters in the FDA file. One that the company was making false claims about its use to prevent Alzheimer’s disease, and then just a short while later that the company may have been hiding safety data that suggested that the nutritional supplement could increase risk of stroke and/or other neurologic diseases like multiple sclerosis. So, you know, it was clear in that case that this patient was going to go ahead and take that nutritional supplement, buying into the marketing and the advertising without actually investigating it. My strongest plea to everyone out there that is thinking about a nutritional supplement, please look into these. Make sure that they are safe. If they’re safe, I think we’re really at a point, Jeff, where as long as it’s safe, if it might help and there’s good science behind it, there is rationale to try to use it. If there are risks, however, one really needs to be concerned and I would be cautious until we have definitive studies. JB: Thank you. I think that’s really sage advice. And I also want to cite—because we’re dealing, here in this series, with medical professionals principally—your review article in Frontiers of Aging and Neuroscience in 2014, volume 6, page 282, which is a public access article titled “Nutrition and Prevention of Alzheimer’s Dementia.” It does a beautiful job of reviewing the literature and you talk about many, many different nutrients and different studies surrounding them, including, obviously, the antioxidant family—vitamin E, C, coenzyme Q10, selenium, lipoic acid. You talk about omega-3 fatty acids and B vitamins and folate. You talk about MCTs as brain fuel (medium chain triglycerides) and their effect on mitochondrial oxidative phosphorylation. And you talk about various types of phytochemical combinations that influence neuronal health, including things like huperzine A, and Gingko biloba, and resveratrol, and turmeric. I think that you’ve got a great review article that helps people to understand this field. Let me ask you a little bit about the concept of how much of these a person needs because there is always a question of do I need to supplement with mega doses, or is it in the diet, or what about this concept of hormesis that Dr. Mattson talks about at NIH, where a little goes a long way and you get unexpected synergy among the right combination of smaller doses and it’s kind of a different dose response curve than we normally think of in pharmacology. What’s your feeling about this whole neuronal hormetic concept and these nutrients that we find in food? Nutritional Supplements: Clinical Trial Experience May Have Little Relationship to Real Life GJ: I think that that is a great point. Dr. Mattson’s research is well respected here. He was at the University of Kentucky many years before I came and before he went to the NIH. But that concept is very real. One of the things that we don’t often appreciate when we read clinical studies, especially about nutritional supplements and the like, is that many of these are remarkable safe, and so we have a tendency to want to push the envelope with them and use higher and higher doses. And actually, in my opinion, the FDA actually propagates this. They always want to know what’s the dose-limiting toxicity and at what dose do we achieve that? That pushes us always when we’re looking at that upper level, maximizing the amount of nutritional supplement one takes in. The other rationale frequently that is done in clinical trials, of course, is we want to saturate the brain as soon as possible because it leads to a shorter clinical trial. So the clinical trial experience may have little relationship to what is actually going on in real life. Meaning, just because the high doses of whatever nutritional supplement will saturate the brain within one month, once the brain is saturated we really don’t know what the dose is that is required to maintain brain health. Equally important is the fact that we know that most medicines have an inverted, U-shaped, dose response curve, meaning we know that too little may not be beneficial, and we also know that too much, via toxic or other effects, is going to be less beneficial than the right amount. I believe, again, everything in moderation. I think that that’s really where we are in the field, and I think we really need to take that as sound advice that we can pass on to others and also apply to our own daily lives. I think that that’s critical. On that concept I’ll just say we have just recently done a study, which we have submitted for presentation at the American Academy of Neurology this spring looking at exercise (types of exercise) on the basis of the intensity of aerobic training, from very low intensity aerobic items all the way up to very high intensity aerobic items, and plotted that out against brain health in our longitudinal cohort we’ve been following for decades, and the answer is an inverted U-shaped dose response curve for exercise. Who’d have thought? If the aerobic exercise is either too low in intensity or too high in intensity, we’re not getting the amount of brain benefit from an intermediate dose, and so I think that that really holds true in the area of nutritional supplements as well, and as we really do more studies in terms of these modifiable risk factors, modifiable environmental mediators of brain health and disease, I think we’re going to find that to be true. JB: Well I want to stop and just take a cerebral hypoxia break for a half-sec and just really honor the breadth and the depth of the information you’ve covered. This represents everything from early assessment to where we’re heading and some of the landscape studies that are opening up new ways of examining function of the brain in intact human beings without intervention using imaging to look at this continuum from early stage into where we have significant neurofibrillary tangles and histopathology associated with Alzheimer’s to the interaction of genes with our environment through inducible factors that give rise to epigenetic modulation of function and then deeper drilling down into the components of exercise and mental and social activities, and lastly diet and nutrition and nutrients and their role on neuronal function. What a landscape analysis you’ve given us in 50 minutes. I was very pleased to see, and I think it is unique, actually, among researcher/clinicians as yourself, in the summary of your article the way that you phrased the future of the field as you see it. I quote, in the summary you say: “A nutritional approach to preventing Alzheimer’s disease appears to be an innovative and safe approach that may be extremely cost effective, allow ease of administration, and importantly serve as socially acceptable intervention or adjunctive approach in the prevention and treatment of Alzheimer’s disease. Despite years of scientific, medical, and clinical advances in this area, much remains to be discovered and proven in terms of specific nutritional interventions for the prevention of Alzheimer’s, but promising agents such as vitamins, energy substrates, flavonoids, lipids, and modified diets functioning as antioxidants, metabolic enhancers, immune modulators, and direct disease modifying agents await further investigation.” I think that is—just in three sentences—a tremendous review of literally hundreds of papers and where we are at this juncture where prevention may trump treatment in terms of Alzheimer’s. What a remarkable contribution you’ve given us, Dr. Jicha. Thank you so much. GJ: I appreciate that, Jeff. You know, I think that the model that is being built medically is early detection, pre-clinical detection, and intervention from either a primary prevention perspective or what we might consider secondary prevention (we can see the process already occurring, but the clinical symptomatology is not yet clearly evident). This is the model that we’ve taken with colon cancer, with screening for that, removal of a polyp before it turns into a cancer. It’s the same model that we’ve used for breast cancers—let’s remove some of the estrogenic agents that may predispose to the development of breast cancers, let’s couple that with mammography or other screening measures (breast self-exams), and let’s defeat diseases like breast cancer. And that is the model that we’re really moving towards with Alzheimer’s disease: biological detection and prevention in the primary and the secondary sense, because of course when the brain has been completely destroyed, we do know that we’re light years away from being able to restore that brain or bring it back from the brink of a degenerative disease like Alzheimer’s. JB: On behalf of all of our listeners and the literally thousands of people that will benefit as clinicians listening to this, and the patients that will get the benefit translated through their practitioner of this information, thank you very much and we will be following your work very carefully and we hope to trace back with at a future time and check in, because this is certainly right at the forefront of the burden that we’re all experiencing in our rising tide of chronic disease. GJ: Fantastic. Thank you so much for having me today. JB: It’s been our great pleasure. Thank you and best to you  

Bibliography

[1] Dubois B, Feldman HH, Jacova C, Hampel H, Molineuvo JL, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2criteria. Lancet Neurol. 2014 Jun;13(6):614-29.   [2] Bachman AH, Lee SH, Sidtis JJ, Ardekani BA. Corpus callosum shape and size changes in early Alzheimer’s disease: a longitudinal MRI study using the OASIS brain database. J Alzheimer’s Dis. 2014;39(1):71-8.   [3] Ngandu T, Lehtisalo J, Levälahti E, Laatikainen T, Lindström J, et al. Recruitment and baseline characteristics of participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)—a randomized controlled lifestyle study. Int J Environ Res Public Health. 2014 Sep 10;11(9):9345-60.   [4] Swaminathan A, Jicha GA. Nutrition and prevention of Alzheimer’s dementia. Front Aging Neurosci. 2014 Oct 20;6:282.   [5] Farooqui, Akhlaq A. Phytochemicals, Signal Transduction, and Neurological Disorders. New York: Springer, 2012. Print.

Welcome to Functional Medicine Update for April 2015. As you know we’re in our functional neurology series and we’re very pleased that once again we’ve got an incredible clinician/researcher to help us understand this complex topic of how, in fact, functional neurological problems are developed, how they interrelate to diet and lifestyle factors, and hopefully how we can apply this information in developing personalized programs for individuals that will improve their neurological function. So this month we’re going to have an extraordinary interview with Dr. Martha Clare Morris, and I think you’ll be very pleased to hear what she has to say and the work that she has done in this area, so let’s shift to our discussion with Dr. Morris.  

INTERVIEW TRANSCRIPT

Researcher of the Month Martha C. Morris, ScD Professor Director, Section of Nutrition & Nutritional Epidemiology, Department of Internal Medicine Assistant Provost for Community Research Co-Director, Rush Translational Sciences Consortium Rush University Oak Park, Illinois So here we are once again at this—for me—the most interesting part of our Functional Medicine Update each month, and that’s our clinician/researcher of the month section. As you know we have been involved in the last few months with this development of a functional neurology focus. We’ve really done a nice job, I think, of looking at the molecular mechanisms that are prevalent as it pertains to the origin of conditions like Alzheimer’s disease and Parkinson’s. We’ve had a review of some of the more recent literature that really talks through the eyes of the investigators and their experience about some of the pros and cons of the new approaches that are being considered for the prevention and treatment of neurodegenerative diseases. We’ve had some very interesting discussion about the multiple risk factor components, including apoE4 alleles and the relationship also to things that pertain to metabolic inflammation and its association with neurodegenerative conditions. And that leads us up to what today I think is kind of the payoff for a lot of this investigative discovery work that we’ve been exposed to over the last several issues, and that’s the work of Dr. Martha Clare Morris. Dr. Morris is at Rush University. She is an associate professor in the Department of Internal Medicine and the Rush Institute for Healthy Aging. She is also the assistant provost for community research and the director of nutrition and nutrition epidemiology at Rush University Medical Center. She received her Bachelor’s and Masters of Science in Sociology at the University of Iowa and her doctorate in epidemiology at the Harvard School of Public Health. Her work is just, I think, really very interesting because it covers quite a large breadth of topics that have been the focus of what we’ve been speaking to for 30-plus years in Functional Medicine Update, dealing with nutrition, lifestyle, risk factors that relate to public health-related issues, and then focusing, in cohort analysis, down to individual, say, presentation types and genotypes. Dr. Morris has a rich publication record that I think reflects very, very nicely the topic that we have been focusing on as it relates to functional neurology and how that really translates directly into communities, populations, and ultimately obviously to individual people. Dr. Morris, it’s really a privilege to have you on Functional Medicine Update and thanks so much for being available for our discussion. MM: Thank you. I’m very honored to be a part of your show. JB: Let’s just start off with some general thoughts. I was very intrigued to look at the department you’ve been a principal in at Rush: the section for nutrition and nutrition epidemiology. How did that originally get started at Rush University? It sounds like a very interesting cross-disciplinary department. University Department Focuses on Nutrition, Aging, and Neurodegenerative Disease MM: Yes, well, I’ve been doing research in this field of aging and dementia for over 20 years. Here at Rush we have a very vibrant group that has focused on community studies, looking at people without dementia living out in the community, and looking at what factors might determine who gets Alzheimer’s disease, who has cognitive decline with aging, physical decline with aging. Our group has been very active in this area for a long time. I had a specific interest in nutrition and had received training at the Harvard School of Public Health and Nutritional Epidemiology, and started a focus within our group to look at how diet might impact cognitive aging and the development of neurologic conditions with aging, like Alzheimer’s and Parkinson’s and stroke and other conditions. At the time that I started this there was really, you know, no activity in the area of nutrition and neurodegenerative diseases. It was wide open, so I really focused my attention, then, just on looking at the most likely diet components that would protect the brain, and really had to focus on just a few animal models. There was nothing else in the literature to guide me in my research. As I got more and more focused in this area, I split off from my group and started this section that was devoted to nutrition as it relates to aging and neurodegenerative diseases. And it’s very new; it’s only about five years old or so. JB: I notice that you’re also the co-director of the Translational Science Consortium, which—to me—sounds really interesting. It’s like taking information and finding a way to go from, maybe, bench to bedside, or having direct application. How does that fit into this whole activity that your department is involved with? MM: That’s more of a university-wide effort, and it has been a new direction of science in the last six or seven years. Rush University, where I’m located, has some, you know, very translational-focused areas, including in neurodegenerative diseases, where laboratory work at the cell level and with animals is related to our community study work, where hypotheses that are generated in the animal laboratories we can then integrate in our community studies, and vice versa—as we see relations with diet and neurodegenerative diseases in our population studies, that can be taken back to the laboratory to try and understand mechanism. That’s just an example of neurodegenerative disease, but we also have areas of focus at Rush around biochemistry, and orthopedics, and bone metabolism, for example, is another area. So I sort of have two hats, one where I focus on nutrition as it relates to aging, and also trying to develop this science university-wide of trying to get science to be more efficient and quicker at taking laboratory ideas and getting them into practice in the community. JB: That really deserves applause. I think that is a growing trend and I think it’s a fortunate trend because there is a lot of extraordinary information and discoveries out there that really haven’t found kind of translation into practice with the speed at which we’d like, so congratulations. Let me, if I can, move to some specifics related to your work. I was really intrigued—I’m intrigued by all of your publications, but one that was in 2014 that appeared in the Journal of the American Medical Association I thought was very topic titled “Vitamin E, Memantine, and Alzheimer’s Disease.”[1] And, of course, Namenda being a trade name for a new Alzheimer’s add-on drug. This was looking at a specific trial that had been published in JAMA by Dysken et al. that looked at the effects of Namenda along with vitamin E in Alzheimer’s disease. Could you tell us a little bit about your editorial? Because I thought it was very, very insightful in terms of the way that you were evaluating outcomes from that study. Could Vitamin E Supplementation Slow the Progress of Alzheimer’s Disease? MM: Yes, so it was a very interesting study where pharmacologic doses of a vitamin E supplement (2000 International Units) helped to slow the need of Alzheimer’s patients to use the help of caregivers in their daily activities, which is really, I think, a phenomenal result.[2] And it’s the second such study that has shown that. But all in all, the studies of interventions—pharmacologic interventions—with Alzheimer’s disease have been fairly disappointing, so we were trying to highlight that preventive measures and focus on research and prevention of Alzheimer’s is so critical because, number one, there is no cure to date for Alzheimer’s and the treatments are largely…in fact, this was an unusual result from this trial. And the results were mild. It wasn’t a reversal of the disease at all, it was just slowing the progression some. JB: And in your editorial you talk about the negative interaction between alpha tocopherol vitamin E, which was—as you mentioned—significantly beneficial alone, and memantine. I think that raises some questions about do these combination of drug and nutrient intervention trials produce results that might be skewed as a consequence of the adverse interaction between the components. It was kind of an interesting observation. MM: Yes, it highlights that we can’t just assume, “Well this trial showed this drug to have some favorable outcomes, and this drug has some favorable outcomes, and if we put them together they’ll be even better.” So we have to be very cautious in what we mix (what drugs we mix) to try and treat a disease. JB: This work plays off a body of work that really, in your group, preceded it and was really pioneering in the evaluation (the epidemiological evaluation) of the role of antioxidant nutrients and the risk of incident Alzheimer’s. I recalled a study that I think you were a principal author of that appeared in JAMA back in 2002 that looked at dietary intake of antioxidant nutrients, and I think made some discoveries as it relates to which (if any) antioxidants might be most valuable as it pertains to Alzheimer’s.[3] Could you tell us a little bit about that work? MM: Yes, so we have a community study, which ultimately—over more than 20 years—we had more than ten thousand people from the community participating who were 65 years and older. We did a comprehensive assessment of the diets of participants in this study and related the diet intake to the development of Alzheimer’s disease. One of the first nutrients that I was interested in looking at was vitamin E because it is one of the more potent antioxidant nutrients. There have been quite a few animal models that found that either deficient levels of vitamin E or supplemented vitamin E prevented—in these animal models—memory dysfunction and showed decreased neuropathology in the brains of these animals. I looked at the vitamin E intake from food sources as well as total intake from food and then multivitamin and individual vitamin E supplements. What was very interesting was that it was the food intake of vitamin E, not the supplements, that reduced the risk of developing Alzheimer’s disease. And that finding has been replicated in numerous other community studies where either you measured in the diet or measured in the serum, which would be a more objective measure of diet. So that’s very interesting. We also looked at vitamin C and found no relation between vitamin C and incident Alzheimer’s disease, which is also a finding that has been replicated in other studies. JB: And I think you also looked at beta-carotene, as I recall, as well, and did not find an association with that either, is that correct? MM: We did not. Now, at the time that we conducted that study, there was no beta-carotene supplement used. What is interesting is that there has been—since that time—a randomized, controlled trial that looked at beta-carotene supplement use. It was in the Physicians’ Health Study. They checked on assessments of cognition after a long period of time that the physicians were on this beta-carotene supplement. And they found that the supplement use—the beta-carotene supplement use—decreased cognitive decline in this clinical trial of the physicians.[4] JB: That’s very interesting. With regard to what you observe with the difference in outcome of the food-based vitamin E intake versus the supplement intake of vitamin E, do you believe that the vitamin E from the food was a surrogate marker for a range of other, say, phytochemicals that come along with foods that are rich with vitamin E, or can we say that it was really the kind of complex nature of a natural mixture of vitamin E and food, or we don’t know the answer to that question presently? Examining Food Sources versus Supplement Sources MM: We can only surmise what would explain that. There are many differences between food sources of certain nutrients—vitamin E, in particular, I can talk about—and the supplement sources. So one difference is that when you consume vitamin E in the diet, there are different forms of vitamin E, and our diet actually contains more gamma tocopherol, and gamma tocopherol is more common in the US diet, whereas alpha tocopherol is the form that is used in vitamin supplements. So the form of tocopherol is one difference between the food sources and the supplement sources. Another difference is dose level. The dose level that you get from vitamin supplements can be up to sixty times the level that you consume through diet. The body modulates very strictly the levels of vitamins in our system. So taking a very high level of one type of vitamin can cause things to happen in the body that you might not expect. For example, there have been some experiments to show that taking of high dose alpha-tocopherol decreases the body’s absorption of gamma tocopherol, and gamma tocopherol is a very potent anti-inflammatory. So by taking these supplements, we’re throwing our body off on other things that would not happen had you consumed the nutrients through food sources. JB: That’s very interesting. I noticed also in your JAMA work that you found that the association between food vitamin E and the reduction in the decline, as a consequence, of Alzheimer’s was not seen in those individuals that had apoE4 alleles, is that correct? So it didn’t seem to be able to modify that expression function in the apo E4-carrying individuals? MM: Yes, we did report that result, however I don’t believe that that result has been replicated, and so it could have been just a chance occurrence. So it’s important to see that a finding in a study is repeated a number of times in other populations by other investigators. Things do happen by chance and it just might be that that was a chance finding. JB: So let’s talk about the whole nature of the RCT evaluation of dietary supplements and conditions that are associated with neurodegeneration or maybe just chronic disease at large. You were a co-author with Christine Tangney of a really interesting editorial, I thought, in the JAMA. This appeared in 2011, April 6 issue, titled “A Potential Design Flaw of Randomized Trials of Vitamin Supplements.”[5] I think it is really worth our listeners understanding your evaluation because I think it was very well said and very on target. Could you tell us what led you to write that editorial and what your thoughts were? Randomized Trials of Nutrients Are Flawed in Design MM: Sure. There’s a lot of controversy around this area. There are many proponents within the nutrition and nutritional epidemiology world that are highly critical of the randomized trials that have been conducted to test nutrient associations with chronic disease. The model used in these randomized trials is more of a medical model, where you take the nutrient, you put it in a supplement like a drug, and administer it like a drug, which is really antithetical to the way the body metabolizes nutrients, and we talked about some of the issues: the idea that in food sources contain many different biochemical components of a nutrient at very different dose levels than what the supplements are. But what I was highlighting in the article that you mentioned was another type of problem with these randomized trials, and that is in the epidemiological studies that find these associations with nutrients and the development of disease, oftentimes it’s looking at people who have high intake from food versus marginal or very low intakes of the nutrients from food. And then the randomized trials completely ignore this in the design of the trial. So basically they are recruiting people into the trial who already are at the highest level of food intake to give them the best physiological benefit. So by giving them even greater amounts of that nutrient, they’re already at the 100 percent level for functioning, so you can’t improve them further. JB: I thought it was very powerful. You described the three randomized clinical trials at the time you wrote this article on vitamin E in cognition and you point out that none of these trials targeted individuals who had low dietary intake and in fact they probably didn’t stratify at all for diet intake in terms of the effects of supplements in those individuals. MM: Right. Now the Europeans have done a better job at designing their diet intervention trials, their nutrient supplements. There is a clinical trial that was done in The Netherlands called FACIT, where they did target people that they recruited into the trial who had suboptimal—they had marginal—folate status based on a number of diet and biochemical measures. And they had higher homocysteine levels, and there was no other reason from their biochemical analyses, other than low folate intake for the high homocysteine. And they, then, randomized them to receive the folate folic acid, which is a synthetic form of folate, or a placebo, and after three years the folic acid group did have a reduction in cognitive decline compared to the placebo group. So that’s an example of a well-designed trial that we have not done in the United States.[6] JB: Yes, and I think that really raises some—as you pointed out—very interesting questions about the complex nature of foods. Let’s take an example with folic acid, as you just mentioned, because we know that folates can be in all sorts of polyglutaminated forms. We know that there is 5-methyltetrahydrofolate as well as folic acid itself. So there are multiple congeners of these bioactive nutrients that may have all sorts of pleiotropic effects on function. Often if we just give a folic acid supplement alone we’re missing that symphony of actions that might occur from the full-food form, I think is what you’re leading us to understand. MM: Yes, and actually folic acid has another issue in that it’s a cofactor nutrient in a very complex metabolic process, along with vitamin B6 and vitamin B12. And based on a number of studies now, there’s this concern that folic acid supplementation in individuals with low vitamin B12 status actually accelerates neurodegenerative decline, including loss of cognitive function. Diet is just such a complex process, and you really have to be careful by supplementing. Studying the Mediterranean Diet and Cognitive Decline JB: So let’s move over to some of the recent work that you’ve done in the area of diet and its relationship cognitive decline. I think that this growing interest in different types of dietary patterns and their interrelationship with cognition and other chronic diseases is very fascinating. One of your recent papers appeared in the Journal of American Clinical Nutrition: “Adherence to a Mediterranean-Type Dietary Pattern and Cognitive Decline in a Community Population.” This appeared in 2011, page 601.[7] I think that this is one, again, of a number of studies that have been published from different investigators recently that seems to pinpoint some beneficial effects of a Mediterranean-type dietary pattern and the prevention of cognitive decline. Can you tell us a little bit about this work? MM: So this is a fairly new focus of nutrition and dementia. The evidence isn’t as consistent as one would like for the Mediterranean and other diet patterns, but there are some methodological issues in the way people have tested these different diets that perhaps have confused the picture. We looked at the Mediterranean diet as well as the DASH diet, which is a very well documented diet that is effective in lowering blood pressure, reducing diabetes incidence, weight gain, so the DASH diet has a very strong cardiovascular history of being protective for cardiovascular disease, as has the Mediterranean diet. In two of our community studies, now, we have found that both of these diets reduce cognitive decline with aging. We’ve developed this area even further. Just recently we had a publication that came out just last week where we took a hybrid of these two diets, but then modified them to reflect the literature that is specific to diet and the brain, because the Mediterranean diet, after all, is a cultural-based diet that has been related to cardiovascular disease. And DASH was originally designed for hypertension and, you know, cardiovascular conditions. So we tried to build upon those diets by specifying certain foods and modifying them somewhat to reflect the dementia literature. And we found stronger associations—more protection—with this MIND derived diet than either the Mediterranean or DASH diet.[8] JB: That’s really fascinating. You know we had the opportunity to interview, some years ago, Dr. Suzanne Craft, who was then (at that time) at the University of Washington and the VA center related to aging. She had made some very strong observations and published her work on the insulin-associated (hyperinsulinemic association) between Alzheimer’s and how that related to prevention through a low glycemic load diet, so she was very strongly encouraging a major determinant would be glycemic response to foods and how that would enhance insulinemic activity. Do you feel, from your work, that there is more to the story than just the insulinemic response or is that a major component of this benefit you’re observing? Biomarkers at Mid-life May Relate to Development of Alzheimer’s in Late Life MM: So there has been very, very limited study in the area of glycemic load/glycemic index/the glycemic diet in relation to the development of dementia, so it’s very difficult to make a comment one way or the other with such limited study. Certainly there is an interesting biological mechanism by which it may, in fact, be a factor (a diet factor) that could help to prevent the disease, but we just need more studies, more research, to look at this carefully. I think one of the problems with this study is that we find, when we look at older populations, there is Alzheimer’s dementia brain change effects on metabolic factors. Blood pressure is an example. Obesity is another example. Hypercholesteremia is another example. When you look at the studies that have looked at those factors in relation to development of dementia, typically there is no association found. It’s only when you go back to the middle age years and you look at who has hypertension, who has hypercholesteremia, who is obese in their middle years, and then they relate those factors to the development of this dementia in late life—it’s only those long-term studies that have found association. Probably what is occurring is that the brain and the changes that it is going through is affecting the level of blood pressure in late life, the level of cholesterol in late life. It is very likely that the same thing is going on with the diet factors. JB: Very interesting, so when you developed this hybrid between the DASH and the Mediterranean diet and picked up certain foods that were to be emphasized, were those foods high phytochemical or nutrient dense-related foods? What were the principles by which certain things were emphasized? The MIND Diet: A Hybrid Approach MM: I can tell you what some of the major modifications were. For one, both the Mediterranean and the DASH diet specify four to five vegetable servings per day. In the literature on vegetable intake and the risk of cognitive decline in particular, it’s really very specifically green leafy vegetables that are important, so we built into our MIND diet score a separate component apart from other vegetables, green leafy vegetables. This literature seems to indicate that almost a serving of green leafy vegetables a day is associated with slower decline. That was one thing that we changed. Another component is the fruit component. Both the DASH and the Mediterranean diet specify about four to five fruit servings per day. Well, in the dementia field, fruits as an individual category have not been associated with cognitive decline or risk of developing dementia. There is, however, a very strong animal literature, and one or two epidemiological studies that have shown that berry in particular—that single type of fruit—is associated with neuroprotection. So we did not specify four to five servings of fruits per day, we specified—several times a week—berry consumption. Those are two differences, and then the Mediterranean diet specifies six or more servings of fish per week. The DASH diet really doesn’t focus on fish. The literature in the dementia field really shows that the level of benefit from fish for developing Alzheimer’s of cognitive decline is at one fish meal a week. There is little to indicate that consuming more than one fish meal a week is even better, so we modified that component of the MIND diet to just one fish meal a week. So those are several of the types of modifications that we made. Certainly we do have a separate component for vegetable servings, but green leafy vegetables, berries, other types of vegetables—those are all very high in micronutrients and phytochemicals. So, yes very high micronutrient phytochemicals in the diet. JB: Taking this extraordinary breadth of work that you’ve been involved with for these many years, and kind of doing the broad brush—moving up to, say, the 30,000 foot level—what is your kind of view as it relates to how we’re going to fight back against this rising tide of Alzheimer’s and other non-Alzheimer’s dementia, which is certainly becoming the big health-related risk and functional problem in our culture. What’s your crystal ball say so far from the work that you’ve see and been involved with? MM: One of the more important things, I think, is to have a diet intervention randomized trial. Prevention is so important for fighting this disease at the public health level for the reasons that I mentioned earlier—that right now we don’t have a cure, there really hasn’t been a new drug on the market for many years now, and they are really largely ineffective anyway. So prevention can do so much. They’ve shown that just delaying the onset of Alzheimer’s disease by five years can have on the financial burden, the resources required to live out the disease, it can have a really significant impact, so preventive factors really need to be studied vigorously. So far there have been randomized trials of physical activity to prevent the disease, cognitive activities, social activities, meditation, yoga; there hasn’t been one diet intervention trial. We’re working very hard to try and make this a reality. Then there can be public health messages and recommendations. If we have a full diet intervention trial, the Alzheimer’s Association, the National Institute on Aging can put out there, you know: “Here are the foods and the type of diets that can help you to prevent the disease.” JB: There is one thing that struck me as very interesting in your work, and that was the association between wine consumption and neurodegeneration (inverse response) and the suggestion that maybe this has something to do with phytochemicals like resveratrol, but it may have an alcohol-related effect as well. What has been the dominant theme about alcohol consumption and neurodegeneration at this point. MM: So if I understand your question it is what component in wine consumption, is that what your question is? JB: I think my question is, first, is this inverse association between alcohol consumption—modest alcohol consumption—and neurodegeneration seemingly replicable, and if so is there a difference in the type of alcohol consumed and the influence it has on neurodegeneration? MM: My focus hasn’t been on alcohol consumption. I believe, from what I know of this literature, there are associations with other types of alcohol being protective in addition to wine. Wine has been vigorously studied because of the resveratrol. There have been hypotheses that the social nature of drinking alcohol might also be a component associated with alcohol consumption that related to lower risk of getting Alzheimer’s disease because social interaction has been one of the factors that has been shown to be important for reducing your risk of getting the disease. So it’s hard to pull apart what drives the alcohol association as a protective factor, but what is so important to emphasize is that the level of benefit—the protective level of benefit—is very low. No more than one glass of alcohol—you know, a glass of wine for a woman and no more than two for a man—is what we observed in the studies. So there is this concern of people taking that to the next level and increased amounts of alcohol are very neurotoxic; they can cause dementia. It’s a two-edged sword, there. JB: Yes, I think again that goes back to your comments that you made in your editorial—the potential design flaw, where you talk about the inverted U effect of many things, that what may be beneficial at one level can turn opposite and become a hazard at another level. Kind of the shape of that parabola determines the relative safety margin for that particular substance. MM: Well put, yes. More Studies are Needed on the Role of Carbohydrates in Dementia JB: Let me just ask one last follow-on question. We often hear debates about the nature of carbohydrate in the diet and whether this is a contributor to dementia in the long term and of course there are all sorts of different ways that carbohydrate can be consumed, from simple carbohydrate sugars to highly refined white starch in either amylopectin or pectin, or we can look at even the unrefined, fiber-rich, nutrient dense types of carbohydrate. What has your work in looking at carbohydrate connection told us? Is there a difference between the complex, minimally processed, whole grain carbohydrates than that that is highly processed? MM: There has not been adequate study in this area at all in relation to brain changes with age and the development of dementia. It’s very limited and that is one area of study that really needs to be developed. It does have the same type of problem that I mentioned before with glycemic index and glycemic load. We may observe a different relation in studying older people than we would if we went to the middle aged years and looked at simple carbohydrate intake versus whole grains and more complex carbohydrates in relation to the development of dementia and brain changes with age. This is a field that has very few studies that have published on it. JB: So let me ask you the last question and that is most of the listeners of this discussion between us will be healthcare providers and they are undoubtedly being asked by patients what should they do if their parents, or loved ones, or colleagues were in this state of Alzheimer’s. They may either in their own lives do something to prevent or to provide the proper advice to their patients. What would you do in that particular situation if you are sitting knee-to-knee with a person asking you what is the best approach? MM: I would take the approach from two perspectives. One is that we know that a lot of the factors that protect or lead toward increased dementia are the same factors that are heart healthy factors, so we don’t know with assurance that some of the factors that look to be protective or harmful for dementia are indeed so, but if you follow the heart disease world, you’re going to be hitting a lot of those factors. If you are a caregiver of somebody who already has Alzheimer’s disease, the approach from the diet perspective might be to be sure that the diet is more similar to the Mediterranean of the DASH diet, or you can look up this new publication on the MIND diet, which was published in Alzheimer’s and Dementia. So you can be sure that their diet is, you know, of the healthier variety, but in addition I think it is very important for anyone who is aging (middle adult to later years) to have biochemical analyses done to determine whether certain nutrients are low. What is your B12 level? What are your vitamin D levels? What are your vitamin E and folate levels? It may be that you, as an individual, are in the marginal status, and then it might be appropriate to take a supplement to correct that marginal status. So I think those two approaches will take you a long way to protect your brain dietarily. JB: We can’t thank you enough for the years of effort that you put into this field and the work that you have published, and also with taking a very complex topic that has still a lot of questions yet to be answered and making sense of all this has really been a great journey you have kind of guided us through here. I think the encouraging thing is it seems like at least people are starting to ask the right questions now. You can’t ever get an answer unless you ask the question and it seems to me, with the quality of work that’s being done in your group and others, that we’re finally starting to at least design studies that will allow us to have answers to questions that have been sitting around for some time without understanding. Thank you very, very much. I think you’ve given us a tremendous amount of news to use and we wish you the very best in your continued work and we’ll be following it very closely. MM: Thank you very much. It’s been my pleasure. JB: Thanks so much.  

Bibliography

[1] Evans DA, Morris MC, Rajan KB. Vitamin E, memantine, and Alzheimer’s disease. JAMA. 2014 Jan 1;311(1):29-30.   [2] Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan 1;311(1):33-44.   [3] Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA. 2002 Jun 26;287(24):3230-7.   [4] Grodstein F, Kang JH, Glynn RJ, Cook NR, Gaziano JM. A randomized trial of beta carotene supplementation and cognitive function in men: the Physicians’ Health Study II. Arch Intern Med. 2007 Nov 12;167(20):2184-90.   [5] Morris MC, Tangney CC. A potential design flaw of randomized trials of vitamin supplements. JAMA. 2011 Apr 6;305(13):1348-9.   [6] Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007 Jan 20;369(9557):208-16.   [7] Tangney CC, Kwasny MJ, Li H, Wilson RS, Evans DA, Morris MC. Adherence to a Mediterranean-type dietary pattern and cognitive decline in a community population. Am J Clin Nutr. 2011 Mar;93(3):601-7.   [8] Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement. 2015 Feb 11. piiS1552-5260(15)00017-5. Doi:10.1016/j.jalz. 2014.11.009. [Epub ahead of print] [9] Barnard ND, Bush AI, Ceccarelli A, Cooper J, de Jager CA, et al. Dietary and lifestyle guidelines for the prevention of Alzheimer’s disease. Neurobiol Aging. 2014 Sep;35 Suppl 2:S74-8.   [10] Morris MC, Tangney CC. Dietary fat composition and dementia risk. Neurobiol Aging. 2014 Sep;35 Suppl 2;S59-64.   [11] Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY). 2014 Sep;6(9):707-17.   [12] Hanson AJ, Bayer-Carter JL, Green PS, Montine TJ, Wilkinson CW, et al. Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides. JAMA Neurol. 2013 Aug;70(8):972-80.   [13] Schiöth HB, Craft S, Brroks SJ, Frey WH 2nd, Benedict C. Brain insulin signaling and Alzheimer’s disease: current evidence and future directions. Mol Neurobiol. 2012 Aug;46(1):4-10.   [14] Subash S, Essa MM, Al-Adawi S, Memon MA, Manivasagam T, Akbar M. Neuroprotective effects of berry fruits on neurodegenerative diseases. Neurol Regen Res. 2014 Aug 15;9(16):1557-66.   [15] Vauzour D. Effect of flavonoids on learning, memory and neurocognitive performance: relevance and potential implications for Alzheimer’s disease pathophysiology. J Sci Food Agric. 2014 Apr;94(6):1042-56.   [16] Davinelli S, Sapere N, Zella D, Bracale R, Intrieri M, Scapagnini G. Pleiotropic protective effects of phytochemicals in Alzheimer’s disease. Oxid Med Cell Longev. 2012;2012:386527.   [17] Mu N, Xu SC, Chang Q, Rao DP, Chen JP, Ma C. Study of lipids, insulin metabolism, and paraoxonase-2-311 polymorphism in patients with different subtypes of Alzheimer’s disease (translated version). East Asian Arch Psychiatry. 2013 Sep;23(3):114-9.

Welcome to May 2015 Functional Medicine Update, and this is the first of what I believe is going to be a very remarkably insightful and information-packed series on functional oncology and this whole remarkable transition/revolution that we’re undergoing right now as it relates to what some people call precision cancer therapy, or genomic-based cancer therapy, or targeted therapy, or personalized medicine approaches to cancer therapy. I think you’re going to learn a tremendous amount through the voices and expertise of our three clinicians/researchers of the month over the next three issues.   Dr. Bland Begins a Series on Functional Oncology This particular issue, however, is going to focus on kind of an overview as to what does the landscape look like as it pertains specifically to the cancer environment/cancer therapy diagnosis in the year 2015. And then we will start moving from there as to where does it look like the future will take us in the subsequent issues? We’re very privileged to have, this month, two experts in cancer therapy that bring—as a husband and wife team—in the specialty of oncology, tremendous breadth and depth of knowledge in this area. I think it couldn’t be better to have kind of this clinical approach first to really talk through some of the challenges and some of the victories that are occurring in the area of oncology from a functional perspective. So let’s move into our discussion with the Vashis, who will tell us a little bit about what is the real state as it relates to today’s treatment of cancer.  

INTERVIEW TRANSCRIPT

Pankaj Vashi, MD and Glynis Vashi, MD Cancer Treatment Centers of America at Midwestern Regional Medical Center 2520 Elisha Avenue Zion, IL 60099 www.cancercenter.com We’re so excited this next three months to be producing a focused course on the progress that’s being made in cancer therapy and I think there is probably no area within functional medicine that could be more concerning and more on the minds of people than what’s being done in this critically important area for which there are decades of efforts and it seems like now things are starting to really change in the whole cancer therapeutic area—aspects of integrated, functional, personalized, and precision cancer therapy are starting to emerge. The genomic revolution is upon us. And we’re learning something about the fundamental nature of cancer that we didn’t know before as it pertains to the immune system and the interrelationship of immune vigilance and how that relates to the body’s own natural management of transformed cells. We’re so pleased that we’re starting this series right at what I would call the top of the ladder. We have two extraordinary clinical experts in the area of the emergence of the 21st century cancer therapy: Dr. Pankaj Vashi and his physician colleague and his wife, Dr. Glynis Vashi, who are working together collaboratively. And I think it is very interesting from an interpersonal relationship perspective as to how two professionals, one—Glynis—in the internal medicine area and Pankaj in the gastroenterology area, can work together collaboratively to create, really, a successful program in integrated, precision cancer management. I think this is certainly the first time that we’ve had husband and wife on Functional Medicine Update, and the first time that we’ve really had a dual perspective for a clinical target. I want to thank both Dr. Vashis for being present for this discussion because we consider this an epic tip-off for this mini-course that we’re going to be doing over this next several months in 21st century cancer therapy, so welcome to Functional Medicine Update. GV & PV: Thank you. JB: How did each of you come into this field? You know, there is always this interesting path that takes us into where we end up, and we may not have planned to be there from the very beginning, but by a series of events we end up being experts in a field that maybe we weren’t initially intending. How did both of your paths lead you to this place at Cancer Treatment Centers of America and the positions of authority that you’re in? GV: I started my practice as an internist in 1992 in the Chicagoland area, and I worked for Midwestern Regional Medical Center, which is now known as Cancer Treatment Centers of America. So I always had an interest in oncology, especially when I was doing my residency and training. And when I started practice and began to grow the practice and began to diagnose cancer in my patients that I had already developed a relationship with, I became more and more interested in cancer and its treatment and management. The hospital then kind of phased out its medical/surgical program and became exclusively a cancer treatment center, and at that point in time I was already onboard as an internist, so I was offered a position to work with cancer patients at the hospital. And since I had already had an interest in oncology, I took up that position about 11 or 12 years ago. What I do now is see all the new patients that come with the diagnosis of cancer and work them up and get them ready to see the oncologists, so that’s how I became interested in cancer care. Patient-Positive Cancer Care Begins with the First Appointment JB: What I have learned, Glynis, from your work and that in collaboration with Pankaj, is the incredible patient-positive reputation that you have developed. Your presence almost precedes you with the patients that I had the opportunity to talk with when I was visiting the facility. It’s quite amazing what you have done, both in terms of treatment and setting a tone and a mood. We’re going to get back into that because I think there is a whole social matrix that interrelates to cancer care and cancer treatment that you seem to have really done something uniquely positive in setting the right environment. So Pankaj, how about you? What led you—as a gastroenterologist—into this area? Cancer Patients Have Complex Metabolic, Nutritional, and Emotional Needs PV: My training in gastroenterology was at the University of Michigan, and during that time—this was in the 80s—nutrition was a pretty strong portion of our training, and the University of Michigan initial work on metabolic support was actually published out of the University of Michigan, so I always had that natural interest in nutrition besides being a gastroenterologist, and so Glynis and I, we both came out here in ’92. I also started my practice as a gastroenterologist in the community. People don’t recognize it, but CTCA was at that point a very small, little hospital with about 20 beds and also the med/surg hospital. So I started working there and obviously you know our chairman very well. I met with him with Glynis and I saw his vision and was excited about working more and more with cancer patients, and so over the last 20 years I phased into taking care of mostly all of GI malignancies. Unfortunately our patient population is mostly complex and advanced patients, so their needs (metabolic needs, nutritional needs, emotional needs) are very different and [more] challenging than dealing with a healthy population. We learned very quickly how to manage those patients and we developed a very robust integrative cancer program incorporating all of the things that you and I believe in. And then I got more and more interested in nutrition and started studying more on the role of metabolic support, nutritional interventions, and quality of life, and we’ve got some good publications coming out within the next couple of weeks showing some of the outcomes from intervention. I think with that and GI as my background, everything goes with the gut. It’s been a fascinating ride for both of us. JB: Well I think it’s been an important ride for the whole field of advancing cancer therapeutics. What you’ve done, and the way you’ve described it—and I would have to say you’ve very politely understated what you’ve accomplished over the years—is taking a conception of an idea of how to evolve cancer care and cancer treatment, and you have just continued to evolve it over those 20 years to really be, I think, a model for what is going to be seen as the premier way of approaching this complex nature of the disease that we call cancer and the psychology that is interrelated to it—the sociology as well as the medical and physiological effects. I want to get into that a little bit more because I think what you’ve done is nothing short of remarkable in evolving the program over those years. As you’ve watched this field advance—and it certainly has made some extraordinary advances over those two decades; in fact, I was just absolutely enthralled by this wonderful public television series that is co-sponsored by CTCA, The Emperor of All Maladies, which is Siddhartha Mukherjee’s wonderful book, which to me is one of the great pieces of medical literature that has ever been written in English. I think what it really lays out is a history of cancer therapy in the United States, and it also opens our minds to how remarkable the evolution of your program has been as kind of a leadership. What kind of training do you feel is important to keep abreast of the extraordinary changes that are occurring in this personalized, integrative cancer therapy area? Because it seems like it is ever changing. GV: I kind of believe that the training should begin in medical school and residency programs, because as far back as I can remember, there was not enough emphasis placed during our medical school training as well as residency training on personalized medicine. We always were taught how to diagnose disease and then treat it, but the pre-disease state (the wellness state) was never emphasized: lifestyle changes/modifications, dietary modifications, all of that I feel is not emphasized in school, so I believe if we ever want to make that much of a difference we should really bring it out in medical school training and in residency training as well, and functional medicine and personalized medicine training should start there. PV: I totally agree with Glynis. That’s one thing that we are now more aware of—the impact of obesity, for instance, or hyperlipidemia, or eating habits (plant-based versus meat-based and the impact of red meat)—all those things we are seeing now because we are seeing the consequences of that, I wish we had looked at it years ago, and it’s never too late. We are still facing this tremendous problem with kids now—obesity in kids and the eating habits in kids—so I think proactive intervention. The thing is most of the healthcare costs and pharmaceutical companies are so much involved in building drugs that will take care of diseases that they don’t feel there is any need for us to look into why they even get it. I think that is where the whole healthcare system needs to recognize the importance and give value to that is what we both feel strongly about. How Has the Treatment of Gastrointestinal Cancers Changed Over Two Decades? JB: Well, thank you. I know that there are many of our listeners of Functional Medicine Update who are strong students and believers and even practitioners who believe that the immune system of the intestinal tract (the so-called gastrointestinal-associated lymphoid tissue) is extraordinarily important in communicating the messages from the outside world, like diet and the microbiome, to the inside world of our body, and clearly as a gastroenterologist you’re right at the cutting edge of that particular association. How have you seen changes over the last 20 years in the whole field of how we view cancer and the specifics of the gastrointestinal system as it relates to malignancy? PV: I think the biggest change I see—not even [over] 20 years but more so in the last decade or last six or seven years—is how much more we have learned about the gut microbiota. I mean we used to always know that bacterial growth—that the symbionts in the GI tract—really had a role to play, but not until recently when we started getting a lot of genomic identification and sequences that we are getting more and more aware of the actual role of gut microbiota, and I was at the clinical nutrition week, which is a large nutrition meeting up in California and one of the presenters blew my mind and said, you know, the gut GI surface is 200 meters square in surface and the skin is only about 1.5 meters square and yet millions and millions of dollars are spent in identifying skin-related problems because you can see it. And so knowing that there are almost trillions of bacteria in the GI tract, I think it’s very fascinating and now we are seeing more and more studies coming out about the immune system (how it plays a role). For instance, the role of inflammation in the GI tract treated by bacterial-producing inflammatory mediators like interleukin-1, TNF-alpha, interleukin-8, prostaglandins, and how does inflammation play a role in not only cancer but in other conditions. Autism has been now shown to have some relation to the gut microbiota. We have incredible data now coming out in the GI literature about the role of gut microbiota in inflammatory bowel disease. You know, the great example is H. pylori, a bacteria that has been known to cause stomach ulcer but there is a strong relationship between H. pylori and inflammation it produces and lymphoma. For instance, the mild lymphoma can be cured sometimes just by treating the bacteria.[1] So this kind of strong relationship between the gut bacteria (the so-called good bacteria, the probiotics) and the role they play in chronic inflammation and modifying the immune system by producing all the mediators, and so we are getting more and more aware of the roles. I think that’s the most fascinating part—the gut microbiota. I think the next few years is going to be even more exciting the more we look at the studies showing the impact of that on different disease processes, including cancer. JB: So Glynis, when you are speaking with patients, do you have a difficult time with them understanding this diet/gastrointestinal function connection to the immune system as you’re helping them through being advocates for their own health? Is this an abstract concept for most people, or do they kind of at some level understand the importance? GV: Actually the patients that do come to us, they do a lot of research. I guess they go on the Internet and get some information. Well, yes and no, because sometimes there are patients who are very interested, and then there are others who really don’t have a clue. We try our best to give them a little education and talk about it. It all depends on their interest as well. Integrating Genomics into Cancer Care JB: You know, we’re kind of in this age of genomics right now in which we’re all being educated as members of our 21st century society about what genes do and don’t do and how they are unique among different people in the way they are expressed. This obviously is having an application to cancer therapy and personalized medicine. How is this being interwoven to the programs you are doing and your discussion with patients? PV: I think at CTCA we have really gone far beyond what the norm is recommended as far as genomic testing is done. CTCA has invested a significant amount of resources and finances in continuing to help develop the specific tests to define genome. You’re very right, each patient’s gene expression is different, so lung cancer in one patient will not respond the same way in another patient and we’re already finding out there are so many targeted therapies that are available. So many of our patients, by the time they come to us, if they have already gone through some first-line treatments and obviously they failed, we are doing genomic testing predominantly on most of those patients. We get some tissue and we do genomic sequences and identifying different targets from them, and then, because of the barrier between cancer types we treat those patients depending upon what targets they identified with. And Glynis is really involved a lot because she is the first person to see them. I’m sure she can speak more on that. GV: Ideally when a patient comes in to us it could be either a very newly diagnosed patient or someone who has been through several cycles of chemotherapy, so for both of the types there is a great interest in doing genomic testing on them. Right from the get go we talk to them about it, and some patients do know. I mean, they do have some knowledge of what genomic testing is all about and they are very, very interested because for everyone, they want to beat the cancer and to do well, so they are very, very receptive and all I have to do is talk to them about it and say we are going to send some of your tissue for genomic testing and based on those results we will be able to have a better understanding of what is causing your cancer and what are the genetic mutations, and if there are any and we can find some targeted therapies to help you, we’ll go for it. And we find a lot of receptive patients. They really are keen on doing that. JB: So this discussion we are having right now is what I would call the high technology part of therapy. It’s the front-edge of the evolving science in cancer therapy. And one of the things that I’ve been very amazed to see that you’ve been able to do is to couple that high technology, leading edge development with what is called high touch. And you know there’s this old concept—John Naisbitt—high touch and high tech have to go together to be successful. How have you been successful in integrating this concept of high touch—this personalized approach that is not just through technology but it’s through counseling, and relationship-building, and nutrition and lifestyle advice. How does that actually work within your facility? The Cancer Treatment Centers of America Care Model GV: Thanks to our chairman, Mr. Stephenson, who had this vision of what cancer care should be, primarily because he felt his mother did not receive it when she needed it, CTCA has been the pioneer in terms of offering integrative cancer care and personalized medicine to patients. And so we have a very robust department: nutrition, naturopathic doctors, mind/body medicine, Reiki therapy, massage therapy, chiropractors. Whatever it is that we can do to improve patients’ well-being overall is offered to them right from day one when they come in. Typically when a new patient comes in I see them, literally as the face of the hospital, because I am able to tell them what they can expect to have from us. So it is always all about doing the traditional therapies, but staying at the cutting edge with the genomic medicine testing, and also offering them everything that can make them feel that they are having treatment in a nurtured environment. I do tell them this is going to be very different from what you’ve already experienced at home. Even when they meet with me they already know that there is a difference in the hospital. PV: I think that I can stress also that in the nutrition department—because that’s the department I head—you can imagine we have one dietitian per physician in oncology. I mean, that’s unheard of. We have 16 dietitians; that, basically, would be what you would see in a thousand-bed hospital. We have less than 40 beds and we have 16 dietitians, so that tells the commitment we have. These are nutritionists who are well-trained not only in metabolic support, but in understanding metabolism. They are all certified (metabolic support certification and oncology certification). So each patient is assigned a dietitian and a naturopath from day one and they basically see them on every visit, they follow them while they are at home, they get their emails, their phone numbers. Unfortunately we have two extremes of patients. We have patients that come significantly malnourished. We have totally different needs for that group of patients where we get very aggressive with enteral feeding, PPN, IV nutrition. And then we have another spectrum of patients who are prostate cancer patients, breast cancer patients, who are early-stage and more so having issues with obesity and poor lifestyle prior to coming to us. So we have different personalized treatment. For people with metabolic syndromes, for instance, we work with them. As you say, anybody can do a genomic test and give a targeted therapy, but what is so unique about CTCA is that while we do that we also have incredible supportive care that we give to our patients. JB: You know, I was very impressed with the research that you’ve been able to do while you’re heavily and primarily engaged in clinical services and clinical support. Your number of publications that you’ve been actively involved in over the years is quite impressive. What nutrients and what areas have you found through these explorations that stand out as problem areas that are found in many of your patients? PV: I started getting interested in vitamin D about 2007/2008, when the initial data started coming out, more of the epidemiological data. There is some relationship between low vitamin D and certain cancer types, mostly the GI colon cancer was the initial one, prostate, lung. That’s when we actually started almost checking everybody for vitamin D levels. We did an initial interesting little study that was a research master’s study for one of my dietitians on just picking 50 of our female employees at Midwestern and 50 patients with breast cancer and just check randomly their vitamin D level. It was shocking that—well, because are in Chicago maybe, we don’t get much sunshine—but 70 percent of our employees…close to 70 percent were deficient and in the patients it was close to 80 percent, so there was not much difference. That’s when I started getting more interested and then we started looking at vitamin D. We actually do vitamin D levels on every patient that comes to us. It is part of the initial nutritional panel that we do that includes vitamin D. We start correcting vitamin D. Initially we have shown the impact of vitamin D in colon cancer, and then we started noticing that just because we supplement vitamin D in these people doesn’t mean that they normalize equally, so we published that on different cancer types and how they respond to supplementation.[2] This most recent article that we presented—this one published March 16 in PLoS One—is mostly on vitamin D in advanced cancer. What I was trying to show is that, yes it is important (vitamin D), but it is not that if you get diagnosed with stage 3/stage 4 cancer, if your vitamin D level is low, the damage is done.[3] That’s why functional medicine and personalized medicine is so important. It’s a lifestyle thing: make sure your vitamin D is good when you are in your 30s and continue to maintain that high vitamin D level and prevent the development of certain cancers. I think that is one of the ingredients that I’ve found that I’ve studied enough to show in colon cancer, lung cancer, and prostate cancer—these are the three main cancer types I have looked into. Another very interesting thing that Gynis should actually get credit for is she started doing vitamin B12 levels in a lot of the patients because of concern of neuropathy from induced chemotherapy. She called me one day and said, “You know, I don’t understand why all of those patients have vitamin B12 levels that are so high.” And it’s not that those people are taking vitamin B12 supplements—not that they are taking it but still they end up finding it high. There are studies that show that many times solid tumors secrete vitamin B12, which impacts B12 levels and you may get false positive normal B12.[4] So we studied nucleations. Methylmalonic acid, in particular, is a very sensitive indicator for B12 deficiency and we found that higher levels of methylmalonic acid was there in patients with normal B12, so not going into the details of the study but that’s another thing that we found out—a nutrient that is low in about 16 to 18 percent of the patients having even normal B12 levels. Those are the two things that I have had interest in, and obviously we brought in calorie malnutrition and cancer cachexia and sarcopenia—those are the other things that we are looking at. JB: Yes, and I think you touched upon a very important connector there: states of inflammation, which are—as you mentioned—associated with malignancy, induce, then, alterations in the myocyte (the muscle cell) to lead to apoptosis and lead to loss of muscle mass, so you get this sarcopenic situation, and also it is clearly tied with appetite suppression and nausea, so it’s like a dog chasing its tail; it tends to break that loop where it just gets worse and worse. And I know that you have—with your dietetic and nutrition intervention groups—you’ve got a lot of attention that you pay around that problem, because as an individual loses muscle mass their overall vitality and their immune system function is adversely affected as well. PV: That’s correct. The Unique Needs of Female Cancer Patients GV: Glynis, I know that—having been to the center there in Illinois and being very impressed with both the staff and the advocacy of the patients there—you have a lot of female patients. What are the unique features—if any, do you feel—as it relates to cancer treatment in women? Are there certain things that differentiate male and female patients in the way that you approach either? Well, obviously women might have breast cancer and men would have prostate cancer—that’s obvious—but are there differences in the way that you approach the discussion or the intervention with women versus men in the center? GV: I think that for women who come for cancer treatment there are a lot of specific issues and I think they are very related to either their socioeconomic status or just cultural issues. For example, we would see breast cancer patients who have been in some kind of a denial. They felt a lump possibly three years ago, or two years ago, and have done nothing absolutely about it. And even when it fungates and breaks through the skin, or if the breast is literally falling off—I mean, we’ve seen all those kinds of patients—and you always sit back and wonder how can these women go through life and know that something so terrible is happening but don’t do anything about it? I don’t know what to say. I think maybe men are more dominant in some ways than females…I think it is possibly cultural or socioeconomic. I think they do not seek treatment or…I don’t know if they are treated differently when they come in, but not at our institution. We have always wondered why women are so late in seeking treatment. I think that is one of the biggest issues that I see that is really specific to women. JB: That’s a very interesting observation. Again I want to commend what you all at CTCA are doing, because I’ve noticed recently a very direct public information program that is being sponsored by CTCA to heighten and increase the relative understanding and sensitivity people have to these problems so they can get on top of it early versus late. I think that advocacy has huge benefits in terms of the potential of arresting cancer and putting a person back into good health. Let me ask you—this is a difficult question and I think all of us in our chosen professions should ask this question of ourselves periodically—and that is: what do you consider the biggest obstacles or challenges that you face in the implementation of the personalized program that you’re advocating? It’s such a forward-thinking and leadership-related program, but undoubtedly it meets all sorts of levels of resistance that you have to overcome at different points. What do you consider the biggest pitch points and concerns that prevent it from really taking off and being what you think it can be in terms of general treatment of choice? GV: I think that at this point in time we really would be getting some pushback from insurance companies on genomic testing—I think if it ever has any negative connotation to it, it will always be because the healthcare dollar is shrinking and I think that would be the major factor that would be a reason for not doing the test in some, or if we found targeted therapies as a result of doing genomic testing, then we’re not allowed to use it simply because the use is off-label, for example, or the insurance companies wouldn’t pay for it. So I think that is the biggest deterring factor in us moving ahead and doing wonderful things with our results from genomic testing. PV: I think I will say that I think the other component of that is people in the field of mainstream medicine recognizing the importance of other components of treatment—the role of lifestyle changes and emphasis on supplements and emphasis on probiotics and nutrients and emphasis on metabolic syndromes and other things…mind/body…all those components of treatment. Unfortunately not enough resources have been put into those fields. We have been fortunate enough to be able to support some of those fields by us knowing that many of the services we provide are not reimbursable. The biggest hurdle and obstacle I see is lack of recognition by mainstream medicine people to understand the importance of other modalities of treatments besides just chemotherapy and surgery and radiation therapy in oncology in particular. I think the burden is on us, for us to show to the world the impact of that, and that’s why we are trying to do a lot of clinical trials to show that these therapies do make a difference. I think that’s another big obstacle. JB: Yes, I really want to commend what you’re doing there because I’ve noted that recently you’re really starting to participate in some of these national oncology meetings and reporting outcomes. As you mentioned earlier, you often get the sicker-than-sick patients that have already failed phase 1 types of traditional therapies so they come there already having been a failure of some kind of intervention with chemotherapy or whatever. And I think it is really meritorious that you’re now presenting data that relates to your outcome because I think numbers often speak for themselves and when people start seeing the results that come out of your integrated precision approach I think it will stand up and speak for itself. It will be a real strong determinant for other people. GV: I think our patients, too, are our best advocates. They come to the hospital, they see the difference, and they see the difference in how it makes them feel. And just knowing that they have all the nutrition support and back-up, if you see them for the second visit and you see that they have really renewed vitality and their fatigue is better, so a lot of the quality of life issues are made better, and I think they go out and are able to tell the world. Because very often I hear patients say, “I asked my doctor about what should I eat and they said cruel things—like, ‘Eat whatever you want, it doesn’t really matter at this point.’” I mean, physicians have told patients this. And this is hearsay, but I hear it all the time. And then when they are able to sit down with a nutritionist, who will go over the whole nutritional screen that we do and tell them that they need to take vitamin D, or we have to replace some iron, and when they feel better within a few weeks, they are our best mouthpiece. They just go out and tell everybody in their neighborhood and so it goes on. JB: Yes, I think that’s wonderful. There’s nothing like the proof in the results, particularly with cancer as such a dominant concern. Once people start seeing a benefit, your reputation is spreading rapidly. Let me finish up with one question which asks you to look a little forward, which I think you can do in your perspective because you’re at the leading edge in the evolution of cancer therapy and cancer care. What are your views about where the field is going? If you were to look out, say, five years—that’s about as far as we can look forward, maybe, five to ten years—where do you see things going based upon the trajectory of change and how you see things evolving? Personalized Medicine Will Revolutionize Cancer Care PV: I think that the biggest change we will see in the next five years is exactly what we discussed already: personalized medicine. I think a time is going to come in our kids’ generation where they will be laughing at us and say that you guys used to give the same chemo to everybody. I think the genomic testing and identifying specific targets will be done. Now we are doing it in patients who have failed the first line. I think that may become the mainstream. We’re already doing that for a lot of cancers. We are doing testing for colon cancer, for mutation up front, to see if they could benefit from certain chemotherapy, so I think that is to me the biggest feature. I think incorporating that, people are going to get more and more recognized as there are more publications of the impact of personalized medicine in terms of nutrition and supplements and lifestyle changes. I think a combination of those two would really be the forefront future over the next five to ten years. GV: I think genomic medicine and personalized medicine has already revolutionized cancer care, and I think we are all moving in the right direction. JB: Well, Pankaj and Glynis, I want to thank you both. I think this has just been a remarkable snapshot. I know there is so much more that we could talk about from the breadth of experiences that you’ve had, but I think you’ve painted a really optimistic picture and one in which there is patient involvement, there is a broader spectrum of management of the patient than just managing their tumor alone. You’ve given us a sense of what the landscape is of the evolving cancer care in the 21st century. I want to thank you both. I know it’s a difficult job. I think that people who are engaged in cancer therapy are warriors in a very, very complicated area of intervention and I think the way that you bring yourselves to your jobs and the way you’re respected by your patients is a demonstration of not only your ability to manage a very challenging environment but the grace in which you do it. I think you both for being available to talk this through. Pankaj and Glynis, thank you very, very much for being part of Functional Medicine Update. GV: Thank you for allowing us to share our thoughts and we really appreciate it. PV: And, Jeff, I have to say that we had an amazing time at your conference. I think that was an eye-opener for both of us because we settled outside our comfort zone, so to speak, but the amount of things that are happening out there and that was a very well-organized conference, so kudos to you and your team. JB: Well, thank you, and we look forward, hopefully, to having your participation in our Personalized Cancer Therapy 2015 version that’s going to be in Chicago in late October. We’re looking forward to your voice and contributions to that meeting as well. Thank you. GV: We’re looking forward to that, too. JB: I wish both of you the best and thank you for being with us.  

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Welcome to Functional Medicine Update for June 2015. This is the second in our series on functional medicine approaches to oncology and cancer therapy, and I think you’re going to find this issue is a very nice next step taken from our first issue that talked about patient management issues and use of integrative care. This month we’re going to focus on how genomics get built into this whole approach towards the emerging 21st century model of cancer care and how it relates to improving quality of life, and also improving patient outcome. And we can have no better guest to do that than our clinician/researcher of the month this month, Dr. Edgar Staren.   So without further ado, let’s move into our discussion with Dr. Staren.  

INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Edgar Staren, MD, PhD, MBA President, Center for Advanced Individual Medicine, LLC 445 N. 5th Street, Suite 600 Phoenix, AZ 85004 www.ashionaim.com We are once again in our series on the developments in cancer and how functional medicine and the field of cancer genomics is interfacing in the development of this 21st century evolution of the field with our extraordinary research and clinical expert Dr. Edgar Staren. Let me just give a quick introduction to Dr. Staren. We could probably take the whole of the interview to fully do justice to his background. I think he is the perfect person to really bring us into the 21st century in this discussion with his background, which has touched upon every aspect in the evolution of cancer care, from being an oncological surgeon to being an expert in chemotherapy to being a PhD in immunology and now the evolution of immunotherapy, and now making transitions as a leader in the area of cancer genomics, and his recent appointment now as the CEO of the Advanced Individual Medicine and Analytics Group that has been born out of the Translational Genomics Research Institute, which as many of you know was kind of a spin-off from the government genomic deciphering project under Francis Collins. Jeff Trent was the Director of Science under Dr. Collins in the NIH deciphering of the human genome reported in 2000, and Dr. Trent then moved on into the Translational Genomics Research Institute. And now Dr. Staren is a collaborator in bringing this new revolution in cancer genomics into the fore. I think you can see just from that brief introduction the breadth and the depth of Dr. Staren in the field. Dr. Staren, thank you once again for being what you are and in the field and also for spending the time with us on Functional Medicine Update. ES: Well, Jeff, thank you so much for that most kind introduction and it really is a privilege to be with you here today. JB: Maybe the way that we could start is if you could give a quick review. You’ve got just such a wonderful family and a tremendous past history of engagement, and your own personal story is, I think, really important for people to understand as it relates to your connection to the whole field of cancer care. When we hear your story, it reminds us that we carry along with our genes our experience in life, which often becomes our epigenetic modifier or modulator of what we do and I think your story is fascinating. ES: Well thank you, Jeff. It’s my pleasure to do so. I first and foremost am very proud to be a husband, father, and—what you don’t know—is most recently a grandfather. My oldest and his wife just gave birth to twins, here, a week and a half ago, and so that’s a pretty exciting deal. My mother used to say if she had knew it was that good she have done that first. That’s our first encounter, there, and I’m sure that’s true. When the Doctor Becomes the Patient: Significant Lessons Learned From a Cancer Diagnosis I am a surgical oncologist and was a very busy practicing surgeon. I did 400+ oncology cases per year, and was very much involved in academic leadership positions as an associate dean as well as a department chairman and a founding director of a cancer institute. Subsequently, as you indicated, I moved more into the full-time executive positions as the Chief Medical Officer for Cancer Treatment Centers of America and led one of the hospitals as a CEO of our western regional facility. And most recently, over the last now year and a half, I have moved into a number of positions and finally as the CEO for Ashion Pain Management and Advanced Individual Medicine. But—I have said it on a number of occasions—despite that rather diverse and lengthy experience in health care, perhaps the most significant learning lesson for me, was now approximately 10 years ago when I was diagnosed with cancer and had a diagnosis of a very aggressive sarcoma in my leg, and remember all too well when after a biopsy which was presumed to take out a benign lesion I got a phone call from my partner. I remember distinctly being in the driveway, just pulling in with my wife and two youngest kids in the back seat, where my partner said, “Ed, I need you and Lisa to come on into the office so we can talk.” Well, I’ve given that same preface before to patients and so I knew what that meant and I said, “PK, I’m hearing that we have some bad news,” and he said, “Yes, Ed. It’s a cancer and it’s a bad one.” Which it was. I knew enough about statistics to now know that based on the size and what I found out to be the histology indicated that my survival was not good, and as we all know, when you talk about survival and cancer it’s in large numbers of people, but on the individual basis it’s either zero or 100 percent. But that being the case, my expected five-year survival was 30 percent and I remember looking in the back seat and seeing my then little four-year-old daughter and wondering if I was going to get to see her be five. That was a huge lesson of the impact that patients go through, but more than that, in very short order I recognized the problems that patients have told me about for years but I didn’t realize how acutely they were in place, and that is the day after surgery I was in the hospital and ended up having severe pain from an excision of this lesion and asked the nurse for a pain medication. She said, “Dr. Staren, I’m sorry, it’s only been three hours.” And I remember thinking how goofy that was and how the pain was really starting to get pretty severe and I said, “Well, please call the resident and see if they can come on up and write me an order to change so I can get something.” And she said, “I’m sorry, Dr. Staren, they are in a level one trauma and not available.” And I said, “Please call my partner”—who had done the surgery—and of course he was down in the emergency room, too. The point being is that no one was available and I sat there in progressively increased pain, and you have to remember I’m the director of the cancer center, the chairman of surgery, this was my department. I mean, this lady worked for me. And I’m thinking how silly this was, and particularly knowing that there was no good physiologic reason why I shouldn’t get any pain medication, but our patients don’t know that. They think, “I’m having pain and they’re not giving me a pain medication. There must be something wrong with me because there is no reason why these healthcare professionals would want to do something purposefully that was going to hurt me and so I must be the problem.” Well, shortly thereafter I also realized the poor way we were dealing with—in addition to pain management—nutritional support, psychosocial support, rehabilitation, and it was a turning point in my professional career: to recognize that in an organization where we thought we were doing mind/body/spirit approach, in fact what we were doing was providing excellent state-of-the-art traditional care, but we were encumbering that with very poor delivery of support services, which ultimately contributed, in an enormous manner, to making that state-of-the-art traditional care successful. And it is really what led me to CTCA, to an organization that approaches medicine in an integrative manner, and a continued quest for a true focus on personalized medicine, which has led me to the position I’m in today. JB: You know, I’m just sitting here and I’ve had the privilege of hearing your story before, but every time you relate it, it comes with such deep compassion and deep humanness that it gives me gooseflesh. It’s a very, very powerful story, and one that I can just feel—vicariously—how it’s one of those transition points in your life that has now influenced, in a positive way, so many thousands of other people as it relates to the bringing of your skill and professional talent probably into a different realm of application (a broader realm of application). It’s magnificent that you’ve given yourself the freedom to tell that story because it’s very powerfully motivating and energizing. So, thank you. ES: Thank you, Jeff, very much. JB: I just finished having the privilege of watching The Emperor of All Maladies public television program with Siddhartha Mukherjee, and the excellent historical review. I think that that six-hour program hopefully will be a teaching tool for every person that’s going in to some part of the field of cancer therapy because I think it’s such a tremendously well done historical review of how we got to where we are and where we can be going. But you, in your experience, are a person who has chronicled so much of this change in cancer therapy and how we view cancer and how we treat it, I’d love to get—if it’s not asking too much—maybe your snapshot review of the evolution of the field in your years of experience. It must be quite remarkable for you to look back in your career and see how things have changed. Diagnostics & Therapeutics: The Evolution of Cancer Care ES: It is, Jeff. The episode that I personally went through is one of those classic personal tragedies that I think turns into personal blessing. I guess every life event has that potential and I feel very blessed to have been given my health back, albeit with some of the sequelae of treatment that are not insignificant in and of themselves. It’s a different subject, but it certainly speaks to that whole global and long-term influence of cancer both on the individual and how it impacts on family and society, etc. But it has been remarkable what we have had in a relative blink of an eye in history in terms of changes on both the diagnostic and the therapeutic side of cancer, and it’s not as if we haven’t known about cancer for an incredible period of time, but to be able to do something about it is really relatively recent. I look at the evolution of cancer care specifically such that in the 20th century it was really based on kind of microscopic observation. We would end up looking at the patient and see that they ended up having a large tumor and perhaps by examination only you would identify that they had lymph nodes involved, or they had evident signs indicating that they had metastatic disease. But it was based on that observational activity that treatments were indicated, and as you well know, during that period of time it was pretty much a coin toss on what the impact of treatment would be, and there are those that believe that in as many circumstances harm was delivered by virtue of the treatment rather than help. It was not intentional harm, of course, but it was based on ignorance. As we progressed we moved more into microscopic, inclusive of even advanced microscopic immunohistochemical analysis and such that made progress from a diagnostic standpoint, and certainly improved our ability to be able to treat based on that diagnostic standpoint. But while progress was made, it really wasn’t a change in the paradigm. We simply were continuing in the little bit more sophisticated manner that observation on large numbers of people based on rather crude assessment tools and taking that information and applying, again, relatively crude therapies. But it’s within, now, the 21st century that we’ve taken what I think initiated in 1971 with the National Cancer Act, where both funding and authority was put in place to understand cancer, to understand the molecular basis behind what caused cancer to occur and therefore translate that information into specific therapies that could be dedicated towards the individual cancer. We can and probably should talk in a little bit more detail how that has progressed—that molecular understanding—and has allowed us to truly translate into personalized medicine approaches for the individual patient. It’s been a remarkable transition in a relatively short period of time. The Business of Cancer Management JB: I want to move into this discussion with you as it relates to the molecular biology of cancer and how that relates to cancer genomics, but before I take that step—because I know that’s going to open an extraordinary landscape of expertise that you have, and insight—I’d like to bear on one other part of your expertise and that’s this management part. The business of cancer management is a very complex business, from the diagnostics to the treatment to the patient management issues. It’s a very, very complex, multi-headed field, and it requires probably a very unique way of managing the complexity when it delivers down to the patient, which for them is just “get me well, make it simple, and hopefully I can manage through the process.” You’ve been really a master in developing management concepts and building teams. Tell us a little bit about what your thoughts are in the organizational structure of managing this multi-headed hydra in ways that make sense. ES: Well, thank you for asking. I believe that at the end of the day, while we pay lip service to it, it is not entirely true that attention has been paid to the patient as the focus of care. We end up having multiple constituents in health care, particularly in the United States, that attend to multiple needs, and that includes of course the patient, but also the doctor, the pharmaceutical companies, the provider at their health system or hospital level, and of course the payers. There are conflicting interests in those participants, and it’s easy to forget that patient in that kind of an approach. One of the things that has been my focus has always been the patient-centric approach, and our chairman at Cancer Treatment Centers of America has a quote that says it is always and only about the patient. It’s really easy to forget that, but if you constantly put that in your mindset and put the others all to the side, at the end of the day water does reach its level and patients then become empowered to be a participant in their care. What I mean by that is that if you end up focusing on the patient, what you focus on is what the patient values, and you’ll find that there is lots of attention paid to things that they don’t value, and which cost a lot of money. Patients don’t particularly care about going into a medical system or a hospital that ends up having a six-story marble façade with fountains and all the other effects. Talking with patients one-on-one, they tend to view that as rather imposing, foreboding, and perhaps intimidating at best. And it costs a lot of money. Well, what do patients tell us that they want? They want to come into a warm environment that feels more as if they were at home, that they end up being welcomed and embraced, that their name is known—that they’re not a number—so that they end up having that personal-type of an approach. Two, patients want to be informed. There is a wealth of information available because of the internet, but it’s also very confusing. When a patient ends up coming in with a three-inch stack of papers that sounds good, but much of that will be redundant and, worse, conflicting information, and so while that would seem to empower a patient it often confuses them, and without being paternalistic it is important to provide information, in terms the patient understands, that is credible information so that they can then determine—based on what’s available, both on the diagnostic side and on the treatment side—what they view as important and then be a participant in saying, “That’s the type of care that I want.” So that they are much more inclined to engage actively in that care, have their emotions and therefore their immune system and their endocrine system all as active participants in support of that successful therapy and outcome. JB: Oh boy, that is a real major paradigm-shift concept. I know you have in excess of more than one hundred publications in the medical scientific literature. A number of those are on metric evaluation of quality of life-related issues in the cancer patient. One always asks the question: Is there a correlation or any connection between quality of life experiences in cancer care versus quantity of life in terms of outcome variables? You’ve done a masterful job of really looking at these quality of life issues across a range of different types of cancer. I presume the takeaway you’ve gotten from that research is very consistent with what you’ve just said? Evaluating Quality-of-Life Issues in Cancer Patients ES: Yes, it is. And first of all, Jeff, I’m so grateful for your most kind compliments to my contribution to medicine and the literature, but this audience probably is aware of all of your contributions. You’ve been a hero of mine—I will say that unabashedly—on the contributions that you’ve done for so many years and, frankly, have been a stimulus for me to do much of this work, so I want to openly say thank you and acknowledge all the work you’ve done. But with that in mind, you’re spot on: the work and global analyses of multiple cancers, as well as diving down more specifically into individual cancers, shows a clear correlate with not just satisfaction with addressing issues concerning quality of life—in other words, pain management, rehabilitation, management of fatigue, nausea, etc. All of those end up not only having an impact on a patient’s satisfaction, but many studies, from not just Cancer Treatment Centers of America where much of the work I was involved in and we’re speaking about, but institutions across the country have been regularly reporting, now, improvement in actual survival, and these are in some of the largest journals by some of the largest institutions. So it is one that the message is getting out objectively and the good news is that that small bell in the distance has now become a resounding bell among all of the institutions across the country, recognizing that they must provide this integrative type of approach and addressing these quality of life issues because it is going to make a difference not just in the satisfaction of the patient but it’s actually going to make a difference in their life. JB: So that obviously bears very directly on the framing of cancer care from a broader perspective than just dealing with the cellular lesion. Some people call that integrative care or comprehensive care. You’ve been a pioneer in that. What kind of push-back, or what kind of resistance or challenges does one encounter when you start widening the playing field, so to speak, in terms of comprehensive cancer care? ES: You know, it’s interesting: people get entrenched in what they were trained to do. That seems counterintuitive because we’re also trained that medicine increases rapidly and, you know, the statistic that I was always quoted when I was in medical school was that medicine was doubling in knowledge base every seven years and now people suggest that that’s every three to five years and that number continues to decrease. Therefore, if you don’t engage in ongoing, continuing learning and have an open mind to that learning, you are destined to be treating patients far less than optimally, and in fact, maybe more stated, incorrectly. Concepts that now are coming forward that make sense, but have always been out there in the distance include this whole concept of systems biology. And again, Jeff, you’ve certainly been a pioneer in this area, but it speaks to the concept that an individual disease, and particularly chronic diseases, of which cancer is more regularly being classified, are not isolated to that particular cell or organ, but there are impacts from the entire and multiple systems across our body that need to be addressed to optimally treat that particular disease process. It makes complete sense. We certainly recognize that on the benign side our bodies have systems interactions and networks, if you will. Why wouldn’t we think that that would not make sense with regard to disease processes, and therefore our approaches to address those disease processes need to be similarly systems based? JB: Oh boy. We’re really talking about the evolution of this 21st century medical paradigm, which is just so exciting to be living through this period where we move from disease as kind of a fixed independent entity to this concept of network and systems thinking and some of the fundamental changing the soil in which the cells reside which then creates the outcome of their phenotype. This is a really powerful paradigm shift. ES: Well, if I might interject just to piggyback on that a little bit. When we think of cancer, and it’s obviously been the focus of my professional career and especially since I’ve had a personal experience with it, which, by the way, we’ve all had. Mine was me, but I daresay there’s not a family that has not been touched closely and so it really impacts on all of us in a deep manner, and it’s a disease that is particularly onerous. You know, you talk about various chronic diseases such as heart disease, and you think, “Well, maybe I could have impacted that, you know, by adjusting my diet, etc.,” But then you move into areas for which traditionally we have thought that you might not impact on, and certainly cancer would be to the extreme in that: “Well, gosh, I didn’t do anything to cause this.” Well, I think the good news on that—on that glass-half-full-glass-half-empty approach—is that increasingly, with a systems approach, we recognize that we can actively impact before the disease occurs. That with lifestyle approaches, we can do our utmost within a range of possibilities—and it would be great to talk about that a little bit—but to understand where that range is by now increasingly available testing opportunities that we can follow along our lives and optimize our lifestyle to avoid those diseases in the first place, and should it be after the fact and the disease has occurred, maximally intervene in a therapeutic manner against those particular chronic diseases. It’s an amazingly exciting time, and as you said, a true paradigm shift. JB: Well, I want to move to that question, but before we move there I want to take a step in between, which is to come back and revisit this discussion of cancer genomics and the life of a cell, to use a Lewis Thomas aphorism. As we know, in the whole field of cancer therapy we’ve gone through the development of surgical techniques and the development of chemotherapeutic techniques, and then we saw the development with taxanes of some interesting approaches towards modulating specific genotypic expression patterns that are associated with malignancy, and then we had this remarkable breakthrough with HER2 receptor and Herceptin, which was really a paradigm-shifting concept. Cancer Genomics and the Age of Immunotherapy Right on the heels of that was Gleevec that got into some concepts of being more targeted therapies that made remarkable progress in patients. And now we’re moving into the age of immunotherapy, of which your background, and training, and your PhD work certainly gives you some really important insight into, and how this all interfaces—all of this—with the modulation of genes and genetic susceptibility factors. That then leads into where we are with next gen sequencing and how important that’s going to be in both understanding of propensity towards cancer, or let’s call it risk factors, and also how to manage individual forms of cancer knowing that each form of cancer carries with it its own unique genetic signature. Tell us a little bit about—now with your new role as the CEO of the Individual Medicine and Analytics Group at Ashion—how you see this cancer genomics playing out in the development of cancer therapy. ES: Well, you know the good news is that we’ve been dancing around this for a long period of time. Much of my work has focused on breast cancer, and I think that that’s a good example of where this evolution is occurring. If we think about it, it’s not as if we haven’t been engaging in personalized medicine approaches for some period of time. Really it was in the early ‘70s that first reports came back with regard to tamoxifen specifically being an important therapeutic intervention against the estrogen receptor in breast cancer. There have been great advances since that time addressing the estrogen/progesterone receptor, and you mentioned Herceptin and we’ll get to that in a moment. But parallel to that, of course, you address the issue of taxanes and such. If I think about it, during the course of my career, we really had 20, 30, maybe 40 chemotherapies over all available that we would alter the number within a particular group, then we would alter the administration, the dose, the timing, etc., but consistent with that paradigm being the same there wasn’t huge advances. Then along comes this concept of molecular classification rather than thinking about tumors based on their organ of origin. I think about some of the early work within the hematological malignancies that has been at the forefront of molecular separation of different cancers—the leukemias and the lymphomas—and how that information was utilized to engage in therapy. I ended up having a picture of a couple of lymphomas that if you looked at by histology you would think they were from exactly the same patient, whereas if you looked at their molecular panel they are radically different and clearly would warrant different interventions. Well, in the area of breast cancer, we’ve done the same thing. We’ve gone from having, “This is a ductal carcinoma and a lobular carcinoma” to at least four different subtypes, each with multiple subtypes within and with characteristic molecular abnormalities, and what we’re finding is—as you mentioned—one of the keys ends up being a marker that HER2/neu, which is part of the HER family of course, of tyrosine kinase activity, and being able to inhibit that particular receptor when it is present on cancers (and which occurs 15 to 20 percent of the time) and the remarkable effect that an anti-HER2/neu therapy or Herceptin has in and of itself and how additive that can be to those state-of-the-art traditional chemotherapies that we’ve had available for such a long period of time. What’s exciting to me is that what we’re seeing in breast cancer we are seeing across the board in other cancers. And to also follow up, you mentioned Gleevec. I think that that’s the perfect example of how this whole concept of genomic therapy—of personalized medicine—has changed our thinking of organ-based therapy. You end up having, with Gleevec or imatinib, a therapy which is targeted at two tumors that could not be more diverse: chronic myelogenous leukemia as well as the GIST tumors (the gastrointestinal stromal tumors). They could not be more diverse. No one would think, at first glance, that it would be appropriate to give a similar therapy to a patient that ends up having a tumor in the lining of the stomach as you would give to someone with a leukemia, yet because of their commonality of this particular molecular marker, we do just that, and we’ve gone from a tumor that was close to uniformly fatal (that being CML) to one that has an 80+ percent response rate. We’ve gone from a tumor such as GIST, that ends up being a highly aggressive tumor with really minimal therapeutic opportunities to one where that is really the first line therapy for the same kinds of reasons. To me the exciting thing is how much we still don’t know. There is a great example in that continuing evolution. You mentioned immunotherapy. I grew up with metastatic melanoma being a tumor that we were excited about response rates of 15 or 20 percent, and that was with some immune potentiating agents, such as IL-2 and interferon. But if you looked at the chemotherapy approaches, which were the standards of care, you’d have response rates (no cure, but simply response rates), which was the summary of both a partial response and one that at least by imaging therapy had the tumor going away, of 10 or 15 percent at best. To now, with some of these targeted molecularly-based therapies having 80-plus percent response rates, and even for metastatic cases, which were by definition incurable before, patients that are actually being cured. It’s mind-boggling to be able to think that that’s happened in this short space of one’s lifetime. JB: I’m reminded, as you’re talking, of one of your more recent publications in the Annals of Surgical Oncology in 2014. The paper is titled “Initial Experience with Genomic Profiling of Heavily Pretreated Breast Cancer Patients.”[1] Obviously these are women who have already been through the standard treatment of choice and have not been successful. The conclusion that you have in that paper I think is a watchword to all of us who are not every day, like you, following the progress that is being made. I’d just like to quote from the conclusion of the paper (I know you probably want to comment on it): “Almost all advanced breast cancers possess at least one well characterized genomic alteration that might be actionable at the clinical level. Further, in most cases a plausible argument can be advanced for the potential biologic and clinical relevance of FDA-approved anti-neoplastic agent not currently indicated in the treatment of breast cancer.” Now that is one powerful statement. Maybe you want to comment on it. I think it’s really, really insightful. ES: Well, first of all, I’m honored that you read my paper, so thank you for doing so. It turns out to be, I believe, the critical statement, and there are several points that can be made from that. One, this field is advancing rapidly and so clinicians, to meet the needs of their patients, need to—in an ongoing manner—educate themselves as to these changes. It’s difficult to do, but it’s a mandate. Two, we need to be, as a healthcare organization—and I refer to that being the providers, the pharmaceuticals, all of us—need to engage cooperatively to make sure that we’re sharing information to get that out there as promptly as possible because at the end of the day these are life-saving opportunities, and if that’s your mother, you want that therapy available yesterday, and it’s a tragedy to think that there would be a molecular opportunity identified and that we delay in the delivery of a therapy that can make a difference to that patient simply because of bureaucracy or ignorance, and so I feel that there is an ethical responsibility to stay on top of this in a rapid manner. But what we are seeing also is that today what we have available ends up growing rapidly. There are 200 drugs actively being pursued in the FDA pipeline that are targeted therapies that can be difference-making to those patients, and so there must be a facile mechanism for those drugs to become approved—to reach that FDA approval—so that clinicians feel comfortable in applying that therapy to their patients, and also with the confidence of knowing that the providers are going to be reimbursed for that, because those drugs do cost money and so in the interest of the patients we need to have a facile mechanism in place to ensure the delivery of those important therapies. JB: In a recent issue of Time magazine, the cover was a photograph of two women, both of whom had glioblastoma brain cancer, one living in North Dakota and the other living in Virginia.[2] The woman in North Dakota was being treated by standard of care at the local oncology center of excellence in her area, but because it was not a large teaching and research-based center, she didn’t have access to clinical trials for some of the more in-development drugs, whereas the woman in Virginia had access to a large metropolitan research-based oncology center and so she had access to these different clinical trials. The argument was posed, in this particular discussion in the magazine, that for the woman who was being treated in North Dakota, that there would be some reticence there to do genomic screening because it would raise questions from that data that probably couldn’t be answered because the person would not have access to some of these experimental drugs and be part of a clinical trial, whereas in the other center, genomic evaluation of the tumor would be more frequent and probably even routine. So there are some really interesting questions about when is it appropriate to start using genomic analysis of tumors in directing therapy. Where do you think we are on that continuum? ES: I think it’s a moving target and that’s the way it will probably be for some time. But I do think that we do have some fairly concrete groups that we can suggest that genomic testing should be performed on. It certainly is appropriate in those patients that end up being refractory to first line therapy or therapies, so those that have already been well-defined by standard guidelines—those that are refractory to those therapies—those patients are clear indications. Those patients that end up having known highly aggressive tumors and for which the choice of therapies are quite limited. Some examples of that: pancreatic cancer is one that certainly falls into mind as a strong candidate therein; those patients that end up having assessment of their tumors and for which there are no identified biomarkers that would help to guide therapy would be an excellent group that would be indicated for genomic testing; and then those that are rare cancers, for which there are not clearly defined therapies and, in the cases that therapies have been proposed, that they’ve been poorly successful—adrenocortical cancer is a great example of that one. Those four, right now, are the ones that we look at as the most likely candidates for genomic testing, but it’s fair to say that that’s going to be a moving target, and the reason for that is that as therapies become available and are shown to be dramatically better than what had been available as the previous therapies, the indications for genomic evaluation will change. If you look at lung cancer as an example, in 1980 the classic definition of lung cancer was adenocarcinoma, squamous carcinoma, and neuroendocrine carcinomas; that was how we categorized it. Shortly thereafter—certainly by 1990—we ended up having at least one molecularly based target—that being EGFR. Thereafter, that continued to increase, where today, over 50 percent of lung cancers end up having a molecular target for which there is a possible therapy. And in fact for some of the subgroups, targeted therapies are actually being recognized as the first line approach, so rather than going through the patient having the “standard” chemotherapies and then, when they become refractory to those, a molecularly based targeted therapy is recommended. In some of the subtypes of lung cancer, targeted therapies are first line. Therefore one could argue that at the very least genomic testing of a number of genes is going to be first line in lung cancer, and in the very near future it’s probable that even large panels will be first line for lung cancer, and as lung cancer goes, I believe the rest of the cancers are going to follow. Cancer and Personalized Prevention JB: That was a very, very remarkably succinct and insightful response. Thank you. I think everyone who heard that had an ah-ha. That was a great summary of a tremendous amount of information. Well, we’ve got one last thing that I said I’d come back to and I would feel remiss if we didn’t spend a moment having you give a comment to it and that’s the concept of early assessment and—I guess you would call it—personalized prevention. You know, one of the things I took away from The Emperor of All Maladies public television show with Dr. Mukherjee is the comments of many experts in the field—the cancer researchers who have been legendary in their contributions to the evolution of the understanding of cancer and its therapy, virtually unanimously came to the same point, and that is prevention trumps anything else. If you could really think of ways of quantifying prevention at the individual level, that would be the biggest breakthrough. They use smoking as an example—you know, look at the effects that anti-smoking had on reduction of lung cancer; I mean, it trumps all therapeutics in terms of its importance to public health and individual health as well. Where are we in the quantifying early assessment and biomarker area, leading into the development of a personalized chemoprevention program for cancer? ES: There are a couple of questions in there and the first one is the approach and then where are we at. There have been a number of things that have occurred of late and certainly this is an area that you are so knowledgeable in, Jeff. People talk about how much there should be a responsibility to oneself on their own actions and their own health support. There are societal implications and the like. The one that has become acutely mind-changing for me is the whole epigenetic concept. I’m going to get back to the focus of your question, but I think this introduction is relevant for the audience, and that is that if you think that your actions impact only on you, then it’s a little more difficult to be critical and say, “Well, they’ve made their choice and, you know, they’re not taking good care of themselves, they’re not decreasing their stress, they’re not eating well, they’re smoking, they don’t exercise, etc.” But when you realize that, in fact, your actions that address epigenetic changes are actually showing to be heritable—that your bad decision to smoke may impact on your grandchildren—it really changes your mindset on the rightness or wrongness of some of your activities. I want to at least introduce that concept to some of the thinking with regard to how we monitor our own activities and what we can do about it. I look at a genomic analysis in a manner that ends up being a framework of possibilities. In other words, it gives us a range, if you will, of the likelihood or the lack of likelihood of developing a particular disease or having a particular malady, etc., but it is not as if we are defined to have that occurrence, and we can certainly modify the likelihood of that occurrence by the actions that we take. A very simple example would be out of the disease realm, and that is if someone ends up having a genetic pattern such that they are a remarkable athlete—they end up having the ability to run fast, jump high, etc., maybe this person has the capacity to be a remarkable basketball player, as an example—but if they did not exercise the activities to optimize that opportunity that they are genetically given, it’s not likely they are going to make a basket. Certainly if they are not practicing, exercising, eating well, etc., they’re not likely to be in the NBA. Well, taking that to the extreme, someone that is predisposed, if they end up smoking, having exposure to noxious gases and a whole host of others that might predispose to lung cancer, they have maximized their likelihood of what would be their genetic likelihood of developing that disease. And we are increasingly showing that with a genomic analysis we can predict for the likelihood of a multiplicity of diseases, but then the importance of the wellness part of it is monitoring, in an ongoing manner, proteometric measures, metabolomic measures in some of the more in depth, monitoring how well we’re doing with regard to prevention of those particular predisposed disease entities. As you know, Jeff, Leroy Hood is a hero of mine and certainly, you know, I think you think the same way, not presupposing. He’s a remarkable individual and his proposed 100K study to look at where individuals fall within that range of an initial analysis, which would include genomic analysis and then doing ongoing monitoring of those patients to determine where they are at and the likelihood of developing those diseases, I believe is a critical way of the future and speaks to this whole concept of personalized wellness approaches to taking care of individuals and certainly bodes very well for the likely success of human beings being able to be empowered to impact on their own health and how that will impact on society going forward. JB: I’m almost breathless from the breadth and the depth of information that you have shared with us in this last 50 minutes. It’s been truly remarkable. It takes a person who thinks broad and digs deep to be able to concisely summarize and to articulate as clearly as you have the range of information that you’ve shared with us. I think this is one of those empowering moments. I’m convinced that everyone who listens to this—they’ll take away a little bit of a new resolve in their lives as it relates to what can be done and where they need to keep their eyes open and their minds clear because we are at the threshold of a great paradigm shift that you’ve guided us to. Dr. Staren, I want to thank you. I know your time is very precious, but we’ve appreciated every moment you’ve shared with us and we look forward to following your work and hopefully have a chance to check back in. I think what you’re doing now with individual medicine and the analytics that will support it is truly going to move the health of not only our country but the world forward very dramatically, so thank you. ES: Thank you, Jeff. It’s really been my privilege.  

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Bibliography

[1] Staren ED, Braun D, Tan B, Gupta D, Kim S, et al. Initial experience with genomic profiling of heavily pretreated breast cancers. Ann Surg Oncol. 2014 Oct;21(10):3216-22.   [2] Park, Alice. “The Cancer Gap.” Time. 19 Mar 2015.   [3] Gupta D, Braun DP, Staren ED, Markman M. Longitudinal health-related quality of life assessment: implications for prognosis in ovarian cancer. J Ovarian Res. 2013 Mar 8;6(1):17.   [4] Gupta D, Braun DP, Staren ED. Prognostic value of changes in quality of life scores in prostate cancer. BMC Urol. 2013 Jul 10;13:32.   [5] Braun DP, Gupta D, Birdsall TC, Sumner M, Staren ED. Effect of naturopathic and nutritional supplement treatment on tumor response, control, and recurrence in patients with prostate cancer treated with radiation therapy. J Altern Med Complement Med. 2013 Mar;19(3):198-203.

Welcome to Functional Medicine Update for July 2015. This is the third and the final of our three-part series on functional oncology and I think we’re very privileged to have Dr. Tom Brown as our clean-up hitter in this three-part series. I think you will find Dr. Brown’s insight, experience, and vision as to where this field is going to be extraordinarily important, both from a mindscape way and also from a clinical utility way. So with that, let’s move to our discussion with Dr. Brown.

INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Thomas Brown, MD, MBA Swedish Cancer Institute 1221 Madison Street, Suite 200 Seattle, WA 98104 www.swedish.org I’m very happy to say that not only do we have an extraordinary treat with our clinician/researcher this month, but also I’m a little bit parochial in that we have an expert who is actually local to our area—Seattle, Washington—who I believe, as of 2013 when he came to join the Swedish Cancer Institute as its new Executive Director, brought a tremendous expertise to the community and really poised this area to continue to be a development center of excellence in the area of cancer therapy. So let me say a little bit about who you’re going to be hearing from, Dr. Thomas Brown. Dr. Brown, when he chose to take this responsibility as the Swedish Cancer Institute new Executive Director, brought a tremendous background. He came from the University of Arizona, where he served as a professor of medicine and their Chief Operating Officer at the University of Arizona Cancer Center. Prior to that he was a professor and vice president at the University of Texas MD Anderson Cancer Center, and while on the faculty at Duke University, he led the development of a multidisciplinary gastrointestinal cancer program and a regional, community-based clinical trial consortium. He also holds a Master’s in business administration from Rice University, and was a graduate of the Medical College of Virginia. He completed his internal medicine residency at the University of Florida and his fellowship in medical oncology at Johns Hopkins in Baltimore. His clinical practice and research focus has been on therapeutic development in gastrointestinal malignancies. His professional and academic interests include healthcare policy and international healthcare delivery systems, and he served on numerous institutional and national/international committees and boards, and among numerous honors I think one that stands out is he was selected as a Jones Scholar while at Rice University and was selected also for inclusion in the Best Doctors in America since 1998. So that’s quite a portfolio and I probably just tipped the touch of the iceberg of the many things that Dr. Brown has accomplished in his years of service. We were very fortunate to have Tom as a presenter at our Thought Leaders Consortium in 2014 in collaboration with Lee Hood’s Institute for Systems Biology. Tom laid out to the audience, during his presentation, a really wonderful vision of where cancer therapy is going and what the status of cancer research and development is in the global community and also specific here to what’s going on in Seattle at Swedish. The Incidence of Cancer is Increasing Tom, it’s with great privilege that we want to thank you for giving your time to Functional Medicine Update and bringing your wisdom and insight to us. Recently in Lancet—I think this was the March 21st issue in 2015—there was an editorial that was titled “Cancer: The Elephant in the Room,” in which they really went back and reviewed what is the status of cancer incidence in the United States and the world at large, and where are we heading, and reviewed or reflected on the Bailar and Smith paper that appeared many years ago that said that we were losing the war on cancer, but now there is evidence to suggest that we’re making some progress. It’s still—according to this editorial—an elephant in a room that requires more and more understanding and appreciation and respect for what’s happening.[1] Can you kind of tell us what is going on in the field of cancer incidence and therapy in terms of its prevalence and concern today? TB: Well, Jeff, first of all good morning and it’s a pleasure to be speaking with you today. The overall perspective in terms of the challenge that cancer represents I think is best thought of in terms of the evolving demographic. That is, cancer is—in many ways—increasing in prevalence. The outlook for many cancers, though, is improving, even cancers with advance stage. Of course part of what has happened over the recent decades is that illnesses that have tended to be major public health issues (certainly in the realm of infectious diseases and more recently in the realm of cardiovascular diseases) have had an increasingly more positive outlook. Certainly in the case of infectious diseases there have been major strides over the decades and that has led to an aging demographic where cancer has, in many ways, become one of the major public health issues, if not the major public health issue, and this is playing out not only within the United States, but on a global level and obviously it’s an emerging issue in the developing world. So I would agree that cancer and the resources that are deployed to address the cancer challenge are, as you say, the elephant in the room in many respects. JB: Kind of fueling this discussion—maybe even bordering on debate—is a recent paper by Tomasetti and Volgelstein that has gotten quite a bit of press, I think both in the medical world and maybe even in the healthcare consumer world, and that was the publication recently that suggested that cancers really are all spontaneous and it’s just kind of the Monte Carlo bad luck of the draw—there’s really nothing that one can do in terms of modulating, to any great extent, the appearance of cancer; these just appear statistically randomly. That caused quite a bit of controversy in the literature. I’m sure you’re familiar with this paper and the argument.[2] Do you have a thought about that whole concept? TB: Well, I think that it’s clear, based on the available evidence, that there are both important biological factors as well as important environmental factors that lead to cancer risk and to cancer. I think you would agree that there is no debate in certain realms with regard to certain environmental factors, for example tobacco, tobacco products, the impacts of unhealthy diets (whether one is talking about a high fat diet or other examples). And of course conversely the positive impact that activities such as exercise can have on both cancer incidence and the outcome of cancer interventions once cancer is diagnosed. Those examples are but a few salient examples amongst many examples of how there are certainly events—whether environmental or biological—that impact cancer risk/cancer occurrence and the outcomes once one is diagnosed with cancer, so I think that would be a clear objective statement against the notion that this is simply a matter of random chance. JB: So when one is—as you are—in a position of managing a very complex, multi-headed organization in the Swedish Cancer Institute, how do you balance the obvious primary focus, which is therapeutic intervention needs, against this concept of prevention, which obviously is another part of the story that relates to these induced forms of cancer from various environment and lifestyle factors? Practicing Personalized Medicine in a Large Cancer Center TB: I think, Jeff, that really brings us into the notion of what many refer to as personalized medicine. Some others use terms such as targeted therapy or precision medicine, amongst other labels. We prefer the term personalized medicine because it has the dual connotation—the double entendre, if you will—of on the one hand caring for the whole patient and their family, their support group, and then on the other hand, addressing the individual biologic parameters that are at the core—the mechanism—of carcinogenesis, so that those two concepts are not contradictory in any way. They are integrated and they address not only the issues that relate to treating existing cancer, but—from our perspective—both the caring for the whole patient as well as attending to the biological phenotype or fingerprint of one’s cancer or the patient themselves. Those issues relate not only to the management of active cancer, but to the entire arc of experience that one might have with regard to cancer, to include early diagnosis, screening, prevention. So again, we consider those two concepts inexorably linked, as one might observe in the world around us. JB: Well on the side of good news—and there is, fortunately, I think, good news in this whole area that we’re talking about—I recently read this paper that appeared in the Lancet titled “40-Year Trends in the Index of Survival for All Cancers Combined and Survival Adjusted for Age and Sex for Each Cancer in England and Wales, 1971-2011: A Population-Based Study,” and one of the summary statements, which I think is very encouraging, and I quote: “These findings support substantial increases in both short-term and long-term net survival from all cancers combined.”[3] In this case, this was done in the British Isles in England and Wales. I believe that this data also translates over the United States as well. So that sounds very encouraging. Are we moving, with this improved survival, to cancer as another form of chronic disease? Are we seeing the transition? With Improved Survival Rates, Is Cancer Becoming a Chronic Disease? TB: I think as a practicing medical oncologist I have observed over the recent decades, as have my colleagues, that it is becoming more and more common to have people with active cancer that is incurable living for extended periods of time. Of course, the focus for those individuals is that they have as normal a quality of life as possible. So the number of people who are living under those circumstances as opposed to succumbing to the cancer in a short period of time is increasing. And yes, in many disease types the notion of advanced cancer as a chronic illness is a reality. A common example would be either a metastatic breast or a metastatic colon cancer, where it is not unusual for patients to live for many years even though their diseases are incurable. And it’s not unusual, increasingly, to see cancer patients who succumb to illnesses that are not related to the cancer and not related to the therapy for their cancer. Clearly that’s somewhat of a victory. I think that all of us would agree that the best way to cure cancer is to not develop it in the first place and therefore the emphasis on population health, on wellness, on prevention as well as screening and early detection, remains so important. We are making very considerable advances in both the management of potentially curable cancer once it is diagnosed as well as the long-term management of advanced cancer, but our collective desire would, of course, be to prevent cancer as much as possible. JB: I had the good fortune of being one of the people that sat for three nights in a row so six hours over those three days show of The Emperor of All Maladies, Dr. Siddhartha Mukherjee’s literation of his book in a TV special format. I found it an extraordinarily well done public information series. Of course I love the book, too. I was worried that I was going to be disillusioned when I saw the video portrayal, but I thought it was very, very well done. One of the things that struck me was this inflection point that is occurring right now in understanding cancer at the cellular and molecular level and at the immunological level and the development of this cancer atlas, which seems like it is a very big step forward in us getting our arms at least around the landscape of cancer. Could you tell us a little bit about that? TB: There’s no question that the revolution in cellular biology that began in the 1950s with Watson and Crick and then subsequently has evolved in what some consider a very slow manner but it’s been a very impressive manner to where we are today, which is understanding, in many instances and in the case of cancer, understanding the details of the molecular mechanisms that take one from a normal cell to a cell with uncontrolled growth. To understand the gene-related steps, whether it be mutations within the DNA sequence or abnormalities in the RNA expression or resultant abnormalities in protein expression, mostly in all cases ending in some perturbation of protein expression, these steps are being understood in the context of both carcinogenesis (what leads to the causation of cancer) and then likewise into possible interventions that might overcome those abnormal steps. And for many, this is still seen as the future. The reality is—to use the hackneyed expression—the future is now, in that we have real-life examples of where this type of information leads to practical steps in the management of our cancer patients. JB: Being one arm’s length away from really understanding what I’m seeing because I’m still on a learning curve, when I look at this cancer atlas, which has really started to catalogue specific genotypic mutations that are associated with specific kinds of cancer, the list looks very, very long, but it appears as if there are specific genotypes, certain mutational frequencies that are much more prevalent than others, which—then—probably is where a lot of the action must be going on as it relates to development of new therapeutic agents that would modulate those specific hotspots. Has this concept really started to pan out as we start seeing how this leads into personalized cancer care? Classifying Cancer by Organ Site is Becoming an Outdated Concept TB: Absolutely, and as you’ve heard me say before, Jeff, I think the best way to reflect on these changes is to look at how cancer in general has been classified or categorized over the many decades. So how have we generally approached our patients? We have generally approached them by the organ site of origin. We’ve organized patients, basically, on whether they have colon cancer or lung cancer or breast cancer. And I do feel that within the next 10 to 15 years we will be looking back at that lengthy period of time somewhat quizzically and thinking that it was interesting that we were treating patients based on that type of organ-of-origin classification as opposed to looking at the unique molecular phenotype or molecular fingerprint of one’s tumor and ultimately at the person themselves. Again, one might have a patient with so-called colon cancer who has a molecular phenotype or molecular fingerprint to their tumor that is very similar to someone who has clinical lung cancer, so that increasingly we’re being focused on the common mutations, the common changes in protein expression, the common epigenetic changes, the common immune-related dysregulation that might characterize a certain tumor or set of tumors as opposed to the organ site of origin, and that’s the true revolution in the way that we think about cancer. JB: Yes, I think that you explained that very, very clearly and it seems that that is a huge paradigm shift, a huge move forward in, as you said, personalization, precision, however you want to term that. I saw a paper just recently in the Journal of the American Medical Association that was titled “Association of Type and Location of BRCA-1 and BRCA-2 Mutations with Risk of Breast and Ovarian Cancer.”[4] For me this was a very interesting article because I’d actually never thought about the diversity of different mutations that can occur within the genes that regulate BRCA-1 and BRCA-2 expression, and that they may have different penetrants into disease and they may have different therapeutics for their management depending on where those mutations occur within BRCA-1 and 2. This is just an example of a more general theme. Am I heading in the right direction in the way I’m interpreting this article? Germ Line Mutations versus Somatic Changes: An Important Distinction TB: Right, well, part of what you’re touching on, though, is a very important subject for clinicians to reflect on, and that is we have gene alterations, mutations, and other molecularly based changes that occur in germ line tissue that is, by definition, inherited at some level, and then we have the similar changes that can occur in somatic tissue or non-germ cell tissue, and, for example, tend to happen in tissues that then become cancerous, effectively being associated with the patient’s tumor, which is more often than not a set of somatic changes, non-germ-cell changes, as opposed to germ line changes. I think that what we will increasingly see is some convergence of those two variants. And another way of expressing that is those who are familiar with the role of genetic counselors know that genetic counselors, almost by definition, spend the majority of their time addressing issues for patients and their families related to germ line molecular perturbations, for lack of a better euphemism. Increasingly, though, I believe—certainly this is gradually becoming the case at the Swedish Cancer Institute—the genetic counselors will also become involved in working in a multi-disciplinary team fashion with patients and their families along with the provider team in addressing non-germ-line molecular perturbations. So that, again, it’s important to recognize the current division between germ line molecular-based events and somatic non-germ-line molecular-based events. JB: So when we take a lot of these discoveries and advancements in understanding about the molecular and cellular etiology of cancer and we translate it over into how does this drive new potential therapeutics, it appears as if we come back—in part, at least—to the immune system, saying, “Well, if there are ways that we could alert, activate, or mobilize the immune system to recognize the friends from the foes more effectively, and we could activate the cataloguing of immune cells for immunotherapy in such a way as we can induce their activity against the right cells that we might have a whole new breakthrough in cancer therapy. What’s the status right now as we see this advancing frontier of consideration? Immunotherapy is One of Many Active Therapies in Current Cancer Treatment TB: Well, there’s no question, Jeff, just as there has been a renaissance in what’s viewed as targeted therapy or molecularly target-based approaches, there has been a long-awaited, foreseeing of immunotherapeutic approaches. That’s no accident. Much of the understanding of molecular biology has, as its endpoint, the understanding of proteomic changes that are tied to changes in DNA and RNA, thus it’s not surprising that that clarity in terms of mechanistic changes that lead to cancer has also informed immunotherapeutic approaches. It is also true that as we find more effective systemic therapies that are not immune-based that allow for lowering of the tumor volume, that in theory at least, immunotherapy becomes an even more attractive approach to addressing low residual volume disease, something that we all recognize occurs naturally when one’s immune system can often manage low volumes of malignant cells. So, again, I think that the evolution in our understanding of the human genome and the related RNA protein and epigenetic changes has informed immunotherapeutics to some degree, but also the proliferation is not an exaggeration. The proliferation of active therapies in advanced cancer have opened the door, so to speak, to the role of immunotherapy in terms of addressing lower volume disease. JB: So it sounds like the toolkit is expanding for the field of oncology, and we didn’t really even talk yet about advances being made in surgical oncology, which are tremendous advances there for debulking tumors and getting rid of cancer at the organ, tissue-specific level. So if we go back to this inflection point that you and I were discussing earlier, which is starting to look at the unique genetic personality of tumors versus just their histological definition of their site of origin and their grading in terms of staging, how is the insurance industry, Medicare, the government viewing next-gen sequencing and actually getting this information that starts our information moving forward in this direction? TB: Well, of course, it is a rapidly evolving field in terms of the science, and in fairness to everyone I think first of all something we haven’t talked about is the acculturation that is necessary amongst providers, amongst physicians. This is a very different way of thinking about illness and of thinking about therapeutic opportunities for patients, so it’s not surprising that the traditional reimbursement system has likewise had challenges in figuring out how to reimburse. Initially reimbursement has been—and to some degree is still being done—on the basis of individual mutations that might have a code and a charge attached. As we enter into organized panels, there are actually codes that have been produced for certain panels, really based on panel size. But in general the federal system, CMS, does not yet have charges attached to those codes. I do believe that probably within the next 6 to 12 months this will be evolving. On the one hand, third party payers are somewhat concerned about the proliferation of this type of testing. I think, though, that as the field unfolds that we’re finding it is an opportunity to, again, focus—target—the way we approach patients, both in their evaluation and in the use of specific therapies. I believe that in the relative short run we’ll find that the molecular phenotyping of tumors and of the patient themselves will lead to greater value in healthcare. Now that’s arguably a hypothesis at this point, but I’m very optimistic about this revolution in the molecular understanding of carcinogenesis as leading to a more value-oriented approach to cancer care. JB: You said something there that I had never thought about that I think is quite fascinating as it relates to these panels that associate themselves across a number of different genes, and that leads one to start thinking about moving away from the one-disease-one-drug mentality into a systems biology thought about cancer, because now we have multiple drugs often being used for the management of cancer like we do with HIV or with Hep C. It’s not like a one-hit treatment because of the complexity of these conditions, so we’re moving from what may be the foundation of the ICD-9 codes and considering independent diseases that all had singular etiologies and have one drug to treat them to a new model that’s really a systems-based model that’s going to require not only a lot of revolutionary thinking, but also procedural organization delivery in terms of how this gets translated into patient management and reimbursement. Am I far away from what’s happening or is that part of the story? Incorporating Data from Genomic Arrays into Clinical Workflow is a Challenge TB: No, Jeff, you’re right on the mark. For example, we’re using a highly actionable, meaning that the gene alterations that we’re looking at (the mutations) have practical steps in terms of commercially available therapies or therapies that can be used off-label for the set of gene alterations that we’re looking at in our panel at the Swedish Cancer Institute. We’re currently using a panel of 68 gene alterations. We’re about to go to a panel of more than 160 gene alterations. There are other commercially available panels that are at least twice that size. The point is that ultimately—and again, in the not-too-distant future—we’re likely to be using, routinely, whole exome sequencing, where one is looking at the broad array of active regions in the human genome, and in addition looking at the downstream expression that results from those changes in DNA, so looking at RNA expression or RNA sequence changes, and in turn looking at the further downstream protein changes that include epigenetic changes, and we haven’t gotten into other areas, like biome changes that can occur in areas like the intestinal tract, etc. So there is gradually, then, a proliferation of data that needs to be put into context, and obviously in some ways it’s the task of finding the needle in the proverbial haystack and there’s only one way to do that in an organized and disciplined manner, and that is with sophisticated IT informatics platforms. Over time, these platforms need to be integrated into the standard work flow, and what I mean by that is into the standard electronic medical record. That is the challenge, because as our audience knows, providers are increasingly tasked with a range of responsibilities that include activities tied to direct medical care, but also activities that are more distant, tied to things like reimbursement or other regulatory issues. And it’s imperative, as the data analysis becomes more challenging, to have this incorporated into the EMR through decision-based tools—that is, tools that enable decision-based medical practice, incorporated into the normal workflow. There are examples of these tools emerging. Clearly, on the one hand, one has to organize the complex medicine that is coming from the patient who is sitting in front of you. One the other hand, you have to put that individualized information in the context of the medical literature’s whole and the context of the experience of other similar patients. Again, there are tools that are emerging to facilitate that process. JB: That was a beautiful summary explanation for a very complex area, which I’m sure we could have spent hours talking about and we still wouldn’t have had a complete answer but that was a wonderfully succinct summary. I’d like to ask one last closing question which I believe is probably on the minds of a lot clinicians as it relates to patient management in the oncology area. This really comes out of a recent Time magazine article in April 2015.[5] The cover issue was about the juxtaposition of two women of about the same age who had the same diagnosis of cancer—a glioblastoma. One was in a more rural area of the country (I think it was North Dakota, actually) and was being seen at the regional medical center there in North Dakota, and the other woman with glioblastoma was in a more metropolitan area that had access to a large cancer research teaching and therapy center. The question that was raised in the article—I mean, there were several questions, but one that I think that was the dominant question—was is there an advantage if you are close to a major metropolitan center where you have access to not only genomic profiling but also, then, experimental drugs and drug trials that are ongoing that might have new therapeutics that are related to your specific mutational type of issue—does that give competitive advantage to individuals that are in centers where that type of research is going on, or is it just asking questions for which you have no answer that produces anxiety and so it’s better not to ask the question as it relates to genomic profiling? That was kind of the theme of the article. Do you have an opinion as to how we’re managing this issue? Key Challenge to Modern Healthcare: Access TB: Well, Jeff, you’re touching on a subject that for me, personally, is one of the key challenges of modern healthcare, whether one is talking about within the United States or globally, and that is access. And the point I would like to make—you were framing this rhetorically in the context of geographic distance—I would argue that yes, geographic distance can impact access so that the short answer to your question is yes, there is some advantage to being close to an urban location where you are more likely to have tertiary quaternary centers that offer these higher level technologies. On the other hand, as you and I know there are socioeconomic barriers that may have nothing to do with geography. You might be living within an urban center but still not have access to a certain level of expertise or the nurturing supportive care that is required because of issues that relate to lack of insurance, or lack of other resources (transportation, etc.). So that these wonderful technologies can be available to us, but they might as well be nonexistent if there isn’t the attendant access for the individual patients. So I think this is very important as we roll out new advances in healthcare and in the case of cancer care to be sure that we’re working on a population-based approach that addresses both metropolitan areas as well as rural areas, and obviously—again—this is another very complex subject that has rather complicated solutions. One of the things that we are striving for in our personalized medicine program is to provide at least universal access within our patient population, so that there aren’t defined financial barriers to accessing this technology. It’s being done in the context of an IRB-approved protocol. We’re attempting to translate the consent forms in the common non-English-based languages that are found in our immediate population. So again, I think that access, which can come in many forms, not just geographic distance but can come in the form of socioeconomic barriers, is a key issue. JB: Thank you. That was a very, very important and moving discussion for us all to consider. Thank you very much. I guess I do have one other quick last question and that has to do with your view as to whether you feel this technology that we’re seeing emerge to quantitate things that were previously only qualitatively understandable, as we get deeper drilling into genomic aspects, whether this technology can find a potential application as we move forward in its understanding and in the informatics area and its analysis into the quantitation of prevention as to really precisely designing personalized prevention programs as well as personalized treatment programs. Do you see this as something down the road in our future? TB: Well, Jeff, as you know from my earlier comments and also from earlier discussions that you and I have made, I feel very strongly about this point. There are many who think of molecular phenotyping of tumors and of patients as being primarily directed at selecting a particular therapeutic intervention, usually a drug—an agent—whether it be an immunotherapeutic agent or a more traditional molecularly targeted agent. But the truth is there is ample evidence now that this molecular phenotyping can be just as importantly applied to the areas of cancer control, so we’re talking again about early diagnosis, prevention, and screening. And effectively assessing risk, whether inherited risk in the context of germ line changes or acquired risk in the context of non-germ line mutations that occur that might lead to either a defined risk of cancer or clearly to the emergence of cancer through a pre-malignant condition. So yes, I feel that this type of molecular fingerprinting, as the lay expression is often applied, will apply to the entire arc of cancer experience to include simply assessing population risk, and this is where the value proposition is for this approach, and there’s an interesting contradiction in this in that on the one hand we’re increasingly talking about population health (wellness on a population basis), but the way this is being applied is by recognizing the individuality that expresses itself through unique biologic changes in an individual and in an individual’s tumor, and through that individualized understanding, be more effective in the way we apply resources to the entire population. JB: Well, Dr. Thomas Brown, I can’t thank you enough and I think the Swedish Cancer Institute and Seattle and the local environment is very fortunate to have you as the executive director of the institute. Your vision and this broad landscape that we’ve had the privilege of discussing with you demonstrate both breadth and depth. It’s been a really exciting conversation for me and I’m sure all of our listeners are taking away a lot of news-to-use. Thank you so much for your vigilance and your leadership and we look forward to following what’s going on with you and the institute and thank you for the time you spend with us today. TB: Well, Jeff, thank you and thank you for what you do. Thank you very much. It’s been a pleasure. JB: I appreciate it  

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Welcome to August 2015 Functional Medicine Update and the first of an extraordinary mini-series on the functional microbiome. I think this is a revolutionary concept that you are all familiar with, but over the course of the next few issues of Functional Medicine Update you’re going to learn a lot more news-to-use as it relates to that. So let’s move into our discussion with our clinician and researcher of the month.  

INTERVIEW TRANSCRIPT

Clinician/Research of the Month Gerard Mullin, MD, MS Co-director, JHH Nurse Practitioner Fellowship Program Associate Professor of Medicine Johns Hopkins Hospital 600 N. Wolfe Street Baltimore, MD 21287 August 2015 Well here we are at that extraordinary time in each of our issues of Functional Medicine Update, with a clinician/researcher that we think is really doing an extraordinary job and cutting edge in moving the whole field of healthcare forward. We’re not disappointed, obviously, this month at all because our lead off speaker in this little mini-course that we’re doing on the functional gut microbiome is a very long-standing colleague, friend, and associate of mine who has done tremendous work in our field over the last 30-plus years. Yes, our history actually does go back that far. Dr. Gerard Mullin, who is a medical doctor, did his medical degree at Rutgers New Jersey Medical School, residency at Mount Sinai, fellowships at Johns Hopkins and University of Arizona in the Andy Weil Integrative Medical Program. He is certified by the American Board of Internal Medicine and is on faculty as the co-director of the Nurse Practitioner Fellowship Program at Johns Hopkins University and is an Associate Professor of Medicine there. And more than all of those things, Dr. Mullin is an incredible seeker. He has been a pioneer. Our relationship, as I mentioned, goes back to the 1970s when we first met and he was one of the early-on people that I invited to participate in our early formative years at the Institute for Functional Medicine. Gerry, it’s wonderful to have you as our lead-off speaker in this mini-course that we’re going to be doing and I can’t think of anyone more appropriate to tip it off, so thanks for being with us. GM: It’s my pleasure. Thank you for inviting me, Jeff. JB: This is also, I think, an auspicious time for you personally because you have a new book out, which I have had the privilege of reviewing briefly, which is called The Gut Balance Revolution. I think that just the title alone illustrates how far we have come in the last 35 years in a general understanding of the importance that the gastrointestinal system plays in overall systemic health. I mean, if you would have had that title of a book 35 years ago it probably would have sold one copy to you, the author, so this is really coming a long way in the general understanding of the role that the gut plays in overall health. I’d like, if you could, for our listeners, just to give a thumbnail biography as to what led you into this path, down this trail less traveled, and now you are really one of the leaders in functional gastroenterology. Honor the Gut: An Ancient Concept Gains Acceptance in Western Medicine GM: All very good questions, Jeff. I think from a personal vantage point, I was a heavy kid, believe it or not, and I had a mother who suffered from irritable bowel. She found her way through holistic nutrition, which eventually led you and I to hook up many, many years ago. She owned her own health food store, and I remember she listened to Paul Frederick, she would go to different conferences, and then I would take her along. In fact, I think she might have been at one of yours early on when you were in the New York City area. But in any event, I was a heavy kid and I found my way through by really what turned out to be this program, more of a microbiome-shifting endeavor. And it really wasn’t so much about I was having bad foods, it was about the fact that they were not feeding my microbiome. So from a personal journey point of view, from more of a science point of view, as you know, for many years, the Ayurvedic systems and the traditional Chinese medicine systems, they honor the gut in terms of knowing that that’s the center and core of our physiology, and naturopathic/functional medicine practitioners also follow the same rubric, and now is the time for the gut, in the last five or so years, because of the genome project leading to technology of the human microbiome project. We now have the tools to explore what the microbiota are doing for our physiology, and clearly understand that there are different axes in the body, such as the gut-brain axis, which show reciprocity, and we know now that the gut has so much controlling influence over the body. This book really describes this influence on metabolism and the ability to have sustainable weight loss just by fixing the gut. Connecting Pancreatic Insufficiency to Gastrointestinal Disease JB: So I want to—with that intro—go back to, believe it or not, 1979 with you, here, for a moment. I think that this will be a little walk down memory lane, but I believe this is an important part of the history of this evolution that a lot of our listeners probably are unfamiliar with and I know that, for you and I, we shared this a-ha-ism way back then. I’m going back to an article in the New England Journal of Medicine that was actually in 1977 on exocrine pancreatic insufficiency and it was written by Regan and DiMagno at Mayo, who were gastroenterologists, on the difference between pancreatic exocrine acute pathology and insufficiency and they were discussing the use of exocrine pancreatic replacement aids in this paper for improving protein digestion.[1] This was kind of novel because I think in gastroenterology up to that point people thought about just complete lack of pancreatic enzymes as being the trigger for oral replacement with porcine or bovine pancreatic enzyme replacement, but this really talked about the state of chronic insufficiency seen as maybe a partial steatorrhea or undigested protein in the stool. So it started staking the difference between acute and chronic and functional differences. Do you recall that paper at all? I remember we discussed it way back when, but it kind of opened up the window for the difference between pathology and chronic insufficiency. GM: It’s a very good point. The particulars of the paper I do not recall. You know, we have our GI modules at IFM, and now we have stool elastase as a marker for insufficiency, but it goes to the point that we look at things more functionally. We’re now able to have a functional marker that people years ago did not honor, and now we understand that there are many patients, and studies actually show in about 5 to 7 percent of people with irritable bowel have functional pancreatic insufficiency that may be a contributor, right?[2] So if you have pancreatic insufficiency, you need those pancreatic enzymes not to only prevent maldigestion, but also to help clear the upper GI tract of bacteria. So we know that there is a strong link of SIBO (small bowel overgrowth) to IBS, and also it appears that pancreatic insufficiency, although subtle or subclinical, you need a functional marker to detect it; it may be part of that pathogenesis. So that’s where, you know, a paper like that…you reflect back that people in 1977 were having that kind of thinking is really incredible. Identification of Exorphins was a Key Event in the History of Gastroenerology JB: So let’s take that a step farther—this is really fun for me, by the way—and that is let’s go to another what I consider landmark paper that probably a lot of the individuals who come into the field now would not be aware of, and this was in the Journal of Biological Chemistry and it was titled “Opioid Peptides Derived from Food Proteins.”[3] This was the first time that the term “exorphins” was used—this was actually defined in this paper. The principal author was a woman who was at the Laboratory of General and Comparative Biochemistry at the National Institutes of Mental Health, Christine Zioudrou, who went on to publish 20-some other papers over the course of the last few decades. This was actually in 1979, volume 254 of the Journal of Biological Chemistry, and in this particular paper what she demonstrated was that peptides with opioid activity were found in pepsin hydrolysates of wheat gluten and alpha-casein. This, to me, is a fairly remarkable first-level discussion. That really started this whole field that we’ve seen advance over the last 30 years, and I think that this paper was the seminal paper that really started this whole thing going because it was the first use of the term “exorphins.” These are proteins that have biological activity that are derived from partially digested food that mimic endorphins, and so they produce this state of hyperendorphemia. Do you recall that step in history and how it has evolved over the last 30 years? GM: It’s amazing the way we now link different food clinical reactions to physiological outcomes. That’s a very nice example. Even looking at the endorphins, but looking at this whole gluten issue that you just brought up and the fact that this was something that, for the person who thought that they had a gluten issue was categorized as being schizophrenic for raising the issue, but now the evidence is becoming so clear that even the experts in my field acknowledge that there is something out there with gluten, although they fail to acknowledge what the possible connectors are, as you just raised. What I find to be interesting, such as in the Gluten Summit, is that you’re taking a lot of different people who are doing really interesting work together and linkages, because of the fact that we know that our gluten has changed—it has shifted in so many ways in terms of our wheat being so gluten rich, the fact that we’re using GMOs and you’re heading Round-Up and herbicide residues that can damage the gut, and so on and so forth. We’re seeing an explosion in gluten-sensitivity in people, and also the fact that celiac disease is clearly on the rise as well and people cannot offer a good explanation. Part of that, I think, takes us back to the gut microbiome because people clearly, in the last 20 to 30 years, their biome is clearly shifting. Those are my thoughts on that. JB: So the next step in this sequence of events is Zioudrou and her colleagues came back in 1983 with a follow-on paper. Again, she was still at the National Institutes of Mental Health. This one was published in Biochemistry.[4] What they did is they actually chemically isolated these peptides that were involved in the partial digestion of wheat and milk protein and they chemically sequenced them. They found out that they were fairly small peptides that had structures that you could easily manufacture in the lab by synthesis. One of those structures was arginine-tyrosine-leucine-glycine-tyrosine-leucine and glutamic acid. And when you synthesize that particular small peptide that was a remnant of the partial hydrolysis or partial digestion of the food protein, and then you tested that in brain slice assays for endorphin activity, it had very, very high endorphin activity, demonstrating the kind of proof of concept that these bioactive, partial hydrolysate peptides could in fact have mimetic activities to endorphins. The question that remained, however, up to that point, was how do these fairly large molecules—these proteoids that are composed of something like 9 or 10 amino acids—how could they get across the GI barrier or the blood-barrier because it was felt that these are semipermeable membranes and they don’t allow peptides, they just allow amino acids to come across? And then it was about that same period of time that a variety of gastroenterologists started publishing papers on M cell vesicle formation of micropinocytosis in the uptake of proteoid structures across membranes. You can actually find that maybe five percent of dietary protein was being absorbed not as intact amino acids, but as these proteoids that may have residual biological activity. So we started to really witness, in your field, a plausible mechanism by which certain remnant, partially digested protein fragments could actually have biological activity all unto themselves and influence immune system, nervous system, and other functional capabilities of the body. Now this seems to me—this is the early 80s—to be a revolutionary period in changing the whole perception of gastroenterology. Do you recall how that all developed in your field? Immune Reactivity to Incompletely Digested Proteins GM: One of the docs here, Mark Donowitz, who was an AGA president or president of the American Gastroenterology Association, I think he did early work along these lines (him and his group when they were up in Boston). I think it’s very important work because we were taught in medical school wrongly that ultimately all proteins that are digested no matter what, even without stomach acid and so on and so forth. I think it’s an important concept to keep in play, is that these incompletely digested proteins are presented to our immune system is because we look for plausible mechanisms for immune reactivity to these various foods that you’ve been walking down memory lane and alluding to. These mechanisms actually explain some of these phenomena that we’re discussing. JB: So that leads us to the next step in my chronology as we’re walking down this trail, and that is the gut has been found—about middle 80s—to not be as impermeable as we thought—that there can be changes in these tight junctions that we later labeled early on as leaky gut. Everyone was calling us crazy back then—that this was a very bad term, there’s no such thing as leaky gut. It’s interesting now that term is being used in all sorts of publications in gastroenterology and other fields. Tell us a little bit about how that concept of gut mucosal permeability evolved as part of the field. GM: That’s very hard to pinpoint because it just—like the microbiome—became an explosion, I’d say in the last five years as well. And it may be in part related to the microbiome, knowing the microbiome does cause loosening of the tight junctions. But when you look at transport and you look at barrier integrity, somehow you’re looking very much in the same models. I think the same group of scientists, including Mark Donowitz, looked at this, and I think what they were finding is that even though there is variability in the junctions, I think once they start to link inflammation to loosening of the tight junctions, then next step—because there is such profound loosening of the tight junctions in the setting of, let’s say, ulcerative colitis or Crohn’s disease and so on and so forth, is to begin looking at subclinical physiology and find that you can have loosening of the barrier and endotoxemia even without overt disease. So I think that in the last five years in particular this became so reproducible that the scientists adopted the term leaky gut, which is more of a functional medicine term. JB: Yes, I think that is really a beautiful insight, and I know that in your book, Gut Balance Revolution, you really have done a nice job of kind of making this user friendly (these concepts) to the reader. These are pretty profound basic and medical science discoveries that were made, and as they’ve gotten translated now into the clinic, they’ve actually become user friendly in the way you’re describing them in the book, so I want to really compliment you because I believe that sometimes these important concepts can be lost because they don’t get properly communicated. I think you’re doing a very good job of getting these concepts across so they can be seen as clinically valuable. So once we’ve opened a portal of entry to these molecules, which may have residual biological activity, and they are now exposed to the other side of the GI, what’s sitting over there is this extraordinary diverse gut-associated or mucosal-associated lymphoid tissue, which is where more than 50 percent of the immune system is clustered. Why is it that the field of gastroenterology was seemingly so slow to really pick up on the fact that they were the seat of immunity and not just a piece of plumbing? GM: I really don’t know because I guess many are of the mindset that—like a plumber mindset—you just go in and you see something broken and you go in and fix it with a medication, and I guess the rest seemed irrelevant to some extent. Thankfully now, with all the science, and even at the meeting they had last month in Washington (Digestive Disease Week), the amount of science on the microbiome was profound and even permeability, so I think docs are starting to get it, but I think—again—because they kind of ride the wave and the wave now is microbiome permeability, but this is something we’ve been talking about for decades in functional medicine, right? JB: Yes, about 30! It’s amazing. GM: I’m just saying…And then in naturopathic medicine, the rubric, we talk about Ayurvedic, Chinese medicine, everything goes back to the core of gut physiology and what’s in the gut: you’ve got microbiome and immune, and a lot of nerves, and enteric nervous system, and hormones, and so on and so forth. It’s all there. Michael Gershon actually was kind of…well, you’re probably going to get to that so I’ll stop there. Neurogastroenterology: Connecting Both the Nervous System and the Immune System to the Gut JB: Well I think that’s great because the next step was really to talk about the second brain, because we have this extraordinary density of nerves as well as extraordinary activity of the immune system all intersecting at the gut level and so Gershon’s book The Second Brain was really a landmark.[5] Take us down that chapter of the story. GM: I think that, if there is a turning point…I mean I would say now, of course, the microbiome, permeability, are big turning points, but that was probably THE turning point, because that book really was the birth of neurogastroenterology. A group of docs started to come together recognizing that there is a very strong enteric connection to the central nervous system, and the book The Second Brain really was mainly about neurotransmitters and the bidirectional communication of the second brain (the gut) with the first brain and vice versa, but I think his work was truly a turning point. And now you have a whole group of docs out there who do neurogastroenterology. We have—at Hopkins—one of the largest groups in the country, led by Jay Pasricha. They have what they call a food-mind-body center. In other words, you look at the brain (they have a psychiatrist), they have nutritionists to look at food, and they have GI docs. I think that model that they have at this point is the future in dealing with irritable bowel and functional bowel diseases, and Michael Gershon’s work really gave birth to that thought process in his book The Second Brain. Metabolic Endotoxemia: The Common Pathway to Many Health Issues JB: That’s beautifully stated. That’s very exciting about what’s going on at Hopkins. This breakdown of gut mucosal integrity, the interrelationship with all these gut hormones, not just serotonin but all the other myriad of hormones that are produced at different regions along the GI tract and so you get regional specificity in terms of messaging to the brain and the brain back to the gut. So we can really see what we were discussing in functional medicine, as you indicated, more than two decades ago really starting to get traction now as a major theme in medicine. So that takes me a little bit on to the next step, which you have already alluded to it: post-prandial metabolic endotoxemia. When I was in school—and I hate to say now that it was in the 60s—the concept of endotoxemia was really related to sepsis and acute septic shock and really life-threatening conditions. But now we’re talking about this functional chronic disorder of post-prandial metabolic endotoxemia, which went from being a sidebar conversation to where there are now papers being published on that topic in human studies. Tell us a little bit about that topic. GM: You know, it’s very interesting, let me put it in perspective. We know that metabolic endotoxemia is the final common pathway to a lot of problems. There are docs even today, believe it or not, despite the evidence, who will say, “Leaky gut, who cares? It’s not going to change what you do.” Well, in the book we’re talking about today, The Gut Balance Revolution, we talk about weight loss, and weight gain, and diabetes. Metabolic endotoxemia is the final common pathway to that, as well as fatty liver, which is seen in about a third of our US population these days, Jeff. I think what we’re looking at is a situation where you have a dysbiotic gut microbiome, which is so prevalent today due to junk food and antibiotics, etc., a breakdown in gut integrity, for a number of reasons medications, the gut microbiome, the result is metabolic endotoxemia, and that in itself turns on inflammation which is turning on a lot of diseases. We’ve got a hundred million people in America with a chronic disease with inflammation as a root cause, and one of the root causes is metabolic endotoxemia. So it’s really profound, and the way you bring it up so elegantly makes me pause and think about one experiment that I can at least mention is that they take these mice and they infuse alcohol. You know, alcohol will not only break down the gut barrier but it will produce metabolic endotoxemia as one of the causes for liver disease. People think that, yes, alcohol damages the liver, but it also damages the liver if you have metabolic endotoxemia. Give those rats probiotics, then give them the alcohol, and it prevents the damage. So not to say go out there and take probiotics and drink it up, but it really shows you the importance of the gut integrity and the metabolic endotoxemia to disease.[6] JB: That’s a beautiful example. Thank you. As you’re saying that I’m reminded again of a paper in the Lancet magazine in which the report was on relapse rates in acute Crohn’s patients. These are people that had been hospitalized from acute Crohn’s episodes. They did lactulose mannitol testing to look at gut permeability in these patients before and after discharge, and they found that those individuals who were discharged with low gut permeability (in other words, normal mucosal integrity) had less relapse rate within the first year. Those that were discharged with a high mucosal permeability, meaning leaky gut, had more probability of relapse in the first year.[7] So we ask the question: how many docs measure gut permeability before they send their patients, post-Crohn’s episode, out into the world? And I would say probably a very small number of individuals, which means you’re almost loading the dice in favor of getting relapse of continued crises episodes because you’re not asking the right questions. If you ask the right questions, then you might be able to do something—as you indicated—by specific types of therapies. GM: Right. JB: So let’s talk a little bit about this microbiome and its connection, as you indicated, to this array of chronic conditions. It relates to obesity, and NASH (non-alcoholic steatohepatitis, and it relates to type 2 diabetes, and it relates to myocellular lipotoxicity and muscle-related problems that are associated with metabolic sarcopenia. Tell us a little bit about this microbiome, because this—to me—looks like where a lot of the action is emerging to happen. The Gut Microbiome is the Core of Our Being GM: The audience is becoming so familiar because of the reports out in the lay and the medical press that we have a hundred trillion organisms in our gut that outnumber us in logarithmic numbers, both in cells and DNA, and really diversity of the ecosystem inside of us really determines and impacts upon our physiology and our health outcomes. The more biodiversity we have of them, the more we improve metabolomics and the better physiological outcomes we see. Back when you were in school and I was in school, I felt that the amount of knowledge and the amount and the importance of the gut microbiome was so minimal it was almost treated like the appendix, being vestigial. And now we’re finding out it’s really the core of our being and we certainly understand now that if you treat your gut microbiome well, they will treat you well and the reverse is also true. Through diet, if you treat them badly by a highly refined, processed western diet they will turn rancid quickly and you will suffer, unfortunately, the consequences. JB: One of the things that I’ve read recently and it would be very helpful if you could give us probably the real story, but what I’ve read is that these two major phyla, the firmicutes and the bacteroidetes, the balance between them appears to be very important. Those individuals that had the higher percentage firmicutes, which is generally associated with a higher meat-based diet versus those that were more vegetarian-based diet that had more of the bacteriodetes, those individuals were more subject to some of these metabolic disturbances associated with gut microbiome connections to metabolomics. I find it interesting because the bacteroidetes are more, really, the Gram negative bacteria, which we know are the ones that have cell walls that have lipopolysaccharides that are associated with inflammatory conditions (this endotoxemia). So it almost appeared a little bit, to me, paradoxical that the firmicutes, which are not as Gram negative (they are more Gram positive) actually have the greater concern if they get predominant. Is there still some sense that measuring these two large phyla—the firmicutes and the bacteroidetes—are important or is that less seen so now? GM: I think in animals it was important that they actually found that relationship between the bacteroidetes and firmicutes. I think between both phyla they compose 90 percent of our microbiome, so by and large you are going to see hundreds of bacteria fall under both phyla, and even—to your point about being paradoxical—even lactobacilli fall under the firmicutes, and in certain studies there is more lactobacilli in obese people, which is mindboggling, but there are a lot of different lactobacilli out there. I think in humans, maybe in those who start out with the large firmicutes-to-bacteroidetes ratio and something is not working quite right in your program for them—their diet and so on and so forth—and you want to shift the curve and you want a way of measuring it just like you want to measure permeability in the Crohn’s, right, maybe there’s a role for that, but I found that early when companies were measuring it, I find that if treated the SIBO or small bowel overgrowth and I fixed their dysbiosis patients got better. I didn’t need the added expense or the added dataset, and I think now biodiversity, which some people are now adding to their tests, I think that’s important as well, more so than looking at those ratios that we used to look at two or three years ago. How Long Does It Take to Change the Microbiome through Diet? JB: That’s a really helpful clinical insight. It’s interesting for me personally. I was just involved with a project where I was measuring a whole bunch of things as part of this Pioneer 100 project on myself each quarter. One of those is was I was doing stool microbiome analysis every quarter. I could actually see, through changes in my diet and lifestyle, very interesting changes both in the ratio of the firmicutes to the bacteroidetes, and also the diversity of my microbiome as I kind of tuned up my diet. So the question is, how long does it take, do you think, for a patient or a person, once they intervene with cleaning up a diet, to actually start changing their microbiome? GM: You know, it’s a very good question. There’s a study by Gary Wu which answers the question in a negative sense, in that in 24 hours you can adversely shift your microbiome on a western diet.[8] You can lower the biodiversity, and as you pointed out before, you can really increase the firmicutes phyla. Now, in a positive way, that’s going to take time. That’s going to take a matter of days if not weeks. But you want it to be sustainable, right? And that’s what my program really is all about is making it so it sticks. JB: So as I read your Gut Balance Revolution, once of the beauties, I believe, is that it nicely describes the application of what we thought of now 25 years ago, which was we called the gastrointestinal restoration program—we just gave it an acronym, the 4R Program, which was Remove, Replace, Reinoculate, and Repair. And I think you’ve done a really superb job of taking that esoteric concept and really weaving it into a clinically manageable implementation program. Tell us a little bit about how you came up with and how it is applied. GM: It really goes back to what you all taught us, Jeff, many years ago. I mean, back at the foundations of functional medicine. You had started with the 4R Program, and once we got the GI Module together we added the fifth R—the Rebalance. There’s a logical order and sequence to approach the gut health. First you want to remove the triggers, right? You want to remove the allergens, you want to remove the bad foods. In the first phase of the book, talking about the removal and getting rid of the bad actors. And also what I try to promote is more of a jumpstart or a rebooting of the system, just like you want to reboot your computer. I really get people on a low net carb, meaning that these highly refined processed foods—the glutens, the dairies, which are high in FODMAPs, which are highly fermentable foods which can give people such symptomatology, but get them off the foods that they are sensitive to, and also just try to cut down on the overall carb content. And you’ll see that you’ll start to transform not only their microbiome, but they’ll start to have this lean metabolism effect immediately. And then just like in the functional medicine model, as we try to weed out more of the less healthy bacterium, we then re-feed and re-fertilize and re-seed the good gut microbiome and get that inner garden to thrive. And then we want to maintain that through life. What I chose was the Mediterranean diet, as maybe the Andrew Weil influence on me with his anti-inflammatory diet. But the Mediterranean diet has so many positive health outcomes that we’re just seeing within the two months the data on the brain and cognition and mood and Alzheimer’s and so on and so forth—dementia and protection against stroke. Mediterranean and anti-inflammatory diet is a great way to live and if your biome is resilient, then you’ll have the flexibility to enjoy life and be able to take breaks and socialize and eat some of the foods that you enjoy without really destroying your biome. Beyond the Scope: How is the Field of Gastroenterology Evolving? JB: Yes, I think you’ve really done a beautiful job of putting the seat of the GI tract right at the head of the table, so to speak, because from that all these messages that take us way back to the Zioudrou work on exorphins, and all through this time we start to be able to manage messaging at the gut immune level, which then has systemic effects across every organ system. So the field of gastroenterology, if I can bring this discussion to a close, has really often been woven, down at the clinical level, to scoping. Where do you see gastroenterology going? Do you think it’s still going to be seen primarily as an end-stage diagnostic subspecialty, or are we really starting to see the profession modifying its diversity as to how it sees the GI tract and GI problems? GM: I think what we need to do…I mean, it sounds profound, but I think if there was capitation in effect—in other words, that we got paid to take care of people better and have better health outcomes and not got paid, whether in money or in work RVUs for scopes, I think it would transform the profession radically and make us think differently. It would force us to think differently, and then people would take a look at this biome and it would be more than just interesting science, and I think it would really force people to partner with their dietitians like I do. Through the years many in the functional medicine community and elsewhere I have worked with. My first book was with Kathie Swift on The Inside Tract, and I’ve partnered with so many dietitians.[9] I think we need to really partner with people for better health outcomes. The data is there. I think that would really force the practice to move forward, and I think that’s coming. And I think that day is coming because we’re getting cut back on reimbursements for procedures, and everybody’s getting squeezed, and there are only so many scopes you can do in a day, and I think people aren’t in private practice anymore, they are in groups. The day will come—and I may be retired by that point, physically at least. But I think that day’s going to come, and I think that’s going to really allow us, and with this data in front of us, I think we’re going to be able to take much better care of people at that point in time because we’re going to be paid to do that and we’re not being paid to do that now. JB: Well I think that was a fantastic overview and it was actually very optimistic and forward-looking, I believe, for both the profession and for medicine in general. Dr. Mullin, I want to thank you personally for more than three decades of colleague-ship and your leadership and advocacy. It really is remarkable to sit here and review what has happened over these last three-plus decades. It really is transformative and I think your book The Gut Balance Revolution captures the spirit of this major change, which is redefining the role of gastroenterology in healthcare. Thanks so much for your leadership over the years. GM: Really, thank you for having such a profound influence over my career, Jeff. JB: It’s my great privilege and pleasure and we’ll wish you the best and catch up with you soon.  

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Bibliography

[1] Regan PT, Malagelada JR, DiMagno EP, Glanzman SL, Go VL. Comparativee effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med. 1977 Oct 20;297(16):854-8.   [2] Leeds JS, Hopper Ad, Sidhu R, Simmonette A, Azadbakht N, et al. Some patients with irritable bowel syndrome may have exocrine pancreatic insufficiency. Clin Gastroenterol Hepatol. 2010 May;8(5):433-8.   [3] Zioudrou C, Streaty RA, Klee WA. Opioid peptides derived from food proteins. The exorphins. J Biol Chem. 1979 Apr 10;254(7):2446-9.   [4] Loukas S, Varoucha D, Zioudrou C, Streaty RA, Klee, WA. Opioid activities and structures of alpha-casein-derived exorphins. Biochemistry. 1983 Sep 13;22(19):4567-73.   [5] Gershon, Michael. The Second Brain: A Groundbreaking New Understanding of Nervous Disorders of the Stomach and Intestine. New York: Harper Perennial, 1999.   [6] Chang B, Sang L, Wang Y, Tong J, Zhang D, Wang B. The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury. BMC Gastroenterol. 2013 Oct 20;13:151.   [7] Wyatt J, Vogelsand H, Hubl W, Waldhoer T, Lochs H. Intestinal permeability and the prediction of relapse in Chron’s disease. Lancet. 1993 Jun 5;341(8858):1437-9.   [8] Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011 Oct 7;334(6052)105-8.   [9] Mullin, Gerard and Kathie Madonna Swift. The Inside Tract: Your Good Gut Guide to Great Digestive Health. New York: Rodale, 2011.   [10] Pert, Candace B. Molecules of Emotion: The Science Behind Mind-Body Medicine. New York: Simon & Schuster, 1999.

Welcome to Functional Medicine Update for September 2015. This is the second in a four-part series on the gut microbiome, and we’re very pleased to have, as our clinician and researcher of the month, Dr. Martin Blaser. Let’s move directly to our discussion with Dr. Blaser that I think you’ll find fascinating as it relates to the microbiome, antibiotics, and gut immunity.  

INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Martin Blaser, MD Muriel and George Singer Professor of Medicine Professor of Microbiology Director, Human Microbiome Program New York University Langone Medical Center 462 1st Avenue #6, New York, NY 10016 www.martinblaser.com I am so excited because I just finished reading a book that was a life-changer for me and that’s a book by Dr. Martin Blaser titled Missing Microbes: How the Overuse of Antibiotics is Fueling Our Modern Plagues.[1] For those of us who have been tracking this field of gut microbial physiology and its interrelationship with the gastrointestinal associated immune system and how that influences systemic health, this book is one of those ah-ha books that is a must read for everyone. Dr. Blaser brings an incredible background and history and a range of experience in this field as an expert. Let me just tell you a little bit about him before we get into the discussion. He’s the Muriel and George Singer Professor of Medicine, Professor of Microbiology, and Director of the Human Microbiome Program at the New York University School of Medicine. He served as a Chair of the Department of Medicine at NYU from 2000 to 2012. He is both a physician and microbiologist. He has an extensive publication record covering a wide range of topics within medical microbiology. He is interested in understanding the relationships between persistently colonizing bacteria and health. His work over the past 30 years has focused on human pathogens, including Campylobacter and Helicobacter pylori. He uses those as model systems for understanding the interactions of residential bacteria with their human hosts, and over the last decade he’s been actively studying the relationship between the microbiome with health and important diseases such as asthma, obesity, diabetes, and allergies that we’ll be hearing more about in this discussion with him. Over the course of his career, he has served as the advisor for a large number of students, postdoctoral fellows, and junior faculty, and has been actively involved in national scientific organizations, many of which are very prominent in steering policy decisions as it relates to medicine and medical therapies. I found his book to be one that takes a very complex topic and distills it down into a reader-friendly format in ways that are really going to guide us in how the microbiome is interrelated to our health and the impact that antibiotics have, both positive and negative, on this whole evolution of human society. With that as a quick, rapid-fire introduction, Dr. Blaser, I welcome you to Functional Medicine Update. Thank you so much for your time and willingness to discuss this topic with us. MB: Yes, thanks for having me and thank you for your very kind words. JB: You know, your resume reads like a lexicon of the history of the last, say, 30 years of this whole evolving field of microbiology as associated with infectious disease, but also as it relates to pharmacotherapy and antibiotics. What was your early education and experience that led you to becoming this world expert in infectious disease and antibiotic use? The Paradox of Microbes MB: Well, I am a medical doctor and I trained in internal medicine, which is a very broad training in medicine, and then I did a sub-specialty training in the field of infectious diseases. That was really when I began to get the first inklings about the tremendous diversity of the world of microbes, and mostly we were focused on the bad microbes—the ones that were making people sick, causing infections in people in the hospital. In fact, I was involved in the very early days of AIDS. I took care of some of the very first patients in the United States, because it was happening on my watch. I took care of the patient with hemophilia who had AIDS. But over the years, as I kept studying the microbes and how they made us sick, I began to appreciate that there was a lot more complexity out there, and that some of the microbes that were dangerous to us also had some benefit, and that’s kind of a paradox, but the more I studied it the more I found it. And that kind of brought me to the present. JB: One of the things that comes across, of the many in your book, is this understanding that in your life as a professional you witnessed the global change in illness and death going from infectious disease to non-infectious disease. And so a lot of people might say why has this occurred? Is it because we’ve been so successful in the use of antibiotics? Why has non-infectious disease now globally exceeded that of infectious disease as cause of both morbidity and mortality? MB: I think there are a couple of answers to your question. The first is that the decline in infectious diseases actually began before antibiotics. It began in the late 19th century. We can prove sanitation, clean water, saved untold millions of lives. Better prevention, vaccines saved millions of lives. Things were coming down even before antibiotics started, but certainly antibiotics have contributed as well. And in terms of non-infectious disease growing, one of the realities of life is that all of us are going to die, and when you die you have to die of something. So if you’re not going to die of an infectious disease you’re going to die of a non-infectious disease. In part, that’s what’s happening: people stopped dying of infection and then other things began to emerge. And then we found that some of these things began emerging more and more and more—illnesses related to obesity and diabetes, for example, immunologic diseases. The Birth of the Antibiotic Age JB: I really like the way you’ve written your book because it is a string of very interesting stories, some of which are your own personal experiences with your patients and others of which are stories about leaders in the field that have helped advance our understanding. One of those stories is about Alexander Fleming. Maybe you could just remind us all as to how this whole antibiotic age was initiated. MB: Yes, thank you. One of the reasons that I wrote Missing Microbes is to acquaint the general reader—not just scientists—with some of the relevant history, and the discovery of penicillin is really important. The story of Fleming is that he was a bacteriologist. He had been a doctor during World War I and he saw the terrible injuries and how soldiers died from infections, and he was interested in finding better cures. He was working with an organism called Staph aureus, which is an organism that causes a lot of disease even today. He was working with Staph aureus. He had plated the colonies of Staph on a petri dish and he went off on vacation, and when he came back a month later, there were the plates sitting in the corner; he had forgotten to throw them out. And as he was throwing them out, he saw that on this lawn of Staph—what you might think of as a lawn—there is this big clear area, a big bald spot, and right in the middle of the bald spot was a mold. And he immediately understood that that mold was producing something that was killing Staph. He found what that mold was producing and he called it penicillin, because the mold was Penicillium. Now it turns out that peasants had been using moldy bread to treat wounds for centuries, so they actually kind of knew it, but it took a scientist like Fleming to find out exactly what the active ingredient was. And it took another decade for a team of scientists to be able to produce it in large enough amounts so that it would be useful, and of course it has been enormously useful ever since. A Census of Cells in the Human Body JB: Yes, and then from that begins your story of Missing Microbes because the feature set of this story, I believe, is that within residence in our body is this fairly large “organ” called the microbiome that’s not connected to our body by the vasculature but through the absorption, across the GI border, of various types of substances that are produced by this, say, two pounds of living organisms that we call the microbiome. So we’ve got these eukaryotic cells—our own cells—living with these prokaryotic organisms, so tell us a little bit about how this microbial world in our gut connects to this whole antibiotic story because it seems like it’s another paradoxical part of our emerging understanding. MB: Sure, sure. First off, start with the facts, and the fact is that if you did a census of all the cells in the human body, you would find that there are more bacterial cells in our bodies than we have human cells—somewhere between 3-to-1 to 10-to-1 more bacteria than humans. And if you did another census of how many unique genes we have in the human body, then it’s about 100-to-1, favoring the bacteria. So ever since there have been animals on this planet, which is at least 500 million years, they have had residential microbes—microbes that call them home—going back deep into time and continuing to the present. Every plant, every animal on Earth has their own residential organisms, and it’s become increasing clear that these organisms are not just passengers—we’re not just carrying them—but they are actually beneficial to us; they help us digest our food, they help us make vitamins, they train our immune system, they keep out bad bacteria (pathogenic bacteria) and viruses as well. There’s a lot of benefit, and the story of penicillin is very important because now we had a tool that we could treat infections, but we kept using antibiotics more and more and more for every different purpose, and no one really considered the possibility that these antibiotics might be having an effect on our microbiome, that they could have some short-term or long-term effects on the organisms that were really present. Antibiotic Use in Animals: Implications for the Obesity Epidemic JB: This may not be a logical segue, but let me jump over to a topic that you discuss quite a bit in your book, which is the sub-therapeutic use of antibiotics in animal feed to enhance weight gain, particularly in cattle. We look at these as ruminant organisms with multiple stomachs and all sorts of microbiological activity going on and fermentation of their vegetable-based diets, and yet we’re giving them low-level antibiotics over the course of their lives. Tell us a little bit about how that interrelates to this whole story of antibiotic use and antibiotic sensitivity. MB: For now almost 70 years, farmers have been giving antibiotics to their livestock in low doses because they found that giving them antibiotics would make the animals grow faster and use their feed more efficiently and this is what’s called growth promotion. In fact most of the antibiotics used in the United States today are used on the farm for growth promotion, and the reason that farmers use it is because it works. About 10 years ago, all of a sudden the question popped into my mind: Well, why does it work—why does giving low-dose antibiotics work? By the way, it’s not just cattle; it’s cattle, it’s swine, it’s chickens, turkeys, sheep, just about all the animals we use for food production, more than just mammals. It works across all of them. The earlier in life they start the antibiotics the more profound the effect. And so I thought, well, if giving antibiotics to farm animals is fattening them up, is it possible that that’s what we’re doing to our children by giving them antibiotics for good purposes, is the inadvertent side effect that we may be destining them to become fatter later in life? And in fact, we’ve found more and more evidence that supports this. Defining the Scope of the Microbiome JB: Yes, I want to come back to that in some greater detail. I think your work is just pioneering and as I read about it and went back and looked at some of your publications it was like oh my word, this is information everybody needs to be aware of. I’d like to, however, go back a step and talk just briefly about the microbiome. It’s a term that’s being used a lot more now, but I think there’s some confusion about what organisms are included within the microbiome and where do they reside. Is it just in the gut? Is it just bacteria? When we talk microbiome, what are we really talking about? MB: Well, the term microbiome refers to all the microbes—these are forms of life that we can’t see with the naked eye; they are microscopic—all the microbes that live in and on the human body, and how they’re interrelating with us. That’s the microbiome. We mostly focus on bacteria, but it also includes the fungi, the yeasts that live in us, the viruses that live in us, and even the protozoa and the worms that live on us. So we have a very diverse zoo of microbes living in the human body, and my zoo is different from your zoo. JB: Does that include things like the lungs, the skin, the epithelia? MB: Yes, it includes, as you mentioned, the gastrointestinal tract, from the mouth at the front end to the back end. It includes, in women, their vagina. In all of us it includes our skin—everywhere on the skin there are microbes, and the populations in microbes in one area of skin are different from the populations in another area (although the left side and the right side are pretty similar). JB: And as we start to think of this microbiome, what number of different species would be the order of magnitude that people would have that colonize their bodies? MB: We think there are somewhere [between] several thousand to ten thousand species on all of us, and we might say that the average zoo in the United States has about a thousand species. So each of us is carrying a zoo much bigger than the average zoo. Diversity is Important in Microbial Ecosystems JB: That’s really interesting. I recall studying, years ago, ecology, and there was a principle in ecology that said that diversity means stability in ecosystems. Is that similar with the microbiome—the more diverse the ecosystem the more stable, the more friendly it is to the body? MB: We don’t know whether that’s true, but I believe that it is true. That hasn’t been proven, but as you point out, that’s a principle of ecology, whether we’re talking about the ocean, or forests, or prairies, and probably the bodies of animals as well. So diversity has been beneficial, and again, one of the reasons I wrote Missing Microbes is to point out to the average person that we used to have a very diverse zoo of microbes in the human body, and there is more and more evidence that our diversity is going down, and so we have lost microbes. That’s why I call it Missing Microbes—we have lost some of our ancient organisms that our ancestors have had since time immemorial and now, in the last 50 years and perhaps even more recently, we seem to be losing them at a pretty alarming rate. JB: As I kind of reviewed—at least at a high level—the emerging literature on the microbiome, there is this discussion that there are two major families—Firmicutes and Bacteroidetes—that seem to predominate in the literature. What’s the story of these two families in the context of the full complexity of the microbiome? MB: What you are referring to, in taxonomy they are called phyla. Those are the two major phyla in the gastrointestinal tract. It’s not just in humans. If you look at any mammal, those two phyla—Firmicutes and Bacteroidetes—are the predominant organisms in the GI tract. In the skin, the phyla are a little different. Actinobacteria are very predominant, and Firmicutes as well. In the mouth it’s a little different as well. So each zone of the body has a different census—different populations that are present. You could think of it like you looked at a map of the world and you’d see different populations in different countries. There is some overlap, and of course the biggest country is the GI tract. That’s where the biggest population of microbes is, but there are untold billions on the skin and in the mouth, etc. Growing Concerns About Antibiotic Resistance JB: And in your book, you talk about antibiotic resistance even being seen in infants these days. How does antibiotic resistance get produced and why is it so prevalent? MB: Actually, when Fleming won the Nobel Prize for the discovery of penicillin, in his speech he talked about that resistance was inevitable. So it turns out that Charles Darwin was right: there is natural selection and there is survival of the fittest. If you have any question about that you just have to study bacteria and how they respond to antibiotics. So if I have a culture of bacteria on a petri dish or in a test tube and I put in an antibiotic, that antibiotic will kill most of the organisms, but a few will survive, and they survive because they are naturally resistant. And now, those organisms are going to grow up. They are going to become the main population because all their competitors are dead from the antibiotic, so that’s the survival of the fittest. When the antibiotic is present, organisms that have resistance have a big advantage, and so the more we use antibiotics, the more we select for resistant organisms. And over the decades, we are selecting more and more for resistance. This organism, Methicillin-resistant Staphylococcus aureus—or MRSA, as it’s called—this essentially wasn’t present before the discovery of antibiotics, but somewhere it emerged and then with all the antibiotics we are using we’re killing off its competitors and MRSA is getting more and more numerous. JB: One of the really great things that you’ve done in the book, I believe, is to talk about the evolution of your own research and your knowledge accrual over the decades you’ve been in this field. Could you just summarize with the extraordinary amount of work that you’ve done, the ah-has that you’ve had as you have gotten into this field more deeply? Lessons from the Story of Helicobacter Pylori MB: Yes, right. To summarize 30 years of work in one paragraph? I’ll do my best. I think what might be most interesting is to talk about Helicobacter pylori, which is the organism that lives in the human stomach. There are several amazing stories about this. The first is that this organism was discovered in the late 1970s/early 1980s living in the stomach, and that was surprising because most of us were taught that the stomach was sterile, that there were no organisms, that nothing could survive in the acid. But two scientists in Australia, Robin Warren and Barry Marshall found these organisms, they cultured it for the first time, and they showed that people who had those organisms were at higher risk for getting stomach ulcers and they showed that if you treated the ulcers with antibiotics you could cure them. So this is a big revolution. This changed our whole concept of ulcers and it created a new treatment. And based on their work—and I was present at some of their earliest scientific meetings—we went on to look at the relationship between H. pylori and stomach cancer, and we found there was a strong relationship there. So everybody began to look at Helicobacter pylori as a typical pathogen—a bad organism causing ulcers and causing stomach cancer. And I was one of the leaders of that. But the more I studied Helicobacter the more it became clear that that wasn’t the whole story; that’s part of the story, but not the whole story. A more complete story, in fact, is that Helicobacter pylori has been present in humans for at least one hundred thousand years, and that’s about how far we can go back with our current method. We believe it’s actually been present for millions of years but we can’t prove that yet. But in essence we can say the Helicobacter has been present in humans for time immemorial, and it’s now clear that Helicobacter is disappearing. It’s going away very rapidly and as a result we now have people who have it or who don’t have it, and that’s how Marshall and Warren could see that people who have it have a certain cost. One of the costs of carrying it is there is a risk of getting an ulcer and then there is a risk of getting gastric cancer as well. But more recent work, including our work, has shown that people who have the organism are more likely to get ulcers, but they’re less likely to get diseases of the esophagus, like reflux esophagitis, or what’s also called GERD. That’s important because GERD has just been skyrocketing. It was a rare disease and now, in almost every household there is somebody who has GERD. The question is where did this disease come from? When we started looking at GERD we began to understand that as Helicobacter is disappearing, ulcer disease is disappearing and gastric cancer is disappearing. Both are great things, but new diseases are arriving, like reflux and its consequences, which is a form of esophageal cancer. All of a sudden it was clear that Helicobacter—an ancient organism—when it disappears there is some benefit and there is some cost, and gradually we’ve been finding that’s a general paradigm for the microbiome in general. We can’t lose our ancient friends so readily without there being some consequences. JB: That is a really remarkable story, and as you said, that’s a model for the whole ecology of our body. I think it’s a good specific example of a more general theme as it relates to species diversity and stability. With that in mind as a context, you’ve done a really excellent job in Missing Microbes talking about how the microbiome, then, and this diverse population relates to metabolic diseases such as diabetes, arthritis, and obesity. Can you take us a little bit down that path because that’s an extraordinary chapter in our evolving understanding? Why Are Microbes Going Missing? A Discussion of Changing Birth Practices and Antibiotic Use MB: I can but I think before I do that I’d like to discuss why our microbes are missing. What’s causing them to disappear? JB: Great. MB: And I want to talk about two issues. The first issue is that a big fraction of the microbes that we have in our body, we got from our mother, and she got from her mother, and she got from her mother, and so on and so forth, all the way back in time. And what is now clear is that when a baby is born they are pretty much sterile, but as soon as they begin the birthing process they start acquiring microbes from their mother, and that’s the way we humans have been doing it for millions of years and all other mammals have been doing it. That’s the nature of mammals; we’re born from a womb and we are given birth as a live birth (we’re not born in an egg). But now we’re doing things that are changing that intergenerational transfer of microbes. For example, more than half the women in the United States are getting antibiotics during pregnancy, and now a third of the babies born in the United States are born by Caesarian section. In some countries it is fifty percent of the babies are born by C-section. Both of these interfere with that normal intergenerational transfer of microbes, and there’s evidence that the microbes that come out are different (the babies born by C-section or their moms were on antibiotics are different). And there are new studies that are suggesting that these kids have increased risk for certain diseases, like diabetes, like celiac disease and allergies in childhood. The second thing we’re doing is that we’re giving kids a lot of antibiotics. Sometimes the antibiotics are absolutely necessary: that child must have antibiotics or they will become seriously ill or even die. But most of the time that kids are getting antibiotics, it’s unnecessary. That’s been recognized for many years, but everybody’s reluctant. They thought, well, it might help, but it won’t hurt. But now we’re getting more and more evidence that it could hurt, so we have to recalculate whether all these courses of antibiotics that kids are getting are really necessary, and we see that there are big differences. In Sweden they are only using 40 percent of the antibiotics we’re using, and their kids are growing up just fine. So our microbes are missing—they are disappearing—in part because of things that we’re doing that are] well-intentioned, but that have unintended consequences. The Role of the Microbiome in Developmental Processes JB: Wow, that’s really a powerful insight. You know, it was very interesting to me—you described one of the unintended consequences could be changes in various types of growth stimulating hormones that are related to alteration of the gut microbiome and you even raised a question about changes in height of various girls and boys as a consequence of the interrelationship they have with their microbiome, not to mention these other metabolic diseases. It sounds like a very complex network that we’re discussing. MB: Well, for a long time pediatricians understood that a child’s height at the age of about two-and-a-half is a very strong determinant of what their final height will be as an adult. They’ve known that for generations. And that first two-and-a-half years of life is really important, and it turns out that’s when the microbiome is getting its shape, its structure. All kids begin with a relatively sparse microbiome and then it fills out, and how it fills out appears to be a determinant of height and weight, and so this leads back into your other question, which I didn’t answer before. If farmers give low doses of antibiotics and their farm animals gain weight more rapidly, what about kids? Well, we began to do studies in the laboratory in mice, and we could recreate in the lab what the farmers have found: giving antibiotics to the mice made them fat. And in another experiment, if we put mice on a high fat diet they got fat, if we put them on antibiotics they got fat, but if we put them on both together they got very fat, and we think that that’s a paradigm for what’s going on in our kids. And sometimes in the mice the fatness didn’t occur until much later in life. They were growing normally and then all of a sudden they started getting much fatter, and that might be the equivalent to somebody who is relatively normal and in their 20s and 30s start gaining a lot of weight. JB: Is there a putative explanation at a mechanistic level for this relationship or is it still work in progress? MB: Well it’s definitely a work in progress. We’re working on it, but we think that what happened over the millions of years is that human development is choreographed by the microbiome. The organisms are there—those ancient organisms are talking to our cells as babies are developing, and that’s the way it’s always been and so there has been a normal developmental pathway for metabolism and for immunity. But now the microbes are different, and in essence the language that they are talking to our cells in is different, and the consequences of that altered conversation are different. That’s how we’re thinking about it. We’re interested in some particular chemical mechanisms that are involved. Looking for Solutions to Stop the Loss of Microbes JB: Thanks to you we’ve outlined a pretty interesting perimeter of a playing field of a problem, clearly, because we’re all living in a similar environment, here, at some level in the developed world, so what do we do about this, where do we go from here, how about probiotics, does our diet play a role, what factors can we modulate to really do something in response to this changing ecology? MB: Yes, well, I’m glad you asked that question because that’s chapter 16 of Missing Microbes: solutions. Where I try to go into what are some of the things that we can do to improve health. The first stage, which is Public Health 101, is stop the damage, try to limit the use of antibiotics, limit the use of C-sections to those cases where it is really necessary (it’s not an elective item). So if we can decrease the damage, that will be very important. Another possibility is that when a child, for example, has to be on an antibiotic, we might want to give them a probiotic that will help them avoid the damage. The problem is we don’t know what those probiotics are yet. I don’t think it’s the ones that you can buy in the health food store; I think they are going to be new ones that we are going to understand scientifically and those are the ones that we’re going to use. Another very interesting issue is that when you look at people in the jungle who haven’t had modern life, their microbiota is much more diverse than ours, and the possibility is that we might use some of the microbiota from those people living in the jungle to help restore what we have lost. Both my wife, Maria Gloria Dominguez, and I are working on this very problem. JB: We’ve heard recently of some pretty remarkable responses that various people have had from microbial transplants through instillation of fecal material into people from people with healthy microbiomes. Do you think this is a therapeutic trend in medicine? Any thoughts on that? MB: Well, I have to give your listeners some background; I also discuss this in Missing Microbes. There’s a very terrible disease called Clostridium difficile infection; it’s also called C. diff infection. And typically this occurs after someone has had antibiotics. This organism, C. diff, overgrows and can be very damaging to the intestinal tract. Sometimes people die from this, and it can be very a severe disease. The typical treatment is with antibiotics, but the treatment is not always effective. In fact, there are often recurrences of this. A number of years ago some doctors found that if they gave people with C. diff infections a fecal transplant, either from the top end or from the bottom end they gave them normal fecal material, they would cure that disease. Now remember this is a bad disease; this is a life threatening disease, people die from it. And that therapy actually has been curative. It was a big randomized clinical trial to test fecal transplant versus conventional therapy, and in fact they had to stop the trial because the fecal transplant was so much better.[2] So that’s now become established: for that infection, the fecal transplant works. Now scientists are working on trying to improve it so that it’s not fecal transplant but maybe give certain specific probiotic organisms, but again that’s work in progress. Could fecal therapy be a pillar of medicine in the future? It’s possible, but I think it’s unlikely. I think if we find that there are conditions where restoring the microbiota in the GI tract are important, maybe for a while such fecal therapy will be used, but scientists will try to come up with something a little cleaner, a little better defined. JB: So there are people, obviously, who necessitate the application of antibiotics for—as you pointed out—certain medical needs. Are there any antibiotics that are more friendly to the microbiome than others or is it just a class effect? MB: Well, I think that all antibiotics are pretty unfriendly to the microbiome, but some are more unfriendly, and we’ve actually just had a paper published. Again this was studies in mice, but when we compared the two major classes of antibiotics that are used in children—we studied beta lactams (that’s the class that includes penicillin and amoxicillin) versus macrolides (that’s the class that includes erythromycin and azithromycin—that’s the Z-Pak—and clarithromycin). So we compared the beta lactams and the macrolides and we found that the macrolides were much more damaging than the beta lactams.[3] I was at a meeting in Europe last month and there was a presentation at that meeting looking at children in Finland, and they found the same thing in human children as well, suggesting that the macrolides, which have been increasingly popular in recent years, may be more damaging to our gut ecology than the penicillin and amoxicillin and the more standardly used items.[4] JB: When I finished reading Missing Microbes and I put the book down and—as you do when you finish a book—you take a few moments of reflective pause to ask yourself what did you learn, I recognized that there was a kaleidoscope of different topics that were very, very well stated in the book that stuck with me. But one of the major dominant themes was the construct that this is all going to lead to significant change in medical and cultural practices and therefore we will be seeing, with this information, some sweeping changes. Maybe it will occur over a longer period of time, but as you look with the history you have and with the future-looking ability that you possess, what do you see happening in medicine and in society at large as it relates to this information as it becomes more well understood? MB: Yes, that’s a good question. Now, as I have to gaze in the crystal ball, I’m afraid that if we don’t do anything it’s going to get worse. So we really have to do something and that’s in part why I wrote Missing Microbes: as a call to arms. It’s to get our citizenry aroused with our pitchforks and try to figure out how to get out of this deep hole that we’ve dug. What it’s going to mean is, for one thing, we’re going to have to be much more restrictive in the use of certain medical practices, including antibiotics, as I mentioned. I think we’re going to have to invent a whole new class of antibiotics that are narrow spectrum. The typical antibiotics used now are broad spectrum; they cover the waterfront. But if I were a parent or grandparent of a child who came in with an ear infection and they needed antibiotics, I would much rather it be an antibiotic that was just targeting the organism that’s present without doing a lot of collateral damage; kind of a laser strike against that organism. We have the capabilities now in general, but we have to do a lot more work to develop those narrow spectrum antibiotics and get them on the market, and then we have to develop diagnostics so that when the parent comes in with that ill child there can be a rapid diagnostic that will help the doctor say this is due to a virus, this is due to a bacteria. And if it’s due to a bacteria, is it bacteria A, B, C, or D, and if it is D, the doctor will take off the shelf narrow spectrum treatment for organism D. I think that’s where medicine in the future is going to go. It’s going to be expensive, it’s going to take more research, and the drugs will be more expensive than the antibiotics of today, but I think right now the antibiotics we’re using are a false economy. You can pay for it now or you can pay for it later in terms of the increased medical bills. I think that’s what we’re seeing are those delayed costs because of these epidemic diseases like asthma and obesity. JB: Well, I think that’s an incredible insightful perspective as it relates to how this concept of stratified disease treatment and personalized healthcare is evolving in the post-genomic age. I hadn’t thought clearly about what you just said, but it seems like it’s another really superb example of how genomic information is starting to really filter down into a different strategic approach towards healthcare by lasering in to personalized individualized care that relates to treating the specific cause and not just the broad brush of hitting all the outliers around the surrounding environment. It’s a really insightful comment that you brought up. Let me ask one last question in close, and that is clearly you’re an advocate, clearly you’re a leader who is willing to step up and have their voice heard. What kind of response have you had to date from Missing Microbes as it relates to your advocacy position? MB: I’m really pleased. People are listening. The book has been reviewed quite a bit. The reviews, in general, have been quite positive. It’s gotten a lot of media attention. It’s being translated into sixteen languages; I’m really happy about that. So far, though, not Spanish, Portuguese, or German; those are the big holes, so if you know any publishers who would consider those, I would like it to be read by a lot of ordinary normal people—people who are concerned about their health and about the health of their children and their grandchildren. So far there has been a lot of very good attention and actually I’ve gotten some awards from my work recently. I think people are beginning to listen. It’s beginning to have an effect, and that’s exactly why I wrote Missing Microbes. JB: As a person who has shared this field, somewhat, with you over the last 30-plus years, a person who is a parent and grandparent I want to thank you. I think your work has been seminal. I think your book is superb, and as I mentioned it was one of those catch me by the frontal cortex of my brain and really shake me when I read it. Dr. Blaser, I want to thank you very much for being available and sharing with all of us. This will go out to health practitioners around the world who are going to make decisions about how they care for their patients and communicate to their mothers and fathers, so all we can say is thanks so much for your tireless work. MB: And thank you for your terrific questions. JB: Appreciate it. MB: Thank you. JB: Be well.  

Bibliography

[1] Blaser, Martin J. Missing Microbes: How the Overuse of Antibiotics is Fueling Our Modern Plagues. Henry Holt and Company. New York, 2014.   [2] Cammarota G, Masucci L, Ianiro G, Bibbo S, Dinoi G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015 May;41(9):835-43.   [3] Nobel YR, Cox LM, Kirigin FF, Bokulich NA, Yamanishi S, et al. Metabolic and metagenomics outcomes from early-life pulsed antibiotic treatment. Nat Commun. 2015 Jun 30;6:7486.   [4] Metsälä J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM. Prenatal and post-natal exposure to antibiotics and risk of asthma in childhood. Clin Exp Allergy. 2015 Jan;45(1):137-45.   [5] Weng M, Walker WA. The role of gut microbiota in programming the immune phenotype. J Dev Orig Health Dis. 2013 Jun;4(3):203-14.   [6] Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, et al. Gut microbiomes of Malawian twin pairs discordant for Kwashiorkor. Science. 2013 Feb 1;339(6119):548-54.   [7] Garrett WS. Kwashiorkor and the gut microbiota. N Engl J Med. 2013 May 2;368(18):1746-7.   [8] Rondanelli M, Giacosa A, Falvia MA, Perna S, Allieri F, Castellazzi AM. Review on microbiota and effectiveness of probiotics use in older. World J Clin Cases. 2015 Feb 16;3(2):156-62.   [9] Hur KY, Lee MS. Gut microbiota and metabolic disorders. Diabetes Metab J. 2015 Jun;39(3):198-203.   [10] Han JL, Lin HL. Intestinal microbiota and type 2 diabetes: from mechanism insights to therapeutic perspective. World J Gastroenterol. 2014 Dec 21;20(47):17737-45.   [11] Garrett WS. Cancer and the microbiota. Science. 2015 Apr 3;348(6230):80-6.   [12] Zhou L, Foster JA. Psychobiotics and the gut-brain axis: in the pursuit of happiness. Neuropsychiatr Dis Treat. 2015 Mar 16;11:715-23.

Welcome to Functional Medicine Update for October 2015. Oh, what a treat we have now in our third installment of our four-part series on the gut microbiome, and that is with our long-term champion and key opinion leader Dr. Robert Rountree, who was with us as an FMU Clinician of the Month a number of years ago talking about pediatric nutrition and immune health. With that as an introduction let’s move directly to our fascinating discussion about the ecology of the gut microbiome with Dr. Rountree.  

INTERVIEW TRANSCRIPT

Clinician of the Month Robert Rountree, MD Boulder Wellcare 75 Manhattan Drive, Suite 1 Boulder, CO 80303 www.robertrountree.md.com So once again here we are with one of the world’s leading experts in the clinical application of these concepts that we’ve been describing over the past few issues. That’s Dr. Robert Rountree. You know Bob is one of our seminal leaders in the functional medicine field, and an individual who graduated Magna Cum Laude from the University of North Carolina in Greensboro in 1976 and received his medical degree from the North Carolina School of Medicine in Chapel Hill in 1980. He did his residency in family community medicine at the Urgent Medical Center in Pennsylvania, and he is certified by the American Board of Family Practice. He has been practicing family medicine, utilizing really a comprehensive approach that integrates much of the functional medicine parameters since 1983. I’ve had the privilege of knowing Bob from the early 80s on, so he and I have shared a journey through this evolution of healthcare over those last three-plus decades, so it’s really a great treat to have not only an expert, but a person who has been a thought leader, authoring chapters in the Textbook of Functional Medicine, Clinical Botanical Medicine, and Clinical Natural Medicine Handbook. The New Breastfeeding Diet Plan was one of his books, and also Immunotics, talking about nutrition and immunology, and Smart Medicine for a Healthier Child. So you can see just from those titles that Bob’s range of interest goes from preconception all the way through the aging process and its application of good medicine. He is one of those individuals who takes very complex information and can bring it down to the level of understandability to the average both clinician and patient. An Ecological Approach to the Microbiome I thought that we could entertain Bob with a discussion theme in this particular issue of Functional Medicine Update around an ecological approach to treating disturbances of the microbiome. And the reason I chose ecological is that Bob is really the master of integration of the big to the small, of the global to the individual. Ecology cuts through all of those. Ecology comes from the Greek word that means “home,” and so we can be at home in our bodies, we can be at home in our world, and we can be home in our universe, and Bob has done a really good job of integrating all of those. Welcome, Dr. Rountree, to Functional Medicine Update and thanks so much for being available. RR: You bet, Jeff. It’s great to be back again. JB: So let’s start with an outlining perspective question. You are the 2015 Institute for Functional Medicine Linus Pauling Award recipient, which is the top award that the Institute gives to individuals of distinction. So maybe you could tell us briefly about your path that led you to the point in your career and the origin of your environmental advocacy in medicine, which highlights much of what you have been able to be as a leader. RR: Well, it really started for me as a small boy growing up in a very rural area in South Alabama, believe it or not. My family owned an area outside of Montgomery, Alabama that was actually used part time as a Girl Scout camp, and that’s where I spent my early years. It was really swampy and very, very biodiverse, and so the early years of my life I spent going out and exploring the woods and was really fascinated with the mixture of wild animals—all the reptiles, in particular, and the rich sounds at night of the frogs and all the insects chirping. I thought that was the way the world was. I think that kind of set the theme for me. As I got older I spent a lot of time camping in the woods and summer camp was always something that I greatly looked forward to, and then when I got older I got into backpacking, and then later sea kayaking which is one of my all-time great loves. So I think that has created this ongoing theme in my life—an appreciation for what nature has to offer. When I went to medical school it was partly because of an inspiration I had studying biology. I still remember looking under a stereo microscope for the first time and watching cells divide, and I just thought that was the most amazing thing in the world. I imagine when Leeuwenhoek first was able to get that famous drop of water and look at it under the microscope and realize it was full of all these living things how mind-boggling that must have been. I would say I shared a similar kind of inspiration. So in the back of my mind it has always been about the biology and the systems (the biological systems) out there that has inspired me. That’s really what’s moved me forward through all this. JB: So taking that as a really great frame of reference and then projecting it forward into your professional life as a medical doctor, you’ve obviously become recognized as a thought leader in the area of human ecology, which connects the external world to the internal world. How do you think this expertise and this perspective influences how you see a patient and the questions you might ask or the communication you have with a patient? It would probably be interesting for individuals to know how that framed some of the interrogation that you have with your patients. Applying Chaos Theory to Perturbations in the Human Body RR: Well, I guess I’m always looking at things on many different levels. In medical school, you’re basically taught the one-disease/one-treatment model, which is very linear, very narrow-focused. But I’m always pulling back with my lens to say, what is the big picture here? When I first started giving lectures for IFM, I put a big emphasis on chaos theory. And part of the reason I was so fascinated by that was the idea that any small change—any small perturbation—in the initial system can lead to huge ramifications. The whole idea that a butterfly flaps its wings in Texas and that sets off a tornado in Brazil. If you think about that in the gut, which gets to our subject of the microbiome, then it has fairly profound implications—that you can have one change in a keystone species of bacteria, or a virus, or a fungus that can have a rippling effect on the whole body. I often talk with patients about this, how small little changes can have huge effects on their overall health. And again, that’s very different than using a blunt tool like a pharmaceutical to try to come in and block an enzyme system and cure an illness. JB: Yes, I think that’s a beautiful segue into the gut microbiome focus of this issue. We know that the outside and the inside worlds connect at the gut microbiome level. This seems like something that those of us who have been in this field for some years might find very sensible, but for the average patient that might be considered quite an unusual concept because first of all they’re not even familiar with the fact that they’ve got nearly two to three pounds of living critters in their intestines, which is the microbiome that is responding to the world. How do you communicate this concept to your patients—this kind of gut-communication microbiome story? Introducing Patients to the Microbiome RR: I kind of start with this notion of how far we’ve come since we developed this DNA probe technology. I attribute that to people like Rob Knight who is right here in my town at the University of Colorado. Once they developed that technology to fairly rapidly identify what’s out there, one of the first realizations was that we are basically covered in microbes, that there are no sterile compartments in the body. That, I think, was a huge development. You know, we have gone from a place in microbiology of being focused on pathogens and thinking well, there’s a handful of bad bugs out there and if you are unlucky enough to get exposed to one of them, and if you’re unlucky enough to get some salmonella in the food that you’re eating, then you can develop a pretty bad gastroenteritis, and so that gets us back to the old Howard Hughes notion that we’ll just sterilize all of our surfaces and we’re not going to have to worry about all these bugs. So it has actually created a bit of a paranoia about microbes and what’s out there because we tend to think that most of them are bad, and what Dr. Knight has done, what Jeffrey Gordon has done in St. Louis, and Peter Turnbaugh who was at Harvard, have basically shown that we’re swimming in a sea of microbes, and those microbes provide—what they say in an ecological perspective—is ecosystems services.[1] You know? In the same way that a salt marsh provides an ecosystem service. So these microbes are doing good things for us, by and large, and we’re swimming in a sea of them, so the first thing is to start thinking of them as our friends: Some of my best friends are microbes. If we can change people’s attitudes toward microbes and stop thinking, well, you’ve got to sterilize everything, you’ve got to be paranoid, you’ve got to be careful, you’ve got to nuke all you food so that you don’t, God forbid, get exposed to bad things, then it’s going to change your whole relationship to microbes and that is especially true for the gut, for the nose, for the lungs, realizing that most of these microbes are acting in a friendly way and that we really need them—we desperately need them. So we need to think about lifestyle practices that will engender the growth of healthier microbes. And it’s not just healthier microbes, it is microbes that exhibit healthy behavior. JB: Yes, I think that you’ve really done a beautiful job of describing this concept. This seems like almost back to the future that we are revisiting the importance of this microbial world that we live hopefully in harmony with. It also reminds me that this microbiome that you’re describing is more than just in the gut. I’m recalling the work that is being done now on COPD and the microbe of the lung and how that’s interconnected somehow with the speciation of the overall body’s microbiome, and so if you have a disturbed microbiome it actually changes your cardiopulmonary functions. It’s really powerful reframing of this whole conceptualization of living in harmony. Maternal Microbes and the Birthing Process RR: Well this whole notion that there really is no sterile surface in the body I think is pretty profound. I recently was reading through Rob Knight’s book Follow Your Gut.[2] It was published by TED Books. It’s a nice book because it’s short and sweet and really gets into the point. And he has some very pithy statements that are, I think, quite profound. One of them is: “Vaginal microbes determine our destiny.” JB: Oh, that’s right because of the birth canal, and in fact when we talked with Dr. Blaser he spent quite a bit of time talking to us about some of the adverse implications of using antibiotics during pregnancy and the birthing process and also about the rising prevalence of C-sections and the lack of having exposure to the vaginal microbial environment. RR: Well we know that those vaginal microbes basically set the tone for what our entire microbiome is going to be—not just the gut microbiome but what’s happening all over our bodies. That critical time of birth is going to have an influence on the rest of the person’s life. And it brings up its own issue that is a very thorny one of almost mandatory screening for Group B strep in pregnant women and then giving them antibiotics even if they have no symptoms or risk factors for neonatal sepsis. It’s a really challenging issue because there’s not a clear answer, and if you are able to show that you prevent neonatal sepsis by giving antibiotics shouldn’t that be a good thing? Well maybe, but what if that also means that child is also more likely to develop inflammatory bowel disease later in life? That’s a bad pay off. Functional Medicine has a Long History of Focusing on Gut Health JB: Yes, fascinating. I’d like to take you back, say 25 years in our evolutionary history in the functional medicine milieu, and talk about two terms that I think were—at least to some extent—birthed out of those discussions that we were all having in the formative years of the Institute for Functional Medicine and the functional medicine model, and those two terms were “dysbiosis” and “leaky gut.” Now, when those were first being used, as I recall, by those of us who were trying to put some legs under these concepts, we were pretty heavily criticized for these concepts. You know, what the heck is leaky gut? And, there is no such thing as dysbiosis. Could you kind of give us some operational definitions of those terms and what they mean and how they have evolved? RR: Well, certainly. I have to say that I really identify with that experience you’re describing in the early days, and I think saying we were criticized is putting it lightly. I remember 20 some years ago getting a letter from an insurance company that had requested my records in my clinic and used both of those terms. They wrote me a letter that said basically that everything I was doing was fraudulent because I was using these terms that were developed by this Dr. Leo Galland and that everyone knew that these were made-up concepts, that they had no basis in science whatsoever. I remember feeling the sting of that years and years ago, and I also feel extremely gratified now to know that these terms are widespread in the medical literature, they are in mainstream articles that are appearing almost every day now. So it has totally become legitimate science; no one questions it whatsoever. Maybe some old-school gastroenterologists that haven’t been to a library in a while might question this, but this is a very proven concept. Dysbiosis, I learned about it from Leo—this whole notion that it’s not just having a single pathogen that is causing an acute illness, but rather an imbalance of the microbes in the gut—so disordered life, really. I have found this to be such a tremendously useful concept over the years. Even though we didn’t have very clear markers to show this was true—it was hard to prove it—but it was one of those things that you knew it when you saw it. I would say even all cases of irritable bowel syndrome are clearly a result of dysbiosis. Cause and effect we don’t know, but dysbiosis clearly accompanies that. There is a problem with the microbiome in gut IBS, there’s a problem with the gut microbiome in IBD, so it’s this theme that carries through in a lot of intestinal disorders. And it has been expanded to include other areas of the body. In fact, I credit Alex Vasquez for using the term multi-focal dysbiosis to describe dysbiosis in, say, the sinuses or in the skin or in the mouth. We know that periodontal disease, for example, is not really an infection per se, as much as it is an imbalance of bacteria in the mouth that cause an inflammatory response. Now the real question of where all of this stuff is going is now that we can identify a lot of the bacteria we’re being asked the tough questions of what are the clear markers that indicate the dysbiosis. There is no doubt that the syndrome exists, but again, we’re having to do the hard work of being able to come up with really clear consistent markers that will say, “Yes, this shows it.” Is it low diversity? Is that an adequate marker for dysbiosis? Is it the appearance of certain bacteria or the lack of certain bacteria? If you have low levels of fecal bacteria, for example, or Akkermansia mucinaphila, is that an indicator? We went from the early days of thinking it was all about Lactobacilli and Bifidobacteria, and now we’re realizing those are good players but they are relatively minor players when it comes to commensal bacteria. The bigger picture is going to be to ask: What is it that is missing or what is it that we have too much of that really defines the syndrome? And then there’s the whole notion of leaky gut, which again I think we have to thank Leo for promulgating this idea. It was never made up; there was always research showing that you could do a lactulose-mannitol test and demonstrate increased permeability, but that was a fairly obscure test at the time that people just simply didn’t know about. It wasn’t that the science was bad; it just wasn’t widely recognized. But the clinical syndrome that was typical for that was the person that would say, “I eat a certain food and then two hours later my joints ache,” or “two hours later I start getting this skin rash.” So we knew that there was this relationship between food and systemic symptoms, even though we didn’t quite understand all the mechanisms. And then it was much later that Alessio Fasano came out and beautifully elucidated what all the mechanisms were, the whole idea of tight junctions opening up, translocation of all kinds of antigens from food and bacteria setting off an inflammatory response. So we’ve gone from this kind of crude notion that leaky gut is this observed clinical phenomenon, to now being able to quantify it, to determine what brings it on (things like gluten, or NSAIDs, or alcohol), and how to treat it. Tests and Assays for Evaluating Gut Health JB: So that leads to a question I’m sure is on a lot of people’s minds if they are just getting into the field, and that is are there any tests or any assays or evaluative tools that you have found useful for understanding better dysbiosis and/or leaky gut? You mentioned the lactulose-mannitol test, but from a clinical perspective how do you feel about various types of tests that are available to define some of these parameters? RR: Well, I do a fair amount of DNA analysis of stool. I will admit that we probably still have a ways to go before we completely know how to make sense out of that. People like Rob Knight have said, “Well, I don’t think this testing is ready for prime time.” But he’s not a clinician. I’m a clinician; I need this information. I need to start somewhere, and I think we’ve really come a long way from doing these basic stool cultures where we’re just looking for pathogens, we’re looking for how much growth we get of Lactobacilli, Bifidobacteria, to being able to look at the overall spread. Now that we can look at the overall spread, then I think we can make certain assumptions about whether dysbiosis may be present or not. We need to come together as practitioners and researchers and have a consensus about exactly what constitutes dysbiosis. We’re not quite there yet, but at the same time I think when you see it you know it. You know what I mean? JB: Yes. RR: It’s a pattern, and the pattern doesn’t always look exactly the same, but there is a recognizable pattern that I think can identify dysbiosis. As far as the leaky gut, I think lactulose-mannitol is still the gold standard. There are other groups that are using similar large molecules. There was a very interesting published study on Parkinson’s disease that you might be aware of, where they gave sucralose and they used sucralose as an indicator. And the interesting thing about that study is that the researchers concluded that Parkinson’s disease may actually start in the gut because they found leaky gut is one of the first signs that something was wrong and it correlated with alpha-synuclein build up in the gut neurons.[3] JB: That is fascinating. So this whole gut-brain connection is just a remarkably evolving…I would call it tributary off this field that we’ve been working on for 25 to 30 years. It’s really fascinating. Okay, given all of this, this sounds pretty darn important. Then how do you approach personalizing a therapeutic intervention to managing dysbiosis and leaky gut? Where do you even start? Dietary Change is Still the Best Therapeutic Intervention for Gut Microbiome Imbalances RR: I think the most compelling research has been on dietary change. I think we still don’t have all the answers yet, but I think when you look at the data that is out there it’s pretty clear that making shifts in the diet can have huge effects on the microbiome in just a couple of days. Rob Knight’s lab did a very interesting study where they had people do a Doctor Oz cleanse, where they made green smoothies and then I think they took high doses of a probiotic, and sure enough they were able to make some pretty profound changes in people’s guts in just three days.[4] Very profound changes with a movement toward some very healthy bacteria. For example, they got big jumps in Akkermansia muciniphila, which is one of the healthier bacteria in the gut. Which is interesting because the probiotic they were taking—it was DSL #3; it’s a very potent probiotic but it’s mostly Lactobacilli and Bifidobacteria—but what they saw was not so much a big jump in those two bacteria, but instead things like the Akkermansia, so that’s telling us that maybe probiotics don’t do exactly what we thought they were doing. It’s not so much that you have a deficiency of Lactobacillus acidophilus and then you take that bacteria and that makes the Lactobacilli grow. Instead it seems to improve the overall ecology of the health to take these beneficial bacteria. So there is probably a lot of interactions between all the different bacteria in the gut, and then what emerges is this healthier pattern. You know, the confusing issue here is that we have this movement toward Paleo diets and telling people to eat fewer carbs and in many cases people are seeing a lot of benefits from Paleo diets, and yet some of the research that’s been done, in particular a study that Peter Turnbaugh did, showed that when people went to these all-meat diets that were high Paleo diets they started growing some bacteria that weren’t particularly healthy. I think one of them was called—I recall vaguely—maybe Bilophila wadsworthia or something like that?[5] JB: Yes. RR: That lives off bile? So that was a slightly foreboding finding, I thought. Whereas I think it is maybe going out on a limb to say this, but Michael Pollan basically has told us that eating plant-based diets is the healthiest thing, and the microbiome research tends to support that, tends to show that eating a wide range of fibers is really one of the best things for growing the healthy bacteria in your gut and preventing dysbiosis. So we’re moving toward answering this question of what’s the best diet for your microbiome? As opposed to what we’ve looked at in the past, which was what’s the best diet for maintaining cardiovascular health? Or joint health, etc.? But now that we can test the microbiome, we can put people onto different diets and see. If I sound a little hesitant here, the reason that there is a bit of concern is that we also have people that don’t digest carbohydrates very well and get a lot of gas and bloating and actually develop SIBO, and here we are telling people to go on a low FODMAPs diet, which would seem contradictory. Something that I see all the time in my practice, people that have low short chain fatty acids on a stool analysis, specifically low butyrate, and yet they get a lot of gas and bloating when they eat the very things that would be presumed to increase their butyrate. Cant’s eat the FOS or the inulin or those other kinds of fibers, and so I think the challenge that is on us right now—the docs that do nutritional medicine and the nutritionists that work with us—is to be able to come up with some really creative ways to help develop healthier microbiomes in people without causing these problems. Clinical Experience Using Prebiotics JB: I think you’ve really done a superb job of defining the landscape in which we find ourselves clinically. That’s really clear, excellent. A lot of what we’re talking about just for the sake of terminology as it pertains to these nondigestible carbohydrates—these fibers—is often called prebiotics, and you’ve mentioned fructooligosaccharides and inulin, and larch arabinogalactans is another member of that family. Have you found, clinically, that you can vary the types of these prebiotics, these non-digestible fiber materials and get different effects on your patients? RR: I think for people that don’t have trouble digesting prebiotics it is probably the single most effective intervention for producing the healthy microbiome. So, yes, there’s no doubt that this is a great way to go for a lot of people. The question is what about that subset of people that don’t tolerate them very well and so the search is on. I’ve learned a lot about dandelion greens, which are a pretty good digestible source of prebiotics, so I’ve been recommending those a lot more lately. It turns out that butter is a really good source of butyrate, especially ghee. I find that now that we’ve kind of moved away from the low fat diet craze and butter is okay again that putting people on ghee is the way to go. I think there is some evidence that resistant starches, like the resistant corn starch, may be useful. Frankly I’d like to see the dietary supplement companies move more in that direction—make more prebiotics that are easier to tolerate and easier to digest. I think there’s a hole there that we need to move toward. JB: Yes, thank you. What about phytochemicals/botanicals? Have you found that there are certain members of that family that have influence on modulating the gut microbiome? Clinical Experience with Phytochemicals and Botanicals RR: Yes, I think there’s a pretty good body of research on all kinds of polyphenols. Even something as simple as grapeseed polyphenols added to the diet can be quite helpful. I use the whole range of those. JB: We think of things like curcumin, or EGCG. Do these have any adverse effects on the microbiome or are they at least neutral if not positive? RR: Well, it’s kind of a million dollar question, isn’t it? Some people have said, “Well, wait a minute. Curcumin does have antimicrobial effects.” And another one that is in that same category is berberine. We’ve used berberine, this plant alkaloid that’s found in goldenseal, and Oregon grape root, and Coptis chinensis—we’ve used that for a long time to treat dysbiosis, to treat overgrowth of Candida albicans and other yeast, to treat parasites, and yet now there is this emerging interest in using it for metabolic syndrome, and one of the theories about why berberine is so effective for metabolic syndrome is that it actually regulates the microbiome. It may help to suppress unhealthy bacteria and allow the growth of healthy bacteria. But that’s created a bit of an argument because some people say, well, an antimicrobial is an antimicrobial; it doesn’t matter if it is berberine, or garlic, or green tea, or curcumin, or oregano oil. It’s still an antimicrobial and that could potentially create a problem in the long run. Well, I’ve had people on berberine for years. I’ve taken it myself for years. And I haven’t had any negative feedback from people. There are always going to be people that have initial reactions to just about anything you put them on, but I haven’t really seen it to be problematic. That being said, I still think it’s a good idea to use probiotics whenever you’re using these compounds because I just think they work well together. Endotoxemia and Inflammation JB: Yes, that’s really a good clinical pearl. So let me shift slightly to another term that has become much more prevalent in the literature and I think it explains a lot, this term, once we understand it, and that’s the term “postprandial endotoxemia.” Could you give some definition of that and what it means and what we do about it? RR: Well, endotoxins are another word for lipopolysaccharides. They bind to the toll-like receptor-4. I think that’s a big part of the mechanism, and toll-like receptor-4 is one of the most inflammatory transmembrane receptors in innate immune cells and other cells. So if you really want to upregulate the immune system, do it with endotoxins, you know? You want to boost the immune system? Endotoxins are the way to do it except that they may boost your immune system so much you go into endotoxic shock. Now, in the early years we only thought of endotoxic shock as being an all or none phenomenon—a very severe situation that would be life threatening. What we’ve realized over the last decade or so, I guess, is that every time we eat there is translocation of endotoxins, and that there are certain foods that seem to be particularly conducive to creating this scenario. The famous example of that was the McDonald’s Happy Meal. You know? Where it was shown that if you gave people a McDonald’s Happy Meal that has that mixture of a lot of saturated fat, and French fries or hash browns, that that clearly increases circulating endotoxins. And the whole problem with that is that those endotoxins are then binding to toll-like receptor-4 and other inflammatory receptors all over the body so you get this low grade systemic inflammation. Of course that can go down in many different directions depending on the susceptibility of the individual. In one person it might lead to polyarthropathy (inflammatory joint disease). In another person it may lead to atherosclerosis. And in yet another, metabolic syndrome and obesity. This appears to be a core phenomenon that’s really of great concern. The question is what can you do about it? The obvious thing is to cut back on the Happy Meals, if that’s the inciting meal, and we know that this mixture of fried carbohydrates and saturated fats seems to be particularly bad for doing it. It would be nice to have good clinical tools that we could use to find out whether other meals are doing that. If you eat a baked hamburger that’s not cooked at too hot a temperature, is that also doing it? In order to be able to do that we’ve either got to be able to measure circulating lipopolysaccharides or get a quick LPS antibody test, and those tests are on the way, but I think ideally we would have something like that available in a clinician’s office to do a quick test so we could say, “Yes, this intervention is going to make a difference.” And that gets us back to, well, can we use L-glutamine, for example? If we make the enterocyte healthier by giving them their primary fuel will that decrease the amount of translocation? So there are questions that are arising as a result of these observations. JB: Bob, you just defined a really, really wonderful little teaching metaphor that I know all of us have used. I really give attribution to Dr. Sidney Baker who is another one of the master teachers in our functional medicine core group, and he talked about that the principal concept in medical therapeutics is to remove things that are doing harm and to replace things that are necessary (replace the things that are missing). RR: Yes. JB: And so you’ve really talked about that. You’re talking about let’s remove the stuff that’s not so good, and then on the other side if you’ve got these endotoxins like LPS that get in the blood and other maybe debris—other small molecules that would be considered metabolic toxins—then it begs, on the other side, what goes on in the hepatobiliary system that’s going to block those from getting access to the rest of the body. So then we get into the detoxification system, which you have been a leader in for many years—this whole cytochrome P450 mixed oxidation Phase 2 conjugation systems, and also the interrelationship with gallbladder bile acid secretion, which is important. Tell us a little bit about how that fits into the schema as you manage patients? RR: Well, I tell you, the numbers that I’m seeing out there for fatty liver—the estimate—is maybe 20 percent of the population? Is that what you’re seeing as well? JB: Yes, yes. The Gut-Liver Connection RR: Where is that fatty liver coming from? A lot of people think it is a direct result of this endotoxemia; that the liver is getting the brunt of all of these endotoxins, it’s creating an inflammatory problem, and that’s causing lipotoxicity (an accumulation of all kinds of fats) in the liver, which then leads to a wide range of problems. Certainly putting the attention on making the liver more effective, keeping the glutathione levels up in the liver, I think is a really good way to do that. And we know how to do that. We’ve gotten a lot of data over the years of how effective things like n-acetylcysteine, alpha-lipoic acid, curcumin, sulforaphane—we’ve got a pretty good sized toolkit for raising glutathione in the liver, so I think that’s one way to improve overall liver function, and you mentioned bile acid secretion. Curcumin both raises glutathione level and increases bile flow, so it’s going to address this problem on two different levels and that makes it one of my all-time favorite nutrients to use for supporting the liver, helping prevent fatty liver, and the consequences of endotoxemia. And then there is the whole NRF2 pathway—the antioxidant response element on DNA that upregulates phase 2 enzymes. I think that’s a really effective strategy, and now we know that there’s this long list of things you mentioned. Green tea is great for upregulating NRF2; so is sulforaphane from broccoli sprouts, so is resveratrol, so is curcumin. So we have a pretty good toolbox for dealing with this once we recognize the problem. Our challenge is to get out there to clinicians and say, “Hey, this is not speculation. We’ve got really good data to support this gut-liver connection.” JB: So that then leads to a really interesting new branch of this theme which I find quite fascinating because it has many subtle implications about the whole nature of how we interrelate with the outside world, and that is the recognition that chenodeoxycholic acid and cholic acid (bile acids) are not just solely emulsifiers for fat, but they also have receptors, like the EGR-5 receptor that really activates signaling of the inflammatory and insulin sensitization pathways throughout the body, so it’s raising this concept that digestion, as it pertains to fat digestion and gallbladder secretion of bile, is much more than just emulsification and absorption. There is something going on here that really triggers and signals to the whole body how genes are going to be expressed in various tissues that relate to inflammation and insulin signaling. Tell us a little bit about your thoughts on that emerging field. RR: Well I don’t know much about the specific receptor pathways that you’re talking about. I do know that bile acids are appreciated as a two-edged sword. Certainly if you have excessive amounts of them then that causes an inflammatory scenario, but then you have to have them. I’m often asked, “What do you do for somebody who has had their gallbladder out? Is that a problem?” Well, we don’t know. Nobody has done the studies to show that that can have long-term implications, but it raises the whole issue of whether the gallbladder is just a vestigial organ or not. Do you think it’s a vestigial organ or do you think it’s still serving a useful function? From what you’re talking about, the implication is that we need it. Maybe we shouldn’t so blithely take it out. Obviously if somebody’s got cholecystitis or gallstones and they have to get it out then that’s one thing, but maybe we need to consider the possibility. I’ve certainly used bile salts in people with liver disease and it’s a very interesting way to go. I know there is some research at the University of Colorado using…I think it’s lithocholic acid? JB: Yes, that’s right. RR: This raises a lot of really interesting questions. There’s really nothing that the body does that isn’t useful. Something I often talk about at IFM is the body is a really elegant machine that has been evolving over a couple of billion years ever since the first microbes started fusing and forming multicellular organisms, so there’s not a lot that the body does that doesn’t have some rationale or some reason behind it. JB: Yes, going back quickly to this bile story, there is a company called Intercept Pharmaceuticals that is now developing a drug, which is in phase 3, for the treatment of NASH (nonalcoholic steatohepatitis)—the fatty liver condition you were talking about—which is basically a modified bile acid that activates these receptors that I was alluding to that then control aspects of metabolism, both from an inflammatory perspective and from an insulin sensitization perspective. And Intercept is suggesting that this is a platform technology—that basically these drugs (these modified bile acids) will, in fact, be demonstrated to be effective in treatment of type 2 diabetes and a variety of inflammatory conditions beyond that of NASH. So I think your point that you’re making about the magic of how things in the body have pleiotropic effects—that have not just one role, they have multiple roles, multiple personalities, and often we tag a substance in the body with a simple definition thinking we understand it, when we really don’t yet understand all the multiple ways that it is influencing function across a broad range of different organ systems. And I think of bile itself as composed of cholesterol, bile salts, and lecithin, and that you can modulate the composition of bile, making it more or less soluble based upon how you eat, and certain dietary factors and certain nutrients. So the composition of bile itself can have very dramatic dietary implications, and that can then secondarily have huge effects on all sorts of systems, including insulin and inflammation. So I think that this web that we have been exploring and interrogating in the functional medicine model is where the mystery is, but is also where the answers, reside for many of these chronic problems. RR: You know it makes me wonder about the old-time naturopathic remedy of using lipotropic agents (betaine, trimethylglycine, dandelion root, celandine), which are basically agents that help improve bile flow. It’s fascinating that they’re coming up with drug solutions for this and I’m just wondering if there are things we can do to induce the body to accomplish the same thing without necessarily having to go to a prescription bile salt analog. JB: I absolutely agree. I think what we learn from pharmaceutical research is how the rationale of what we observed clinically from observational work with diet and lifestyle may work at the cellular level, and then from that we can tune those programs up using the natural balance points in physiology rather than overriding the system with one too strong a signal that we often get from a pharmaceutical. There is a symbiosis, I think, between understanding what’s going on in the pharmaceutical world and then finding how that really gets applied properly in the body’s rhythm—it’s orchestration of function—with natural remedies. RR: I couldn’t agree more. I’ve learned so much from the drug companies. I mean really, they are great at elucidating mechanisms. Increasing Awareness about Gastrointestinal Health JB: Yes, exactly. Let me thank you. This has been an extraordinarily kaleidoscopic and interesting journey that we’ve been on, but let me give you a chance to be a little of a soapbox philosopher, which I know you are. So you’re the 2015 Linus Pauling IFM Award winner. That comes with a certain pedigree of perspective. So what changes would you make in medicine if you were a Surgeon General, that would bring the functional medicine concept of gastrointestinal function and its relationship to health and disease into greater understanding and clinical application? RR: So specifically how would I bring awareness of GI health? JB: Yes, what would you do if the president said to you, “Dr. Rountree, I want you to find a way to incorporate these concepts into healthcare paradigm and practice.” Would there be something you think is most important that we do to get that to happen? RR: You know I would have to say I would probably start with birth practices, because that’s where I think we are really going awry and I have to attribute some of this thinking to what Martin Blaser has told us about the more C-sections we have the more we lose generations of microbes that have taken billions of years to evolve. And so I think the first thing I would say to the Surgeon General is let’s do some pretty extensive research about what’s happening around birth with the microbiome so that we can start kids off with healthier guts that then can presumably have healthier lives and fewer inflammatory diseases, allergies, etc., because we have this huge epidemic of kids getting allergies and inflammatory bowel diseases are on the upswing. That’s an area where if we can address the root cause of it by how the genesis of the microbiome is being impacted with birth practices that can make a huge difference for people. I think the other thing is that we need to get this concept out to the public about the importance of gut diversity—of biodiversity and intestinal microbes. And it’s going to be a challenge to get that science across to people, but I think it’s a message that once it’s well-crafted and once we can translate it into some simple dietary things like eating less refined food, which Michael Pollan has been telling us—a lot of people have been telling us this—for a long time, but this is from the perspective of making your microbiome healthier, getting good fibers in your diet, getting a lot of greens in your diet. All these things are going to be good for your microbiome. I think those are two messages that I really want to get out there. JB: Well, once again, for all of our listeners we want to thank you. There was a lot of wisdom in the last hour of discussion with you (a lot of experience and wisdom). And on a personal level I just want to thank you for 30-plus years of great friendship and collegial relationship. You’ve contributed a lot to me and it’s been really a great pleasure to have the chance to be on this journey and watching this model evolve over the last three-plus decades. RR: Thanks, Jeff. It’s been great sharing this journey with you. JB: Best to you, Bob, and keep spreading the news. I think the change is right in front of us. RR: Yes, it’s happening  

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Bibliography

[1] Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006 Dec 21;444(7122):1022-3.   [2] Knight, Rob. Follow Your Gut: The Enormous Impact of Tiny Microbes (TED Books). New York: Simon & Schuster/TED, 2015.   [3] Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One. 2011;6(12)”e28032.   [4] Thompson, Luke. “What Does A Three-Day Cleanse Do To Your Gut Microbiome?” Americangut.org. Web. 10 October 2015.   [5] David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014 Jan 23;505(7484):559-63

Welcome to Functional Medicine Update for November 2015. This is the fourth and final installment of our specific focus on the microbiome and what a remarkable first three parts we’ve had in this series to introduce this extraordinary diverse biological community and its interrelationship to the gut immune system and health through the lens of three experts. Now we are at that threshold of our fourth and final contribution to the series with who we would consider—those of us in functional medicine—our master teacher, Dr. Sidney MacDonald Baker.   What have we learned over the years from Dr. Baker? Elie Metchnikoff won the Nobel Prize in medicine and physiology at the turn of the last century. Metchnikoff’s contribution as the Director of the Pasteur Institute was to really understand, at the fundamental observational level, innate immunity. From that, then, he started to talk about the relationship of living organisms in our gut—remember he was at the Pasteur Institute at the dawn of the age of microbiology—and the role that these bacteria have in what he later called prolongation of life in a classic book of that title. In that book he talked about the use of probiotic therapy—utilizing organisms to recolonize the gut with friendly critters and the impact that would have on human health. As we have moved over the last century, we have seen an incredible advancement in the understanding of the role that the microbiome plays in human health, but we’ve also started to kind of [go] back to the future and recognize that some of these early observations that were made on a descriptive level, as we’ve gotten more into the mechanistic understanding really have support in terms of being reproducible and being actually clinically accessible. And it’s that particular part of the story that we want to really focus on in this fourth of our four-part series because we’re going to be introduced by Dr. Baker to a new threshold in the area of gut restoration therapy and the modulation of the microbiome and its relationship to immune function. I’m going to allow Dr. Baker to take us down this path to this introduction of this new chapter that is unfolding. It’s a chapter that we’re starting to see clinical application and ability to access this information, but it’s a chapter that was actually started to be written some nearly 20 to 30 years ago with observations that were being made at an epidemiological level between helminth infections (worm infections) in children and the absence of atopic disease in those children, and that is things like asthma and allergy and other atopic-type of conditions that had to do with skin disorders.   When we start to really look at this evolving connection of the gut to the immune system, we need to recognize that the gut microbiome is much more than just thousands of different types of bacteria. It is yeasts, it is viruses, it is archaea, and it is also these things that are members of the helminth family. So it is with that in mind that we move into our extraordinary discussion—our fourth and final part in this 4-part series—with Dr. Sidney MacDonald Baker.  

INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Sidney MacDonald Baker, MD Private Practice Sag Harbor, NY sidneymb@gmail.com Dr. Baker, as you well know having been in this field at all, is an individual who has, over four-plus decades, made extraordinary contributions to the development of what I call the best medicine. We like to think it is part of functional medicine—whatever you want to call it, it’s good medicine. He is a former assistant clinical professor of medicine at Yale. He was also one of the early developers of medical informatics in the computer science area, showing his breadth of skills and talents. Also an extraordinary contributor and developer in the field of child behavior-related issues as Director of the Gesell Institute and actively involved for four decades in autism research and clinical development. Just an amazing bibliography and biography of extraordinary accomplishments. But it is this last discussion of the microbiome that we’ve been engaged in that I really want to jump off with Dr. Baker, because once again he is ahead of the pack and leading us, and he’s leading us in the area that I’ll let him describe to you, but I think you’ll find this is the perfect next vision of where intervention is going in what we call gastrointestinal restoration and how we speak to the immune system of the gut in effective ways to reduce that imbalance between the gut immune system and the outside environment that often ends up, in the gut inflammation being the result (systemic inflammation). Dr. Baker, thanks so much once again for being a contributor to Functional Medicine Update. You’ve been a tireless contributor both in clinical development, but also to FMU over the last three decades. This is our 34th year and I can say your contributions over those 34 years on a number of occasions have been some of the high points in our history, so thanks once again for being available. Clinical Experience with Taurine Supplementation SB: Well, it’s been a pleasure and of course an honor and an extraordinary pleasure to have you as a friend, Jeff. And I would like to begin what we have to talk about with a little reminiscence that relates to me driving down Dixwell Avenue, just about to go underneath the bridges that carry the Wilbur Cross and Merritt Parkway through Connecticut and on my seat next to me was Jeff Bland on audio telling me about taurine. I had a patient who had had her gallbladder removed after years of birth control pills for endometriosis. She was one of the youngest people to get endometriosis in those days. She started out this problem with yeast treatment and magnesium, but then she ended up with the gallbladder trouble, and she had pain persisting after her gallbladder was out. After hearing you speak about taurine I said, “Take some taurine,” and she was thereafter completely free of symptoms. I have tried this with people with post-gallbladder pain over and over in the years since then, always saluting you for your input on taurine. Most recently I had a little boy and I was going through this story with him—a little autistic boy—and I was going through the clue of him having light-colored stools and how it would be an important test—not a treatment but a test—to see if his stools darkened on taurine. What else might happen? In the course of the conversation, which his grandmother was listening to, I covered the question of sensitivity to chlorine, as in swimming pool water. At a subsequent visit the grandmother came back and said, “You know, Dr. Baker, you saved my life. I’ve had all my life—for the last 30 years—a horrible skin condition which doctors have given every possible name and treatment to and it was all a failure, and after you told me about chlorine and water I thought I might be sensitive to that. I started taking taurine, my skin is perfect, and thank you very much.” So, thank you, Jeff, you have saved the lives of many people. There’s a kind of relationship between you and all the people who listen to FMU and to members of our tribe. We owe you a huge debt of gratitude. This then opens the question that I’d like to provide some context about the HDCs. We’re talking here about small molecules. Taurine is a small molecule; maybe 177 daltons, I think. And in another meeting of functional medicine, we heard Albena Dinkova-Kostova, a member of Paul Talalay’s team from Hopkins, tell us about sulforaphane, another small molecule that comes from plants. And now we come across small molecules like naturopathic treatments for Lyme disease, which are germ killers that come from mixtures of small molecules. The Individual is the Target of Treatment, Not the Disease: A Core Functional Medicine Principle The impulse to use them in the case of the little boy and the case of the grandmother came from details of people’s stories which remind us that the target of treatment here is individuals, and in the functional medicine model, individuality is the scientific fundamental principle underneath all of what we do. The individual is the target of treatment, not the disease. And so everything should be particularized to the symptoms of the patient; this is where information technology comes in. But now, in the small molecule department, which includes what I’ve learned to call recently essential oils, we have another paradigm sneaking in on us, which has to do with the worst abomination in medicine—the worst heresy: that you have something that’s good for everything (a cure all). As you know there are certain doctors who publish violently about this issue—that are down on people who have a contrary argument in the field of medicine, that instead of having a particular treatment that’s been given double-blind, placebo-controlled validation for a given disease, here we are—these functional medicine people—giving treatments for individuals. With the HDCs, and I think essential oils, we have the beginning of using small molecules or small ideas to treat just about everything. At a 2009 meeting of the Ratna-Ling group that was gathered by some of our colleagues (Gordon and others), we heard from Dr. Shoenfeld, Yehuda Shoenfeld, who stood up and the first sentence in his talk was also the first sentence in his big volume called Infection and Autoimmunity. And he said: “Until proven otherwise, all chronic illness—all chronic illness—is autoimmune.” Now that puts us under a very generous umbrella that says, well if all chronic illness is autoimmune, gee Sid, what do you have for autoimmunity here? Actually I didn’t want to go to that conference because I thought it would have a lot people who were just into steroids, literally and metaphorically speaking. But when I heard what Shoenfeld said—coming from the 72nd floor of the ivory tower (Shoenfeld is arguably the most influential immunologist in the world)—is this very simple idea that if all chronic illness is autoimmune, then we have a situation in which restoration of immune tolerance is the byword of what we clinicians are aiming at. And restoration of immune tolerance then becomes suitable for basically everybody who has a chronic illness—not just the ones who have an autoimmune label on them like alopecia or lupus erythematosus or all the other bowel and skin and organ-oriented diseases, but basically he is saying all chronic illness has this feature of representing a loss of immune tolerance, and that’s where I think the HDCs fit in very nicely and after you have something to say I may have a couple of stories that illustrate how I came about turning over this leaf. JB: I want to acknowledge that you have now piqued the interest of every listener as to—if they haven’t heard, they will in a moment—what is HDCs? We’re going to go through that. I want to do it sequentially because this is a big story that requires big fanfare with big marquee lettering. I’d to walk back slightly to the start of the story before you unload the goods, here, and really tell them about what HDCs are and how are they used. I’d like to go back with you, if you would. You did a little bit of a retrospective with me; I’d like to do the same with you. When I think back to the extraordinary relationship that I’ve shared with you over the years, which has had many, many different extraordinary and brilliant moments, one of those, which pertains to this discussion, was a meeting that we had at dinner—I’m not sure if I’m calling forth memories that are as clear for you as I because this dinner meeting with Dr. Candace Pert at one of the IFM symposia really had a moment of “ah-ha”-ism for me, because you asked a question of Dr. Pert at that meeting. She was one of our presenters. She was very new after the publication of her book, Molecules of Emotion, and was kind of a leader in this whole neurotransmitter ligand receptor connection to behavior function. You asked a question of her. You said something like (I’m quoting as best I can going back these decades now): “Are we are sure that the interactions that occur with these mitigating triggers always occur by direct close proximity relationships between a ligand and a receptor, or whether these things that trigger functional changes within cells might occur at a distance through other mechanisms, presumably electromagnetic or something that doesn’t require physical contact of the ligand with a receptor in order to trigger across membranes and cells and organelles ultimately the change in their function?” I thought that was an extraordinarily profound question because it has to do with so many variables that are in our environment that may influence our function but not actually “touch” the specific receptor for which that activity is seen. And that concept has stood with me all those decades since. We certainly know there are good examples of where receptors and ligands interact tightly or loosely, depending upon their binding coefficient, that then influence function. But you raised some bigger questions for me about the broader array in which the environment can influence function without direct touching. Has that been part of your thinking that has traveled through the years in guiding some of the ways that you’ve looked at your patients and various treatments and therapies? SB: Yes. The image that Candace’s work had put into my brain was of the signaling that takes place between a receptor site and a molecule that is destined to touch it. I thought to myself, well, how does the receptor site become “found,” so to speak, by the ligand? The ligand, as we think of it in some of the imagery of medicine, as floating along in the blood or somewhere in a cellular environment that’s more proximate than in the blood. But still, the size of the molecule and the distance between the molecule that is trying to get to the receptor site…it’s pretty intimidating to think of trying to find the light-switch-in-the-dark kind of thing. I was posing a question that made me ask Candace if she thought there is an interchange that occurs on sort of a vibrational level. That is, the receptor site and its partner (the ligand) can communicate with each other in a way that allows direction to be established and attraction to be accomplished, and what is the deal with this kind of vibrational or some kind of signaling that takes place on a…when I say vibrational it has to do with the signature that all molecules have, it has to do with electromagnetic energy that is emitted from the molecule even though it isn’t glowing in the dark, but something like that. And yes, I think that the thing that impresses me the most about the relationship with small molecules to their function is that they have an extraordinary power. We think of the kind of molecules like enzymes, which are great big molecules that take in a little molecule and do stuff to it to make it happen. But these tiny molecules accomplish their goals even though their molecular mass is way under 200 daltons. They are pretty flimsy little things and yet nature’s strong impulse toward being parsimonious—getting a lot done with a little bit of effort—uses these very small molecules to make signals happen in the way that I was talking about in terms of the role of sulforaphane and inducing—that was the word that Albena Dinkova-Kostova used and it just turned the lights on for me: like “inducing” glutathione. We’ve been talking about “giving” glutathione—you know, rubbing it on your skin and putting it up your rear end or swallowing it. There are all kinds of ways of getting glutathione into people; here what she was talking about was induction of it, which really got me. And then after that I wrote that article about the oceanic disease because all the different specialists were talking in this meeting about different ways of understanding glutathione’s function came from different specialties and yet they are all talking about the same glutathione. So here’s this tiny molecule. Sulforaphane has maybe a molecular mass of 125 or so daltons, and yet it can trigger this enormously central feature in all chronic illness, which is making sure you have enough glutathione to deal with oxidative stress. And ditto for all these tiny molecules that occur in what we’re calling essential oils now, which, you know, go right back to frankincense, for example. When I started learning about essential oils recently and I saw frankincense, I thought well where do you find frankincense? I’d have to go to the Bible to find that. No, you can find it at the store, and when I banged my head viciously the other day and got a big cut on the corner of my eye I slapped some frankincense on there and, boy, it healed right up. The role of these small molecules, then, I think is something that we need to consider in the context of this other HDC phenomenon, which of course is dealing with small critters. They have a function which is so subtle and yet so powerful. The numbers of HDCs required to turn around a person with a serious chronic illness is just stunning. JB: Okay, hold just a sec. I don’t want us to spill the beans yet. I’m going to walk you down the road, here, for the big fanfare with the drumroll. So where I was going—and you did a beautiful job of taking off and riffing off my question—was if we look at a milieu where there is a tremendous amount of information present that’s able to impart different kinds of signals to receptors, either by direct interaction or by vibrational effects at a distance, the gut would certainly be the place because we’ve got a lot of stuff going on there from the microbiome and from all the complexity of the diet and the immune system, which has both innate and acquired immune system activities going on simultaneously with the MALT and the GALT. And so you’ve really got a symphonic orchestration going there that is going to signal out to the rest of the body (a first level barrier) what’s going on. And you’ve been, obviously, a leader for many decades in helping us to understand this and how it relates clinically. That takes us to this whole microbiome connection, which is kind of the new buzzword: the “microbiome.” I’m proud to say that those of us in the field of functional medicine have been talking about the microbiome for the better part of three-plus decades, maybe post-Metchnikoff. It certainly has caught the news, caught the wave, and it’s really getting focused on today as it relates to a potential source of signals that are creating alternative systemic effects in terms of signs and symptoms, including autoimmune disease. Helminth Therapy: Implications for the Gut Microbiome So with that, now I’d like to take the next step down our HDC discussion. I’m going to go back to another IFM symposium. This is 2001, Palm Springs, in which I invited a gentleman, John Croese, to come out from Australia because I’d been following his work, and his work had been—with a variety of other investigators from around the world, particularly developing countries—looking at the relationship of asthma to hygiene in children, and particularly looking at helminth infections and showing that there was an inverse prevalence: decreasing asthma with increasing intestinal worms. At first this was just an epidemiological association, but then the group, which had been looking at this since the late 80s/early 90s, started to really focus in, thinking there was something about these worms that was having some impact upon the etiology of asthma. When I look at the present Pub Med publications, and this is where we’re going to jump off to HDCs, it’s interesting with regard to fecal transplant, which we’ve talked about in a previous edition of this four-part series on the microbiome and gastrointestinal restoration, which now is also a therapy that is getting attention. As strange as it might have seemed five years ago, now it’s kind of getting the approval of medicine that we can do this fecal transplant of microbiota from heathy people’s feces, basically, into individuals who have a variety of metabolic disturbances, and there are about 1633 Pub Med-cited publications presently that talk about the use of fecal transplant. Now, if we compare that to what John Croese was starting to help us to understand when he spoke at the IFM symposium in 2001, which is helminth therapy, which is going to take us right into our discussion of HDCs and your extraordinary work, if I go to Pub Med—the same Pub Med that has 1633 citations for fecal transplant—has 20,434 publications cited on helminth therapy for various forms of both localized intestinal inflammatory diseases ranging from inflammatory bowel disease and IBS to systemic problems related to arthritis, atopy, eczema, and asthma in children. The question is how does this work? And what is this all about? And can it really be contained into a regimen that can actually deliver reproducible success? And that is the extraordinary breakthrough that Sid Baker is once again helping us to cross that threshold. I don’t know if you remember John Croese back in 2001, Sid, but you have—with HDCs—now taken us to a whole other level of clinical specificity. So tell us how you, then, got into the Hymenolepis diminuta cysticercoids (HDC) organism. I probably pronounced it wrong and you can help me. How did we get there? Introducing Hymenolepis diminuta cysticercoids (HDCs) SB: It took me a little while to roll that off my tongue, but you came very close. Hymenolepis diminuta cysticercoids. I got there by having a patient about 15 years ago—I don’t remember how long now—with inflammatory bowel disease. And I had told the mom of this boy that I knew that a publication by Joel Weinstock was out there and he could use these TSO (trichuris suis—“suis” for pig—ova) to restore immune tolerance in people.[1] When I read that paper I said to myself, “Wow, this is an amazing thing and where am I going to get TSO eggs?” He had done this in Iowa, where there are a lot of pigs, and you know what? It comes out of pigs. But soon after that, this very crafty mom said, “You know, you can get these now. You can order them from Germany.” And within the next couple of months they became available on the web. So I started using TSO very early in the game in the United States, and immediately developed an experience that was really stunning to see people with very complex, very serious illness get better with the TSO. These were rather expensive—you had to order them on the internet—but they were very effective. The first time I took a dose just for seeing what it tasted like—I wasn’t at all expecting anything of it because my health is quite good—my allergies, which had been present in my existence forever (my summer allergies—since I was six years old at camp years ago I’ve had a handkerchief and a lot of sneezing and running nose all my life), they went away four days later after one dose of TSO. It caught my attention, and I can tell you more stories about TSO, but having done this for a few years I was having dinner after a meeting when we were both talking with William Parker, who is a professor of surgery at Duke and is really the person that we all owe a tremendous debt of gratitude to for refining this concept in a way that gave him an answer to my question, which was: “Gee, William, I think that in the long run the kind of worm that we’ll end up with as the best one for doing what we’re trying to do here, right?” “No,” he said. “Tapeworm, for sure.” Because he had looked into it with his keen, keen mind and experiments. He’s a professor of surgery at Duke, but he’s a biologist and not a surgeon (he does cancer research). I said, “Well, tell me all about it.” So then we corresponded for about a year and he finally said, “Look, there is this thing called an HDC and we think this is a good bet for now. Ultimately there will be something that can be put in the human diet like iodized salt that will spread this influence throughout the population and stop this epidemic of autoimmune disease.” That’s his dream, but my dream, of course, was to help my patients. I flew down and spent some time with him and he showed me how this was done and he has written it up and I can provide to people who are listening a copy of his notes on this.[2] And I came home and I got a microscope and started raising these beetles and getting the little HDCs and giving them to my patients. And right away I had the joy that clinicians can have from time to time of seeing people with really dreadful things wrong with them get better in ways that made it perfectly clear that this was what was needed, and this was not just autistic children but people with all sorts of autoimmune problems. I can give you a couple of stories in a minute when it’s my turn again. JB: Thank you, and I think that now we’re crossing an extraordinary threshold because on the surface of these specific helminths are certain kinds of mucopolysaccharides and other molecules that they elaborate from their own metabolism that have immune active effects and whether they work directly by membrane-binding ligand, direct-receptor activity or other effects that we talked about earlier to modulate signaling that is associated with the gene expression of inflammatory cassettes of genes. I don’t think we fully understand that mechanism, but we certainly clinically understand the benefit. In fact, John Croese himself was a co-author of a recent paper from the Royal Society. This is a London publication. This was a 2015 publication titled “Suppression of Inflammation by Helminths: A Role for the Gut Microbiota.”[3] In this paper he goes on to say: “Recent investigations have highlighted the promise of helminth-based therapies for the treatment of inflammatory disorders.” These have direct effects on lowering inflammatory gene expression and shifting M1 to M2 macrophage activities and putting the proper balance in between proinflammatory and anti-inflammatory mediators. And this was, as I said, just published in the Royal Society Journal in 2015, and it’s one of twenty thousand-plus citations over this evolving last three decades that have really talked about the important role that these specific worms have in modulating immune function through gut signaling. Where you are taking us is across a threshold of a new way of looking at the microbiome in a more complex way; it’s not just bacteria and primitive organisms, but it is also helminths and has influence on the signaling processes. You talked about “raising” HDCs from beetles. That’s probably a story that in itself is kind of interesting for our listeners. Can you tell us a little bit about that? History and Background on the Presence of Worms in the Human Food Supply SB: Yes. At some point to say a little bit about to help patients cross the threshold you just described, because as soon as the word “worm” gets used, obviously you’ve introduced much more of barrier than a lubricant to the idea that you’re trying to put across. The pamphlet that William has produced gave me the guidelines to go out and find the necessary tools to do this. It’s important to understand that what we’re talking about is something that is already in the food supply. Human beings began to raise grains ten thousand years ago, and I’m sure right away that if you’re going to store it for a while you can’t let it get wet. A grainery has to be extremely dry. When I was in Africa and if you go to a little village—and maybe the architecture in different villages in different parts of Chad where I was a Peace Corps volunteer and a doctor for a couple of years in the 1960s—it’s quite different from place to place, but everybody has a way of building a grainery where they can store their millet so it doesn’t get wet. Now, the other thing that they need to have not get in the grain is rats. When people started raising this kind of stuff (grains), rats caught hold and rats became, now, as you probably know, more numerous in New York City than people (and that’s just in New York City, nevermind the countryside where we grow crops and rats like to eat). So rats get into graineries; no matter what, you can’t keep them out. Even if you get Monsanto in there to spray it all and ruin the food you still couldn’t get it out. So the rats are in there, and as I just said it has to be really dry. There’s another kind of critter that likes grain, and that’s grain beetles. And we all know what grain beetles are like as a general genus, so to speak, because in your pantry from time to time you see these little moths flying around and it turns out you have a box of something on the shelf that’s been there for three years and has developed from the eggs that were in there—stray eggs that were in the grain that was used to make the Wheaties of whatever is in the box—and these critters that are in grain, they live there but it’s very dry in there. But what do they have in the grain, but rat poops, which are just moist enough to satisfy the thirst of various kinds of small organisms in the beetle family that live there. Now one of these beetles is the so-called grain beetle. There’s a particular one of them that is suitable for what we’re talking about, which is having in its flesh the eggs of the rat tapeworm. So the rats are in the grain to eat the grain, they poop and they have the tapeworm eggs in there. The rat tapeworm has a deal with the rats, which is first come first served, so a rat has only one tapeworm. And then these tapeworm eggs get into the grain and then the beetles eat the poop to get the moisture out of it and they get infected with—or they get a gift, you might say—these eggs. Now these eggs don’t develop into worms in the beetles. There certainly isn’t enough room in a beetle for a worm. Instead they develop into this very cute little organism that has a little round head with two dots in it that looks a lot like eyes (of course they’re not, but it’s very anthropomorphic in a way). It has a little line between the eyes that looks like a nose, and it has a tail on it which lengthens with the health and the age of the HDC, which takes a few weeks to develop in the beetle. It’s in the flesh of the beetle. So I put the beetle down on the dissecting microscope. I take off his head so he doesn’t suffer too much, and I dissect out (under saline) these little critters. And these things, if you put them in a little vial, which we do for shipping—we’ve just finished now shipping these boxes of things to people on ice—if you hold the vial up and look through it under a certain light you can just barely see these little flecks of white, like the smallest fish you ever saw. We serve them up in doses of 1, 2, 3, 4, 5, 10, maybe 20. There’s a certain knack to raising them. I’ve been doing it now for nearly two years and learning all the way. I have now finished building a clean room, and it is a lot of fun, and the stories that I get back are just great. Now I’ve taught another doctor in our tribe how to do this and he’s going to get started soon. In the meantime I have been supplying HDCs to his patients under his consultation, because I don’t want to be sending these things to people around the country who aren’t my patients but I can send them to other doctors’ patients. Clinical Availability and Use of HDCs Now, there’s a way to get these things at a website called Biome Restoration. And this is run by a woman named Judy Chinitz; she’s the mom of one of my patients. We’ve been friends for many years, and she took off on this. I introduced her to William Parker and she took on sort of a different model. Mine is a consultative model for people with pretty complex illness, and hers is this is kind of good for everybody (sort of the precursor to what William is thinking about, like this should be in the food supply somehow). Her HDCs come from England. They are much less expensive. Mine are farm fresh, so to speak, and hers are a little bit old and not quite as strong (William says) as mine, but they are effective, and so it’s a very accessible thing for patients to try. And the downside of it is…if you look at the basic clinical decision-making formula BROCS (benefit, risk, odds, costs, and stakes), the stakes for the patients that I’m treating are very high. The stakes for the people who are getting this from Biome Restoration can be much lower: just to improve your health or see if your eczema will clear up or so on. And the cost is minimal (bearable, let’s say). The odds of success are way over 50-50 for people with chronic illness, so you don’t need to dicker too much about that; they’re good. And the risk is basically as close to zero as you get in any kind of a doctor’s office. And the benefit, then, is huge. So the idea of giving this a try seems attractive. JB: Last month an article was published. The principal author is the head of gastroenterology and hepatology at the University Hospital of Zurich (Zurich, Switzerland), and the title of the paper, which is in Translational Research, is “Helminth Therapy for Organic Diseases?”[4] I thought the abstract was very timely given what you’re talking about. Let me just quickly give the listener the abstract. It goes on to say: “Autoimmune and chronic inflammatory organic diseases represent a ‘post-industrial revolution epidemics,’ and their frequency has increased dramatically in the last century. Today it is assumed that the increase in hygiene standards reduce the interactions with helminth parasites that co-evolved with the immune system and are crucial for the proper functioning of the immune system. Several helminths have been proposed and tested in search of the ideal therapeutic. In this review the authors summarize translational and clinical studies and review the caveats and solutions for the optimization of helminth therapy.” So this pioneering that you’re doing, Dr. Baker, is quite interesting because it appears as if right with you or behind you is this extraordinary research that is being published—part of these twenty thousand-plus different citations in this area in Pub Med. SB: That’s a wonderful summary of what we’re talking about and what he is saying. You know, when I was in Chad as a Peace Corps volunteer I saw a lot of sick people, and you could see what was called in medical school pathology. You could see pathology just walking around the marketplace or out in the countryside, although most of the people there, I must say, were beautiful, healthy, just stunningly handsome people. But then if you had somebody who had something bad wrong with them it was also visible. And yet over two years there I basically never saw anybody with an autoimmune disease and in speaking to missionaries and others who had been there a long time they would point out how different the health of the Africans was from ours, along the lines that your quote just described. You know, we are all, I think, in our field—those of us a little bit on the older side—are keenly aware of the fact that we see the incidence of autoimmune disease just rising and sometimes in really conspicuous ways. I have a patient, who is the husband of one of my very longstanding patients going back 30 or 40 years, who is a successful businessman, a very active man, and an absolutely champion golfer. For a man of 60 years old he really wins championships in whatever league he’s in. And he got Hashimoto’s thyroiditis, you know with antibodies and all that, and he was feeling lousy. He’s been seeing his doctor in Rhode Island about this and he finally got around to complaining to Sid about it and he said, “Hey, Sid, can you do anything for me about this because the doctor said there really wasn’t anything to do except take some thyroid medicine” if it got to that point, so to speak. I said, “Yeah, I’ve got something for you.” I gave him some HDCs, and I was speaking with his wife a month or so ago and she said, “George is so happy with the HDCs.” And he hadn’t even bothered to tell me this. But what happened was his golf score really got bad when he was sick with the Hashimoto’s, and for him that was a disaster; I mean, golf was everything to him. You may know some golfers. I’m not a golfer, but you know how it is with golfers. His golf score was everything and it went from low 70s up to 80, and he just thought he was getting maybe too old and the game was over. Once he was on the HDCs he started feeling wonderful and his golf score went to 72, he won the tournament, and his Hashimoto’s antibodies (anti-thyroid antibodies) went away. I mean, there you are. What a thrill that is to see somebody benefit that way. I’ll give you another one, and this is a good one because it goes through the history of my whole thing about the microbiome. In 1977 I was lecturing in Chicago and another lecturer was Orian Truss, and when he finished talking I thought to myself, “Holy feces. This is really an amazing thing that he said about the role of Candida in people’s health after antibiotics and other reasons.” So I went home and I started working on fixing that part of the microbiome, killing yeast. And that’s been something that I’ve been into for all these years. I owe a tremendous debt to Orian Truss for getting me started with that. An Anecdotal Case Study of Alopecia So now just recently—just a year ago, in fact—I had a little girl come to me from Connecticut with alopecia. Well you know hair loss is a really distressing thing for people. Even if it is minor hair loss, especially in women it can be something that is really vexing, and of course if it is the alopecia areata version it is really terrible. Here is purity in autoimmunity. Here is a disease with antibodies in your hair follicles and your hair falls out, and the rest of you can be pretty healthy. So I said to her mom, “You know, for years I’ve been treating alopecia with antifungal drugs. Not because it’s a fungal infection of the scalp, mind you. This is because it’s an autoimmune thing where the yeast problems in the gut are the trigger for this mistaken identity process that we call autoimmunity, and so we should probably give her some antifungal medicines, but I’ve also been using these HDCs now for a little while, and so we should give her that too just to cover the bases both ways and give her the benefit of things. We might get a little confused by success but that’s okay.” So six months later I haven’t heard from her and I’m sending her the HDCs every couple of weeks and I call her up finally. I usually don’t track down my patients, but this time I was so curious to know. I called her and she said, “Oh, her hair is beautiful. It’s all grown in.” And I said, “Gee, I guess now we’re a little confused about whether it was the Saccharomyces boulardii that I gave her for the yeast or whether it was the HDCs.” And she said, “Oh, she didn’t take the Saccharomyces boulardii. She didn’t like to swallow it and she said Dr. Baker probably wouldn’t mind.” And so she was a pure case of the HDCs for alopecia, and this is something that is not easily treated through any other means, so I would encourage our listeners to tune into that possibility. To get it you can get it from Biome Restoration dot com or call me up or something, but alopecia is a pretty good place to start. So whether it’s golf scores or alopecia, you’ve got a metric that’s so visible that it takes away some of the mysteries of what we do clinically. JB: So, what do you think is going on here, Sid. Do you have kind of a hypothesis as to how these specific ova are influencing immunological function? As you said, it’s almost a hormetic effect because you’ve got a very, very small signal having a very, very big physiological effect. A Concept to Consider: Has the Absence of Certain Pathogens in the Gut Led to an Increase in Autoimmune Disease? SB: You couldn’t have said it more clearly. I think the notion of restoration is a very important word in all this because if people think you’re doing something that has never been done before and it’s kind of creepy and scary, that’s just not the way it is. What’s wrong is beautifully wrapped in the title of the book to read, which is An Epidemic of Absence by Moises Velasquez-Manhoff.[5] Moises is a science writer and has written this beautiful book that describes all this. The idea is it is an epidemic of absence: this is being caused because we’re missing something that we should have. So its presence and the way it has kept the immune system tolerant…that’s the baseline. And then you have to say, “Well, how did the loss of it cause intolerance?” Now we have to come back to the point that is the fundamental point in functional medicine: that we understand that health and the biology of health is a systems problem. We live in an environment where hierarchical thinking—and our training has been largely (not necessarily in naturopathic medicine, but I mean in the way I was trained)—is the way that we think. In fact, if you look up in the dictionary for the antonym to hierarchical, there isn’t even a word for it in the English language. It’s non-hierarchical, right? But we don’t have word that embraces this notion of systems thinking, so the system in which human beings have lived has had this precious quality of tolerance. If you look at the two most valuable features in a healthy system, whether it’s a political system, an economic system, a biological system, even mechanical systems, tolerance is a very important feature, and the other of course is diversity. So diversity and tolerance are two features of complex systems that need to be preserved. And it happens that when these organisms became absent from the human gut, the human gut lost tolerance. Now we have to go back to your question, which is what were they doing there that was so good for tolerance? Well, I think that’s a tough call because if you look at it from a political standpoint, what were people doing that made them peaceful? If you look at tribes of Native Americans, some of them were peaceful and some of them were war-like. What was it that the peaceful ones had figured out that kept them the way they were? I think that turns out to be a systems problem that is not insoluble, but it would take a lot of data to really get a handle on it. Now, of course, now that people like Yehuda Shoenfeld and others are looking at the biochemistry of this and immunology, they will come up the kinds of compounds that you mentioned that are the messengers of tolerance. But I think to frame it within an understanding of tolerance is a very good way, and I must say for talking with patients about it I think that the first thing that they have to understand is that the immune system is like the customs and immigration at JFK airport or at Los Angeles airport. These people who are passing all these passengers through the gate every day are there to tolerate just about everybody that comes through. It’s an enormous tolerance project. Rarely, they catch somebody who has a name, is on a list, and then it usually turns out to be a case of mistaken identity, which is what autoimmunity and allergy is all about. And then rarely they catch a bad guy, which of course their whole reason for being there is to catch bad guys, but really the reason for their being there—the functional reason—is that they’re there to tolerate everybody with a passport. And when that goes wrong—when you lose tolerance—you have a real mess, and that’s what we are talking about can be restored by adding in these very simple little critters, which are so powerful. I mean the subtlety of it is just so stunning when you see a little girl’s hair grow back when she’s taking like five HDCs every two weeks. It’s just crazy. JB: Well, you know, again I’m probably overemphasizing something, but it takes me once again back to the dinner discussion we had with Candace Pert that evening and your very insightful question. Because maybe a lot of these things we’re talking about don’t have stoichiometry that comes from simple chemistry and one effector gives rise to one unit of activity, and that there are other things that are going on in this complex milieu that we call physiology that really speaks to the system that you don’t get with individual reductionistic piece-part analysis. I mean I don’t have the answer to that question, but it certainly raises across a number of different observations that we’ve made about the difference between complexity and simplicity in terms of whole organism effects. It just keeps coming back to tell us there is lots yet to completely learn about what’s now being called the regulome. You know, that’s the new term I’m reading: What is the regulome, that is the master orchestrator for all these things that are downstream that we call our functions? This story of HDCs is, to me, a brilliant example of things that we still don’t understand completely—this whole concept of action greater than that which we expect, not a linear dose response curve. This hormetic effect is still a very, very big and important part of our physiology. We all are familiar with the terms probiotics and prebiotics and symbiotics, but now we’ve got to add to our microbiome terminology a new term: primobiotics. Are you getting some stickiness, to use a Malcolm Gladwell term, for the term “primobiotics”? Will “Primobiotics” Someday Become a Common Term? SB: Well, there’s a story behind that. I have a patient who is former significant foreign correspondent for a news agency from back in the 1960s who was stationed in Europe, and she had horrible chronic eczema. And when I started treating her with the HDCs, we were calling them HDCs or I also called them “little dudes.” That came out of the conversation I had with William Parker and his wife over breakfast and I inquired, “Don’t you have something cuter than HDCs to call these things?” And that came out of that conversation. So then my patient said, “Sid, you know, these are very powerful things and ‘little dudes’ is kind of too cute. You should think of something that is more serious than that. And after all, they’re kind of like probiotics, right?” And I said, “Thank you so much for that comment.” And I said, “I will think about it.” And about ten minutes later I came up with the term “primobiotics.” And actually I decided, heck, why not trademark it, and there was nothing like it out there so I trademarked it. Whether that will get around, I don’t know, but I think it is a good word because it does have this strong connotation—and realistic connotation—that this really is just another kind of probiotic. Not that probiotics themselves aren’t very good, but this is so much simpler and so much more dramatically effective than most of the probiotics that are out there. I should say that one of the things I’ve learned from William Parker just recently is that the Lactobacillus genus doesn’t go well with the HDCs so you need to give them a little bit of distance, and I now have patients take Lactobacillus-free probiotics while they’re doing the HDCs to get them the most benefit. It won’t spoil the deal, but you get a little more bang for your buck if you don’t take the Lactobacillus-containing probiotics along with them. JB: Well, I think that where the tire meets the road, here, probably for our listeners, which are always—I like to think—right at the cutting edge of this evolving new field of functional and systems biology in medicine, they probably want to know how would they follow up with you? What’s the best way, knowing you’re a very busy guy? What would be your recommendation so they can follow up and learn more about HDCs? SB: Number one, I would get ahold of Moises Velasquez-Manhoff’s book, An Epidemic of Absence. It’s a very sober and readable book. Patients should read it as well. Let me know and I can send copies of the materials that I had to begin with. And then if you’re looking for sources, the website Biome Restoration is accessible. And if you have complex patients and it would be more important to be in sort of a consultative arrangement, then that’s also an option. We’ve finally reached stability in our little farm here so that our production is pretty reliable, but of course I’m just one guy and there’s another doctor now who is gearing up to do this, a respectable member of our tribe. He came here and we trained him…I say “we.” My assistant is a woman who has taken on the job of being the chief rancher after I trained her and she has taken it many steps beyond what I was able to tell her, so we’re setting up to be able to answer people’s needs, but our production is limited. I think for people with complex chronic illness there is a consultative role that may be entered into. JB: That’s great, and should they contact you through email? SB: Yes, email is good: sidneymb@gmail.com is my email address. JB: Well, Dr. Baker, as always these opportunities we’ve had over the decades to check in and be reenergized with a vision of where things are going with conversation with you has been inspiring. But I think beyond inspiration there is also this news-to-use component that this is a whole new tool. This is a whole new way of looking at the microbiome as a therapeutic opportunity. I think there couldn’t have been a better way in our four-part series on the microbiome to have our clean-up hitter as Dr. Sidney Baker to take us into the 21st century, or maybe back to the future would be a better way of saying this. We thank you again for your tireless work and introspection, vision, and ability to synthesize and then make it all work. Moving from theory to practice is not easy. We might have 20,334 publications in helminth therapy but we only have one Sid Baker helping to guide us forward, so thank you very much. SB: Thank you, Jeff, and if I could just say as a final word that the thing about this that’s alarming to me in a certain way is that here is something that really is a kind of panacea, a kind of cure-all, which as I mentioned before is one of medicine’s most awful heresies or abominations, so one has to be careful when walking this walk because there are people in our profession who are ready to pounce on those who claim that they have something that works so well as this, but it certainly is the thing in my whole career that has worked better than anything else and so I’m thrilled to be able to talk about it, I’m grateful to you, Jeff, for all that you’ve taught me, and for the chance to have this conversation. JB: Likewise, thank you. The best to you and we’ll be following up. Thanks so much, Sid.  

Bibliography

[1] Summers RW, Elliott DE, Qadir K, Urban JF Jr, Thompson R, Weinstock JV. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenterol. 2003 Sep;98(9):2034-41.   [2] Weinstock JV. Autoimmunity: the worm returns. Nature. 2012 Nov 8;491(7423):183-5.   [3] Giacomin P, Croese J, Krause L, Loukas A, Cantacessi C. Suppression of inflammation by helminths: a role for the gut microbiota? Philos Trans R Soc Lond B Biol Sci. 2015 Aug 19;370(1675).   [4] Leonardi I, Frey I, Rogler G. Helminth therapy for organic diseases? Transl Res. 2015 Jul 3.   [5] Velasquez-Manhoff, Moises. An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases. New York; Scribner, 2012.

Hey, here we are at the year-end December 2015 Functional Medicine Update and, oh my word, do we have something in store for you and me as well, and that is a discussion with two of my favorite clinician/functional medicine resource/thought leaders/extraordinary parents and citizens, and that is Drs. Michael and Leslie Stone. If you are in the functional medicine community both their names are very well known.   Just to give you a quick background of the Stones, they both were University of Washington Medical School graduates. Michael came up through Washington State University. He was at Washington State and got his Bachelor’s and Master’s in nutrition there. Leslie did work in psychobiology at Washington State, so presumably many years ago—we won’t say how many, but a couple—they met and later then became husband and wife and have practiced medicine for many years. They took over Dr. David Jones’s practice in Ashland, Oregon to free him up to become the president of the Institute for Functional Medicine, and they have done an extraordinary job in Ashland after being in practice in Idaho for a number of years prior to that. They are both extraordinary thought leaders, as you know, in bringing their background and vision as it relates to how to do good medicine into the training of practitioners coming up the ranks in functional medicine.   FMU Closes One Chapter and Begins Another I’ve asked them if they would be our celebratory last clinician-of-the-month interview in Functional Medicine Update under the terms and conditions that we have done it for 34 years, which has been a subscription-based service that Jay Johnson and I have been producing. Hard to believe 34 years, so since 1982, without the loss of a month. That’s a testament, probably, to Jay’s and my endurance, because there have been times where we probably would have liked certain issue to have passed, but we’ve been very fortunate over those years to have an extraordinary number of thought leaders that passed over our frontal lobes, and really I consider myself a mosaic of those many, many people we’ve been privileged to interview.   I thought the Stones would be a perfect vision of what we’ve been trying to accomplish in Functional Medicine Update all these years, not just because they’re experts in the field, but also because they represent everything from pre-conception care up through conception, infancy, childhood, adolescence, young adult, adult, mid-life, older age, geriatric, and end of life. They are really the quintessential examples of where functional medicine really applies, which is throughout the whole life process, starting even pre-conceptionally. That’s a topic that we don’t spend a whole lot of time over the years actually exploring, and there’s no better place to explore it than with Michael and Leslie. And in fact they were authors of what I think is an extraordinary study that was published recently that we’ll talk about. This is titled “Customized Nutritional Enhancement for Pregnant Women Appears to Lower Incidence of Certain Common Maternal Neonatal Complications.”[1] I think that that title alone gives you the landscape of what we want to talk about over the course of the next, say, 50 or so minutes.   Both Leslie and Michael, welcome to Functional Medicine Update and thank you so much for being the last of our 34-year process as we move into this open-access in 2016.  

INTERVIEW TRANSCRIPT

Clinicians of the Month Michael Stone, MD and Leslie Stone, MD Ashland’s Comprehensive Family Practice 595 N Main Street Suite #2 Ashland, OR 97520 www.ashlandmd.com MS: Well, what an honor to be on this program with you and we’ve talked to so many people who have been influenced and their lives have been changed and there are thousands of patients that you’ve touched through this work, so everyone on your production team and you bringing this stuff forward so people can listen to it and apply it every day, Monday morning, as we say, has truly changed hundreds of thousands of lives and we just honor that, for all that you’ve done. It’s a wonderful vision and just a great, great, great service you’ve provided. LS: Absolutely, thank you. Diversity in Undergraduate Training Lays Foundation for Functional Medicine Path JB: This is kind of the proverbial starting place because some of our listeners may not be so familiar with how your journey in life got you to this point where you’ve really refined your model and you’re applying it and you’re recognized opinion leaders. I mean, we start off on a journey and we’re not sure exactly where it’s going to take us, so maybe, Leslie, we can begin with you and this background you had in psychobiology. I can identify with that, actually, because one of the most interesting courses I took as an undergraduate at the University of California at Irvine was in psychobiology with Dr. Weiner. We did animal taxonomic surgeries and things, and I’m thinking back to how extraordinary that was in enlightening me to how things like taste, and thirst, and all sorts of biological functions are tied to perception and neuroanatomy. Tell us a little bit about your background. How did you get from where you were to where you are today? LS: Well certainly my initial interests were in large animal veterinary care. It turns out my undergraduate research took me to the vet school, which was looking at behavior of dry- versus wetland rodents, and I think this is at a time period when neurochemistry was just a new thought, and the idea that we could measure different neurochemicals in specific areas of the brain, isolate their pre- and post-synaptic locations, and be able to predict or describe their behavior was novel and new and quite exciting. JB: So from there, what got you then to say, “Okay, medical school is where I’m going to take this background and training,” and then from that into where you have found your niche and ultimately to Ashland, Oregon? How did that travel for you? LS: So, my interests have always been based in that concept of what is it about us—biochemically, neurochemically—that is both impinged upon our behavior but also predicts our behavior, drives our behavior? That seemed to translate very much to me in that early developmental time period. The question was always, in my mind, as we were going through the education process learning how to take care of patients, why is it we do what we do, and how is it that I can influence that? It became more obvious to us that as technology allowed us to understand the influences on behavior, such as that early undergraduate research, morbidities that we had accepted as static and unchangeable such as hypertension in pregnancy, such as diabetes in pregnancy, such as these chronic diseases of aging, instead of accepting those as static and unchangeable, that by influencing our health in a pre-conceptual manner in those early time periods—that plastic time period—that we can truly impact our global health. This came to us over 30 years of observing maybe not the fastest change in health that we really wanted to achieve, and yet not being willing to accept that as something that was unchangeable. The good news is we do have some tools in our toolbox that let us investigate and drive change that is going to improve our health in first and second generations. JB: That’s a powerful summary. Maybe I could just ask you a quick sidebar: What made you then decide not to, say, go into OB or pediatrics, and to stay in family practice? Family Practice: The Magic of Caring for Patients at Every Stage of Life LS: Well, I’ll just take it from a personal note, and that was I did take it into OB/GYN initially as an intern, and I came to the end of my internship year, and having been totally enamored with the concepts of reproductive endocrinology and all of the shifting remarkable mutable changes of physiology throughout the woman’s body and the changes that happen with development, and found that, boy, at the end of that one year I have to say goodbye to the concepts of what happens next to that neonate as an adolescent and as an adult and as one of our treasured elders—what happened to them and how did what I did during this one year with their lives impact their future health? As an obstetrician I was not able to ask those questions or observe those questions and be able to see what it was that was going to make a difference—a true difference—in their lives. And so I stopped and decided to go into family practice because I knew that that was something that came across the life cycle. And of course that combination, along with an additional education experience in high-risk obstetrics, gave us that unique perspective that says all that we do pre-conceptually, which for me starts as soon as that baby is out of the womb all the way through to the point where they are now of reproductive capacity—all of that plasticity impinges on that health. I think of that neonate as an 85-year-old healthy elder. JB: Yes, I have to honest up to you and do a mea culpa here. The reason I asked that question, which you and I have never spoken about personally nor did we do any preparation on this, was because my intuition told me that you were going to answer that question exactly as you’ve answered it—that your thought process was the timeline approach. I guess I give myself a gold star; I must have hit the right intuition. LS: You’re right, the concept of timeline, of context, of each event impinging on the next, that’s exactly how to think about this, and our position here gives us a unique perspective to be able to observe and query it and ask it and demand more of it. I mostly deal in a low-risk obstetric process population, but for the most part even those morbidities that we were experiencing seemed like they just didn’t change and so we really needed another way of making a difference in those lives. We needed another way of asking the questions, another way of intervening on those answers, and remarkably I believe that we have some really different outcomes. JB: Thank you. Michael, let’s move over to you. A Master’s in nutrition…clearly you had some thoughts as to where your professional life was going to take you at your completion of your work at Washington State. So how did that then travel into your medical school training and how do you think that that forged your template—your epigenome, so to speak—as you moved forward? MS: It was very impactful because I always say that my undergraduate/graduate degrees and training in nutrition in which we spent laborious hours in pathophysiology of nutritional and medical issues with some brilliant professors in nutrition was so influential because once I made a shift to human nutrition from zoology at Washington State University I was suddenly in a very applicable, bite-by-bite world of understanding. Through my Master’s work in which I dove deeper into the mesenteric work—I looked at rats and seeing how they adapted to different monosaccharides and disaccharides—and I got into the University of Washington School of Medicine, it was really washing my medical education over my nutrition foundation, and so I saw things differently. JB: Yes, I bet you did and I bet your fellow classmates probably wondered why the heck you were asking or thinking about certain things that were not even on their radar screen, I have a suspicion. MS: Well, that’s true. In fact, one of my summer projects as a TA was to help assess the nutrition knowledge of the third- and fourth-year medical students and residents at the University of Washington. I documented that and in the whole curriculum, if you cobbled things together, there were only 15 ½ hours of any nutrition exposure during the whole medical school experience at the University of Washington, which wasn’t necessarily taken kindly to as I brought that forward as maybe something we should change. But then what really totally changed my life and perspective was when Leslie was starting her fourth year of medical school and I was finishing my first year of medical school we were at the headwaters of the River Kwai on the Thai-Burma border. She had a lot more experience and had a lot more rotations under her belt, so in a one-doctor hospital with two hours of electricity a day through a generator and a hand-crank centrifuge she could participate primarily in surgery and all that, and for me, I was an observer. But my task was to do a nutrition assessment on all the children in an orphanage in the Karen tribe—over 250 kids—and trying to do a nutrition assessment on those kids with the same gifts and tools that the physicians of the millennia had: they had their eyes, they had their ears, they had their sense of smell, they had the ability to look, listen, feel, and in this case, set out difference bowls of food to try to do, through a translator, some idea of a 24-hour recall. And the results of that experience, with a hanging scale and a hand-crank centrifuge if the child had to have a formal hematocrit checked, really catapulted me into this love and appreciation of the physical exam. So we could take those tools, and eventually, through a functional medicine model, begin to develop points of connection. So between the patient’s context that you see this physical exam finding, the context of their story with the company that it keeps, you immediately begin to tie it to the quality and quantity of their lifestyle and diet. We can take the same launch point and we can begin to see more through our understanding of epigenetics and the genome now. I would say that the nutrition foundation, washed over with the medical education, and then catapulted forward through the functional medicine model has totally changed how we communicate and how we see the patients. Development of a Nutritional Enhancement Program for Pregnant Women JB: Well now I want to thank you both. That was a really great landscape understanding of this extraordinary training and background that you bring into your work and how it has evolved over the decades now. I’d like to take you both back to a little story that you may not be familiar with, and that’s a David Jones story—Dr. David Jones, your colleague there in Ashland. David and I were speaking—and I’m going back now to the early 80s, actually—and we were talking about an impact that Dr. Brewer made on him as it related to toxemia pregnancy. As I recall the story—and this is coming from memory—when he was a medical student at the University of California at Davis he was very impressed with the work that Brewer had done on trying to reduce the adverse effects of toxemia pregnancy through nutrition and he was considered to be a heretic in his own profession as I recall (Dr. Brewer), and was excoriated for whatever reason that this was not how you reduced hypertension and preeclampsia and so forth, and eclampsia was not a nutrition-related problem.[2] Now we move up to 2015 with what you all are doing in this nutritional enhancement program for pregnant women to lower both maternal risk and neonatal risk, and it seems like we go back to the future; we learn old things in new ways and support them. Am I making a story, here, that has any sense from your perspective? LS: Absolutely. I know that even currently the concept that we can manipulate the expression of our genes, that we can manipulate the enzymatic activities in such a way as to promote or reduce the morbidities in pregnancy and developmental programming is a concept that is hard for people to wrap their brains around. You know, it still remains so, and yet we now have available to us great epidemiology that what we do in this peri-conceptual time absolutely without a doubt influences our chronic diseases as we age. That leaves the question hanging out there: Okay, then, if our nutritional and our stressor inputs during this very plastic time period…if it can give us a deleterious outcome, that means that it can be manipulated and if it can be manipulated for the worse, it also means it can be manipulated for the better. And that is what actually provoked us to take a look and say, okay, where are the vulnerabilities in that peri-natal time period? Where are they? Because you’re obviously not looking at them now. Let’s find them. And, as a course, as a happenstance of where we are in our technological timeline, it turns out that we do have a human genome from which we can draw enormous amounts of data that apply to how we are intervening, that if we can do it prospectively and say, “Oh, we now know that if you have certain constellations of single nucleotide polymorphisms, we already know their metabolomes.” We know where we ought to be able to intervene, and then all we have to do is take that and apply it and say, okay, here’s the study population that has nutrient sufficiencies that let them be vulnerable, and then here we have the ability to take a look at their genome in a small way—we’re not where we need to be, we’re not going to be as good as we are in the future, right, but we can still take a look right now—and apply that information, and lo and behold, get better outcomes in our immediate measurement tool, which is in the health of the mother and health of the neonate. JB: So let’s take that from the broad brush into the more specific, because when you talk about customiz[ing] that sounds like some degree of personalization, so the questions we ask determine the answers we get, so if you want to be personalized you’re going to have to ask probably a different set of question than you’d ask just for one-size-fits-all. How do you actually approach this? What’s the schema that led to development of your program and ultimately to your study? MTHFR: A Metabolic Kingpin LS: Well, as we’ve learned more about the genome itself and specific single nucleotides, I think the kingpin for us was a single nucleotide polymorphism: MTHFR. And we realized because it is such a centerpiece in setting the pace on many, many metabolisms in the body—you know, inflammation, detoxification—we realized that would be a great place to start, and we knew enough about what its predispositions would be. If somebody had an MTHFR single nucleotide polymorphism we knew that they were going to be at increased risk for such things as Alzheimer’s and such things as depression, and autism, and several other issues. The most important sentinel study that I think I’ll let Michael talk about was certainly about the risk of autism in the face of an undernourished population: a mother who is not receiving B vitamins in the proper amounts, and if she has a certain set of polymorphisms and her offspring has yet one other, then the chances of that baby developing autism is dramatically, dramatically increased. MS: Yes, that was a study out of UC Davis, and I would say that was one of our go to papers. It came out in 2011 in Epidemiology, and it was looking at one carb metabolism in prenatal adequacy of methylation factors. It looked at whether the mom had MTHFR homozygous recessive along with cystathionine beta synthase and if the fetus had certain CMT SNP.[3] If the mother didn’t have adequate methylation factors three months prior to conception and one month after then there was this increased relative risk of autism in the offspring. Now, that combined with our population here in Ashland really having significant insufficiency of vitamin D, along with our growing understanding of the role of carnitine and the carnitine shuttle and free fatty acid elevations in early pregnancy turning on IGF-1 issues and the whole interplay between IGF-1 and IGF-2 is setting people up for gestational diabetes and the frequency of MTHFR heterozygosity/homozygosity in our population. With the understanding and our assurance based everything from socioeconomic disease the diet was worsening, we posited that our population would be nutritionally insufficient, and so we started looking at just the basic SNPs (MTHFR, COMT), we started looking at zinc levels, vitamin D levels, we were doing diet records and seeing that their essential fatty acid levels, magnesium levels, were low in their diet and we started looking at carnitine levels. What we did is with clinical nutritionists in our clinic, Emily Rydbom and Lindsay Jones initially, we really started trying to put together how could we educate the moms? How could we bring this forward in such a way that was empowering and we could start seeing shifts in not only the degree of morbidities during pregnancy, but how could we improve outcome? And so to answer your question, we had a very finite number of things: we looked at COMT, MTHFR, we looked at SNPs 1298 and 677, and then we started doing a few more additional labs. We call it the standard of care plus, so our plus was checking zinc, and carnitine, and 25-hydroxyvitamin D levels, and being more aggressive about augmenting nutrition in the different trimesters, focusing on whether it’s organogenesis or proliferation, and then really in your zinc, and vitamin A, and magnesium, and essential fatty acid low patients, putting together supplement bridges and food bridges through education that would allow this to happen. JB: Wow, every neuron in my frontal lobe is lit up if we were doing some kind of a scan here—a spectral scan—because I’m being taken back by this discussion, believe it or not, to 1985 FMU: Dr. Derrick Lonsdale, who was our clinician of the month. I don’t even know how I remember this was 1985, but it’s just beaming through. Dr. Lonsdale at the time was a professor of medicine at the Cleveland Clinic. Later he went into private practice, and his colleague was Raymond Shamberger, who was his laboratorian, and they developed a considerable body of data about preclinical beriberi and preclinical pellagra and its effects in children. And they published, actually, a paper in the American Journal of Clinical Nutrition—I think it was 1981 or 82—and they talked about this condition.[4] They proposed that psychological disturbances occur in these children well before you would ever see frank signs of beriberi or pellagra. In fact Victor Herbert even wrote a rebuttal to their paper—I recall it in the same journal—saying that this was an interesting observation and was probably not true because you only have vitamin deficiency or sufficiency, you don’t have any intermediary states, but I think we’ve proven over the years that’s not true. So you get into the question of what is a deficiency and what is an insufficiency, and that’s what you guys are really pioneering. And then even to go back to Leslie and your point about MTHFR, we now recognize that there are a number of polymorphisms within any specific gene, and some have different penetrance to the phenotype than others, so with MTHFR you have three or four major types of SNPs—maybe CT677 is the major, but there are several others that can also participate. So if you’ve got several SNPs in your MTHFR, which is certainly possible and people do have that, it becomes a loaded dice with increasing frequency into the phenotype, and now you have this graded response, right? You’re still not deficient, but your levels of insufficiency become more tissue specific, and I think that’s what you are speaking to and it’s a brilliant evolution of the model that, when we didn’t have these tools of nutrigenomics back in the 80s, that people were observing just phenomenologically. Nutrient Deficiencies are Alarmingly Common in Healthy, Well-informed Communities LS: Yes. You know, I think the other piece of this that alarms me is that as we began looking at different nutrient insufficiencies/deficiencies and struggling with that definition, we found that even if we used a standard definition of deficiency—a laboratory definition of deficiency, not a functional one—we’ve found that, remarkably, in our healthy, middle class population here we had a large story here—the underlying, seeded story—is that we also have those kinds of deficiencies that in my mind should never occur in a healthy, smart, educated, activated community. We found that 60 percent of our population were laboratory zinc deficient. Well, if zinc is one of those enzymes that is required in over 300 different metalloenzymatic reactions, and we know—to emphasize that further—that it’s the neural development, and we actually demonstrated that we have these deficiencies, what about that functional deficit that we are leaving out? If we don’t treat that, what does that mean for the intellectual capabilities of that offspring? What does that mean if we’re not investigating and intervening in these underserved populations? Are we holding them under the thumb of their underprivileged, nutrient-deficient beginnings? We have something that is malleable that we can deal with, and we’ve got to get in there and get it done. JB: Well, Leslie, if I can just once again throw a parenthetical in here…this is really so much fun for me because in 1987 we interviewed K. Michael Hambidge at the University of Colorado School of Medicine pediatrics department, who at the time was the reigning expert in zinc and development in children. He had published a number of papers on Hispanic children in the Denver area and had shown that short stature for age was tied to their zinc status—that these kids just weren’t born with genes to make them short.[5] LS: That’s right! JB: So here we are…this is 30 years, right? It’s even scary for me to say this—30 years ago ago—that this thing has evolved to where now you have really codified this. This is the back-to-the-future ah-ha. LS: This is the moment. It seems like all of these giants, all of these thought leaders, all of this good information, all the technology now says, “Okay, apply it, make it happen.” And that’s what we’re trying to do. MS: And isn’t it that the pressure of the application is our worsening morbidity in our population. The pressure of the application is recognizing that autistic children and their mitochondropathies, and Frye’s work looking at NADH and NADPH levels, and is autism an aspect of that as a mitochondrial pellagra? You know, we can begin to look at mitochondrial exhaust, and we can begin to see how we might influence, in the setting of the timeline of the family and the setting of the pregnancy timeline, if we know X and Y, then we can get just a glance at the genome just by using food and nutritional bridges, and doc[umenting] observable insufficiencies, and we can have altered outcomes and we can have an altered imprintome. We can have a different outcome and trajectory for that child and for that mother and for that father taking care of that child, when we begin to use and capture and enlighten and show and inspire change in the time of life that there is no greater desire to change and that’s during pregnancy. JB: Oh boy, was that well said. And again—this is so fun—Leslie, do you remember the first time we met, which was at an IFM meeting I think that you were coerced into coming to, in which the theme of my presentation was on mitochondria and biochemical energetics? LS: I do. JB: And I recall you said something to me about intellectually interesting, but where does it actually apply? And I think we’ve all been on this path of recognizing how many of these discoveries do apply clinically as we get down the wormhole, right, and we start to really understand how they interconnect into the web of function. It’s just another little interesting memory factoid about this whole process of this community that we’re developing this model and putting the right kind of robustness on the model as we subject it to scrutiny. LS: Exactly. JB: So Michael, your story of the young man that you have as a patient and the unbelievable response that he had to this whole concept of methylation has become the buzz of our field and it’s dramatic. Tell us a little bit about how you think that that observation—because we often learn from our most remarkable case histories—how that can be generalized into other conditions that maybe aren’t quite as dramatic. Functional Medicine is Personal and Local MS: Well, thanks for asking. There are a couple of sentinel cases. One was our daughter, who started having 20 to 30 syncopal episodes a day after being a two-time All American while in college. We took her through all the regular, allopathic physicians—neurologists, cardiologists—and in the end, her youngest brother ended up being her catcher because he could tell when she was about to have a syncopal episode at just over the age of 21. And for about five months there was quite a bit of care and then Leslie staying with her, and shortly after the international symposium where I was asked a talk on vitamin D, essential fatty acids, and folate, and role in mood disorders, where I really began to understand a lot more of the work in neurotransmitter balance and sympathetic tone, that it came bubbling forward. And she has the SNPs and it was a miraculous response to fairly high dose methylfolate, and then we started looking at not just methylfolate and improving neurotransmitter balance, but we started looking at all the different B vitamins and their roles and that chicken wire of one carbon metabolism and the different minerals, and we started bringing balance and seeing that it was really multiple different cofactors that would help to bring balance in the sympathetic/parasympathetic nervous system and neurotransmitter balance. And she went back, after taking a medical red shirt year, to be a third time All American, and that was a stunning, very personal story. JB: Oh my word. MS: And it stops us in our tracks, because all functional medicine is personal and local. JB: That’s beautifully said. Wow. MS: And then we start looking. Lindsey, our canary MTHFR person in our family, helped us look at 300 different people. We checked MTHFR SNPs and, in some, COMT, and she looked at medical symptom questionnaires that came, as you know, out of the whole functional medicine movement. And I said, after looking at all of these, “Lindsey, what you just saw. What are some of the first symptoms?” She said, “In women, it is hormonal disruption. It’s disruption in their menstrual cycles, and once they start seeing that, that’s followed with neurologic issues: depression and anxiety.” She said, “I saw that pattern all the time.” A Remarkable Case History of Autism So then, feet forward with the autism issue and that one case. I was asked to give a talk about methylation and rheumatologic disease, and it took me into methylation and medications (methotrexate and varying metabolism of seizure meds), which ended up taking me into the whole concept of cerebral folate deficiency. How did it do that? It’s because in autoimmunity, if you have a trigger and you have a permeability issue and you trigger immunologic response and you develop an antibody to a homolog that is very similar to a protein in your body, as in bovine milk folate receptor protein in bovine milk or in mammal milk, then it can actually bind to your blood-brain barrier folate receptor (one of the two main receptors), and you can have normal serum folate levels or methylfolate levels and you can be deficient in the CSF. In autistic kids, in variable size studies, up to 70 percent of kids who are autistic have some component of cerebral folate deficiency, a compartmental deficiency.[6] And if the only thing you do is through folinic acid or through methylfolate, you encourage different transport of that folate precursor or methylfolate into the CSF, then you get marked improvement—marked improvement—in these cerebral-folate-deficient autistic children. JB: When you say high dose, probably our listeners are thinking, “I wonder what high dose means,” given that we talk about 800 micrograms. What are we talking about when we say high dose? MS: Well, in the studies that were done with cerebral folate deficiency and autism, they moved toward giving 1 to 2 milligrams per kilogram of folate.[7] LS: Milligrams per kilogram. Not micrograms. MS: Milligrams per kilogram. So in that one case with the video, through tertiary care center, we had a cerebral folate level that was the lowest point of normal, and Frye’s work showed that if you were in the lower half, and especially the lowest quartile, of normal folate levels in the CSF and autistic kids and the only thing you did is you gave folinic acid or methylfolate that you got a response. And so in this child, where there had been a tertiary care workup and I saw the cerebral folate level being lowest point of normal and this desperate mother and this 4-year-old who could say one word—“eat”—after she stopped the cow’s milk, it was those points of connection, and I just asked her if she was willing to give a therapeutic probe to see if we could follow this hunch that he had cerebral folate deficiency as one of the layers of the onion that we are trying to understand as autism. And within three weeks, he had a profound turnaround, and we continue to uncover different layers of the onion in him, but it was such a remarkable single nutrient, compartmental deficiency case of cerebral folate deficiency that it has forever changed our perspective of the power of targeted nutrition at the right point at the right time in the right life. JB: Did he, then, receive more than 10 milligrams of 5-methyltetrahydrofolate? MS: Yes, actually he did. This was just in the early phases of where we are beginning to understand the terrain of the different B vitamins, so he received phosphorylated or activated Bs, including pyridoxine-5-phosphate and methylcobalamine, and then his peak dose then we were able to back off. He received about 40 milligrams of methylfolate. JB: Yes, I think that’s really, really an important little point for all of our listeners to take into consideration because that’s 40,000 micrograms, right, when we say that above a thousand micrograms you get into all these issues that people are talking about, which are really non-issues, but they become issues for some. I think that this is, again, another back to the future. I’m now talking about 1968—I’m even going farther back than FMU—to Linus Pauling and what I consider to be a landmark paper in Science magazine, “Orthomolecular Psychiatry,” in which he lays out this whole concept of mass action, that you can’t change an enzyme so you have to change the substrate or you have to change the apo enzyme and you did try to drive things to completion.[8] When people say that you’re just making expensive urine and this has no effect, the question we would always ask them is then why does megaloblastic anemia need several thousand micrograms a day of vitamin B12 in those genetically inherited individuals to get their B12 to be “normal” for them? And I think this is what you’re talking about, and of course Bruce Ames talked about this in his article in the American Journal of Clinical Nutrition as well.[9] I think this is just a fantastic clinical example of how that mass action principle works, because normal for these individuals is super-normal or super amounts for another individual. MS: It absolutely is true and isn’t that the shoulders of giants? You know, you mentioned very quickly the people that we pull on and have built our understanding, who helped form our neural network that allows us to see therapeutic possibilities in the people on the other side of the stethoscope, and you joined those ranks in this translation from Linus Pauling to Bruce Ames, Jeff Bland, David Jones. These true thought leaders who help us make these points of connection—this constellation—that allows us to have, in many ways, the courage to step forward in communication with our patients to together try therapeutic interventions that may be the first time in the literature, if we were to write them up, they occurred. That is really what this is, isn’t it? It’s really looking across the stethoscope, or listening to the mother or the parent who says, “Is there anything else that can be done? Is there anything else we can do? Do you see? Can you help us figure out how we can help our child, or our mother, or our aunt, or our spouse?” I mean, that’s what this is all about, isn’t it? JB: Yes, absolutely. With that said, you know, both of you are extraordinarily thoughtful about how you proceed with your patients. Someone listening to this who may be unfamiliar with this whole concept might be saying, “Well, everything is toxic at some level, even air and water, so how do you know that you’re still within the boundary of not doing harm?” Tell us a little bit about how you deliberate on that issue of threshold relationships to safety. MS: That’s a good question. We do a couple of things. First of all, we try to see if we’re in the ballpark when it comes to the literature, okay. For example, methylfolate—some of the early work with schizophrenia and severe depression, when you go back, they were dosing folate using 50 and 100 milligrams of folate in these studies with variable response and not marked untoward effect for a short period of time. So you look at it the body of the history. Then we look at it in the body of symptoms. So if there is a toxicity issue, or if there is an untoward symptom, we follow those folks pretty closely. If we’re going to mess with neurotransmitters, we’re going to talk about if you have increased depression, increased anxiety, increased dizziness, please we need to know. Then thirdly, we look at metabolomics. If you have some idea from their family history or from their genomics what they’re doing, then we look at the cell exhaust. We will look at organic acid levels in these folks frequently, and we will use that as a buffer to help us fine tune. Those are different lenses that help us begin to approach therapeutic trials. And when it relates to methylfolate, we appreciate the combination of SNPs, whether it’s MTHFR with COMT. If you crank up serotonin, dopamine, norepinephrine, and they can’t break it down via the COMT enzyme (the catechol-O-methyltransferase), then yes, people have increased anxiety, increased bad dreams. So we don’t start at massive doses. We will gradually go up. We appreciate the dynamism of the metabolism. In short, we try to put it in the context of the timeline and their genome, if we have it. We try to put it in the context of metabolomics, if we have it. And then we put it in the context of the symptomatology and the relationship you really have with them, especially in a primary care family practice setting. JB: Leslie, did you want to add anything to that? LS: I think I would like to approach it from the other end of that spectrum. If we are using what seems like incredibly super-physiologic levels to deal with a complex state within an individual that might require the super-physiologic levels, we also understand theoretically, using Ames’ triage theory, that it may not be that we’re aiming for these super-physiology levels. It may be that we are looking for complexity of different nutrients and looking for their activities in concert. You know, when we talk about nutrient deficiencies, the question is: is this a deficiency as measured in the serum, where it may or may not actually be active? Or is it a deficiency at the receptor site, where it may or may not be a deficiency? Or is it intracellularly within an organelle, within an enzyme, is that where the true deficiency lives, and is it that we really don’t have the sorts of tools at our fingertips at this point that can let us investigate, give us a functional answer, at least a biochemical functional answer, at that very molecular and sub-molecular level? So what we have to rely on, then, is the macroscopic function. So then we blow it right back out to, so, if I know the richness that is necessary to make MTHFR function at its best, if I know that it’s multiple micronutrients, and that I can’t really say how much of each one of these pieces it is (not in a mechanistic sort of way), but that I can answer that question by being excellent in my critical thinking, making sure that my perspectives are broad, and take into consideration all the information, all the context that I can gather, and then I apply those more like a complex soup, a complex dish, and I give that to this patient, this n-of-1, and then I look at their response. I look at do they have less pregnancy-induced hypertension? Do they have fewer small-for-gestational-age babies? And that functional definition tells me if we’ve gotten it right or not. MS: And I would also say that what we, in our transition…you know, if you only have a hammer in your toolbox then everything looks like a nail, so I would say in the triad of important components in this program, one of the most important is really the education and the power of food, and the phenomenal orchestra of phytonutrients and minerals and vitamins that you can bring forward in the food form and let the prenatal supplement pack, or the essential fats, or the different minerals, or the different vitamins, be really a bridge while you develop a food model that really has the wisdom of the ages that allows and empowers the patient to really change their choices and change their physiology and then change the outcome of the child. LS: And then also knowing that that very state of empowerment influences electrochemically the effect on their biome, right? So we have to take that into consideration as well. It’s not just what I give them, it’s how I give it to them and how they receive it. MS: So some people ask us in this program, is it the prenatal vitamins that are nutrients that are far more extensive than what you normally get in a prenatal vitamin, or is it the nutrition classes (the empowerment), is it Emily Rydbom, the nutritionist who coaches these people so exquisitely, is it the app that she developed so they can track and follow, is it the sense of caring and nurturing that occurs through nine months of belief and experience all the way through delivery? What is it? And I would say the answer is yes. JB: Yes, that is exactly right. This is a new way of looking at the systems biology of health, right? That’s what we’re talking about. And it’s very interesting. You both said something—I just want to make a little parenthetical for people that may be new to this model—if we start using the serum to measure what’s going on in cells, then we have to ask, when we’re measuring blood sugar in the diabetic and it’s very high, does that mean the cell is deficient of glucose? And the answer is no, it’s the opposite, right? Or if we start asking what does high cholesterol mean? Does high cholesterol mean you’re making too much or does it mean you’re not converting enough into bile salts and getting rid of it? The concept of systems thinking is a whole different way of looking at the network of biology versus just the simple-minded “this high, then I give this; this low, I give this.” It requires you to look at these interconnections, as you are so beautifully describing. And so some people might say, “Well this is way too complicated and too time consuming, and, you know, I just have an algorithm and I plug things in and it’s a six-minute office visit, so how the heck am I going to do all this?” And so, what do you say? Incorporating Functional Medicine into an Insurance-based Family Practice MS: Well, we say it’s a lens that you look through, and then you meet the patient where they are at. And so you learn more as you look through this lens. So we have an insurance-based family practice model. The longest appointment is one H & P a day, and the rest are 15- or 30-minute appointments. You meet the patient where they are at, so if they are at the place in their allopathic travels that they just need a prescription, then you keep bringing up, “Well, I’ll write this prescription. However, why aren’t we getting any movement in your hypertension?” And then you start working with them. That’s the power of the relationship in the primary care setting. So when you have nurse practitioners, and physicians assistants, and nutritionists, and physicians, providers, all in the same family practice clinic looking through a lens—a systems lens—at ICD-9, ICD-10, in coded conditions, you don’t see that condition only in itself; you see the person, and then why isn’t there movement, and are they ready to move? And then once they are, you can tie it together in the systems point of view. It is really a different set of glasses that you’re putting on that you can apply in the ER, in the ICU, and on the OB suite, in primary care, you can apply this across all healing paradigms, and that’s just our belief, and our knowledge, and our experience. JB: You know I started this discussion off with you, here, nearly an hour ago in which I said that you’re my model of how this form of healthcare should be and will continue to be evolving to be practiced. The model that you have been describing, which we focused a lot of our discussion on pre-conceptual/conceptual and neonatal care, but the model is—as you just described, Michael—applicable across the whole life process. I mean, the same interrogation process goes into childhood, adolescence, young adult, adult, midlife, older age, geriatrics, and even at end of life because you’re asking similar questions but in a different context at each of those stages. So this is an applicable system—it’s like what we call an operating system—for the way you take information in. MS & LS: Yes. JB: And I think for a lot of people, when they hear the term “functional medicine,” and this is a great place for us to complete this part of our journey in our December 2015 issue after 34 years, they think of it as, okay, what’s the lab test and then what’s the supplement? That’s not really what we’re talking about. We’re talking about a way of processing information: taking it in, asking the right questions, and interconnecting that information in ways that tells the patient’s story in a meaningful way that helps you to develop a program that they’ll participate in to improve their outcome. MS: Absolutely. JB: In the final closes, here, are there any words to the wise or words to the aspiring wise that you’d like to share from this vast experience that you’ve amassed over the many years of your collaboration? LS: Yes, I’ll go first with that. If it sounds intimidating to folks at the beginning, to think in this systems manner, what reassures me about the human body is that there is not just one way. If methylation is important in the human body, then the human body is going to be able to do it in multiple, multiple, multiple ways. There is an economy of redundancy. Rather than having efficiency, the human body—our life around us—is that of redundancy. And so in our journeys as we are finding the answers in our patients, when you ask a question, there’s going to be more than one answer. There’s going to be more than one solution. Even if you don’t get it 100 percent on every single answer, because of the multiplicity of answers, because of the redundancy of the human body in all of its crucial functions, you can get most of it right and get great outcomes. So the more elaborate, the more elegant you are about your hour interrogations, I believe the better outcomes we will get, but that means start down the path, ask the questions, do the interrogation, be critical, and then apply the push and pull to those systems that we do understand, and then carefully observe the outcomes. JB: Michael, your comments? MS: I would say no matter where you are in your interaction with somebody that you’re trying to help, the important question is to ask how they got there. What were the balances and imbalances? What were the issues that allowed them to turn toward more health or turn toward more disease? And then once you ask that question, then it is the inspiration of seeking answers, and it is the power of instilling hope in movement, in change. And that’s the hope in human. We’re at a wonderful spot here, Jeff, after your 34 years of doing FMU. When you look across the landscape and you see residency programs incorporating functional medicine as the standards in their training, and you start hearing about Fellows in functional medicine, and you start talking about systems medicine, and centers for functional medicine at Cleveland Clinic, and you start getting the conversations across all healing paradigms that tie the millennial brilliance of the traditions of the past with the genomic/epigenomic/omic revolution where we are now…tie that in with the informatics and we are about to blast off into one of the most exciting times in medical education and changing the paradigm and in changing our understanding of healing and health. We’re at the beginning of this new frontier. So I just want to say that this is a spectacular time. I hope people just join in and enjoy the ride and enjoy the wonder and enjoy the miraculous, as we do every time we see a child being born. JB: Wow, I don’t think there would be a better and more fitting transition from our 2015, 34-year experience than Leslie, you and Michael’s advocacy. I am, as I close here, reminded of the interview that I did in 1982 with Linus Pauling in his office, which was the start of this whole journey for us on this celluloid version back in the cassette tape days. So much of what he talked about—the reduction of human suffering and the preservation of the uniqueness of the individual and this whole concept of individuality—was expressed by him that initial first issue of the recording I did at his office desk, actually. It’s a tremendous back-to-the-future enrichment that we all share in this legacy. I just personally want to thank you for the contributions you’re making, obviously, to all of your many patients that are benefitting from this process, but also from the extraordinary number of people that will be affected through the training of functional medicine practitioners in their service to their patients, which will be—we hope—millions of people that will catalyze this transformation. So thank you very, very much. What a great way to move to our 2016 version, which will be an open version of Functional Medicine Update going into next year. Thank you very, very much for closing this chapter of our book. MS: Thank you so much. LS: Thank you. JB: Much love to you both. We’ll talk soon  

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Bibliography

[1] Stone LP, Stone PM, Rydbom EA, Stone LA, Stone TE, et al. Customized nutritional enhancement for pregnant women appears to lower incidence of certain common maternal and neonatal complications: an observational study. Global Adv Health Med. 2014 Nov;3(16):50-5.   [2] Brewer, Thomas H. Metabolic Toxemia of Late Pregnancy: A Disease of Malnutrition. Springfield: C.C. Thomas, 1966.   [3] Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. 2011 Jul;22(4):476-85.   [4] Lonsdale D, Shamberger RJ. Red cell transketolase as an indicator of nutritional deficiency. Am J Clin Nutr. 1980 Feb;33(2):205-11.   [5] Chase HP, Hambidge KM, Barnett SE, Houts-Jacobs MJ, Lenz K, Gillespie J. Low vitamin A and zinc concentrations in Mexican-American migrant children with growth retardation. Am J Clin Nutr. 1980 Nov;33(11):2346-9.   [6] Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013 Mar;18(3):369-81.   [7] Frye RE, Sequeira JM, Quadros EV, James SJ, Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013 Mar;18(3):369-81.   [8] Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968 Apr 19;160(3825):265-71.   [9] Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic diseases and polymorphisms. Am J Clin Nutr. 2002 Apr;75(4):616-58.

Welcome to Functional Medicine Update for January 2014. You know, each year, when I introduce a new year, it seems quite remarkable to me, given that we’ve now been doing this going on 32 years. It just strikes me as both amazing how quickly time goes by, but also the breadth and depth of material that has gone over these 30-plus years as it relates to the evolution of medicine. I was reminded of this when I read, just this last week, a very interesting report from the University of Washington School of Medicine. Two geneticists have just determined that there is a code that lies underneath the genetic code that we all learned from the Watson and Crick days in the early 1960s, things that I committed to memory for tests that I took in the early sixties when I went to college. And now we find out that there is another code that lay dormant, quiet, stealthily below the code that we all had learned, that actually informs how the other code is going to be read, meaning it’s a code within a code.[1]   Think of the implication of what this means for just the advancing understanding of genetics. We think we know so much, and we do know a lot, but yet there is so much we don’t know. This, of course, is what separates the sophomoric wise fool from the individual who is always seeking the frontier of new knowledge, knowing that what they knew yesterday may be replaced by something they learn tomorrow that actually revolutionizes thinking. That’s exactly what we are going to be confronted with, here, in the first two issues of the 2014 year of Functional Medicine Update. You are going to be privileged, as I was privileged, to be informed by two world leaders in the area of gastrointestinal health, from a perspective that I would call remarkable, game-changing, ground-breaking, paradigm-shifting, and revolutionary. It’s almost, however, back to the future, because it takes us back to some of the early reports of people like Ilya Mechnikov, who at the turn of the last century was speaking about prolongation of life by the installation of Lacto bulgaricus forms of bacteria into the rectum for reinstilling proper bacterial flora into the gut for health—the prolongation or life—or consuming orally various forms of yogurt or kefir that were cultured products that had these live bacteria for improvement of health. And of course this was ridiculed for so many decades as being facetious, silly, nonsensical, nonscientific, artifactual, and all sorts of words, some less complimentary than others, that would marginalize this concept, saying that it was a thought without proof. But as you will learn through the lens of two extraordinary investigators, Dr. Alessio Fasano at Harvard Medical School, and Dr. Gasbarrini, arguably one of the top gastroenterologists in Italy, who will be our February Functional Medicine Update clinician/researcher of the month, you’re going to learn that what was old is new—that we have actually been able to start understanding this complex interrelationship between our diet, our living microbes in our gut (the so-called microbiome), and our systemic health, to the point that it’s leading to a whole revolution in thinking about the origin of chronic illness and both how to prevent and manage it, and also to understand the epidemiological epidemic that we’re seeing—almost a pandemic, globally, of the rising tide of chronic illness as we start seeing changes in diet, changes in environmental pollution, changes in stress patterns, and how that translates into just a virtual pandemic of incidence of diseases that used to be relegated to a small fraction of the population at the terminal end of their life, and now we’re seeing it start to penetrate down into younger years with greater prevalence, things like type 2 diabetes, neurologic nephropathic ocular injury, dementia, cardiovascular disease, dyslipidemias, inflammatory conditions, arthritis, autoimmune disease, digestive disorders of nonspecific origin. All of these which we see as changing patterns of health are interrelated to this extraordinary paradigm shifting revolution in understanding that we are being confronted with, that you’ll learn more about from our clinicians of the month—our researchers of the month—in these, what I would call, epic January and February issues, 2014, of Functional Medicine Update. Jump on the train. We’re just about ready to leave the station, and you’re going to be having a really interesting journey with us over the next two months. With that, let’s turn our attention to one of the world’s foremost experts in what we consider gluten-related dysfunctions, Dr. Alessio Fasano, and get some direction from him as it relates to this transition/transformation that’s occurring in thinking, and then we’ll come back and regroup and have some thoughts after his discussion.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Alessio Fasano, MD Director, Center for Celiac Research Chief, Division of Pediatric Gastroenterology and Nutrition Massachusetts General Hospital for Children 55 Fruit Street Boston, MA 02114 www.celiaccenter.org We are fortunate to have as our clinician/researcher of the month an individual who is arguably, I believe, probably the top—or one of the top-rated—presenters that we have ever seen at the Institute for Functional Medicine International Symposia over the last 23 years. For those of you that were at the meeting, you know who I’m speaking to and that is Dr. Alessio Fasano, whose name and reputation really precedes him. It’s remarkable to see what Dr. Fasano has done in terms of opening up this field of understanding of this complexity between food and the immune system through the interaction of certain reactive proteins in food that are members of the family that we call gluten, but then really beyond that to this whole threshold issue of how information and food can be picked up by the immune system of the body and translated on an individual basis based on genetic uniqueness into information that would be considered alarm information that we often call disorders of inflammation or autoimmunity. I think we have had a lot of history of working around this topic, but we have never had the privilege until the last 10 or 15 years of having someone with the insight, precision, and doing the heavy lifting in science of a Dr. Fasano to really add substance to the understanding of this topic. Alessio, it’s wonderful to have you here. You are, I know, extraordinarily busy in your position as the Director of the Center for Celiac Research at Mass General Hospital, and being a visiting professor at Harvard Medical School in Pediatrics, and publishing widely, engaged in research and grant writing, and really, I would have to say, being a central figure in changing the context of medicine to really look seriously at how nutrition, diet, and reactive substances in food influence health. Thank you for being part of our Functional Medicine Update. AF: Thank you, Jeff, for having me. They are very flattering words. JB: Well, certainly well-deserved. For those listeners that were not fortunate enough to hear you speak, which—by the way—was one of the most eloquent presentations I’ve had the fortune of hearing, where you talked about the research method, and the development of a hypothesis, and what led you down the trail into this extraordinary detective story surrounding gluten and celiac disease. Maybe, for our listeners that were not so fortunate to be there, you could kind of give a brief overview as to how you traveled through your intellectual journey from Italy, to North Carolina, to Maryland and to the Mucosal Disease Research Center, and ultimately, now, to Mass General—how your intellectual process evolved. Studying Pathogens: The Interplay Between Host and Environment AF: Sure. I mean, it’s a story of serendipity, as usual. When I was a medical student I was very much interested in diarrheal diseases, while I was in training I joined a lab that was a strong lab in terms of diarrheal diseases and gut physiology. I studied, for several years, how the intestine really reacts when attacked by microorganisms that cause diarrhea. Then I reached the point at which I felt that I knew one side of the coin and I needed to know a little bit more of the other side—what bacteria do in order to cause cross-talk with the host. My mentor suggested I spend a couple of months in the United States to learn a little bit about bacteria pathogenesis, and particularly cholera; that was the pathogen that I was very much interested in because it was still causing tremendous amounts of morbidity and mortality in the population. He sent me to Baltimore, to the Center for Vaccine Development, to spend a couple of months there. And this couple of months became two years because I was in the right place at the right time with the right people, and several discoveries were made. That became quite an exciting time of my professional career. You know, after these two years I had to go back to finish up my fellowship and to wrap up what I was doing in Italy. This was in the late 80s. By October 1992, I got a phone call from the department chair (pediatrics) in Maryland who said, “We want you to come back and for good, to be our division chief.” Talk about a total shift of lifestyle. My English was still broken English, and I didn’t know anything about the rules of medical practice in the United States. I didn’t even have a visa. But, bottom line, I decided to jump on this opportunity at a relatively young age; I was in my mid-30s. In 1993 I moved for good, and from there I started this journey from the diarrheal diseases, to trying to understand how pathogens cross-talk with us and trying to understand what are the mechanisms they engage? Interestingly enough—not because by design but because science brought me from one point to another—this kind of discourse led to better understanding of the interplay between the host and the environment that leads to autoimmunity. Celiac disease was already a clinical interest of mine, and it became a unique model to study this interplay in terms of autoimmunity, and the rest is history. JB: I think that “the rest is history” is so fascinating to watch the evolution of your publications. I’ve had the privilege—I can’t say I’ve read all of the more than 200 of your publications, but I have read, I think, a critical number of them to kind of get the ebb and flow of the texture of your work. You can actually, I think, by following your publications, almost do a history of the evolution of gut immunology and this complex interaction between the microbiome, the gut enteric immune system, and the diet. I think through your own work we’re actually seeing the evolution of a historical paradigm shift in medicine. Have you had support from your colleagues in the broader gastroenterological field for this—what is a remarkable, I think, kind of perspective of change and thinking about the GI system and its relationship to the gut bacteria and the diet? Transformational Science Leads to Discoveries About Celiac Disease and Autoimmunity AF: Well, Jeff, there are two kinds of science I believe. There is the incremental science, so you go from Point A to Point B, from Point B to Point C, and so on and so forth. So you know where you are starting and you know where you are leading to. This is a science, and in general it is supported by peers because they see it. They understand what you are trying to do, and in general you do this incremental science by relying on what has been out there in terms of the literature, so it’s their own work that is cited, that is the basis of what you are doing this on. That is the accepted kind of path. And then there is transformational science. The one that is really a total shift of paradigms, think out of box, the stuff that is high risk because of the time you are wrong, but if you are right, really you change, completely, the landscape and open different kinds of avenues. By definition, this is not that popular, because you go against wisdom, you go against the establishment. It’s a little bit more complicated and hard to be accepted. Not because of design—I didn’t decide that way—but most of my scientific career has been transformational science, because I stumbled upon it, and therefore I really had a hard time. I can list many times in which, for example, starting with celiac disease, when we started to claim it was not as rare as was believed to be in the United States, but was overlooked, I can’t tell you how many times people criticized that point of view to the point in which some of my close friends and colleagues said, “What are you doing to yourself? You are ruining your accreditation and therefore your career. Why do you do this to yourself?” Again, it turns out to be that, indeed, that was the story, and now nobody will even dispute that celiac disease exists in the United States. Same story in terms of autoimmunity. For example, the general wisdom that still holds true to many classical immunologists is that autoimmunity is a one-way street. Once you get in there, you can’t come back because it is totally irreversible. There is nothing you can do about it because it is the result of antigen mimicry, or by standard effects, so you lose the capability, and there is no way that you can rewind the tape. Celiac disease is just otherwise. If you can really block this interplay between the host and environment—and in celiac disease we know the environmental trigger, so you can really do that—you can stop autoimmunity. This was a complete shift of paradigm that was really not well accepted and now I believe most people would not dispute that. When we had trouble with the most complicated part of the story…when we put into the picture of the recipe of autoimmunity—a third ingredient besides the genetic disposition and environmental trigger—namely, the loss of intestinal barrier function so that intestines can’t keep out the “enemies,” the cell antigens that will instigate the immune system to lead to autoimmunity, that was another major shift in paradigm that created all sorts of criticisms because, of course, many colleagues say, “Now you are embracing the leaky gut theory that is bogus, it’s not true, and so on and so forth.” Again, in all these examples, you can just express your opinion based on your honest, humble observation, because what a scientist does is not invent anything, or to score anything; you just listen to nature, because the stuff is already written. Either you are a good listener or not. If you are a good listener and therefore rather than to try to force on nature your concept, you are just are there to serve what is already out there. The chance exists all the time, even at the beginning you will have a really hard time, the facts will speak for you and not “my opinion versus yours.” Again, in all of these examples I gave you, when we proposed that kind of shift of paradigm we were not well accepted, then the evidence in the literature and the accumulation of data became so overwhelmingly clear that I think that nobody will dispute again that autoimmunity requires three elements including the intestinal barrier dysfunction—that the autoimmune process is not a one-way process anymore, but if you can find a way to stop this interplay between environment and host you can do that. You can really bring back these people. There is definitely an element that is crucial—that is, change the environment—to explain these epidemics in plus-50 years of autoimmune diseases. Nutrition is probably the key element that changes everything and these impinge on the composition of the microbiome that seems really to be the yin and yang between tolerance and immune response in people that are genetically disposed. All these concepts that we are at the forefront of out-of-the-box thinking, I believe are now coming into the mainstream pipeline of thoughts and we’re glad. JB: Let me take a deep emotional and intellectual breath with the listener, here. I think every senescent human being that just listened to what you said over this last few minutes, which was so eloquent and so word efficient in projecting many, many thoughts about the evolution of ideas, the change of culture, discovery, innovation, reduction of human suffering—that was all incorporated so eloquently in your previous thoughts. I hope every one of us listening are taking this in, because it’s a model for how humans progress in time and culture, and overcome barriers of static thinking, and produce a dynamic change in society. I’m reminded that this hinges on the scholarship of your work, because in the end, the more revolutionary the discoveries the more it requires the diligence of the heavy lifting of proof of concept, which you’ve done very, very nicely through exquisite science. Your discovery of Zonulin, and the interrelationship of these interesting proteins that are messenger molecules that interrelate gastrointestinal environment to systemic responses and things like how calprotectin interrelates with the barrier function of the gut and how that connects to Zonulin. These are all new concepts that have come out of your laboratory. Was it a consequence of you bringing into your laboratory individuals with diverse talents that help to make discoveries out of the area of the common path, or did you, yourself, kind of travel into these uncharted waters to find out how to explore these processes? AF: Oh Jeff, this kind of science required a team and not a single individual. The single individual can come up with intuition, but it takes a village, so by all means whatever we accomplish is a consequence of a team of dedicated individuals that share the kind of vision. I personally believe that if you want to do good science, you have to have very clear in mind what is the ultimate goal. In my experience, if the ultimate goal is career success, fame, you’re going to fail, because you are blind to what is really the ultimate goal. If the ultimate goal is to improve quality of life for people and try to understand why people eventually move from a state of health to a state of disease, then the fame, the discoveries, that will become as part of a collateral—not a primary—goal. Now the key element is to choose the team that sees the same way as you see, and that’s the only thing that I did. In other words, I may not have had in my lab, as collaborators, maybe ten Nobel Prizes, but definitely I had the people that were raising the same concept of what is our ultimate goal? Not seeking fame, or money, or God knows what—promotion and grants—but make sure that we never got distracted from what is our final destination. This brings also some interesting facts about dichotomies that I still don’t understand. For example, traditional medicine versus complementary medicine, functional medicine versus evidence-based medicine. I just don’t get it. And again, these are polarized points of view that I believe are making a disservice to what is indeed our final mission, here. Because I’m pretty sure that a functional medicine doctor and a classically trained traditional doctor have the same kind of final goal. It is the methodology that changes, maybe, but not, definitely, the goal. I don’t understand why one has to be right and, by default, the other one has to be wrong. If you look at just the history of medicine and discourse, Chinese medicine, clinical medicine, Arabic medicine, the Greek and Romans, they were healers, so they were taking care of the single individual. Over time we decided we had to make rules, because otherwise you cannot really come up with some intellectual explanation for what are the phenomena we look at, and therefore we move to the large numbers, the epidemiological studies, the evidence base, the algorithms, i.e. the way that we now function. We made these kinds of rules because we assumed that there is homogeneity in that disease. When you talk about celiac disease, we talk about the same thing, and therefore the assumption is that the approach has to be the same, the solution has to be the same, no matter who you are. Now we realize that we were wrong. Indeed, now we move to the next phase in which everybody will agree that personalized medicine, physician certification for customized approach is the way to go. So what is the difference between these two worlds? I don’t see it. It’s just a matter of methodology. JB: Very well said. I want to give you a gift, just quickly. I know you get these gifts all the time, which are feedback from patients who have benefitted from these ah-ha moments that you have helped provide to them. We have two leaders—clinical leaders—interviewed on Functional Medicine Update years ago about their own personal experiences (what I would call the classic “ah-ha” personal experience) with their own health issues that tied back to discoveries that they made in themselves thanks to you. These two individuals both spoke about the fact that they had developed progressively more serious neurological issues, one leading to multiple miscarriages and very serious musculoskeletal disability. They were in an academic setting as a faculty member, seeing the best of their colleagues, not finding remediation, and they happened to come on to your work. They went on to a gluten-restricted diet and within about a year they had completely recovered their health. This woman went on to successfully have a child after these multiple miscarriages, who now, by the way (it’s enough years) that child has turned out to be a star student who is going to go on to medical school, and credits her life in finding your work. In that same issue of Functional Medicine Update, another clinician—a doctor in private practice, in this case—was a woman who started to develop nonspecific kind of encephalomyelitis. It looked like she was becoming demented. She was losing her memory, losing her language skills, thought it was MS but it really wasn’t MS. She just couldn’t come to a clean diagnosis. She was unable to drive her car, had to give up her practice, and then, again, found your work through someone who suggested that maybe this work of Dr. Fasano might apply to her situation. She went on a gluten-free diet and again talks about her story in this interview, which has completely transformed her life—put her back on the path to good health and has transformed her practice now in New Hampshire, where her focus is dealing with this problem with patients. This translational concept, from the lab to the bench, from the bench to the bedside, to the clinic, to the individual, this is something that very few people in research ever get a chance to see. It must give you a great sense of joy to actually see these discoveries you’re making actually make such a meaningful difference in people’s lives. Perseverance: The Best Trait of a Good Scientist AF: Oh Jeff, first of all I sincerely appreciate that you shared these stories because we live for this kind of stuff. The purpose of science without applicability really doesn’t satisfy or give you the sense of accomplishment. But when your science really makes a difference in the lives of individuals, even a single one, that is worth any kind of price that you can imagine, because that’s really the kind of legacy that I personally believe will make sense and justify the tremendous amount of work and sacrifice that you do in embracing this kind of profession. We talk about the results that you publish and the success, but for each one you probably did hundreds and hundreds of experiments that didn’t go well. I keep telling my students and fellows, I say, “The best trait that indicates a good scientist is perseverance because you need to delay rewards.” It doesn’t come right away. But when you have stories like the ones you just shared with me, these are priceless. I can’t really put the right value to what this means. Again, studying a molecule like gluten that is a protein from a grain—supposedly it is supposed to be a friend—and try to make sense of why this friend has become a foe, it has been quite an extraordinary journey for us. And again, it is a shift in paradigm when we start really to find out that this is creating a problem not just for people with celiac disease, but everybody, we get hammered by our colleagues with, “What are you talking about? The only way that you can get in trouble with gluten is celiac disease, and if you don’t have celiac disease there is no reason to even consider gluten-free diets or to do anything about it.” And then over the years we realized something that I found extremely fascinating: that gluten is treated by our immune system as a component of the microorganisms, so it induces the same response that we would have if we had been exposed to bacteria. As such, we see this response that is common to everybody. This must be the consequence that gluten was a mistake of evolution—that we’re not supposed to eat this gluten because it came into the picture only in the last second of the 2.5 million years of humankind evolution, with the advance of agriculture ten thousand years ago. Again, I believe that like bacteria, even if everybody, when exposed to them, they have an immune reaction, but not everybody develops an infection. So not everybody who eats gluten will get sick because of ingesting it. The vast majority, as a matter of fact, will eventually fight this enemy through the immune system, and will not even know this fight is occurring. There are a few that will lose the battle that will eventually develop problems like the outcome that is celiac disease, or the allergic reaction like with allergy or like these two examples you just gave that may not be celiac but gluten sensitivity. JB: You just authored a fascinating paper that is co-authored with many of your colleagues, which I find just philosophically interesting. It’s titled “Non-celiac Gluten Sensitivity: The New Frontier of Gluten-Related Disorders” and appeared in the journal Nutrients in 2013, volume 5, page 3839.[2] It’s a very powerful review, but it’s also very interesting philosophically because the co-authors on this paper represent leaders in their field across many countries—Italy, France, Spain, Germany, Buenos Aires in Argentina, United States (Columbia University). This is a tour de force. Tell us a little bit about how this article actually was put together with these multiple authors. Non-Celiac Gluten Sensitivity: A Multi-Disciplinary Group Comes Together for Discussion AF: Again, because there are very few facts and a lot of fantasies, we decided that the best way to make the point of what is the current situation of non-celiac gluten sensitivity was to really put around the table the who’s who about celiac disease and gluten-related disorders. Jeff, needless to say this was a very interesting exercise because there were believers and non-believers, traditional thinkers and progressive thinkers. These two days of brainstorming around the table with these 30-plus people, coming to meet from every corner of the world, was an open mind experience for me that I was motivating the discussion. Again, you can see how, during these two days, you started with preconceptions and walls of consideration about the topic, and while discussing this, these walls came down and people started to really open up to constructive possibilities to try to understand what are the facts and what are the fantasies. The result is that is the review that you just mentioned that indeed is a scientific review but also a philosophical testament, if you wish, of what is a critical thinking of an open mind approach to a topic that is fascinating to say the least. I don’t think that anybody, even the most skeptical, will doubt the existence of this new entity. And again, this was something that we put forward three or four years ago with a couple of papers that proved that this was different from celiac disease. This news was not accepted that well by the establishment, but now even some of them reluctantly admit it exists. Now, what exactly this is all about is still an object of discussion, and that’s where I believe the line of research will materialize over the years. I was skeptical myself, but when you have examples such as those you mentioned of these two colleagues, there is no way that you can support the notion if you don’t have celiac disease you don’t have any business going on a gluten-free diet. How do you justify this tremendous improvement of symptoms in people they have experienced for so long just going on a gluten-free diet without having that open-mindedness that there is something beyond celiac disease that can bother people when exposed to gluten? That’s pretty much what materialized in this consensus conference that led to this publication. JB: I want to spend the last couple moments, if I can, with you, kind of crossing a very interesting bridge that I know you’re crossing or have crossed. I’d like to vicariously cross this with you for a moment. That is, you have chosen in your life to take on two extraordinarily dominant paradigms that have a lot of what I would call intellectual sclerosis associated with them, one of which is autoimmune disease, which you very gracefully talked about—this shifting paradigm that maybe it’s a two-way street and the environment and genes interact in a way that can go both ways, meaning remission plus progression. That’s a pretty remarkable concept in itself. And now you have crossed another bridge, and I’ll just cite three recent papers that you are an author of that illustrate this bridge. It’s part of this overall theme, but it is certainly taking on another level of visibility, and those three papers include your 2012 paper, “The Expression of Caspaces is Enhanced in Peripheral Blood Mononuclear Cells of Autistic Spectrum Disorder Patients.”[3] That appeared in the Journal of Autistic Development and Disorders in 2012. And then the paper, “Gastrointestinal Conditions in Children with Autistic Spectrum Disorder: Developing a Research Agenda.”[4] That was in Pediatrics in 2012. And then most recently, “Cannabinoid Receptor Type 2 But Not Type 1, is Up-Regulated in Peripheral Blood Mononuclear Cells in Children Affected By Autistic Disorders” in the Journal of Autistic Development Disorders.[5] This is—as we both know, and you are a pediatric gastroenterologist, so you know it much better than I—a very colored area as a consequence of the work of Andrew Wakefield, who has gotten himself obviously into some muddied water over his purported discoveries in England of this relationship between what he called ileal nodular hyperplasia and autistic spectrum disorder. I’m wondering, as you have moved across this bridge with such precision and such science, how you have managed the legacy of what might be considered colored information in this area. Autism and the Gastrointestinal Tract: Controversy Put Research on Hold for Years AF: Well, Jeff, you put that in a very polite way, but this is a very heated, extremely controversial field of the role of the gastrointestinal tract in autism spectrum disorders. Again, this was an unfortunate situation in which it doesn’t matter which part of the fence you are on. It created tremendous confusion in the field—distrust on the topic—and who ultimately paid the price have been the patients. We saw a deceleration of science that really put the entire field on hold. What are the facts? The fact that I don’t see anybody dispute is that there is an axis that puts in touch and cross talks gut with the brain. That’s pretty much a concept that everybody now accepts; there is a brain/gut axis. This applies not just to autism, but to schizophrenia, it applies to multiple sclerosis, and so on and so forth. The basic science to explain the mechanisms that are engaged in a situation in which you have an inflammation of the gut that eventually will affect the behavior of individuals, and now specifically there is concern about the autistic kids. Again, I was pretty much brought into the picture by force by some people in the autistic community because they honestly appreciated that there is some involvement of the gut. There has been this unfortunate situation that I don’t think we need revisit, and they decided, rather, to ignore the possibility the gut has anything to do with autism. It was to start all over again in doing this right. And therefore with the understanding that my expertise in autism is extremely limited, and I mentioned this right away to these people that asked me to give my opinion, I had the opportunity also, in a very unbiased way, to take a look at the situation and I find it is fascinating. Everybody agrees that autism is a situation that you can develop via different links. In other words, metabolic disorders, genetic problems, you can have metal exposure, I believe that vaccination can be involved, definitely food intolerance, and so on and so forth. So everybody agrees there are different paths that can bring you to your final destination, yet everybody was looking for a single magic bullet that will fix them all. That, to me, is counterintuitive. There are different theories, not mutually exclusive, why people eventually develop autism through a GI-initiated process. For example, for food intolerance, going back to gluten. People believe that some of these fragments are not digested that mimic endorphins that cross the intestinal barrier and cause leaks, and go through the blood-brain barrier, and interacts with the receptor endorphins and make these people change behavior and then with specific genetics translate into autism. There are theories about what is called neuroinflammation. Same first step: you eat gluten and undigested fragments will create an immune response and then the cells that fight this enemy are activated, so they can create inflammation, but somehow they are programmed to leave the intestine and to reach, as the final destination, the brain, and on specific regions, create neuroinflammation that leads to autism. This second theory now is the one I have been following more closely because the results of the papers that you just mentioned seem to point to this new inflammatory theory I find fascinating, absolutely fascinating. And again, the instigator can be gluten, it can be a virus, it can be a bacterium, it can be a metal, whatever, but somehow these new cells, on the battlefield of the intestine, they are supposed to protect us against these enemies, but they are programmed to go to the brain. Who makes this decision? How they are programmed? Why do they go to one part of the brain and not another? And why there are different outcomes, because the same mechanism for autism applies to schizophrenia and depression and chronic fatigue syndrome. These are the same cells that go there—maybe different regions of the brain—and generally have a different clinical outcome. I find this effect of neuroinflammation instigated by response of the level of the gut-immune system extremely fascinating, and very, very difficult to tackle. But I think you need to go step by step and start to ask specific questions and see if you can have specific answers. JB: That was…once again, you have such an extraordinary gift in summarizing and bringing together a huge amount of information in a very concise way. I just want to pass on once again our deep respect and admiration for your courage. I think this is not an easy area politically to work in. It requires the best of science to convince sclerosed minds that there may be something on the other side that they didn’t take advantage of trying to understand and were unconscious to. I’m thinking of a psychiatrist (MD, PhD) from Belgium who has published extensively about work associated with depression, and chronic fatigue syndrome, and fibromyalgia related to gut barrier problems and metabolic endotoxemia, or Patrice Cani and Nathalie Delzenne at Catholic University of Louvain, the work that they show with endotoxemia and an association with neurotoxicity.[6],[7],[8] There is an emerging family of colleagues that you share the universe with that are all very courageous. Good scientists, good observers, that are creating the new medicine. Just as one small observer in this world I want to give thanks to you for what you’re doing, for your team. I hope you will thank them on behalf of us at Functional Medicine Update, and continue with the extraordinary work, because it is the quality of the work that will ultimately change the people’s minds. AF: Jeff, thank you so much for your kind words, and again, on behalf of the entire team we will appreciate your help and support and the fact that you see the value of what we are doing. I want to stress, once again, the entire team works towards the goal to improve quality of life for people, nothing else. As far as we reach those goals, even if we have been wrong, so be it. We will be delighted to say that we were wrong so long as we move the field forward. JB: Thank you, Dr. Fasano. We wish you the very, very best and be assured we’re going to keep in close touch with what’s going on with your laboratory. AF: Thank you so much  

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Bibliography

[1] Stergachis AB, Haugen E, Shafer A, Fu W, Vernot B, et al. Exonic transcription factor binding directs codon choice and affects protein evolution. Science. 2013 Dec 13;342(6164):1367-72.   [2] Catassi C, Bai JC, Bonaz B, Bouma G, Calabro A, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013 Sep 26;5(10):3839-53.   [3] Siniscalco D, Sapone A, Giordano C, Cirillo A, de Novellis V, et al. The expression of caspases in enhanced in peripheral blood mononuclear cells of autism spectrum disorder patients. J Autism Dev Disord. 2012 Jul;42(7):1403-10.   [4] Coury DL, Ashwood P, Fasano A, Fuchs G, Geraghty M, et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics. 2012 Nov;130 Suppl 2:S160-8.   [5] Siniscalco D, Sapone A, Giordano C, Cirillo A, de Magistris L, et al. Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J Autism Dev Disord. 2013 Nov;43(11):2686-95.   [6] Maes M, Kubera M, Leunis JC, Berk M. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord. 2012 Dec 1;141(1):55-62.   [7] Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des. 2009;15(13):1546-58.   [8] Geurts L, Neyrinck AM, Delzenne MN, Knauf C, Cani PD. Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism: novel insights into molecular targets and interventions using prebiotics. Benef Microbes. 2013 Jul 25:1-15.

Welcome to February 2014 Functional Medicine Update. Well, I promised you in the January issue that we were going to start off this year with a bang, with one of those epic “a-ha’s,” those clinical news-to-use, those paradigm-shifting concepts that may translate in health care to alleviating suffering for millions of people. That’s a pretty big claim, I might say, but I think we can deliver on it. This month we’re so fortunate to have as our clinician and researcher of the month probably the only person that I could think of that I know in the world that could follow on from the extraordinary presentation that we had from Dr. Fasano in January, and that’s Dr. Antonio Gasbarrini, who you will learn, from his own background, is arguably one of the world’s great functional gastroenterological researchers at Rome University. He is highly published (in excess of 600 publications), and I believe he is creating the work that relates to how gastrointestinal function is related to health and systemic long-term health span. Dr. Gasbarrini, as you will hear from him himself, has a wide-ranging series of interests in gastroenterology—ranging from the effect of PPIs (proton pump inhibitors) on nutrient absorption, to pre- and probiotics, to the microbiome, to translocation of Gram-negative bacteria and activation of the immune system, to partial protein breakdown products and how they influence the MALT and the GALT, and interestingly enough, he and Dr. Fasano were colleagues in Italy before Dr. Fasano came to America, and were contemporaries in their research. So there is a consanguinity here with regard to intellectual background between the two of them, and I think between the two, you will hear in the months of January and February, they are carving out a new extraordinary paradigm-shifting concept that is not just esoteric , but it’s really that which can be applied, starting now, for the alleviation of so many chronic conditions that were previously of unknown origin. With that, let’s move to our discussion with Professor/Doctor Antonio Gasbarrini.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Antonio Gasbarrini, MD Faculty of Medicine and Surgery Catholic University of Rome Rome, Italy Well as I promised, we are so privileged. In fact, I would say we’ve never been as privileged as we are in this back-to-back discussion with two—what I consider the pace-leading, paradigm-shifting—science clinicians that are contributing to our understanding of the complex milieu of the gut and its relationship to systemic immunity and how the gut/diet/microbiome/liver interconnects with systemic function across many different organ systems and disease states. As you probably heard from my preliminary introduction, we are privileged to have as the second heavy-hitter in this series of discussions, Dr. Antonio Gasbarrini, who I had the privilege of meeting and listening to this past summer in Milan, Italy at a seminar that we both presented at. I was just thoroughly overwhelmed, to say the least, by the scope, the magnitude, and the depth of Dr. Gasbarrini’s work over the many years in the area of gastrohepatology and its interrelationship to systemic function and systemic disease. Let me just give you a quick kind of thumbnail of just the tip of the iceberg of Dr. Gasbarrini’s background. From 1990 to 1993 he was a Clinical Research Fellow at the gastroenterology and liver transplantation department at the University of Pittsburgh and became an assistant professor of internal medicine at the Catholic University of Rome in 1995 and associate professor in 2000, of internal medicine. He teaches postgraduate courses in internal medicine, gastroenterology, and digestive endoscopy, allergy and immunology at the University Medical School and Catholic University in Rome. From 2006 to 2008 he was the Secretary General of the Italian Association for the Study of Liver-Related Diseases and the President of the Italian Foundation for Research in Hepatology. He is a member of—as you can imagine—many national Italian societies in the area of medicine and is an international luminary, publishing in excess of 800 papers, 460 of which as full papers or indexed in international scientific journals, and co-authored more than 1200 abstracts presented at national and international meetings in this area. His work has an overall impact; his publications number over 1200 with a high index of over 55, so his work has always been considered very, very significant. When I heard him speak in Milan, I was almost mesmerized because not only did he present such a wide volume—expansive volume—of material about the gut immune system and its interrelationship to the microbiome and to function, but he also gave a paradigm-shifting view of a topic that we have been speaking to indirectly, without the benefit of all the work that Dr. Gasbarrini has done, that we called leaky gut some 25 years ago—metabolic endotoxemia, transcellular transport of molecules across an injured GI epithelium. His work has done the heavy lifting to really understand that. Dr. Gasbarrini, thank you so much for being available all the way between Seattle, Washington and Rome, Italy. We really appreciate your availability to talk with us. AG: Yes, thanks to you. I think it is a great honor for me to be here now. JB: Could you tell us a little bit—with this volume of work that you’ve done over the many years—how your path led you into this whole association and understanding of gut mucosal barrier function and its interrelationship ultimately to diseases? Gut Mucosal Barrier Function and Disease AG: Yes, I think that this is a really great area, because as you know, I am a gastroenterologist and an expert in liver disease, so basically when I try to put together all of the diseases that I work with—and I mean inflammatory bowel disease, irritable bowel disease, celiac disease and gluten sensitivity, but also liver disease—what I found is there were kind of key words that put in common all these diseases and the function of the gut barrier. First of all, we have to know that the gut barrier is not only the small bowel, because with the gut barrier we can say the barrier of the esophagus, the barrier of the stomach, the barrier of the small bowel, and the barrier of the colon, so I mean every different anatomical tract of the GI has its own peculiarity. Probably the most intriguing part of the gut, however, is the small bowel, because, you know, it is a six-meter-long organ with a lot of different functions, and basically most of the functions are dedicated to digestion and to immune control, because as we know, most of the GALT or the lymphoid tissue of the human body are located in the small bowel—more than 70 percent of all the lymphocytes are resident in the small bowel to keep in control everything that we eat, because you can understand that to be controlled very, very well by the gut. The point is that this bilayer—this six-meter-long bilayer—is made by different components. We have enterocytes, we have the mucus layer, we have for sure the good gut microbiota, but we also have—below the enterocytes—the immune system and the enteric system. You know, all of these systems have to work together in a very, very balanced equilibrium. There are a lot of conditions that can determine an increasing permeability. Permeability can be physiological. In particular, for example, there are conditions of physiological hyper-permeability. When we are stressed we can have physiological hyper-permeability. After a very important sport we can have increased hyper-permeability. And some peculiar foods can increase or decrease gut permeability. This means that in the physiological condition, we can have an increasing permeability and a decreasing permeability. There are some pathological conditions where the permeability is increased for a long, long time in a very severe way. The typical example is the people with celiac disease, but with celiac disease you have a disruption of the gut barrier with an increased permeability. Or another condition—when you are cirrhotic patient (a patient with chronic liver disease), for example determined by hepatitis C, or by steatohepatitis, or by alcohol where there is portal hypertension, in this case where the small bowel is suffering because the pressure of the vein is too high. Now, in all these conditions, we have pathological gut permeability, also called leaky gut. And another condition that seems to be not related to liver disease, but to some form of irritable bowel syndrome, you have—again—a leaky gut. All of these conditions are characterized by translocation of fragments of the bacteria that are resident in the gut. I mean the fragments of the good bacteria that are found in the gut that go into contact with the immune system, and some of them can enter into the bloodstream, determining the so-called endotoxemia. Leaky Gut and Microinflammatory Disease Another thing that is very important in this situation is that you don’t translocate only fragments from gut bacteria, but you can also translocate the peculiar part of what we eat. So we can have a translocation, for example, of macro components of the food. As you can understand, if this barrier is interrupted, you can have a kind of inflammation below the enterocytes, and this can be a kind of pathological microinflammation. This concept is so important. Now we know that at least 30 to 40 percent of people with irritable bowel syndrome, they already have a microinflammatory disease characterized by a leaky gut. So really the leaky gut condition is a kind of peculiar condition that puts together many areas of medicine that probably, in the old times, were not considered linked one to the other one. So the leaky gut is some people with irritable bowel syndrome, people with Crohn’s disease, people with liver disease, and for sure people with extra digestive diseases, such as, for example, people with metabolic syndrome of diabetes. In all of these conditions, the leaky gut is characterized by endotoxemia and a systemic kind of inflammation. Causes of Leaky Gut So the main point, I think, for a gastroenterologist, now, is to try to identify the people with a leaky gut, in order to try to determine the causes of leaky gut. For sure it is open to all of us, a new theoretical possibility, because we know, for example, that leaky gut can be determined by an infectious disease, can be determined by an autoimmune disease, can be determined by a stressful condition, can be determined by the diet, so it is not so easy for a doctor to identify what is the reason for the leaky gut. Number two, it is also important to say that it is now so easy to assess the leaky gut. In my unit, for example, we utilize a nuclear medicine test (the EDTA banded with chromium 51—it is a nuclear magnetics test) that isn’t quite easy, but not all of the units perform this kind of test, so the main problem is, number one, to recognize the leaky gut condition; number two, to try to assess what is the reason of the leaky gut; and number three is to try to correct the leaky get. And for sure, you know, there are different possibilities. If you have an autoimmune disease, you have to use a monosuppressor, but if you have a disease of the mucus layer, you have to try to reestablish the mucus layer. If you have an increase in gut microbiota or an imbalanced gut microbiota, you have to work with the gut microbiota. If you have a bad diet, you have to control the diet, for example to eliminate all the food that can somehow be responsible for the leaky gut. Really, I think that with the leaky gut concept we are opening a broad area of research, and I think that all the new physicians of the future have to absolutely recognize leaky gut and try to treat it. JB: That was absolutely brilliant. Thank you so much. I tell you, that was a whole lecture in five minutes. Incredible! I’d like to go back and maybe just trace through a couple of things you said in a little more detail. Let’s first talk about the transport of these macro components, like protein components of the diet that are partially digested, and then get exposure as protein breakdown products to the immune system. Are these things that are genetically preprogrammed? Are they related to such things as secretion of hydrochloric acid from the parietal cells and digestive enzymes from the exocrine pancreas? What are the determinants for these transports of these small bioactive/immune active protein fragments? Genetic and Epigenetic Determinants of Gastrointestinal Conditions AG: I think this is a very, very, very difficult question. For sure there are some conditions that are genetically determined, but in a lot of other conditions there is a kind of epigenetics. I mean, you can have a genetic predisposition, but is the factor seen in your life when you are a child or when you are an adult, because that is so important to determine the expression of peculiar genes. So, if I can do another example, very often we used to take a proton pump inhibitor for a kind of small gastritis, and there are so many people that take a proton pump inhibitors to handle acid for a long, long time. In this case, you are blocking the gastric pH, and the gastric pH is so important to control the bacteria that come from the colon and can overgrow in the small bowel. You know, if you have an overgrowth of colonic bacteria in the small bowel, you can also have damage of the gut barrier. So it is very difficult at this moment to say if this is a genetic predisposition, or if it is an epigenetic manifestation, or if it is just determined by something that we do wrong. One example is to do an excessive anti-acid. Another example: Helicobacter gastritis. Helicobacter can determine atrophic gastritis. You don’t produce acid anymore. You cannot control the microbiota in the small bowel that can determine leaky gut. I think it is a very complex combination of factors, and we have to be somehow very human in order to understand what is happening in this peculiar person. JB: Thank you. Very, very good explanation! Let’s move on to the next area, which is this translocation of bacteria, and/or bacterial cell wall debris—lipopolysaccharides (LPS) from the Gram-negative bacterial cell walls. I would presume, from what you’ve said, that your work must indicate that there are a variety of different severities of expression of this, because one could imagine a very leaky gut, meaning one that is highly permeable to fairly large molecules, or one that was not so permeable, maybe only to selected smaller molecules. Is it true that you would have different severities and different responses to things like LPS? Translocation: Lipopolysaccharides and Other Fragments AG: Yes, yes, I think—again—this is a great problem. Because, for sure we have a physiological translocation of LPS (lipopolysaccharide), but not only LPS, because we know that there are a lot of other fragments that translocate. For example, LPS is just one of the many pathogen-associated molecular peptides (the so-called PAMPs) that can translocate in the bloodstream. Physiological translocation happens every day, and probably the physiological translocation is absolutely important to keep, somehow, our acquired immune system activated. So probably a low level of translocation is absolutely physiological. The big problem is when we have a pathological level of translocation. In this case, we need other cofactors. The typical example is people with chronic hepatitis due to C virus or B virus. In this case, you have damage of the liver determined by hepatitis C or hepatitis B, and then determined by chronic hepatitis. When you have the constant chronic hepatitis and you have a portal hypertension, you start to have a translocation of LPS from the small bowel to the liver. When LPS enters into the liver in these people with chronic hepatitis, you have the activation of toll-like receptor 4, and this determines the position of collagen, and this is the main cause of cirrhosis. So I mean, in this case, you have two different conditions—hepatitis C or hepatitis B—that determine the chronic inflammation in the liver and portal hypertension, and number two, when you have portal hypertension you have a translocation of LPS that arrives in the liver, and this is the main determinant of cirrhosis. So the point is that very often we don’t have only one factor involved. It can be a combination of different conditions. Another thing that now is very, very important, because from an immunological point of view it is so increasing, is the metabolic syndrome and the steatohepatitis. This means that when you have a bad diet you can have liver steatosis, and after a while, when you have bad steatosis, again you have portal hypertension, and when you have portal hypertension, LPS can translocate—it can arrive in the liver—and if you have other cofactor events of inflammation, at this point you can start to have steatohepatitis. We absolutely know how important the leaky gut condition is in the progression from steatohepatitis to liver cirrhosis. So again, very complex mechanisms, many cofactors that go together at the same time, and are important in determining the progression of the liver disease. JB: That is so clinically helpful for us. In the United States, we are seeing a virtual epidemic of what has been termed nonalcoholic fatty liver disease that is associated with marginally elevated liver function tests (LFTs). People have said, “Well, this is a consequence of fat infiltration into the liver due to insulin resistance, hyperinsulinemia, and metabolic syndrome.” But it sounds to me—the way you’re describing it—that it’s more complex. It’s the interplay between insulin resistance, hepatic function, and gastrointestinal barrier function, and the potential role that endotoxemia plays in this complex etiology. Am I interpreting correctly what you just said? AG: Absolutely right. Absolutely right! I am a gastroenterologist, so I see everything from the gut. But I can say that really the gut is a big organ—a huge organ. You know, six meters long. Everything has to be absorbed by the gut, and we know, at the moment, that the community of bacteria is very important for us in order to extract all the good things from the diet. But, as you know, these bacteria can become very dangerous. When a person dies, the putrefaction of the body is determined by these bacteria—if they are not fed in the right way, they can be dangerous. They can destroy the body. So we have to have a lot of respect for these gut microbiota. We have to feed the gut microbiota the right way, with good, healthy food, and for sure we have to avoid all the kinds of food that can determine an imbalance of the gut microbiota. Leaky gut is a very important concept because it means that the gut barrier is a very complex system, and the real interface between the internal and external body. For example, if a person has a heart insufficiency, what can be the relationship between a heart insufficiency and the gut? If you have a heart insufficiency, you have an increase in the venous pressure, and this again is a determinant of portal hypertension and bacterial translocation, and we know very well how important inflammation is in the progression of heart insufficiency. So I mean that the gut barrier concept is not a concept for gastroenterology but is a concept for all the people that deal with the human body. Explaining PAMPs and DAMPs JB: That’s very, very powerful. You used a little acronym earlier on. I’d like to come back and just define it for some of our listeners. You talked about PAMPs, and then there are DAMPs. Could you tell us a little bit about what these are and how they are players in this whole scheme? AG: Yes, absolutely. As we say, the gut microbiota is a very complex ecosystem that is made by different microbes. I mean, we have bacteria, we have histamine, we have bacteriophage (kinds of viruses). All of these components of these microbes can translocate in the bloodstream, especially dealing now with bacteria, we know that most of the bacteria are anaerobic type of bacteria. We know that usually they don’t survive in the bloodstream because there is too much oxygen for this kind of bacteria. Very often, these bacteria, when they die, bacterial fragments can translocate and enter into the bloodstream. We have a lot of different kinds of bacteria: Gram-positive, Gram-negative—many, many, many different species and many different strains. Every species is characterized by different fragments, so when we say a pathogen-associated molecular peptide (or PAMP), this means the peculiar peptide of these bacteria can translocate in the bloodstream and they can activate specific receptors in the human body that are called pathogen-recognition receptor. A typical case of pathogen-recognition receptor are the toll-like receptors that are present in all the body. So, you know, for example, LPS can activate and can bind the toll-like receptor 4 that is in the liver, that is in the joints, that is in a lot of different parts of the human body. So this means that physiological translocation can be very important to activate pathogen recognition receptors , but pathological translocation can activate too much pathogen recognition receptors, and this can be a very important driving force of inflammation and the concept of inflammation. JB: That was a great primer course in immunology. Thank you, that was very, very specific. Let me talk just briefly with you about a study that I recall that was published a number of years ago in the Lancet in which they looked at patients that had had hospitalization from Crohn’s disease, and they measured their gut permeability. They showed that those patients on discharge from the hospital that still had a permeable gut, had very high relapse rate versus those that were discharged from the hospital after a crisis event with Crohn’s disease who had a low permeability who had very low relapse rate, suggesting that if you were to discharge patients at a hospital and not be attending to their gut mucosal integrity, you were just asking for a readmission later.[1] Is that something that has been proven correct from your experience? Leaky Gut Can Manifest for Different Reasons AG: I think this is a good point, but I have to tell you that I think we are really in the first step of understanding what is the role of a leaky gut as a determinant of diseases. Because I have also to tell you that in my studies we also have a group of control people, who have kind of a leaky gut and they don’t have diseases. For sure a leaky gut is highly important in order to maintain a lot of inflammation, but the problem is that at the moment we cannot say what are the real consequences of a leaky gut. It is something that for sure is involved in all the pathology of the human body, for sure is involved in higher bacterial translocation, but I have to tell you I really cannot say at the moment that for sure we have to correct leaky gut in every condition. Because remember that after a very stressful condition, you can have a leaky gut that is just a consequence of the brain-gut activation. I mean, a leaky gut in a very stressful condition can be a good condition of how the brain decides to activate the immune system. So the point is that we have to absolutely discriminate leaky gut as a momentum of pathology and leaky gut as a momentum of a transient condition, because probably in some conditions a short time of leaky gut can be good for the human body. JB: That’s a really interesting observation. I recall a study on trainees. These are men and women that go into very severe training for combat readiness. And they actually measured, as part of the study, the pre- and post-gut permeability. I think they used the lactulose mannitol test in this particular study, and they demonstrated a very significant increase in gut permeability after the training, which was sleep deprivation, and marching, and all sorts of…you know, probably gunfire over their heads and things. But they showed that stress had a very significant increase in their gut permeability, which seems to be consistent with what you just said.[2] Then I guess the question is, was that a desirable adaptation to the stress for the moment that gave them higher immune function or their brain was enlightened in a different way? I guess that’s a very interesting question. AG: Yes, yes. I think, you know, there is another study that was performed after a triathlon competition.[3]So the point is this one. Probably a transient leaky gut is just a physiological consequence of a stressful or tiring condition. The problem is this one. If in this moment, when I have a leaky gut as a consequence of a stressful condition—if in this moment I have a bad diet, and if in the same moment, I also have, for example, a rotavirus gastroenteritis, this could be damaging because I already have a leaky gut (I can have an extremely bad leaky gut in this condition), and if I have a genetic predisposition, for example—I don’t know—DQ2/DQ8 that can predispose you to develop celiac disease, you know, in this time you can become celiac, or in this time you can activate a pattern recognition of microbial PAMPs and I can develop Crohn’s disease. The point is when you have two or three bad conditions at the same time. JB: Yes, thank you. I know you’ve been doing quite a bit of work on this microbiome, which seems to be at the center stage of people’s interest now, recognizing how much DNA there is in the genomes of our enteric microbiota and how that may influence our function. What are your thoughts about how this research is progressing, looking at the microbiome and its interrelationship to diet in health and disease. We Are In the Era of the Gut Microbiome AG: I think now we are in the era of the gut microbiota, or microbiome, or gut metabolome. Probably it is not so much important what kind of bacteria do we have, but it is what do they do? The main problem is that these incredible communities that are distributed both in the colon and the small bowel, there are so many, many functions. In the small bowel, basically, they control the immune system and they can help us in order to degrade and digest what we eat. In the colon they have a very, very important metabolic function. The point is that there is a kind of common concept in all the inflammatory disease of the bowel (irritable bowel syndrome and inflammatory bowel diseases). The common thinking is that we decrease the heterogeneity of these bacteria. I mean in a good condition we have a lot of different bacteria, and every bacteria is somehow specialized into something. In a lot of inflammatory conditions, we have a decrease of the species, and this is very important because this can determine inflammation. The gut microbiota concept is really the concept of the future, and if you see the studies that were published last year in the top journals—Nature, Science, and PLoS—all of the studies are being performed not only be gastroenterology, but are being performed by diabetology, people that deal with rheumatoid arthritis, people that deal with obesity.[4],[5],[6] You know, the gut microbiota concept is not only a diving force for inflammation, but it is a driving force of nutrition, obesity, and so-called metainflammation. JB: I remember during your presentation you talked a little bit about this ratio between the Firmicutes and the Bacteroidetes and how those might be markers as we’re looking at stasis of health versus disease relative to the microbiome. Does that seem to be proving true? AG: I don’t know because really the papers are coming out every month. You see so many new concepts. Number one, we have to be somehow careful, because most of the disease data, and also the Firmicutes-to-Bacteroidetes ratio that we know is different in obese people, is determined by the concentration of Firmicutes-to-Bacteroidetes in the feces, so the point is this: is the bacteria found in the feces really the expression of what’s happening in the gut microbiota? Because there are also studies out that say that fecal microbiota is very different from the mucosal gut microbiota. You know, in the real world probably we have to assess the fecal microbiota and the microbiota taken by the biopsy directly. And number two, is the microbiota of the colon is the same as the gut microbiota in the small bowel? Probably not. So, I mean, we have to work much more on this concept. But what is true is that the gut microbiota is actively involved in obesity, and metainflammation, and metabolic syndrome. There are plenty of papers out that say that if you transplant the gut microbiota from obese mice, for example the ob/ob obese mice, to wild type mice, the wild type can become obese. And if you transplant the microbiota from lean mice to ob/ob mice, the ob/ob, which are fat mice, become lean.[7] This has been also demonstrated in a human being. There is a paper out published by De Vos in Gastroenterology that showed that if you transplant the microbiota from a lean subject to a person with insulin resistance, you can determine a significant amelioration of insulin resistance, both parathyroid hormone insulin resistance and hepatic insulin resistance.[8] This means the gut microbiota can really help us in controlling metainflammation and controlling the way we take the energy from what we eat. JB: That really relates to one last question, and thank you so much for your time. This one last question is a follow on. What about pro- and prebiotic supplementation? Do you feel that there is a role or a place for this in restoring GI function? Pre- and Probiotics: What Role Does Supplementation Play in GI Health? AG: This is a very difficult question. I hear some good things and some bad things. Good things are that for sure there very nice papers out that show that some probiotics—and in particular, the most important are Lactobacillus and Bifidobacteria (a combination of Bifidobacteria and Lactobacillus) and for sure Saccharomyces boulardii—they can have a good action in some peculiar clinical conditions. In particular, it has been demonstrated they can help us in infectious viral diarrhea, they can help us in antibiotic-associated diarrhea, and in some peculiar cases of inflammatory bowel disease and irritable bowel syndrome. However, the main problem is that the more important bacteria that are in the gut—the more important species of the bacteria where we have most of the evidence of their function—at the moment are not produced as probiotics. So really the main problem is that the probiotics that we have in the market are not the most important species we have in the gut. I think that to have a good answer to your question, we have to wait for when a big company can produce the real species that are in the gut in order to give this kind of species. So my idea is that probiotics is a great option for the future, but we have to work a lot. And the same for prebiotics. It would be very nice to have the possibility to feed specific bacteria with specific prebiotics, but the real fact is at the moment a prebiotic is utilized by ALL the bacteria (probably also by the bad bacterial). So the real answer is we have to wait in order to have great probiotics and prebiotics with specific functions for specific bacteria. JB: I think that’s a very good place for us to leave because we’re moving into—again, as you said—a personalized differentiated therapeutic, looking at each individual’s genotype and microbiome in unique ways and personalizing therapy for their individual condition. What I would like to say in just close, is having had the privilege now of meeting you personally and listening to you speak and reading now a number of your papers, you’re really creating the new medicine. You’re really taking the concept of gastroenterology well beyond that which it has often been narrowly defined, and on behalf of all of our functional medicine docs and researchers and clinicians over the years, I want to thank you. I think this is very, very challenging work. Very difficult, complex work, but you have really started to, I think, establish a path of clarity through this confusion that’s going to open up this field in ways that we never even believed were possible. Thank you so much, Dr. Gasbarrini. You’re a guide and a vision for all of us. AG: Okay, thank you, Jeffrey. Thank you to everybody. JB: You be very well. Thank you.  

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Bibliography

[1] Wyatt J, Vogelsang H, Hübl W, Lochs H. Intestinal permeability and the prediction of relapse in Crohn’s disease. Lancet. 1993 Jun 5;341(8858):1437-9.   [2] Li X, Kan EM, Lu J, Cao Y, Wong RK, et al. Combat-training increases intestinal permeability, immune activation and gastrointestinal symptoms in soldiers. Aliment Pharmacol Ther. 2013 Apr;37(8):799-809.   [3] Jeukendrup AE, Vet-Joop K, Sturk A, Stegen JH, Senden J, et al. Relationship between gastro-intestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men. Clin Sci (Lond). 2000 Jan;98(1):47-55.   [4] Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012 Sep 13;489(7415):242-9.   [5] Zhang X, Shen D, Fang Z, Jie Z, Qiu X, et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One. 2013 Aug 27;8(8):e71108.   [6] Markle JG, Fran DN, Mortin-Toth S, Robertson CE, Feazel LM, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013 Mar 1;339(6123):1084-8.   [7] Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008 Apr 17;3(4):213-23.   [8] Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroeneterology. 2012 Oct;143(4):913-6.   [9] De Vrieze J. The promise of poop. Science. 2013 Aug 13;341:954-957.   [10] Hoffmann DE, Fraser CM, Palumbo FB, Ravel, J, Rothenberg K, et al. Science and regulation: Probiotics: finding the right regulatory balance. Science. 2013 Oct 18;342(6156):314-5.   [11] David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, et al. Diet rapidly and reproducibly alters the gut microbiome. Nature. 2014 Jan 23; 505(7484):559-63.   [12] Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, et al. The long-term stability of the human gut microbiota. Science. 2013 Jul 5;341(6141):1237439.   [13] Xu Y, Wang L, He J, Bi Y, Li M, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013 Sep 4;310(9):948-59.

Welcome to Functional Medicine Update for March 2014. Oh my word, do we have a wonderful March episode for all of you that really follows on from our extraordinary first two issues of the year 2014. Just to kind of recount and recap where we have come so far in 2014 and what has emerged to be a mini-course in what I call functional gastroenterology that is really pace setting in the 21st century of a systems biology approach to medicine. You recall that in January we were very fortunate to be able to interview Dr. Alessio Fasano from Harvard, who arguably is one of the select group of people in the world that understands and is elucidating the effects of gluten in immunologically sensitive individuals and the role it plays in immunological activation and alteration. I believe that Dr. Fasano’s interview really opened up the discussion of gluten and gluten-like protein molecules and their effect on the immune system in a way that was much more expansive than we had previously even thought of, moving it into areas of childhood development and things like autistic spectrum-like disorders, and discussing the effect on seizure disorders, and the effect on autoimmune disease in later-age individuals. These are all extraordinarily interesting emerging topics to come out of the gluten story, that’s much more than celiac. In fact, he talked about non-celiac-related gluten sensitivities and the cooperative work among European gastroenterologists that have put together a position paper illustrating the importance of this topic in medicine. From Dr. Fasano’s extraordinary discussion we then moved into the second of the three parts of this mini-course, which was Dr. Gasbarrini—again, arguably one of the world’s renowned gastroenterologists and certainly a leader at the University of Rome, School of Medicine. He has published over 400 papers on a broad range of activities and discoveries. His focus was on gut permeability, you might recall (or “leaky gut”), which we discussed as being considered an artifact term when it was first used some 25 years ago in Functional Medicine Update. People thought, what the heck is ‘leaky gut syndrome’? You know, it was pretty much a term that was considered artifactual to good gastroenterological knowledge. But over the past two-and-a-half decades, this term has become much more frequently used and, in fact, if you do a PubMed search now under the term “leaky gut” you’ll come up with a variety of high grade publications, some of which have come out of Dr. Gasbarrini’s laboratory itself. Dr. Gasbarrini helped us to understand the tight junction physiology of the gut mucosal cells. He helped us understand the goblet cell activities and these intercellular junctions which then become permeable to larger molecular weight molecules and how that activates the immune system and can induce systemic inflammation. Therefore I thought Dr. Gasbarrini, who is really a very traditionally focused and trained gastroenterologist who has undergone this conversion experience in his understanding of the role of the gut immune system and the influence that diet and microbes have on gut permeability and gut mucosal integrity, has really reflected the change in the field in general. So that was an extraordinary chapter 2 in our three-phase discussion as to how the gut influences systemic health. And that leads us to this issue this month with Dr. Patrice Cani. You might recall (those of you who have been long term Functional Medicine Update subscribers), we had the privilege of visiting with him and his colleague, Dr. Nathalie Delzenne, at Catholic University in Louvain in Belgium, in which he and Dr. Delzenne described their earlier work as it pertained to the gut microbiome and its interrelationship with immune function—the so-called gastrointestinal associated lymphoid tissue (GALT) of the gut and how that influences systemic immune system function. Much has occurred, as we’ll hear from Dr. Cani, since our interview with he and Dr. Delzenne some years ago. In fact, nearly a hundred publications later, over these but few years, illustrates his productivity out of their laboratory in the Metabolism and Nutrition section at Louvain. This is, I think, a very remarkable time of change. And what you’ll hear from Dr. Cani in his discussion with me is the emerging understanding of the outcome that occurs from the leaky gut and from gut inflammatory processes that may be associated with things like gluten and other perceived foreign molecules that induces what is called postprandial or metabolic endotoxemia, another term that would have been considered but 10 years ago to be an artifactual term to good understanding of gastrointestinal function. It was not thought that there could be such a thing as a chronic inflammatory burden from metabolic endotoxemia—that you were either suffering from systemic toxemia, which was a critical septic condition in emergency room medicine, or you had normal gut function. But now we see that there is a graded effect and you can, in fact, observe this so-called metabolic chronic endotoxemia that’s associated with high fat/high sugar meals (so-called postprandial or post-eating metabolic endotoxemia). And Dr. Cani and Dr. Delzenne have certainly been in that smallest group of investigators around the world that are really pioneering discoveries in this area and helping us to understand how important it is and the consequences of the sequelae associated with inflammatory systemic diseases, but also what we can do about it by modulating and modifying the gut microbiome, the mucus layer of the biofilm of the gut, and also the gut mucosal integrity. So with that said, why don’t we move into our discussion with Dr. Cani and let him enlighten us as it relates to this extraordinary emergence of understanding of the role that lipopolysaccharides from Gram-negative bacterial cell walls in the gut have on our immune system and endotoxemia  

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INTERVIEW TRANSCRIPT

Researcher of the Month Patrice Cani, PhD Louvain Drug Research Institute (LDRI) Metabolism and Nutrition (MNutr) Catholic University of Louvain Belgium http://www.uclouvain.be/en-269734.html Well here we are, and what a fortune we have with Professor Patrice Cani, who many of you might favorably remember from our visit with him a few years ago from his Metabolism and Nutrition laboratory at the Catholic University of Louvain in Belgium. He and his colleague, Nathalie Delzenne, who have taken over the laboratories of Marcel Roberfroid, have just really advanced this field in ways that are truly remarkable. As I look at Professor Cani’s publication record over the last few years, it would rival any top investigator in the world: over 130 publications in top peer-reviewed journals. But more than that is the substance of each of these publications—the breadth, the scope, the depth, and the impact of these discoveries that he and Dr. Delzenne are making are really world changing, and I think that they will have such an impact—a seismic effect on medicine—that we will look back to think of this as a golden age. I think that Professor Cani must take great pride in watching how the ripple effects of his discoveries are influencing so many other investigators. Patrice, it’s wonderful to have you once again as a researcher on Functional Medicine Update. On behalf of all of my colleagues I want to greatly acknowledge and tell you our appreciation for the work that you are doing. It’s tremendous. PC: Thank you so much. That’s very kind. JB: Let’s start with postprandial endotoxemia or endotoxicity. This is a topic that not too many years ago would have not been considered respectable to talk about in a mixed scientific audience; there was believed to be no such thing as chronic postprandial endotoxemia. But certainly your work has greatly changed that landscape and understanding. Tell us a little bit about how you got into this discovery and what are the fundamental features that have allowed it to suddenly be recognized as a real phenomenon? Postprandial Metabolic Endotoxemia: Now Recognized as a Real Phenomenon PC: That is an interesting point. As you mentioned, this metabolic endotoxemia—this increase in plasma lipopolysaccharides (LPS)—it took a long time to demonstrate to the scientific community…not to demonstrate, to accept that this phenomenon exists. And we came to this theory because we had in mind that obesity and type 2 diabetes are associated with a low-grade inflammatory tone. We are still seeking the triggering factor, but at that time (10 years ago) we were investigating the role of gut microbes following prebiotic treatment, and we knew that prebiotics were able to change the gut microbiota composition and were able to improve the phenotype of obesity and diabetes and reduce low-grade inflammatory tone.[4] And we had in mind that some signals coming from the gut’s microbes might be, in fact, involved in this crosstalk between the intestine and the different organs, thereby leading to the development of low-grade inflammation. So we investigated whether some specific compounds from bacteria might be found in the circulating blood, and we knew, of course, from the previous work and old work that our cells are able to express receptors (specific toll-like receptors), for instance, that are able to sense different signals from the microbes.[5] And we decided to measure LPS in the portal veins of mice fed with a high fat diet, or mice that were obese and had type 2 diabetes due to a genetic mutation. In fact, we found that in both models—I mean nutrition-induced obesity or genetically induced obesity—the plasma LPS levels were increased.[6] But this increase was around two- to three-fold the basal level. So we are not in the context of an endotoxic shock. It’s completely different, but it was really consistent. In all the different experiments that we performed we found this increase in plasma LPS. We decided to verify whether this increase in plasma LPS might be the triggering factor involved in insulin resistance and in the level of inflammation associated with obesity. By using different models—we’ll not enter into details, of course—but we used models of gut microbiota modulation, we used models of mice that were created for specific receptors of these LPS or core receptors (toll-like receptor 4 or CD14 knockout mice), and we found that these mice lacking the receptors for this LPS were resistant to diet-induced obesity, and low-grade inflammation also.[7] And then we investigated in humans whether we could find a relationship between high fat diet feeding, obesity, and plasma LPS, and we do find this positive relationship between plasma LPS levels and obesity, or plasma LPS and fat feeding. In normal chow-fed mice or in humans we could demonstrate that eating fats is associated with an increase in plasma LPS, so in physiological conditions, fat feeding increases plasma LPS.[8] But we do believe that during obesity and chronic high fat feeding, there is a permanent and persistent increase in plasma LPS, leading to this low-grade inflammatory tone. This is exactly what I am still believing, but we investigated the gut barrier function, because we know that we are living with a tremendous amount of microbes within the gut, and almost no bacteria are in the circulating blood, so this gut barrier must be really efficient. And we found, indeed, that in obese and type 2 diabetic mice, there is increased gut permeability, so not good gut barrier function.[9] We decided in the following years to investigate this gut barrier function at different levels, because we know that the gut barrier is composed, of course, of epithelial cells, the tight junctions are really important, the antimicrobial peptides produced by the epithelial cells are also important, but we also know there is a mucus layer, and this mucus layer can also contribute to this gut barrier function. And so we found by using different models that all these different barriers might be altered during obesity and type 2 diabetes. For instance, we found increased gut permeability by mechanisms linking tight junction distribution; I mean, localization and expression. We found also a reduced mucus layer thickness, for instance, in diet-induced obese mice.[10],[11] We found that high fat diet feeding reduces the expression of anti-microbial peptides, so this crosstalk between microbes, the host, epithelial cells, and finally metabolism exists, but we are still now trying to understand exactly all these complex pieces of the puzzle. But anyway, what I think is that there are some signals coming from the gut microbiota that will lead to the development of inflammation through changes in this gut barrier function. Developing LPS-Measuring Technology JB: What you just said obviously validates my introduction: life-changing, world-changing, paradigm-changing concepts. Let me, if I can, ask a little sidebar question. Often we see these major discoveries occurring on the shoulders of certain kinds of technologies that were not available before. In other words, we can ask certain questions to find answers for those questions that we couldn’t find answers for in the past. I think your ability to measure accurately LPS at very low levels at high sensitivity was a major advance because it appears to me that before people might have speculated, but they didn’t actually have the technology available to measure LPS at low levels. How was it that you were able to define an LPS-measuring technology that would give you the kind of sensitivity and precision you needed at these low levels? PC: That’s a good question. I have to mention that measuring LPS is still a nightmare. I mean, you have to be careful because when we are measuring LPS, we have to perform very good blood sampling. We know that, for instance, LPS can bind to plastics. We know that LPS, or endotoxins, are everywhere, so we can contaminate samples or we can also find false-negatives. We are still using the gold standard method, which is based on the limulus amoebocyte lysate (LAL) assay, but we are now in the conditions where we know that we have to introduce in each of the samples a known amount of LPS to calculate a recovery. So what we do now when we measure LPS is to measure and duplicate each sample, but we have to also duplicate a recovery. So we spike the samples with a known amount of LPS, and when we are measuring LPS, if the recovery is below 100 percent—let’s say, for instance, 20 percent—it means that we are in a condition where the samples are inhibitory. It means that we cannot trust in the data. And that’s the reason why sometimes, and most of the time, people said, we couldn’t find LPS in normal conditions because there were inhibitory conditions, I guess. So they didn’t try to verify if indeed the plasma was inhibitory for the reaction. And it means that now that we know that LPS measurement is really a tricky method, we have to be careful about not only the contamination, but also about the specific inhibitory reaction. I can give you a very simple example. We have a sample where, when we measure the plasma LPS by using these methods without recovery, for instance, the method will say, “None detectable.” So you have no LPS. But if you perform exactly the same measurements with the same sample but you put a known amount of LPS, you know that you have LPS in your sample. But the method will say there is zero LPS in your sample. And the recovery means that you have zero recovery—you couldn’t find, you couldn’t measure, the LPS you put in your sample. So I think that now knowing that we have to move toward this kind of measurement to really trust in our data, to be sure that in each of the samples that we are assessing we have a known amount of LPS and a good recovery, that for me is the key point. This has not been performed previously in most of the studies. So, in other words, I think that now we have data in hand to measure in a very accurate manner and a very low and high sensitivity manner the plasma LPS by using LAL methods, and I’m using for instance, kinetic color measurements, and we can measure through 0.005 ug per mL, so it’s a really low, low level. But this recovery point is a really important point, because otherwise we can say there is nothing, and it’s a false-negative, in fact. JB: Thank you. That’s very, very helpful. For the sake of our listeners, would you just give us a quick thumbnail of the nature of lipopolysaccharides? We know they come from the Gram-negative bacterial cell wall. But I don’t think for most people they understand, what is LPS? Is it a class of molecules, is it a specific molecule, are there different variations on a theme? Could you just quickly give us a thought about what LPS is? Lipopolysaccharides Explained PC: Yes. So, LPS is, in fact, a complex molecule composed of different lipids, so it is quite a big molecule. I will not really enter into all the details, but the components of LPS are different. You have a chain. You have what we can call a core, and the Lipid A. All these different parts of the lipopolysaccharides are in fact specific to the different bacteria. I mean, for instance, we know that the lipopolysaccharides coming from E. coli, this serotype will be different from another one. You’ll see also conferred to this LPS this capability to induce, for instance, inflammation. I mean, with one molecule of LPS, from one E. coli and from one salmonella, for instance, we know that the antigenicity or the capacity to induce inflammation will be different. We are speaking about LPS measurements, but we have to keep in mind that it’s a lipopolysaccharide or an endotoxin activity, so it’s a capacity of the LPS to induce the inflammatory tone, because we know that some LPS will have poor impact on the inflammatory tone. So this complex molecule—this macromolecule—has a different composition at the level of different lipids, but also carbohydrates. And so far, nobody can really discriminate in the blood sample the different types of lipopolysaccharides, so we are still measuring the endotoxin activity. JB: Got it. Thank you, that’s very, very helpful. When you then look at, say, different species of bacteria, different strains within the gut microbiome—say the Firmicutes versus the Bacteroidetes—your bacterial cell wall fragments—your LPS fragments—between those two families can have very different inflammatory tone I would presume from what you’ve said. PC: Yes, sure. JB: So as you speciate the microbiome, what have you started to learn about those bacteria that have the greatest potential for inducing proinflammation? PC: So honestly maybe seven or eight years ago I had in mind that the more Gram-negative bacteria we have in the gut microbiota, the more important the inflammatory tone will be. And then I had to change my mind because of some recent discoveries from the lab. And, indeed, we are still trying to understand what kind of gut microbiota we induce along with inflammatory tone. But we know from our data, including deduced from other researchers, that the gut barrier function is really important. It’s what I mentioned before. I think that although the Bacteroidetes/Firmicutes ratio is something important, we cannot say if we have an increase in Bacteroidetes (I mean, mostly Gram-negative bacteria) that will induce a low-grade inflammatory tone, because between the gut microbiota and the host there is the epithelial cells and the gut barrier. Akkermansia muciniphila: Revealing Research on Prebiotics I can give you an example regarding one specific strain we have identified and characterized. This is Akkermansia muciniphila. This bacterium—this Gram-negative bacteria—and we in fact investigated the role of prebiotics (we are now in 2007), and in 2007 I had the chance to measure by using power sequencing, so a high-throughput method, the composition of the gut microbiota in mice that were fed with prebiotics. So we knew from Marcel Roberfroid’s work and from Glenn Gibson that of course prebiotics will increase Bifidobacteria, and in some cases Lactobacilli.[12] But we decided to investigate more into this gut microbiota, and we found—this was serendipity—we found that prebiotics were able to increase by about 100-fold, one specific strain: Akkermansia muciniphila (see reference #6). And honestly when I received the data, and I saw that—that it was a Gram-negative bacteria—I said, “My God, it’s impossible.” Because we have published data and we still have data in hand showing that prebiotics in the context of obesity and type 2 diabetes reduces plasma LPS, and here I have data in hand showing that I have a very huge increase in one Gram-negative bacteria, and this is Akkermansia muciniphila. And finally, by using different methods, and we have published this paper now, we found that this Akkermansia muciniphila was not so bad. It’s not really a bad guy. We know that this Akkermansia muciniphila, although it is a Gram-negative bacteria, it’s LPS. It’s like lipopolysaccharide. It’s a very poor LPS to induce inflammation. And we also found that this bacterium improves the gut barrier function, so the more Akkermansia muciniphila we have, the better is the gut barrier function. And we found that in diet-induced obesity Akkermansia was decreased, and there are also some data now in the literature showing that in obese patients or in type 2 diabetes patients, this Gram-negative bacteria is, in fact, decreased (see reference #11). I mean, the abundance is lower, suggesting that this specific Gram-negative bacteria may have a positive impact. So it might be really difficult now, from my point of view, to say we have to blame all the Gram-negative bacteria. I think that we have to look more precisely at the gut barrier function. Of course, you know that from many, many years, but I think that in the scientific community, most of the scientists that were not really aware about this gut barrier function are now jumping into the story, and this is true for hepatic steatosis, also, and different diseases, where the scientific community is coming back to this previous story of the gut barrier function and nobody was trusting it, and now they are. I think they are interested, at least, in this investigation of the gut barrier function. So I think that this Gram-negative/Gram-positive story is one thing, but we have to put in between the function of this gut barrier. JB: That was beautifully stated. I certainly would agree with your assessment that the scientific community is moving in this direction. If you just look at the number of publications since you and Dr. Delzenne started publishing in this area, it is exponentially increased, and I think a lot of that is a consequence of the great science that you’ve done. Let me, if I can, talk about this concept of the receptors for which these bacterial debris have their influence. You talked briefly about toll-like receptor 4. We also know about the endocannabinoid receptors. We know about them as members of the G protein-coupled receptor family. You’ve done some work and published on GPCR 43.[13] What do you think the receptors are that are being influenced by these metabolites from bacteria. Are there multiple receptors or are there specific families that are more dominant in controlling this inflammatory tone? PC: Okay, that’s a very good question. I think that based on the pharmacological properties, we cannot say there is a unique type of receptor involved in the crosstalk between microbes or metabolites coming from microbes and host. For instance, as you mention, there are some receptors for metabolites that are just short-chain fatty acids, so GPR 41/43. There are some receptors for endocannabinoids—GPR 119, for instance—or others. And we have had some data indeed suggesting that we have to take into account not only the expression of these receptors—where they are localized on the gut or on the different organs or on different cells—but also how the gut microbiota are able to crosstalk with the host through these kinds of receptors. And we, and others, have investigated the role of GPR41 and 43—how they can contribute to the improvement of, for instance, secretion of GLP1 or GLP2, so two key peptides that we have investigated. But I think the picture is not clear so far. We are at the beginning of the story, I think. This is my point of view. I think that we still have to discover different types of receptors. Whatever the kind of receptor—GPR receptors or ion receptors or whatever the type of receptor—but I think that we are at the beginning of the story. Because it might be possible that we have endogenous receptors that have been described so far for endogenous molecules that are able to respond to some specific metabolites from the gut microbes. So we may not exclude—and this is probably the case for the endocannaboids also—that some microbes are able to produce metabolites that will be considered as a ligand for specific receptors, and finally, will probably contribute to explain the impact of the gut microbiota composition—it’s functional activity. I mean, we are still trying to understand not only the gut microbiota composition, but also the metabolic functions encoded by these microbes. Adipocytes May Respond to Specific Metabolites in the Gut Microbiota I think also that we do not have to consider only the receptors present on the epithelial cells, but also receptors that are present in innate immune cells or immune cells at the level of the intestine, but also in the adipocytes, for instance. So we have data now that suggests that the adipocytes may respond to specific metabolites coming from the gut microbiota (I mean short-chain fatty acids). So it’s really an expanding science. I would like—and I look forward to seeing—whether some other kind of family of receptors will in fact be specific receptors for metabolites coming from microbes. We are speaking about gut microbes, but we may not exclude that some viruses or components of viruses might also contribute to this phenomenon. I mean, we have in mind, for instance, MyD88, which is a component of the toll-like receptors. JB: What you’ve said is extraordinarily important because you’ve talked about the crosstalk among macrophages, adipocytes, and these gut receptors that are activated by bacterial metabolites. This is a whole new systems biology approach towards health care. I want to shift just quickly to the diet influence, because you’ve published some very interesting papers in which you talk about things like curcumin and its influence on these inflammatory processes of the gut, and a paper you did on tetrahydro-iso-alpha acids derived from hops and its influence on endotoxemia.[14] The question that one might ask is, are these phytochemicals coming from various foods and spices directly acting as antagonists of the endotoxemia, or are they indirectly working by modifying the gut environment, changing the bacterial speciation? In other words, are they influencing the receptors of the endotoxins or are they actually changing the bacterial flora so that there are different endotoxins being produced? Do you have a thought about that? PC: That’s also a very good question. I think that I have no clear answer. I mean, all these different mechanisms might be involved. For instance, we know that some phytochemicals are able to change the gut’s microbiota composition. Is it directly through the targeting of specific microbes, or is it through mechanisms changing, for instance, the pH or the environment within the gut? It’s possible. Is it through the modification of antimicrobial peptide secretion from the host? I mean, it’s also possible. So I think that so far I have no clear explanation. What I can say is that the different components we have tested are able to improve the gut barrier function. They are able to reduce plasma LPS levels, and to improve the phenotype (I mean, to reduce inflammatory tone), and this is associated with the change in the gut microbiota composition. But honestly, we are still investigating these kinds of questions: if it is directly through the modulation of the gut microbes, or through any modification of this crosstalk existing between host-microbes/microbes-host? But anyway, I think it is important just to keep in mind that they are efficient, so some specific phytochemicals are really efficient to improve the phenotype. Then, what kind of mechanism it is, it is also an important point maybe to design specific drugs, but we have so far enhanced natural compounds that might be useful. We spoke about the prebiotics, of course, but there are so many different compounds, and we have worked—and you know that, of course—with different alpha acids that were really efficient to reduce this, for instance, inflammation, to reduce body weight gain, to improve gut barrier function. And I’m still looking for what are key mechanisms: who is doing what and how it works. How Does Gastric Bypass Surgery Influence Obesity and Diabetes? JB: Thank you. So, let me shift maybe to the last question. I would love to engage in this discussion for hours but I know time is limited, so let’s talk a little bit about the extraordinary discoveries you’ve made as it relates—as you’ve alluded to—to the role of these inflammatory processes, both in obesity and in diabetes type 2/insulin resistance and the manifold effects that occur as a consequence of insulin resistance. When I look at that series of publications that you’ve had from your group, which I think are extraordinary in helping us to understand that the gut and its speciation within the microbiome has something to do with obesity and with inflammatory disorders associated with diabetes, it then raises a question as it relates to medical practice today, in which we’re seeing a lot of gastric bypass surgery like Roux-en-Y being done for people with morbid obesity: how does gastric bypass actually influence obesity and influence diabetes? It’s not just strictly a calorie control/malabsorption syndrome. I know you’ve published at least one paper in this area.[15] What is your thinking right now as it relates to the influence of gastric bypass on these complex mechanisms of the microbiome and inflammatory signaling? PC: Yes. Honestly, I’m pretty convinced that there is a link with gut microbes. There are data, and really ligand studies that have been published now. I have in mind one key study published by Lee Kaplan’s group in Science Translational Medicine magazine last year. And they have found that gut microbiota coming from mice that were in fact treated—I mean, they had surgery, this kind of RYGB surgery. So what they did is to treat mice by this surgery, and they found that the mice fed with a high fat diet of course were losing weight, and the gut microbiota was completely different between the RYGB and the sham operated mice. When they transferred the gut microbiota from the RYGB-treated mice into naïve germ-free mice, and then they fed the mice with the high fat diet, they were as resistant to diet-induced obesity. So it means that by simply transferring the gut microbiota harvested from these RYGB donors into naïve germ-free recipient mice, they could replicate the phenotype of the surgery itself, meaning that indeed there is something really crucial, but what, exactly, we don’t know—but something coming from the gut microbiota leading to this protection. And in this context—and in this study—they also found a very strong link with Akkermansia muciniphila, so this bacterium that I discussed before that we discovered, they found that following this surgery, Akkermansia muciniphila abundance increased really highly—toward 20 percent of the gut microbiota was represented by this bacteria. And it has also been demonstrated in humans that RYGB treatment increases this bacteria.[16] Now the question is: is it through this bacteria, or through an interaction with other bacteria? I don’t know, but we have evidence showing that indeed RYGB treatment changes gut microbiota composition, and we can replicate the phenotype by simply transferring the gut microbiota into naïve germ-free mice. So my answer is yes, we have to look more specifically, at this level of the gut microbiota. What kind of metabolites are produced? Is it through a specific activity, a complex of microbes, can we, for instance, design three-, four-, five different bacteria and put together these bacteria to replicate the phenotype? It might be possible. But the RYGB treatments, yes indeed, contribute to the decrease in body weight I guess through a gut microbiota-determined mechanism. Now we have to prove that in humans, of course. It’s clearly and nicely demonstrated in mice. JB: And do you feel that there is, at least early stage evidence from fecal transplants that are being done in humans, some positive directional indication that this model will prove useful therapeutically? PC: So far, the transfer that has been published—I mean, in humans—they have shown an improvement of insulin sensitivity without any change in fat mass or inflammation and body weight.[17] I think that it is still too early to say that will be the next treatment for obesity, but I think that also if we can improve the phenotype of an obese subject—I mean, if we can reduce insulin resistance, reduce low-grade inflammatory tone, and improve the mobility, that’s the first step. Then, if we are able to reduce fat mass, it’s the second step. But in a clinical point of view, I think that one day we will be able to design, maybe, a specific mix of bacteria, or we will maybe find a super donor—we don’t know—that will help to improve the phenotype. But we have to keep in mind that when we are transferring (I mean in humans) microbes (gut microbiota, or fecal transplant), it is also associated with a transfer of different viruses and different other components. So it’s complex. I mean, we are at the beginning of the story of obesity, not in the context of Clostridium difficile resistance. I mean, really in the context of obesity. So my point of view is yes, I think it’s a good model to understand the relationship between microbes and host. If it’s the next treatment, I’m not yet convinced. JB: I want to thank you, Dr. Cani. Your work and that of your colleague, Dr. Delzenne, is just truly paradigm-shifting. It’s so exciting to check in with you and see the progress you’ve made just in the last few years, since our previous discussion on Functional Medicine Update. We wish you, obviously, continued great success. This is, to me, changing the way that people actually view not just specific therapies, but the whole nature of medicine, because what you are doing is tying together gastroenterology with immunology, with rheumatology, with cardiology, with neurology. I mean, it’s really breaking down the barriers among different medical disciplines and creating a whole system of biology that will create an effect on reduction of incidence of, I think, preventable and treatable chronic disease. Thank you so much from all of our listeners. We wish you the very best and hope to keep in touch with you and follow your publications very closely. PC: Thank you very much. Bye-bye. JB: Bye-bye.  

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Bibliography

[1] Catassic C, Bai JC, Bonaz B, Bouma G, Calabro A, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013 Sept 26;5(10):3839-53.   [2] Scaldaferri F, Pizzoferrato M, Geraldi V, Lopetuso L, Gasbarrini A. The gut barrier: new acquisitions and therapeutic approaches. J Clin Gastroenterol. 2012 Oct;46 Suppl:S12-7.   [3] Garcovich M, Zocco MA, Roccarino D, Ponziani FR, Gasbarrini A. Prevention and treatment of hepatic encephalopathy focusing on gut microbiota. World J Gastroenterol. 2012 Dec 14;18(46):6693-700.   [4] Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007 Nov;50(11):2374-83.   [5] Abreu MT. Immunologic regulation of toll-like receptors in gut epithelium. Curr Opin Gastroenterol. 2003 Nov;19(6):559-64.   [6] Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes. 2011 Nov;60(11):2775-86.   [7] Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007 Jul;56(7):1761-72.   [8] Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des. 2009;15(13):1546-58.   [9] Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008 Jun;57(6):1470-81.   [10]Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009 Aug;58(8):1091-103.   [11] Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013 May 28;110(22):9066-71.   [12] Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995 Jun;125(6):1401-12.   [13] DeWulf EM, Cani PD, Neyrinck AM, Possemiers S, Van Holle A, Muccioli GG, et al. Inulin-type fructans with prebiotic properties counteract GRP43 overexpression and PPARγ-related adipogenesis in the white adipose tissue of high-fat diet-fed mice. J Nutr Biochem. 2011 Aug;22(8):712-22.   [14] Everard A, Geurts L, Van Roye M, Delzenne NM, Cani PD. Tetrahydro iso-alpha acids from hops improve glucose homeostasis and reduce body weight gain and metabolic endotoxemia in high-fat diet-fed mice. PLoS One. 2012;7(3):e33858.   [15] Cani PD, Osto M, Geurts L, Everard A. Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes. 2012 Jul-Aug;3(4):279-88.   [16] Liou AP, Paziuk M, Luevano JM Jr, Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Trans Med. 2013 Mar 27;5(178):178ra41.   [17] Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JF, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct;143(4):913-6.   [18] Thornton KA, Mora-Plazas M, Marín C, Villamor E. Vitamin A deficiency is associated with gastrointestinal and respiratory morbidity in school-age children. J Nutr. 2014 Feb 5.   [19] He CS, Handzlik M, Fraser WD, Muhamad A, Preston H, Richardson A, Gleeson M. Influence of vitamin D status on respiratory infection incidence and immune function during 4 months of winter training in endurance sport athletes. Exerc Immunol Rev. 2013;19:86-101.   [20] Khoo AL, Chai LY, Koenen HJ, Sweep FC, Joosten I, et al. Regulation of cytokine responses by seasonality of vitamin D status in healthy individuals. Clin Exp Immunol. 2011 Apr;164(1):72-9.   [21] Ferri N, Corsini A. Clinical evidence of statin therapy in non-dyslipidemic disorders. Pharmacol Res. 2014 Feb 15. Pii: S1043-6618(14)00016-4.   [22] Neves AL, Coelho J, Couto L, Leite-Moreira A, Roncon-Albuquerque R Jr. Metabolic endotoxemia: a molecular risk between obesity and cardiovascular risk. J Mol Endocrinol. 2013 Sep 11;51(2):R51-64.   [23] Estadella D, de Penha Oller do Nascimento CM, Oyama LM, Ribeiro EB, Dâmasco AR, de Piano A. Lipotoxicity: effects of dietary saturated fat and transfatty acids. Mediators Inflamm. 2013;2013:137579.   [24] Spiegelman BM. Banting Lecture 2012: regulation of adipogenesis: toward new therapeutics for metabolic disease. Diabetes.2013 Jun;62(6):1774-82.

Welcome to Functional Medicine Update for April 2014. Oh boy, do I have a treat in store for you this month. You know, sometimes my own zeal gets the best of me, but this is, to me, one of those very special moments because we have a chance to do a back-to-the future issue. We’re going back to really the start of functional medicine and origin. What were the fundamental groundings that led me to even come up with the concept of functional medicine as a term, knowing that it had been used for some time for geriatric medicine, or for psychosomatic medicine? Why would I choose a term that had already seemed to get tainted by other definitions? The reason I did that was because of the impression of the article that was authored by our clinician/researcher of the month this month in the April issue of Functional Medicine Update, Dr. James Fries. You probably recall he authored what I consider a luminary paper in the New England Journal of Medicine in 1980. A few years—in fact a decade—before we started the Institute for Functional Medicine. From the day that article was read by me in 1980 until the origin of the Institute for Functional Medicine and functional medicine as a concept, it was the driving force of that article, “Aging, Natural Death, and the Compression of Morbidity” that really set me on this path.[1]   We’re now very fortunate. As you know it’s a few years since 1980. You can do the math: 34 years. With that length of time, a lot has happened in Dr. Fries’ life as well in the life of the Institute for Functional Medicine. Let’s move into our discussion with Dr. James Fries, Professor Emeritus, Stanford University School of Medicine, in the immunology and rheumatology department.  

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month James Fries, MD Professor of Medicine (Immunology and Rheumatology) Emeritus Stanford University School of Medicine Palo Alto, CA https://med.stanford.edu/profiles/james-fries Well here we are once again at that point of Functional Medicine Update that gives me the greatest sense of enjoyment and I hope you as well as a listener, and that is our opportunity to visit with someone that we consider to be really treating the medicine of the 21st century. It couldn’t be more appropriately forecast that this particular issue will go down as a legacy issue, because we’re tracing back with the individual who I think, if I was to review my 35-to-40 years in the field, probably has been the seminal impactful person in terms of my thinking, and that’s Dr. James Fries, Professor Emeritus at Stanford University Medical School, immunology and rheumatology. Those of you who have heard me on Functional Medicine Update over the years or in other venues or read my writings, probably recognize that the most cited article that I have used over those years has been the seminal paper that Dr. Fries authored in 1980 in the New England Journal of Medicine, “Aging, Natural Death, and the Compression of Morbidity.” When that article was published it was like a mega lumen bulb went off for me and has lit a path forward that ultimately led to the birthing of the Institute for Functional Medicine. The Relationship Between Organ Reserve and Chronological Aging In that particular paper, Dr. Fries talks about this concept that really was a term that I believe he formulated called “compression of morbidity,” which seems so logical to me. He related it to things like organ reserve—that as animals undergo chronological aging that they tend to lose organ reserve that they had as a more youthful animal, and that then makes them more at risk to environmental perturbations that may exceed their reserve and cause what we call a catastrophic event, maybe even a life-threatening event. So the concept was holding onto organ reserve and compressed morbidity in the last phase of a life, which hopefully leads out to the limits of your biologically determined lifespan as an organism. That model seemed so extraordinarily logical to me that I was just overwhelmingly surprised when I saw the letters to the editor that followed that article that appeared in the New England Journal of Medicine in which people were vehemently criticizing this model, which I couldn’t even believe how any intelligent person would criticize what seemed so logical and so well laid out. But their criticisms were things like, well, this argument would just keep people alive longer and they would require more medical expenditures because we know that the older you get the more medical expenditures and the more medical services you require, so this was going to not save money, it was going to cost money to the healthcare system. And then other people said, well, you know, this concept will take focus off disease care and it will prevent us from really developing our disease care model as effectively as we should because there is no proof that prevention really pays dividends. So you had all these outlier opinions that sometimes were in such a language that didn’t sound, to me, anything other than polemical, as if people were just into self-protection and were not really engaged in the appropriate type of dialogue about this very important concept. With that in mind, it seems like a very, very appropriate time to come back and revisit with Dr. Fries what all has gone on in his more than 300 publications and seminal contributions to the field over these many years. Dr. Fries, thanks so much for visiting us at Functional Medicine Update. I think maybe the first question is, what led you—in 1980—to the classic paper in the New England Journal of Medicine, and were you as surprised as I with some of the criticisms to what seemed like such a sensible proposition? Gerontology and the Failure-of-Success Paradigm JF: Yes, I was. I’ll give you a little bit of background for it. It was amazing prior to this set of reasoning and development that people had thought about aging in such a basically nonsensical way, and it led them into all of these contradictions. The idea was called the failure-of-success paradigm and it was leading the field of gerontology, and it was that the more that science extended life, the worse the health of the population was going to be. So what you thought were successes in that they affected diseases, were in fact not; they actually contributed to more disability, morbidity, than you’d had before. And it was very strange, but the science of gerontology at that time was referred to colloquially as the “science of drawing downwardly sloping lines.” There was no way, given that paradigm, that one could improve human health. You were locked in to the fact that you were going to lose every time you thought you had gained. There were some metric problems and some other issues that were contributing kind of underneath the radar. One was that there was not very much multidisciplinary research into human aging. There was limited scientific research, but there was not the kind of thing that brought historians and psychologists and clinicians and athletes and trainers and all of the things that have something to bear on the phenomenon that we call human aging. They didn’t talk with each other. The concept of gerontology should be to improve human health and human life, and this had exactly the opposite connotation, and it had an abiding faith that molecular science was going to give you things which it hadn’t yet done. The metric that I think failed the field at that time was that there was pretty good evidence on mortality, but there was no evidence on morbidity, so that one couldn’t actually find out how impaired and how disabled the human populations were, what the risk factors were for them getting disabled more seriously or more earlier. You couldn’t do that because you didn’t have any data. Now after the compression of morbidity hypothesis came out we began to get data about two years later because there were funded long-term studies, which we’ll probably talk about later in this period. But the metric which said that you knew that people were living longer and longer but you didn’t have any data on how sick they were. There was a whole point in the life course which had not been recognized, and I would argue that it’s the most important point in the life course if you’re talking about health, and it’s the age at which you first begin to get chronically ill and impaired. That date was unknown, but it was implicitly assumed that it was unchangeable. So you had a paradigm which was built upon the fact that people were living longer and longer, but you didn’t know what was happening to their health as they proceeded through. It was that and there was a lot of dogma, and there was a lot of self-serving behavior. People were trying to get NIH money, and there were ways in which they could get that and ways in which they couldn’t. They couldn’t talk about soft sciences, like what’s the role of exercise and so forth. It was a discouraging time, and there were not a lot of brilliant people studying aging back in the 70s and 80s. Changing the Paradigm from a Disability Focus to a Functional Focus JB: I think one of the things that struck me immediately when I read your 1980 paper, and it stuck with me—there has probably been an epigenetic change in my neuronal genome ever since—was your changing the definition from that of a disability focus to a functional focus (to measuring function), which is really like changing the paradigm from a disease focus to a health focus. I thought that was a very, very profound—subtle, but very profound—altered perspective, going from everything built on disability to a model built around relative range of function. That seemed like an amazing change in thinking. JF: Well, we started saying, all right, let’s take a new metric; let’s study disability, which was what, as a rheumatologist, I studied. The broader term is morbidity. So, thinking about the quality of life and the things that affect that as more important, potentially, than the length of life, was a radical change, and there have been many, many shifts from the preceding paradigm to what we have now, which is still evolving. But it has changed and essentially reversed its own side, because it really got into the concept of prevention being the only way to improve human health, that is, the only really meaningful, really powerful way to improve human health because things that happened after you’d passed that point in life when you were now disabled to some degree and going to get worse, that was ill health ahead. So the key concept was to go into a longitudinal life-type of thinking and talk about how to postpone disease. Not talking about preventing disease or curing disease. Postponing disease is by far the strongest approach that you have, and we now know that. We know quite well what exercise does. We know quite well what smoking did. And we’re improving rather dramatically in a lot of these ways. But it required getting the observation point and the paradigm that you were trying to quantify in an entirely different fashion. JB: It was very interesting to me because naysayers are always easy to come by because it doesn’t require any discipline for proof other than being a critic. You then, later, with Anthony Vita and your group, came back in 1998 in the New England Journal of Medicine with what I consider really a very profound proof of principle paper on Penn alumni, on aging, health risk, and cumulative disabilities.[2] Can you tell us a little bit about that work and whether it helped change the naysayer opinions at all? JF: Sure. We were studying risk factors and diseases with the Framingham study before we started thinking seriously—I started thinking seriously—about these issues. And there was pretty good data, as I indicated, there. What we didn’t have with risk factor models, though, they were directed at cardiovascular death and learning more about that. But in fact they didn’t have anything to do with the trajectories of illness, and there were not longitudinal studies other than those which had their endpoints as mortality or disease-specific morbidities. We knew that you had to change those endpoints. It isn’t always connected with our work, but a big area of work that I have also done, and they had connection in the way in which the thinking developed, was that we had to have a better metric. We developed a health assessment questionnaire, which had a lot of distinctive features, but it measured disability/disablement in a quantitative way. It used a series of dimensions, and it used a quantitative scale, and it gave you a score. And you could go to people every six months and get that score for them. You could tell when they first began to be subnormal in some area of behavior, and you could see what progressed from that point on. So you had to have a metric, and the Health Assessment Questionnaire disability index is now the most widely used scale. It and the SF36, which came on a little bit later on, and they have changed the way in which people have looked at disease. Two Long-Running Longitudinal Studies Continue to Collect Data I recognized in 1980, actually, that we had to get longitudinal data on aging, so we began two longitudinal studies—the Runner’s Study began in 1984 and the University of Pennsylvania study that you were alluding to began in 1986.[3] We have studied those people and continue to study them now 30 years later. We have been able to follow people through the period of time when they were aging, and dying, and their disability was directing and we were able to pay attention with what happened to the speed of progression of illness with age. That is, the development of disability or the development of morbidity with age, because you had longitudinal studies. And then with the longitudinal studies, we found out quite early on, that people were moving too fast between their providers and between their towns and their jobs and everything else to keep track of them in a normal medical follow-up technique. Framingham, for example, used a small town in Massachusetts, which had very little mobility and you could follow people for a long time, but they still lost a third of the people that were under their follow-up. The concept that we had for our longitudinal studies was that we would look at a subgroup of people physically in person, but we would follow people with what are now called patient-reported outcomes—levels of disability and so forth by mail and telephone. And we would get people enlisted and we would keep them enlisted a very, very long time and we did that. The findings have been reported about every five years for each of the studies and the follow-up has gotten longer, the subjects have gotten older, until now we’re studying 90-year-olds, and we’re continuing to learn that the inputs—the major interventions which people take for themselves and many of the other ones that your organization looks at as well—the major interventions are things that improve your physical fitness. They are aerobic exercise, they are intellectual exercise, they are things that challenge the limits and maintain the vitality of the individual, and they really do that, and now we can look at what actually happens when people do this for a lifetime and what are the major risk factors, or in this instance, the major health factors? Major health factors are exercise, absence of cigarettes and other forms of tobacco, and obesity. Those are the risk factors that make a large change, so the question is, how large was this change? Studies like Framingham indicated that you could detect differences of these kinds of risk factors, particularly cigarette smoking when they were looking at it. And they didn’t have exercise variables at all. Cardiologists at the time Framingham began did not believe in exercise as a preventive force, but we now know, after 30 years, that the exercise variable accounts for as much as 16 years of slowed aging. So if you’re looking at aging as a morbidity phenomenon, and it has a tendency to progress from midlife to the end of life, then that morbidity variable can be postponed by up to 16 years by regular vigorous physical exercise, for example. That was the Runner’s study. The University of Pennsylvania study was a study of alumni from the University of Pennsylvania classes of 1939 and 1940. They were looked at for three variables: the exercise variable, the smoking variable, and the obesity variable (the BMI variable). Again, the differences were very large between people who had good health risks on these dominant variables and the people that did not, and the differences were on the order of eight-to-ten years in postponement. So notice we don’t talk about cross-sectional differences anymore; we try to talk about how much have we postponed the onset of disability? Postponement is a term that should take precedence over prevention, because things are generally not prevented; they are postponed, and the postponement is the variable that is most explanatory. JB: You know, it’s interesting, as I recall the way you stratified exercise in the Penn Alumni study, was the top exercising group was greater than 60 minutes a week of exercise, which seems, in context today (in your Runner’s study) to be fairly low-level commitment to exercise, but yet it had a profound effect on the outcome of compressing morbidity. JF: Yes, but the Runner’s people ran between a thousand and two thousand miles a year when they started, and their exercise throughout life was there. So a good number of them were way beyond the physical fitness goals that people had, so a lot of people were running marathons, they were exercising and running a lot of miles a week. (As was I, at the time.) We all knew how much it was improving. JB: But wasn’t it true that in the Penn Alumni study, as contrasted to the Runner’s study, that the way you stratified exercise there was greater than 60 minutes a week of exercise was considered your top group? JF: Yes. Let me explain a little bit about how you build a hypothesis into a study. In this instance we wanted to be careful, in the design of a longitudinal study of morbidity, that we didn’t get trapped by the non-biological variables that we knew were profoundly important. They were important to morbidity and they were important to mortality. You had to study populations that were favored populations because otherwise education, lack of education, and poverty were profound affectors—so socioeconomic class, independent of any of the biological risk factors was a determinant. So if we really wanted to look at aging by itself we had to study people who were favored people—they had good educations, they had good family histories, they had adequate incomes. Those people we found at the University of Pennsylvania, for example, because those were the attributes that people who were attending the University of Pennsylvania—a prestigious university—had. And they also were more reliable. They key was we didn’t want to get into a position where we were confounded with socioeconomic factors and couldn’t determine what was happening on the biologic side. The Runner’s study was our first concept in this area and in it we took elite runners—running devotees. They were fanatics about exercise, and they put a lot of time and effort into it. And they did extremely well as a result of that. But at the same time, they were nonsmokers, they were fit and not obese, and all of these other things were contributing as well. But you had people that all had 16 years of education, for example. You had to have people that the social factors could not confound the results, and then you had to compare potentially confounding variables, as you do with any longitudinal study. The key was looking at a group that was going to demonstrate a phenomenon if it were there. Those were the people who were already free and had all the health advantages and how much could they get? Well, it turned out the runners could get 16 years additional benefit when they were compared with controls that also were very favored. Exercise Shown to be Most Effective Variable in Preserving Health and Improves Joint Health JB: I think that’s just absolutely profound. There is an interesting…there are many interesting papers that you have published, but another one that kind of follows on from that is the study that you published on vigorous physical activity and disability development in healthy overweight versus normal weight seniors, which was part of this 13-year longitudinal study, and finding—probably against a lot of people’s bias—that exercise even in people with elevated BMI had a very protective effect against premature disability. There is this view that if you are high BMI maybe you shouldn’t be running or you shouldn’t be exercising because it could be damaging to your joints and you’re just going to get arthritis. But it appeared as if your data really spoke to the opposite of that.[4] JF: Yes, and that’s been the general lesson—that if you had to pick a single anti-aging remedy of all of the ones which are touted and talked about by some, the one that is most effective in preserving health is exercise. I’m talking to a group of people who understand things very well now. It works through strengthening the physical body, increasing the organ reserve. It turns out in retrospect, because we even thought the opposite when we started studying the effect on joints, but it turns out that exercise improves the joints. We have a more recent study in which, when we are looking at the runners after many years, the number of destroyed and the controls, about 500 of each, and the runners had four destroyed joints out of the 500 people—destroyed knee joints that either were bone-on-bone or had knee replacements. And the control group had twelve.[5] So the thesis that pain-free exercise is almost inevitably good for you went against the people who had not studied the renewal aspects of exercise. The joints, for example, contain living cells, but they have no excretory system, and they have no oxygenating system. There is no blood flow to the cells that are in the articulate cartilage and the articulate cartilage is what degenerates in osteoarthritis. In fact, you can get osteoarthritis accelerated in joints that are casted. The self-lubricating design is really an amazing one because as you compress the cartilage when you put weight on the joints you squeeze out water with waste products and it goes into the joint fluid and then it gets removed, and you do the opposite with oxygen, so that oxygen is brought in and fertilizes and allows the cells to live even though they have no blood supply. So there are a whole lot of reasons that are now understood pretty well as to why we don’t see the deleterious effects of exercise that were postulated at the time we began our study. We were afraid of them, also, but it turns out if you are doing pain-free exercise activity, and you have to sometimes search around to find the activity that you can do most comfortably, but if it is pain-free then it is good for you. If it’s a joint which has been subjected to sideways trauma, for example, or a variety of things that make it function abnormally, then there are potentially problems of overuse, but there aren’t for pain-free exercise. Evaluative Tools: The NIH PROMIS Program JB: That’s really good news-to-use. As I have watched the evolution of your work over the years I’ve recognized that as you’ve started to focus on terms like “healthy aging” and “successful aging” and “increasing health span,” that it led you more and more into looking at how you assess the range of functions from those like in your Runner’s study, that may be more elite (all), to those that are fairly disabled with a disease like rheumatoid arthritis, where they might have significant limitations in their function. I know you’ve been expanding your assessment program, this NIH PROMIS Program (Patient-Reported Outcome Management Information Systems). Tell us a little bit about how you’re broadening the range of kind of psychometric and evaluative tools that are used for evaluating function.[6] JF: Well, I told you a few minutes ago that the HAQ which I created was a real advance in being able to assess people’s morbidity over time. That metric has been now improved again—probably another order of magnitude—by the development of some new measurement sciences so that there is item response theory where you move from a questionnaire to a bank of items and computerize adaptive testing, which allows you to more quickly and more accurately assess the level that a person is in. These are better rulers, and it’s important when you get the rulers in that they develop new hypotheses as you get along. To get to the point you were sort of alluding to, the WHO, in 1948, came out with a prescient definition, which is that health is not merely the absence of disease. It is total, physical, mental and social well-being. Now, that’s been ignored in the breach, through most of the time since 1948, but it continues to be the WHO definition of health. And now we get to a point in which we begin to look at the implications of that for…let’s take the most-studied dimension of morbidity: physical function. We’ve called it disability, and we did that because we were docs when we were starting and we saw enough illness as the thing that we were after, but in fact to define “normal” as the center of a population, on a scale which starts at zero for being normal (which means being average), goes against the fulfillment implicit in the WHO definition of health, because you can have better-than-average health. In fact, even if you have rheumatoid arthritis you can sometimes have better-than-average health. It means that you don’t accept return to normality (you know, the average of a population) as success. No, it may be getting the patient with scleroderma to complete a marathon. There are many things than can be done that can raise people who have disability or morbidities to where they have less of it, and quite frequently it will take them up to a scale that didn’t exist that is better than normal, because normal was defined as zero. Now you have to have physical function with two scales (scales going in both directions) because you want to be able to applaud and be happy with having someone who is already very fit become even fitter. Today the Olympics is testing this thesis out at some scale. People can get really good when they practice and seek ideals and are competitive about it even, or when they are just doing it for fun. But the whole idea is that you change the entire vision of medicine around. Medicine is not just trying to get rid of disease. It’s not very good at that, anyway. But it’s total physical, mental, and social well-being. So that’s a fundamental paradigm shift. PROMIS has now adopted a physical function scale which absorbs the old HAQ dimension and the old SF36 dimension, and allows you to go both directions. It is fundamentally extremely important that we have a scale that measures the entire system. We called what we had floor effects and ceiling effects, and ceiling effects are that if you go to a population of fairly “normal” people, then half of them will be above normal, and half of them will be below normal. Now if you call zero normal, then everybody is either zero or lower, so there is a ceiling effect that is present because your scale won’t measure certain kinds of health, and they are very important kinds of health.[7] So PROMIS now is a group, and because it’s been well-funded and there are a lot of very good people in it, it’s gradually moving this over to where we can talk about health as well as sickness. JB: Yes, and I really want to applaud your contribution because I think that over these years, the impact of your model, in this compression of morbidity model, has really had its impact on things like the Patient-Reported Outcome Management Information System as to what questions need to be asked. Unless you know the questions to ask, you’re never going to get any of the answers, right? That’s a simple philosophical conundrum. I really want to applaud the origin of much of this discussion back to your 1980 article. I think the work that you have done helps to give these instruments that have the broader breadth of functional capability so we can measure, as you said, both ceiling effects and floor effects. As a rheumatologist and an immunologist, obviously you’ve watched the development of disease-modifying, anti-rheumatic drugs over the years, and the effects that they have on morbidity and on function. You probably—I know you have because you’ve published papers on this—looked at some of the pharmacogenomics and how different people respond to these different drugs. What do you think the role of genomics will be in this whole area of lifestyle medicine as we move forward? Do you think that we’re going to get more tailored approaches to help individuals achieve their optimal function? Will Genomics Disappoint Us? JF: Yes. That’s a big subject area because I think that we’re going to be overall—if you take the dreams of the past—a little disappointed with genomics, because the environment and lifestyle approaches (psychological as well as physical) to improving health operate pretty broadly against most people. Sometimes you need very targeted things, but I would put a different criticism on, let’s say, rheumatology and the search for disease-modifying drugs. We’re anxious to use these when they are there and to move people as well as we can from sickness into health, or from disability into normal or above-normal functional levels. But we have to do that in conjunction with the broader environment, and we have to recognize the narrowness and the limits of the tailoring. Ultimately, genomics is disappointing to many people right now, certainly compared with ten years ago because it has had a limited ability to do breakthrough things. We’re learning in rheumatology, for example…we have these very, very expensive drugs which have come in and they appear to be much better than what we had before. But the concept that we were trying to turn off the disease process entirely was present all along, and now we know, for example, that almost always you can do just as well with three of the old drugs as with one of the new drugs. So there is a combination targeting which is not exactly genomics, and it’s not exactly at the molecular level, but it is using several different approaches to reducing an inflammatory load and finding out that maybe for ten cents on the dollar you can get the same kind of result using older drugs which are less of a nuisance to administer and much less expensive for society. The things that are sort of readily available to all of us that impact on health are extraordinarily important and I think will remain the most important and then we’ll be trying to pick out particular sense of disease mechanisms which are dominant in a particular patient and then targeting those correctly. So you have to do both, but I think to move away from the foundations of health would result in much more problem than gain. JB: Thank you. That’s very insightful. Your paper that you had published in 2011 titled “Compression of Morbidity, 1980 to 2011: A Focused Review of Paradigms and Progress” I think is a really great seminal work that ties together so much of what you’re thinking has related to in terms of advancing the process of how this gets applied in practice.[8] The concept that you had mentioned earlier of downsloping curves—this presumption that we had early on in gerontology that it was kind of genetically preordained that we’re just going to be on a downsloping curve of function over time with increasing disability, so those curves would kind of be mirror images of one another—is a very deterministic model of an outcome which requires more and more crisis care because there is nothing you can do about it other than be there when a person starts falling apart. Your model of multiple curves I think is a very, very important part that people, working with enlightened health providers can find a little bit what curve they want to be on, and they’re not relegated to the predestined downsloping curve. Is that a fair assessment of some of the takeaways? The Concept of Diagnosis Can Hold Back Thinking in the Field of Aging Research JF: Yes, and it takes me to sort of a related point. We’ve probably been held back in our serious thinking by the concept of diagnosis. Diagnosis—when I was in medical school—it was the linchpin of everything. That is, you gathered a lot of data on the patient, and you made a diagnosis, and then you looked up in the book what the treatment was, and you gave the treatment, and then you got the cure. But it turns out that when one is talking about the phenomenon of aging and morbidity and so forth, that the diagnosis is not really very helpful. I can take people with rheumatoid arthritis who are healthy and people with rheumatoid arthritis who are not. I can take heart attacks, let’s say, or coronary artery disease, and say, “That’s a disease. We have an entity there.” But the lifetime morbidity curve of people is very, very different. There are actually identifiable trajectories. Let’s take the person with coronary artery disease who has a fatal heart attack at age 40. Now, there’s very little morbidity associated with that, but there is a tragedy in that the life is terminated in what seems very, very early. Then you’ve got people that have multiple heart attacks, and congestive heart failure, and go on with illness for 20 years and then finally die at an average age. That’s an entirely different trajectory. It has many, many times the morbidity of the sudden death trajectory, yet they are all the same diagnosis, but there are at least four or six major trajectories of coronary artery disease. And then if you start combining those with the concomitant diseases—the emphysema, and the peripheral vascular disease, and other things…well, I guess the thing is we’re now trying to say that we need to study trajectories, not diagnoses, because we’d like to change the distribution of the different trajectories if we want to get the overall diagnosis of behaving better than it was. This is another paradigm shift in which the different levels of disability of morbidity within a particular diagnostic category is huge, and it goes from nothing to very severe. So clearly what you want to do is to be moving people from some trajectories to other trajectories and that requires a different kind of thinking than that which we had when we labeled people all with diagnoses. JB: I think that’s absolutely wonderfully stated, and actually you relate that very nicely in one of your recent paper titled “The Theory and Practice of Active Aging” that was published in Current Gerontology and Geriatrics Research in 2012.[9] It’s ironic because I have just authored a book, which unbeknownst to me until I read your more recent papers, the title of the book really relates indirectly—maybe even directly—to what you’re speaking of. The title of the book is Disease Delusion, and it’s built on this very same theme—that we’ve had the sine qua non in medicine of the diagnosis of a disease, and that had very great utility so I don’t want to throw the baby out with the bathwater, but it also can become a limiting concept as it relates to the promotion of a healthy population. I think your model is absolutely prescient for where we are right now in the evolution of our healthcare system. Let me ask one last quick question. You have a colleague—you have many great colleagues there at Stanford, but one that I’ve had the privilege of getting to know a little bit who has some very shared common interests in the themes that we’ve been discussing, and that’s Dr. Halsted Holman, who is a Professor Emeritus there and has done a lot on self-care and the need for a new clinical education in medical school. Have the two of you had discussions or collaboration at all, because it seems like you’re working off the same tapestry? JF: Oh, yes, and his office is two doors from mine. I’ve known Hal for a long time. We’ve co-authored books together, which made some conceptual changes. He’s been very interested in the social side of medicine and the way in which care is organized. There are so many things that are wrong with the current approaches to maintaining and improving health that it’s hard to know where to start. But partly you could say we need to start at the training, or we need to start at the paradigms, but we have to get to a place where our measurement terms are the appropriate ones, and our study techniques and methods are the appropriate ones. Hal has been a very broad contributor to the broadening of concepts and the use of multidisciplinary groups of people in the care process. He’s just been a very effective contributor. JB: Yes, I can see the two of you as being great thought leaders, that’s for sure. With your kind of senior perspective over the years as to what’s been going on in health care and how the system is evolving and knowing the challenges that it now has as it relates to the rising cost of health care and the burgeoning of this chronic disease epidemic globally, what’s your forecast? What’s your scenario look like as you look out over the future? JF: There are still many things that need to be rethought. We’re going right now through a debate about a particular approach to health and health care which is based on the financing of health care. It’s not going well, and it is almost certain not to go well over time. That is, not as well as it could have because it is designed to be very expensive and to do a variety of things that I actually consider a little bit immoral. I think that taking the money from the young people and using it on the old people is not a good thing to do. We all remember when we were starting out, and it was not the time when we had excess funds to support everybody else. I’m afraid that if you were really going to organize a system that was going to give better care, it would have to start with self-care and with education and how to take care of yourself and how to deal with most minor things by yourself. Capability in the family, in the friends network that you have to get some mutual assistance with things that are often low-tech but of tremendous power. Getting those things organized in a really effective way, as compared with trying to throw money at the problem, or change the social structure of the country. I just don’t think that any of the things at the systems level—that is, the health plan level—are improvements. We have, for example, a lot of single payer systems. We have the VA, we have Medicare, we have government employees, we have a number of single payer systems, and they are okay. But they are not fundamentally better than things which are paid for by thousands of insurance companies, because that’s not the big deal. This last year I went from a fee-for-service system to Medicare. Now, when you are going to say which is better, there’s not very much difference. There’s a lot of difference in the polemic, but not in the health results. I would like to see something that starts with self-care and ends with outcome improvement. I’ve had a saying that the two things that you have to have if you’re going to change the health plan is that it’s got to cost less, because ours is way too expensive by any national thing, and it robs a variety of other needs in the society, and it’s got to get better outcomes, so that nobody who is currently involved in the debate on any side says of Obamacare, for example, or any other alternative, “We’re going to get better health. We’re going to have a metric in and we’re going to have a healthier society as a result of this.” Now if you work backwards from how you get a healthier society, it’s going to mainly do prevention. It’s going to have to keep people healthy longer. When people make a lot out of a change and it doesn’t have the ability to lower costs and it doesn’t have the ability to improve outcomes, I don’t see this as an advance. I see this as a wasted effort in large part. JB: What certainly hasn’t been a wasted effort I think is the impact that your 1980 article in the New England Journal of Medicine has had on the changing dialogue, discussion, and ultimately research and development within health care. I think moving from a disease-based model to a functional-based model focused on compression of morbidity is a way that we’re going to get on top and ultimately manage the epidemic rise in chronic illness in our society. I just want to thank you for all of your years of contribution and service, and as just one of literally probably millions of people that have been positively impacted by your thinking, to thank you, and on behalf of the Institute for Functional Medicine, really for the germ seed that led to its origin in 1990. JF: Thank you, and I, in turn, am tremendously impressed with what you’ve been able to accomplish along this line and with the thinking and contributions of your group. We can have a mutual admiration society, here, and maybe we can come out with a world that’s healthier. JB: Thank you so much. The best to you and your family and I look forward to talking again soon. Thanks so much, Dr. Fries. JF: Thank you, Jeff.  

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Bibliography

[1] Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980 Jul 17;303(3):130-5.   [2] Vita AJ, Terry RB, Hubert HB, Fries JF. Aging, health risks, and cumulative disability. N Engl J Med. 1998 Apr 9;338(15):1035-41.   [3] Lane NE, Bloch DA, Wood PD, Fries JF. Aging, long-distance running, and the development of musculoskeletal disability. A controlled study. Am J Med. 1987 Apr;82(4):772-80. [4] Bruce B, Fries JF, Hubert H. Regular vigorous physical activity and disability development in healthy overweight and normal-weight seniors: a 13-year study. Am J Public Health. 2008 Jul;98(7):1294-9. [5] Chakravarty EF, Hubert HB, Lingala VB, Fries JF. Reduced disability and mortality among aging runners: a 21-year longitudinal study. Arch Intern Med. 2008 Aug 11;168(15):1638-46. [6] Fries JF, Bruce B, Cella D. The promise of PROMIS: using item response theory to improve assessment of patient-reported outcomes. Clin Exp Rheumatol. 2005 Sep-Oct;23(5 Suppl 39): S53-7. [7] Bruce B, Fries J, Lingala B, Hussain YN, Krishnan E. Development and assessment of floor and ceiling items for the PROMIS physical function item bank. Arthritis Res Ther. 2013 Oct 3;15(5):R144. [8] Fries JF, Bruce B, Chakravarty E. Compression of morbidity 1980-2011: a focused review of paradigms and progress. J Aging Res. 2011;2011:261702. [9] Fries JF. The theory and practice of active aging. Curr Gerontol Geriatr Res. 2012;2012;420637.

Welcome to Functional Medicine Update for May 2014. This month, as you know, is part of this series that we are putting together starting with Dr. James Fries in the month of April of 2014 on what I call the origins of the functional medicine model, and how the functional medicine model derives its basic formalism from that of systems biology, the advancing frontier of understanding how systems are interconnected to give rise to whole-organism activity. This might seem like an old concept because it really goes back to traditional Chinese or to even Greek and Egyptian medicine of old. Certainly it is also embedded within Ayurvedic medicine, so it has thousands of years of fundamental understanding at an empirical level. But it is only really within the last, say, 25 years, as we’ve gotten the ability to integrate and collect huge amounts of data, where we start to understand, at a mechanistic, cellular, and tissue, organ, organ system level, the nature of systems biology in health and disease. We had a very remarkable introduction to this concept talking to Dr. James Fries in our last issue in April, in which he introduced the aging/compression of morbidity/natural death concept. He really was a pioneer in 1980, in the New England Journal of Medicine, of a new concept for what I would call personalized or individualized health care. You’re going to be very pleased that we’re going to continue this theme with another extraordinary leader, visionary, innovator in this field, Dr. Leroy Hood, the co-founder and president of the Institute for Systems Biology in Seattle, WA, but—as you will learn—far more than that. He is a Renaissance man, a person who has spanned tremendous domain as it relates to innovation and creation, a medical doctor and PhD who has created environments within genomic science that has catapulted us forward in understanding what personalization really means at the individual, cellular, and organismic and systems biology level. Through this lens of Dr. Hood we’re going to, I think, take the model of Dr. Fries to the next level of understanding of what the nature of 21st century medicine might look like as we start to not only have access to these technologies, but apply these technologies successfully in patient management and promotion of a personalized approach towards health care, based on the genes and environment of every individual patient.   So with that in mind, let’s turn to our discussion with Dr. Leroy Hood.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Leroy Hood, MD, PhD Co-founder & President Institute for Systems Biology 401 Terry Avenue N Seattle, WA 98109 www.systemsbiology.org Over the 32 years of my doing Functional Medicine Update I’ve had extraordinary privilege in dealing with a number of luminaries in the field, internationally—many Nobel Prize winners, many pioneers of medicine and health. But I’d have to say today is an epic moment for me. I’m going to have the chance—and you will have the chance as well, vicariously—to meet one of my heroes. As you know, I had the wonderful couple of years with Linus Pauling back in the early 80s and worked with Bruce Ames for a while, but certainly Dr. Lee Hood has been on my list of amazing figures in the transformation of health care. The Genomic Era of Today Made Possible By Early Biotech Equipment Development For those of you that may not be entirely familiar with Dr. Hood’s background, his range of impact on science and medicine is extraordinary. He has been involved with molecular immunology, biotechnology, genomics. Although he’s an MD/PhD and I have always wondered how an MD could have such far-ranging expertise, he is credited—and I think appropriately so—with he and his colleagues at Caltech developing the DNA gene sequencer and synthesizer and the protein synthesizer and sequencer—four pieces of equipment that really pioneered and heralded the age the genomic era in which we live today, and the whole deciphering of the human genome. He’s been really a pillar in biotechnology and played a role in founding more than 14 biotechnology companies—some names that you are probably familiar with, like Amgen, Rosetta Inpharmatics, Integrated Diagnostics, and the Accelerator. He has co-authored numerous textbooks, and really a book that for me was very pivotal called The Code of Codes, obviously about the Human Genome Project.[1] He’s a recipient of virtually every major scientific award and honor that you can get, from the Lasker Award for studies of human diversity, to the Kyoto Prize in advanced technology, the Delores Russ Prize, and most recently—and probably most prestigiously—the National Medal of Science. He has in excess of 890 publications. A pretty formidable bibliography, and it ranges across so many fields that it would take us several days to do adequacy in describing it. Dr. Hood, such a privilege to have you as a guest for Functional Medicine Update. I guess the place I’d like to start is we had the privilege last month of interviewing one of your former medical school colleagues, Dr. James Fries, who obviously spoke very highly of you. How did you and Dr. Fries connect, and how did your paths end up going such interesting and different ways, with you moving into this whole area of molecular biology with your background? It’s really an interesting kind of historic question. LH: Well, you know, I think that had to do completely with Johns Hopkins as a medical school and the flexibility it gave its students. When I was an undergraduate at Caltech I had really a terrific technical background. I decided there I’d like to do human biology and medicine and disease. So I decided to go to medical school, and Hopkins had this accelerated program, where if you had an unusual career path in mind, you could go through the summers and get done in two-in-a-half to three years. So when I went to Hopkins I did the accelerated program because my intent was to learn human biology and pathology, and then to go back and get a PhD and continue my fundamental research rather than getting into the clinical side of things. Jim was a classmate there at Hopkins, and I think all of us who went to Hopkins experienced this enormous encouragement to think ahead and take unusual paths and unusual kinds of opportunities. They no longer have that program. I think it’s a real shame. Hopkins, at that time, really had some exceptional people, and I’m still good friends with a number of them that have again reached out. One of them is head of the National Cancer Institute’s Surgical Branch at NIH, and Steve Rosenberg has been a pioneer in immunotherapy and all sorts of things, and on and on. So it was just a marvelous place to go to medical school and it encouraged interesting career paths. JB: That broad thinking obviously is symbolic of all the contributions you’ve made over the years. Let’s now segue over to Caltech and how you happened on with your engineering mind, with your group, into the development of pieces of equipment that people really thought were going to be impossible to develop. I recall early in my career in the 60s doing DNA analysis one nucleotide at a time. How did you come about these extraordinary discoveries? If You Want to Change a Field, Invent a New Technology LH: You know, that’s really an interesting question, Jeff. When I went to Caltech as a young assistant professor in 1970, I determined that my laboratory would have two major thrusts. One was to develop technology, and that came about as a consequence of having a PhD mentor, Bill Dreyer, at Caltech. One of his fundamental theses was if you really wanted to change a field, invent a new technology that opens up new dimensions of data space. And the second area was molecular immunology. What was really interesting, as I got deeper and deeper into molecular immunology I really became convinced that the challenge for both biology and medicine (the study of disease) was biological complexity. Darwinian evolution operates by a random and somewhat chaotic process, and as a consequence, it builds solutions to biological problems that are Rube Goldberg-like in complexity, and that meant we had to have much better tools and strategies for dealing with complexity, both in biology and then in medicine than we had early in the mid-1970s, and that’s really when I first started realizing that we had to think about disease, we had to think about biology, in a systems way. That is, we had to take a global and comprehensive view of it and not just look at a narrow slice of it. The challenge was in the mid-1970s there weren’t the tools, nor was there the conceptual framework for dealing with complexity—for being able to look at systems in a global and holistic way. Interestingly enough, that analysis of biological complexity then pushed me into a series of interesting paradigm changes that I think position us very uniquely with systems medicine and P4 medicine, which we’ll talk about later today. One was the paradigm of change of bringing engineering to biology. We actually ended up developing five instruments that did several important things. One is they generated new kinds of data rapidly, and hence high-throughput biology, and hence they really ushered in the whole realm of big data, and that was an important element. One of the instruments led me into the second paradigm change, namely the automated DNA sequencer got me invited to the first-ever meeting for the Human Genome Project. Twelve of us were invited and we were asked to comment on the validity, the technical feasibility, of this approach. What we concluded was, one, it was feasible (although in 1985, technically difficult), but, two, we were split six to six, for and against, and the six against it were really against it and that was when I first realized how conservative most scientists are. Now, when you make arguments about new ideas, people tend to map whatever you say into what their preconceived notions are, and so it took us five years to finally push the genome project through. What that did from the point of view of my story was it gave us a parts list of all the genes and hence all the proteins, and that parts list is really a key component of this thing we’ll call systems biology. Bill Gates Funded First Cross-Disciplinary Department of Molecular Biotechnology The third paradigm change was the realization, in developing the automated sequencer, that we had to bring together an engineer, a chemist, a computer scientist, and a molecular biologist to really solve the problem, and it made me realize that biology departments in the future had to have embedded in them a cross-disciplinary series of talents that allow you to take leading edge biology and use that to drive the development of new technologies, and in turn use those data to create new analytic tools. So I proposed at the end of the 80s at Caltech that I do such a department there and the biologists absolutely opposed it, so Bill Gates made it possible for me to move in ’92 to the University of Washington and I created there the first cross-disciplinary department of molecular biotechnology, and it was really spectacularly successful. It created the first key technologies for the field of proteomics, the study of complex protein mixtures. It developed the software that was utterly essential for the Human Genome Project. We developed my fifth instrument there—an instrument called the inkjet synthesizer, which allowed us to synthesize rapidly DNA and hence DNA arrays. And we developed a multi-speed, multi-parameter cell sorter that was a revolutionary new principle, and on and on. Institute for Systems Biology Established in 2000 What happened at the university was a bureaucracy that wouldn’t let me take the next step I wanted to take and that was to create an Institute for Systems Biology. The reason for that is bureaucracies are evolved from the past, and they are honed to deal with the present, but they really have difficulty dealing with the future. We just needed so many things to make systems biology work that I resigned in 2000 and created the first Institute for Systems Biology that has spent the last 14 years very successfully pioneering systems science—this holistic and global approach to studying biological problems, and very soon to studying medical problems, and of course that led to this thing we call systems medicine that is a systems biology approach to disease, and the realization that systems medicine had two central features that begin to let it deal with the complexity of biology. One was that the image that in the future every individual patient will have a virtual cloud of billions of data points of many different types of data (molecular, and cellular, and genetic, and organ, and higher level phenotypic data, and even social network data of individuals). These were all needed to be seamlessly integrated together and dimensionality reduced to be able to create models that allowed us to optimize wellness and minimize disease for the individual. And the second feature was the realization that in disease, the reflections of the disease are embedded in what we call the network of networks. That is, there are networks that operate at the genetic level, at the molecular level, at the cellular level, at the organ level, at the individual level, and these networks, in an integrated manner, handle the information of life. Disease causes networks to become disease perturbed. That alters the information that they can display, and if you can capture those changes in disease-perturbed networks, you gain deep insights into disease mechanisms and have new strategies for doing both diagnostic and therapeutic approaches to the disease. The Tipping Point: DNA Sequencing Will Soon Be Third Generation That kind of approach—this systems medicine—I would argue has reached a real tipping point in that it has pioneered a whole series of new technologies and fundamental strategies for doing things. I’ll give you just a couple at a very high level. We’re pushing the idea that DNA sequencing will be soon third-generation. We’ll look at individual molecules and put them through nanopores and analyze the signals electronically. What that means is you can get very long reads of DNA very, very rapidly and we envision a time in five to eight years where we’ll have a hundred dollar genome that can be done in 15 minutes and that is going to make the genome the equivalent of a simple medical test. Yet the genome is one of the two foundational types of biological information that lead to both normal and disease phenotypes—the second, of course, being how the environment impinges on the organism and modifies the genome readout. Some of the things we’ve done, then, is we’ve looked at diseases dynamically, studying them in animal models, being able to look at them at their origin when we induce the disease and follow the progression of the disease all the way through, and understand multiple biological networks become disease perturbed and they describe beautifully the phenotype and the deep mechanistic nature of a variety of diseases. We’ve looked at neurodegenerative diseases, we’ve looked at cancer, and we’ve looked at liver toxicity in this way. A second thing we’ve done with systems medicine is to show that sequencing the genomes of families gives you a really powerful new approach to identifying disease genes. We’ve now looked at almost 2000 complete human genomes, 14 or 15 different diseases, and in all cases we’ve had deep and fundamental new insights into what’s happening into diseases that have at least a partial genetic basis and so forth. New Discovery: A Systems Approach to Blood Diagnostics Maybe the most spectacular thing we’ve done is we’ve worked out a systems approach to blood diagnostics, which deals with the horrendous signal-to-noise issues you see when you look at normal bloods and diseased bloods and there are lots of differences, and 99 percent of the differences are noise; they are not reflective of the disease. We’ve used these systems approaches recently to create a panel of 13 blood proteins that give us the ability to distinguish benign lung nodules from their neoplastic counterpart. And that simple identification will end up saving the healthcare system north of 3.5 billion dollars a year, and the reason for that is so many people with benign nodules undergo expensive surgical procedures and that can be prevented by saying, “No, this nodule is benign. You don’t have to take a guess and try and do the surgical procedure.” We’ve taken a similar approach to post-traumatic stress disorder from looking at soldiers that are back from Afghanistan, and again, for the first time, we have a quantitative panel of biomarkers that distinguishes, at the 95 percent level, PTSD soldiers from their normal counterparts, so this means it’s the first time ever a neuropsychological disease has had a quantitative assay, and it means a big revolution not only in diagnosis, but especially in therapy because for the first time big pharma will have concrete markers that it can use to assess the effectiveness of drugs. I could go on. We have computational methods for identifying new kinds of drug targets and we can make drug discovery more efficient, infinitely cheaper, and on and on. But the bottom line is that there is a convergence of systems medicine of big data and its analytics, and of patient-activated social networks, that go together to give this thing we describe as P4 medicine (namely, predictive, preventive, personalized, and participatory). And I just want to say a word about the patient-activated social networks. They are really going to be important because I think they will be the driving force for catalyzing the transformation that is to come in our healthcare system, in a move toward this P4 medicine, and I’ll describe how I think we can carry that out in just a few moments. Six Ways P4 Medicine Differs From Traditional Medicine What I would emphasize is P4 medicine differs from traditional evidence-based medicine in six really important ways. One, it’s proactive. Number two, it’s focused on the individual. Number three, it’s really focused on wellness. Number four, It’s focused on, for each individual, generating this virtual data cloud of billions of data points so you can carry out the analytic assessment of what’s needed to optimize wellness and minimize disease. And five, and I think this is one of the most important of the revolutions, it acknowledges that the system we use currently for clinical trials and drugs is utterly broken and is not working at all. The approach is to take thirty thousand patients that you’re testing a lung cancer drug in, give them either the drug or a placebo, and to abstract from that set of patients the responses and the curves, and from those curves to make predictions: (A) about how the population of patients will respond, or (B) about how effective the drug is. The reason that is utterly the wrong way to go about it is each of those thirty thousand patients is unique genetically and each is unique environmentally and you can’t conglomerate all of those responses together. What P4 medicine does is it analyzes each individual uniquely, and then it aggregates these individuals based on what characteristics you’re interested in, and I would say only in that manner can you get sepsis patients that are going to respond effectively to a given drug, or you know won’t respond to other kinds of drugs. And then the sixth thing is this patient-activated social network and its real importance. So the question, which I think is really interesting, is how then do we impose this heretical, radical new vision of medicine into the healthcare system? The approach that we’ve come up with is to create a large pilot project which is going to involve a longitudinal Framingham-like study of a hundred thousand well patients, and to be able to make many, many measurements across time over a period of up to 20 or 30 years, and from that set of patients we’ll see the individuals dividing into two categories: there will be a set of patients that remain well and perhaps get even healthier, and there will be another set of patients that will over time transition from wellness into disease. And the idea, then, is for the first time we’ll be able to study: (A) the entire longitudinal development or progression of the disease, but (B) we’ll be able to look at the very origins of the disease and come to understand mechanisms that are operating and new diagnostics for very early detection of disease. If we can, then, change that trajectory very early on from a disease trajectory back to a wellness trajectory, you’re going to save the healthcare system billions upon billions of dollars. And the only way to do these early wellness-to-disease transition studies is through longitudinal studies of normal individuals in exactly the way we’ve talked about. So the idea, then, would be to look at six or seven different types of data—genome data, clinical chemistries, quanti-self data (heart rate, sleep quality, all of those kinds of things). We’ll look at the gut microbiome and how it changes. We’ll look at fingerprints in the blood for brain, heart, and liver that can distinguish wellness-to-disease transitions very, very early, and so forth. It means we will soon have this virtual cloud of billions of data points that we can analyze, and what we hope in this case to come out with are for each patient a list of actionable opportunities that will uniquely give them the opportunity to improve their health. And we think a lot of these actionable opportunities will revolve around the area of nutrition and optimizing nutritional deficiencies that arise because of genetic variance in the genome, and we know lots of these already. I have a friend, for example, from Microsoft, who started getting early-onset osteoporosis in his mid-30s. He had a genetic analysis done and discovered a calcium transporter that was defective and he took, for a year and a half, twenty times the normal amount of calcium and he brought his bone structure back to normal, and now 12 years later he’s a perfectly normal healthy male individual. So a deficiency led to a calcium defect that he can cure by dealing with increasing the concentration of intake of calcium. We feel that for every single individual there are going to be multiple actionable opportunities. So this kind of study will do three things. One, it will let us create a data cloud for each of the individuals, which, when analyzed, will optimize wellness and minimize disease. Two, we can take the data from those individuals that remain well and mine it for metrics of wellness, which we’ve never had before. I mean, wellness now is a fuzzy, soft, psychological definition, and it frankly is just exactly what PTSD was prior to our development of this quantitative blood assay. And number three, we’re going to see transitions from wellness to disease in the hundred thousand for virtually all major diseases, and we’ll be able to look at these early disease mechanisms at early diagnosis and try to begin attempting early diversion back to a wellness trajectory. Wellness 100K: Ambitious Study Will Follow One Hundred Thousand Individuals How are we going to scale up? We’re going to start with a hundred individuals, then in a year a thousand, then in another year ten thousand, and finally go to a hundred thousand. In fact, for the first 100, which we call the Pioneer 100, we’re starting with 108 individuals that have been recruited. It’s under IRB. We have coaches that will transmit these actionable opportunities to the individuals. We have a panel of experienced physicians that will oversee this whole process to make sure that we don’t run into the kind of difficulties with the FDA that 23andMe did. And of course in the long run, what we really hope to be able to do with the 100K Well Person Project is to discover the new kinds of technologies we need to measure immunity, inflammation, a whole variety of things we don’t measure very well now. What we plan to do at the end of this next year is spin off a company that will be the vehicle for scaling this kind of approach eventually up to billions of people. It is what we see as reaching across the world and beginning this democratization of health care that was inconceivable even a few years ago. But the important point is, if you think about it, this hundred thousand longitudinal wellness person study has every one of the six fundamental features of P4 medicine that I described, and I think it will be the opening wedge into the transformation of medicine from this traditional evidence-based approach to a P4-based approach. We’re looking forward in a really exciting way to the next 10 or 20 years as we see this revolution playing out. A long answer, Jeff, but at least you have a quick synopsis of how I see medicine being transformed. JB: Well, Lee, to say that was a tour de force would be one of the great understatements that I’ve ever made in the 32 years of Functional Medicine Update. That was absolutely brilliant and what an extraordinary landscape you took us across. I mean, no one who is listening to this could be without goosebumps. That was a transformative discussion that you provided for us. As you were talking, I reflected back on a conversation I had two weeks ago with Bob Langer at MIT and Denny Ausiello, who you probably know, who is the head of medicine at Harvard and Mass General. LH: I do know Bob really well. What a wonderful person and scientist. JB: In this conversation I was having with the two of them I asked them about you. I just said, “You know, Lee Hood has made such incredible contributions and now at the Institute for Systems Biology his group is doing just pioneering work.” Both of them almost simultaneously said the same thing to me. They said that Lee Hood is one of the few people that has crossed all boundaries to consolidate information and make it clinically relevant and social changing, and that is a very unique feature that characterizes your brilliance in terms of the impact of your work. I thought that was probably one of the most complimentary things that a person could receive. I wanted to pass it on to you. LH: It is an enormous compliment coming from people like that, that’s for sure. JB: What was it in your life that…I’m not going to say gave you permission because I’m sure you’ve never asked for permission, but let’s say gave you the sense that you could cross these boundaries that often are kind of defined by disciplinary myopia. I had the same conversation with Dr. Pauling 25 or 30 years ago and asked him how he did this because it comes at some professional peril. How did you do this? LH: I would say that it really all starts with my upbringing in Montana. My father was an engineer and he embedded engineering in me and that’s how I’ve always viewed biology. My mother was an interesting only child that grew up with what she felt an inappropriate dependency on her parents, and she was determined to have her kids be free and unfettered of constraints. She encouraged us from our very earliest years to go out and climb mountains, to explore new possibilities to do whatever really turned us on. And I would say a third thing that was really transformational for me was that in high school I had three of the best teachers I had in my entire career: a chemist, an historian, and a mathematician. All three of them were really terrific at saying, “You know, what do you really want to do? Have you really thought about what your potential is? Do you want to go to a state school?” And one of them—my chemistry teacher—had gone to Caltech during World War II and he decided any good student he ever got he would send there. He started pounding on me at the beginning of my third year, so I ended up applying to Caltech. I went there as an undergraduate, and it gave me this deep fundamental mathematical/chemical/physical background that was just wonderful for doing science. Had I gone to one of the classic liberal art schools I was thinking about I suspect I would have never gotten that background. I think these things end up being the serendipity of your early life and that they frame, in a very powerful way, the potential you have for the future. JB: Obviously that speaks so highly to the importance of education and the education n-of-1 experience—almost like we’re talking about the medicine of n-of-1, we have this educational epigenetic events n-of-1 with our mentors. How do we get this kind of excitement, vibrancy, fearlessness, courageousness to cross barriers down to bright women and men, girls and boys, that are being educated today? How do we do this? The Institute for Systems Biology Offers K-12 Science Education LH: You know, ISB actually has a group of eight full-time people that are working on K-12 science education, and we’ve created a cadre of strategies that starts bringing powerful, inquiry-based science thinking as early as elementary school, it goes through middle school, and then into high school, and we really encourage independence and free thinking. I think the key is to train the teachers as to how they have to deal with their students to give them this sense of unboundedness, to give them this sense of opportunity and their own potential. I think we’ve done really a good job in transforming education—K-12 science education—in the Seattle school district. We’ve worked with the Renton school district more recently, and in all cases we see significant improvement in student scores, and what’s interesting is the biggest improvements we see are in the students from disadvantaged families. They’re the ones that come the farthest when given these kinds of opportunities. You are so right. Education, K-12, I think really sets the boundaries as to will we go into a technical field, will we become a scientist or an engineer, and even the important point of how do we think about the problems of society? Do we have emotional, irrational senses of what’s right and evolution is evil, or can we think about things analytically and try and dissect pros and cons of global warming and all the other kinds of things? I think education is key, and I think, frankly, the education we do on our own kids is where you really want to start because you can put them in a frame of mind where you give them the sense that being unbounded. Both of our kids, I think, very much came away with that and they’ve been really successful. One’s an environmental scientist at the University of Alaska in Juneau and one is a discrimination lawyer just setting up her own firm in Los Angeles now. We have the power to transform our kids if we have the energy and the knowledge of how to do it. JB: Yes, I think this is very, very proactive for our listeners. Certainly I, as now a grandparent of five grandchildren, am reminded every time I’m with them and I’ll be reminded by this conversation that the models that we’re setting up for their inquiry process in life will stick with them and become part of them as they move into adulthood. LH: You know, what I did with both my children and now I’m doing with my grandchildren, actually, was to tell stories about a mythical science fiction character who gets into all sorts of difficulties, and I have the kids problem solve about how to get him out of the difficulties. My son and daughter both have off-scale analytic skills, and I’m convinced that it was because I spent four or five years telling these stories and having them problem solve all sorts of different kinds of things. You can do marvelous things with your kids. JB: That’s fantastic. Let me ask one last question. I don’t mean to put you on the spot but I think everybody listening probably has this in the back of their mind, and that is with all this extraordinary optimism that you shared with us—in a sense, for vitality of the future—there is the reality of today and how medicine is practiced. Docs are down in the trenches and they’re caught up with these reimbursement codes and uninvited third-party reimbursement people that are in their offices (called the insurance companies) that they didn’t really invite but they are there to oversee and proctor how they are doing standards of practice. As a participant in your Pioneer 100 Wellness Project, which I’m very excited to be one of those 100 people, I recognize I’m going to be experiencing something very different, probably, than the average patient that goes into their offices. What’s your view as to how we are going to transform the kind of daily grind of medicine? Is it going to be a long process, do you think, or do you feel like we will have a shifting paradigm that’s like Thomas Kuhn’s paradigm-shift mechanism/tipping point? Insurance Companies Will Come to Understand the Cost Savings of P4 Medicine LH: Well, I think it will be a shifting paradigm, but I think it’s definitely going to take some time, and I see the origins as arising in some of the most progressive healthcare systems. Geisinger is a really progressive healthcare system. Inova in Virginia; we’re collaborating with them on interesting ways to do similar kinds of things to what I’ve talked about here. I think what we’ll see is some of the most progressive healthcare systems will adopt this and what will happen is the savings will be so enormous that people will be forced to respond in kind even if they are skeptical. It’s going to take a while to begin moving things around, but I think it is going to happen. I will say when we announced this Pioneer 100 program that is very much focused in Seattle, I’ve had three physicians, now, from the community come to me and say, “I’d like to move my practice over to focus in increasing ways on wellness and to become involved with this program so that I understand it in depth.” I think it is going to be a paradigm change, but it’s going to be incremental in the sense that good functional units will use it and see its power, and then it will become increasingly important. I think as the insurance companies, as the payers, come to understand, “Look, you can use systems medicine and save 3.5 billion on lung cancer patients,” those are compelling arguments quite apart from the fact you’ve improved healthcare quality as well. You know, it isn’t going to happen overnight, but I think over a ten-year period we’ll see an enormous transformation. JB: Well, Lee, I can’t tell you how much I appreciate you giving all of us this infusion of energy, optimism, excitement, and commitment to excellence about where the future of healthcare is going. I’m so excited that we’re going to be able—thanks to your graciousness—do a collaborative program with the Personalized Lifestyle Medicine Institute at ISB in October of 2014, and the chance to be a participant in the Pioneer 100 program will get me more engaged in P4. I think what you’ve described as an unbounded opportunity for reducing human suffering and improving quality of life of hopefully billions of people in the years to come. There’s probably no better way to spend a life than focusing on that objective. LH: I couldn’t agree with you more, and we’re looking forward to our interactions with you and the meeting this October as well, so maybe we’ll see some of your listeners there. JB: I think you will definitely do so. Thanks a million. We really appreciate it. LH: Thank you.  

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Bibliography

[1] Kevles, Daniel and Leroy Hood. The Code of Codes: Scientific and Social Issues in the Human Genome Project. Cambridge: Harvard University Press, 1993.   [2] Annas GJ, Elias S. 23andMe and the FDA. N Engl J Med. 2014 Mar 13;370(11):985-8.   [3] Gibbs WW. Medicine gets up close and personal. Nature. 2014 Feb 13;506(7487):144-5.   [4] Feero WG. Clinical application of whole-genome sequencing: proceed with care. JAMA. 2014 Mar 12;311(10):1017-9.

Welcome to June 2014 Functional Medicine Update. This is the third in a series of what I would call foundations of functional medicine, and we’re very pleased that this month we have an individual who I have a long and rich history with, Dr. Kenneth Pelletier. Dr. Pelletier is going to really help extend this functional medicine/systems biology model from that of the individual to that of the workplace environment. That is, to a broader model where hopefully more people can be influenced in a positive way as it pertains to how to access this systems biology thinking. As you probably know Dr. Pelletier was the author of a book that was, for me, very transformative when I was a professor at Evergreen State College. We actually used his book, Mind As Healer, Mind As Slayer, as a very important part of the curriculum of the course that I was teaching, which was really the presaging for me of my thinking about functional medicine.[1] I’d have to say that Dr. Pelletier’s book and his concepts of the mind as healer, mind as slayer as a systems thinking model, and then moving into Dr. Fries and his work, and then of course later my knowledge of Dr. Leroy Hood’s work as it relates to his concept of systems biology—those three together—framed an important foundation and cornerstone of what gave birth to the concept of functional medicine back in 1990. With that in mind, we’re really pleased to have Dr. Pelletier tell us about this history that he has been involved in as a principal in really opening up the construct of how these concepts can be applied both institutionally and organizationally to affect millions of lives. So with that, let’s move to our discussion with Dr. Pelletier.  

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Kenneth Pelletier, PhD, MD Corporate Health Improvement Program Director Arizona Center for Integrative Medicine Clinical Professor of Medicine University of Arizona School of Medicine University of California School of Medicine, San Francisco (UCSF) www.drpelletier.com Here we are once again at certainly my favorite part of Functional Medicine Update and that’s our clinician or researcher of the month section, which we really use to frame each month’s issue, and we’re very, very fortunate, and I personally feel extraordinarily fortunate to have an individual that I think can give us both a historical context for the evolution and development of the field that we all share, and also a forward-looking vision-tender as to where this field is going. I’m speaking to a colleague and friend who has actually been a mentor of mine and a great figure of my own education, and that’s Dr. Kenneth Pelletier. Some of you probably go back, as I do, to the 1970s and what was his absolutely frame-shifting book called Mind As Healer, Mind As Slayer that I believe really gave birth to the field of psychoneuroimmunology and this whole burgeoning concept of the body as a web—as a network—rather than as a collection of piece parts of organ systems. That was really a step in the understanding of the new biology of the 21st century that presaged it by more than 20 years. It was the textbook in a number of courses that I used in the university where I was teaching. I taught literally thousands of medical students using that as a book. Dr. Pelletier has gone on and just done extraordinary things, so let me give you a couple of vignettes of his extraordinary background. Presently he’s a clinical professor of medicine at the Department of Medicine and Family Community Medicine at the University of Arizona School of Medicine, and he also has adjunct activities at the Department of Psychiatry, University of California School of Medicine, San Francisco. He was previously at Stanford. He’s worked with UCLA in corporate health areas with Jonathan Fielding who was another colleague that I had the fortune of knowing back in the 80s. His work on corporate health promotion and integrated systems of health care are truly pioneering, and he probably has more feet-on-the-street experience in how to implement integrated health systems into corporate environments than anybody that I’m aware of that is presently living or maybe has ever lived. His ability to take divergent information and distill it down, integrate it together, and then find institutional places for it to be implemented I think is truly unique in our field. He’s also an active scholar and has published more than 50 papers in the peer-reviewed literature over the years that have really codified and I think defined the nature of this domain of corporate health promotion from an integrated perspective. He’s been able to bring so many of these principles that we now consider new that are really—to Dr. Pelletier—old principles that he pioneered that have now become new in the minds of many who are just learning them, and starting to implement them successfully into systems that really I believe are going to improve cost effectiveness of health care and help us beat back this rising tide of chronic illness. Ken, it’s just so wonderful to have you as a Functional Medicine Update contributor. I could say so many other laudatory things about your background but I hope I have at least given a sense as to the domain and scope and breadth of your contributions over the years. Welcome to FMU. KP: Thank you very much and thank you for those kind words. I would reciprocate with my admiration for your work, which I have followed for many years as well. This is actually quite fun. I’ve been looking forward to this conversation. JB: As I. Let’s start back as the Mind As Healer, Mind As Slayer level. What led you into writing that book and really creating what I think has become a major discipline? What were the kind of presaging things that led you into that? Experiences Led to Structured Studies on Individual Ability to Regulate the Autonomic Nervous System KP: Really two things. One was a personal experience; the other was professional. The personal experience was that I had spent some time in Greece and North Africa and Europe and the near East traveling (just hiking around). I had the time in the 70s to do that. And I happened to end up on an island in Greece named Kenos, and on Kenos there is a small chapel that is the equivalent for the Greek Orthodox religion of Lourdes in the French tradition—a place of miracles. I was there when there were pilgrimages taking place to that chapel. And at the time, I saw things that to me made no sense. People that were in extreme pain and would pray and enter the chapel and come out and they’d be walking and moving seemingly without pain, with greater limb movement. Skin conditions that would clear. I didn’t see miraculous regeneration of limbs, but I saw enough that violated everything that I had been taught about how our physiology was supposed to react and I began to think, what was the role of belief? What had modified their ability to believe in themselves and believe what was possible to make these changes? So that was my personal experience and personal question. I came back to UCSF School of Medicine and at that time Dr. Joe Kamiya was doing really the pioneering research on clinical biofeedback. And at that time there was a controversy about whether or not a human person could control their own sympathetic nervous system—their own autonomic nervous system. I had read about some research that Elmer Green had conducted at the Menninger Clinic with several adept meditators who were capable of controlling bleeding, pain, infection, but it had been done in a non-controlled way; it was really anecdotal. So in Joe’s lab at UCSF, I set up the first structured studies where we looked at a series of adept meditators, in particular a man named Jack Schwartz, who was a Dutch survivor of a Nazi concentration camp who did a very unique thing of puncturing his bicep with a sharpened knitting needle and not bleeding, not experiencing pain, not having any infection from an unsterilized needle. And we documented his ability to do this and he made it very clear that we are able to regulate our own autonomic nervous system. So the two events together made me really start to think about how powerful is the influence of the mind on our physiology, and the last thing I would add is it’s not a matter of mind over matter. That’s not the issue. My focus is that mind does matter, that it is a critical variable in determining our health and states of illness. JB: I would say the impact that your book had on me when I picked it up was one of those great “ah-ha” experiences. I bet this was a general reaction that literally tens of thousands of other readers had as well, and that is you, for the first time, really started to help me understand the system that we later called systems biology and integrated systems—that there is no this division like angels on the head of the pin. There is this interactive system, which I think later got codified into terms like psychoneuroimmunology and where we have these integrated web-like interactions, and your book did an absolutely fantastic job of introducing that concept, and I think set forward this movement that we’ve seen over the last 35 or more years that has become the medicine of the 21st century. KP: I would agree with that. One of the interesting things about Mind As Healer, Mind As Slayer is that, one, it is still in print and I’m always amazed at that, but in 1992, Dell Publishing decided to publish an updated anniversary edition of the book, and they sent it out to reviewers and they asked, should we update the text, or should we leave it as is and just have a new foreword? And the overwhelming response back was, leave it as it is, because it really did create the template. And we actually, even in the book, use the term psychoneuroimmunology way before it was in widespread use, but it was a way to try to describe this systemic linkage between mind and body, between mental states and physiology states, and also subtle energy systems. So we just had an updated foreword to the book in 1992, and to me what was fascinating is when I had to go back into the book and write this update on the foreword, I realized that the science had progressed. Our understanding of the nature of mind/body interaction in a systems model—dietary influences, stress influences—had really progressed. But, the actual practices—the meditative disciplines that modify the mind/body interaction—have not changed in thousands of years. There was really nothing new to say about the meditative and mind/body practices that were new, except for the fact the science had finally caught up with the experiential part of our lives. JB: I’d like to segue a little bit from there. I don’t want to skip over some critical parts of history, here, but I’d like the listeners to know about how these observations and communications that you brought to the field translate into some of the things that you have focused on to make them implementable and executable. I’m just going to cite a few of your earlier PubMed publications because I think it gives a little bit of a tapestry as to where you’ve taken these observations. A paper titled “A Wake-up Call for Corporate America,” a paper titled “Mind-Body Medicine in Ambulatory Care: An Evidence-Based Assessment,” a paper called “Population Health Management as a Strategy for the Creation of Optimal Healing Environments in Worksites and Corporate Settings,” a paper on “Developing Self-Report Outcome Measure for Complementary and Alternative Medicine,” “Care Management Program Evaluation: Constituents, Conflicts, and Moves Toward Standardization,” “Review and Analysis of the Clinical Cost-Effectiveness Studies of Comprehensive Health Promotion and Disease Prevention,” “Management Programs and the Worksite from 2000 to 2004.”[2],[3],[4],[5],[6],[7] I’m just touching on the surface here just to give a little bit of a vignette as to how you’ve taken this information into implementable, executable strategy. It’s interesting. Through the years you’ve—I know—worked with all sorts of major Fortune 100 companies, including Cisco, and IBM, and American Airlines, and Prudential, and Dow, and Disney, and Mercer, and Merck, and Pepsi, and Ford, and Pfizer, and Walgreens, and Microsoft, and NASA. BlueCross, United Healthcare. Tell me how you bridge these gaps. This is a pretty amazing domain to have impacted. Early Mind-Body Work Leads to a Focus on Corporate Health and Wellness KP: It is, and it is interesting to think about that progression initially from those first studies and demonstrations around mind-body and how we can influence and self-regulate our autonomic nervous system. What I began to think about is how often does that occur out of awareness, i.e. we create states of illness through decisions, through beliefs, through actions, through lifestyle changes that are dysfunctional, that are negative for us and create poor conditions for health. So that took me down the clinical path. But the other questions, as part of the Mind As Healer, Mind As Slayer, the mind as healer part always interested me more, which are the preconditions for health? How do we experience optimal health? And as I looked at that, a light bulb went off. In 1980, actually, Bob Beck, who was the Senior Vice President at IBM, convened a group of five of us that were supposedly experts in preventive medicine. There really weren’t any experts, but we were the closest I think they found. And we were going to develop the bid specifications for IBM’s first health program for their total population of employees. It took us about three or four years of meetings to do that, and when we came up with the bid specs and put it out into the world we found there were no vendors—there were no providers—that could actually develop that program. You mentioned Jonathan Fielding earlier. He started a company called US Corporate Health Management, which was the provider of those programs for IBM, and I worked with Jonathan to develop the very first programs. That company was subsequently bought by Johnson & Johnson and became their Live for Life™ program, which was sold throughout the corporate world. But the light bulb that went on for me then and remains driving my interest to the present day is that if you look in our society and you ask who has a vested interest in health, it’s the private corporate sector. Companies want productive, active, functional employees. They have no interest in disease. They have no interest in hospitalization and dysfunction. They really want people who are alive and healthy. That led, in 1985, when I started the Corporate Health Improvement Program (or CHIP), and Bob Beck at that point moved from IBM, and became Senior Vice President of Personnel at Bank of America in San Francisco. He invited companies that he thought would share this interest. I invited my academic colleagues, and we began a dialogue. This was at UCSF from 1985 to 1990. It was the beginning of that program. Our mission since then and to the present day remains the same, which is to demonstrate the clinical and cost outcomes of health promotion and integrative medicine programs in worksites. So that’s what we’ve done, and you mentioned some of the companies that we’ve worked with. CHIP is a group of 15 companies. We keep it at that level because our meetings, which are twice a year, are really as a working group. We develop projects that have been as short as one year with a mammography program. We did the first mobile mammography screening program at Levi Strauss in the early 80s, and for 10 years we were the worksite branch for the Women’s Health Initiative. So we’ve really covered a lot of ground over that time, but my main thrust—so the common element—is how does an individual achieve optimal health, and what is the supportive environment that motivates, incentivizes, and supports optimal health? And since we spend so much more time at work than anywhere else (including sleep), that is a logical place where I would focus my attention. JB: You, in 2011, had an article published that you authored titled “Reflections on Developments in Health Promotion in the Past Quarter Century from Founding Members of the American Journal of Health Promotion Editorial Board.”[8] I think that that reflections concept is a very powerful concept with your perspective that probably is a unique n-of-1, looking at the past, present, and the future. Could you help our listeners understand a little bit of what I would call the good, bad, and the ugly of where you think we have been, where we are, and possibly where we’re going in this field and how it can really help transform health care? KP: Yes, that’s a great question. I think to begin with, if you look at the private corporate sector, about half of the total annual medical expenditure in the United States is governed by what private companies do and do not select for their benefits plans. So that’s a huge financial leverage point within a medical system that is disease-obsessed. I’ve actually referred to it in my publications as a disease management industry rather than a healthcare system. “Disease management industry” really sounds pejorative, but it really isn’t—I mean, disease is the focus of medicine, management follows from that, and at one-eighth of the total US economy—2.2 trillion dollars in 2013—it’s certainly an industry. So we have this disease industry out there, but when we look at the corporate sector, to me the positive thing is that there is a potential for an industry that believes in better diet, improved nutrition, use of supplements, early detection, and exercise and nutrition, and the use of alternative practices that are evidence-based. If you can demonstrate, as we did with Ford, that a combination of chiropractic, mindfulness meditation, and acupuncture is more effective with back pain than traditional care in terms of clinical and cost outcomes, they have implemented that model in all 12 of their onsite clinics that are devoted to back pain. So there becomes a point of leverage where you can take an idea that may or may not be acceptable as an idea, but when you demonstrate that it really works, the private corporate sector is very practical and they’ll say, “That’s fine. It’s safe, it’s efficacious, it’s cost-effective. We will implement that.” So there’s a very receptive place out there for all of your listeners, all of your people that are in this network, to be able to think about taking your clinical skills and bringing it into the worksite. There is tremendous receptivity. Addressing Criticism of Corporate Health Programs I think you know the downside has been the hue and cry that somehow these programs are intrusive. That it is Big Brother. That people are being coerced into certain ways of being and certain ways of acting. But the reality is that if you look closely, these are really based on informed choice. No one is coerced into stopping smoking, or reducing their hypertension or cardiovascular risk, or changing their diets. They are incentivized. They are very often given financial or recognition incentives, which motivate all of us in our lives, but they are not coerced into doing that. Most recently there has been some press from several critics of the field saying, “Well, the return on investment figures are not real.” I’ve written eight reviews of this literature over the last 25 years, and it is unequivocally clear that there are about 200 studies of worksite-based interventions. About half of those have been evaluated for cost outcomes, and of the cost outcome studies, only one failed to demonstrate a return on investment and that was because they factored in the cost of a two million dollar gymnasium into the cost side of the equation, so of course you’re not going to see an effect with that much money piled up on the cost side. But they are cost effective. They are clinically effective. If I look out into the future with the Affordable Care Act, really what’s happened is it has placed more burden on the companies to begin to seriously take the role of themselves as promoting optimal health for their employees. I think there are more opportunities for individuals, for vendors, for companies to go in and demonstrate by whatever clinical method you have, be it nutrition, exercise physiology, chiropractic, herbal medicine, demonstrating that you can make a difference in a major chronic disease that, for them, they would like to be rid of, both in terms of carrying employees and in terms of cost. So I’m very optimistic about the future of this area. It’s certainly growing very rapidly. We’ve had more activity and interest from companies, both in the United States and abroad in the last two or three years than we’ve had in 26 years. JB: That is very encouraging, and just for our listeners, to give you a couple of citations from the bibliography of Dr. Pelletier’s published papers, the Ford Motor Company discussion you had I think you included in a paper you published in the Journal of Occupational and Environmental Medicine in 2010, volume 52, page 256 titled “Integrative Medical Intervention in a Ford Motor Company Assembly Plant,” and then your most current review of the cost-effectiveness was also in the Journal of Occupational and Environmental Medicine, “Review and Analysis of the Clinical Cost-Effectiveness Studies of Comprehensive Health Promotion and Disease Management Programs at the Worksite.”[9] That was a 2008 to a 2010 review, and that was in the volume 53, page 1310 issue of 2011.[10] I just wanted to put those citations into the mix for people that might want to follow up on them. So if we go back to ask the question why we, then, with all this very positive information in this more than three decades, going on four decades of rigorous work and evaluation, why there are still outlier—I’d like to call it—naysayer opinions. We see these things being written almost on a regular basis by people who have good pedigrees that are associated with good institutions who are saying all of this is bunk. It’s all just a bunch of smoke and mirrors. None of this really works. It has no science. It’s pixie dust. What is it that generates thinking people to come to this conclusion? KP: Well, it’s interesting because you’re right. That has occurred and it continues to occur. Part of it is sheer inertia—the unwillingness to really look at the data and to take a serious unbiased, thoughtful look at the literature. What I have found in some of the recent critiques that have been written is that either the data is overlooked, or there is clearly a lack of citation of the enormous numbers of studies that are available. Now, on the defense, if you will, of the critics, there is a great deal more to be done. The study designs are not as rigorous as they should be. It is very difficult to conduct a randomized clinical trial in a worksite. Some ways of getting around that is you’ll intervene in one worksite and have a physically distant worksite as the control, so you have the same kinds of workers and the same kinds of issues. So there are ways to address the methodological limitations, which admittedly exist. If you look back over these two hundred studies, you find that a lot of the early claims of return-on-investment were excessive. You had 10-to-1, and 15-to-1, and these really overblown estimates of return-on-investment. When you look at the more recent literature—the more rigorous studies—they look at around a 3-to-1 or 5-to-1 return on investment, so you’re getting to more objective, more realistic kind of assessments that are taking place. I think that’s a variable, and the critics are correct. The methodology has not been the best. It is getting better. The last thing that I would say is that if you read…for instance, when Rand just this year published a study and the critics seized on that and said, “Well, the Rand study is proving that these programs do not work.”[11] But if you look at the Rand methodology, it’s terrible (the methodology by which the study was conducted). And the principal investigator has publicly and a then subsequently written up clarifications about the study saying, “Look, our study did not, in fact, disprove that these programs work.” In fact, the evidence would indicate that they do, but they had extreme limitations on the size of the sample, the number of companies that they could look at, the nature of the database they received from the companies. So there are some methodological flaws, if you will, in studies that are most often cited by the critics. But overall, when I look at my own analysis, usually every two or three years when I publish the review, the vast majority of studies indicate that these are both clinically and cost-effective, and becoming more so over time. We’re learning. We’re learning how to do these things better. JB: People in this field, I think we can say that these are people that have decided to walk a different path—maybe a road less traveled. They’ve often given up certain economic incentives. They’ve often taken on some degree of scrutiny from peers. It’s not necessarily the easiest decision for a career path to take to move your training into what I would consider the new medicine of the 21st century. They’ll often ask me, “Do you think I can actually make a living doing this?” Because all of the incentives, as you pointed out, Ken, are really for ICD-9 coded disease treatment and not really related to what I would call a systems biology approach towards health promotion. As you’ve reviewed over the last three-plus decades (nearly four decades) do you feel that the environment is improving to incentivize docs to actually be in this field so they can make a living? Integrative Medicine: Better Training, Higher Compensation, and—Now—National Certification KP: It is, and it is grudgingly slow. You’ve traveled this path as well in your own career, and you know what it’s like when you break outside of the normal reimbursement and compensation system to follow your own path, to make a contribution that’s greater than compensation-only model. But having said that, it is more possible now for integrative medicine physicians, for integrative medicine providers of all type—nursing, exercise physiology—to all be providers of these programs direct to the general public. Certainly the spa industry—the day spa industry—is growing phenomenally quickly. Those provide positions and entre points for services that didn’t exist a few years ago. Secondly, the Center for Integrative Medicine at the University of Arizona, which is where I’m a faculty member, has trained over 1100 physicians in integrative medicine. That’s a two-year postdoctoral program in integrative medicine. So there are now 1100, I think, and with the exception of maybe 40 or 50 they are all domestic (about 40 or 50 are international). So they are out there, back in clinics, in the hospitals, in free-standing practices, delivering integrative medicine services and being compensated for them, and being openly compensated for them by having appropriate coding of their billing. So it is possible for them. And the third, to me a major development, is national certification, which we have in every medical specialty. In the fall of this year—the fall of 2014, probably October, I believe—will be the first national exams that will provide national certification in integrative medicine. There are thirteen of us that have been on the board developing the questions for the exams. These include Andy Weil, and Tieraona Low Dog, and Victoria Maizes, and Patrick Hanaway. These are people who have had a leading role in the field already—Roberta Lee, Mimi Guarneri—so it’s been a very exciting group. But the national certification will certainly help to establish the credibility of providers, and credibility, then, in turn, compensation, and changes in coding will change. I take all of those as indications that the tide has not turned. The predominance of compensation is still for staying within the conventional medical model, but it is changing, and it is changing in ways that there are now many more people making a good living teaching, training, delivering programs, delivering clinical services than has ever been up to this point in time. And it’s going to continue. JB: That is a really, really nice statement of great optimism about our future. I’d like to ask one last question. I will precede my question by saying I know there is no specific answer to this question, but you’re such a great thought leader I would be interested in how you might approach an answer. The question goes something like this: We have a variety of individuals who are in decision-making positions within the disease-care delivery system, both from the insurance side and from the health delivery side and institutional side, who are very resistive to change and feel that the system that we’re now operating under is really the solution to the problem; it’s just a question of providing excellence with regard to the present way that we’re approaching the burden of disease. Yet when we look at the statistics on the cost-effectiveness of this system, even the most favorable observers would say that the cost-effectiveness is problematic and that we’re really seeing some very distinctive trends where the global, or at least the United States economic system could be brought to its knees just on the basis of the burden of the nature of Alzheimer’s and diabetes and other chronic disease that are so costly. My question is if there is this rising tide of recognition that the present system is not working, why is there, then, a resistance, do you feel, to something of change? Is it because we don’t know how to change, or is it because that’s the nature of systems that will resist change? Why is it that people will fight so hard to retain the present system when the evidence is it’s not working? KP: You’ve asked a very powerful question. Just a few thoughts about it, one with regard to the effectiveness of the current disease management industry in the United States. When you look at international health outcomes—heart disease, cancer, chronic diseases, infant mortality, homicide, etc.—we rank 37th in the world. That is the same as Bosnia; 37th in the world. And among the top 12 post-industrial nations, we rank last, or most expensive in terms of outcomes. So we are spending the most for the youngest, average-age population on the planet, and getting the least in terms of health outcome, so that’s a given and there’s really no arguing with that. Why do we not change is because of the extraordinary vested interest and lobbying that occurs. If you look at the top ten lobbies in Washington, DC, in the top ten you have the California Medical Association, the American Medical Association, the American Pharmaceutical Association, the American Hospital Association. So four of the top ten lobbies in Washington have a common thread of business-as-usual—of keeping medicine as it is and as it is supposed to be. That’s a lot of weight weighing against change. Countervailing that is the fact that we literally cannot keep going in this direction. This is a cost-inefficient model to prevent disease in the way that you’re describing, to use the kinds of alternative methodologies which are frequently less costly, fewer side effects, with better outcomes. The data is getting better, and that data is beginning to have an effect. For instance, just this morning I had a conversation with the President and CEO of Parker Hannifin. It’s a company in the Great Lakes area. They have had a policy for the last almost ten years now of providing 80 percent compensation to an employee to seek any—literally any and all—treatments, be they conventional or alternative. It’s a worldwide company. It’s a thirteen billion dollar manufacturing company. They want to begin to look at the outcomes: How do you collect data on how well these people are doing? What’s the clinical and cost-effectiveness of doing this? But that’s astounding that such a company would have done this. They’ve seen their pharmaceutical costs go down. They’ve seen their chronic disease incidence go down. Hospitalizations have been decreased. Use of supplements has increased. Use of preventive services has increased. Exercise, etc. So they’ve seen, by having this policy in place—now, not all of their employees are using it, and they do want to see more people do that—but they are having to educate, and to me, I think the bottom line is informed choice. What we really need is for every individual that looks at what they can and cannot do with his or her health to make informed choices, be it conventional or alternative or a hybrid of the two, that’s why I like the integrative medicine. Integrative medicine is basically taking the best evidence-based conventional medicine and the best evidence-based alternative medicine and fusing them into one treatment methodology that’s effective for the individual. That, to me, is the future, and I think we are moving toward that partially out of economic necessity, and partially because the research is getting better and the awareness of these methods through the Internet, through programs like this, is increasing people’s awareness of what their options are to exercise informed choice. JB: I can’t tell you how much I feel privileged to have this conversation and also to have had our friendship and collegial relationship over the last 35 years. It’s truly remarkable when you take a snapshot of a person’s life—you as a Woodrow Wilson Fellow, back when—and see where you’re career track is taking you and the impact that you’re discoveries and explorations have had on social change. I want to applaud what you’ve done. I want to say we’ve got a lot of work ahead of us, but the voice that you’ve given us is a very, very optimistic and forward-looking thought that the paradigm will shift and that we’re near something that I think makes really good sense in light of the new biology of the 21st century. I want to thank you very much for spending this time with us on Functional Medicine Update. KP: Thank you, this has been very enjoyable. It’s really a pleasure to talk with you, Jeff.  

Bibliography

[1] Pelletier, Kenneth R. Mind As Healer, Mind As Slayer. New York: Delta Publishing Company, 1977.   [2] Whitmer RW, Pelletier KR, Anderson DR, Baase CM, Frost GJ. A wake-up call for corporate America. J Occup Environ Med. 2003 Sep;45(9):916-25.   [3] Pelletier KR. Mind-body medicine in ambulatory care:an evidence-based assessment. J Ambul Care Manage. 2004 Jan-Mar;27(1):25-42.   [4] Chapman LS, Pelletier KR. Population health management as a strategy for creation of optimal healing environments in worksite and corporate settings. J Altern Complement Med. 2004;10 Suppl 1:S127-40.   [5] Eton DT, Koffler K, Cella D, Eisenstein A, Astin JA, et al. Developing a self-report outcome measure for complementary and alternative medicine. Explore (NY). 2005 May;1(3):177-85.   [6] Long DA, Perry TL, Pelletier KR, Lehman GO. Care management program evaluation: constituents, conflicts, and moves toward standardization. Dis Manag. 2006 Jun;9(3):176-81.   [7] Pelletier KR. A review and analysis of the clinical and cost-effectiveness studies of comprehensive health promotion and disease management programs at the worksite: update VI 2000-2004. J Occup Environ Med. 2005 Oct;47(10):1051-8. Review.   [8] Allen J, Anderson DR, Baun B, Blair SN, Chapman LS, et al. Reflections on developments in health promotion in the past quarter century from founding members of the American Journal of Health Promotion Editorial Board. Am J Health Promot. 2011 Mar-Apr;25(4):ei-eviii.   [9] Kimbrough E, Lao L, Berman B, Pelletier KR, Talamonti WJ. An integrative medicine intervention in a Ford Motor Company assembly plant. J Occup Environ Med. 2010 Mar;52(3):256-7.   [10] Pelletier KR. A review and analysis of the clinical and cost effectiveness studies of comprehensive health promotion and disease management programs at the worksite: update VIII 2008 to 2010. J Occup Environ Med. 2011 Nov;53(11):1310-31.   [11] Caloyeras JP, Liu H, Exum E, Broderick M, Mattke S. Managing manifest diseases, but not health risks, saved PepsiCo money over seven years. Health Aff (Millwood). 2014 Jan;33(1):124-31.   [12] Grumbach K, Lucey CR, Johnston SC. Transforming from centers of learning to learning health systems: the challenge for academic health centers. JAMA. 2014 Mar 19;311(11):1109-10.   [13] Saloner B, Sabik L, Sommers BD. Pinching the poor? Medicaid cost-sharing under the ACA. N Engl J Med. 2014 Mar 27;370(13):1177-80.   [14] Schwenk TL. The patient-centered medical home: one size does not fit all. JAMA. 2014 Feb 26;311(8):802-3.   [15] Antman EM, Jessup M. Clinical practice guidelines for chronic cardiovascular disorders: a roadmap for the future. JAMA. 2014 Mar 26;311(12):1195-6.   [16] Mitka M. Ezetimibe prescribing fails to keep up with evidence. JAMA. 2014 Apr 2;311(3):1279-80.   [17] Krumholz HM. The new cholesterol and blood pressure guidelines: perspective on the path forward. JAMA. 2014 Apr 9;311(14):1403-5.   [18] Emerging Risk Factors Collaboration. Glycated hemoglobin measurement and prediction of cardiovascular disease. JAMA. 2014 Mar 26;311(12):1225-33

Welcome. This is Functional Medicine Update, July 2014, and this is an epic issue.  Well, if you hear excitement in my voice, it’s real. I am totally excited about this time that we’re going to spend together with our researcher of the month, an individual that I had the privilege of meeting, oh, I guess nearly 10 years ago who I’ve followed very, very closely, his work. It’s pioneering, groundbreaking, paradigm-shifting, mind-expanding, and probably—if I was to be really realistic—I think it is the closest to really forecasting where medicine and health care is going in the 21st century. It’s part of a movement of individuals who are really creating the new medicine. I’m speaking about Dr. Eric Schadt. Dr. Schadt is Professor and Chair of Genetics and Genomic Sciences, Director of the Icahn Institute for Genomics and Multiscale Biology. Don’t you love that term? Multiscale biology. I think that says a lot in itself. He’s an expert in bioinformatics, computational neuroscience, epigenetics—both human genomics and genetics. But more than that, he’s an expansive thinker. This is one of those visionaries that makes news-to-use from the theory to the practice. He and his colleague, Stephen Friend, have really, I think, pioneered a landscape within health care that is uncharted territory. Just to give you a little bit of his background, because it is certainly symbolic of the breadth and expansiveness of his thinking because he does have kind of a non-traditional background, he has degrees in mathematics, ultimately went on to become a doctoral student and a successful candidate for a doctoral degree at UCLA and was faculty there. He then moved on from there to do a whole bunch of things, including Rosetta Inpharmatics, where he was Director of Information Sciences, and from that went on to a series of steps and you’ll hear more from him about this. Prior to joining Mount Sinai in 2011, he was the Chief Scientific Officer at Pacific Biosciences, and through all of this work at Rosetta, the work at Pacific Biosciences, the work at Merck (which as you probably know Rosetta was a company owned by Merck), he has left an irreversible impact on the field. His publication record of over 200 publications since 1998-99 is legendary in top-tier journals. And his work with Dr. Stephen Friend has really opened up kind of a new concept as to how we even do big data analysis by collaboration, by opening up the blinders, by getting rid of academic pedagogy and self-protection, and moving to the democratization of ideas and sharing of data and information. Kind of a novel concept in the academic world of discovery, but they have been pioneering this concept very successfully. If you look at a number of his papers, they are authored by more than 20 authors from collaborative centers. Clues from the Resilient: Looking at Genetics in a New Way We’re very fortunate to actually have an article that was just published in Science magazine authored by Stephen Friend and Eric Schadt, which for me, when I read it, it just blew me away. It just stopped me in my tracks. This was in the May 30 issue of Science, volume 344, and the title of it is: “Clues from the Resilient.”[1] I don’t want to steal the thunder—I’d like you to hear about this from the brain and mouth of the convener and the author of this paper, but this, to me, is the “ah-ha” paper, because we have so focused our concepts of genomics on disease. Our whole culture is tied to disease. It’s all this fear-based mentality of skirting around the edges and hoping your number doesn’t get pulled by the Monte Carlo effect of life and ending up with a disease diagnosis when locked in our genes is extraordinary symphonic information related to health and related to function. If it wasn’t there, we as a species would not have survived. So this penchant to always deal with the disease construct and the fear-based mentality, which by the way is the economic driver of our system, is turned on its head when talking about resilience: how it is that people that may carry genes that might encode for what we consider disease susceptibility don’t express those characteristics as a consequence of other governors on their genetic expression? And this is the article that I think is the “ah-ha” that Dr. Schadt and Dr. Friend recently authored in Science. With that as a probably longer-winded introduction, Eric, than you ever got, thanks so much for being part of us here at Functional Medicine Update

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INTERVIEW TRANSCRIPT

Researcher of the Month Eric Schadt, PhD Professor and System Chair, Genetics and Genomic Sciences Director, Icahn Institute for Genomics and Multiscale Biology Mount Sinai School of Medicine One Gustave Levy Place New York, NY 10029 http://www.mountsinai.org/profiles/eric-schadt ES: Thank you, Jeff, certainly for all those kind words. Hopefully I’ll live up to that height and thanks for the opportunity to be on your program. JB: Could you tell our listeners about the basis and the understanding of this “Clues from the Resilient” article, because I think it’s a good way to contextualize where we’re going to go in our discussion. ES: Sure, well this idea of studying resilience in the genetic context grew out of more a frustration of having been part of the pharmaceutical industry and seeing how diseases were being approached from this—very much as you said—a very disease-oriented perspective where only diseased individuals are studied and healthy subjects are brought in only as controls to better assess the diseased individuals, and how that hasn’t really delivered the amazing therapeutics that one would have imagined could come out of that. So it’s not as if using that kind of approach has led to dramatic improvements into well-being through pharmaceutical interventions, and the reason for that—I believe—is that the types of hits that happen to a system, especially if you take, at the extreme, the rare Mendelian disorders that are highly penetrant and lead to catastrophic disease, that these diseases are not occurring because of a gain of function; they are typically occurring because of a loss of function. And when you have a loss of function (a protein that’s broken), to come up with a small molecule that can fix that broken protein, it’s a very, very hard problem. Unable to achieve that, we have fell short, I believe, in addressing a lot of these human conditions. On the other hand, if you can identify individuals who harbor these highly penetrant, highly deleterious mutations, yet nature has found a way to circumvent and buffer against those mutations, then however that individual has buffered, that becomes the therapeutic. While it’s sort of obvious when you hear it, it’s not something that the human genetics community and beyond has addressed on a systematic level, so our idea was: Let’s look for those individuals who have something either in their DNA or in the environment in which they are part of that has enabled them to circumvent these hard-hitting mutations, identify what those are, and then pursue that as a preventative measure. JB: That would seemingly bring into discussion some very, very interesting questions related to where these buffering messages might reside within our genome. Do they reside in coding regions, or do they reside in noncoding regions? It would also beg questions as it relates to are there signals from the environment—diet, lifestyle, chemical exposures, whatever—that transduce these messages into functional phenotype? So this opens up the door to an extraordinarily robust, different way of approaching health and disease, it would appear to me. There is No “Bad” DNA ES: Exactly, and I think it’s sort of a different perspective in that we think of, in the disease community, DNA having mutations that are bad, right? So they increase your susceptibility to a given disease, so we think in terms of good and bad DNA, and if you have these mutations that’s bad and that gets to the whole fear-mongering that you were talking about. We’re doing testing on individuals and then what they are expecting to get back is do you have some bad DNA that’s causing perhaps the potential to cause bad things in you. Our view would be more from the perspective that there really is no bad DNA, per se, in general—that it is all about, for your genetic background, how do you create the right environment that maximizes the potential that’s built into your DNA? So whether it is taking a certain therapeutic that may change microenvironments in certain cells of tissue types that then enable you to live a normal life, or changes in your diet, or changes in your exercise patterns, or other behavioral changes that can then create the right environment and maximize what the DNA is able to do for you. That’s the way we’ve started thinking about it—that it’s all about how do we create the right microenvironments and macroenvironments in an individual’s life to optimize the gift they have been given through their DNA? JB: So you authored…well, you’ve authored many articles—over 200 of them—but a previous article to the article on the resilient was found in Science in 2012. I love the title. It was titled “A GPS for Navigating DNA.”[2] If I was to really look at the body of your work over the last 20 years that you’ve been actively publishing, that would be a good sound bite—an elevator speech—of your work, that you are helping us to understand how to navigate our genome and its complexity. Tell us a little bit about this “GPS for Navigating DNA” article that you authored with Rui Chang. I think it was a very interesting insight. ES: Yes, so it is built on the idea that during your life course you have coinciding with that your health course, and the health course is a very complicated trajectory that is based on the DNA you’re born with, the environmental context in which you’re living, your lifestyle choices, and many, many different variables that are defining all the different susceptibilities to diseases, your protections against disease, and so on. What we really want to be able to provide individuals isn’t the subfraction of a percentage of medical advice when they happen to visit their doctor or a medical center one time during the year. You know, if you think about, the amount of time you’re in a doctor’s office or in a medical center is probably, for most of us, less than one percent of our time and that’s not really giving you the right kind of snapshot of what is going on in yourself. So if we can instead take into account what’s going on in you at the molecular level, what’s going on in your environment, and all the other variables that we can collect on an individual longitudinally, can we define the landscape in which they are operating? If you imagine your health course as being this vast expanse—this vast landscape—of peaks and valleys that may represent disease peaks or valleys of wellness, and that you’re moving through this complicated landscape over your life course, what we want to be able to do is at any given point in time, we want to be placing you on that landscape, identify the trajectory that you are on, identify whether that trajectory is leading to overall good improved wellness, protection against disease, unless you are on a trajectory that is going to lead with high probability to certain diseases, or maybe you’re in a disease state trajectory and how do we bounce you out of that? But the main idea is can we more accurately identify the trajectory you are on, whether it’s good or bad, and then by using quantitative, probabilistic methods that are taking into account the vast expanse of data that we can collect on individuals, so it’s building these predictive models, can we identify what are the features in you, whether it’s your behavior, whether it’s therapeutic intervention and so on, what are the features that will either maintain you on a positive trajectory to realize all the benefits on that trajectory, or how do we move you off a trajectory that’s moving you towards disease or keeping you in a disease state? So it’s this more continuous time monitoring. It’s not going into the doctor’s office once a year to have your blood pressure checked and your glucose levels and so forth; it’s continuous monitoring, and continuous feedback to you that can help you progress. We Fine Tune the Performance of Machines—Can We Do the Same for Humans? And I’ll say this isn’t something that’s foreign, right, to people who want to tune machines. If you look at the Oracle America’s Cup team (from Oracle), on that boat—the very sophisticated boat that they race in the America’s Cup—they have over 300 sensors on that boat monitoring every aspect of that boat’s operation including the crew. They are sampling data at roughly ten Hertz and they are generating around 300 gigabytes of data a day on that boat, crunching that data in real time, making decisions in real time on how to tune parameters to optimize the function of that boat. They do the same thing for the Honda team and the Indy car races have the same sort of set up on their cars for monitoring all these features. If we can do that on cars and advanced machines, why can’t we do that on people and why can’t we do the same kind of modeling to tune the performance of every individual so that their maximum potential is achieved? JB: Holy mackerel! ES: Sorry if I’m getting carried away, here. JB: I love it! No, you’re not. We want you to be carried away. That’s the vision that Eric Schadt has really stood for. I guess the question is these are lofty, aspirational goals, but then a person might ask: Well, that sounds like a huge amount of data, and that sounds like, wow, it would crunch supercomputers and bring them to their knees. Can we really do this? Is this technology that’s really possible? ES: It’s a perfect question, and I would say that maybe ten or twenty years ago this sort of vision would have been great, but I think very difficult if not impossible to carry out. But what we have seen over the last decade-plus is such an amazing advance in the technologies—those in the biotech arena and beyond—to allow assaying of individuals in a very comprehensive fashion, whether it’s whole-genome sequencing, or whole-transcriptome sequencing, or proteomic or metabolomic profiling. These assays can now be carried out cheaply enough and comprehensively enough to be done on a more routine basis, so I think the ability to generate very large-scale, high-dimensional data on individuals and longitudinally is now possible, and you’re seeing companies like Theranos that is now appearing in Walgreens—you know, where you can go right down to your Walgreens and, with a drop of blood, choose from a panel of tests that you can have run for very low cost, a lot of which are covered by your insurance provider. So you’re already seeing this go direct-to-consumer. Complementing that molecular revolution is the physiological-sensing revolution, so many of your listeners probably have Fitbit devices, or Jawbone Ups, or the Flex Fuel Bands, or whatever—a variety of these wearable devices that today are doing measures that are maybe somewhat primitive, but the next generation coming is getting more and more sophisticated. So whereas today maybe it is measuring your activity and sleep cycles with a now hand-held EKG devices that snap right on to your iPhone and then in 30 seconds deliver you an EKG that rivals what you get in a hospital and that device costs fifteen dollars. There are wearable devices that are simultaneously measuring blood pressure, and skin conductants, and bioimpedance, and pulse oximetry, and all these different physiological measures that absolutely can be informative as to your current state, and if you are in a disease condition, the mobile glucometers, the Bluetooth-enabled inhalers, the portable spirometers for people with COPD and asthma—all of these measurable devices getting cheaper and cheaper, where you can have these in the home, you can wear them on a routine basis, and collect large-scale amounts of data without thinking about it. And Apple just announced their foray into the health arena with what they call the HealthKit, which is a whole number of tools that are enabling the building of apps that will aggregate data from all these wearable devices and your electronic medical records. JB: The possibility of measuring physiological metabolites by the same mechanism? ES: Exactly. So I think all of the ability to generate these really large-scale and informative sets of data on individuals over time is no longer an obstacle. In fact, that will be the next big wave that hits the consumer market and it’s already emerging. How you make sense of that data, of course, is the game. So to be able to manage very large scales of data, to place it in the context of the digital universe of information so that you’re using as much data and knowledge that is available to make interpretations on an individual—that does require supercomputing hardware, it requires people who know how to manage that scale of data, it requires people who know how to integrate the data and build these predictive models that requires how do you apply those models in a clinical setting to produce results that a physician will buy? That they can interact with, understand, and help guide their thinking as well as the thinking of the consumer? I don’t know if we’re there yet to do this to the mass market, but one of my moves to Mount Sinai was to figure this out. This was a medical center—the fourth largest network of hospitals in the US—so a very large patient population and a leadership committed to figuring out how do we take all this information, build those models to improve the well-being of our patient population? So we’ve hired the right kinds of teams to help flesh this out, and I think in the next five years you’ve going to see real examples of this absolutely aiding the more appropriate diagnosis and treating of patients that are improving outcomes of the patients and also reducing the overall healthcare burden. We’re in the midst of that revolution right now. JB: Let’s move from this extraordinary vision level down to maybe the ground level for a second and talk about 23andMe, because I think that’s a very interesting model discussion about how culture, regulatory environments, and maybe even people are going to integrate and make part of these opportunities in terms of our social system. We know we can do GWAS, we can do exome analysis, we can do whole-genome sequencing, when there is even now starting to be epigenetic analysis of methylated promoter regions of various genes, and then we take that down to a $99 test of specific SNPs offered by 23andMe and the FDA’s incursion into what they consider a company that’s providing a medical device without proper checking of the boxes. Tell us a little bit about how you see the 23andMe example being a history lesson for us as we move forward. ES: Yes, it’s somewhat of a complicated landscape. I think the regulatory agencies have been completely overwhelmed by the pace of technology, so I think this hit them all very hard and very fast to the point where they, you know, were sort of just not knowing what they should do. They’re used to looking at tests as being this very simple here’s the measure you’re taking, and this measure could be over this threshold or under this threshold and based on that you’re going to make a recommendation as to the diagnosis or treatment of a patient, and now we’re moving into the space where it is no longer a single feature that’s predicting that it’s constellations of hundreds of thousands, or maybe even tens of thousands, of features, and it’s more probabilistic, and it’s more dynamic from the standpoint of the models that exist today are rapidly evolving on a daily basis as we learn more, as we apply it to patient populations and look at their outcomes we can refine those models, and so that sort of adaptive learning is not something that the FDA, in a probabilistic context, was fully able to comprehend and take up. So I think companies like 23andMe that were definitely revolutionary from the standpoint of hitting out to the consumer and getting this kind of information generated and played, I think a really big service on how to convey complicated information to a population that doesn’t understand any of the underlying science or complexity, but being able to convey that information to them in ways that they understand, can appreciate, can act on, that that’s a really hard problem and one I think that 23andMe has hit really well and has been effective and they now have probably one of the largest collections of individuals with DNA assays on the planet. So I think that has been a very big positive. On the regulatory side, though, if you’re going to use this information to convey risks or treatment courses to a patient, there does need to be some bar that you are going over to both protect the patients but also protect the medical community from the standpoint of how patients’ treatment is being driven. So I think probably one of the mistakes of 23andMe was providing more and more risk information without the appropriate validation, without showing that there is clinical utility, without showing that they had really protected the patients’ interest and had all of the protections in place to be able to address a patient’s concern if they learned that they were at high risk of a disease like Alzheimer’s, where there wasn’t necessarily an effective treatment to prevent their slide into that disease or being able to tell that patient what to do. You don’t want to cause more damage—more anxiety—to the patient than you have to, especially if you can’t do anything about what you’re telling them. If you’re going to give, for example, a patient their breast cancer risk or ovarian cancer risk score, you want to be basing that on all the known risk factors for those disease. So if you’re giving, for example, breast cancer risk information without understanding the variation of, say, BRCA 1 and 2, well that’s a very misleading resulting. You shouldn’t be conveying that kind of risk information without taking the most important risk factors into account. So I think there are a number of missteps that way in both how risk information was being conveyed and how the regulatory agencies were being integrated into that process, and the bottom line is today, you need to be working in that framework to push forward while maybe simultaneously pushing forward disruption and transformation of these regulatory agencies to fully appreciate all that’s coming up. JB: So with that in mind, then, it begs the question: Who helps to be the navigator for the consumer through this landscape? I know you have authored a very nice jointly authored paper that recently appeared in Genome Medicine on informed decision-making among medical students analyzing their personal genomes on the whole genome sequencing course and how this education of them becomes very important because if they’re going to become the providers of interface with their patients they better be informed.[3] So, this question of who teaches 21st century medicine based on this genomic revolution is a very, very powerful question. I have the privilege of being in a study club with a variety of practicing physicians and I’ve been amazed at how vigorous, aggressive, and dedicated they are to their own self-education: reading papers, every week we have a discussion leader who takes us through various concepts that are related to how these genomic discoveries relate to patient management. So there is at least a body politic within medicine who wants to be informed. It’s not just medical geneticists. Tell us a little bit about how we’re going to transfer this information properly to docs who are going to be the interface with patients in terms of translation. Clinical Utility of Genomics Needs to be Demonstrated to Physicians ES: Yes, I think there are a couple of things related to that. First is in order to get a physician buy-in, in order to demonstrate to a physician that they should be paying attention, their biggest criticisms on the genomics revolution more generally are the variants that are being identified that predispose you to risk of any sort of common human disease, that the effect sizes are so small, even when taken in aggregate over all the variants found, that the clinical utility of their increase or decrease risk that is given is so small that it’s not something that a physician would take into account in managing a patient. So I think we have to be really thoughtful in how we push things forward into the medical community in ensuring that the things we’re pushing forward will have some actionable benefit. So there are definitely genetic findings, a lot of them relating to the metabolism of drugs for example, that are immediately actionable and should be standard of practice today even though they’re not. But then we have to also be protective against giving risk for obesity, and diabetes, and Alzheimer’s based on genetic findings that may not increase your risk enough to have any meaningful clinical utility. So I think teaching not just the physician, but the practicing geneticist who push these models, where that balance is and what kind of studies do you have to do and to what extent do you have to build the evidence to provide to the physicians is important. But equally important is how do you educate the next generation of physicians and other healthcare professionals? And it’s not just the genomic data, although that’s maybe one of the most well-known and comprehensive and widely available today, but as you know, there are metabolomic and proteomic and RNA sequencing. So in addition to the genomic information, there are other high-dimensional data that can be assayed now, whether it’s RNA sequencing, metabolomics, proteomics, microbiome—what are the bugs that are living in and on you and how predictive are they of your current health condition. All of that information and how it gets integrated and the models that get built and how that modeling can be leveraged in the clinic to actually base decisions on a patient’s care, those are all things that are going to require pretty significant changes to the curriculum and medical schools and other related disciplines to appropriately train this next generation coming and how to accommodate this. A Novel (and Controversial) Experiment: A Personal Genome Interpretation Course for Medical Students One of the things we attempted to do towards that end was the first course of its kind in the country—a personal genome interpretation course—where students, which were medical students, genetic counselors, and other healthcare professionals who are in training, where they could take this course and have the opportunity during the course to have their genome completely sequenced, and through the course learn how to analyze and interpret their genome. So it’s a way to directly engage that next generation on all aspects from the generation of this whole-genome data, to the analysis, to the interpretation, to how do you appropriately counsel people based on what you’re learning and the fact that they would experience that first hand I think gives some advantages. Of course, that course was not without significant controversy. There were many thoughtful leaders in the genetics community who were very, very opposed to students sequencing their own genomes and learning about themselves in that way through an actual course, but our thought was this information is going to become so prevalent, so cheap to generate—the fact that you can go to 23andMe without anybody’s approval and get that information (if you don’t live in the state of New York), you don’t need anybody’s approval to get that information generated and why should you be left on your own to try to figure out how you see that. That doesn’t seem like the most efficient way to be educating people on how they interact with that data, so we think this type of course could be very instrumental for helping change the thinking and the mindset of what’s going to be needed in the practice of medicine in the future. JB: Well, it’s my deep hope that that course, as it moves forward, will become an e-learning opportunity. That could be one of the great contributions to all our education. There’d be no better person that I think than you to help arrange the right kinds of resource people to really make that available. That could be a paradigm-shifting opportunity. ES: Yes, and I’ll just add, you know, one of the most interesting findings from the course—and we have a paper coming on this as a follow-on to the genomic medicine one—is the students who were having their own genome sequenced spent much more time analyzing the genome and learning how to identify things of concern or things that were protecting. Like just the investment—the amount of time they spent learning, playing with the data, and so on was much higher if it was on their own genome versus if it was some anonymous reference that they had no personal interest in, so we think even from the pedagogical standpoint that there is going to be an argument there—that you’re just going to pay more attention to something that’s informing on you. JB: Let me, if I can, shift bench to bedside to some of the clinical applications that come out of your—and your colleagues’—work. I’d like to take a little walk down memory lane with you. I can’t say that I’ve read all of your 2014 or more publications, but I have gone back and read a good portion of them, so I’d like to just cherry pick a few to kind of help our listeners to understand the landscape of how intellectual thoughts and discoveries evolve. Let’s go back to—this is not the start of your publications, but in the earlier stage—2001, Toxicology and Applied Pharmacology, this article titled “Clustering of Hepatotoxins Based on Mechanism of Toxicity Using Gene Expression Profiles.”[4] I think that’s a very interesting way of addressing pharmacogenomics and also addressing the concept of toxigenomics and how various substances may influence different people in different ways based upon gene expression patterns. In fact, I think in the close of this paper you say something like, “The results suggest that microarray assays may provide a highly sensitive technique for safety screening, not only for drug candidates but also for environmental toxins. Tell us a little bit about how you think that can apply to this future application of the concepts. ES: So the RNA data holds a special place in my heart because DNA is fixed—at least largely fixed. We’re learning more and more that it may be more dynamic than we appreciate, but basically you’re born with all these different variants and with this blueprint that then defines much of what you become at the physical level; whereas RNA is changing in real time. It’s reflecting what’s going on in your system in a given cell, in a given tissue, at any given point in time, so because of that, RNA is just an exquisite sensor for reflecting on what is happening in a system at any given point in time and the fact that whether you smoke or not, whether you eat fruits and nuts or not, whether you take a particular vitamin—all of these different environmental stresses or perturbations affect, you know, ripple through your system, in very unique ways, whether it’s a toxin or a natural helpful product that’s in a food or whatever, that they will have a certain impact—a certain signature on your system—that we can then map to these interpretive models and go back to the landscape map that we were talking about earlier. The fact that I can take all of the toxins that NIEHS has generated across hundreds of cell lines to understand what’s the RNA-based perturbation that this toxin induces in this type of cell that we can map this back to the landscape map and understand that the trajectory you’re on, is it going to be promoted by any one of these toxins, or is it going to promote you onto another trajectory that may be worse or better? And not just for the toxins. We can do that for any marketed drug, we can do that for any food type or any natural product that occurs in food types. The fact that we can be mapping, using the RNA as the intermediate to map between the action of that compound and the effect it has on your system, that’s how I view that earliest work. It was the first representation of how we can use RNA as an exquisite sensor to determine, on a much more rigorous basis, whether a given compound or other such element was having a favorable or unfavorable impact on that part of the system. JB: So for the listeners, we’ve been talking about gene expression and how that regulates the phenotype for many, many years and use the simple sound bite saying food is information to our genes. We don’t just eat calories and nutrients, we eat information, and so this is one application for that construct that you’re describing, here: using RNA expression as a marker for how the pluripotential of the genome gets translated into some message or signal that controls our phenotype. ES: Exactly. JB: Very powerful. So let me move from there to 2005—a fantastic paper titled “Embracing Complexity, Inching Closer to Reality.”[5] I quote from this article that you and Stephen Friend authored, in which you say, “Drugs designed against targets and presumably simple linear signaling pathways found to be associated with disease are often less effective than predicted. One reason for this is the overly simplistic view of the molecular mechanisms underlying common human diseases. This viewpoint is a consequence of biological reductionism brought about by the need to form a basic understanding of the fundamental attributes of biological systems and by limitations in the set of tools available for the analysis of biological systems.” Now you go on to say, “However, complex biological systems are best modeled as… fluid systems.” So tell us a little bit about moving from targets to networks. ES: So that’s probably one of my more favorite papers because it sort of occurred at a time when this thinking that biological pathways, for example, weren’t linearly ordered with respect to the action of any given enzyme or receptor, but that they are occurring in highly nonlinear network-based structures just wasn’t something that many were thinking was true or were wanting to accept as true and that a lot of biology was still done in this very reductionist sort of way. So one of my favorite papers to just begin challenging that status quo that the most important pathways that we study, whether they’re metabolic, or signaling, or whatever, they’re not simple, linearly ordered pathways. Those simple, linearly ordered pathways are occurring in the context of thousands, or hundreds of thousands, of different variables, different proteins, and metabolites, and RNA species, and different constituent components of cells, and so on. So it’s a very, very complicated network of interacting parts that if we really want to understand how a given pathway or feature is operating we need to understand the context in which it is occurring. So we know a given enzyme is going to catalyze some event that’s going to go on to produce something meaningful to the cell, that if we really want to understand the operation of that pathway we need to understand the context in which it is operating: what are the other genes that are modulating the levels or the activity of that particular enzyme and how can it affect the flow of that pathway? So what are all the different features that are impeding on that? And so it sort of introduced the fact that even the most simple constructs of an enzyme producing some action was occurring in the context of thousands of different variables and that if we understood those thousands of different variables we could understand how it was operating in a given context—whether it was a normal functioning context or a disease context that was precipitated by increased stress, or some toxin, or something in your diet. The fact that we can now model this more holistic representation of what state these constituent pieces are operating in, we can just make a more holistic model that at the end of the day is just a better reflection of the system. I don’t think anybody would deny that our systems are really complicated and there are literally hundreds of thousands of variables at play in a given cell and these cells are interacting with each other to form tissues, and the tissues are forming organs, and the organs are communicating through complex signaling—the endocrine system, the nervous system, the immune system. So all of those pieces are showing a degree of connectivity, a degree of integration that, from an engineering standpoint, you have to model if you want to best understand the system and how to manipulate the system to achieve a good impact. So I think that shift in thinking away from the reductionist ideas of the earlier biology, which was really driven by the reagents—the tools we had available, the query biology—are now well-complemented by these systems level views that I think in the end are going to lead to a better understanding of living systems. JB: Okay, so let’s take that beautiful, paradigm-shifting concept to now how you start applying that as we go to 2005. Again, I’m just cherry-picking a few of the tremendous number of publications you’ve authored. This one is in Nature Genetics titled “Integrating Genotypic and Expression Data in a Segregating [Mouse] Populations to Identify 5-Lipoxygenase as a Susceptibility Gene for Obesity and Bone Traits.”[6] Now the reason I chose this article is it ties together different disciplines of medicine. We might say orthopedics or endocrinology owns one aspect and internal medicine and diabetology owns another aspect, and then immunology owns lipoxygenase and inflammation. Gee whiz, it seems like we’re all pushed together into one network of thinking, so it seems like it’s an application in this paper of what you were describing in the previous work. ES: Yes, exactly. One of the, what I think, cool concepts to come out of that paper was, so if you have all this complexity, all of this interaction going on, how do we resolve down to something that’s actually actionable? And the only way you can do that is through understanding causality. In this vast network of interactions, of correlations, how do we understand which is the driver and which is the responder or passenger? How do we start resolving that? In that paper we sort of laid out that naturally occurring variations in DNA could be considered as a systematic source of perturbations as opposed to an unnatural perturbation, which would be something like knocking out a gene on purpose, or overexpressing it at ten thousand times the normal level, or chemically perturbing it. Here what we’ve said is if we leverage naturally occurring DNA, we can leverage that as a perturbation source and resolve causality between variables in a very data-driven fashion. We don’t need to get into the complexity of that kind of modeling, but just to know that we’re now making causal connections in a completely data-driven fashion—we’re not accepting anything as true, a priori. We’re saying we’re going to generate the data, we’re going to let the data speak, and then come up with these relationships in a completely de novo fashion. And what came out of that was this concept that pathways aren’t simple, linearly ordered constructs, that they are very complex, integrated, nonlinear constructs that connects things that had previously been thought to be independent or unconnected. So whether it’s the impact certain genes can have on obesity as well as bone growth, or whether some of our later papers on linking diabetes with Alzheimer’s, these different conditions—these different perturbations—that hit our system aren’t isolated events to one part of the system generally. Generally, they are affecting multiple parts of the system and we’ll start linking diseases together into different classes that before the network view would have been considered completely independent. JB: Yes, and I could spend at least an hour talking to you about this specific paper because this integrates, also, basic biology. We now know that lipoxygenase—5-lipoxygenase—which controls the production of a series of inflammatory mediators, that those inflammatory mediators interconnect the immune system with cell types like the adipocytes, so they have an effect on what I call angry obesity, which is this inflammation, disease-related form of obesity. It ties together with osteoporosis and the change of the osteolytic/osteoporotic situation that is driven by inflammatory signals in the bone, and it ties together with other conditions that are associated with inflammation. So you have demonstrated through this model of segregating gene expression with genotypic data that, in fact, we can predict biology in ways that you can’t do by looking at monogenetic traits. Objectivity is the Strength of a Data-Driven, Network-Based Approach ES: Exactly right. Some of the findings can be so surprising. I just like to tell this little story because it pre-dated the 2005 paper. It was all the way back in ’99 when I was at Roche, where I started before I went on to Rosetta, and it sort of pioneered what we called genetics and gene expression approach there, and studying allergic asthma. One of the genes I identified in using this approach was the complement system C5 and complement 5 receptor, the C3 receptor, and so on. That was completely nearly heretical to the assay field at the time, and I remember giving the presentation at Roche on my analysis of this allergic asthma mouse population where we applied for the first time ever this new gene chip from Affymetrix to be able to assay all the genes being expressed in the state of allergic asthma. So I was able to put together this picture where I said this complement gene is really coming up as the top hitting thing, and the response to the asthma experts in the room at the time were if you knew anything about asthma, you would know that the complement system is absolutely not involved, therefore you must not understand anything that you’re talking about and so we don’t believe your conclusions. So it was sort of a depressing thing, but several years later, every pharma company thinking about asthma had a complement program going because ultimately that was all validated and shown to be one of the key mechanisms involved in allergic asthma. So it’s, again, the ability to be completely objective, completely data-driven, making completely novel connections is really the great strength of this network-based approach. Perturbagens: Food and Pharmaceuticals Can Push Molecular States Toward or Away From Disease JB: Let’s move that on quickly, and I think that people will see the intellectual lineage here of the discovery. So we move on to articles like the article in 2007 on the pharmacogenetics of metformin response, in which the subtitle is “A Step in the Path Toward Personalized Medicine.”[7] That article ties together with a number of your other subsequent publications, but one that I want to talk about specifically was in Human Molecular Genetics in 2010, “The Effect of Food Intake on Gene Expression in Human Peripheral Blood.”[8] The reason I’m tying these two together is that you point out in the metformin discussion that these drugs that are used to manage type 2 diabetes all have different mechanisms of action. They hit different genes and different gene expression patterns, but also diet and lifestyle play roles in modulating these different genes and different expression patterns as well, and therefore if we’re really going to understand how to personalize or tailor—because if you have a hundred type 2 diabetic patients you have a hundred different diabetic patients; they’re not all the same, they may have the same diagnosis, but they have different molecular etiologies and so you start asking, how do things like food, in that individual, affect mRNA expression and how that could influence the progression of what we later call type 2 diabetes? I think there is a theme of this series of articles that really is showing the transformation of medicine to open up the therapeutic window to the whole array of things that cause perturbations or have influence on gene expression patterns. ES: Yes, I love it. I think that’s exactly right and I think it comes down to what I was saying earlier in response to your characterization on the toxicogenomic stuff, that the RNA…not only is it a key driver and is playing a role in defining the processes that are carrying out functions in your cells, but it’s this amazing sensor, and so, again, the way your diet pushes the molecular states of the system and whether it is pushing it in a favorable protective way against disease or is encouraging disease, the things we are eating are perturbagens, just like a drug is a perturbagen, albeit food is more complicated. But the beautiful thing is through these advanced technologies we can understand the molecular response to the system in response to different types of diet, different food groups, different types of drugs. And again, back to the landscape map, we have the ability to project these different perturbations onto the same map to understand how are they connected? Which parts of the system are they hitting? Are they hitting those parts of the system in ways that promote or protect against disease? And they define the different subtypes, as you were getting at. They stratify patient populations into different subgroups because the underlying molecular mechanisms can be directly observed. So all of those combined does take you more towards molecular-based medicine/precision-based medicine that enables you to connect the molecular biology to the physiology. If there’s one thing we learned in molecular biology through the one-protein targeting approach, is that if you ignore the physiology as a system—if you’re not connecting the molecular biology with the physiology—your ability to impact clinical medicine is severely limited. So what I view in all of these maps that we talk about—these different connections—is the ability to directly link molecular biology to the physiology of the system, and through that have the right impact on clinical medicine. JB: So I hope everyone is catching this. This is a kaleidoscope of how a great medical/industrial complex changes overnight. This is absolute frame-shifting, perspective-changing, reference-point altering perspectives. I think this article that you published in Pharmacoeconomics in 2011 used a term that I find a very, very nice term because it ties together much of what we’ve been talking about, and that’s “integrated genomics,” elucidating the complexity of response to an environmental agent.[9] In this case you’re looking at complexity of a drug response, showing variation from person to person. We now know that CYPs, the cytochrome P450s from one person to another, may vary in their functional state by a factor of a thousand, three orders of magnitude. These are tremendously wide variations in biological response, processed by the same name enzyme based upon different both genomic SNPs and different expression patterns. So integrated genomics is really forming a new type of healthcare system that is this heuristic that really relates to integrated physiology, which relates to function. All of what we later call pathology, changes in time and space based upon the lens that we use to define it. What doesn’t change is the perturbations of function that ultimately give rise to the dysfunction that we later call disease. I think this article “Integrated Genomics,” which was the first time I saw you use that term in print, is a very powerful placeholder. Future of Medicine: Mastering Information and Integration ES: Yes, and I think maybe the one thing in the earlier days that drew me to the work you were doing in the great state of Washington was having the exact right kind of vision, that viewing things from that functional perspective and the need to integrate these different dimensions of data to sort of achieve a more comprehensive view of how functions were being impacted and whether they were being impacted in the right or the wrong direction. That was just the right…in my mind, you know, it was the right kind of thinking at the time, and it’s awesome to see that over the last decade since that time we’ve seen a lot of this play out on a level that is even surprising to me and I think the future of medicine is going to clearly be in those who can master this kind of information and integration, and that the patients who are being interpreted in that way are going have far better outcomes, and so that will keep driving this revolution. JB: Well, obviously I could go on and on ad nauseam because your work has been so expansive, but I think, being sensitive to your time, let me just bring this to close by saying that your studies, Eric, are quite remarkable because of their collaborative nature. I’m thinking of one of the studies, “Novel Loci for Adiponectin Levels and their Influence on Type 2 Diabetes and Metabolic Traits,” this multi-ethnic meta-analysis of 45,891 individuals.[10] So if people say there’s not enough data, I think you’re covering a pretty wide swath, and I look at the number of co-authors on this paper. I didn’t count them up but there must be over a hundred co-authors from different international consortia, so you’re really creating a new science. You’re not just creating a new paradigm, you’re creating a new way of gathering data, using data, analyzing data, and creating solutions to complex problems for which one-pill-for-one-ill is not going to work. Those models are over and a new model has to emerge, and you’re actually generating that new model. You’re looking at how genomics plays roles in protection or increasing the relative risk to macromolecular damage and how that relates to biological aging and age-related diseases. You’ve done collaborative studies on hypertension, breast cancer, ovarian cancer, coronary heart disease, diabetes, obesity, increased BMI and cardiometabolic disease, osteoporosis, and the list goes on. This model that you designed and you’re working on with your colleagues is a scalable model that is transformative in terms of health care. It takes a while to get with it and understand it when we come from a pill-for-an-ill mentality—you know, the antibiotic mentality of the past century where you had a drug that was so selective you could interrupt a specific differential effect in bacteria in terms of cell wall biosynthesis and you could solve the disease entity. This complex model requires a different stretching of our imagination, our thought, and our information gathering, but you’re doing it. You’re doing it in a very, very logical step-wise fashion by collaborating with some really broad thinkers, mining the human phenome so that we can actually use the Lille scores to look at these biological effects, and analyzing our exome and whole-genome sequencing so we can really apply these to clinical problems. I just want to applaud you and give you one small voice in the wilderness, here—an extraordinary “attaboy.” I just think what you’re up to is actually going to be the medicine of our 21st century that is going to reduce the burden of unnecessary disease and provide solutions to these complex chronic conditions by integrating the best information that we can use, which will be lifestyle, environment, diet, new drugs, new biologics, new ways of thinking about disease that empower people toward wellness. Thank you, is my answer. ES: Thank you, Jeff, for that very kind interpretation. You know, we always feel like we’re maybe not quite nailing it, and it is very complex, and there’s a long way to go, but I think we’re on the right trajectory and groups like yours as well and I think the future is going to play out that we’re going to improve outcomes in a dramatic way by generating and interpreting information in this fashion. JB: Well, we wish you the very, very best of success to you and your colleagues. Be it known that the functional medicine field is following right along with you and are some of your strongest cheerleaders. ES: Thank you, Jeff.  

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Bibliography

[1] Friend SH, Schadt EE. Translational genomics. Clues from the resilient. Science. 2014 May 30;344(6187):970-2.   [2] Schadt E, Chang R. Genetics. A GPS for navigating DNA. Science. 2012 Sep 7;337(6099):1179-80.   [3] Sanderson SC, Linderman MD, Kasarskis A, Bashir A, Diaz GA, et al. Informed decision-making among students analyzing their personal genomes on a whole genome sequencing course: a longitudinal cohort study. Genome Med. 2013 Dec 30;5(12):113.   [4] Waring JF, Jolly RA, Ciurlionis R, Lum PY, Praestgaard JT, et al. Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. Toxicol Appl Pharmacol. 2001 Aug 15;175(1):28-42.   [5] Schadt EE, Sachs A, Friend S. Embracing complexity, inching closer to reality. Sci STKE. 2005 Aug 2;2005(295):pe40.   [6] Mehrabian M, Allayee H, Stockton J, Lum PY, Drake TA, et al. Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits. Nat Genet. 2005 Nov;37(11):1224-33.   [7] Reitman ML, Schadt EE. Pharmacogenetics of metformin response: a step in the path toward personalized medicine. J Clin Invest. 2007 May;117(5):1226-9.   [8] Leonardson AS, Zhu J, Chen Y, Wang K, Lamb JR, et al. The effect of food intake on gene expression in human peripheral blood. Hum Mol Genet. 2010 Jan 1;19(1):159-69.   [9] Kasarskis A, Yang X, Schadt E. Integrative genomics strategies to elucidate the complexity of drug response. Pharmacogenomics. 2011 Dec;12(12):1695-715.   [10] Dastani Z, Hivert MF, Timpson N, Perry JR, Yuan X, et al. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. PLoS Genet. 2012;8(3):e1002607.

Welcome to Functional Medicine Update. We have what I hope will be a special treat for you this month, and that is, given where we have been going in the discussion of big data and the concepts of systems biology in medicine, and some of the extraordinary insight that we’ve had shared with us from luminaries like Dr. Lee Hood and Dr. Eric Schadt, I thought it might be very useful to just take a deep breath this month on Functional Medicine Update and really go back to basics, as they say, and do an issue on what I would call bridging big data with clinical practice.   The question is, how do these two…what might appear…disparate concepts intersect to improve the quality of patient care and to address the rising need for new ways of managing the dominant diseases that not only are plaguing the United States, but really are global in their prevalence. And in so doing, when we ask that question, it takes us into a very, very interesting reflective process as to what have we learned at this point in this complex field of systems biology in medicine that really we can, with some security, say applies directly to patient care in our advocacy for patient-centered medicine? So there is the focus of our attention in this issue. And fortunately, upon reflection, I think we can say there is extraordinary news to use that we can derive out of this evolving field, and it is my hope that by the end of this issue of Functional Medicine Update that we’ll have pinned down a few of the how-tos, as well as the whys and hows that relate to this emerging, extraordinary revolution that’s occurring in medicine.  

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INTERVIEW TRANSCRIPT

  This full-length issue features commentary by Dr. Bland without an interview Framingham Changed the Practice of Medicine, But How Long Did It Take? Let’s go back for a moment, if we can, and ask the question in historical perspective: how long did it take for the Framingham studies to gain traction and start to change medicine, and the concept of risk factor analysis become a dominant theme in health care? The reason I ask that question is it helps to give us some perspective as to how long it might take for these extraordinary revolutionary concepts of big data and systems biology in medicine to infiltrate patient care and ultimately transform medicine. Well, if you go back and study the Framingham work, you recall that it was in the late 1940s that advocates really set the tone for this large epidemiological prospective study to look at the relationships of people’s lives to their disease patterns. In fact, somewhere around 1948 to 1950 was the inception of the concept of this serial analyses epidemiological study that has now gone on for the better part of five-plus decades. It took until the 1960s, however, until the concept of the now very famous Framingham cardiovascular risk factors started to emerge and become general conceptual foundations of this new medicine related to prevention and risk factor reduction that was born out of these Framingham evaluations—these epidemiological associations between disease and lifestyle. And now we are all able to recite on demand the so-called Framingham cardiovascular risk factors—the hypercholesterolemia, the diabetes, the smoking, the obesity, the maleness, the age over 40, the hypertension, the risk factors that associate themselves with specific numerical increases in relative risk of an individual to have, within a certain period of time, a cardiovascular event. New Concepts Must Be Accompanied By New Technologies It was that concept coupled with the emergence of new technologies, particularly the fingerstick cholesterol blood test, that led to the emergence of this extraordinary development of pharmaceuticals that really were not there to treat an existing disease, but rather to prevent a disease, and I’m talking about the emergence, first, of lovastatin, or Mevacor, by Merck—the first marketed statin drug for lowering cholesterol that was delivered to the market. And then following on, the panoply of other pharmaceutical companies that developed their own statins, including what at the time was the most successful drug in the history of the pharmaceutical industry, atorvastatin, which as we know is Lipitor. These drugs—these statin drugs—were not really designed to treat a disease, but to treat a risk factor, which was hypercholesterolemia, which had been associated out of Framingham and then follow on studies with a variety of other kinds of epidemiological association and animal interventions and looking at the various effects of hyperlipidemia on vascular function. Eventually this became codified and made cardiology into a form of preventive medicine, because now the cardiology field had a tool called the statin drugs that they could use to not only treat disease but also prevent disease. As I said, if we really were to examine how long it took for that concept to get incorporated into standard of practice, it was somehow from the time of the late 40s—say ’48—into the middle 60s, so one could say 15 to 20 years it took to incorporate these concepts. Big Data is Here: The Steps Toward Change So with that as a background, let’s now talk about the bridging of big data with clinical practice—the present state that we’re in in this concept that we see emerging called systems biology and medicine. I’ll first talk about James Fries, once again. You probably recall in the extraordinary interview we had the opportunity to have with Dr. Fries recently. We talked about his landmark paper that appeared in the New England Journal of Medicine in 1980, the paper that really talked about aging, compression of morbidity, and natural death.[1] And then the follow on paper that he and his colleague, Anthony Vita, published in the New England Journal of Medicine in 1998 titled “Aging Health Risk and Cumulative Disability,” in which they were able to demonstrate, after 18 years from the publication of his first paper, that this concept of the way people treat their genes through their lifestyle and their activities of daily living—their diet and the way that they see their health patterns—translates into demonstrable improvements in both life expectancy and the reduction of disability associated with chronic disease.[2] Meaning, the age of first infirmity is longer in these individuals who self-select to participate in certain lifestyle habits (no smoking, control of weight, good nutrition, and regular activity). They have an age-to-first-infirmity that is much later than those individuals who just take the luck of the draw. So this concept that there is something within this interface between genes and environment that gives rise to the outcome that we call our health, which may seem like a very simple-minded concept, has a powerful potential influence on the trajectory of health and disease over the subsequent future. And then we ask the question: well, how does that actually get related to the individual? Is it a one-size-fits-all, or is it a personalized patient-centered approach, and what is emerging more and more through the genomic, or ‘omics, revolution that we’ve been seeing since the announcement of the deciphering of the human genome in 2000, is that the personalization of these messages that relate to how an individual’s genome intersects with their lifestyle and environment will improve efficiency of outcome and be more effective in reducing disease than a generic, one-size-fits-all message. And that is where the new medicine has an opportunity to be extraordinarily successful. I find it really interesting that as we learned from Dr. Fries in our interview with him that he was a rheumatologist that really started to consider disability in his patients with rheumatological autoimmune diseases, and how he could improve their function over time. And it was through that that led him to recognize that this construct of improving function in patients with autoimmune disease that had musculoskeletal disabilities and pain and various infirmities could cross over into many other conditions, and it wasn’t just specific to rheumatological diseases, but this concept of function really pertained to all diseases, and then it led him into the organ reserve concept and the maintenance of organ reserve by practicing the right types of things in one’s life through good diet, nutrition, exercise, proper environmental management, to maximize the opportunity for the genes to express the function of good health, rather than the alarm function that we associate with inflammation and disease. So I credit Dr. Fries as a rheumatologist as being a philosopher cum physician, really expanding his view and perspective beyond that of his own discipline to look at the impact that these concepts had on health care and medicine in general. In fact, there’s a wonderful article that appeared in the American Journal of Public Health in July of 2008, volume 98, page 1163 that talks about Dr. Fries as a healthy aging pioneer and how he really set the tone for this whole field over those years.[3] So now we are in 2014 and watching the effects of medicine that’s focused principally on diagnosing a disease and treating the outcome of the biomarkers of disease rather than implementing the Fries model of compressing morbidity and improving organ reserve. And as we start to look at those impacts they are pretty alarming. I recently read an article that appeared in Pharmaceutical Executive magazine titled “The Peace Dividend,” in which the editorial talked about the rising tide of type 2 diabetes, not just in the United States, but globally—talking about the epidemic increase in type 2 diabetes that’s occurring, not because the genes of these populations suddenly changed, but because their environment changed and the genes were receiving a new message: the western lifestyle of stress, and pollution, and poor quality diet that was then creating—almost overnight—an exponential increase in the appearance of type 2 diabetes.[4] He talks, in this editorial, about the Middle East, and I was a little naïve to the severity of this same problem (the epidemic of type 2 diabetes and obesity) in the Middle East. Saudi Arabia, for instance, recorded four hundred thousand deaths from diabetes last year alone. More than half of these victims were under the age of 60. And the cost of this is over 12 billion dollars in 2012, which is a small fraction of the nearly 120 billion dollars spent on arms purchases, I might add, but yet represent an extraordinary condition that is associated with the social and environmental aspects of the people living in these countries—their diet, their stress patterns, their environment, their pollution, and so forth. We’re starting to witness almost what I would call exporting chronic disease to the rest of the world as a consequence of the adverse impact—I would call it the hostile interrelationship—between these environmental lifestyle principles that have been part of the western lifestyle, with the genotypes of other cultures around the world. In the Lancet medical magazine, recently, there were a variety of very interesting papers that talked about improving health in the United States and progress and challenges. You know, although life expectancy at birth is now up to 78.7 years (which is 76 years for men and 81 years for women), one might say, “Gee whiz, that sounds really great. We’re achieving longer life.” However, if we start looking for age-adjusted death rates for the four leading causes of death—heart disease, cancer, chronic respiratory diseases, and stroke—we would say, “Yes, they’re falling, but we’re seeing early-age of morbidity, meaning, early-age of need for medicines and intervention.” So we might be misled into thinking that although the quantity of life is increasing the quality of life is equally increasing, and that’s not the case. Actually what we are seeing is a decrease in the quality as increasing infirmity starts encroaching on younger age. But we are able to keep people put together with baling wire and bubble gum—that’s kind of a little exaggeration, but we’re able to keep them still alive for longer periods of time, but the quality of life is not necessarily that which gives them the freedom to do what they want, the high functional capacity. So it’s this chronic disease incidence that is really the problem, the unremitting progression of chronic disease. And if we start looking at differences in health outcomes in the United States versus other countries, it’s quite interesting. In 2012, you probably know we spent 2.8 trillion dollars on health care, or about $8915 dollars per person per year, which accounted for a little over 17 percent of the gross national product. And these expenditures exceed those of all other high income countries in Europe, Asia, and North America. However, in World Health Organization grading of health outcomes, we’re down in the world. So, there is some interesting paradox between spending more, keeping people alive, but health outcomes are depreciated. It would suggest that maybe our model that we’re using is in need of revision. And so that leads into a very, very interesting article that just appeared in the Lancet, volume 384, July issue of 2014 titled “Prevention of Chronic Disease in the 21st Century: Elimination of the Leading Preventable Causes of Premature Death and Disability.”[5] And in this particular article they go on to say that basically what we are witnessing is an extraordinary increase in many of these chronic illnesses that are plaguing not just the late-age individuals who are at the terminal end of their life expectancy, but also starting to encroach on younger-age individuals and put a greater demand on burden in healthcare delivery systems. Things like kidney dialysis are going up dramatically. Ocular problems that relate to retinopathy are going up dramatically. Issues that are related to neurological conditions, particularly peripheral neuropathy, are going up dramatically. These are all associated risk factors with type 2 diabetes and with this insulin resistance pandemic that we’re seeing not just in the United States but in the world at large. And there’s no drug that has yet been developed that is going to beat back this rising tide. It requires a different model—a different approach. And so that has to do with making primary care patient-centered in the 21st century, and there’s another very, very interesting paper, in the Lancet again, volume 384, page 281—this is the July 26 issue—talking about how primary care should become really focused on managing through this gene-environment-lifestyle interaction, the individual risk factors that people have that can be modified in their phenotypic expression so that the outcome is reduction of risk to early-age-related chronic illness.[6] And I think this is something we all know. It’s intuitively obvious, but then the question is: what do we do about it? So that’s really the focus of what I want to talk about in the remaining time in this issue of Functional Medicine Update. It’s how we take this extraordinary knowledge that’s emerging from pioneers like Dr. Eric Schadt and Dr. Lee Hood and his colleagues and translate that into operational and executional practice policies that really create a different standard of care. The Patient Value Equation is Driving Information Availability, Technology, and Business Models Now one of the wild cards we have today that is going to help this, obviously, is the Internet. You know, we don’t have the patience, probably, to wait 25 years to get all of this implemented. Fortunately, thanks to the Internet, the compression of information and timeline that we can get things out more quickly to people and informed consumers can start making decisions for themselves and this is going to become much more a patient engagement process than it’s been in the past. In fact, the Affordable Healthcare Act, as you probably recognize, is pushing more responsibility back to patients to make individual decisions about health, and fortunately we have the benefit of the Internet to do so. Recently I read a very interesting editorial—actually it was an interview—with the present CEO of WebMD, David Schlanger, who was talking about how he views (as the CEO of WebMD) the future of this information service, and of course what they see is that the patient is at the center of their universe.[7] The patient value equation is what will drive WebMD’s business model over the years to come. In fact, there’s a very interesting discussion about how they view the dissemination of information and patient management technologies and interfacing with wearable devices and biometrics, and start accumulating all this information in real time and providing competent data reduction and information to the consumer about how to tune up their metabolism and how to personalize their program. They see their business model—as WebMD moves forward in the future—as being one of the providers of this type of what I would call personalized, lifestyle, medical information. Clearly this is just one of many companies that we’re going to see in the fray. We know now that Apple is certainly focused on this direction. We know of Google’s enterprise in this area. We’ve heard that Microsoft has had, certainly, interest in this area. And you will find many, many companies emerge to become the providers of health care through this big data analysis and real-time evaluation of how a person is functioning that will really transform medicine. It will provide tools for the physician to be able to better understand the warp and weft of their patients so that they can really design individualized programs for them rather than defaulting to medicine for the average. As Roger Williams said—and I’ve quoted this many times—“Medicine is for the real person, statistical humans are of little interest.” So I think this patient value equation component is going to be a very big part of this translation of big data into patient management. Three Fields Already Embracing Translational Medicine So that really relates to personalized medicine moving from the bench to the bedside. And so where is it happening right now? Where can we say that we’re actually seeing this translational medicine occurring? Really there are three places where it can occur, two of which we’re starting to see significant change in, one of which is already a standard of care. Let’s talk about those three areas. Personalized Oncology The first is oncology, and you can already see personalized oncology centers rising up around the country. In fact, virtually every cancer treatment center now has to have a genomics unit because we’re now seeing personal tumor typing becoming the standard of care in many cancer treatment centers, where the cells from the tumors are analyzed for their specific mutational injuries and then specific drugs that are influencing that mutation can be administered. I think Gleevec and Herceptin are two really good examples of drugs that have come out of the kinase inhibitor research that relate to specific mutations or specific genotypes that are responsive to certain drugs, making this patient-centered so that basically what you get is a drug cocktail patterned and personalized to your own genetic need for your tumor type. And interestingly when this has been done—and there are companies like Translational Genomics that are doing this commercially, and many others in the field—what is found is that many times off-label drugs (drugs that were approved for other uses) may be actually effective for individual types of tumors in a person, and they are not even really thought of as oncology drugs, but they have a unique sensitivity to that specific genetic type of tumor in that person. So this is truly a front edge of how we translate this concept of systems biology into clinical practice and start getting a personalized medicine to emerge, and we’re starting to see now that full human genome can be analyzed using the aluminum platform and that the FDA has now approved genome analysis as a medical technology test/device, it has really started to open the door for this to become a fairly routine type of analysis, particularly in oncology, but moving on into other fields as well. Now you recall this is built around an economic model to say that the analysis of the genome now is moving down to a thousand dollars or less, which makes it comparable to a standard kind of high-end laboratory test, and once this genome has been analyzed, it’s kind a universal test of all tests because you don’t need to analyze it again; you’ve got that record for the rest of your life. There might be an occasion somewhere in your life where—if you have an oncogenic event—you want to measure the tumor DNA to see if it’s mutated, but in terms of a record of your book of life that stays with you for your life—your human genome. Genetic Disease and Inborn Errors of Metabolism I think this is another extraordinary sign of major changes as we start seeing the thousand dollar genome being able to be routinely analyzed, and then the question is, once it has been decoded, or been chemically analyzed for the nucleotide sequence, then how is that information going to be developed into a personalized program that is uniquely applicable to the individual and can be done in real life, not in a lab animal? And that’s where, I think, the next area of application of personalized medicine is occurring, which is in neonatal inborn errors of metabolism (diseases of infancy). You know, we’ve always known about things like Tay-Sachs, Wilson’s, Gaucher’s, Fabry’s, megaloblastic anemias, things that relate to these genetic inborn errors that we’ve been searching for solutions to. And now, with better understanding of the variant forms in which these exist, and that they are not always expressing the same phenotypic outcome—use Down’s syndrome as an example. I mean, Down’s can exist in the phenotype in all sorts of different levels of severity. The more mild forms can be very well managed with good personalized intervention, again, a lot dealing with lifestyle: diet, nutrition, exercise patterning, visual training, intellectual stimulation, things of this nature. And so there are many different things—as we broaden the construct or the lens of medicine—that can be included within a personalized medical therapy other than just a pill for the ill—that we’re looking at a much broader platform of therapeutics that can be deployed to the personalization of even these genetic metabolism diseases of infancy. Chronic Degenerative Diseases The third area is the one that has the greatest obvious consumer application potential, but also poses the biggest issue of challenge, and that’s these common garden variety chronic degenerative diseases. This includes things like type 2 diabetes, and coronary vascular disease, and arthritis (or let’s call it autoimmune diseases), and dementia, chronic obstructive pulmonary disorders, and this wider range of chronic diseases is where the big pay-off can come from personalization, but it’s also where the challenge resides, because we recognize that not one of those diseases I just mentioned is the result of a single gene-inherited problem. They are not monogenetic; they are polygenetic. There is no gene for type 2 diabetes that sits alone in the book of life, or no gene for rheumatoid arthritis, or no gene for myasthenia gravis, or multiple sclerosis. These are polygenetic disorders that relate to genetic strengths and weaknesses and susceptibilities and tolerances that have to do with the environment, lifestyle, and situation that that person has found themselves in probably from the moment of conception on—so in utero, post-utero, and throughout their developing period. So this is a much more complex problem. But the nice thing about the problem is that even if we don’t answer at all, even first steps along the path of understand can produce some significant improvements in outcome. So I think that’s how we have to approach this knowing that there is lots left to learn—and probably will be for decades to come—but even at this point in time, with our relative infancy about the genomic relationship to these disorders we’re starting to pan some gold and starting to recognize how to better improve outcome and efficacy through personalization. And so that’s where I want to take this next part of our discussion. And of course we learned quite a bit about this from the extraordinary interview we had with Dr. Eric Schadt, who talked to us about this clues-from-the-resilient concept. You know, we often focus all of our concerns in our genomic information about the relative risk that we carry in our genes to a disease, as if we want to skirt all risk and stay at the sidebar of life because we might have gotten a bad gene somehow stuck into our book of life. But his point is that actually we should be looking at it from the other side and say, “What are the genes that we have that provide resilience?” Because if we didn’t have these resilience genes, none of us would survive to adulthood. So our genes—our book of life—has many, many strengths that we need to understand more as to how to optimize our relative expression of these strengths into the phenotype and not just skirt around through the fear of our “weaknesses” or our susceptibilities. And the way we understand more about our strengths or our resilience factors is to study those who are resilient: study the 90-, 100-, 105-year-old individuals who have lived a very healthy life, have probably gone through life not having an optimal environment at all times, but somehow are still functional and have had a great percentage of decades of their lives as disease-free, and ask, “What are those resilience factors that are within their genome?” I think this is going to be a very powerful part of our dialogue with regard to the understanding of our genetic inheritance over the years to come. Because right now when we get our gene analysis back it’s always about our relative risk to disease. Wouldn’t it be neat if we got an analysis back that was about our relative strengths in the prevention of disease? And then if we actually worked on these things and we supported them with the appropriate tools that are necessary for those genes to be expressed that we would become a member of the resilient family, not a member of the disease family? And I think that’s what Dr. Schadt is talking about and you recall he spoke to this very nice article that he and Stephen Friend, his colleague, authored in Science magazine in May of 2014 in volume 344, page 970, talking about clues from the resilient—how genetic information from individuals who do not succumb to disease points to new therapies and ideas about wellness, and it’s about wellness that we should be focusing our attention, not just on disease risk and the Framingham old model of risk factors.[8] The Role of Genetics in Chronic Disease Now with that said, let’s move now into how this all applies clinically. I’d like to take, for the sake of our discussion, the representative series of conditions that you are all familiar with that are dominant members of the chronic disease family. Let’s start with type 2 diabetes. What do we know about genetic susceptibility to type 2 diabetes and its companion phenotypic issue, which is central obesity (central adiposity)? Now we know that central adiposity is associated with a fairly easy-to-assess characteristic, which is increased waist-to-hip ratio? So when we see people who have waist-to-hip ratios that exceed 1.2 or greater now we start to consider some type of what we call central adiposity. This is where intra-abdominal adiposity starts to become a potential health risk hazard. Now you recall—just for the sake of review quickly—that we have subcutaneous fat which seems to have a differential impact on health risk from that of intra-abdominal fat (or visceral fat). There’s actually some evidence to suggest that subcutaneous fat is associated with relative reduction of certain health risks because it provides a reservoir to soak up excess lipid in a fairly neutral way without adversely impinging upon cellular signaling that we associate with disease. So we might say subcutaneous fat is a different personality in terms of health risk than intra-abdominal fat. It’s fat that sticks around our organs that is associated with what’s often called belly fat is that which releases various types of mediator substances directly into the portal blood, which then affects the liver and affects systemic circulation in such a way as to produce what I would call angry fat, or a chronic state of inflammation that some people call metabolic inflammation (or meta inflammation). It’s that condition that we often associate with the origin and the etiology of many chronic diseases, including, obviously, type 2 diabetes and vascular disease as well (or cardiometabolic disease). What are the relative risk factors, or what we might call genetic susceptibilities? Are there any specific genes that stand out? There have been many studies—what are called GWAS studies (Genome-Wide Association Studies) to try to identify in large populations specific SNPs that are highly associated with this personality archetype (this metabolic personality type of meta-inflammation)? I think it is very interesting that when you look at these GWAS studies, you’ll often find because of the large size of these studies, sometimes with thousands of patients that have had their genomes analyzed, that the relative significant correlation coefficients are extraordinarily strong between a specific SNP and a specific disease. And that is, I think, quite interesting because you might say, “Oh, now we have a solution to the problem.” But actually what has often happened is when you take that information and you try to direct a certain pharmaceutical for that SNP, it doesn’t prove to be very successful clinically, and the reason for it is that although there is a high association of that SNP with that disease, it’s also associated with many other genes. It doesn’t work just by itself. So correctly just one gene doesn’t solve the problem as it relates to these chronic illnesses. It’s a complex network biology disturbance, so I call this disturbed metabolism, and disturbed metabolism is a consequence like if you pull on a net: if you pull on one little frame of a net it distorts the whole net, it doesn’t just distort that one little area that you’re tugging on (that corner of the net). This is the way chronic disease really manifests in genealogy (in gene expression patterns)—disturbance or distortion of one portion of the web creates a perturbation in the web at large. So just changing one cell doesn’t change the whole of the pattern. However, with that said there are certain genes that do appear to be prominent in terms of their SNP connection to cardiometabolic disease and this metabolic inflammation, and those are genes that relate to mitochondrial oxidative phosphorylation, oxidative stress, energy economy (bioenergetics, in other words), which takes us back once again to an interesting confluence of how energy is produced within cells (like the endocrine beta cells of the pancreas or cells in the neurons that are highly rich in mitochondria, or cells in the heart, which, as you know, seventy-five percent of the volume of a cardiocyte is occupied by mitochondria, which are the energy powerhouse of the cells). I don’t want to say that all paths lead to enlightenment, but what I do want to say is that this mitochondria/bioenergetic connection to chronic disease across a wide range of clinical diagnoses, including diabetes and heart disease and dementia and even into inflammatory autoimmune diseases, is an interesting unifying principle, and what is it, then, that causes dysfunction with regard to these bioenergetic pathways? Well there are many factors that I guess we would tease out from a functional medicine perspective. There’s a very nice review paper on the genetic susceptibility to type 2 diabetes and obesity, the follow-up from findings over the last ten years of the genome-wide association studies. This appeared in the International Journal of Endocrinology in 2014 in the July issue.[9] I think it’s a very good overview of both some of the positive things that we’ve learned from these association studies, but also some of the things that demonstrate to us that these chronic diseases are much more complex than single monogenetic disorders. Will Drugs of the Future Address Genetic Expression Rather Than Symptoms? We need a systems approach to diabetes is really what comes out of this. The single drug for a single outcome, although we’ve got the DPP4 inhibitors, we’ve got the integrins, which are things like the GLP-1 analogs, we’ve got metformin, we’ve got the TZDs (the thiazolidinedione drugs for diabetes), we have insulin, obviously, sulfonylurea. So there’s a variety of different classes of diabetic drugs, but none of them really treats the disease, they treat the effect of the disease, and so the question really comes down to, can you move upstream from these through a systems approach to diabetes to actually improve the expression of genes that are associated with a downstream phenotype that we call diabetes? And that model is starting to gain some traction. I think this is the new “ah-ha” that is emerging out of this systems biology approach to health care that Dr. Hood and Dr. Schadt were speaking to in their concepts. In fact, in a very nice review article that appeared in Frontiers in Genetics just recently titled “Perspective: A Systems Approach to Diabetes,” the authors go on to talk about how the modulation of a variety of factors within the environment can improve genetic expression into the phenotype, improve insulin sensitivity, reduce demands on the beta cell to produce insulin, reduce lipogenesis and hypertriglyceridemia, and significantly reduce postprandial area under the glucose and insulin curve.[10] Here we’re starting to say maybe the treatment of choice for type 2 diabetes is not the single drug or poly-drug therapy, but rather this complex systems approach that we have talked about as personalized lifestyle medicine. Personalizing the Diet is Just as Important as Personalizing Pharmacology So what are the tools that we have? Well, fortunately we’ve learned quite a bit over the years. Dr. David Jenkins, University of Toronto, Department of Endocrinology/Gastroenterology, is the father of the glycemic index, which was the first approach to try to understand how diet puts demands on beta cell secretion of insulin and has an effect, then, on glucose metabolism. I think that that contribution to our understanding was the cornerstone of building this new view as to the extraordinary impact that diet has and the components of diet and the ingredients and the constituents within our diet on the regulation of insulin signaling and what’s called intracellular signal transduction that leads to GLUT-4 receptors, ultimately transporting glucose across cellular membranes and controlling mitochondrial oxidative phosphorylation processes and glucose metabolism. From the glycemic index was developed the glycemic load concept—that glycemic load is the postprandial effect of a diet or a meal—not just one food at a time, which was the glycemic index, but a complex meal—on the postprandial excursion of insulin and glucose. And what we found is you can start measuring glycemic load effects of diets and compare them from individual to individual, and we found that not all people respond to the same pre-prepared meal in the same way relative to their management of that glycemic load. So this gets into personalization. And people say, “Well what’s the best dietary approach? Is it the high protein/higher fat/lower carbohydrate approach, is it the Paleo approach, is it the Pritikin/Ornish approach high complex carbohydrate/low fat/high dietary fiber approach, or is it the Atkins approach, or is it the Sears approach of the Zone? What is the way that we should move on doing this?” And my answer is, “It’s probably all and none of those particular approaches. Meaning, the individual has their own response to the macronutrient composition and the physical nature of their diet. It’s built on their unique genotype. No Single Dietary Approach Will Work for Everyone So we shouldn’t lock ourselves into one dietary approach for all. Again, it’s just as dangerous as saying there is one drug for all—that statins work on everybody. We need to recognize there is extraordinary difference among response in individuals to the same diet. If you take the same, what we consider “good” meal—let’s call it the low-glycemic load, modified Mediterranean diet with no gluten—and you give that to a hundred people, all of whom have some degree of glucose intolerance, will you get the same result in all 100? Of course you don’t. You get a wide range. Some people have elevations of their postprandial glucose on that approach. And other people—in fact actually most people—will have fairly significant lowering of their insulin and glucose response from that kind of dietary approach. So I think what I’m trying to really advocate is that we should become students of all of these kinds of dietary studies that are relating macronutrient composition and the physical nature of an unrefined diet (or minimally processed diet) on insulin and glucose, and be able to harness those concepts for individualization of the diets of the patient. Not just say, “Here is one sheet we give to every patient and that’s the program you’re going to be on and—come hell or high water—that’s the answer to all questions.” I don’t think there is such a diet for all people that is the answer to all questions. But we do know there are certain dietary principles that are important, and minimally processed is one. Diets higher in plant-based foods is another (complex plant-based foods). The third is not to be overly attentive to the worry about excessive fats, but try to stay away from excessive levels of the long-chain saturated fatty acids. These are the fats that easily solidify at room temperature (become solid). I think we want to move more to the oils and fats that are liquid at room temperature. These are the mono- and polyunsaturated fats of differing families, omega-6 and omega-3. I’m not saying that a little bit of saturated fat in the diet is going to create serious problems. I’m just saying that if we were to look at fat overall, a significant percentage of it should be that which is liquid at room temperature if we were to isolate it. I think that this also falls into things that we call medium-chain triglycerides. Those are lower melting than the long-chain fatty acids that I described earlier (the saturated long-chain fatty acids). Your medium-chain triglycerides or medium-chained fatty acids like propionic, butyric, caprylic—those particular fatty acids have a different physiology. They are more easily regulated by mitochondrial oxidative phosphorylation than these long-chain saturated fatty acids. So I think there are certain principles that we can employ, recalling also that dietary fiber is a very important component for flattening out the postprandial glucose curve and putting less demand on the beta cells to secrete insulin, and specific soluble fibers—there’s a whole range of these—that can also serve as prebiotics, so you get a double-barrel benefit because they also can be food for friendly bacteria and we know how important the microbiome is for modulating insulin sensitivity, so you want a friendly microbiome to give friendly communications between insulin and your cells. So, you get a double-duty benefit from use of certain prebiotics: arabinogalactans, large fructans, various types of what we consider non-metabolizable carbohydrate that’s often called plant fiber that’s soluble. These are all beneficial for smoothing out the glucose postprandial curve. We also recognize that there are forms of starch that can be more resistant to immediate breakdown by amylase enzymes, and this resistant starch slows the release of glucose into the blood and therefore has a salutary or beneficial effect on flattening the postprandial curve. There are all sorts of dietary variables, right? And by the way, when I talked about fiber and starch, I’m obviously talking about plant foods. You don’t get a lot of fiber and starch in animal products. That’s why I think that this concept of a very high plant-based diet makes very good sense on many levels, particularly if we were going to talk about the additional benefit that phytochemicals have, which we’re going to be discussing. And also, minimally processed, plant-based foods bring a lot of good vitamins and minerals with them, too. Magnesium obviously is part of chlorophyll—a very important regulator of glucose tolerance. And we have things like biotin, which we know is extraordinarily important, and thiamin, which is very important—in fact, these can be given in supplementary doses to improve glucose tolerance in a person that has insulin resistance. We know that therapeutic doses of biotin can be helpful. Similarly with thiamin. Benfotiamine is a derivative or an analog of thiamin, which has been found also to be very useful for improving glucose tolerance in individuals who have insulin resistance. So we know there are a variety of nutrients in the mineral family. Of course it’s legendary, the Klaus Schwarz work done on chromium and its effect as a glucose tolerance factor in helping to regulate insulin sensitivity. So you get these substances in higher levels in minimally processed plant-based foods. Again I want to emphasize, let’s not lock ourselves into a religion about diet; let’s look at the dietary principles that give rise to improved insulin sensitivity. What I have been summarizing is a very interesting paper that is titled “Prevention and Management of Type 2 Diabetes: Dietary Components and Nutritional Strategies.” This is authored by Frank Hu and his colleagues at Harvard School of Public Health, who is a world leader in this complex understanding of diet and its relationship to chronic disease. This article appeared in the Lancet, volume 383, page 1999 in 2013, so I think this is another very interesting citation that helps us to understand the important role of how you personalize an approach towards these chronic diseases.[11] Dementia: Examining the Question of Genetic Risk versus Lifestyle Factors Let’s move from there to brain aging and dementia, because we now know from Suzanne Craft, who you probably recall was one of our clinicians of the month that talked about the interrelationship between insulin resistance and hyperinsulinemia and dementia and that it cuts across both diabetes and dementia. In fact, there is now evidence to call this type 3 diabetes with Alzheimer’s disease. So there is a greater and greater need for us to recognize a cross-relationship between the comorbidities of type 2 diabetes and dementia, and there is a very interesting question as to whether all of this dementia is really just a consequence of our inheritance: did we just inherit in our genes the risk to dementia? And of course there is some relative risk that’s associated with certain genetic susceptibilities. The one that is most commonly talked about is the apo-E double 4 allele with Alzheimer’s disease. It’s interesting, however, to note that the apo-E4 double allele is also associated with a significant increase in risk of cardiovascular disease, which suggests that they share common etiological pathways of some aspect of oxidative injury and inflammation. And so this is an example where a double E4 requires a very vigilant review of diet and lifestyle. And these are individuals that are very sensitive to high saturated fat intake. In fact, the evidence would suggest that they translate high saturated dietary fat quickly into oxidative inflammatory injury when they carry this double E4 allele. So these are people that need to rigorously exclude high saturated fats from their diet. They need to be very assiduous about the higher complex carbohydrate/higher fiber/low glycemic load-type approaches with higher amounts of plant-based protein and improved intake of plant-rich polyunsaturated fatty acids. For most individuals, however, the genetic linkage to dementia is fairly low. And in fact there is a very interesting paper that just appeared in the Current Opinions in Psychiatry in March of 2014 in which they looked at the Swedish twin studies.[12] As you probably know, because of the socialized medical system and medical record-keeping in Sweden and in other Scandinavian countries, that there is very good ability to interrogate identical twin and health information over the course of living. And there is no better control, from a genomic perspective, than your identical twin. And so the question is, what’s the concordance of diseases like dementia between pairs of identical twins? The answer to that is that there is very little concordance for mild-to-moderate dementia between pairs of identical twins, suggesting that the environment plays a very important role. So there’s not a high hereditability of the mild-to-moderate forms of dementia. These co-twin control studies support the role of mid-life lifestyle factors as being the most important determinants for cognitive aging and late-in-life dementia. I think this is a very important point for us to keep in mind. Pathology-Supported Genetic Testing And so when we start looking at the pathology-supported genetic testing and treatment of cardiovascular disease and Alzheimer’s disease, it leads us into new conceptual frameworks. Now what did I just say? Let me stop for a moment. I said, “pathology-supported genetic testing.” Now what’s that mean? What it means is that having a gene that you ascribe as a risk or a susceptibility factor to disease, does not mean that that gene is expressed into the phenotype of the disease. It just means it’s there. It doesn’t mean it’s expressed. So how do you know if it’s expressed? You do the expression by looking at the phenotypic markers, don’t you? Which is the pathology-supported genetic testing. It’s the combination of genotypic testing and phenotypic testing. So, for instance, you might say you have a gene SNP for a specific form of interleukin 1-beta, which gives you an increased susceptibility to inflammatory disorders. But if that gene is not expressed, then you will not see in the phenotype higher levels of inflammatory mediators, like TNF-alpha, or IL-6, or hs-CRP. You need the combination of understanding the relative susceptibility, which is your genotypic analysis, and then the pathology-supported phenotypic marker to see if it’s really expressed. It’s a combination of the two. So it’s not just what’s in your genes alone. It’s what is expressed in your genes that’s really the most important feature, and that is a very important takeaway from what we’ve learned in this whole field of genomics or ‘omics (how genomics gets translated into the ‘omics of proteomics and ultimately into metabolomics into phenomics). This article that I’m really speaking to, which is in Metabolism of Brain Disorders and was published in 2012, talks about genetic relationships between cardiovascular disease and Alzheimer’s disease.[13] Because it is now recognized that individuals who have CVD in middle life have a higher incidence of Alzheimer’s disease because they share co-variable susceptibilities for the etiology of both diseases. So, what do we know is one of the major susceptibility factors? Well, I talked about one: apoE. Apo-E4 double allele is a major risk factor. It’s not a death sentence, but it’s a susceptibility factor that one has to manage by rigorous lifestyle intervention. The other one that you’re familiar with is methylenetetrahydrofolate reductase (MTHFR). MTHFR also plays a very important role in relative risk to both cardiovascular disease and Alzheimer’s disease, and we know, don’t we, how to manage a polymorphic change—say a CT677 SNP—for MTHFR. We do so by increasing folate intake. Now, the best way of increasing folate, based on evidence that’s been published over the last few years, is 5-methyltetrahydrofolate versus folic acid itself. 5-methyltetrahydrofolate will not mask, by the way, vitamin B12 deficiency, which folic acid will. So you won’t get alterations in MCVs with 5-MTHF. My suggestion whenever you use 5-methyltetrahydrofolate as your folic acid, is that you also just for security give concomitantly methylcobalamin. That’s a methylated form of vitamin B12, or at least hydroxylcobalamin. And you also give pyridoxine and you give betaine. Betaine is a methyl transfer agent. They should be given in combination. So what would be a good formula that one might consider? It would be a formula that would deliver a thousand micrograms of 5-methyltetrahydrofolate, something on the order of 5 milligrams of pyridoxine, something on the order of 100 to 500 milligrams of betaine, and it would deliver something on the order of a hundred micrograms of methylcobalamin or hydroxylcobalamin. That’s kind of in the range of what I would consider to be early-stage therapeutic range, not into heavy hitting therapeutic range. You might use, in some cases, several thousand milligrams of 5-methyltetrahydrofolate for a real resistant MTHFR polymorphism, but I think as a get-started cocktail of nutrients, that’s a fairly good range of balance between the various members of the 1-carbon pathway (the nutrients that influence the transfer of methyl groups through s-adenosylmethionine). And you probably recognize that a surrogate marker in the phenotype for this concern is methylmelonic acid. Methylmelonic acid can be evaluated as well as homocysteine, so those two analytes that you can measure in the blood, homocysteine probably being the more common of the two in terms of routine clinical evaluation, both give some evidence and allow to interrogate the sufficiency of intake of those nutrients that are associated with the folate cycle. You might say, “Well what would be considered a level of homocysteine that would be of some concern?” I think when you get above 11 nanograms per mil of homocysteine that you’re into a range of concern. We also are concerned about homocysteines that are too low, and there are examples. You know, the edge of the bell curve on both sides is an indication of dysfunction in metabolism, so if you get homocysteines that are below 5, then you probably also are experiencing defects in methyl transfer. So too low a level of homocysteine or too high a level of homocysteine is a surrogate for further evaluation of the sufficiency of these pathways that regulate 1-carbon methyl transfers through s-adenosylmethionine. A very, very critically important pathway for neuronal and cardiovascular function, for hormonal function because this is the methyl that is used for metabolism of adrenalin into noradrenalin, so we start getting into very important regulatory pathways that are associated with the MTHFR (the methylenetetrahydrofolate reductase pathway). And as you probably recall, this is the fundamental best-understood area of nutrigenomics presently because we recognize that something on the order of 30 percent of the population at large has a mixed MTHFR genotype between the wild type and between these SNPs that are lower activity transfer agents for folic acid methylation. We also recognize that about ten percent of the population has the double allele of MTHFR CT677, so that would be your double hit, which has even a more serious adverse impact upon methyl transfer reactions. So the MTHFR 677T polymorphism contributes to increased risk to both vascular disease and dementia. There is a variety of very important studies that have been published over the last few years that show this relative risk factor, one of which appeared in the Journal of Neurological Science in volume 294, page 74 that shows the co-variable relationship of risk to these two diseases—vascular disease and dementia, and of course vascular dementia—and the appearance of this particular SNP, and also how this can be modified through augmentation of those specific nutrients that are necessary to overcome this genetic kind of weakness or block.[14] A companion SNP in this pathway of methyl transfer is the enzyme catechol-O-methyltransferase, or COMT. We recognize that COMT polymorphisms also can contribute to increased risk to these disorders, and also contribute to increased risk to things like fibromyalgia pain and other chronic pain syndromes, and this probably has to do with the effects COMT has with catecholamine metabolism. So what do you do if you have a slow COMT? A SNP that slows your COMT activity? Again, activating your levels of s-adenosylmethionine, which is the cofactor, helps to drive that equilibrium of a sluggish COMT to completion. So how do you do that? Again, you come back to augment the intake of these folic acid active nutrients, which is 5-methyltetrahydrofolate, methycobalamin, pyridoxine, and betaine to improve the conversion to SAM, which then, as a cofactor for COMT, helps to drive COMT to improved methyl transfer reactions. And it’s been shown that the COMT gene polymorphisms are associated with chronic human pain, particularly in fibromyalgia and some of these other chronic pain syndromes. This is in Pharmacogenetics and Genomics in volume 22, page 673, that made these associations.[15] So we know, then, there are certain genotypes that do have increasing relative risk based upon their SNP presence, but we also recognize that you can overcome many of these chronic SNP associations by augmentation of your nutritional intake. This recent advance in understanding of how nutrition plays a role in driving genetic sluggish enzymes to completion is really a consistent concept with that of Dr. Roger Williams and that of Dr. Linus Pauling years ago. You probably recall that Roger Williams has this genetotrophic theory of disease in the 1950s and Dr. Pauling talked about orthomolecular medicine. Similar concepts of using these natural precursors to help improve enzyme function in the individuals with specific genetic limitations. And in fact, there is a very nice paper that appeared in the Proceedings of the Nutrition Society in volume 71, page 581, talking about how nutrition can be utilized in therapeutic levels to modulate the expression of genes that are associated, then, with improved brain function/brain health, and treat things including potential mental disorders like schizophrenia.[16] This, of course, is Abram Hoffer’s work that we were so fortunate to have as a clinician of the month years ago, now deceased. But Dr. Hoffer was really one of the founding fathers of the field of orthomolecular psychiatry and the use of things like niacin and pyridoxine and ascorbic acid for the management of certain neurological diseases. Modulation of Gene Expression by Phytochemicals Now since then we’ve recognized that plants contain substances that help to augment this function as well. These are called the phytochemicals associated with xenohormesis, and you recall we had Dr. David Sinclair from Harvard, who was discussing the xenohormetic concept with us as it pertains to various plant phytochemicals that can modulate, favorably, gene expression, and he talked specifically about epigallocatechin gallate from green tea and he also talked about curcumin from turmeric and he also talked about resveratrol from grape skins and peanut skins and how these are phytochemicals that xenohormetically modulate the inflammatory pathway and things like the sirtuin pathways. The sirtuin pathways are NAD-dependent reactions that relate to genomic structure and allow opening up of the genome so certain regions of it can be read. And the person who has probably done the most work in this area as it relates to neurological diseases and phytochemicals is Dr. Mark Mattson at the National Institutes of Health. He has a wide range of papers over the last ten years that really talks about hormetic phytochemicals and neurological disorders, one of which is a very interesting paper in Neuromolecular Medicine titled “Hormetic Dietary Phytochemicals” and talking about the role that higher levels of intake of these particular phytochemicals like curcumin can have in reducing the risk of neurological degenerative disorders, including Alzheimer’s and Parkinson’s disease, and that these modulate pathways like the nuclear regulatory factor 2 antioxidant response element pathway (NRF2-ARE), which is a fundamental pathway that is engaged in mitochondrial function that has to do with both detoxification and protection against oxidative stress.[17] And that these particular phytochemicals—curcumin, epigallocatechin gallate, and resveratrol being three examples—are very powerful in their ability to help regulate the intercellular signaling that regulates the NRF2 expression and the antioxidant response element expression  

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Bibliography

[1] Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980 Jul 17;303:130-5.   [2] Vita AJ, Terry RB, Hubert HB, Fries JF. Aging, health risks, and cumulative disability. N Engl J Med. 1998 Apr 9;338(15):1035-41.   [3] Swartz A. James Fries: healthy aging pioneer. Am J Public Health. 2008 Jul;98(7):1163-6.   [4] Looney W. From the editor: the peace dividend. Pharm Exec. 2014 Jul;34(7):3-4.   [5] Bauer UE, Briss PA, Goodman RA, Bowman BA. Prevention of chronic disease in the 21stcentury: elimination of the leading preventable causes of premature death and disability in the USA. Lancet. 2014 Jul 5;384(9937):45-52.   [6] Making primary care people-centred: a 21st century blueprint. Lancet. 2014 Jul 26;384(9940):281.   [7] Comer B. CEO profile: the patient value equation. Pharm Exec. 2014 Jul;34(7):34-39.   [8] Friend SH. Schadt EE. Translational genomics. Clues from the resilient. Science. 2014 May 30;344(6187):970-2.   [9] Basile KJ, Johnson ME, Xia Q, Grant SF. Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies. Int J Endocrinol. 2014;2014:769671.   [10] Kussmann M, Morine MJ, Hager J, Sonderegger B, Kaput J. Perspective: a systems approach to diabetes research. Front Genet. 2013 Oct 16;4:205.   [11] Ley SH, Hamdy O, Mohan V, Hu FB. Prevention and management of type 2 diabetes: dietary components and nutritional strategies. Lancet. 2014 Jun 7;383(9933):1999-2007.   [12] Lee T, Sachdev P. The contributions of twin studies to the understanding of brain ageing and neurocognitive disorders. Curr Opin Psychiatry. 2014 Mar;27(2):122-7.   [13] Kotze MJ, van Rensburg SJ. Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer’s disease. Metab Brain Dis. 2012 Sep;27(3):255-66.   [14] Liu H, Yang M, Li GM, Qui Y, Zheng J, et al. The MTHFR C677T polymorphism contributes to an increased risk for vascular dementia: a meta-analysis. J Neurol Sci. 2010 Jul 15;294(1-2):74-80.   [15] Tammimäki A, Männisto PT. Catechol-O-methyltransferase gene polymorphism and chronic human pain: a systematic review and meta-analysis. Pharmacogenet Genomics. 2012 Sep;22(9):673-91.   [16] Dauncey MJ. Recent advances in nutrition, genes and brain health. Proc Nutr Soc. 2012 Nov;71(4):581-91.   [17] Son TG, Camandola S, Mattson MP. Hormetic dietary phytochemicals. Neuromolecular Med. 2008;10(4):236-46.   [18] Vojdani A, Kharrazian D, Mukherjee PS. Elevated levels of antibodies against xenobiotics in a subgroup of healthy subjects. J Appl Toxicol. 2014 Jul 18.

Welcome to Functional Medicine Update, September 2014. As you know, we’ve been putting together a small, intensive mini-course on the nature of change of medicine, going from a disease-care focus to a healthcare and wellness focus. Big data and systems biology in medicine is going to revolutionize this transition. To understand the context of this I think we have to go back and say, “What is medicine doing today in the chronic disease area?” How is it actually managing people who have diagnoses of various chronic diseases? I think the best window of understanding to that question is to look at what drugs people are using today to manage these symptoms of chronic disease. How do they relate to the business of medicine, which is focused on these disease endpoints?   Examining Big Pharma’s Role in the Treatment of Chronic Disease It’s interesting. If we go down the major Big Pharma companies and what their blockbuster drugs are, we start with the number-one-ranked pharmaceutical company in the world today, which is Novartis. Its top-selling drugs are Gleevec, and Diovan, and Lucentis. So you’re talking about cancer, and you’re talking about metabolic disease. Pfizer is Lyrica, which is surprisingly their number-one-selling drug now—almost four-and-a-half billion dollars of annual sales. As you know, it was approved originally for fibromyalgia syndrome and now there are other kind of chronic complaints for which it is being used. And Enbrel, at 3.7 billion annual sales for arthritis.   Then we go to Roche: Rituxan, so that’s oncology, Avastin (oncology), and Herceptin (oncology). So we would say that right now, with the acquisition of Genentech by Roche, you have pretty much transitioned the company into an oncology company. Sanofi: Lantus, Plavix. Lantus, as you know, their insulin delivery system—seven-and-a-half billion dollar sales for diabetes, principally type 2 diabetes. Merck is the number five largest company, with Januvia, which as you know is a GLP-1 agonist, and Zetia for cholesterol management (a cholesterol-binding agent), and Remicade for arthritis (a TNF-alpha-blocking agent).   Then you go down to cases where you’re looking at companies like Lilly with Cymbalta, and its effects on behavior and mood (antidepressants). And then number ten, is AbbVie, which is the pharmaceutical spin-off from Abbott Laboratories, with their giant blockbuster, ten-point-six billion dollar annual revenue drug that has replaced now the statins as the number-one-selling pharmaceutical in America, and that’s Humira. Humira, which as you know is another TNF-alpha-blocking agent drug/biologic for arthritis.[1]   Earlier Screening and Intervention Will Shift Focus from Disease Treatment to Wellness So you can start seeing just from that list that the medications that are being used are really treating the end-stages of various types of chronic illness by blocking signals or modifying various endpoints in the cycle that are related to disturbances in metabolism. So what do we do if we want to move earlier in the intervention—move away from the disease-based model to the wellness-focused model? We need to screen earlier, and as you probably recognize, there is now a very strong motivation through the genomic testing and the proteomic testing. I call it the new biology in medicine—the systems biology—to start taking broader swaths of data on individuals that are not yet diagnosed with disease, so we might call them early symptomatic, or people at relative risk.   And so we go from the general concepts of risk from the Framingham study, like risk to heart disease (smoking, maleness, age after 40, obesity, diabetes, elevated cholesterol, elevated blood pressure) to more broad-based genetic risk factors and proteomic risk factors. And there is a very interesting article that appeared in the New England Journal of Medicineearlier in June of 2014, volume 370, page 2442, in which the authors talk about what are the criteria for screening an asymptomatic person for genetic risk to a later-stage disorder?[2]And of course, this is a very dramatically changing playing field, because we’re not only now looking at diseases that are life-threatening and have serious genetic implications, like that of the BRCA1 and BRCA2 mutations that give rise to very significant increased risk to breast cancer and ovarian cancer, but we’re now looking at a variety of families of genes whose SNP forms increase the relative susceptibility to virtually every one of the chronic age-related diseases, and how we use that data, and how we manage, then, patient risk in this medical environment that really rewards more crisis care and is less focused on both emphasizing and reimbursing for early-stage chronic care.   Which then leads us to the more recent article in the New England Journal of Medicine titled “Genotype Phenotype Correlation.” The subtitle is “Promiscuity in the Era of the Next Gen Sequencing.”[3] As you probably know—as we’ve spoken about over the last several years in Functional Medicine Update—we’re witnessing a remarkable breakthrough in technology as it relates to the genomic sequencing and analysis. Whereas the first genome to be fully sequenced was over a billion dollars of expense (well over—more like two billion), the cost of sequencing the genome now is being driven below a thousand dollars, which makes it like a standard expensive lab test. And so we’re seeing an extraordinary number of people now using the Illumina technology (the next generation genomic sequencing technology) who are having full genome sequences done in which this big data is now available for interrogation. And that is really creating a much more interesting and robust opportunity to connect together these genomic patterns that are buried within our legacy, with that of increasing risk and incidence in the phenotype of chronic illness. And so what we’re really saying is that the whole exome sequencing using this next gen technology is getting us to understand much better the correlation between our phenotype—these biomarkers that are associated with early-stage assessment of susceptibility or early-stage disturbance associated with chronic illness—and our genetic information and how that gets translated or expressed into function.   Now what is that going to do as it becomes more prevalent in medicine as a theme that will kind of bend the curve and really produce a different way that a doctor looks at their patient, and a different way that a patient has expectations for the health care that they are going to be delivered? That’s this concept of promiscuity in the area of next generation sequencing that is described in the New England Journal of Medicine article, really saying that we don’t know exactly how this is going to shape the forces and the technology and the business of medicine, but we’re very sure that it will shape it. It’s going to come out of collaborative studies that have been done in individuals who are not yet ill, who are on certain trajectories towards chronic illness, that you’ll be able to make these genotype/phenotype correlations. And in fact that will come out of what is called the n-of-1 trial, not just the large, statistical, average, randomized, clinically controlled, placebo trial, but n-of-1 trials in which the person is a control against her- or himself.   When we talk of n-of-1, this is a clinical trial in which a single patient is the entire trial. It’s a single case study, but it’s being done under the principles of good data selection, good data collection, and appropriate data analysis. This trial is one in which the patient is evaluated against themselves after either the placebo or the experimental control system. This type of study has given rise to a new way of looking at the development of therapeutics, which is called patient-guided therapy, which is how you assess the dose and response in an individual patient by using their own response against themselves rather than against some average recommendation of dose-per-body-surface-area or for some other physiological group average parameter (like a number—like get the number below a certain level with a drug).   So this patient-guided therapy is really kind of more of an n-of-1 procedure. If there is an uncertainty about the specific approach or dose to use of a therapeutic, the n-of-1 trial can be very, very useful. And the n-of-1 trial is going to be extraordinarily useful in determining this genotype/phenotype correlation with an individual. So the kind of group aggregate understanding—cohort analysis, where the big data sets might emerge to be of clinical interest and not just lost in the noise of the average—can start to be seen.   The Pioneer 100 Project: Step One of an Extraordinary Longitudinal Study And of course, this is the foundation of an extraordinary study that is now ongoing out of Seattle, Washington at the Institute for Systems Biology that you heard Dr. Lee Hood talk about, which is called the Pioneer 100 Wellness Project, in which a collection of a vast amount of data, including genomic, proteomic, and sociobiologic data is being accumulated on a hundred apparently healthy individuals, from which, then, correlations will be made between secondary biomarkers (things that are in their phenotype) and genomic information. I’ve been very privileged to be a part of this project, as I’ve mentioned to you, from its beginning—one of the hundred participants. And we’re very fortunate to have this month as our key opinion leader, the director of this program, Dr. Jennifer Lovejoy, who is going to talk about how this n-of-1 concept is embedded within this large, big data study, from which hopefully will emerge information that connects certain cohorts of genotypes together (or patterns of genes together) with certain phenotypic outcomes that relate to early understanding of chronic illness, that then intervention using lifestyle management/lifestyle medicine that is personalized to the individual can have dramatic and positive impacts upon their health outcome.   This is a very, very different strategy than a drug trial in a randomized, placebo-controlled fashion for looking at the effect against a single endpoint with a single drug. What we’re really looking at here is complex interaction of the individual in their genotype with their environment to produce an outcome in their phenotype, and then how that correlates with, in this case, 99 other people who are going through similar n-of-1 experiments. A very different strategy that is going to focus on the development of a “health” care industry and not just a disease care industry. A new methodology is needed to build this health care science base, which is the discussion that we’re going to engage in with Dr. Lovejoy as it relates to this Institute for Systems Biology-sponsored, Hundred-Patient Pioneer Wellness Program.   So with that as an introduction I hope you are as excited about this as I. It fits together wonderfully with the previous discussions we’ve had with Dr. Lee Hood, the founder and director of the Institute for Systems Biology, and Dr. Eric Schadt, who told us from the work that is being done at his institute about how systems biology is manifesting in our understanding. I think you will find this as a next step in really seeing how the tire meets the road and how it’s going to bend the curve in health care. Now with that, let’s turn to Dr. Lovejoy.  

INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jennifer Lovejoy, PhD Vice President, Wellness Programming Pioneer 100 Hundred Person Wellness Project 411 1st Avenue S, #600 Seattle, WA 98104 www.pioneer100.systemsbiology.net We’ve been very, very fortunate over the last couple of years to have some extraordinary luminaries who have expanded our understanding of what this universe of health care is going to look like in the 21st century. No surprise this month again, I have to say. We’re very fortunate to keep that precedent going. Dr. Jennifer Lovejoy is our expert, our key opinion leader this month. She comes with an extraordinary background. I’ve had the privilege of knowing Jennifer now for more than ten years, I believe. She comes with a biology background—a zoology BS from Duke University, and then on to get her Masters and ultimately her PhD in physiological psychology at Emory and then did a postdoctoral fellowship in endocrinology and metabolism at the school of medicine at Emory. Her publication record, her teaching, her leadership I guess we would say would focus on the areas of eating, eating disorders, obesity, bariatrics, metabolic disease, lifestyle management across a wide, wide range of experiences, both as past dean of nutrition and exercise science at Bastyr University, as an executive director in the weight nutrition program for a company called Free and Clear that was ultimately acquired by Alere, where she made contributions to the development of extraordinary patient management/patient interactive programs for weight, diet, and lifestyle management and other lifestyle habits. Most recently—and that’s what leads us into this interview—a role that I’m extraordinarily interested in, not only intellectually and academically, but I’d have to say personally because I happen to be one of the participants in this program under her and her team’s leadership, and that’s the Hundred Person Wellness Project that’s being overseen by the Institute for Systems Biology in Seattle. That name should mean something to all of you listeners, knowing that we had the privilege of interviewing Dr. Lee Hood, the founder and president of the Institute for Systems Biology. They’ve advanced, as you heard from Lee, this extraordinary, innovative and first-step-forward project to assemble complex data sets from a hundred individuals to really track aspects of their network of physiological function interfaced with lifestyle and their environment, diet, and tease out, then, what we really mean as “personalized” from the data that is being collected on these individuals over the period of them being tracked. As a participant in this study, I’m one of the one hundred in this initial pioneer project, which as you probably know and we’ll hear more from Jennifer, leads into maybe a thousand, and then ten thousand, and ultimately a hundred thousand subjects in this 21st century Framingham study that you heard Dr. Hood talk about. What I’ve learned so far…it’s one of the most exhilarating and exciting ways to see a lot of what we talked about up in the blue sky of theory get translated down to the ground in terms of really how it infects individuals, and in this case the individual happens to be me and it’s been really a very, very fun project to date and we’ll talk more about that, both from I’m sure my personal experience but more importantly in terms of the experience of the hundred people that have been involved. Jennifer is sitting on top of this large data set. Dr. Lovejoy, welcome to Functional Medicine Update and thank you so, so much for your time and being with us. JL: Oh, yes. Thank you for having me. I’m very glad to be here. JB: Let’s jump right into this. You know, this is a very ambitious and exciting project to try to track this complex web of function, the interaction of genes with environment in a hundred different people. Let’s talk about what gave birth to the project. How has it kind of been organized? It sounds like it almost has to be a military operation in terms of its execution to manage all the variables, here. Give us a little of the landscape as to what led into it. Study Goal: New Metrics for Wellness that Will Revolutionize Healthcare JL: Well, it certainly as you know evolved out of Lee Hood’s vision for P4 medicine—what’s really going to revolutionize and he believes democratize health care in the future. It’s a huge vision and it has to start with a small pilot study, which is where the idea for this came from. The things that I think are driving this pilot for the hundred that as you say we’ll ultimately take forward into the thousand and ten thousand and beyond are fascinating because it’s really not only looking at the scientific discovery and the potential for the scientific discovery is just phenomenal and very, very exciting. The things that we can discover will be new metrics for wellness, which are very much needed because we don’t have a whole lot of concrete metrics for wellness, early transitions to disease (much earlier than the healthcare system can detect them today), but then on the personal side, really optimizing wellness for the individual in an extremely personalized way, something that you’re very passionate about, I know. That integration, I think, of the scientific vision with the personal optimizing health for an individual—really seeing life-changing stuff, and we’ve seen some life-changing stuff already in the study, which is so exciting. I think it is really what drives this project and what’s going to carry us forward. We’re learning a lot. This, in many ways, is a feasibility study, and that’s how it was conceived, I think, that we just need to know who our partners are going to be in this, what vendors are we going to use, what sort of operational things and logistical things do we need to learn, as you say, for this military operation, and how do we analyze the big data. So all of those things have been a huge learning experience, but very much with the foundation that we want to change the way health care is done to make it more effective, more personalized, and more proactive. JB: Wow. Congratulations. Let’s go to the structural parts of this. How did you actually sit down and take these laudatory and expansive goals and get them designed into a program that can be implemented? Organizing Data in Quadrants: Genetics, Microbiome, Quantified Self, and Functional Laboratory Testing JL: Well I’ve been with the project since January, so I have to certainly credit the team because some of this work was done before I joined. The concept of the study started being discussed last fall, and thinking about what was actually going to be done, how we would recruit, what would go on, going through the IRB process to get it approved as a formal clinical study with the appropriate human oversight. All of that was in the works when I joined the project, but for me it is taking the huge picture and trying to figure out what are the elements that can be expressed? So much has been done with functional medicine and the matrix, and you take this massively complex web of interactive systems and try to draw it down into its fundamentals. One way that we did that was to look at the different sectors of information, if you will—the quadrants—that we’re going to be collecting data in. So we have genetic data; we’re doing whole genome sequencing on everybody in the study, so not just the SNP analysis that is often done. We’re looking at microbiome data, which is a very unique and novel aspect of the project that we’re just starting to get data back on now and it’s very, very fun. It’s obviously early science. We don’t know a whole lot. There’s not a whole lot of research out there to base things on, but it has been quite interesting to look at the results from that. We’re doing quantified self—kind of what I call personal trait data. That’s everything from having people wear a Fitbit activity monitor to tracking their weight to personality tests and medical history (family and personal medical history)—all of those things that really drive the trait or quantified aspect of it. And then we have the functional laboratory testing. We’re doing a mixture of what I consider to be conventional classic laboratory testing (chem panels, that sort of thing), but also a lot more novel functional testing around, particularly, nutrition. We’ve very focused on nutrition in this project because obviously that is an entry way into optimizing wellness and things that tend to go wrong early on in the transition to disease often relate to a person’s diet, so we’re really focusing in on a lot of those nutritional variables, but a number of other things as well. So, bringing together and thinking about those four broad quadrants of data is one way to take the huge cloud of things and start to simplify it. Then, as the data started coming in, even just with the laboratory work, which was the first data set that we got back, it was still a lot of data. It was hundreds of data points, and so I started thinking, how can we sort of organize this, just to talk about it and make sense, and for the coaches to be able to talk to participants about…you obviously can’t talk about 200 or 250 data points on a single 30-minute coaching call so how are we going to narrow it down? From there I think it went for me into clusters of actionable opportunities. So we look at a cardiovascular cluster, a pre-diabetes cluster, a nutritional insufficiency cluster. Things just started to fall out as I looked at patterns in the data to say, “These things tend to cluster together.” And sometimes people have more than one, sadly; we see that as well. Everyone in the study—I can say 100 percent of people in the study—had at least one actionable item just out of their lab work. One of the questions we had going in was, are we really going to find actionable stuff (this is a pretty healthy group for the most part), and the answer is yes. We are finding actionable things, and of course as we go on now with genetics and the microbiome and quantified self we’re finding more and more things that we can do, so I think we can put that one to bed. Everyone can optimize their health. JB: Yes, as a participant I can absolutely attest to that. It’s been very, very illuminating for me. I just got back the gut microbiome information and it just opened up a whole new window of understanding about my own physiology. And then, of course, the other things that you mentioned. I would suggest that you have recruited, I think, probably a hundred thoughtful people about their health, so this maybe a very interesting select group of the total wash of the population. In fact, you might talk a little bit about who are these hundred? How did you recruit them? Are there any characteristics of the psychographics or demographics of this first group of pioneers? JL: Yes, these people truly are pioneers. They are individuals who really were part of the social network of the leadership of this project (Lee and other people who have been involved with the team)—individuals that Lee and the team knew were interested, passionate, intellectually curious, and would want to be part of this, would want to be on the ground floor. Not just be part of it, but be on the ground floor. They are definitely an interesting and not really typical Main-Street-America group because we’re getting their input and value from the things that they’re giving us feedback on, that they’re teaching us about in the project as much as the other way around and that’s really part of the feasibility and operational aspect of this: What’s working? What’s not working? How can we take your experience as a participant (for these hundred people) and really apply that to be able to grow the project the way we want to in a better way going forward. We were looking for people that we knew would not hesitate to give us that sort of feedback. JB: You mentioned the complex array of data points. How many data points do you estimate your project will ultimately acquire, just to give our audience some sense as to what we mean by big data? So Much Data: How Much is Appropriate to Share with Patients? JL: Well, we know there are billions of data points just in the genome alone, so we’re definitely in the billions. We’re doing metabolomics, so that’s up in the thousands. Proteomics, which can obviously expand also quite large into the thousands. It’s very big. It’s well into the billions. Now, obviously again we’re not sharing all of that information. We can’t share all of that information with individuals because what would you possibly do with it? Even a hundred data points is overwhelming for an individual, which is really where the behavioral coaching becomes so key, and the clinical oversight. And we do have a study physician that we’re working with. We have a medical advisory board that is helping us to really think about this clinically and behaviorally: how do you give the most appropriate information? How do you help people to prioritize the information that is most likely to optimize their health? The excitement about big data is on the analytic side. Really as our analytics team starts diving in to the much larger data sets than just the top layer that we’re right now sharing with participants, that’s where the discoveries are going to come from and ultimately those may be things that we share with participants. We might find a new variant that is very important for wellness—that might be a wellness metric, or we might find something in the metabolomics that links with a blood value and all of a sudden we’ve got something that’s really a new story that we can tell people that’s going to come up in priority, compared to where it might be today when we just don’t have the data to back up talking about it. The big data aspect of it is definitely very central to what we’re doing. JB: So I think this is a really new science method. I hope our listeners are catching this because in the past we always think about the randomized, double-blind, placebo-controlled trial. This is an n-of-1-type study, but—by the amassing of many n-of-1s—it has a group effect that gives other opportunities for discovery that you would not have anticipated, so you’re getting a twofer, basically. The twofer is, number one, you’re giving personal information of that person against themselves as a control, and number two, you’re aggregating all of these n-of-1 data to create the opportunity to discover cluster, as you pointed out, that might emerge as dominant themes that would allow us to take an overwhelming amount of data and get it down into buckets that are manageable in terms of aggregate group cohort intervention. I think this is very different than a traditional type of drug trial or epidemiological survey. Was this part of your design from the very beginning? Because it’s even a little different than Framingham in that respect, I believe. New Statistical Techniques Needed for n-of-1 Trials JL: Oh yes, absolutely. And I have to say that it was a new one for me. I had spent my entire research career doing randomized clinical trials or classic observational epidemiologic studies, so the idea of an n-of-1 trial was new and not something that I had really given a lot of thought about, and part of the audacious vision, I think, of this is we not only have to integrate and develop the medicine and the practical applications, but a lot of the statistical techniques that are going to be needed in order to do this type of n-of-1 trial need to be developed and will be developed, I’m sure, by leading thinkers in that field. That’s a piece of it that is needed as well. I think for me it just made fantastic sense to approach it this way. Having done clinical trials, the notion that taking a large population, randomly assigning them, and then looking at aggregate average responses of the population…it tells you something—I mean, it’s not completely without value—but to really get at the kind of personalized medicine and optimized wellness that we want to get to, it’s not going to get us there. I had directly experienced this in many cases in my own clinical trials that I conducted earlier in my career, where there was always one or two or three or more outliers that just didn’t behave the way the rest of the population did, and that’s fascinating. Those were always the ones who were the most interesting: why did this happen? And that’s true for behavioral trials and lifestyle trials as well as drug trials, where obviously that’s been clearly shown in many kinds of drug trials. I did primarily more behavioral and lifestyle trials, but you still see it—people who don’t respond to a lifestyle intervention, or respond in a completely opposite way. You can have people exercise—I was talking to someone about this the other day—and their V02 max actually gets worse based on their genetic profile and other things. So thinking about those sorts of things and trying to consider doing that as an aggregate measure in a clinical trial, I really understand the benefit of this approach and really trying to move medicine forward. JB: Let me talk about one things learned, and this is going to seem, probably, like a “duh” to you being an expert in physiological psychology and the whole nature of how the mind and the body interface. So my observation was wearing the FitBit and doing this telemetry with blood pressure management is kind of a real-time, 24/7, reinforcement of your engagement with your health. Even if the information in and of itself is not always exactly practical, it introduces you to your function in a different way and makes it very intimate and sentient. It’s not like somebody else’s data. It becomes your life, your response. If we could do continuous glucose monitoring, that would be like wow. You would know every stress and how it affected your endocrine system. Have you seen this as a general theme in the participants when they start measuring these things in real time on themselves? Wearable Technology: Accountability Appears to Drive Motivation JL: Absolutely, and it tends to kind of build. It builds motivation and then people want to track more things. The FitBit has been really well-received (just doing that sort of tracking). People find that it keeps them accountable, which is very important, because it’s right there—you’re looking at it, you’re seeing how many steps, how many minutes of activity you’re getting, how much sleep you’re getting, if that’s an area that you’re working on. That accountability is often what drives motivation and then as you say it is reinforcing. When you have a good day—when you get your 10,000 steps—you feel good at the end of the day because there’s that sense of accomplishment about it. I think it really is that sort of reinforcement and accountability that honestly drives the quantified self movement in general—that people just start getting so fascinated about tracking these aspects of themselves. And the more they can do that and get the detailed sort of thing, I think in the future we are going to have the kind of devices that can measure not only blood glucose, but give us continuous heart rate monitoring, we can look at heart rate variability, which is an area I’m very interested in, and other things that we’ll have the technology to do that we don’t quite have today, but then I think it will really take off even more. Just what we have right now, with a very basic monitor, is giving us some great accountability and motivation for people. JB: Have you found any pushback at all at this point? Now again, we have to contextualize this—that these hundred pioneer people are maybe uniquely self-motivated—but is there any kind of feedback you have gotten of “Well, this is too much work” or “I really didn’t want to know that much about myself” or “Gee whiz, it’s easier just to wait until something happens before I do anything about it.” What kind of feedback have you gotten on that side of the equation? Engagement is Variable, Even in a Compliant Study Group JL: Yes, by and large this is a pretty compliant, pretty engaged group compared to an average clinical trial. But that being said, we do have somewhere between maybe ten to twenty percent of the group that is just not particularly engaged. They are not particularly doing anything. They might have shown up for their baseline blood draw, but we’re having a hard time connecting with them beyond that. So there is variation, even within this group, in terms of their engagement in the project. The other thing on the flip side of that that has been very fun to see is that we had people who at the start of the project, as far as they knew they were healthy, and their goal for really joining the project (that they told the coach on the first call) was “I’m just curious.” So they didn’t particularly have any sort of motivation about actually changing lifestyle, changing health. That all changed when they got their first set of bloodwork back and the coach could actually talk to them about variables that were not perhaps in range, that might be leading to something, and it was like flipping a switch in people just to say “Wow. I didn’t think I had anything to work on. Now I see that I really do and that I can be healthier,” and so they are very, very motivated, and that’s been a lot of fun. JB: So let’s talk a little bit about your coaches because I think this is a very important part of the human side of this whole concept. I think you have done a tremendous job. Sandy is a brilliant coach. Tell us a little bit about how you selected those people, what your expectations are for them, and what they have learned so far as it relates to their engagement with participants. Coaching is Key in a Study on Lifestyle Change JL: It’s a great question, and I have to say that Sandy, for the hundred, is our only coach. We have one coach and she has done just an absolutely amazing job. Sandy’s background is she is a registered dietitian. She also has a pretty broad base of knowledge of functional medicine coming in; she was trained at Bastyr. We had a lot of discussion early on about who should the coaches be for this project? Should we go with Bachelor’s level kind of lay health coaches, which is what we did at Free and Clear? Or should we use nurses, should we use naturopathic doctors? I mean, we really discussed the whole gamut of what would be optimal background in terms of the coaching. We settled on registered dietitians. We’re feeling pretty good at this point about that decision because of the emphasis on nutrition and the ability that dietitians have to coach to a broad set of lifestyle change. We’re not practicing medicine, and we don’t want to do anything that might appear to cross the line of practicing medicine, so it really is about lifestyle, it’s about health education, but with the sophisticated knowledge that a highly trained registered dietitian brings to the mix. How we’re going to scale that going forward is something that we’re having active discussions about (what we might do from here on out). It is an awful lot of information, and it takes a very special person—a very sophisticated person—to be able to integrate not just lab value, which most RDs are obviously used to working with, but getting into gut microbiome and genetics, which is fairly foreign to many allied health folks anyway, and MDs as well honestly. I mean, it’s just not an area that’s very familiar to people. That’s one of the big discussions we’re having right now, about how do we scale that? But I think that choosing to use RDs as a coach was a really good way to go. JB: Well, and she—as you said—is very special in her broad-based understanding of the connection among many of these buckets. Let’s talk about the buckets, here, for a second. I’d like to get maybe, for our listeners, a little more granular. You talked about the four sectors, so let’s start with genomics and the new next gen analyses. Tell us about how you approach this concept of genomic evaluation and where you think the greatest richness will be, at least at this time in our understanding, for clinical payoff. JL: How do we take this huge thing and organize it into logical patterns that we can actually coach to? We have three broad areas. We’re looking at medical genetics and we’re using the American College of Medical Genomics and Genetics list of 56 genes, so that’s the serious inherited genes conditions, but the ones ACMG says, “These are medically actionable and people should know if they have these.” So that’s our medical genetics side. We’re looking at pharmacogenomics, so that is how your genetics influences your response to drugs, and we have about 35 genes that we’re going to be reporting to people on, mostly focusing on drugs that are more commonly used. That definitely will be valuable, I think, for people to know about their response in case those things come up. But the area that I think is going to be the most fruitful and the most interesting is what I’m calling behavioral genetics. This is really the nutrigenomics. It’s your response to nutrients, your ability to absorb and metabolize nutrients, so things like your vitamin D receptor status. If you have variants there we know that you don’t absorb vitamin D as well. If you have a variant in the MTHFR that regulates folate absorption, we know that is something that is very common and very actionable. We have a number of genes, there, that relate to a number of areas that will be very familiar to listeners, I’m sure: detox, and absorption, and so forth. That’s going to be big. We’re also looking at genes that impact the response to exercise, so we can tell people, in a broad-based way, whether their genetic propensity leads them more towards being an endurance, kind of aerobic, type athlete versus a power or strength athlete and how they can use that in their own training to motivate them. And then lastly we’re looking at weight loss, genes that impact obesity and the ability to lose weight, and the response to diet from a weight loss perspective, which is an area that, with my obesity research background, is of considerable interest and I think the science has really come along far enough that we can begin to make some ideas there that get away from the kind of hit-or-miss approach that we currently take with weight loss diets of, you know, “Well, try this. If that doesn’t work, try this. Low carb. Do whatever.” This is really going to say, “Your genes say you’re most likely to have a beneficial weight loss response to this type of diet, so let’s start there.” There still may be personal or other biological variables that impact your response to it and it may not always work a 100 percent for everyone, but we think we’ve got a much better shot and I’m very excited to see how that plays out in our study. JB: That’s really exciting. So when you assemble this information, clearly this is another example of picking a little window of clinical usefulness out of this broad array of data, for which, once this data has been collected on the whole genome, you can come back and reassess that information as time moves forward with new advancing knowledge. It’s a one shot; you don’t need to have multiple lab tests over the course of your whole life, so it’s like the universal lab test (to have your genome sequenced). When people ask you about this, how do you communicate that? Because that information will be in the database forever, presumably. If they say, “I don’t really want all my information to be known to the world,” how are you handling the privileged information? JL: Right. It is a huge, huge part of it, and probably the area, when we were recruiting people for the study, that there was the most concern about, was the genetic information. So we’ve taken a lot of steps, both in terms of the electronic security as well as personal security. Pretty much once people enter the study they are known to us as a seven-digit number, which sounds rather cold and impersonal, but as far as from a data perspective that’s really the safest way to do it—that we distance any personally identifying information and everything gets analyzed and reviewed in terms of an ID number that cannot be linked back, at least electronically, to the data. And obviously the coaches know who they are talking to and what they are doing there, but that has been a big issue. The other thing that we’re doing…I mentioned the different types of genetic data that we’re talking about. Everyone is going to get their behavioral genetics and their pharmacogenomics data, but people will have a choice of whether or not they want to receive their medical genetic information. We know already that some of our participants just don’t want to know. If they have inherited a risk for a really serious disease, they don’t want to know. So we are giving people the ability up front to either opt-in or opt-out of receiving the medical genetic data. And we’re even getting a little bit more granular than that because we know that there are a couple conditions in particular that people are worried about: breast cancer (the BRCA genes); the Alzheimer’s risk, which is really more of an association, it’s not a single gene inheritance like BRCA; and Parkinson’s disease risk. People could opt in to all of the medical genetics except for those three, or they can take it all, or they can take none of it, so that’s how we’re kind of handling people’s concern about getting information. I don’t feel that there is anything in the behavioral genetics or pharmacogenetics that is going to upset anybody, so we’re just saying you’re going to get that and it’s probably going to be really enlightening and really interesting, and hopefully fun to see, you know, “Wow, I had no idea that this was going on.” But the medical stuff we get can be psychologically pretty challenging for people and some people may just not want it, so we’re giving them that choice in the study. Microbiome Analysis: Determining Actions Based on Diversity Score JB: Very, very wise, I think. So let’s move to bucket two, which is the microbiome. As I said, I just had a chance to evaluate my own data. I think it’s very nice, the way that this data is being done. This is not a full microbiome sequencing. It’s more speciation, so you’re looking at the Bacteroides and the Firmicutes and other families of bacteria, and the way that the data is presented I really thought was very good because your data from your own sample is presented in the context of everybody else’s in nomogram (not obviously naming people, but you can pick out your data in the sea of other people’s data), so you kind of get a sense as to how you fit into that community of those other 99 people, and it also allows you to see what species diversity you have in your microbiome and also the ratio of Bacteroides to Firmicutes, which is emerging more and more from the literature to maybe be a risk factor for various steps of metabolic disturbances. How are you handling this, because this for most people is probably a very new concept? JL: It’s very new, and of course the science—what we can say about it—is fairly limited because there haven’t been a whole lot of studies done on it. We are focusing, in terms of the actionability part of it, primarily on the diversity score, which is an indication of essentially how many different species of bugs you have in your gut. And so what is really consistent in the literature, even at this point, is that low diversity is bad. No matter what health condition, what metabolic condition, whatever you’re looking at—if you don’t have a richness of…the target I would say is probably somewhere between a thousand and twelve hundred (at least) different species in your gut, it’s almost like you don’t have the resilience, environmentally, to deal with what might be coming to you in your lifestyle, whether that’s an illness, whether it’s a drug, whether it’s a dietary change—that lack of diversity seems to really raise the propensity to illness. We are focusing in our coaching on individuals who have a low diversity score and looking at ways that they can improve that, and there are two main ways. One is to really shift the emphasis to a plant-based diet. The bugs in the gut really love plants, and that’s really going to help to improve the diversity. And then we’re also recommending a prebiotic supplement to help the beneficial bacteria to really take hold and to build that diversity because that’s also been shown, at least in randomized trials, to help to increase diversity. We’re focusing there. The Bacteroides and Firmicutes ratio is a little bit too conflicting right now in the literature to say a whole lot about should you be trying to boost one or the other? The one “ah-ha” for me was looking at the hundred people and how big a range it was even though these are folks who are fairly similar in terms of lifestyle and diet and where they live and so forth. We have a huge range in that ratio of those two predominant families, so that was quite an interesting thing. We have seen a couple of interesting things around the families, though, which is that apart from those two primary ones that were looking at the ratio, there’s a couple of minor ones that show up sometimes, and in people who have those we found one individual who had a high proportion of bacteria that are associated with inflammation (research has shown that it is associated with inflammation), and it turned out that this particular person has very high inflammatory markers in the blood and had no idea why. Great lifestyle, great diet, slim, no inflammatory processes going, and so when the coach was first talking to her about her blood results and they were talking about the inflammation and had no idea what was going on (and neither did her doctor have any idea what may be going on), and then we found these high levels of proinflammatory bacteria in the gut microbiome. Now, obviously n-of-1. We can’t draw a firm conclusion about that, but I think that’s where we’re really going to start getting some interesting clues from the microbiome data in particular. JB: That’s really exciting. Talk about getting into the systems biology concept of health and wellness. That’s really exciting. So let’s move next to the quantified self bucket because that can be huge. That can be very expansive. Tell us a little bit about how you’re collecting that data and what you’re doing with it. JL: We have a mix of questionnaire data. We have the personality tests, the medical history, and those are very important, certainly on the analytic side because we think those are going to be important predictors of things long term. But on the coaching side, the personality questionnaires, in particular, have been helpful too, so that the coaches can kind of tailor their discussions with people based on what they are most likely to be behaviorally responsive to. So that has been good. And we’re tracking changes over time in things that are just going on. You know, “Did you get a cold?” “Did you travel?” We had someone who went to Africa for six weeks. So those things potentially can have a very big impact on the things as we are measuring them every three months and looking at fairly short term changes in measures. And then we’ve talked a bit about the activity tracker and how that is monitoring the activity and sleep, giving us feedback and giving participants immediate feedback on how they are doing it. We’re using that in the coaching calls primarily when we see that someone perhaps could benefit from, say, more activity, and the tracking data that we are collecting clearly shows that they’re not getting very much activity, and so the coach can weave that in to other things if their blood sugar is high, or whatever it might be, to talk about the benefits of perhaps getting a little bit more and looking at it over time. And then you have your own accountability because you can see it yourself, too. JB: So that takes us to the fourth bucket. As I have read recently, there are now expected to be in excess of 25,000 biomarkers that people have done some work on. Clearly that’s an overwhelming number. What did you select out of that wide array of things that you wanted to look at and some of these functional, maybe nontraditional tests? The Value of a Broad Nutrition Blood Panel JL: We’re doing a broad nutrition panel that looks at both urinary markers of nutritional metabolites as well as blood markers of metabolites, of actual nutrient values of environmental toxins. I wish we had more of an environmental toxin screen, but we were taking too much blood. We had to cut back. We couldn’t do everything we wanted to do. I think that is definitely giving us a lot of information and that panel alone is, I would think, over a hundred different values that we’re getting out of that. We’re doing a fairly deep metabolic syndrome panel that includes the inflammatory markers as well as measures of leptin, insulin, adiponectin, glucose, and so forth. That’s giving us some very rich information and we do see that about 35 percent of individuals are actually prediabetic in the study, so we’re finding some good things in that panel, and the inflammation, of course, is such a fascinating area and very hot topic that we’re now linking to all kinds of other things and so that’s providing some rich information for us. JB: And when I looked at my own data I thought it was very, very fascinating to see the interrelationships between things like heavy metal analysis and some of your parameters relating to your fractionated lipids because you’re doing nontraditional lipid gradient evaluations, which I think is very helpful (particle number and so forth), and also looking at the interrelationship that has with some of these more sophisticated markers of fatty acid composition because you have also done a very nice laboratory detailing of fatty acid intake. There are some patterns, I’m sure, that will emerge out of the interrelationship of those variables. JL: Absolutely, and we’re also doing four-point salivary cortisol and DHEA to look at the adrenal axis and that has been very interesting to relate to other parameters as well as just to look at in individuals who, again, may be fairly healthy in general but have some abnormalities in their diurnal pattern of cortisol or have relatively low DHA for their age. JB: So clearly we could spend a day, I’m sure, and you’d still have much more to say about this program, but I hope this is going to be a point on the curve of us checking in with you as you move forward, because this is going to be an “ah-ha” experience both for you as a leader in the group, but also for the individuals within the group. There are going to be all sorts of “ah-has” down this path over the months to come. So if you were to grab your sound byte, and I’m sure you give many talks about this and people want to know what’s the bottom line, how do you summarize where you are in your discovery? Do you feel that the effort is worthwhile? Do you feel that the pilot study is starting to obviate the value of this kind of work? Do you think it will ultimately help us to engage in a 21st century Framingham that will be focused on personalized biometrics? What’s your takeaway? JL: Absolutely. I would say that we are in the very, very early stages, and that we’re just beginning. So last night, we just started getting genomic data back, and I started to look at related individuals who had similar family histories but came out with very, very different recommendations from a personalized lifestyle approach to what you would do based on the genetic variants they had, their bloodwork, their BMI, and their self-tracking information. So it was the first time that I had personally been able to take things from multiple quadrants and really start to tie it together in a way that let me see how powerful this is going to be for people, and we’re just beginning to get there. I think this is going to grow. We’re going to learn more and more as we go on, and I have absolutely no doubts that it is going to really change the way we practice medicine and the way we do science. JB: We know that the system that we call the healthcare system, which is economically modeled, is really a disease-care system. The incentives are all around disease care. We take some of the brightest minds of women and men and we train them to become really good disease diagnosticians and treatment agents and we build infrastructures around disease. And by the way, I’m not saying that this is wrong. I’m just saying that this is the focus that we have seen over the last 70 or 80 years in the development of the medical-industrial complex; it’s focused on disease. Now we’re starting to witness, through this work, the potential infrastructure based upon a quantifiable science that would be a health-focused industry. So we would have some balance between the professionality of disease care with the professionality of health care. Do you think that this will create an economic transition in emerging new businesses, similar to what we saw happen with, say, Microsoft and Apple as we went into to the age of personal computing, in which prior to that people said, “Who wants to have a personal computer? I mean, that’s like for IBM to do.”? Do you see some analogy, here, as to what this data will spawn in terms of transition in business? JL: Absolutely, and that really is a huge part of Lee’s vision as well, that the future of the business of health care is really going to be much more focused on wellness and on prevention and that the economics of it will be more driven by that and much less driven by the disease care that we have today. I think everyone sees that the healthcare system is broken. We just can’t keep focusing on disease. I saw a report from the CDC that 40 percent of Americans are predicted to develop type 2 diabetes, now, and that kind of thing cannot be sustained in the healthcare system we have today. We have to prevent. We have to focus on wellness, and I think that’s where the economic growth is really going to be in the future. JB: Well maybe a good close would be to turn the tables around here for a second and ask you, is there anything you’d like to ask me as a participant in your extraordinary project? Anything that I—as a person who has really valued from watching how this all works at the personal level—might share with you? JL: Yes, so can I get two quick ones? JB: Sure. JL: First, have you had any “ah-ha” moments from the data that you have gotten so far (and I realize it’s only a piece of the data, we haven’t really hit all the quadrants yet)? And then, what motivates you to stay engaged with behavior change and a big data project like this? JB: Yes, I think number one, the answer is yes. You know, I probably have had a little bit of a benefit that most of the Pioneer 100 people probably have not, and that is I have been able—because of having a laboratory—to do, every six months, my own blood chemistries for the last 15 years. So I had a pretty good trajectory of understanding of a whole series of secondary biomarkers as to where the aging Jeff Bland was going. But I have to say that coupling that together now with the other things that you have done, and for me, although most of this information was familiar at some intellectual level, to personalize it and start seeing it as my information—this is once again the n-of-1—has really helped me to focus more tightly in on things like managing stress, which I think has been a very interesting personal discovery because I can see how my variables are influenced by the warp and weft of the life that I select to lead. So I think that that has really been a very, very good “ah-ha” lesson reminding me that we’re living in real time. Our physiology is responding in real time, and it’s not just the big variables; it’s the small stuff that gives rise to the big stuff. I think that has been a very, personally, maybe reemphasized story. You know, a number of years ago, I actually gave, at one of the IFM meetings, my whole blood profile to the audience, before and after. A lot of people were very alarmed that I would be so audacious as to show my own stuff up there, but I found that it was actually very empowering for me to show my before and after, after I had gone through a six month program. And I think this program that you’re orchestrating here is really the next step up. More information produces more knowledge which produces more opportunity for action. So that would be my long-winded response to question one. Question two—the reason that I think I continue to be ever increasingly excited, is not only because like many people that volunteer for research projects because they want to help science and the want to help discovery, which I believe will occur out of this data set, but they also really are just very intrigued about how their bodies are operating in time, right? Having been in this field over 40 years and watched its evolution from Roger Williams and the concept of biochemical individuality to Linus Pauling with the orthomolecular concept of disease, I really see these are fulfillments of a lot of what our pioneers were speaking about 50, 60, 70 years ago, even going back to Archibald Garrod at the turn of the last century who was the discoverer of the first inborn error of metabolic disease. He talked about “in the future” maybe we would see this kind of thing occurring. So this is a little Watson and Crick-ish. This is really a transformational moment in the history of knowledge and how it can impact on people’s health and wellness. It’s almost like a calling. It’s really, really for me extraordinary to be a participant and I just feel very fortunate to be part of your 100, so that keeps me engaged. JL: Great. Well, we’re delighted that you are part of it. JB: Thank you. I want to thank all of you on behalf of the functional medicine community and what we’ve been trying to do in Functional Medicine Update for 33 years. This is the embodiment of that, and I think it follows so nicely. Lee Hood’s discussion with us and then talking with Eric Schadt about the fact that you need to go beyond GWAS to really understand this phenotype/genotype connection, and now into this, which is where the tire meets the road for individuals. Jennifer, thank you and you’re an eloquent spokesman for your project. I can see it’s in great hands. We look forward to checking in with you months in the future to see how things are evolving. Thanks a million. JL: Thank you.  

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I’d like to welcome you to an exciting month of Functional Medicine Update. This is the first in what we will have as a three-part series on this advancing epidemic that we call insulin resistance, type 2 diabetes, metabolic syndrome, hyperinsulinemic-driven health issues. And as you probably recognize, this is the issue of our age. It’s the metabolic disease age that we live in as a consequence of the messages that our genes are getting from our environment—our diet, our lifestyle, our stress patterns, things that are being exposed to us as a consequence of the chemical industry which now are being recognized to have subtle effects on mitochondrial bioenergetics, which is a form of internal energy production that relates to things clinically like insulin sensitivity and glucose transport and the ability to process and utilize energy effectively in the body. This concept of insulin resistance, type 2 diabetes, hyperinsulinemia is a very, very interesting concept related to the functional medicine model, because what we’re observing is a transition from a view that a disease is caused by a specific singular mechanism, or a specific singular infection with an organism, to this pleiotropic model—this model where there are multiple different routes to get to the same disease that we call a diagnosis, and in this case the diagnosis is often type 2 diabetes. But the route by which a person got to that diagnosis may be very different from individual to individual.   So this month, which is the first in this three-part series reviewing this extraordinarily important area, both where it comes from and what to do about it, we’re going to have the opportunity to hear from Dr. Philip Kern, who is an endocrinologist of repute, respect, and highly published. As you will learn, he is head of a diabetes research institute as well as a diabetes and obesity clinic at the University of Kentucky, Lexington, School of Medicine. He is a person who is going to help us set the tone for understanding the endocrinological challenge that the rising spectrum of insulin resistance and type 2 diabetes is presenting to the medical system. And I think one of the things we’ll take away from this is that there are varying degrees of concern as it relates to this spectrum of disorders. At the extreme edge are the clinical signs that occur with fulminant type 2 diabetes, such things as neuropathy, nephropathy, retinopathy, liver failure, kidney failure. These types of very acute illness situations present in the extreme edge of the type 2 diabetes or the type 1 diabetes spectrum. In the earlier stages, however, the signs and symptoms of presentation are much more subtle because they don’t ring out so clarion as a pathology. They may be things as cognitive dysfunction. They may be seen as obesity. They may be seen as hypertension. They may be seen as chronic kidney-related dysfunctions. They may be seen as immunological dysfunctions. They may be seen as a host of cardiometabolic signs and symptoms, including dyslipidemia.   Global Health Shifts Due to Changing Lifestyles, Socialization, and Environment So it’s not easy just to pinpoint a specific target presenting sign and symptom when we’re talking about this wide spectrum of conditions that are under the umbrella that we call insulin resistance, type 2 diabetes, and hyperinsulinemia. As it pertains to the prevalence, I think there is no doubt that we see this as a rising tide—almost an epidemic or a pandemic—that’s not only seen here in the United States, but we’ve exported this now, with the Western lifestyle, to many other countries in the world, including what is the country of greatest concern right now as to type 2 diabetes, which is China.   Twenty years ago, type 2 diabetes was virtually unheard of in China. It was a disease that was only seen in the United States with great prevalence, and now it is starting to be recognized as an epidemic in China. And as a consequence, people have asked, “Well, how could this occur?” The Chinese genotypes haven’t changed so dramatically in 20 years. What has changed, obviously, is the industrialization, socialization, diet, and lifestyle patterns, which, in the Chinese genome, there are sensitivity or susceptibility factors obviously that are being presented through the phenotype as a consequence of the adoption and the uptake of the Western lifestyle. And so this is almost a laboratory experiment without a control, and that is what we’re observing is a self-elected study on how to get a culture to transition from a disorder that didn’t exist to that which becomes the standard of fare for the average person to become diabetic as a consequence of changing lifestyles, socialization, and environment.   So I think there is much to learn—much to be also concerned about—if we were to go to the United States as a model study and look at the prevalence of type 1 and type 2 diabetes among children and adolescents. We used to think of type 2 diabetes as being adult onset diabetes. That was the name, but it had to be changed into type 2 because there were so many adolescents and children that were starting to present with this condition. So if you look at the prevalence of this condition from 2001 to 2009, what you see is virtually a hockey stick of exponential increase, and I’m now quoting from an article that just appeared recently in the Journal of the American Medical Association titled “Prevalence of Type 1 and Type 2 Diabetes Among Children and Adolescents From 2001 to 2009.”[1]   What I found to be interesting and I didn’t recognize until reading this article in greater detail, is that type 1, which we used to call juvenile onset and we considered it to be kind of a tightly genotypically inclined disorder, it is also increasing significantly, and we recognize that type 1 diabetes is associated with an autoimmune disease of the islet cells of the beta cells of the pancreas, and therefore whatever it is that is initiating this autoimmune insult to the children’s own endocrine pancreas is on the increase. It’s not that their genes are increasing, something in the environment, or some things, obviously, are triggering increased autoimmune response of the child’s immune system to their own pancreas, killing their beta cells, making them insulin requiring. And I think that this insulin-dependent type 1 diabetes phenomenon really ties together the autoimmune condition with the metabolic disease condition, and I believe that this is a topic that we’ll be discussing in greater detail throughout the course of this three-part series on insulin resistance and metabolic syndrome/type 2 diabetes. That there is ever-increasing understanding that these metabolic diseases are tightly tied to our immunological disorders (the autoimmune family of disorders), or what used to be considered as the body allergic to itself.   Immunological Disorders Do Not Result From the Body Becoming Allergic to Itself I think that is, by the way, a very false misnomer. I don’t think the body becomes allergic to itself. I think what happens is our immune system of certain individuals becomes hyper-reactive to foreigners that are produced within the body, and these foreigners are foreign molecules that have come from the damage of cells and tissues or biomolecules that then present themselves within the body as an endogenous foreigner which then the immune system responds to by producing an antibody reaction or cell-mediated reaction. This is the innocent bystander response where you start getting collateral damage to the tissue itself because the body is actually responding to this perceived foreigner in such a way that it’s found in situ within tissues, and the tissues become the secondary outcome of the body’s defensive system that’s trying to handle a mischievous foreigner when the foreigner looks like it is part of us. So I think that this concept that we are allergic to ourselves is misleading because it leads us into a circular reasoning saying, “Well, there’s nothing we can do about being allergic to ourself because we are ourself so what are we going to do?” In this case, however, is, “It’s not really ourself, it is something that has transformed ourself into a foreigner, or at least a portion of ourself into a foreigner, for which our immune system, which is unique to each one of us, responds in a unique way to start attacking that foreigner.   Let me give you an example that we’ll be discussing in greater detail in the subsequent parts of the series, and that is glycosylated proteins. We recognize that one of the hallmarks for following diabetes is hemoglobin A1c, or glycosylated hemoglobin. And this is where the hemoglobin molecule has been non-enzymatically glycated, meaning that glucose has reacted in a specific type of chemical reaction in the aldose form of the glucose molecule by reacting with the epsilon amino groups of lysyl residues on hemoglobin to produce these shift spaces. So what we’re really saying is that there is a covalent chemical connection then between glucose that ties itself onto hemoglobin and makes a funny hemoglobin. That’s not the natural hemoglobin; it’s now a modified hemoglobin. So that becomes a foreign molecule.   We then measure glycosylated hemoglobin as a percentage of total hemoglobin. We say that people that have glycosylated hemoglobin, or hemoglobin A1c greater than seven-and-a-half to nine percent of the total hemoglobin are people with glucose intolerance and they are diagnosed as diabetic. But in the form of the body’s immune system we say the increasing prevalence of these glycosylated hemoglobin molecules floating around in our blood means the presence of more foreigners, and so at a certain point, our immune system, based upon our own unique genotype, can say, “Oh, just a minute. There are all sorts of these hemoglobin foreigners that are floating around in my blood, I need to form an antibody against them, or I need to form a reaction.”   Now, it’s not just hemoglobin that gets glycosylated. Virtually every soluble protein that’s floating around in the presence of excess sugar in the blood can be glycosylated, so what’s the most significant protein in the blood? It’s albumin. So can albumin become glycosylated? Of course it can, so now we get glycosylated albumin. Well, that’s a foreigner. And so now the immune system says, “Oh, here’s another foreigner. Maybe I’ll form an antibody to that foreigner.” And so forth and so on.   The point I’m trying to make is the more that we have modified our body through certain kinds of chemical reactions with either internal molecules like glucose, or external molecules like foreign chemicals that we absorb or ingest, the more likely that our immune system may have a reaction to those foreigners, producing, then, damage to specific tissues. And if those reactions happen to reside within the beta cells of the endocrine pancreas, now what we see is apoptosis (or death) of those beta cells. And as they get depleted, that means less cells available to secrete insulin, and less cells available to secrete insulin mean we become more sugar sensitive and we eventually get to the point where, in the type 1 diabetic, we need insulin in order to maintain control of the blood sugar at all.   Genotypic Susceptibility to Type 2 Diabetes And so this article in the Journal of the American Medical Association in 2014 does a very nice job of describing both the increased prevalence of type 2 diabetes, but also of type 1 diabetes among children and adolescents, suggesting that there are common features that are associated with both of them. Now there are specific genetic types that appear to be emerging to have greater susceptibility or sensitivity to some of these derangements that I’m talking about in internal cellular milieus—some of the alterations in various molecules that come through these metabolic networks. We can’t say that there is a single gene that causes type 2 diabetes, because type 2 diabetes is not a single disorder. It’s all these different things that cluster together to give rise in a person to the inability to manage sugar well in their system.   Now there are a couple of interesting papers that have appeared recently talking about genotypic susceptibility, again showing that there are many genes probably that give rise to different responses that we would ultimately see as mutant genes that could increase the relative risk of type 2 diabetes. One is mutation of the gene DYRK1B, which has been found just recently to, in a mutated—what we would call SNP form, single nucleotide polymorphic form—to be conferring an increased susceptibility to both metabolic syndrome, meaning hyperinsulinemia/insulin resistance, and then later type 2 diabetes. This appeared in the New England Journal of Medicine in 2014, volume 370, page 1909.[2] What they found, looking at various kinds of genome-wide association studies, was that there was an early-onset coronary artery disease profile that related to hyperinsulinemia, this is what would be called cardiometabolic disease, where there is a heart disease risk that’s associated with the insulin resistance that was tightly tied to this mutation of DYRK1B, which is involved with the regulation of the key gluconeogenic enzyme glucose-6-phosphatase. Here is just one example, and I don’t want to go into great details about that other than to say this is one recent example of where a gene controls a susceptibility factor. It doesn’t confer the necessary outcome called diabetes, only under certain specific kinds of environmental conditions does it express itself, then, into a diabetogenic form.   Another example of that is a paper that appeared again in the New England Journal of Medicine looking at PTEN mutations as a cause of constitutive insulin resistance and obesity.[3] Again, another gene controlling an activity that relates to regulation of sugar and how that then attracts itself against ultimately increased increasing risk to type 2 diabetes, metabolic syndrome, and obesity. Here is where we start looking at the PTEN monogenetic cause of constitutive insulin sensitivity and how that relates to obesogenic effects that ties together the insulin connection to obesity—that when you have dysfunctions in insulin sensitivity, you have derangements in energy economy, you have adipocyte functional changes, and you have more storage of fuel (the energy that we take in from our diet for a rainy day that never comes), and so people tend to get central adiposity. Their waist-to-hip ratio increases. This doesn’t mean that obesity causes diabetes, it means it comes as a consequence of these metabolic derangements. So obesity is an effect, not always a cause of diabetes. They come together as a consequence of disruptions in the metabolic network that regulates sugar metabolism.   So I think that these are themes that you’re going to be hearing in greater detail that we’ll be discussing in the subsequent issues of this three-part series on insulin sensitivity, type 2 diabetes, metabolic syndrome, and cardiometabolic disease. And with that, let’s move to our extraordinary expert who will lay the groundwork for us from an endocrinological perspective, as to what is this field of diabetology all about in the 21st century?  

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 INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Philip Kern, MD Professor, Division of Endocrinology and Molecular Medicine Director, Barnstable Brown Diabetes and Obesity Center Director, Center for Clinical and Translational Sciences University of Kentucky 521A Charles T. Werthington Building 900 South Limestone Lexington, KY 40536 Once again we’re at that portion of Functional Medicine Update that really drives, I think, the interest and the currency and really makes the news-to-use happen, and that is our clinician or researcher of the month section. We’re very fortunate this month that we have a person that I think fulfills the bill on both of those accounts—both as a clinician (endocrinologist) by training and also an extraordinary researcher in the field of obesity, diabetes, insulin resistance, and the attended effects that occur with diabetes. I’m speaking of Dr. Philip Kern, who is a professor of the Division of Endocrinology and Molecular Medicine, Director of the Barnstable Brown Diabetes and Obesity Center, and is engaged at the Center for Clinical and Translational Sciences as its director. I had the privilege of going out to Lexington, Kentucky to visit for a day with Dr. Kern at the University of Kentucky Medical Center and had a chance to really explore the breadth and also depth of his expertise, both as a clinician and as a researcher. His publication record is stellar. We’re going to dig into some of the newest stuff—what I call news to use—getting a little bit into the discussion of beiging of fat and how it turns into brown fat and all these new things that are starting to help us understand better the role of the adipocyte in health and disease. Dr. Kern, what a privilege and pleasure to have you as a clinician/researcher of the month on Functional Medicine Update. Thank you. PK: Yes, thank you. It’s great to be here. JB: Let me start just with your clinical side of the house, here, for a second, knowing that you’re a regional center at Barnstable Brown Diabetes and Obesity Center for patients with those kinds of clinical conditions. What’s your clinical observation concerning the prevalence of type 2 diabetes and that we’re told that diabetes is growing to be more than ten percent of our population as a diagnosable disease? I remember in school in the sixties we were told it was three percent and would never change, and certainly there are things afoot. What’s your observation as a clinician as to what’s going on in this domain? Perceptions About Diabetes Have Changed Over the Last Several Decades PK: Yes, the obesity epidemic, of course, is making us all look silly in terms of predictions that might have been made some time ago. Once upon a time we used to define diabetes in terms of juvenile diabetes and adult diabetes. Those terms are no longer used, and they are no longer used for a variety of reasons, but one of which is that type 2 diabetes—the kind that is driven by obesity and insulin resistance—is now being seen in children. Of course it has always been known that type 1 diabetes can actually occur in adults, but our pediatric colleagues have now had to learn quite a bit about type 2 diabetes because they’re treating it all the time. JB: So I think the takeaway, just to make it simple, is that this condition that was maybe previously—at least in my education in the sixties—was considered principally a genetic disease has taken, now, a variation of a theme in which we see the environment playing a pretty important role. PK: Yes, it is highly genetic and that’s very true. In fact many people don’t realize that type 2 diabetes is actually more strongly inherited than is type 1 diabetes. Some people seem to mistakenly think that type 1 diabetes is “the severe diabetes,” and it is in that they require insulin. But type 2 diabetes is strongly inherited, but it is genetic and environmental interaction. Obesity tends to drive the process in people with appropriate genetic background. And the genetic background, of course, is very common. There has been a lot of research into the genetics of type 2 diabetes. It is very complex. There is not “a” gene; there are many, many different genes that are involved with type 2 diabetes, and in fact probably many of us have some combination of these genes. So if a very large segment of the population has some genetic predisposition to type 2 diabetes, then all you need is an insult like obesity to start driving the process to very high percentages. JB: So for our clinicians, as a quick review, what are the companion issues that you see that are of greatest concern that ride with this obesity/diabetes epidemic? Obesity is a Risk Factor for Many Diseases Beyond Diabetes PK: Well, obesity causes many problems. In addition to diabetes, there is the sleep apnea and hypertension, which all, of course, tends to promote cardiovascular disease. The wear and tear on the joints, and so our orthopedic colleagues are doing more knee replacements and hip replacements because of just the extra wear and tear on the joints from carrying the excess weight around. And then, of course, diabetes has downstream effects on kidney disease and eye disease, and so there are many, many different medical problems that are all flowing from this. And heart disease is, of course, the ultimate medical problem that causes premature mortality and death. So on the one hand, we have made great progress throughout the decades in cholesterol-lowering medications, antihypertensive medications, coronary care units and other systems that help save lives of people with coronary disease, but on the other hand we have this obesity epidemic that is causing all these risk factors: the diabetes, and the lipids and hypertension, and other things. So it’s this perfect storm, in a bad way, that seems to be making coronary disease worse. JB: I recall reading recently a number of papers that have been talking about cardiac disease associated with diabetes and I think, as I recall, some of the conclusions of these studies were that very tight control over blood sugar levels didn’t seem to relate to the reduction in incidence of cardiovascular disease, suggesting that there wasn’t a direct linkage between blood sugar and cardiovascular disease. What’s the story on that emerging front? PK: You’re right. It’s a complex story, however, throughout the years there have been many studies that have tried to examine the relationship between glycemic control and coronary disease. One thing that is very important is that improving glycemic control certainly does not reduce the incidence of coronary disease as well as. One thing that is very clear is that improving glycemic control certainly does not reduce the incidence of coronary disease as well as does, for example, lipid lowering, or antihypertensive treatment. And there have been a lot of negative studies. There are a couple of caveats to that. Now there was one study—the UK PDS study, some years ago. It was a complicated study that there was a signal to suggest that maybe coronary disease was reduced in that study. And then in the Diabetes Prevention Program trial, which was a study with type 1 diabetics where they randomized type 1 diabetics to tight control versus intermediate versus poor control, that study completed, but even looking downstream years later from that study, there was a suggestion that the previous tight control had an improvement in coronary disease. But then on the other hand there are other studies, like the ACCORD study. ACCORD took type 2 diabetics, and many of these type 2 diabetics had a full court press done on them to get tight glycemic control—multiple medications getting their A1c down to 6.5 range or even lower, and actually they saw an increased incidence of coronary disease and coronary death in these patients. We’re at a point right now where we feel that with type 2 diabetics, when you are trying to improve glycemic control, the main reason you’re trying to improve glycemic control is to prevent the nephropathy, the retinopathy, the neuropathy. You might improve the triglyceride levels and the HDL levels in these patients, but if your real goal is to reduce the likelihood of coronary disease, then you really need to focus on lipids, hypertension, and other cardiac risk factors, and glycemic control by itself is probably not going to be a strong means of reducing coronary risk. Are Peripheral Neuropathy and Retinopathy Reversible? JB: That’s a very good bit of clinical news-to-use. Thank you. Let me speak with you just for a moment about the chronic renal disease, the peripheral neuropathy, and the retinopathy issues. If an individual gets their blood sugar under control and drops their A1c down to a level at or below 6.5 percent, what I always heard was renal disease, or chronic renal injury, or peripheral neuropathy, or retinopathy are irreversible. Is there any evidence that one can rolel back or improve function, or is it just preventing the increase in dysfunction? PK: It’s mostly a stabilization of the process and preventing further progression. There is evidence that once the nephropathy gets to a certain point, that point would be when the creatinine is clearly elevated to 2 or more, when there is significant nephrotic range proteinuria. At that point it is very clear that the renal disease is going to progress. Now if you are at other stage, where the creatinine has not elevated yet but you have microalbuminuria (so there are trace amounts of protein or albumin in the urine), that stage is still amenable to tight glycemic control and slowing down the process with, of course, ACE inhibitors and other antihypertensive treatment. I think the farther the disease progresses, the less likely it is to stabilize or reverse with tight glycemic control. Same thing with ophthalmopathy. By the time you need laser treatment for your eyes, then tight glycemic control still may be important to prevent further eye disease, but you’re still going to need the laser treatment; the die has already been cast and there is only so much you can do. JB: That then obviously raises the question as to how do we get good, early interrogation so we can intervene before we have this irreversible pathology. You’ve talked about two analytes, one being A1c and the other being urinary microalbuminuria. Are either of those, or both of those, useful tools in early assessment of changes so one can intervene more early? Patients Should See an Endocrinologist Once a Year PK: Yes, and that’s one of the important roles for the endocrinologist. I have a lot of respect for the general practitioner, the family medicine or internal medicine doctor, or the pediatrician, because when you’re seeing a patient you’ve got a lot of things to think about in terms of prevention. And then when you add diabetes to all this, then there is other preventive measures, and so typically you follow the A1c as a great indicator of glycemic control, you want to get a urine microalbumin once a year, the patient needs to get their eye exam. You need to look at their feet periodically just to make sure there are no lesions on their feet. You need to do testing of their feet for sensation. There are a lot of things that need to be done. I encourage our generalist colleagues—our family medicine and internal medicine doctors—maybe to send their patients to the endocrinologist maybe just once a year for a check-up so all these boxes can be checked just to make sure that everything is optimized. I think that’s a very good system for trying to prevent diseases before they occur. JB: So let me speak briefly with you about the A1c. I recently read a couple of papers saying that this driving to lower A1c, which is a desirable objective, you can drive A1c too low—that the curve turns the other way and you start seeing increased incidence of vascular and other diseases with too low an A1c, presumably maybe as a consequence of hypoglycemia. Any evidence, in your experience, on that curvilinear relationship of A1c, say, below 5? PK: Yes, there is some evidence. A lot of it is a little bit speculation. Now a lot of this comes from the ACCORD study, as I had mentioned before. The ACCORD study was a very ambitious study in type 2 diabetics to look at a full court press on glycemic control, lipid control, hypertensive control, and what they found is that sometimes that full court press actually results in increased mortality. Now exactly why was there increased mortality? That has not been totally clear. There is speculation that some of these patients may have been having hypoglycemic episodes, and so if you have an older type 2 diabetic maybe with some coronary disease (coronary disease may not be clinically apparent but it may still be there), and if you are provoking frequent episodes of hypoglycemia, then that hypoglycemia produces catacholamines and will put a stress on the heart and perhaps could result in an MI or sudden cardiac death or some other adverse event. So that’s the speculation. And I think anecdotally, clinicians have seen this. We’ve all seen patients who did have some kind of an adverse event of hypoglycemia, but it’s hard to make that conclusion precisely from the study. So my take on this is I think as clinicians we should use our clinical judgment. Examples of Clinical Judgment So I see a patient in the office, for example, and this patient is on ten different medications. They are on a medication or two for their lipids, for their diabetes, their hypertension, for their coronary disease. They may be on an antidepressant. They may be on something for their bad back. They may be on a proton pump inhibitor for their stomach. You do get the picture; they are on a lot of different medications. And so they come in and their A1c is 7.5, and their blood pressure is 140/85, and their LDL is 130 or 120. Basically, there are a lot of different things that could be better. So what do I do? Do I start pumping up the blood pressure medicines and the cholesterol medicine and the diabetes medicines? Or do I focus on one or two and maybe saying, “Well, let’s save the other ones for another day?” This gets into a medical judgment. In the ACCORD study, you’d pump up the insulin; you’d do everything. But in real life, I think often we tend to choose the battles that we’re going to try to achieve in this particular patient. So we may focus on the blood pressure and the lipids and to say, “Let me just leave the A1c at 7.5; it’s probably good enough.” And I think that’s kind of where we are right now with A1c and especially in type 2 diabetics, is that there is a certain point where it’s probably good enough and we don’t need to make it perfect. JB: Thank you. That’s very insightful. If you were to pick a range as to what you think is an optimal A1c, is there a range that you would feel would be a good target? PK: Well, an A1c of 7.5. Below 7.5, you probably will improve microvascular disease—you know, nephropathy and retinopathy—by going below 7.5. But you’ll get much more bang for the buck going from 9.5 to 7.5 than you will from going below that. I tend to focus more on getting people down to 7.5. Below 7.5, it depends on the circumstances. It partly depends on who we’re dealing with. Now, if the patient is 75 years old and already has, say, coronary disease, then why am I trying to get below 7.5? Because the person is probably not going to live long enough to get nephropathy or retinopathy. On the other hand, if the patient is 38 years old and is relatively free of complications, then I can focus more on prevention and then I may want to get that A1c down to 7 or 6.5 or 6.8 if I can do it without significant side effects, because then there is a real opportunity to prevent disease in the future. So I think you have to individualize it to who the patient is, what the comorbidities are, and what your long-term objectives are. JB: Let’s say I had a patient that came in and they had a fasting blood sugar, on average, in the morning, of somewhere around 115, 120. Let’s say their A1c was something like 6.9, 6.8, something like that, percent. And you were putting them on a lifestyle intervention program before you were starting to medicate them. Would you try to get a target A1c (in that case you’re kind of in a pre-diabetes situation), down into the 5s, or would you be more moderate in your objectives? PK: Yes, you’re absolutely right. The optimal intervention would be lifestyle in a patient like that. Now if that patient had a fasting glucose of 120 or so, but then the A1c is 6.9, so the A1c is in the range of diabetes; the fasting glucose is not quite diabetes. But whether you label that person as diabetes or impaired…you would probably label them as diabetic if you look further. But regardless of how you label them, if that person is overweight or obese, and if that person loses even a modest amount of weight, it’s very possible that the blood sugar will totally normalize, and so you really want to emphasize that very strongly and have a program hopefully that they can go to help them out with this. On the other hand, in that same patient, if that patient had, say, a triglyceride of 400 and that patient tells you they have a strong family history of heart disease or maybe the patient has heart disease, then you might have some secondary objectives that you might want to shoot for: treating lipids, and you might want to become more aggressive with lifestyle, and you might choose to use a medication in that patient earlier than you would in somebody else. So I think doing a little bit of office genetics—trying to assess the patient as to where they are going. Is this a generally asymptomatic “healthy” person with an A1c of 6.9, or is this someone who is a train wreck waiting to happen with an A1c of 6.9. Sometimes that will help push your treatment one way or the other. JB: Yes, that’s very, very helpful. A number of years ago we had the privilege of interviewing Dr. Suzanne Craft, who was at the VA and at the University of Washington School of Medicine, who had been doing some work on Alzheimer’s dementia related to insulin resistance and diabetes and came up with a concept called—I think she or someone else termed it—“type 3” diabetes. What’s your view of this connection between dementia and diabetes and hyperglycemia? Insulin Resistance in Nerve Cells Versus Insulin Resistance in Adipose Cells PK: Yes, I’m not sure where this is going. I know this is a very hot topic in the Alzheimer’s field, and a lot of people are studying insulin resistance in nerve cells, and I think insulin resistance in nerve cells is a very different phenomenon than the insulin resistance that we describe in type 2 diabetes. Insulin resistance in type 2 diabetes is mainly driven by skeletal muscle insulin resistance, with contributions from adipose in the liver. Whereas nerve cell insulin resistance I think is a totally different phenomenon and I’m not sure it’s connected to them. The other issue is I know that dementia is more common in diabetics, per autopsy. To what extent is this being driven by vascular events, since of course diabetics have higher risk of stroke and other vascular events compared to non-diabetics. So I’m not really sure where this is going right now in terms of trying to decipher this, in terms of whether it is a “type 3” diabetes or is another of the many manifestations of the diabetes that we already know, and I’m not sure about that. JB: Let’s shift over to a discussion now of the adipocyte, which seems to be central in all discussions recently due to this epidemic of BMI increases that we’re seeing in the population. David Ludwig just authored an interesting editorial in the Journal of the American Medical Association talking about is obesity causing disease or does metabolic disturbance due to lifestyle and other environmental/gene connections cause a sequence of events that leads to obesity?[4] So is obesity the cause or the effect of this pandemic that we’re seeing of things related to insulin resistance? What’s your thought? Maybe it can be an either/or and it doesn’t have to be one or the other. PK: Yes, well our change in lifestyle is clearly driving all this. Our biochemistry—all of our metabolic pathways—evolved over the course of many millions of years. If you look at the DNA—you sequence the DNA—of archeological digs, you know that the human genome has not changed in at least ten or twenty thousand years. So we are the same people, genetically, as our hunter-gatherer ancestors. Our biochemistry evolved at a time when one of the biggest risks to human civilization was starvation, number one. So we’re designed to get through the lean times when there is no food and no game. Also we’re designed to hunt and to gather. We’re not as fast as the deer, but we can outrun the deer; we have more endurance, so we can chase the deer until the deer gets tired and then we eat. We can work in the field day in and day out to gather crops and gather food because if we don’t get the food in before the next storm or the next something happens we don’t eat. So we’re designed for really quite extraordinary physical activity. But then, of course, what’s happened? Then, of course, over a relatively short period of time, our life has become totally sedentary. Now we have to do comparatively very little. And so our biochemistry is still designed to store calories as fat—to store it up for the times when there may not be food, and there are behavioral issues with this: we’re prompted to eat, we like certain types of food. It’s behavioral, it’s metabolic, and we’re designed to store fat in all kinds of places, not just our fat cells, but maybe our liver, and our muscle, and other places, just—again—to prepare for the lean times. I think a lot of this really is being driven by the change in lifestyle that occurred very quickly in evolutionary terms, whereas our biochemistry…we’re still the hunter-gatherer of our ancestors. Changing Metabolic Parameters with Gastric Bypass Surgery JB: Some people call that the thrifty gene hypothesis—I think that Neel first talked about it with the Pima Indians—so let’s take that on to an individual who has a morbid obesity situation (a BMI of 40, let’s say), they are on multiple medications based on the principles you were talking about earlier, and they go in and they have gastric bypass Roux-en-Y surgery, and voila, within a period of very short post-op, without losing a lot of their extra fat mass, their metabolic parameters normalize. How does that occur? PK: Well, this has been a subject of considerable discussion and debate. There is one side that claims there is something special about the surgery, and a lot of the focus has been on some of the GI hormones—ghrelin and a number of other GI hormones. It is suggested that these things are altered by the bariatric surgery, and that this has a metabolic effect both on shutting off appetite as well as with improving glucose, lipids, and other things. The other side of the camp suggests that, well, you’ve just shut off the spigot of food intake. The person is not eating. Yes, they haven’t lost that much weight yet, but just the fact that they are stopping eating actually has a big effect. And so I tend to be a little bit on the stopping-eating side of that fence, although I think that there is truth to both sides. I used to direct a metabolic weight-loss program where patients paid a lot of money and they would go on a liquid diet where they would all of a sudden go to, say, six or eight hundred calories per day, and you would see the same kind of thing. When patients really stuck to their diets, you would see fasting blood sugars go from 350 down to 120 in literally a couple of days, dramatic changes in lipids, and so you would see this kind of dramatic thing just by stopping the food intake. I think that the rapid improvements that are seen with bariatric surgery, some of this is entirely predictable based on stopping the eating, but I think there probably is something to the story of GI hormones and ghrelin, in particular, that seem to be influenced by the GI surgery. I’m thinking it is probably 75{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} stopping the food intake and 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} other GI hormones that may be involved. JB: That’s very interesting. I know that there has been some work done not just on ghrelin but things like GLP-1 (glucagon-like peptide-1) and its influence, and of course that then raises the whole things about Byetta and other pharmacological compounds that are used to modulate GLP-1 concentrations, so I think there is this, as you say, probably mixed story that’s related to these incretin hormones and how they are influenced by Roux-en-Y surgery, and also the mass of food consumption that’s changed by making the alimentary canal so small and getting rid of the stomach, basically. PK: Right. Adipocyte Physiology is Now Leading the Field of Bioenergetics JB: So let’s move from there to this emerging story about the adipocyte, which I think is really interesting when we go back and think 30 years ago that if you were an adipocyte physiologist, the last question that people would be interested in knowing is what you did for a living because it was so considered unimportant and maybe even socially unacceptable to call yourself a fat cell physiologist, but now it has moved to head of the class and it is where the action is. So tell us a little bit about this white adipocyte, beige adipocyte, brown adipocyte story. I think it sounds like an amazing new development in the whole field of bioenergetics. PK: Yes, getting back to our hunter-gatherer ancestors, so one thing our hunter-gatherer ancestors had to do was prevent starvation. Another thing they had to do was to stay warm, and so if you were hunter-gatherer out—especially in a northern climate where it gets cold—that becomes a real issue. Now, all mammals, including humans, have significant amounts of brown adipose tissue at birth. This is particularly apparent in rodents—you can see large amounts of adipose tissue—and the brown adipose tissue is located typically around the neck and between the scapula and in the back. Newborn babies have this, and of course this is an important evolutionary adaptation—when the baby is suckling the baby needs to stay warm, and so you can see why a tissue that is designed to generate heat, to burn lipid, but instead of burning lipid to create energy it is actually burning lipid to create heat, and that’s an important evolutionary adaptation and is present in all mammals at birth. But then, what always used to be said is that with growing up and becoming older, by the time humans were in their teenage or young adult years, the brown adipose tissue was gone. Well, with the advent of PET scanning, and PET scanning is typically done to locate tumors, they started noticing the PET scanning was picking up brown adipose tissue in humans. There have been many studies documenting the presence small depots of brown fat in humans. Now, how important is that brown fat in humans? It is fairly metabolically active, but is this really burning a lot of calories? Can we capitalize on this? So these brown adipose tissue depots are typically located in the back and the neck, but if you take a mouse, for example, and you put a mouse in the refrigerator for a while and you chill it down, the mouse will not only activate its brown fat, but it will also take his white fat and make it brown-like (more brown), and that’s been called a browning process or actually it is now even called beige fat, because the white fat never becomes as brown as the brown fat, but it does darken. And this darkening is because it accumulates mitochondria. As it accumulates mitochondria it is burning lipid, it uncouples oxidative phosphorylation, and it starts to generate heat. So in a mouse, it has been well-documented that his white fat can adapt the same way. I think it is very possible that humans have the ability to do this as well—that we have the ability to also make our white fat a little bit beige in response to cold. Now of course as humans we don’t chill ourselves out as much. We wear clothes. We have thermostats. We heat our houses. And so I think it’s a little bit trickier to demonstrate this in a human, and humans naturally use our brain to manipulate our environment so that we don’t have to be exposed to cold as much as a mouse that is living in a hole in the ground somewhere. But I think this process in humans probably parallels that in a mouse, probably not as robust, but still it’s probably not totally absent. JB: When I look at this story, I’m reminded that these mitochondria that are being activated—a kind of biogenesis of mitochondria—that the mitochondria have all these cytochromes in them and those cytochromes, which are the energy shuttle system for these electrons that are involved with energy production, all contain the trace mineral iron. So iron is the origin of the chromophore that ultimately turns these tissues brown, stains these tissues brown. So what we’re really doing is inducing, then, gene expression, it would appear, of the energy processing centers, which I guess the emerging view is that mitochondrial inactivity is associated with poor bioenergetics and diabetes and mitochondrial activity, as you get with exercise for instance, is associated with improved bioenergetics and improved insulin sensitivity and increased glucose utilization and lowered diabetes. Is that how this model is all kind of fitting together? PK: Yes, the mitochondria is very important in different tissues and in different ways. A minute ago we were talking about the mitochondria in the fat cell and its role there might be to burn lipid and to generate heat in this beiging or browning process. Now muscle, of course, uses a lot of glucose, and in fact when you are measuring insulin sensitivity in humans usually you’re talking about muscle as the main organs of this. Muscle mitochondrial function is also critical for not only the burning of lipid, but also the improvement of the whole glucose uptake process in skeletal muscle, and so many studies have been done trying to look at muscle gene expression and muscle function in humans, and it is very strongly correlated with insulin sensitivity: the better the mitochondrial function, the more insulin sensitivity. JB: So that leads to a clinical question that I’m sure our listeners are thinking about, and that is, “Okay, how does a patient beige their white fat?” Can You Convert White Fat to Beige? PK: I don’t know. Could we develop a drug that could do this? Should we just get out more? Well, there are lots of reasons we should get out more. Perhaps we should not just go to the gym and exercise in a controlled temperature environment. Maybe we should get outside and expose ourselves to the elements more. Usually I tell my patients to exercise, and I don’t care how you do it, just find a way to exercise. If you hate going outside, then go to the gym by all means, because any way you get it done. But I think maybe the exposure to colder weather probably does stimulate something. JB: Yes, I think that the interesting combination, as you’re saying, between exercise, which does have a noradrenalin effect obviously on activating brown fat, and also doing it in a cooler place, might be an additive effect. There are some studies that I have seen in animals where they have shown that synergy in improving energy economy. Let me move to an area that I know you have considerable experience in. I have seen some extraordinary work that you have done and published in humans related to omega-3 fatty acids and its relationship to insulin signaling and lipids and inflammation.[5],[6] Tell us a little bit about this emerging story because it seems like that’s a very controversial topic at the moment, the whole omega-3 fat story. Examining the Effect of Omega-3 Fatty Acid Intake on Adipose Tissue PK: Right. There have been studies on omega-3s and fish oils for many decades now, and it’s very clear that omega-3 fatty acids lower plasma triglycerides, and there are fish oil preparations that are pharmaceutical grade on the market now that do this and are indicated for this. Omega-3 fatty acids also have a slight effect to decrease platelet aggregation, and this might be important in coronary prevention. To be clear, omega-3s are not as potent as an aspirin, but again, in population studies, when you look at omega-3 intake, you often find that omega-3 intake is correlated with a lot of benefits, including coronary prevention, and this might be one mechanism. Omega-3s also have an anti-arrhythmic effect on the heart, probably through membrane stabilization in preventing of arrhythmias in the heart. Another interesting thing about omega-3s is that they are anti-inflammatory. There have been many, many studies that have looked at the anti-inflammatory effects of omega-3s for rheumatoid arthritis, or inflammatory bowel disease, or asthma, and for other chronic inflammatory diseases. And there is variable benefit. I think probably for rheumatoid arthritis there is a clear-cut benefit of omega-3s. Now, it’s not as potent as anti-TNF antibodies and other types of treatments, but certainly omega-3s do have a role. So we wondered whether omega-3s have an anti-inflammatory effect that would be useful in patients with metabolic syndrome, so we did a study where we recruited patients who were not diabetic, but they were pre-diabetic. Most of them had impaired glucose tolerance and they had multiple features of metabolic syndrome, and we randomized them to 4 grams a days of omega-3 fatty acids or placebo. What we found is that there was a decrease in the number of macrophages in their adipose tissue. We found some other signals that were beneficial signals, such as decrease in certain cytokines and an improvement in adipose tissue capillarization. If there is better blood flow to the adipose tissue then probably there would be less dysfunction. However when we looked at insulin sensitivity, we did not find an improvement in insulin sensitivity. So we saw some benefits on reduced inflammation, but not an improvement in insulin sensitivity. Maybe we just need to give more omega-3s or we just give them for a longer period of time. I mean let’s face it, some drugs are just TZDs, which are relatively slow-acting and it takes at least three months even to see an effect, so maybe omega-3s need to be given for a longer period of time. So I’m interested in further pursuing the possible role of omega-3 fatty acids in metabolic syndrome, in particular, as an adjunctive treatment. And we certainly recommend a drug right now for treatment of hypertriglyceridemia, and as even if there is a suggestion of coronary prevention (there may be a coronary preventive effect). JB: Dr. Kern, as you look out at this landscape, you’ve got this portfolio of drugs that are now available for the management of type 2 diabetes, and we see a rising tide of insulin resistance, and there are a huge number of not-properly-diagnosed diabetics and certainly even a greater number of pre-diabetics. So what would you, from your crystal ball, see as the future for managing this epidemic? Where are we going to go? We can’t build renal dialysis centers fast enough. We don’t have enough endocrinologists. There must be some solutions on the horizon. Where do you think they reside? PK: Well, the Holy Grail will be a good obesity drug, certainly, because obesity is driving the whole process. There are a small number of obesity drugs on the market right now. They are not the greatest in terms of effectiveness versus side effects. I tell my patients right now: ten pounds of weight loss is far more effective than any drug I could possibly give you. So I push this with patients very strongly. But of course, we live in a free society, and so we can’t stop the TV commercials. We can’t stop the restaurants from offering food that we really, really like to eat, and so there are lots of pressures. I think one solution to this would be an equivalent of a statin. I mean, look at what the statins have done for lipid management. Anybody can manage lipids now; in 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the patients all you do is write a prescription for a statin. Whereas there was a time, which I remember, before statins, when you were struggling with trying to use cholestyramine and niacin and other drugs which were just not terribly effective and very cumbersome. So I think we’re still in the niacin/cholestyramime stage in terms of treating obesity. We’re using drugs that are just not terribly good, and we need a statin-equivalent. If we could come up with that, that would be the single best thing. Now, in addition, to the extent we could find drugs that target the problem, and if the primary problem is insulin resistance, then we’d like to have better insulin sensitizers. In many ways, the TZDs, like pioglitazone that is still on the market, was a great drug in terms of improving insulin sensitivity, improving lipids, even a slight anti-hypertensive effect, but unfortunately it is caught up in a morass of post-hoc analyses and lawsuits. There are some side effects which are of concern. Unfortunately TZDs and the PPAR gamma agonists, at least the PPAR gamma agonists that are out there right now are not the answer, but I think if we could find better insulin sensitizers that don’t have the same off-target effects, I think that will also be a very important treatment. JB: So that then raises a question that you were addressing earlier about lifestyle intervention, exercise, diet, nutrition, food supply, all these various complex questions. In your experience, having run large clinics and individual patient management, what do you think the receptivity is, or is it changing it all, as it relates to people starting to take charge of some of these variables that send the signals that encourage obesity and insulin resistance? The Behavioral Side of Obesity Management PK: Well, there are many people out there who are taking charge of their lifestyle and doing a really good job. But unfortunately there is a large mass of people who really don’t have the insight or the ability to manage things terribly well. So, yes, on the West Coast, in California, you have people, who, whether it’s cosmetic reasons, health reasons, or whatever, will go out jogging on the beach every day and take really good care of themselves and eat tofu and bean sprouts, but unfortunately in many other areas of the country, such us Appalachia in Kentucky, that doesn’t happen. And in fact there are many cultural things that have been done over the years that work against us. If you look at a couple of generations ago, if you look at just life back in the 1920s and 30s, people had to walk a lot. You walked into a building, and you had to climb the stairs to get up a few flights. You would take walks in your neighborhood. You didn’t have convenience foods that you pop in the microwave. So you actually had to work a little harder just to eat. And now there are so many things that are working against us. If there is a stairway in a lot of your buildings, it’s a fire stairway in the back someplace where you don’t even know how to get into and it takes you outside, so people don’t use the stairway. People don’t get out and walk. Food is way too easy. Everywhere you go there is food in front of you. You go into some office somewhere and the secretary has a bowl of M&Ms on her front desk right as you walk in. Why is that there? There are so many things that work against us now, lifestyle-wise, that it becomes very hard. JB: And do you think that maybe part of this, and I’ve heard the term sociogenomics, that there is a social structure that is one of the major parts of this difficulty, that we lack the peer reinforcement, we lack appropriate messaging, we lack finding how to do this in a fun way with people that would develop a social support system rather than insulated, isolated patients who are fighting against disease and have this fear model of how am I going to survive against the onslaught of a serious disease rather than having a peer support group. Do you think there are social structural changes that can be implemented within the context of medicine, or do you think that’s a bigger problem outside the purview of medicine? PK: The people who focus on behavioral management of obesity…I mean, there are many people who work very hard on the behavioral side of obesity management, and one of the fundamental principles to try to change your social structure: get the food out of your house; if you want to lose weight, get your husband to lose weight with you because you don’t want your husband to sit around eating donuts while you’re trying to diet; don’t go to that buffet; bring your own bag lunch with you. There are many different things to try to address the social situation, and some people are successful at doing that. But we live in this toxic environment and it is very hard for people to keep this up. It’s not impossible, but it’s very hard since food is everywhere. And there is a huge economic driver to this. Food is relatively cheap. We produce a lot of food, and usually the worst food, of course, is the cheapest food. And people want to please you, so you go someplace and someone throws food at you as a way of making you happy and pleasing you. It’s a social thing. You go over to someone’s house, you bring a casserole. You bring food with you. It’s built into our social structure, but of course some of that social structure is back in the Depression days when we brought food because people were hungry. We’re not hungry anymore. I think some people are very good at navigating the social structure, but it’s all around us and it’s very hard to navigate it forever. JB: It would seem to me from what you were talking about earlier that this emerging understanding of beiging of fat and activating thermogenesis and even bringing into it some of the things that we’ve learned from the metabolic effects of Roux-en-Y gastric bypass surgery and how that influences incretin hormones and regulates blood sugar control, it seems that these may be some frontier discoveries that are really going to change the landscape, both from a nutrition and lifestyle intervention perspective, but also from a pharmacological perspective. So there may be some bright lights here that is not a train coming from the other direction, it is maybe bright lights at the end of the tunnel. At least I would hope from what you’ve described that we’ve got some options that we didn’t have, here, five years ago. PK: Yes, I certainly hope so. JB: Well, I want to thank you very much. I think this has been an extraordinarily good clinical news-to-use overview of both the nature of the problem and some of the things that can be done and where the future might take us. Your work is really seminal. I think the work that you’ve done on adipocyte physiology and looking at the interaction between the immune system and adipocyte physiological function and how that connects to insulin resistance, this—to me—is where the action point is in the future of getting grips and a handle on what really what is a pandemic—it’s a global pandemic. So keep up the great work and thanks so much for sharing this information with us. PK: Okay, thank you very much. It’s been a pleasure to be here  

Bibliography

[1] Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, et al. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA. 2014 May 7;311(17):1778-86.   [2] Keramati AR, Fathzadeh M, Go GW, Singh R, Choi M, et al. A form of the metabolic syndrome associated with mutations in DYRK1B. N Engl J Med. 2014 May 15. 370(20):1909-19.   [3] Pal A, Barber TM, Van de Bunt M, Rudge SA, Zhang Q, et al. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N Engl J Med. 2012 Sep 13;367(11):1002-11.   [4] Ludwig DS, Friedman MI. Increasing adiposity: consequence or cause of overeating? JAMA. 20114 Jun 4;311(21):2167-8.   [5] Finlin BS, Zhu B, Starnes CP, McGehee RE Jr., Peterson CA, Kern PA. Regulation of thrombospondin-1 expression in alternatively activated macrophages and adipocytes: role of cellular cross talk and omega-3 fatty acids. J Nutr Biochem. 2013 Sep;24(9):1571-9.   [6] Spencer M, Finlin BS, Unal R, Zhu B, Morris AJ, et al. Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes. 2013 May;62(5):1709-17.

Welcome to Functional Medicine Update for November 2014. This is the second of our three-part series on diabesity. We’ve been so privileged to have as our lead-off presenter in October Dr. Philip Kern, as you recall, who is the director of the Barnstable Diabetes and Obesity Center at the University of Kentucky School of Medicine, and an endocrinologist (both clinician and researcher). I think Dr. Kern did a fantastic job of tipping us off as to what does the landscape of diabetes and diabesity look like (this interconnection between obesity and diabetes). And what types of parameters do you use to evaluate patients, and what are some of the difficulties that you have in managing this complex condition, and what are the available tools that sit in traditional medicine today and their strengths and limitations. I think that that was a very good landscape analysis as to the state of affairs as it pertains to type 2 diabetes and obesity.   In this issue—in the November issue—we’re going to move this on to the next level with our clinician/researcher/expert of the month, Dr. Osama Hamdy. Dr. Hamdy, as you will learn, is from the Joslin Diabetes Center at the Harvard Medical School and is a respected world expert in this area of the behavioral management of type 2 diabetes and the diabesity area. And so without further ado, let’s jump right in with Dr. Hamdy and get his perspective on how lifestyle medicine is an approach towards the management (both prevention and treatment) of type 2 diabetes.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Osama Hamdy, MD, PhD Medical Director, Obesity Clinical Program Assistant Medical Director, Professional Medical Education Clinical Investigator, Section on Clinical, Behavioral, and Outcomes Research Joslin Diabetes Center One Joslin Place Boston, MA 02215 http://www.joslin.org/diabetes-research/osama_hamdy.html As you know, we’re doing this three-part series on the epidemic that we call type 2 diabetes, insulin resistance, and all the panoply of clinical affairs and effects that are a result of the downstream inappropriate modulation of insulin and the disturbances of glucose transport, and we’re very privileged to have as one of our three top global opinion leaders, Dr. Osama Hamdy, who is at the Joslin Obesity Clinical Program. He’s actually the medical director of that program at Harvard Med School. He’s an endocrinologist (both a research and a clinical endocrinologist—MD, PhD). Remarkable publication record. You probably would have heard of work indirectly in that his group made the outstanding discovery a number of years ago—I think it was back around 2002—that individuals who were obese that lost about seven percent of their body weight had a significant improvement in their vascular endothelial function as measured by flow-mediated dilation, and that translates, obviously, to a very significant contribution to the prevention of atherosclerotic disease and coronary artery disease in individuals with insulin resistance.[1] It helped us understand you don’t have to get to your ideal body mass index to have improved clinical and metabolic function, and that was a very nice contribution of Dr. Hamdy and his group’s work. He has had many publications over the years and you’re going to hear about a number of them over the course of this discussion. Osama, we want to welcome you to Functional Medicine Update and thank you both for being able to share your insight with us and also for the years of contribution you’ve made to the field. OH: Jeff, it is my pleasure. Your program, I hear, is enriching thousands and thousands of physicians. I will be more than happy to add a little from the amount of knowledge that we have about obesity and diabetes. JB: Well, thank you. Let’s start down the road and let you tell a little bit about yourself. What led you into your work as both a combination researcher and clinical endocrinologist? I know you did your medical work in Egypt, and then you did a fellowship and postdoctoral work at Harvard. How did you travel down your path to this point? OH: You’ll be surprised. This is my passion, you know? I grew up in a family. All my family are overweight and all of them have type 2 diabetes, and many of them died at a very young age. My father died at age 48, and I wished that we were able to help them. I had been almost craving for knowledge about obesity and diabetes—what is the core of the problem and why people develop diabetes when they gain weight. What is the role of body fat distribution in this problem? So I decided to move to the US in the early 90s to complete my research, and my study, and my clinical work as well around that area, and I found that Joslin is the best place to be and I have been with Joslin for almost 17 years. Why WAIT: Weight Achievement and Intensive Treatment Program JB: Yes, and I think you’ve made really remarkable contributions to our body of knowledge, and I’m sure contributed significantly to your patients at the Joslin Clinic. You’ve developed this program with your colleagues at Harvard Joslin that I’m very interested in knowing more about. It’s called “Why WAIT” that really stands for Weight Achievement and Intensive Treatment program. Tell us a little bit about where that came from and how it uniquely provides opportunities for the patients there. OH: For almost 15 years we have been doing research around the impact of weight management on the cardiovascular outcomes, and on diabetes control, and many of the fundamentals of the theology and pathogenesis of type 2 diabetes. We decided in 2005 to start this program, which as you mentioned is Weight Achievement and Intensive Treatment, which means that we are trying to target diabetes from its core problem. We believe that the core problem of type 2 diabetes is body weight. If someone has a genetic background that will dispose the person to diabetes and that person gains weight—especially the weight gain in the central area, especially the increase in the intra-abdominal visceral fat—those people become very high risk not only for diabetes but also for coronary artery disease. And we found, interestingly, that there are many ways that we can review that risk and help those people to lose weight—not only to lose weight but to maintain that weight loss for a long duration. When we started the Why WAIT program in 2005, we implemented the method that we thought at the time would be very effective in weight loss, but over time we have been fine tuning this program, and we’re reaching the point where this program is very, very successful. Everyone who participated in the program lost a very good amount of weight, but the most important [thing] is that they maintain the weight loss for a long duration and they reduce their medication by around 50 to 60 percent. And of course this will be translated into huge savings. JB: Well, I know that you have done a really nice job of capturing some of the concepts in that program in your new book, The Diabetes Breakthrough: Based on the Scientifically Proven Plan to Lose Weight and Cut Medications.[2] I had the privilege of reading your book. I think it’s a very nice summary for the general reader on some of the details of the program in providing some news-to-use as to how to get going on it. The interest I have is this word “intensive,” because I think a lot of people feel that they can just back into these programs and just put their toe in the water, but the word “intensive” in “Why WAIT” (Weight Achievement and Intensive Treatment) I think is very important. Could you tell me why you chose the word “intensive” and what it means? Maintaining Muscle Mass During a Weight Loss Program is Very Important OH: Yes, “intensive” means that we are developing every single tool that we know that will be effective with management and in diabetes control. So it is a multidisciplinary approach. It is not a dietary intervention or exercise intervention or behavior intervention, but it is a multidisciplinary approach that includes the diet part, the exercise part, the behavior part, the education part, and also it includes modification and adjustment of diabetes medication. The program is very interactive. Over 12 weeks, every week we keep changing medication and also adjust the program to fit the individual who is in the program. And as you mentioned, we explain that in a very clear way in The Diabetes Breakthrough. It is a 12-week program, and the main philosophy in the program is that during weight loss we would like to maintain the muscle mass. We realize that if people, during weight loss, are able to maintain a very good amount of their lean muscle mass, the chances for them to maintain the weight loss for longer duration is usually the case. JB: So let me, if I can, just go down a little bit of a laundry list of certain questions that I know you discuss in more detail in your book and in the program. First is, what about diet composition and a source of nutrients? Is there some guidance on the overall composition of the diet? Dietary Composition is More Important that Calorie Count OH: Yes, we believe seriously that dietary composition is the most important factor in weight loss in comparison to the general belief that it is all around calories. We don’t believe that calorie-in-and-calorie-out is the case. There are several clinical trials that have shown that changing dietary composition can have huge impact not only on weight loss, but also on diabetes control. We implemented Joslin Nutrition Guidelines, which we developed in 2005, where the amount of carbohydrates and type of carbohydrates had been dramatically changed. We reduced the amount of carbohydrates down to around 40-to-45 percent, an also we reviewed the significance of the glycemic index of carbohydrates. But at the same time, we increased the amount of protein and the type of protein that people consume, and aim to maintain the muscle mass. As I mentioned, this is very important. People with diabetes, in general, lose nearly around one pound of their muscle mass every single year. During weight loss, when the protein intake is lower because of the reduction in the caloric intake, people lose even more muscle mass, and this will lead to rebound weight gain. At the same time, we give our patients a very high quality fat, and we give a fiber, and we review the sodium, and provide them with a meal replacement designed specifically to match the Joslin Nutrition Guidelines. We find that this intervention is extremely successful and easy for people to follow with an instructional plan. JB: So let me talk a little bit about this protein. I know that you’ve been involved in some research about composition of proteins, both in terms of bioactive peptides and also certain amino acids (maybe some of the branched chain amino acids and even proline). Can you tell us a little bit about the composition of protein and how it interrelates to insulin management? Protein Composition and Insulin Management OH: Yes, we have found recently that protein in the body will ultimately be in the form of glucose, so every time you eat 100 grams of protein it will be translated to around 56 or 60 grams of glucose inside your body. The only difference is that blood glucose will not go up with protein, and—contrary—blood glucose will go down every time you add protein. And the reason is very simple. Many of the amino acids are very strong stimuli for insulin secretion, but we also know that several amino acids accumulate GLP-1 hormone. This is the same hormone that we use now to treat type 2 diabetes. So for example, glutamine is a strong stimulus for GLP-1 hormone. Arginine is a very strong stimulus for insulin secretion. So even if the pancreas or the beta cell loses sensitivity to the glucose stimuli, they retain their sensitivity to the protein stimuli. And many of the good research has shown that people who increase the protein intake from 15 percent up to 30 percent showed significant reduction in the A1c, even within a short period of time, which would signify that we have been missing that part for a long time—adding protein in a good amount to the diabetes diet. The fear has been always for the kidney, but data shows definitely that if someone has normal kidney function, increasing protein intake will never cause any damage in the kidney or increase microalbumia. At the same time, reduction of protein has not shown, in any clinical trial and in a very big data analysis, that there is any impact in preserving kidney function. So I think we have been in a mess around protein for a long time and it is time for us to correct that mess and give our patients enough amounts of protein. JB: Now, I notice when you said glutamine and arginine, that those, as I recall, are in the ratio to, say, lysine are higher in vegetable proteins than in animal proteins on a per-gram basis. Is there any difference in the sparing effect of muscle between vegetable and animal protein as far as you know, at given equivalents? OH: Yes, that’s a very good point. In reality we know that plant protein is more beneficial. The only problem with plant protein is that it is deficient in essential amino acids. So many of the trials that have been done among the vegetarians showed that actually a vegetarian diet reduces the risk for type 2 diabetes and also has some good impact on lipid profile and cardiovascular risk in general. But the problem is that it put people at higher risk for deficiency or abnormality in some of the coenzymes and hormones that are dependent on essential amino acids. On the other side, protein that comes from meat and processed meat is a problem. This is the protein that has a higher amount of heme, or iron, and that amount of iron actually increases insulin resistance to a higher level and makes diabetes, in general, worse. Plus the fat in this type of protein—the meat and processed meat—is actually the worst type of saturated fat. JB: That’s very helpful. And now let me shift, if I can, to micronutrients for a second. There are a few micronutrients that I have read that seem to be associated prominently with the important role they play in glucose management. Those include biotin, thiamine, chromium, inositol, and magnesium. I’m sure there are many other vitamins and minerals as well, but those are the ones I’ve seen kind of prominent. Is there any experience that you have had about the ratio or balance of these pivotal micronutrients in managing blood sugar? OH: Yes, there is a lot of research. None of that research, I would say, rates to the quality that we can use it as a guideline. The only two micronutrients that I will trace on is the magnesium and vitamin D. There is data to show that higher magnesium and higher vitamin D actually reduce the risk for type 2 diabetes. But the rest, you know, there is some little data about chromium, some little data about thiamine and others, but I would say that magnesium and vitamin D are most associated. In many meta-analyses they have been shown to be associated with a reduction in the risk for type 2 diabetes. Fiber Intake Can Have A Huge Impact on Diabetes JB: So now let’s talk about the topic that you mentioned, which is fiber. We know that there are different kinds of fiber from the soluble and insoluble family, and different types of oligosaccharides that make up different kinds of non-digestible carbohydrate. Are there any guidelines as to the type of fiber? Or as long as it is non-digestible carbohydrate it is good? OH: Yes. In general, the US population is eating very little amounts of fiber. If you look to the Canadian guidelines or the European guidelines, they recommend fiber close to 30-40 grams per day. Our recommendation had been staggering around 25, 30 grams per day. The reality is if we were to increase fiber and to raise fiber up to 50 grams per day, it has a huge impact on diabetes, because it slows gastric absorption, it slows transit time in the GI tract, and it reduces the sudden spike in the blood glucose in response to carbohydrates. But regarding the soluble and insoluble fiber, in reality soluble fiber is a major fiber that has huge impact on LDL and also on the risk for diabetes. You know, when data analysis compared fiber from leafy green vegetables and fiber from fruits, which is soluble fiber mostly, they found that there is always a reduction in risk of diabetes with a soluble fiber. So people who will be able to increase the amount of soluble fiber get two benefits. The first benefit is a reduction in the risk for diabetes, but the second benefit, which is also very important, is the reduction in LDL. JB: Yes, I’m very interested in watching the evolution of this story. Fiber has been around in my life as a topic since the oat bran craze about 25 years ago. Now we start seeing things of the soluble fiber families—like inulin, for example and other oligosaccharides—where the gut microbiome can make the short-chain fatty acids (proprionic, butyric, acetic acid) and how they influence aspects of glucose regulation, so this interaction between fiber and the microbiome and insulin signaling appears to be a very fascinating chapter that is evolving in this field. OH: You are absolutely right, Jeff. You know, there is new data which is still fresh but I hope it can be confirmed, that when you give any slowly digested carbohydrates, the fermentation that is caused by the microbiota in the intestine could be the reason for the assimilation of the GLP-1 hormone production in the intestine. What I have seen in many of the diabetes is a specific formula that use a resistant starch which is not digested in the GIT and remains, you know, in the GIT for longer duration to reach the terminal part of the ileum and the large intestine. There is data to show that giving them increases actually GLP-1. I have seen the same with monounsaturated fat and also with saturated fat. So it is a very interesting concept, how the microbiota react and may be beneficial for people with diabetes, but time will tell us more because this is a fresh and new area of research. JB: Let’s move over to a huge study that you’ve been involved with as a principal investigator. It’s a very important study—the Look AHEAD study. For those that are not familiar with that could you tell a little bit about the design of that study, where we are and what the results have been? You’ve, I know, published progress reports on this very interesting, forward-looking study.[3] The Look AHEAD Trial: A Successful But Misunderstood Study on Lifestyle Intervention OH: Yes, Look AHEAD is probably the third largest study that has been done in the history of diabetes research, after the DCCT trial and the Diabetes Prevention Program. The whole idea of the Look AHEAD study is to see if people with diabetes lose and maintain weight loss (7-to-10 percent weight loss) for 10 years or more, and will this intervention lead to reduction in the mortality and cardiovascular events (fatal and nonfatal heart attacks and so on). The first data results of the study were very promising after one year and four years, but unfortunately the study had been terminated earlier because of futility (there is no difference between the intensive intervention arm and the control arm). It sent a shock of the wrong message to many in the community when the study was stopped because people started to feel that lifestyle intervention would have no impact on cardiovascular mortality and cardiovascular events, but in reality, people who know the design of the study and how the study had been conducted can easily understand what is the impact. When the study was initially designed, there was a calculation of the rate of mortality per year from cardiovascular reasons, but over the last decade, actually the deaths from cardiovascular events went down in the entire nation by close to around 50 percent. So the study, in reality, started to lose its power over time. The other part, which is very important, is that the other arm of the study, the control group, had been freely increasing and changing their lipid-lowering medication and antihypertensive medication. Both of them are very strong in protection from coronary events. The intervention arm, in reality, would use this medication and they use also diabetes medication, so when we see there is no difference between the two, we can actually conclude that you can prevent coronary artery disease either by adding more medication, as had been shown in the control arm, or by lifestyle intervention, and it is the choice for the individual to choose between increasing medication or losing weight and maintaining that weight loss. The study, in reality, showed many, many benefits of the weight loss. Hospitalization had been less. Cost had been less. Risk for depression had been less. Risk for chronic kidney disease had been less. Quality of life improved significantly as well. So I will say the study had been very successful, but the design of the study and the conduct of the study was not controlled enough to make the difference show up over time. Opinions on Surrogate Biomarkers JB: Thank you. So that raised a question for me from a clinical perspective, and that is we have a variety of surrogate biomarkers that are used to track the progress of a patient, knowing that not everyone is going to have some type of a vascular analysis done, either EBT, or FMD, or something, so we use things like hemoglobin A1c, or hs-CRP, or adiponectin. What surrogate biomarkers do you think are clinically useful in tracking the progress of these therapies in individuals at risk. OH: This is a very good point. I personally believe that the core of the problem of both type 2 diabetes and atherosclerosis is subclinical inflammation going on. That subclinical inflammation is not manifested in the form of fever or white cell count, but you can easily assess that subclinical inflammation by measuring the cardio CRP. They have showed over and over that any intervention that reduces CRP actually reduces the risk for heart attack. To our knowledge, two major interventions can reduce CRP. One of them is the statin, and this has been seen in the JUPITER trial, even in patients with normal LDL. When the CRP was high and reduced by rosuvastatin, the risk for cardiac events and mortality had been lowered. The other intervention that we know for sure and we have data to show that clearly is lifestyle intervention. Lifestyle intervention has been very, very effective at reducing CRP. Some newer medications like GLP-1 analogs also have been shown to reduce many markers of inflammation. So I think markers of inflammation are very important. Adiponectin indicate improvement in insulin sensitivity, but the measurements are a little bit complicated or a little bit difficult and costly, and it is not suitable for clinical practice. I believe CRP is easy—very simple—a non-fasting sample can be done and you can get very good results. The Strengths and Limitations of Measuring Hemoglobin A1c JB: So can you give us the state-of-the-art right now as it relates to the use of hemoglobin A1c for measuring glucose, what it’s strengths and limitations are? OH: Yes, the problem with A1c is that A1c has very low sensitivity and very high specificity, which means that when the A1c is high it always signifies there is a problem going on, or even diagnose diabetes in a very effective way. But when A1c starts to go down, it doesn’t exclude that there is damage going on and people may still have diabetes even with A1c in the pre-diabetes range, between 5.7 and 6.4. But in general, A1c is a simple, easy tool that can be used for diagnosis, for screening, because it doesn’t require fasting and it is also summary of every three months because it’s not just one measurement. Diabetes is a Continuum and Numbers are Arbitrary JB: You know, I’m taking a little bit of a look back with you here for a second. I was in school in the late 60s and I recall that the course I had in discussing diabetes and endocrinology said something like diabetes started when the fasting blood sugar was greater than 200. And so at that point in the sequelae of events, many people that presented with diabetes already had nephropathic or neurological injury. They might have had ocular problems. And so you had a whole bunch of attendant secondary pathologies that were involved when a person was diagnosed with diabetes. Today, the definition for a diabetic patient is, I think, a blood sugar (fasting) greater than 126 milligram per deciliter. So it seems like we should be getting people earlier, which would make them more of a candidate for these lifestyle intervention therapies, yet we see our dialysis centers just filling up with more and more patients that are in renal failure. How does this all fit together? It seems like there is something that I’m missing. OH: Yes, you are absolutely right. The problem is that diabetes, in relation to complication and risk, is a continuum. We created those arbitrary numbers of 200 or 126 or 140, but in reality the risk is a continuum, and the risk starts very, very, very early, even before people develop pre-diabetes, which means that if we would be able to identify those people of higher risk early enough, we should immediately intervene. The problem right now is that we wait until the car makes a crash and then rebuild the car. We need to protect the car from getting into that crash. Most people wait until the patient develops diabetes and confirm the diabetes to treat them, but studies show that actually people with pre-diabetes, or even relatives (first degree relatives) of people with type 2 diabetes have exactly the same risk, so intervention should be started very, very early once those people have been identified that they have a family history of diabetes. You know, using the blood glucose level as a parameter for diagnosis is a problem by itself. JB: So that leads us to where the tire meets the road right now. We have these increasing numbers of patients that are coming in in early-stage diabetes. We know that over the course of therapy that they’ll probably be started on metformin as the first pharmacotherapy and then they’ll be graded up with maybe TZDs or with incretins and GLP-1 agonists and then they might go through ultimately ending up in insulin therapy. How does this all compare to an effective intervention of lifestyle therapy? If we had to go on the basis of the data today and we didn’t have to worry about the behavioral determinants and the compliance and adherence components, which would win? Does the lifestyle intervention win, or does the graded pharmacotherapy win in preventing the terminal states of diabetes? OH: Yes, Jeff, this is a very, very important question. We have to understand that the major problem in type 2 diabetes is insulin resistance. I personally believe it is more than 90 percent of the problem, is the insulin resistance in people with type 2 diabetes. So unless we improve insulin sensitivity, we cannot control diabetes in a very efficient way. To our knowledge, the best and the most effective [approach] in improving insulin sensitivity is not medication like metformin and TZDs, it is the weight loss. And the subject you referred to earlier showed that when people lose seven percent of their body weight, insulin sensitivity improves by 57 percent. Fifty-seven percent is equivalent to two medications for diabetes at maximum dose. Metformin improves insulin sensitivity, but was not able to prevent type 2 diabetes in comparison to lifestyle and the Diabetes Prevention Program. In the Diabetes Prevention Program, people who lost weight and maintained weight loss reduced risk of full conversion to type 2 diabetes by 58 percent, while with metformin it was only 51 percent. So you can see there is a big difference. If lifestyle is done very, very early and people lose that seven percent and maintain that weight loss, this is a glorious period of diabetes because during this period people are still making enough amounts of insulin, and that insulin can put into function back and diabetes can be reversed entirely or maybe it will go into remission. In the Why WAIT program, we have seen around 17 percent of our patients stop their medication and back to partial or complete remission from diabetes. So it is a time factor—when to start—and how aggressive you are, but the key also is to maintain that weight loss for longer duration. JB: That was beautifully stated, and I guess one of the things that you imply in this is that when you talk to a diabetes cell biology researcher they will tell you it’s all around beta cell preservation. If you can preserve beta cells, which is what you’re telling us, that you’re going to be able to prevent the onslaught of this progressive diabetes. Is there any evidence that you’re aware of that lifestyle intervention, when successfully applied, such as the Why WAIT program, does preserve beta cell function, or do we just assume that from surrogate evaluation? OH: You know, the reason for the strain on the beta cells is to try to overcome the insulin resistance. So the best preserver of the beta cell is actually the improvement in insulin sensitivity. So any intervention that improves insulin sensitivity actually put beta cells to some rest, and we have seen this after bariatric surgery, after nonsurgical weight loss—insulin levels start to go down and there is improvement in insulin sensitivity. So, in my personal view, the best way to preserve the beta cell or to prevent further loss function of the beta cell is to improve insulin sensitivity, and the best way, of course, is the weight loss. JB: Well I can tell you that this has been extraordinarily helpful and informative for all of our listeners and certainly me as well. I want to thank you both for the time you’ve spent with us today, but also for the extraordinary work and commitment you’ve made over the last 15 to 20 years in helping to better understand. And it sounds to me—if I can do a sound bite takeaway—that this type 2 diabetes epidemic that we’re experiencing is really a lifestyle disease, and that you need to treat a lifestyle disease with a lifestyle intervention. It’s not an infectious disease that you treat with antibiotic; it’s a lifestyle disease that you treat with the proper lifestyle. That’s kind of my takeaway from what we’ve talked about. OH: Yes, Dr. Bland, you framed it very, very nicely. I would like to call it lifestyle diabetes. It is not type 2 diabetes—lifestyle diabetes. You know, during the time of Elliott Joslin, in the old days, they used to call it fatty diabetes because they understand that the core problem of type 2 diabetes—the bacteria of the disease—is the body weight. The fever is the blood sugar. So if we spend all our effort, our time, our money just treating the fever by drugs without dealing with the core problem, which is the body weight, I think we’re wasting time and effort. This is a lifestyle disease. For prevention, for management, for prevention of complications—primary, secondary, tertiary—it is a lifestyle disease. JB: That’s a fantastic place to leave this. I’m thinking it’s an optimistic message because lifestyle is modifiable, genes are not. I think you’ve done a wonderful job in your book, The Diabetes Breakthrough, in laying this down in a way that people can understand. Dr. Hamdy, thank you so much for the time spent and continue on with your great work and we’ll be following it very closely. OH: Thank you very much for inviting me. JB: Appreciate it. Bye-bye.  

Bibliography

[1] Hamdy O, Ledbury S, Mullooly C, Jarema C, Porter S, et al. Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome. Diabetes Care. 2003 Jul;26(7):2119-25.   [2] Hamdy, Osama and Sheri R. Colberg. The Diabetes Breakthrough: Based on a Scientifically Proven Plan to Lose Weight and Cut Medications. New York: Harlequin, 2014.   [3] Unick JL, Hogan PE, Neiberg RH, Cheskin LJ, Dutton GR, et al. Evaluation of early weight loss thresholds for identifying nonresponders to an intensive lifestyle intervention. Obesity (Silver Spring). 2014 Jul;22(7):1608-16.   [4] Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403.   [5] Gerstein HC. Do lifestyle changes reduce serious outcomes in diabetes? N Engl J Med. 2013 Jul 11;369(2):189-90.   [6] Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013 Apr 4;368(14):1279-90.   [7] Mann J, McLean R, Skeaff, Morenga LT. Low carbohydrate diets: going against the grain. Lancet. 2014 Oct 25;384(9953):1479-1480.   [8] The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013 Jul 11;369(2):145-52.   [9] Gregg EW, Chen H, Wagenknecht LE, Clark JM, Delahanty LM, et al. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA. 2012 Dec 19;308(23):2489-2495.   [10] The ORIGIN Trial Investigators. N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367(4):309-18

Welcome to Functional Medicine Update, December 2014, the third of a three-part series on diabesity. As you recall in the first of this three-part series we had the pleasure of interviewing Dr. Philip Kern from the Barnstable Diabetes and Obesity Center from the University of Kentucky School of Medicine who really laid the groundwork for understanding—in the field of clinical endocrinology—what is type 2 diabetes? What is the nature of its problem in our society today? How does it relate to obesity, and what are the kinds of things that a clinician should be aware of as they diagnose, assess, and ultimately develop a treatment program for their patients? In the second of this three-part series we had the privilege of interviewing Dr. Osama Hamdy from the Joslin Diabetes Center at Harvard Medical School who did an extraordinary job in helping us to understand how lifestyle intervention could play a very important role in modulating type 2 diabetes both in the early stages and then in the sequelae of events of more severe consequences. In this particular discussion he helped us to understand how important personalization of the program might be, and also the important role that medical nutrition therapy might have in helping to accelerate the benefit in patient management and make compliance and adherence more successful. In the third of this three-part series we are going to be very fortunate to hear from arguably one of the world’s—if not the world’s—leader in insulin signaling, Dr. C. Ronald Kahn, the director of the Joslin Center, who will really help us to understand what the 21st century view of this disease is (its etiology), and how it presents in multiple forms based upon different types of disturbances and the understanding of how genes are translated into the phenotype. So without further ado, let’s move to our discussion with Dr. C. Ronald Kahn.  

INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month C. Ronald Kahn, MD Chief Academic Officer and Senior Investigator Head of Section on Integrative Physiology and Metabolism Joslin Diabetes Center One Joslin Place Boston, MA 02215 http://www.joslin.org/diabetes-research/Ronald-Kahn-MD.html Well, you know how excited I am each time we have this opportunity to share with a world-renowned clinician/researcher and of course this month we are, I would say, at the top of our game. We have the opportunity to be speaking with Dr. C. Ronald Kahn. I think the name alone, for those of you in the field of diabetology or metabolic diseases, already know much about what I’m going to say. He is a world-recognized expert, obviously, in diabetes and obesity research, and a preeminent investigator in the area of insulin signal transduction. As to his professional background, presently he’s a senior investigator, head of the section on integrative physiology and metabolism at the Joslin Diabetes Center and the Mary K. Iaccoca Professor of Medicine at Harvard Medical School. He served as the research director at Joslin from 1981 to 2000 and served as the president of Joslin from 2001 to 2007. He is currently the center’s Chief Academic Officer. I could spend the whole of our time just talking about Dr. Kahn’s achievements. I was first introduced to his work when I started to recognize that the emergent understanding of diabetes was really tied to the personality of the insulin receptor and its insulin stimulated receptor, tyrosine kinase, which was really Dr. Kahn’s discovery. The Kahn Lab is focused on understanding how the event—this tyrosine kinase activation within the insulin receptor and insulin receptor substrate—activates the complex signaling network that leads to the multiple actions of insulin. And his group, over the years, has showed that following activations, several insulin receptors substrates become tyrosine phosphorylated, so this whole kinase intracellular signal transduction process is mediating this process and, as intracellular messengers, they then talk to other intracellular signaling proteins and we get into this very complex nature of how genes are ultimately signaled and how we alter glucose transport and see the manifestations across the pleiotrophy of what we call type 2 diabetes. I think we would have to say over the 660-plus publications of Dr. Kahn’s career, that he has been the pioneer in really helping to understand, at the molecular cellular biology level, what is type 2 diabetes? We use that as just an introduction to the vast panorama of work that you’ve been involved with, Dr. Kahn. I guess I would just ask, how did you get started down this road, being a pioneer? You know, it’s always one of those remarkable things—that some “ah-ha” must have occurred on your path that led you into these extraordinary discoveries. Major Discoveries About Insulin Took Place in the 1970s CRK: Well, my own experience really began as a fellow at NIH. I was with Jesse Roth and Phil Gorden, who back then were really leading the charge on trying to understand the new frontiers of hormone action. It’s hard to believe that really only 40 years ago we really had no understanding of how insulin worked at the cellular level. There were theories that insulin might get into the cell, and interact with enzymes in the cell, that it might covalently attach to these enzymes or to cell proteins through disulfide bonds (because insulin has disulfide bonds), and many other theories. But going back now to the early 1970s, there were a series of discoveries in several laboratories, but particularly in the laboratory of Jesse Roth, that really began to say that insulin and other peptide hormones were acting through membrane receptors in a way that would allow the hormone to signal the cell from the outside and create an intracellular signal. And there were many other discoveries that also supported this kind of view; certainly this was not alone. So initially we got started looking at the insulin receptor mainly as an insulin binding protein, that we could show that it bound insulin in a way that was consistent with biological activation rather than like an antibody binds insulin, but not in a way that is related to its biological activity but the receptor binds related to its biological activity. And then we were able to do many studies that got us into beginning to understand the structure and after about really almost a decade from the time we did the first insulin-binding experiments, we came to realize that the receptor was the tyrosine kinase. There had been one previous example of the tyrosine kinase receptor, which was the EGF receptor, and nobody really knew that the insulin receptor would be like that because it has very different structure from the EGF receptor. But we thought, well, since we had this new potential mechanism, let’s try. And Misako Kasuga, and Anders Karlsson, and I set out on a series of experiments that initially were a little bit disappointing, but we stuck with it for a while and sure enough after several months we were really able to see that this receptor had tyrosine kinase activity, and that changed the whole paradigm of insulin action.[1] JB: When I think back to my own training in medical school in the late sixties, I am reminded that we had very little discussion at that point about the different voices of insulin and the fact that there could be this form of diabetes that was associated with hyperinsulinemia as a consequence of blunting it with an insulin signaling mechanism. It must have been quite a remarkable shifting paradigm within the field of diabetology when you made these discoveries and started to really explicate how these signals could be both created and could be inhibited. The Insulin Receptor and Its Substrates Control Insulin Response CRK: You’re right, Jeff. I’m pretty much contemporary with you in when I did my medical training and basically I think that most people thought of diabetes as really insulin deficiency, although we knew that there were type 2 diabetics who were insulin resistant, but the question of how that resistance occurred was completely mysterious. There were some studies that suggested that maybe these people had increased insulin degradation, or perhaps they had insulin binding proteins in the blood (not antibodies, but other proteins that interacted with insulin in the blood), and that these substances might somehow create insulin resistance. But once we got the receptor, and once we knew that the receptor was there, we showed that the receptor itself is regulated. Just like insulin levels can go up and down, the receptor levels can go up and down, and of course if you have more insulin you get more insulin action; if you have less insulin you get less insulin action. But likewise, if you have more receptor you get more insulin action, and if you have less receptor you get less insulin action. And that’s true through every step in the process, so the substrates of the receptor and the intracellular signaling enzymes and transcription factors which relate to the receptor all can become factors in controlling the insulin response. In fact, you could think that there are really many more controls on insulin action/insulin signaling than there really are on the controls of insulin secretion because of all of the different steps that are involved in this process, and of course all of the different tissues that are responding, which can have not only some differences in the exact signaling cascade, but can certainly also have differences in how they develop insulin resistance. Kinase Intracellular Signaling: A Metabolic Relay Race JB: You know, one of the things that I think you can help us with probably better than anyone I know is to assist our listeners, which are principally clinicians, to understand a little bit more about this kinase intracellular signaling transduction process, which is a little bit like a molecular relay race with some degree of feedback control. Could you help us understand…I know it’s a very complex network…but maybe you could help—for the clinician—to understand what goes on inside the cell relative to this complex kinase array. CRK: Sure. This is really somewhat complex but I think it’s pretty simple if you think of it this way. The receptors for insulin and other peptide hormones and neurotransmitters sit at the surface of the cell, and their job is to recognize their hormones or ligands, whether they be insulin or growth hormone or other peptide hormones or catecholamines, to recognize those hormones by binding them with a high affinity and a high specificity. Once they bind, the hormone doesn’t really ever enter the cell for signaling purposes. It may enter the cell eventually to be degraded, but it doesn’t enter it for signaling purposes. What it does is it triggers a change in shape of that receptor (a change in confirmation). In the case of the insulin receptor, this activates an enzyme activity that is on the intracellular part of the receptor, and that is tyrosine kinase activity. And what the words “tyrosine kinase” mean is it’s just an enzyme that can put a phosphate group onto tyrosine residues of proteins. And the insulin receptor puts phosphates on tyrosines, both on the insulin receptor itself and on intracellular proteins that are its substrates. These are called insulin receptor substrates 1, 2, 3, and 4. So these substrates then have this little extra addition to certain tyrosine residues. And they become the intracellular messengers of insulin action. They do that because now other proteins in the cell can bind to the sequences around these phosphotyrosines in a way that allows them to become activated, and so it is kind of a relay race. I think your analogy with a relay race is a very good one. The receptor is kind of the first person in the relay. The receptor hands the baton—in this case a phosphate group—off to the substrate, IRS-1 or IRS-2. And then the substrate actually in this case doesn’t pass the phosphate group (it doesn’t pass the baton), but what it does is another protein in the cell, maybe an enzyme—like there’s an enzyme called PI3 kinase that’s an enzyme that is involved in insulin signal transduction—and it binds to this tyrosine phosphate group, and it gets activated, and then it carries on the chain. So it is kind of a relay race. In some steps a signal branches out, so you can have two or three different directions it goes. In some steps there is regulation. And so this allows the whole signaling of insulin at the cellular level to be finely tuned so that each cell type can respond in the way that is most appropriate for it. JB: So as we go down that pathway—as you go through PI3 kinase and down into Burton’s tyrosine kinase and into SYK and ultimately through GSK-3—there is a confluence of that network of that pathway with the inflammatory pathway, which is interesting from a physiological perspective and may account for some of the things that you see clinically with patients that have inflammatory crisis, say, in the ICU and they end up with hyperglycemia. So how do those networks interrelate—the inflammatory pathway and the insulin signaling pathway? CRK: Right, so there are many hormones and growth factors that use some of the same similar components for signaling. There are a number of tyrosine kinases; they have different substrates. Many hormones and many growth factors activate this PI3 kinase pathway that I was talking about, and some of the downstream pathways that you mentioned, including AKT and others. I like to call these the critical nodes of insulin signaling. Because these are the parts that not only insulin acts on, but other hormones may act on them in similar ways, or in ways that inhibit the action of insulin. So you mentioned, for example, inflammatory cytokines. We know that in states of inflammation, there is insulin resistance. In fact, this is, in part, what goes on in the insulin resistance when people have infection: inflammatory cytokines go up, those inflammatory cytokines create resistance to insulin action at the tissue level. And so in a normal person we can compensate by making more insulin, but of course a person with diabetes may not be able to compensate and their diabetes may go out of control. So the way that works is that these inflammatory cytokines also activate a signaling network and some of the steps are similar, but there are also some that are different. For example, when these inflammatory cascades get activated, there is a group of kinases—those are intracellular enzymes that can phosphorylate (put phosphate groups onto protein)—that can modify serine residues of IRS proteins. Now I told you that the insulin receptor modifies tyrosine residues, and that has a positive insulin action. When these inflammatory cytokines are activating their system, they cause serine phosphorylation—a different amino acid in a different place in the chain—and that’s a negative signal. So we’ve got tyrosine phosphorylation as a positive signal, and serine phosphorylation as a negative signal, and it’s kind of a balance of how these things will play out in any given individual. JB: So if we had a patient—trying to take this from the bench to the bedside a little bit, in this discussion—who had, say, a chronic inflammatory state as a consequence of, say, activation with lipopolysaccharide from gram negative bacterial cell wall debris, and so they had an activation of the toll-like receptors that activated their inflammatory pathway. It seems there could be cross-talk, then, with their insulin signaling to precipitate these serine phosphorylation events, which then could blunt insulin sensitivity. Is that a reality? Inflammation—Major and Minor—Can Influence Insulin Signaling CRK: Yes, that’s actually correct. And there is a lot of evidence for that. In fact, there’s also evidence that not only in states of major inflammation—like you were talking about: infection, and bacterial infection, and so forth—but these can be chronic inflammatory states of a mild degree, like associated with obesity. Obesity is associated with inflammation. There’s actually inflammation in adipose tissue in obesity, and those inflammatory cells and the inflammatory cytokines that are produced can do the same thing; they are creating insulin resistance at the cellular level, interfering with these downstream steps and insulin action, and when that occurs, that will lead to insulin resistance. JB: So let’s take it one step farther a little bit as we head on towards the promoter regions of genes inside the nucleus. So we have these so-called orphan nuclear receptors, which are agents that are kind of communicating the message from the kinase signaling pathway ultimately into the specific regions of the genes where the genes are going to be expressed. The one that obviously comes up often in type 2 diabetes and ultimately adipocyte physiology is peroxisome proliferated activated receptor gamma or alpha. Tell us a little bit about how these nuclear orphan receptors play a role in this process. CRK: Yes. Well, I’m going to back you up one step. First let’s do the normal part and then we’ll do the sort of cross-talk part because I think you’re going right already to the cross-talk and I’m going to finish up first the normal part. So the normal part is that the enzymes that are activated by insulin—PI3 kinase that activates this downstream enzyme called AKT—what they actually do is act on transcription factors, and the most common or important one that they act on is a transcription factor called FOX01. This transcription factor normally sits in the nucleus of the cell, and what it does is it turns on genes that make enzymes for gluconeogenesis. That is, enzymes that are going to make more glucose in the liver. So when FOX01 is in the nucleus, which it is in the liver normally (in the nucleus), it’s telling the liver cell: make more glucose. And that of course will bring the blood sugar up. What insulin does is through its cascade it causes phosphorylation on a serine residue of FOX01, and that actually keeps FOX01 out of the nucleus and keeps it in the cytoplasm of the cell, and that’s where it’s inactive, so that brings down the level of gluconeogenesis (glucose production by the liver). So that would be the normal example of how insulin regulates gene expression. Now, as you were pointing out, at this level there is also a lot of cross-talk. There is cross-talk between other factors that can regulate FOX01, for example, directly, but also other transcription factors and even nuclear receptors, both some which have known ligands and some which have unknown ligands. Nuclear receptors are really the other big class. I said the insulin receptor is a membrane receptor, so peptide hormones and neurotransmitters use membrane receptors, as do certain other chemical substances like taste receptors and other sensory receptors, and then the other big class of receptors are nuclear receptors, and of course that includes the receptors for steroid hormones, thyroid hormones, and also receptors for a lot of small molecules. PPAR gamma is a nuclear receptor that is thought maybe normally to bind some lipid molecules, but nobody really knows for sure which lipid is the most important for PPAR-gamma, so it’s sort of been considered not a true orphan receptor, but it’s somewhere between a defined receptor (a normal binder) or not, but we do know that certain drugs, like the thiazoladinediones (piaglitazone, troglitazone, rosiglitazone, all of this class of drugs) bind to PPAR-gamma. PPAR-gamma is mainly in fat cells, and in those fat cells it turns off that inflammatory response that is going on in adipose tissue and it actually allows the insulin resistance to improve. Insulin Events Are Cell Specific JB: So when we look at this whole extraordinary symphony, and we’ve only probably talked about a few instruments in the orchestra—there’re are lots of other ones we haven’t talked about, I know, or probably many that we are yet to even discover and understand—and you then put the additional complicating factor that these events are occurring in cell-specific ways, so there might be a difference in how these are orchestrated in the macrophage versus the adipocyte versus the cardiomyocyte versus the beta cell of the endocrine pancreas. Are there some general principles that we take away or is there a cellular voice that is stronger like the adipocyte or the hepatocyte that helps orchestrate this process? The Four Most Important Tissues in Insulin Signaling CRK: Well, this is a bit of a tricky question because many different tissues play a role. In terms of insulin signaling, the four most important tissues in terms of insulin signaling are the liver, where insulin turns off glucose production; the fat cell, where insulin helps the fat cells store the bits and pick up glucose; the beta cell (the insulin secreting beta cell), because actually insulin action in the beta cell helps the beta cell have normal glucose sensing, and you know that one of the defects in type 2 diabetes is the beta cell doesn’t respond normally to glucose, that’s why you get relative insulin deficiency. The beta cells are there, but they are just not functioning very well, and that’s—we believe—also part of the insulin resistance problem. And then of course the newest frontier of insulin action is the brain. Traditionally both the beta cell and the brain were not thought of as insulin sensitive tissues, but in fact both of them are insulin sensitive tissues. Not a lot of insulin gets across the blood-brain barrier but some does, and in particular around the hypothalamus, the important part of the brain for control of metabolic functions, it’s a very key spot for some insulin action, so that insulin resistance in the brain can also be quite a contributor to the overall problem in type 2 diabetes or metabolic syndrome. JB: Does this tie at all to what I’ve read in the literature as euphemistically termed “type 3” diabetes? Thoughts on Insulin Resistance and Alzheimer’s Disease CRK: Well, I think that what the connection is with the brain that people are thinking of as type 3 diabetes is also that there is some evidence—we’ve actually shown this in our own laboratories but others have shown it as well—that insulin resistance at the brain, or at least a lack of insulin action at the brain, may cause changes that could contribute to neurodegeneration, and potentially contribute (at least in a collaborative way with other factors) to the pathogenesis of Alzheimer’s disease. So that some people have now actually written articles and have given lectures titled “Is Alzheimer’s Disease Type 3 Diabetes?” It’s a little bit of a stretch to say that it is “type 3” diabetes because Alzheimer’s disease really isn’t diabetes at all in the sense of blood glucose control, but what we’re trying to say is that maybe insulin action of the brain really does have some protective roles in brain function, also IGF-1 (insulin-like growth factor 1) action at the brain. And so one of the great, new, exciting research areas just developed in the last two or three years has been to actually do some very small clinical trials looking at the potential for giving insulin (potentially intranasal insulin, which might get to the brain at a little higher concentration) and see if that would change the course in some way of Alzheimer’s disease.[2],[3] We don’t think that this is the primary problem, so it’s not going to necessarily stop it or prevent it completely, but if you could slow the progress, that would be great. JB: Let me, if I can, go back with you for a second. I know of your many publications, one that you were principal author on in 2014 related to cell surface markers in the different types of adipocytes.[4] I recall in my cell physiology studies way back when, we didn’t really think about types of adipocytes. Now we’re talking about both white and brown and these beige adipocytes. Could you tell us a little bit about how that fits into the story and the work that you are doing? Research is Looking at Brown Fat to Burn Energy and Control Weight CRK: Well, this is actually another story that has evolved rather dramatically over the last five-to-ten years. I think all of us (all clinicians—MDs) know about white fat. That’s the fat that is spread throughout the body, under the skin, inside the abdomen, around blood vessels, around the omentum and so forth. All of these fat cells, which are either white or yellowish in color are referred to as white fat, and they are fat that is specialized for storing triglyceride. And of course their special function is to store that fat from energy we’re taking in now so that if at some time in the future we don’t have access to food, we have energy stores to help live on. Now, most of us, even the leanest out of us—I mean even people who have BMIs down at 20 or 21—have still a few kilograms (sometimes several kilograms) of white fat. But there is a second kind of fat that has been known to exist for quite a long time, but people thought wasn’t so important in adult humans and that’s called brown fat. And brown fat is different from white fat in many ways. First of all, as the name implies, it has a brownish color. That’s because the fat is loaded with mitochondria, and mitochondria have a lot of enzymes that are iron-containing enzymes, so it gives the fat a brownish color. In mice and in rodents, this brown fat is collected into a single collection that is located on the back, between the shoulder blades (the interscapular region). In newborn humans, there is also interscapular brown fat, but what we found about six or seven years ago using PET imaging is that in adult humans most of the brown fat is scattered in little collections in the neck and the anterior part of the neck: the anterior cervical area, the supraclavicular fossa, down the axilla, and down in paravertebral areas, going through the thorax and even down to the pararenal areas in the retroperitoneal space. And this brown fat, spread out through all these areas, is really not a big organ. It’s not like you can go in there and simply cut out all the brown fat because it is kind of mixed in with the white fat, and we believe that whereas most people have kilograms of white fat, probably the average human has somewhere around 50 or 70 grams (not kilograms—50 or 70 grams) of brown fat, but this is very important, because this brown fat can burn energy. A hundred grams of brown fat can burn 350 calories a day if it is fully stimulated, and that’s a pretty good amount of energy. It does it and it generates heat, so a lot of interest now is can we convert white fat to brown fat or have people give drugs that will make more brown fat that might help then either lose weight or at least keep weight off that they’re losing by other means? And then, as you mention, there’s this new third kind of fat, which is called beige. And as the name implies, it is somewhere between white and brown. And what happens that defines beige fat is that in both experimental animals and in humans. If you put people in the cold chronically, you stimulate brown fat or beige fat to make more energy (burn more calories to keep you warm), and when they do that, some of the fat cells that are mixed in the white fat will start to show up as these kind of beige fat cells. So, what’s important about all this in terms of insulin is that the more white fat you have, the more insulin resistant you’re going to be, particularly if it is intra-abdominal visceral fat. On the other hand, the more brown fat—or perhaps brown and beige fat—you have, the more likely you’re to be lean, be able to burn calories, even without exercise (this is thermogenic calories), therefore you’ll also be leaner, less insulin resistant, and because the brown fat uses a lot of energy, the good news is that also helps you keep your weight down and your glucose down. JB: So as we look at the emerging story around beige fat—things like cold and other factors that may be beige fat-inducers—is there some hope that lifestyle modification might actually be a component that could activate beigeing of fat? CRK: Yes, I think that what people are looking at mainly is the possibility of developing drugs that could promote more beigeing of fat, but at least in experimental animals we can show that you can also activate beige and brown fat by putting them in a cooler environment, and you can do that in humans over the short term. You can put them in a cooler environment. It doesn’t have to be all that cold. It has to be 60 or 62 degrees Fahrenheit, and as long as people are not dressed warmly—as long as they are dressed in light clothing—we usually, for these experiments have people dressed in a hospital scrub suit—so if you’re in a hospital scrub suit in a 60 or 62 degree room, that is enough to activate your brown fat, and if you did it chronically it would probably make some beigeing of fat, and this would probably help with energy expenditure, but of course if you still eat a lot, that isn’t going to be able to overcome eating everything, so one would want to do this along with trying to lose weight through other means. JB: Two quick additional questions, one of which is this emerging belief that the gut microbiome plays some role in modulating this whole glucose control/insulin control process. What’s your thinking about the emergence of this concept? What Role Does the Gut Microbiome Have in Modulating Insulin Control? CRK: Yes, this is an exciting new area of research. We’re actually doing some work in this area ourselves. The gut microbiome refers to all the bacteria that are in the gut. These bacteria are not only living in our gut, they are helping us metabolize food, they are making various bacterial products which can affect our metabolism, and they are also doing other metabolic processes like helping us metabolize bile acids to make different bile acids. So the gut microbiome can be a big contributor to overall metabolism and health. The gut microbiome has been certainly linked with weight gain. Different microbiota seem to promote more weight gain and others seem to protect less weight gain, and that’s certainly one aspect. What we’re trying to find out now is are there also microbiota that can promote more insulin sensitivity and others that would promote less insulin sensitivity for example, because not everybody who is overweight is insulin resistant as the next person and maybe that’s also a factor of the microbiome. But this is really a new area and I think we have yet a lot to learn there. JB: I have also been following the literature of David Jacobs and Duk Hee Lee that seems to be getting some degree of interest in the field at large that there is an association between accumulation of persistent organic pollutants and insulin resistance or altered insulin signaling.[5] Does that seem to be tracking in a way that has any support? The Environment: “The Last Frontier of Medical Research” CRK: Well, what I would say is that I sometimes call the environment the last frontier of medical research, and what I mean by that is, you know, nowadays we have terrific tools to investigate genetics. We can sequence your genome or my genome and we can know every base on every chromosome from the beginning to the end, virtually, if we wanted it, right? So we have the tools to know in-depth genetics and we have tools to know in-depth how those genes are expressed by gene expression analysis, and how those expressed genes make proteins by proteomics, and how those protein functions by metabolomics. But I think that the great unknown factors in common diseases like diabetes, metabolic syndrome, obesity, and even cardiovascular disease are other environmental factors. You know, we focus right now on the obvious things: how much we eat, how much fat is in the diet or how much simple sugars are in the diet, fructose or other things, but we really don’t have a good handle on all the environmental factors. They could be airborne environmental factors, like air pollutants. They could be other things that are taken in by mouth which are non-nutritive, including both contaminants and natural contents of foods and other foodstuff. And of course they could be other kinds of organisms. We talked about the gut microbiome, but it could be, of course, other microbiota too. So all of these things I think are really going to be important modifiers of genetic risk for diabetes, obesity, insulin resistance, and so forth, and I think one of the hopes that I have for the future but I think we’re still a long ways from this is to really have the same kind of research tools to study the environmental factors that we do to study the genetic and other molecular factors that we look at. JB: So I don’t want to put words in your mouth and this is probably a little bit of a leading question. Given what you just said, which has kind of an epigenetic ring to it, do you think that the concept of healthcare lifestyle medicine will have a role to play in the combatting of this rising tide of type 2 diabetes as we move forward? CRK: There’s no doubt that lifestyle modification even of the factors we already know can make a difference. This has been shown by the Diabetes Prevention Program, Da Qing Study in China, by the Helsinki study, by many—studies show that the lifestyle interventions (just doing the things we know: exercise, lower calorie diet) can make a difference. I think that what we don’t know yet is what will be the lifestyle modifications of the future and how will we effect those, because, for example, if we want to affect the microbiome in a certain way, will people need to take probiotics or prebiotics to do that, or if we want to affect some other factors like different pollutants, or different environmental toxins that might modify our system, how would we change lifestyle to modify those? But I do think that a lot of these things will be lifestyle variables, some of which will be easier to control than others. JB: Well Dr. Kahn, on behalf of the listeners and clinicians around the world that will have the privilege of listening to you, I want to thank you for both the extraordinary breadth of things that you were willing to talk about and how very clear your responses were and really news-to-use in condensing down all the years of your contributions and more than 660 publications is not an easy thing to do, but I think you did a very, very good job of it. We thank you very much and I think this will positively affect literally thousands of clinicians and hopefully therefore hundreds of thousands of patients as they listen to this message, so thank you for the time spent with us. CRK: Thank you, Jeff.  

Bibliography

[1] Kasuga M, Zick Y, Blith DL, Karlsson FA, Häring HU, Kahn CR. Insulin stimulation of phosphorylation of the beta subunit of the insulin receptor. Formation of both phosphoserine and phosphotyrosine. J Biol Chem. 1982 Sep 10;257(17):9891-4.   [2] Craft S, Baker LD, Montine TJ, Minoshima CW, Wason GS. Intranasal insulin therapy for Alzheimer’s disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38.   [3] Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008 Feb 5;70(6):440-8.   [4] Ussar S, Lee KY, Dankel SN, Boucher J, Haering MF, et al. ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes. Sci Transl Med. 2014 Jul 30;6(247):247ra103.   [5] Kim KS, Lee YM, Kim SG, Lee IK, Lee HJ, et al. Associations of organochlorine pesticides and polychlorinated biphenyls in visceral vs. subcutaneous adipose tissue with type 2 diabetes and insulin resistance. Chemosphere. 2014 Jan;94:151-7.   [6] Freychet P, Laudat MH, Laudat P, Rosselin G, Kahn CR, et al. Impairment of insulin binding to the fat cell plasma membrane in the obese hyperglycemic mouse. FEBS Lett. 1972 Sep 15;25(2):339-342.   [7] Kahn CR, Neville DM, Jr., Roth J. Insulin-receptor interaction in the obese-hyperglycemic mouse. A model of insulin resistance. J Biol Chem. 1973 Jan 10;248(1):244-50.   [8] Shao W, Yu Z, Chiang Y, Yang Y, Chai T, et al. Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathways in adipocytes. PLoS One. 2012;7(1):e28784.   [9] Cani PD, Osto M, Geurts L, Everard A. Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes. 2012 Jul-Aug;3(4):279-88.   [10] Gu JJ, Gao FY, Zhao TY. A Preliminary investigation of the mechanisms underlying the effect of berberine in preventing high-fat diet-induced insulin resistance in rats. J Physiol Pharmacol. 2012 Oct;63(5):505-13.   [11] Sartorius T, Peter A, Schulz N, Drescher A, Bergheim I, et al. Cinnamon extract improves insulin sensitivity in the brain and lowers liver fat in mouse models of obesity. PLoS One. 2014 Mar 18;9(3):e92358.   [12] Shen Y, Honma N, Kobayashi K, Jia LN, Hosono T, et al. Cinnamon extract enhances glucose uptake in 3T3-L1 adipocytes and C2C12 myocytes by inducing LKB1-AMP-activated protein kinase signaling. PLoS One. 2014 Feb 14;9(2):e87894.   [13] Kumar P, Bhandari U, Jamadagni S. Fenugreek seed extract inhibit fat accumulation and ameliorates dyslipidemia in high fat diet-induced obese rats. Biomed Res Int. 2014;2014:606021.

Welcome to Functional Medicine Update for January 2013. You know, I love the start of each new year. It’s just amazing to think of this continuing opportunity to talk to key opinion leaders around the world as to the future of what medicine will look like as it evolves. As I look back over the last 30-plus years, it’s amazing to see the distance we’ve traveled and to recognize that many of the things that we were talking about 20-plus years ago now seem to be common thoughts, and to be themes that people are saying, “Well, yeah, that’s the way it works.” I’m not saying that on Functional Medicine Update we’ve achieved 100 percent hit rate in all the things that we’ve discussed, but I think we’ve had a pretty good efficiency ratio on the things that we were led to understand through some of these key opinion leaders 30 years ago that over time now, with more and more work and evaluation, have become kind of standards of care, even standards of practice. It’s a good record for us and I hope to continue it as we move through the years to come.   Certainly we are very, very excited to have as our Functional Medicine Update Clinician of the Month a researcher/clinician that would stand head and shoulders above the crowd as a key opinion leader in the area of vascular medicine, in the area of metabolic medicine, in the area of lipidomics. Someone who really crosses many, many boundaries and would certainly, by all definitions, be considered a translational medicine expert, and that’s Dr. Robert Eckel, who has a pedigree that is quite remarkable, and a fluency in topics that relate to what we call personalized lifestyle medicine or functional medicine that puts him in that small reserved group of true global experts. So with that in mind, let’s move to our discussion with Dr. Robert Ecke

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Robert Eckel, MD University of Colorado Anschultz Medical Campus School of Medicine Endocrinology, Metabolism and Diabetes http://www.ucdenver.edu/ January 2013 Well, here we are once again at that section of Functional Medicine Update that I look forward to with such great anticipation, and I think you do as well because it becomes the real core of the focus of each of our issues. We’re very privileged this month to have a clinician/researcher that I had the pleasure of meeting for the first time personally last summer at the Kern Lipid Conference in Vail, Colorado. Dr. Robert Eckel, who is at the Department of Medicine at the University of Colorado at Denver, is quite a remarkable clinician/researcher. His breadth of expertise is beyond that which we probably can do justice in a short bio. He is obviously an MD. He is the Charles A. Boettcher Endowed Chair in Atherosclerosis, Division of Endocrinology, Metabolism, Diabetes, and Cardiology. He is a professor of physiology in biophysics, program director of the Adult General Clinical Research Center, and is very involved also in preventive cardiology and in developing new approaches towards it. His research experience includes studies in animals and humans, and spans a unique range of perspective on topics from lipidology to metabolic diseases, diabetes, metabolic syndrome, insulin signaling, and more. He is truly a cross-disciplinary (I call it translational medicine) expert, and you are going to hear from him over the next half an hour. Dr. Eckel, it’s really a privilege to introduce you to the Functional Medicine Update audience and thanks so much for being available today. RE: Great, Jeff. Good working with you. Good meeting you this summer, and I look forward to our conversation this morning to follow. An Update on the Relationship between Cholesterol and Cardiovascular Disease JB: Let’s start right into it. I think that you have been at the forefront, the leadership, cutting edge, so to speak, of the development of cardiology and its relationship to lipids. Could you tell us a little bit—give us kind of a clinical update—as to where are we on this whole lipid hypothesis, or lipid model, as it relates to coronary heart disease etiology and atherosclerotic etiology. It seems like we’ve moved beyond cholesterol and LDL, and maybe you can give us some insight as to where we are now in this whole field. RE: I think it’s important to begin with the concept that, for many years the relationship between cholesterol and cardiovascular disease was questioned because there weren’t adequate ways to prove the hypothesis by lowering cholesterol , and I think we’ve gone beyond that stage. However, the database for cholesterol lowering is largely statin-based. We have now a substantial number of randomized clinical trials that show that patients treated with statins who are at high risk, or who have cardiovascular disease, benefit in terms of a reduction in heart attacks, and strokes, and also cardiovascular disease-related mortality. The statin story is pretty clear, and I’ll just go down a bit of a tangential path for a second, in that at the University of Colorado, at my lipid clinic almost 50 percent of new patients who I see are referred for statin intolerance. So, despite the fact that statins are out there and have proven beneficial in terms of cholesterol-lowering and heart disease risk, I see the more complicated people who can’t tolerate statins, mostly because of muscle symptoms and sometimes liver side effects. But the world is living longer and with a higher quality of life because of this pharmacological development. Now keep in mind—I think just to be consistent with the program—I feel very strongly about healthy lifestyles and the importance of a healthy lifestyle in preventing cardiovascular disease. We know that diets reduced in saturated fat, particularly trans fat, are beneficial in terms of lowering LDL. We know that an active lifestyle is probably beneficial because of blood pressure and lipid effects. Overall, healthy lifestyle really contributes to a substantial amount of risk reduction, but then the statin story I think is replete with benefits to high-risk patients. Now I think when we venture into other lipid arenas, it’s a little more confusing. Hypertriglyceridemia is a known risk factor for cardiovascular disease, and that relationship between high triglycerides and cardiovascular disease is apparently more independently related in women than it is in men. I think the reason for that is in men we see a lower level of HDL cholesterol just like we do in women who have high triglycerides, but the HDL cholesterol story is the most important aspect of triglyceride, HDL, and cardiovascular disease. With high triglycerides, the low HDL that accompanies high triglycerides in men appears to be the more important issue, and in women there is much more independence of the hypertriglyceridemia in relationship to the cardiovascular disease. Unfortunately, Jeff, what we don’t know is whether lowering triglycerides independent of lowering LDL cholesterol ensures additional benefit. We have to be careful in making conclusions about trials at this point that are inadequate or show no convincing evidence of benefit. What’s really needed is the right kind of triglyceride-lowering trial where the LDL cholesterol is not further modified. Such a trial is actually being conceived right now, and will be potentially funded in the near future to test the effect of a drug when LDL in fact is fixed at a low level. We’ll have to await that data to make a strong statement on triglyceride lowering in terms of the benefit for patients who are hypertriglyceridemic. And then finally, the HDL story is really an interesting one in that we know people with low HDL cholesterols have higher risk, and that’s epidemiology, and epidemiology then ultimately requires mechanisms to explain that relationship, and I think what we know about HDL is it has a number of properties that look potentially beneficial, including what we call reverse cholesterol transport—in other words, downloading the macrophage that has a lot of cholesterol in it and taking it back to the liver for disposition. But HDL is also an antioxidant, it probably improves vascular reactivity. In other words, it makes the blood vessels healthier, and has anti-platelet effects. So HDL in many ways is a benefactor in terms of lipoprotein metabolism. But just like triglycerides, despite these plethoric properties of HDL—and I didn’t mention anti-oxidative metabolism, anti-inflammation—we just don’t have the clinical trial evidence showing that HDL-raising therapy is capable of modifying risk. Now, there’s a whole new line of drugs in studies right now called the cholesterol ester transfer protein inhibitors that ultimately raise HDL substantially. We’re talking sometimes about a two- to three-fold elevation in HDL. But the problem with this class of drugs right now is that they also lower LDL a lot. Now, that’s not a problem for the patient if these drugs work, but it is a problem for data interpretation. Is this the HDL-raising effect of this and that property of these drugs, or in fact is it mostly the LDL-lowering effect? To summarize, Jeff, I think the story for LDL and statins is there. For other therapies and LDL, it’s not quite as convincing at this point, with the inadequate trial evidence to say whether ezetimibe or Welchol or other agents we use to lower LDL are additionally beneficial. And for triglycerides and HDL cholesterol, while the relationships have been indicated epidemiologically, the benefit of therapy at this point remains uncertain. We’ll leave it at that right now, and we can talk a little bit more about lipoprotein a if you want, but that’s something that clearly is not evidence based, but we know it’s a risk factor, and we don’t know what to do about it when levels are elevated. Statins: The Controversy between Primary and Secondary Prevention JB: I’d like to go back and just re-explore with you this concept of statins and cardiac disease prevention. I know there has been quite a bit of controversy back and forth as it relates to primary prevention with the statins, where there is obviously very clear benefit in the secondary prevention, but it appears to be perhaps more ambiguous with regard to primary care, particularly in women. What’s the status of that discussion these days? RE: Well, I should just reveal that I’m part of the ATP4 panel, which is currently updating our cholesterol guidelines, and that report is still not available for public report. Although it should be fairly soon, it is difficult to really make strong statements about what’s going to be included in that report. But I think the evidence for primary prevention really requires patients to be at moderate or higher risk, and in that setting ultimately I think the benefit of statins is reasonably well documented. The male-female comparison, I can share minimally about that; clearly, women of younger age are less likely to show benefit than men of younger age who are at higher risk. I think honestly, Jeff, this is kind of a mistake of the Framingham 10-year risk predictor. Now, the Framingham database is a reliable database to make predictions for cardiovascular disease risk. But the problem when it is used in a 48-year-old woman or a 53-year-old woman, is that the 10-year risk is still relatively low compared to men, and so when we’re looking at a 10-year risk we don’t really have the database to suggest that primary prevention in women is convincingly beneficial in terms of reducing cardiovascular disease events or death from cardiovascular disease. Now as women get older, I think when we’re looking at 65-to-70-year-old women where heart disease now is the major primary cause of death, then those equations may be much more predictable in identifying women who may equally be benefitted in primary prevention settings as men. I think a closing comment on this inquiry, Jeff, is the fact that if we look at coronary calcium scores, meaning looking at the coronary arteries by CT and look at the presence of calcium in the coronary arteries, when men and women get older, many people have calcium, so they do have some atherosclerotic risk. And so when we define primary prevention, we’re looking at people with no symptoms or no history of events that relate to the cardiovascular system, whereas if we were going to do coronary calcium scores on everybody—which I’m not recommending—then I think we’re in a position of identifying people who already have disease who don’t know they have disease, and that’s a somewhat different question, and at this point in time, an unclear approach clinically. Extended Risk Factors for Cardiovascular Disease JB: That’s very helpful. Thank you. You’ve touched upon another area that I know has a lot of interesting controversy back and forth relating to these extended cardiovascular risk factors, things like high-sensitivity CRP (the Paul Ridker model) and how that relates to the JUPITER trial. Where are we on some of these discussions of extended risk factors, particularly maybe the high-sensitivity CRP inflammatory models? RE: I think that Paul, in addition to other risk factors that have been examined, has nicely identified high-sensitivity CRP as a cardiovascular disease risk factor. But the consistency of that observation, though, unfortunately is not there and it’s not really clear at this point in time who should have measurements of high sensitivity CRP. What’s recommended in ATP3 is that people who have a 10-to-20 percent risk of an event over the next 10 years are in a position to have some of these other emerging risk factors identified and used to determine whether a decision for therapy should be seriously considered. So in settings like that, the CRP can be informative. We certainly know from Paul’s JUPITER trial, which is a very, very important trial and really well-powered for outcomes in that for people who have higher CRPs, ultimately lowering their LDL cholesterol and the hs-CRP with statins was effective in reducing risk substantially, and it was a primary prevention trial.[1] So if we’re going think hs-CRP may have its importance in terms of identifying risk, it perhaps is in the patient who is a primary prevention-type patient rather than someone with existing heart disease. And an interesting point in the JUPITER trial is the fact that the benefit of lowering CRP and LDL cholesterol occurred in many people whose LDL cholesterols were quite low. So, that’s an interesting open door to a trial that is very much needed, and that would be the use of an anti-inflammatory agent that modifies hs-CRP, but does not modify LDL cholesterol, and that would presumably be in people who were on statins and at high risk. Those trials, I think, are going to be started. Paul informed us last week in Boston at the Cardiometabolic Health Congress that NHLBI, the National Heart Lung Blood Institute, is instituting a trial using methotrexate. Most of us know that methotrexate has been used for a number of years now in the treatment of rheumatoid diseases, specifically rheumatoid arthritis, but also in other connective tissue diseases. Methotrexate has very few side effects when given chronically at lower dose, so that would be a trial to look at how lowering c-reactive protein without changing lipids might modify risk. And there is a company that makes an anti-IL1-beta antibody, and that is a second trial that Paul will be overseeing in terms of the benefit of an anti-inflammatory monoclonal antibody to modify inflammation in a way that could modify risk, again without changing LDL cholesterol. The hs-CRP story is an interesting one. I think the evidence for modifying CRP independently from modifying LDL cholesterol is an important task for the near future. JB: Thank you, and I guess one other quick insight on another extended biomarker that’s been discussed with some controversy that you might comment on is homocysteine. We interviewed Kilmer McCully years ago on Functional Medicine Update concerning his thoughts about homocysteine. Where does that stand these days? RE: Homocysteine identifies patients at higher risk. I think it’s well accepted epidemiologically that homocysteine is a potential prothrombotic biomarker that is related to events, but ultimately the data we have at this point in time are somewhat disappointing in that there are many B-containing vitamins, which we know can modify homocysteine levels in a favorable direction. In other words, they reduce the levels modestly to moderately. But the outcomes there have not been, actually experienced. Lowering homocysteine alone as a biomarker for cardiovascular disease has not proven to be beneficial, at least by using B vitamins. That story remains an incomplete one in terms of why homocysteine puts people at risk and therefore, lowering it does not improve that risk, so we have more work to do here, Jeff. Insulin, the Metabolic Syndrome, and Cardiometabolic Disease JB: So that leads us into another area where you have done quite a bit of work and published extensively, which is the connection between insulin and cardiometabolic disease, and CVD etiology. Can you give us an update as to where this discussion is emerging? RE: Well, I think that takes us into the avenue of metabolic syndrome-related biology. What is metabolic syndrome? We often call it the elephant in the room because we kind of know metabolic syndrome in terms of what it represents and that’s insulin resistance, but yet, the criteria are at best modestly supported scientifically. Ultimately, metabolic syndrome can be like feeling the elephant, depending on what part you want to feel. As we all know, it requires 3 out of 5 components. Two of them are lipids, one of them is fasting glucose, another one is blood pressure, and the final one is waist circumference. We know people who have big waists tend to have altered lipids and have altered glucose metabolism and altered blood pressure, and that all is at least a consequence—at least most of those components—are a consequence of insulin resistance. The idea of insulin, itself, being an atherosclerotic biomarker is really validated by some studies, but not validated by others. And I think it is important for the clinician to understand, as well as the patient, that measuring insulin in the clinic is not a recommended test. Insulin levels are used in research studies to examine various aspects of insulin-related biology, but in the clinic, insulin assays are not very reliable; they are not standardized. And ultimately, the clinician is in a position to be making decisions really on other biomarkers that we have much more information about than we do about insulin. Now, an important part of this relates to the fact that in obesity, fasting insulin levels are elevated. But many people with obesity do not have substantial cardiovascular disease risk. About 80 to 90 percent of obese patients do have at least one other of the components of metabolic syndrome, but there are a few that have none, and so fasting insulin would be elevated, but not necessarily related to any other biomarkers that reflect systemic insulin resistance. And then, is Type 2 diabetes involved, where we now have fasting insulin that remains elevated. Insulin secretion, after a glucose stimulus, is not adequate. So, these people have an inability to secrete enough insulin, despite the fact that their fasting insulins are elevated. Again, I just want to caution our practicing community about not using fasting insulin as an assessment of cardiovascular disease risk or even insulin resistance. It’s a poor biomarker for making strong statements. Now, the idea that insulin may be a contributing factor to atherosclerosis comes from science that relates to insulin as a mitogen. In other words, insulin can stimulate cell proliferation, and can stimulate pathways that activate many of the kinases that relate to cell growth and differentiation. That’s the mitogenic effect of insulin, which is to be distinguished from the metabolic effects of insulin, which really confer effects on protein, carbohydrate, and lipid metabolism. Insulin resistance, as we describe it, as metabolic syndrome and beyond, is clinically a metabolic resistance to insulin action, not a resistance to the mitogenic effects of insulin. So, this remains a scientific dilemma that hasn’t reached clinical space, and, again, insulin levels themselves are not adequately informative to make decisions. However, in the setting of metabolic syndrome, we know that effective lifestyle modifications, such as weight loss and physical activity, modify at least some of the components of metabolic syndrome and presumably work independently to modify cardiovascular disease risk. JB: So, some individuals…in fact, there are a number of studies that have been published that looked to postprandial glucose and insulin as a better surrogate biomarker after an oral glucose tolerance test. Is that at all a stronger predictor as it relates to cardiovascular risk, when you get exigencies to our postprandial insulin and glucose? RE: Well, Jeff, you continue to ask very challenging and difficult questions. There is a lot of debate right now whether the postprandial excursion is an independent marker from fasting glucose in terms of cardiovascular disease risk. There are studies that have been contrived and are actually implemented to try to address that issue, mostly in patients with diabetes, not in those who have impaired fasting glucose or impaired glucose tolerance. In general, the issue falls down to a very simple kind of inquiry. For any given level of hemoglobin A1c, which of course is the average blood sugar for three months, if you have an A1c of 6.5, which is right at the cut point for the diagnosis of diabetes, if you have 6.5 with basically limited variability of glucose throughout the day, versus a 6.5 which is a wide swing of glucoses post-prandially and then back to baseline, is that A1c conferring the same risk for cardiovascular disease? This is an unanswered question. In general, I think most diabetologists and people who work in the intervening Venn diagram space of diabetology and cardiovascular disease would say more glycemic excursion confers additional risk, but that has not been proven. But yet, for any given level of A1c, our goal currently is to maintain the A1c under 7 percent, which is the position of the American Diabetes Association, the International Diabetes Federation, and also the European Association for the Study of Diabetes. Excursion is relevant, but excursion in its own right at this point is not a therapeutic decision-making variable. The Look AHEAD Trial: Why Did the NIH Discontinue This Clinical Trial on Lifestyle Intervention in Type 2 Diabetes? JB: Good. Thank you. You’ve touched, also, on this concept of lifestyle intervention, and it strikes me that we just saw the NIH suggest discontinuance of a very large clinical trial called the Look AHEAD trial that was a trial on lifestyle intervention in Type 2 diabetes to see what effect it would have—hopefully a positive effect—on reducing the incidence of cardiovascular disease. They called the trial after, I think, in its third year, now, in that they did not find any evidence of reduction in CHD risk in what they considered an aggressive lifestyle intervention.[2] Are you at all concerned about that? Are there things that we should know about that as it relates to why they didn’t find this connection? RE: Yes, Jeff, great question again. The Look AHEAD trial was designed in patients with Type 2 diabetes to look at whether weight reduction itself conferred a benefit in terms of the reduction of cardiovascular disease events and related mortality. The trial was successful in having patients lose weight. During the first year of the trial, they lost 7 to 8 percent of their body weight, and there was some recidivism. By year four of the trial, ultimately the body weight came back to about half as much weight reduction. And the control group lost a minimal amount of weight, but not very much, and there was still a highly significant difference in weight loss in the patients in the intervention versus the control group. However, if you look at risk factors for cardiovascular disease, the major one, I think, which is evidence based, was the LDL cholesterol level, and weight loss did not reduce the LDL cholesterol level any differently between the two groups. In fact, it didn’t really reduce it at all. So, we know that LDL relates most to dietary composition, not so much to calories. And I think it is important to point out, Jeff, that when people are actively losing weight, their LDL falls. But after they lose the weight, unless their dietary composition has changed, they really have an LDL that comes back to baseline. Now, why didn’t LooK AHEAD prove successful? I think there are a couple of reasons. These are patients with Type 2 diabetes who were deemed to have high risk for cardiovascular disease not only because they have diabetes, but because they’ve had diabetes for awhile. So we have a group of patients who have, if you will, more prolonged disease, and we know diabetes duration itself is a risk factor for cardiovascular disease events. Secondly, and very importantly, there is a lot of management of cardiovascular disease risk both in patients with diabetes and in those at high risk without diabetes nowadays, so that ultimately some of the benefit of weight loss may have been trumped by the fact that blood pressure was very aggressively managed and also lipids were aggressively managed. And the fact that in the control group, maybe there was more statin usage; that may have been another issue that could have conferred the benefit. Keep in mind we’ve not seen the final report yet. We’ve just been told that the trial has been stopped because of lack of benefit. And, you know, because we’re reducing cardiovascular disease events substantially by other risk factor modification, I think clinical trials nowadays are very difficult to contrive that are going to have more minimal or modest effects on risk, including weight reduction. Now, to redesign such a trial I think it would be great to take patients with Type 2 diabetes who were just diagnosed and then undergo a more intensive lifestyle modification to see whether we can delay new drug treatment of Type 2 diabetes and then perhaps affect cardiovascular disease outcome. I guess I think today we’re working in a space, Jeff, where aggressive management of blood pressure, lipids, in addition to glucose, is part of the clinician’s mandate, and he or she is really aggressively dealing with these other risk factors, and weight loss itself may not be so beneficial. In closing, to answer this question, Jeff, I would say that weight reduction in the impaired fasting glucose patient, or patients with impaired glucose, has really proven effective in reducing diabetes onset, which thereupon could ultimately generate some enthusiasm for reducing downstream cardiovascular disease events. Mitochondrial Biogenesis and Cardiometabolic Disease JB: By the way, that was a brilliant explanation. Thank you. And I think for those who have heard some of the other reports, it’s going to be very helpful for them to have listened to you to kind of give a…at least on-target discussion if they are questioned about that particular study. You hit a certain concept, to me, as I’m listening to you—and I’m going back to some of your other work, as I mentioned in the introduction, the breadth of your work is quite expansive—and you’ve published some papers on mitochondrial biogenesis and its relationship to insulin resistance and how that tracks with Type 2 diabetes and possibly cardiometabolic disease. I’m wondering could it be possible that these approaches like Look AHEAD may have had favorable transient effects, but didn’t affect some of the central cellular pathology, like effects on mitochondrial biogenesis and how that relates to oxidative phosphorylation and preservation of beta-cell function and all those things that occur with intact mitochondrial activity. Is there something here that we should be looking at, do you think? RE: We know that mitochondrial biology is incredibly important not only for insulin action in insulin-sensitive tissues, not just muscle, adipose tissue, and liver, but critically important for glucose stimulated insulin secretion by the beta cell. I think there is no question that there is a defect in short term glucose sensing in the beta cell , but we still don’t understand in detail what that defect is in glucose sensing in the beta cell; whether it is in transport, glucose metabolism, or in fact whether it relates to myocardial dysfunction. There is quite a bit of evidence that oxidative stress and ER stress is really an important mediator of the glucose-dependent defect in insulin secretion in the beta cell in Type 2 diabetes. But there is no question that in the study of weight reduction and insulin action, during active weight reduction, and ultimately immediately after weight reduction, insulin sensitivity can be improved. Long-term, that’s preserved if the weight loss is maintained, but keep in mind, Look AHEAD, Jeff, was a study in which there was initially about 7 percent weight loss, but ultimately the recidivism was to 3 to 4 percent weight loss at 4 years, and I think it’s difficult to have people lose weight and keep it off long term. Therefore, the benefit on insulin sensitivity is going to be probably less clearly modified favorably after the weight regain has ensued. Back to basic cellular mechanisms, I think clearly they are implicated in defects in both insulin action and insulin secretion. JB: Yes. It just strikes me that coupling together this emerging…this cellular pathology with that of the clinical outcome in these types of studies might be very helpful to try to understand short-term transient effects versus long-term maintenance effects on bioenergetics. If this is a central mechanism, it seems like it would be really desirable to try to connect them together from the clinical side with the biochemical side. It just seems like something was missing there. RE: Well, that’s the one thing that’s really fun about science as a physician. We tend to think of translational research as going from bench to bedside, and bedside to population, and ultimately then to public policy. But it’s fun to think about translational research as an arrow going from right to left where observations made in epidemiological settings then give rise to mechanistic studies in humans and then back to the preclinical animal cellular/molecular level, and that’s what makes science so much fun is that every question that’s addressed here deserves three more new weeks to follow, ultimately drilling down on basic mechanisms. And if we look at disease modification and cures, it comes from understanding basic mechanisms and mitochondrial biogenesis, and function really is part of that paradigm. Adipose Tissue Physiology and Coronary Heart Disease JB: I’d like to close with two last questions. Another area that you have been very actively involved in is this whole changing view of the what used to be considered the lowly adipose cell—the adipocyte—which we thought was just this energy storage cell that was metabolically inactive and just kind of sat there just collecting extra calories in the form of triglyceride accumulation, but now we recognize it’s a pretty active part of the endocrine system through adipocytokine stimulation. Could you tell us a little bit about how you see adipose tissue physiology interrelating with the etiology of coronary heart disease? RE: Very timely topic, Jeff. I mean, the biology of adipose tissue has really matured substantially over the last decade, and I think this began with identification at Rockefeller and Columbia that ultimately the adipose tissue contained bone marrow-derived monocytes that then could be differentiated into macrophages. I think what’s occurred now is the concept of proinflammatory cytokines or adipokines being produced in adipose tissue having local effects, and some of those local effects are on insulin action itself in terms of blocking insulin sensitivity in adipose tissue and that gives rise certainly not only to defects in insulin-mediated glucose transport and metabolism, but also to increases in mycolysis. In other words, if you produce a lot of IL-1 beta or IL-6 or TNF-alpha in the adipose tissue, that drives lipolysis, which is a breakdown of adipose triglyceride stores. Those free fatty acids are released and they are systemic and cause insulin resistance in other organs such as liver and muscle. Not only that, but the released cytokines from adipose tissue sometimes do reach systemic circulation and can be measured as excessive in circulating plasma. In fact, back to an earlier discussion, the hs-CRP we see elevated in patients with insulin resistance is often derived in part from this defect in adipose tissue of an overproduction of adipose tissue proinflammatory cytokines. Jeff, where the debate is really at right now in this area of biology and potentially pathophysiology is that maybe the macrophage in adipose tissue is there to do a clean-up job, too. Adipocytes, we know, don’t do turnover with time. The old thought that you’re born with a certain number of adipocytes and those are maintained for the rest of your life is not true; that was a fallacy and that’s been put to rest. So the idea that fat cells do turn over and ultimately apoptose and die, the macrophage may be there favorably to do a clean-up role. So there is some debate now in terms of what types of monocyte-derived macrophages are there. Are they there to be helpers, to scavenge dead adipocytes, or are they there just to be injurious and cause harm? I think there’s another view, too, that perhaps ultimately, the induction of adipocytokines in insulin resistance and adipose tissue may be a way ultimately to have body weight not increase further, because if you’re breaking down fat in the adipose tissue maybe you’re going to prevent further weight gain; while I think that’s more of an obtuse view, it still is brought into consideration. JB: Yes, and I think it’s very interesting, isn’t it, as we look at Spiegelman’s recent work, and others that have been looking at these base cells that sit within central fat and subcutaneous fat, that have thermogenic potential that we used to think were just kind of non-thermogenically active that can be modulated by things like exercise and maybe other lifestyle and dietary factors, that can alter then the kind of bioenergetics balance in subtle ways that might contribute to weight regulation that may be, in terms of the lifestyles that people have right now, blunting kind of the base cell conversion into these thermogenically active cells.[3] So it seems like there is a whole revolution that’s occurring in fat cell physiology right now. RE: Yes, I think what Bruce has done in addition to other investigators, including the Stockholm Group in particular, has identified the fact that the beige cell is of a different lineage than, brown fact per se, and Bruce’s work in the animal, and I think there is some evidence to support this in humans now, that brown fat itself is minimally present in adult humans. Using a series of techniques we can now pick it up using PET scanning, and the brown fat is probably of a different lineage actually it’s of a skeletal muscle lineage. I think this concept over the fact that brown fat may ultimately be a way to modify body weight either by preventing obesity or treating it is maybe fraught with a bit of a problem in terms of how much energy expenditure can you really expect from the beiging of light fat? In other words, the percentage of brown fat cells within the white fat depot is typically fairly minimal to moderate, and can there be enough additional energy expenditure through that depot to really confer reductions in body weight and ultimately improved insulin action That’s a really major task before us, to understand that better. JB: Let me close—thank you, this has just been an incredibly information-dense discussion, as I would have expected from you, Bob, so thank you—but the last question is, what do you see as the trajectory of where we are going in terms of the accumulation of knowledge in this whole area pushing us towards an individualized or personalized type of lifestyle medicine intervention? I know we have had, from Framingham, a lot of public health guidance through generalized risk factors, but it is sounding more and more to me as I listen to you and also watch the evolution of the literature, that we’re moving towards the era of more individualized or personalized intervention. What’s your read on this possibility? RE: I think it’s a fascinating topic and I think it’s in its infancy right now, Jeff. We know that certain drug adverse effects may be predicted by certain gene sequences and pathways that relate to that ligand and how it’s metabolized. A most recent example of this that I find interesting is the Harvard School of Public Health Study, in both nurses and physicians, that was published in the New England Journal last week. In this study, the sequences of certain genes related to obesity predicted how children and adults would respond…actually I guess this was the adults only study (there was another study on children in the same issue)…would predict how nurses and physicians would respond to the intake of sugar-containing beverages.[4] Let’s just think where we will be 20 years from now, perhaps we’ll get DNA testing in our children to see if there is an obesity risk, a prevalence of genes that had modified sequences that would predict excess weight gain, and maybe we should selectively restrict sugar-containing beverages in those children and not so much in others. I think my position would be that we probably need to restrict sugar-containing beverages more in all children, but all that aside, I think we’re really at the edge of now making individualized medicine or tailored medicine very possible, knowing the interaction between genes, gene modification, and response to environmental factors. JB: Well, Dr. Eckel I want to both personally thank you on behalf of all of our listeners and those out there that are benefitting from your extraordinary work and that and your colleagues. This is really ground-breaking work and I consider it integrative translational research that takes, as you said, from bench to bedside, some very, very important concepts that are going to deliver improved health outcomes for many people. And the way you describe it is so lucid and so easily understood. It’s a real skill that you have. Thank you so, so much for sharing this with us. I hope this information has some stickiness as our listeners take it in and are counseling their own patients. Thank you and keep up the great work and we hope to keep close tabs on what you are up to. RE: Great, Jeff. Good talking to you today and I hope what we have talked about here today is beneficial to all. Thanks very much for inquiring and it’s been fun being with you

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Bibliography

[1] Ridker PM, JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003;108(19):2292-7.   [2] Brancati FL, Evans M, Furberg CD, Geller N, Haffner S, et al. Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study. Clin Trials. 2012;9(1):113-124.   [3] Wu J, Boström P, Sparks LM, Ye L, Choi JH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012 Jul 20;150(2):366-376.   [4] Qi Q, Chu AY, Kang JH, Jensen MK, Curhan GC, et al. Sugar-sweetened beverages and genetic risk of obesity. N Engl J Med. 2012;367(15):1387-1396.   [5] Bain JR, Stevens RD, Wenner BR, Ilkayeva O, Muoio DM, Newgard CB. Metabolomics applied to diabetes research: moving from information to knowledge. Diabetes. 2009;58(11):2429-2449.   [6] Mannino GC, Sesti G. Individualized therapy for type 2 diabetes: clinical implications ofpharmacogenetic data. 2012. Mol Diagn Ther. 2012;16(5):285-302.   [7] Bergman BC, Perreault L, Hunerdosse D, Kerege A, Playdon M, Samek AM, Eckel RH. Novel and reversible mechanisms of smoking-induced insulin resistance in humans. Diabetes. 2012;61(12):3156-3166.   [8] Brown WV, Brunzell JD, Eckel Rh, Stone NJ.  Severe Hypertriglyceridemia.  J Clin Lipidol,2012; 6(5): 397-408.   [9] Eckel, RH, Eisenbarth, GS.  Autoimmune Diabetes Inflames the Heart.  Sci Transl Med.  2012 4 (138):  138fs18.   [10] Rehrer CW, Karimpour-Fard A., Hernandez TL, Law CK, et al.  Regional Differences in Subcutaneous Adipose Tissue Gene Expression.  Obesity, 2012; 20(11): 2168-2173.   [11] Morino K, Petersen KF, Sono S Choi CS, et al.  Regulation of Mitochondrial Biogenesis by Lipoprotein Lipase in Muscle of Insulin-resistant Offspring of Parents with Type 2 Diabetes.   Diabetes, 2012. 62(4): 877-87.   [12] Eckel RH. The complex metabolic mechanisms relating to obesity to hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2011;31(9):1946-1948.   [13] Steig AJ, Jackman MR, Giles ED, Higgins JA, Johnson GC, et al. Exercise reduces appetite and traffics excess nutrients away from energetically efficient pathways of lipid deposition during the early stages of weight regain. Am J Physiol Regul Integr Comp Physiol. 2011;301(3):R656-667.   [14] Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, et al. Obesity and type 2 diabetes: what can be unified and what needs to be individualized? J Clin Endocrinol Metab. 2011;96(6):1654-1663.

Welcome to Functional Medicine Update for February, 2013. Complex metabolic disease:  how does it relate to systems biology in medicine and the functional medicine model? Well, we’re going to have the opportunity to explore that in some depth with a leading expert in this month’s issue, a practitioner who bridges the gap between what I would call the standard of care/practice and the development of standard procedures in medicine, and that of opening the mind to this future of medicine—a systems biology-based approach—looking at emergent structures.  I think you’ll find this discussion is both interesting from a philosophical perspective, but probably more importantly from a patient management and evidence-based perspective. So, with that in mind, let’s turn to our clinician/researcher of the month, Dr. Jeffrey Mechanick.

INTERVIEW TRANSCRIPT

Jeffrey Mechanick, MD Mount Sinai Hospital 1192 Park Avenue New York, NY 10128 www.mountsinai.org Here we are once again at that part of our Functional Medicine Update each month that we look forward to because I’m sure you’re asking, “Who will Jeff Bland have the privilege of talking to this month?” And for me it’s always, “Wow, what a great opportunity to speak to one of the great leaders in establishing a platform and landscape of medicine in the 21st century.” Today I have the fortune of speaking with Dr. Jeffrey Mechanick, who is a clinical professor of medicine and a director of Metabolic Support, Division of Endocrinology, Diabetes, and Bone Disease at the Mount Sinai School of Medicine. He has an MD degree with an endocrinology focus from Baylor College of Medicine, and an endocrine fellowship at Mount Sinai. He has authored more than 200 publications on endocrinology, metabolism, and nutrition. Dr. Mechanick is the past president of the American Board of Physician Nutrition Specialists, and is currently the president-elect of the American Association for Clinical Endocrinologists, and the section editor of Current Opinion in Clinical Nutrition and Metabolic Care in Current Opinion in Endocrinology and Diabetes. As I’ve reviewed his publications—as I mentioned, over 200 of them—his breadth of impact and expansive interest spreads throughout all of his publications, so we’re very, very pleased to have an expert in the field that we might call personalized lifestyle medicine, or functional endocrinology, or let’s call it just good, plain old medicine. Dr. Mechanick, thanks so much for being with us on Functional Medicine Update, and what a privilege and pleasure it is to have a chance to talk to you about the exciting work that you’re doing. JM: Thanks, Jeff. It’s a pleasure to be here. A Transcultural Approach to Optimizing Diabetes Care and the Need for Clinical Practice Guidelines JB: So let’s—with no necessary priority or ranking of order of importance of what you’ve done–let’s start with one of your recent contributions, which I found absolutely fascinating, that speaks directly to this rising global burden of chronic disease or chronic illness that we’re seeing. A recent Lancet issue was entirely focused on global trends in disease, and that is looking at your work on this diabetes-specific nutrition algorithm—this transcultural approach towards optimizing diabetes and pre-diabetes care, which I think has been a very big question in the minds of many people.[1] How do you translate discoveries or programs that might be developed for one population group to another knowing that there are very significant differences in ethnicity, regionalism, cultural habits, and so forth? You’ve really done a creative and innovative job in this transcultural approach. Could you tell us a little bit about its origin and its development and what it can do? JM: Sure, Jeff, and thanks for that introduction because I think you hit the nail on the head. One of the things to bear in mind is that sometimes it’s better to approach clinical problems from a systems perspective. Certainly when you have an individual patient in front of you, say somebody with a nutritional disorder or diabetes, you want to address that individual person, and it’s very scientific and very empirical. But when you want to ask a research question, sometimes you need to zoom out and take a wider look, so from my standpoint I have always been interested in optimizing lifestyle. You know, in this country, one of the overt shortcomings in the delivery of health care is this de-emphasis, even absence, of formal training in nutritional medicine or lifestyle medicine. Clearly, there is a very important role for that, so how on Earth are you going to be able to learn about lifestyle and the role that it plays in treating a metabolic disease such as diabetes, and you can even include obesity, and the whole spectrum of prediabetes and diseases of dysglycemia? How on Earth are you going to address that just focusing on the narrow, single patient, or maybe a single disease, without really gleaning a lot of rich information from the diversity of human biology? So that was the set-up for this, and I was actually requested to propose a research project, and it occurred to me that in the development of clinical practice guidelines—and I participated on a number of these clinical practice guidelines as part of my role with the American Association of Clinical Endocrinologists—as part of those clinical practice guidelines, let’s say in diabetes, it’s great to put something together and have something that is very academic, and very evidence based, and very scientific, but it really falls short of the mark if you can’t implement it. And beyond that, how are you going to implement it on a generally wider scale when you’re not even taking into account the diversity of your patients? This diversity can be viewed two ways. It’s the diversity in your own particular clinic, so in my office practice here in Manhattan I don’t just see the average or standard patient; I have patients from all sorts of ethnicities and socioeconomic classes, and from different nations of the world, and then you can ask questions—well, what about treating diabetes and nutrition? How are those disorders expressed with the different genomics and epigenomics and cultures in Ghangzhou in China, or in Brazil, or in some of these other countries that really represent points along a broad spectrum? So that was the set up: that we have these very good, evidence-based clinical practice guidelines, but they are not portable. They are just not portable in order to implement them in different patient populations. JB: We’ve experienced that same challenge in our work, touching with Functional Medicine Update more than 35 countries with practitioners who are listeners. They have often come back to us and said: “How can you regionalize this or how can you take this message that you are transmitting—this systems biology approach to health care—and focus it in on our area of specific interest or need based on our culture?” Can you tell us a little bit how you approach that with regard to taking the general and making it specific to a cultural need? Solving Clinical Problems within a Narrow Time Constraint JM: I think the first step is to recognize that human disease is complex, and it’s not complex just from the standpoint of science. I mean, it certainly is complex scientifically, but you have a lot of other platforms that need to be integrated into a complete or successful solution. You have factors such as economic factors, and cultural factors, and socialization factors, and psychological factors, and when you try to bring all these complex factors into play, you need a different way to solve it. Bear in mind that there are these imperatives of solving clinical problems that are within a narrow time constraint: you have somebody in front of you, and you need to be able to come up with some sort of a solution, or advice, or counseling, and you don’t really have hours to do that and you need to have some framework—some approach that takes into account that complexity. So I think that’s where the common ground is, Jeff, between what you’re doing in functional medicine, and when you’re dealing with the interaction of environment on biology, with what I’m doing with a specific problem, which is the role of nutrition for a specific disorder—diabetes—but both have a very large scope. JB: So let’s take that as a specific example, now, into the area of metabolic syndrome, pre-Type 2 diabetes. You’ve authored some very interesting work in that area. One of the papers I saw is with Dr. Potenza titled, “The Metabolic Syndrome: Definition, Global Impact, and Pathophysiology” in Nutrition in Clinical Practice a couple of years ago.[2] Tell us how using the metabolic syndrome/insulin resistance concept relates specifically to your thoughts. The Best Disease Management Plan Will Be Preventive JM: Right. So I think what I would like the listeners to consider is not that obesity and diabetes exist as solitary, isolated, or insular pathophysiologic states, but rather they are points along a timeline, which begins with someone’s preprogramming, or basic biology and genomics, and then migrates through these states—these physiologic states, for lack of better word—that we now call a pre-disease, so pre-hypertension or pre-diabetes. We have overweight, which is really a pre-disease state for obesity. And to recognize those—to understand that they exist, to understand that they identify patients who are “at risk.” And just to segue from there, Jeff, I think it’s a very important concept to understand the differences among primary, secondary, and tertiary prevention, because they correlate to where you are along that timeline for an individual patient as they migrate through a latent phase into a pre-disease state, into frank disease, then into complications that eventually exceed our ability to manage them. I think the other point of the paper is that we in the US, as well as others around the world, we need to migrate from this disease management paradigm more into a preventive medicine or a health promotion paradigm; we can ill afford all the disease that we’re seeing now. Our treatments really just can’t keep pace, and as it turns out, the best management plan is going to be one that is preventive. JB: You know, what you just said, I actually had a goosebump experience, and the reason for it was not only the clarity of what you express, but I reflected back immediately in my own life to 1979. I’ll just give a quick vignette. In 1979 I was asked to speak at a symposium that was sponsored by the University of Washington School of Medicine, and it was actually chaired by (then) the head of the Department of Endocrinology at the Medical School who had actually authored the book on endocrinology that I had studied as a student. I had a great amount of respect for him—a tremendous diabetologist/endocrinologist, and the topic of this was hypoglycemia (so-called reactive hypoglycemia), which was, in the 70s, kind of a very big thing around consumers (low blood sugar). I was a young guy back then—early-stage academic professor—and really prepared, I thought, for a presentation, and I was the presenter right before he was to present. So I went up and gave my presentation and I thought I did a pretty good job, and then he got to the stage and he said, “You know, this gentleman, Dr. Bland, that just spoke obviously was very enthusiastic and gave a lot of very interesting information, but I do want to say one thing about his presentation: there is no such thing as a gradient effect between optimal glycemic regulation and diabetes. It’s a step function; you either have it or you don’t.” And that was 1979, so clearly, from what you’ve said, we’ve come a long way in understanding this gradient transition into different stages of metabolic dysregulation. JM: Yes, I would agree. Integrative Physiology and Bone Disease JB: So let’s, if we can, take that concept and look at how it spreads out into what you called ‘integrated physiology’ in several of your articles. I really like that term integrated physiology because it really puts what some people call integrative medicine on a more evidence-based foundational footing in that integrative physiology is really another term for a systems biology approach to examining health and disease. The article I’d like to review with you is one of your recent publications in an area of your deep expertise, which is bone disease/osteoporosis, and this article appeared in Current Osteoporosis Reports in 2011 on “Nutrition, Bone, and Aging: An Integrated Physiological Approach.”[3] In this, you talk about how bone is more than this thing that is a skeleton we hang up in the closet that seems like a piece of dead physiology. You talk about it as a very live, dynamic part of the interface among other organs in a systems biology approach. Can you tell us a little bit about that? JM: Yes, and thanks so much for giving me the opportunity to do this. This has really been a pet project of mine, and I’m very passionate about it, and here’s a little bit of the history. Going back to the early 90s, I became very involved in recognizing this state of chronic critical illness, which is sort of a later truncated part of the timeline when patients are critically ill. These patients who are critically ill don’t die from their critical illness; they are essentially technologically immortalized, and eventually receive a tracheostomy, and it’s a very difficult pathophysiologic state to treat, and I don’t know if we’re going to have time to discuss this concept of allostasis, but basically through the process of adaptation they enter into a stage where there is no evolutionary precedent for what’s going on, and the cost of adapting to prolonged stress—eventually you can’t pay off that metabolic debt. So here we find these patients, and I was noticing some electrolyte abnormalities, some abnormalities with calcium phosphorus and urinary calcium. We put together a model that these patients were hyper-resorbing calcium, not only as a result of immobilization, but as a result of the influence of cytokines, and we actually in parallel started to investigate this in spinal cord injury patients, where we were able to demonstrate that this bone hyper-resorption was not dependent on the level of injury but rather the completeness, and that was also consistent with an inflammatory model. We started a study and we found these very high prevalence rates of vitamin D deficiency, upwards of 92 to 96 percent bone hyper-resorption. We started to intervene with activated vitamin D and intravenous bisphosphonates like pamidronate. We were getting some biochemical responses. And then fast-forward a good ten years or so, and through corroborations at Mount Sinai, mainly with Mone Zaidi—he’s a personal friend of mine, extremely active and productive in the field of molecular biology as it applies to bone—and what they found in their lab really was a paradigm shift. It was always believed that, for instance, it was thyroid hormone, or the end-organ endocrine hormones that have this direct effect on coupling of osteoblasts and osteoclasts, but instead it was the pituitary hormones: TSH, and LH, and FSH (primarily FSH). But the pituitary glycoproteins were affecting bone, along with cytokines, and then paracrine effects, the effects of monocyte macrophages, and now you’ve built up this complex system. Now, you have the results of Karsenty over at Columbia showing this amazing feed-forward loop with fat, and now you can see how this applies to bariatric surgery. Fat to brain, via leptin, through the sympathetic nervous system, through beta adrenergic receptors in the bone, clock genes in the bone, a feed-forward system, and now you start to see that the bone is intimately integrated with multiple organs. There were then some subsequent studies looking at enterochromaffin cell metabolism, of tryptophan to tryptamine to serotonin, and effects that that mechanism has indirectly on bone, the effects of osteocalcin and osteopontin from bone on beta cell activity, which then affect insulin, and diabetes, and insulin then affecting bone and fat, and now you have a complex system. This is not simply a motif of A-to-B, B-to-C, C-to-A. This is now a complex network that really requires a higher level of mathematics to solve it, and if you talk to the systems biologists, the threshold effect for our ability to solve these problems has been the advent of the supercomputers and the accessibility of the supercomputers using this top-down type of research where you build up these models, you build up these networks, based on information at hand, and then you discover these emergent motifs, and then based on those discoveries you can then feed hypothesis-driven component research, and that was the point of these papers. The point of these papers was to say, “Look, you have a disease like critical illness, or rather a pathophysiologic state—a state, not necessarily a disease, but a pathophysiologic state like critical illness—and what if we explore? What’s the rule of thumb?” Now who on earth would start working up bone, or discussing bone, on rounds in an ICU? But when you start to look and examine the integrated physiology, you then learn. And where that helps is when patients simply don’t behave the way they should a priori. You give a certain medicine, they’re supposed to get better, but when they don’t—and many times they don’t—that’s when you need to zoom out, consider these physiologic networks, and try to come up with alternate hypotheses. JB: That was unbelievably eloquent and it hit on so many of the areas that we have been exploring in Functional Medicine Update over the last 25 or so years. We could obviously use this as a springboard for hours and hours of discussion, but I’ll try to keep it succinct, so let’s talk first about this concept of stress that we call allostasis. I’m reminded of our discussion—in my case, going way back to the extraordinary luxury that I had a chance to meet Hans Selye at the end of his life and have conversations with him about his so-called general adaptation syndrome (or GAS). A lot of patients, he said, would run out of gas (run out of GAS) because they would go through arousal, adaptation, and then exhaustion of their endocrine system, and so he used to talk about adrenocortical fatigue and how that related to long-term adaptation to unremitting stress. And then later, that was really transitioned into a more robust concept of allostasis that you mentioned. The concept of allostatic load and how the body responds to it, and how it affects the whole of the system means you’re not just affecting one organ, or gland, or one tissue, you’re really putting an environmental perturbant into the system that then disturbs the whole web. So in the network, you can’t just affect one tendril of the net without affecting the whole. This model that you’ve developed ,how it applies to bone, and ultimately to bone disease, ultimately leads to a better understanding of early-stage changes in the bone because it uncovers different predictive biomarkers for physiological disturbances that associate with allostatic load. And then from that, earlier intervention with hopefully lifestyle personalized characteristics. This seems like a whole new paradigm for health care to me. Am I on the right track? JM: I think you are. The only thing I would add, Jeff, is that these are not mutually exclusive. And remember, I’ve sort of been a student of this. I’ve only been introduced to this over the last five, six, seven years, and the way I was introduced to it is really the way your listeners are being introduced to things: they hear things, they think, they take notes, and then they move forward. And one of the things that I was struggling with early on is I thought this was an either/or type scenario, but it’s not. The systems biology paradigm, with these complex networks, actually acts to inform the component biology/traditional scientific method. Then the results of the scientific method feed back to inform the network, and what you have is an iterative process that learns. So what I would do is just add to what you’ve said for the benefit of the listeners to realize that network analysis or network-based classifiers can work together with component biology or statistical-based classifiers, and the two can resonate. Emergence: A New Concept Starting to Inform Medicine JB: That’s very, very helpful. Thank you, that’s a really great insight. You mentioned a term, which is a term that seems to be getting a little bit of lift in the medical vocabulary recently, and that’s “emergent structures”—that you start to get these things happening cooperatively across structures in a network, that is, an emergent new steady state. We used to call it homeostasis, but homeostasis kind of defines a healthy state, but actually you could have a steady state, or an emergent structure of a disturbed metabolism, like diabetes, for instance, or osteoporosis, that would appear from this model, so maybe we have to redefine what we mean by “steady state,” always implying that homeostasis means good. JM: Yes, I think emergence…you could sit around a coffee table and talk about this for a long time. I can share with you an anecdote of how I got involved in it. I was seeing a patient, and the night before I had just read Brian Green’s book on string theory. I was talking to this patient and I found out he was a theoretical physicist, so I thought: “Wow, we can have a little bit of discussion, here, on string theory,” and when I finished he said, “You know what, that’s just nonsense. What you really need to read about is emergence.” As a result of that brief conversation, I went to Amazon and got some books and started reading about emergence, and it really fit in well with a lot of the issues that I’ve written about, going back to medical school, and creativity, and incompleteness in medicine. Medicine—perhaps other than the military—is probably the only profession, or field, where one must act based on incomplete knowledge. And when you look at evidence-based medicine, there’s this tremendous resistance against that philosophical tenet that you have incomplete knowledge, and bearing in mind the issues of Godel’s proof, and the fact that we live in an incomplete world, we just need to reconcile ourselves to the fact that information is incomplete, and the way we solve problems is by trying to capture those emergent data. On rounds, when we are trying to solve a problem, it isn’t so much that we need to guess the problem. It’s not that you have to get that problem right off the bat—that you guessed three or four things and hopefully one or two of those things will be the right answer. The target is actually to create a state—a network, or a state, or a framework—where eventually that correct answer will emerge. And it’s a different way of thinking. It’s a different way to approach problems. But it is the way that I find that I approach medicine in my own practice. The Interrelationship between Bone and the Gut JB: I think that is an extraordinary insight. This is the example, isn’t it, of being a life-long learner, being a seeker, being able to give yourself the permission to broaden your field of vision and to feel comfortable with going outside your disciplinary definitional biography into areas that help pull you into unexpected discoveries that can really make meaningful differences either in the communication you have with patients to help them along their path, or maybe even open up doors for new therapeutic avenues that might be extraordinarily important that were previously not understood. So I want to really compliment you. That’s a characteristic that you have that is a very unique and is a precious characteristic that really leads to advancements. Let me if I can go back to your discussion about bone for a second, and you threw out a whole bunch of really important news-to-use, there, but one that stuck with me that ties together with some things that we’ve discussed in FMU over the last few years has to do with serotonin. As most of our listeners know if they’ve been following us, it’s recognized that two-thirds of the body’s serotonin is produced by the enterochromaffin cells from the gastrointestinal mucosa, so this concept that the gut talks to bone and bone talks to the beta cells in the endocrine pancreas may have sounded like a very ridiculous concept a decade ago, but now it seems to be emerging that it’s interrelated and it may help us to understand things like inflammatory bowel disease and its comorbidity and disease adjacency with osteoporosis. Is this part of what your systems biology approach to bone disease is telling us? Bariatric Surgery and Remission of Diabetes JM: Right. I think there’s two ways to look at it. You build up the model, just like I think you and the listeners have all appreciated and you’re running with, and then you look to substantiate that model. You look to find clinically relevant examples of that model to sort of bring it home; to have context. Now, one way to do that is to say, “Okay, let’s look at inflammatory bowel disease or celiac disease, where bone loss is part of it, and try to explore that mechanism.” But there’s another way. The other way is to look at either natural or man-made experiments, and to substantiate that concept, what we’ve done is looked at bariatric surgery. If you examine the literature on bariatric surgery and some of the history of the way it’s been managed, and we had our first clinical practice guidelines on this published in 2008, and we’re actually just finishing up our update now.[4] We know that there is bone loss; there is unloading. In fact, probably as a result of obesity—just the mechanical forces, but also some of the hormonal effects. There’s also concomitant vitamin D deficiency due to sequestration of vitamin D in the adipose tissues. And then the patient loses weight and unloads. The bone mass goes down, and the clinical question was: Do you intervene? Do you now treat, at one year, when that bone density shows bone loss, are you obligated to treat? And what we found is that bone recovers, and there is really this complex network of interactions that we still haven’t figured out, but that is really a man-made experiment that can be very fruitful for us to understand what’s happening in this complex physiology. JB: That is an absolutely fascinating example of emergent structure, isn’t it? So you put a perturbation, which is bariatric surgery, in the system. It responds to develop its immediate kind of traumatic response. That leads to bone loss through this changing web. And then, over time there is a self-correction as the emergence of the steady state occurs and then you’re saying that bone starts to accrete back again, so that’s a very, very interesting example of adaptation, it seems, in response to a changing environment. JM: Right. I mean, there are other examples, for instance the “cure”—let’s use the word “remission”—of diabetes after a Roux-en-Y gastric bypass. Far beyond what you would expect from the weight loss, because we see the differences in the remission rates for the same amount of weight loss between a Lap band, for instance, or one of those adjustable gastric banding procedures, and the Roux-en-Y gastric bypass, and for that matter, a biliopancreatic diversion with duodenal switch, where you could have 100 percent, in some series, remissions (long-term remissions) of diabetes. Now bear in mind long-term is not really long-term the way everybody else defines it. It may be only for several years, and that’s what the critics are looking at. But this effect of bariatric surgery on diabetes was emergent. That was not something that was predicted or designed a priori when bariatric surgery was being innovated. JB: I think that’s, again, another really powerful example, isn’t it? It’s interesting how we keep coming back to the gut, here. We’ve talked about gut and bone; now we’re talking about altering the gastrointestinal environment and its influence on beta cell function and insulin sensitivity. It seems like there is a pretty interesting signaling network around gut-related neurology, immunology, and endocrinology. JM: Right. We’re learning all of these interactions, and then for the benefit of your listeners, the next step afterwards is the validation process to see if this can actually become relevant and we can implement it in routine daily care in clinical practice. So for instance, even though it’s very sexy that bariatric surgery “cures” diabetes, whether these procedures should actually be offered as a primary intervention for diabetes is very controversial. If you look at our clinical practice guidelines, in 2008 for bariatric surgery we didn’t recommend them at all; in 2011, that is for diabetes (not for obesity, but for diabetes), we actually had some stipulation that there was a role for bariatric surgery in certain very recalcitrant cases of diabetes; and now in our updated version that will be coming out we have even more attention devoted to this controversy. There’s a lot more data, and some long-term information about the role of bariatric surgery in diabetes remission. The problem is in the interpretation of the clinical trials. So, Jeff, you start off with the network that you build up, which is theory-based, and then you do an analysis, but ultimately this must be translated to an individual patient with the help of actual clinical trials to see if something really works, and there the listeners need to be able to read these studies and make sure that the comparator groups are appropriate, that the risks and benefits are appropriate, that an intent-to-treat analysis was done, that they are generalizable, and in fact that the treatment is durable. And for that matter, we still don’t know whether this anti-diabetic effect is a durable effect with a net benefit. Thyroid Function and Subclinical Hypothyroidism JB: Very, very helpful. Thank you, that’s really good news-to-use. I’d like to finish up with two areas in the range of the many, many things we could talk about with you. One is related to thyroid function evaluation, and the other is this recent paper you’ve published about vitamin C and its relationship to bones loss, which I thought was quite fascinating. Let’s start with you being a member of this clinical practice guidelines group for hypothyroidism in adults and a recent paper that you were a co-author of in Endocrinology in Practice in 2012.[5] This is a big area of discussion—maybe even controversy—within the field of docs in the functional medicine milieu. Could you tell us a little bit, what is coming out of this in terms of assessment of thyroid function, subclinical hypothyroidism, where are we in this whole area right now? JM: Right. You have to recognize that clinical practice guidelines, by their very definition, need to be evidence-based, and there is a level of transparency where you can track the recommendations through the evidence and the evidence levels. What is missing—and this is what causes a lot of the controversy—is anecdote. So, we incorporate subjective opinion, but it is not based on subjective opinion. It is based on evidence. So many times the evidence changes and recommendations can change. So let me offer that just as a preface to my remarks. What I’ve learned in working with the clinical practice guidelines—and Jeffrey Garber was the chair of this, this was co-sponsored between ACE and the American Thyroid Association—is that contrary to maybe 10 or 15 years ago, where the interpretation of TSH really needed to adhere to very strict cut-offs for upper limit and lower limit based on clinical chemistry, we’re recognizing that some of those cut offs may change again based on—and you’re hearing this term again—different physiologic states. For instance, in pregnancy, a TSH of 2.5 or higher might indicate—and in fact, the recommendation is that it does indicate—the need for supplementation or treatment with Levothyroxine. The way in which we manage patients who are older, the way in which we interpret thyroid function tests in patients who are critically ill, or patients who are on different medications, can change the way in which we interpret thyroid function testing. But still, the TSH test reigns supreme when you look at the evidence. Now, when you look at controversial topics, those controversial topics are obvious. One of them is the use of T3. And that’s a big area. Right now, our opinion, based on these clinical practice guidelines and based on the evidence, is that there is insufficient evidence for the widespread, general use of T3. And that stems from lack of studies. The T3 preparations that are available are short acting, and really, is there truly a need to add T3 when you’re giving T4 and the TSH is in the normal range? The critics would say, “Well, the blood tests really don’t give you the whole story, and if somebody still has symptoms then you should treat those symptoms with an intervention, and then the evidence would indicate.” But that’s an unproven claim, because a lot of those symptoms are not specific, and, in fact, my experience is that I’ve had a number of patients who have come in with dramatically suppressed TSH levels who have been given escalating doses of T3 that have been titrated against the metric, which is “I don’t feel well” or “I’m tired” or “I’m lethargic,” and then as a result, you do witness some of the adverse effects of T4 overdosage. I think the bottom line is—and clearly I have a biased and polarized view because I’m really preferentially putting weight on the evidence—is that I would go by what the evidence is, but individual doctors can still use their judgment in managing individual patients. I think that your listeners are going to go on the internet and they’re going to find contrary opinions, and certainly patients have the right to seek out the management that they desire, but we felt that there was a need to express this evidence-based perspective, and again bearing in mind that the evidence can change, that there should be better studies looking at the effect of T3 (I’m just picking that out as one of the controversies), and then if the data are different, then we can change. For instance, there are polymorphisms as you are well aware and you may have discussed it on some of your other tapes, that there are polymorphisms in deiodinase, where some patients just are not efficiently converting T4 to T3 that well. This isn’t necessarily Refetoff-type thyroid hormone resistance syndrome, but there might be some inefficient conversion. I’ve had patients in the ICU where I have treated, from time to time, with low dose T3, and there is some mainstream literature on the use of T3 in critically ill patients. So there is a gray area, and I think ultimately there is this philosophical issue of whether you base your clinical practice—and I’m speaking as a physician now—do base your clinical practice on evidence, do you base it solely on anecdote, or do you base it on what I would term informed judgment? Is Hashimoto’s Thyroiditis on the Rise? JB: Thank you. Once again, very, very helpful. I want to just ask your opinion. We have the impression from watching the literature and feedback that we’ve gotten from docs in the field that there is a rising tide (a rising prevalence) of Hashimoto’s thyroiditis. If that’s true, it begs a question—why? I don’t think thyroid glands are suddenly being born that are imperfect. Is it true that that’s an increasing problem, and if so do you have any idea what its origin is? JM: Right. In large part it’s due to increased detection. That’s one of the reasons why we’ve seen this increase, for instance, in capillary thyroid cancer, particularly these microscopic forms, because we’re just detecting them easier. We have better high resolution ultrasounds. In the case of Hashimoto’s thyroiditis, a lot of practitioners are sending off antibodies more commonly. But there are pitfalls. For instance, just because you have the presence of antibodies does not mean that you have Hashimoto’s thyroiditis. Hashimoto described a goiter. There has to be lymphocytic infiltration and hypothyroidism. And just the simple presence of an antibody as a marker of some autoimmune process is not equal to a diagnosis of Hashimoto’s thyroiditis. On the other hand, if you want to zoom out and look at autoimmune disease in general, that’s something worthwhile studying. In the environment, there are endocrine disruptors; there are various pollutants and chemicals that have been associated with some increased rates of autoimmune disease. We don’t really have mechanisms and whether these are, again, a consequence of increased detection modalities, or whether there really and truly is some underpinning of some mechanism remains to be seen. We like to detect things early because we like to prevent disease instead of, as I said before, being in a disease management paradigm, so it’s laudable to look for these diseases, but I would caution that you don’t want to draw a test, or look for a particular disease, unless you have a sufficiently high pre-test probability using a little bit if Bayesian inference. Otherwise, your posterior distribution, as you know, can be very confounded, and the likelihood of actually making that diagnosis if you don’t really suspect it at the beginning can be quite low. One of the things that we discussed in the guidelines was the appropriate use of screening, and the appropriate use of aggressive case finding, and that’s another important take home message from those clinical practice guidelines. I think one of the interesting points that I came across when I was working with our committee and we were updating our bariatric surgery guidelines is, do you have to screen patients who are obese with a TSH? That’s a very interesting question. And it turns out that the evidence doesn’t support it. That obesity is not a physiologic state that warrants—just by itself, just having a high BMI—doesn’t warrant screening with TSH. Now, if you have symptoms—if you have some symptoms that make you think of it—then that’s fine. That’s an indicated test. But just by virtue of a BMI being high is not sufficient to justify screening with a TSH, and one of the reasons is that TSHs physiologically run a little bit high in obesity. And we know that after bariatric surgery those TSHs normalize. That was a very interesting observation—something that I learned in the process of developing those guidelines. Iodide and the Management of Thyroid Disease JB: Thank you. Another point of great news-to-use. Let me close—and you’ve been very kind, by the way, and gracious in giving us so much time—but I want to close on this thyroid connection to iodine. Everyone knows that iodine or iodide is incorporated into the formation of T4 and ultimately deiondated form, T3, and the important role that that plays, as you indicated in regulating nuclear orphan receptor activation of certain gene expression patterns that are associated with metabolism. What is not so well understood, I think, and there seems to be a swirling controversy, is whether we are, as a general rule, getting enough iodide, or too much iodide, or whether iodide can be used as treatment for things like thyroid-related dysfunctions as a nutritional agent. What’s the general sense right now of iodide in this whole picture? JM: Well, there are certainly certain endemic areas that have iodine deficiencies as a result of geologic issues and the amount of iodine in the earth, and then in vegetation, and making it along the food chain into adults, and those areas have been recognized and foods have been supplemented with iodine, and TSH levels, on average, have come down, and goiters have improved. But I think the point that you bring up is a very interesting point, which is the use of iodine in the management of thyroid diseases. One of the problems that I see is patients who are flocking to use iodine as a dietary supplement to “boost” their thyroid. Number one, there is no evidence that in the absence of an iodine deficiency, that using iodine pharmacologically can boost thyroid function. And in fact, iodine has a pharmacologic effect of inhibiting thyroid hormone release, and then we use it in medicine to inhibit the formation of thyroid hormones, something that’s called the Wolff-Chaikoff effect, where iodine somehow inhibits the activation in free radical activation that’s necessary to attach an activated iodine molecule to an activated carboxyl residue in thyroglobulin and in the formation of thyroid hormone. So you see these detrimental effects of iodine in patients in theory. Now, in practice, you probably don’t see that much of an adverse effect, and when we use it in medicine we’re really using iodine to treat hyperthyroid (overactive thyroid) conditions. If you have a normal thyroid and you’re taking iodine you’re probably just urinating it out and it’s excreted, but it’s unlikely to have a salutary or beneficial effect unless you truly have an iodine deficiency. JB: I think, again, that’s extraordinarily helpful news for many of our listeners. We’ve exceeded our goodwill with you. This has been a very, very rich discussion. Obviously we could go on for hours with the background and information you have at hand, but we want to thank you so much, Dr. Mechanick, for your extraordinary work and sharing it with us. You know, this bridging of the gap—you’re really a translational medicine expert from your background in nutrition, and endocrinology, and internal medicine, and really I would call it systems biology. This is the pattern characteristic of the physician of the 21st century. Thank you so much for kind of being our standard. We appreciate everything you’ve shared with us, and wish you the best and look forward to revisiting you in the future. JM: Great. Jeff, thanks so much for having me. I enjoyed it. JB: Likewise. Take care of yourself.  

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Welcome to Functional Medicine Update for March 2013. What a way to end our first quarter of 2013,  by  focusing this issue on women’s health problems that we recognize are rising in prevalence—things related to perimenopause, things related to dysmenorrhea, things related to what I guess you would categorize as disturbances of hormone signaling as women go through different phases in their development process. We’re very excited this month to speak with a noted clinical expert, a person who has really been studying this area in depth, way back from her early studies at MIT in bioengineering and later at Harvard Medical School, and that’s Dr. Sara Gottfried, who you’re going to be hearing from just in a moment.   I want to just set a couple of ground rules for our discussion that will follow. Those ground rules are related to how we view the symphony of information that comes into the body through different proprioreceptor systems that stimulate certain receptors that then activate certain downstream processes, and ultimately give rise to what is our function. That complex orchestration is obviously tied in part to how our genes respond to this information, so we have different genotypic responses (no two people are identical). We have epigenetic modulators, as you know, that have put different kinds of tags onto our gene code that say either “read here” or “don’t read here” that relate to how certain expression patterns of our genes are realized under certain circumstances. We can say that we are hard-wired from our genes, but we’re also soft-wired with our software called our epigenome. We’ve studied that extensively in Functional Medicine Update over the past 10 or more years. And then, there are the environmental modulators that influence the way that metabolism actually works, so these could be things like simple nutrients like the B-complex vitamins that are precursors to the co-enzymes that regulate enzymatic function at the metabolic level.   All of these things, when woven together, give rise to this control of the complex orchestration of our individual response to our environment. As our environment has continued to change in the 21st century, with even more time urgency, with even more digital connection, with even more environmental perturbation through the development of and environment contamination by new chemical species from which the human genome is only now getting its first information. All of these things are starting to create different signals that then translate through the genome and the epigenome into the phenotype that then produce different kinds of health patterns, and those disease patterns or chronic illness patterns then become the dominant reflection of the gene-environment interaction of our time.   I think this is why many of the things that we’re going to discuss in the women’s health area have started to demonstrate shifting sands of prevalence because we’re seeing different types of information being delivered to the genome through lifestyle and environment that is then translated into the phenotype with different types of outcomes as it relates to these messages and how they’re translated into function.   I believe that Dr. Gottfried has a wonderful way of contextualizing this, of actually helping us to understand the complexity of these interrelationships at a level that people can actually deal with. Sometimes, the scientific, high level, mumbo jumbo is a little off-putting and you need to translate this down into news-to-use where it can actually be effective in people’s own life process and how they’ll manage their own challenges of environmental pressure. I think you’ll find, in discussion with Dr. Gottfried, that she does a beautiful job of helping to assemble this information in a user-friendly way that can be dealt both at the clinical level and ultimately at the patient-management level.   It’s all about self-management, isn’t it? In the end, self-regulation has to engage the person in their own life in a different way. This is not all going to be a solution from a pill, or a solution from outside. It’s going to be a solution from the inside, from the way that person constructs and ultimately delivers their own life experience through the environment in which they find themselves.   So this will be, I think, a very interesting conducted tour through a functional medicine perspective on women’s health, taking what I think is a broader context of this post-genomic era that we’re living right now, in how the genome, the epigenome, and the environment interact to give rise to function. I hope you’ll enjoy this. You’ll note that we are going to travel across some uncharted terrain. We’ll talk about upstream and downstream modulators, we’ll talk about various types of factors that engage women in altering physiology in response to environmental stress and pressure, and then we’ll talk about how these can be remediated and modulated based upon sensible programs. So, a lot of stuff, here, ahead of us, but I think you’ll find it very, very useful and fun to listen to Dr. Gottfried and the way she describes this. Let’s move on into our interview with our clinician of the month, Dr. Sara Gottfried.

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INTERVIEW TRANSCRIPT

Sara Gottfried, MD Gottfried Center for Integrative Medicine 2625 Alcatraz Avenue #369 Berkeley, CA 94705 www.saragottfriedmd.com Once again I’m at the place in Functional Medicine Update where you and I both collaborate in wondering: who’s going to be the clinician or researcher of the month? You know, we’ve not been disappointed, have we, over the last several years, in some of the most remarkable luminaries who have brought clinical news-to-use, or new conceptual frameworks to our thinking about health care, and you’re not going to be disappointed this month. A long-standing colleague, friend, and person who I have tremendous respect for professionally in the way that she has chosen to orchestrate her practice, Dr. Sara Gottfried is an endocrinologist—well, actually, obstetrician/gynecologist, but you’ll find that she also is an endocrinologist from the way that she has done her own training and her own work to apply some of the recent breakthroughs in understanding of the female endocrine system and how it interrelates with obstetrical and gynecological issues within the female of the species. The Hormone Cure: Reclaim Balance, Sleep, Sex Drive, and Vitality Naturally with the Gottfried Protocol She has a new book out, a book that I think is an extraordinary contribution to our literature and I’m sure we’ll be speaking through, about, and around the book, and the book is titled, “The Hormone Cure: Reclaim Balance, Sleep, Sex Drive, and Vitality Naturally with the Gottfried Protocol,” so that leads us, obviously, into the news-to-use part, because we’re going to discuss some things that Dr. Gottfried, over the years, has discovered through really hard work and by understanding the complexity of the interaction of the female genome with the environment, and how that weaves its way through messenger molecules, called hormones, into function. Let me give you a little bit of a background on Sara. She’s quite a remarkable scholar, having been involved with both Harvard Medical School and MIT in her training. She completed her residency at the University of California at San Francisco, and she is still involved with teaching medical students and is board-certified in OB/GYN. As you probably recognize, California has a very interesting population of proactive, get-real, resist authority, female patients who are looking for the right answer, which keeps her sharp all the time. I think you’ll find that she has obtained that balance between the left and the right hemispheres of the brain, between the seductive rational thinking and the emotional and—I would call it—intuitive thinking, to really weave together quite a remarkable approach to her practice. You will discover that she is very, very skilled in some of the body/mind components—what I call comprehensive or integrated delivery systems (kind of functional medicine systems). So, we have a very skilled, diverse, constant learner that we’re going to be listening to. Dr. Gottfried, thanks so much for being with us. It’s such a pleasure to have a chance to share your work with our functional medicine group. SG: Thank you so much, Dr. Jeff Bland. I’m so delighted to be with you and with your tribe. JB: It really is. I think it’s a shared tribe, probably, between us, here, or among us. Let’s talk a little bit about how someone with your extraordinary educational background might have, by some perspectives, ventured off the beaten path and ended up in the kind of practice that you have, which I think is a very broad-based comprehensive practice using complementary and functional concepts. How did this happen, because one might look at your resume and say, “Well, this must be a purveyor the most scientific, rigorous, analytic, reductionist form of staying-in-the-lines practice.” How You Eat, Think, Move, and Supplement SG: Well, I would definitely agree with the rigor, Jeff, and I think the reductionist part is where I want to make some changes. My story actually dates back to childhood. I’m 46 years young now, and I grew up with a great grandmother who really taught me about functional medicine 40 years ago. I was living in suburban Maryland, and she would show up at our house (she lived in Palo Alto, California). She would show up at our house not with Barbies and See’s Candies like my friends’ grandparents, but she would show up with kale, and omega-3s, and she really believed that you find the answer to health in how you craft your lifestyle, and how you eat, move, think, and supplement. She practiced yoga, she was a whole food-ist, and this was at the time of Pop-Tarts and Charlie’s Angels. You know, it was quite radical at the time, but it wasn’t really something that I understood completely, Jeff, until I was in my 30s. I had finished all of that medical training that you so nicely described, and I found myself as a working mother, two kids, married, working in McMedicine (I was working at the local health maintenance organization). I just was miserable. I felt chronically overwhelmed. I was burning the candle at both ends. I blamed my husband for much of this. I had PMS. My sex drive was low, and I know most doctors don’t reveal these kinds of things, but I actually think it’s important to speak the truth. And I did what many folks do in that situation. I went to my primary care physician, and I was offered vitamin P, so he really thought that Prozac was a good idea for me, and that was a defining moment, Jeff, because I really felt that it was wrong—that it was exactly the wrong treatment for me—because I wasn’t depressed; I was chronically stressed out, and yet, I didn’t have the sort of training (conventional training) to address it. But I was able to take my medical training, at that point, and apply it to myself because I had a hunch that it could be that my hormones were off. Ultimately, it turns out, that’s exactly what it was. I started testing myself—doing something that here in California we call ‘biohacking’. I started testing myself, and I found that my serum cortisol in the morning was 30. So it was about three times the ideal level, and this was not Cushing’s syndrome; it was stressed out mom in her 30s. Once I started to correct my cortisol and stared to apply what I later figured out was functional medicine, systems-based thinking, that’s when I started to really feel better. It took me about four to eight weeks to really get my hormones back in balance again, and I realized that this was a gigantic gap in conventional medicine, so that’s what ultimately led to me bringing these functional medicine tenets to the next 10,000 people that I took care of, and to develop what I now call the Gottfried Protocol, and to write the book “The Hormone Cure.” JB: First of all, thank you so much for your direct honesty. I think that sets a really great tone for the conversation we’re going to have. It makes this very authentic, and I think we can all identify and tap into the pico-second, time-compressed society in which we live, and sometimes the last thing on our list is us; everything else comes first and then we wonder, where are we in this this whole equation? So I think you’ve laid that out beautifully. You just crossed an interesting line with me, however, that I want to come back and pick up, and I’m sure there are other listeners that are thinking the same thing. In my introduction to you, you notice I made a Freudian slip, and that is I talked about you as an endocrinologist, when you’re really a board-certified obstetrictian/gynecologist. I think that was my subconscious mind kind of at play because your work is very, very skilled—what I would call functional endocrinology—applied to the female, and it crosses disciplinary boundaries. You know, we’re in this interesting world where we know more and more about less and less until we know everything about nothing kind of model, so how does this work that you can cross this boundary and remain intact in your medical community, because that’s one of the challenges in functional medicine we all have, are these boundaries? Reproductive Endocrinology SG: Sure. Well, those boundaries, I think, are often artificial and unnecessary, right? I think many of them were developed at a time when we were very disease-based, and we know that the healthcare system is failing, so first of all, let’s just question the dogma of the boundaries to begin with. But you raise an important point, and also hat’s off to you, Jeff, because you similarly are a totally genre-bending thinker when it comes to these issues. But dialing back to the whole question of endocrinology, I’m board-certified in gynecology, and it’s definitely true that most women, I believe, start with their gynecologist when it comes to the most common endocrine problems that come up. So, if they’re feeling premenstrual, or their sex drive is low, or they just feel tapped out, like their energy is not where they want it to be or it’s inconsistent, I think they often will start with their gynecologist. As part of my training, one of the subspecialties in OB/GYN is reproductive endocrinology, so I definitely learned a ton of reproductive endocrinology when I was in my medical training at UCSF. In fact, at the time the chairman was a foremost authority on reproductive endocrinology, and that definitely influenced our training, and that’s Robert Jaffe. His focus is actually on the fetal adrenal, but that’s maybe a conversation for another time. Anyway, I learned a lot of endocrinology in my training, but you’re right that I’m not board-certified in endocrinology and yet I really found that women, especially, come up against this gap between what they want to solve: being overwhelmed, their sense of being stressed out, their sense of being hormonally out of whack, and certainly what is offered by traditional endocrinologists. I think endocrinologists are great when you have a crisis. So if you have Cushing’s, or if you have Addison’s, which as you know, are the only two extremes of adrenal function that are really recognized by conventional medicine, there’s definitely a time and a place for endocrinologists, and I would say that’s a good example, but for the rest of us that are in that middle road between Addison’s and Cushing’s, and we have what I would call dysregulated glucocorticoids such as cortisol, then I think we’ve got to look at other solutions. When I saw that gap, when I came up against it myself, I had that “a-ha” moment of just realizing, “Okay, endocrinologists are just going to dismiss anyone who goes to them with a problem related to cortisol, so why don’t I start addressing that?” And what I found, ultimately, is that most of the hormone problems women face trace back to stress hormones, especially cortisol. So that’s like the longest answer ever to your simple question. JB: No, that was a brilliant answer. Thank you. As you are speaking, you’re giving me an “a-ha” here, so thank you. The “a-ha” I’m having is when I think about your both professional training and then your after-traditional professional training, things like becoming a yoga expert and yoga instructor, I’m thinking that often in our downstream training—let’s call it our professional training—we learn about things that are specific to that discipline, whatever we call it (let’s say, in this case, gynecology), and so the vocabulary that we have for that field, and the topics that we discuss, and our expertise are designed around that body of information that specifically relates to those target organs. And often those are maybe downstream messenger molecules, so let’s talk about steroid hormones. Cortisol is one of those. Aldosterone is one of those. Testosterone is one of those. Estrogen is one of those (the estrogen family of molecules). DHEA is another one of those. So we have a family of these downstream modulators we call steroid sex hormones, or let’s just call them steroid hormones, that are all related to tissue-specific effects that occur as a consequence of the upstream things that are going on in our life. You might ask, then, “Well, what controls the downstream effects? What are the upstream players?” And so we get things that are not hormones from a traditional steroid hormone sense; we get releasing peptides, like luteinizing peptide, or like corticotropic-releasing peptides, or like hypothalamic-releasing peptides, thyrotopic-releasing peptides. So these are proteins that are upstream from these hormones that come from specific tissues that regulate tissue activity. And then we think, “Well there are other peptides that are upstream that also weave into this symphony, like the peptides that we call cytokines, these inflammatory immune modulators, and there are endorphins that are peptides that are produced by the central nervous system that interface with these downstream mediators.” And then I think of your training in yoga, and I think, “Well, hold it. Training like that often has an effect upstream. It influences the releasing substances that control the downstream regulators of these steroid hormones.” And often we spend all of our time talking about the downstream things, and maybe we forget a little bit about the upstream things. It seems like your approach—your 3-step protocol—really deals with both up- and downstream relationships. Am I on the right track, here, or is this taking us in a funny place? Start Upstream: Focus on the Brain and Steroid Hormones SG: You’re exactly on track, and this is why I love having conversations with you, Jeff. It just makes me do the happy dance. You’re exactly right. If we look at that upstream control system…I’m an MIT bioengineer, so I always like to think about, “Okay, what’s the control system? How do we modulate this?” And I completely agree with you that you want to look at, really, the brain, and I would say starting with the amygdala, where we perceive stress and we perceive threats. I like to think about, for instance, the HPA axis (the hypothalamic-pituitary-adrenal axis) and all of those peptides that you described (the corticotropin-releasing hormones), as well as those other mediators that you’re describing (the endorphins, the cytokines), and you’re correct in that I’m not a big fan of just addressing the downstream modulators. You know, if I were just trying to focus on cortisol and maybe creating a better balance between estrogen and progesterone for a woman who is in perimenopause, or if we’re just focused on trying to improve T3 levels (free T3 levels) in someone who is suffering from thyropause, I don’t find that you’re as likely to get a cure if you approach it that way. I really believe you’ve got to go as upstream as possible. There are many ways to do that. I’ve tried to address that in my book through a number of strategies. In fact, I’ve got about 97 ways that you can do it. And then another upstream piece that I want to bring in that was a topic of conversation the last time I was seated next to you at dinner, Jeff, was the gene-environment interface. Right? I remember…can I put you on the spot for a moment, because I asked you a very direct question. You had just come from some big meeting, I think in Colorado, maybe it was in Aspen, where you were having the latest immersion in the gene-environment interface, and I asked you, “So, Jeff, what about epigenetics? Where are we with understanding the opportunity of epigenetics? What percentage of our DNA can be modulated with epigenetic effects, or as my great grandmother would say, how you eat, move, think, and supplement?” I don’t know if you remember your response. Should I say what I recall you response was? JB: Yes, please. You’re doing a beautiful job. I love it. SG: Okay, good. You said that you really felt that 50 to 80 percent of our DNA, and the way it is expressed (the expression of our DNA), could be modulated by epigenetic effects. Does that still feel accurate to you, because this was a few months ago that we talked? JB: Yes, yes. I think that is what is emerging to be seen, that the big, maybe, regulators—these things that we call the promoter regions of genes that control whole systems of gene expressions—are very heavily impacted by epigenetic triggering. So, yes, I agree. Glucocorticoid Resistance: An Example of Upstream Thinking SG: Yes, and I’ve gotten super interested mostly because I’m a board-certified gynecologist, although I also work with men. I’ve gotten very interested in what is that epigenetic opportunity for women? So as we talk about this upstream control system…maybe I’ll just give an example, here, so it feels a little less abstract. Maybe what we can do is just talk for a moment about the serotonin transporter gene (SLC684). What stymies me is that somewhere around 40 to 45 percent of Caucasians have one or two copies of the short serotonin transporter gene (the normal version is to be long-long). What we know is that folks who have one or two copies of the short genes, and especially two copies (who are homozygous), they have an increased susceptibility to depression. They don’t move serotonin around the brain in an ideal way, so the communication system is faulty. They also are much more likely to have what I would call a hot amygdala. So they are more likely to perceive danger, especially of the emotional type. Another piece that I think is interesting—and this has mostly been shown in monkeys (I like to be really clear about the evidence that we have)—what we know is that women who have a normal amount of estrogen (well, female monkeys, in this case) behave as if they have the long-long, or the normal version, of this gene, and once their estradiol starts to drop, they behave as if they have the variance (one or two copies of the short gene). So to me this is really interesting and it sort of was another “a-ha” moment for me when I thought, “Okay, this is why so many women who are of a certain age—let’s just call it maybe 45 to 55—perhaps this is why they feel like they suddenly go into survival mode where they’re perceiving threats and we also know that they have something called cortisol resistance, or glucocorticoid resistance, meaning that they become bathed in cortisol at a high level, and feel this chronic stress that keeps getting reinforced, and they are unable to respond to glucocorticoids the way that they normally would.” So, similar to insulin resistance, there’s this phenomenon of glucocorticoid resistance. How is that as an example? I was trying to keep it ridiculously simple. I’m not sure I succeeded. JB: No, you did, and I think that raises a couple of really important points. First of all, you know, often in our society what we would do when we look at that kind of information of the short-short versus the short-long and the long-long versions of that serotonin transporter gene is we might say that those individuals born with the short-short homozygous are people that have flawed genes—that they’ve got some disease propensity because they got this inheritance factor that made them more susceptible, or made them more vulnerable or brittle in our society. And so we put a stigma on them—and we do this continuously as it relates to these genetic characteristics. It’s really a form of discrimination in some sense because what we start doing is saying, “Oh, well, you didn’t really get good genes.” What really we should be saying is, “Those genes that you have are genes that maybe at a certain time in history were selected for, in your distant ancestors, that gave them survivability in the environment in which they found themselves, so in a certain set of circumstances those genes would be considered advantageous, not flawed.” Like the thrifty genes of the Pima Indians, you know, that make them more at risk to obesity and diabetes, aren’t flawed genes; those are genes that are really selected for the biggest threat that they had in their history, which was survival against starvation. So in a certain environment of low calories, these are really desirable characteristics, just as maybe a hyper-responsive/hyper-vigilant/perceived-danger gene might be very good in an environment where you’re worried about your survival every day and you’re a mother trying to protect your young. I think these constructs that we often use as labels end up being off-putting and stigmatizing, and sometimes keep a person from really recognizing that what might be perceived as a weakness may be a strength if we were just to put them in the right environment. So that’s point number one that I would make from your discussion. And secondly, is this concept of, “Okay, are these modifiable factors?” Once you recognize that you have this genetic characteristic, can you change its expression or the pattern by which it—in the phenotype—produces an adverse outcome? In other words, it doesn’t allow the person to properly manage daily living in a way that gives them great pleasure and joy, and I think that’s what your program really does. Your three-step Gottfried Protocol—is it is a way of designing an environment for those individuals whose genetic uniqueness, not necessarily genetic flaws, to be successful, to be victors? Am I on the right track, here, as to what I heard? SG: You’re totally on the right track. You’ve just described precisely what I love the most about you, Jeff. I mean, I just think you’re such an incredible integrationist when it comes to thinking about these things, and I also really appreciate how you’re talking about these genes, not in a stigmatizing, but rather in what I would call a glass-half-full way. So you’re absolutely right that this propensity to be hyper-vigilant if you are homozygous for the short serotonin transporter gene, the propensity to have depression, to not shuttle serotonin around very well, to have glucocorticoid resistance and a hot amygdala, what I have found is exactly the point that you’re making. Yes, there must have been a time where this was advantageous from an evolutionary point of view, and I would also add that anecdotally, in the people that I have tested, I’ve only gotten short results (homozygous short) in my female patients. In the people that I’ve tested, I would even say that they have some mystical qualities to them. I don’t want to get too woo-woo; I’m going to stay with the data, here, but you’ve got to remember I’m also trained as a yoga teacher. These folks have really found a way, I think as they’ve been challenged by this short serotonin transporter gene (maybe there are other genes that we don’t know about that relate to this). They made their mess their message, and they’ve become really world experts at how to reverse the effect of this particular gene. So, I really love where you’re going with this in terms of understanding not from an either/or dualistic way of looking at genes, but first of all to say, “There might be an evolutionary benefit to this,” and then to say, “Okay, and here’s what we know about how to influence those genes.” As I mentioned, what we know in monkeys when it comes to the short serotonin transporter gene is that estradiol seems to help. It seems to help folks with the short variance behave more like they are long-long. We need to collect that data in humans, but it might become one of those really important decision points, especially as women hit perimenopause, that second phase of perimenopause where estradiol starts to drop. You know, it may be one of those important decision points on their dashboard when they are making decisions about whether to take hormones or not. And then the other one that I wanted to mention—another epigenetic influence—is P5P (pyridoxil-5-phosphate). That’s another one that has animal data showing a benefit in terms of the effect of the short serotonin transporter gene and how it’s expressed. It seems to help with the cortisol resistance. JB: You know, I’m absolutely fascinated with where we’re going in this conversation. For those that are listening, this wasn’t premeditated and rehearsed. I think this is the magic of what happens when you have conversation and true communication with people that are experts like Dr. Gottfried, and that is what often happens in medicine, I think, particularly with this gene era in which we live (the post-genomic era), is that we get into discrimination and kind of a meta-eugenic argument and what I call genetic determinism. It becomes very, very disempowering for people because we start thinking somehow that because of these genes we’ve just analyzed that they’re determined to get a certain disease. It’s kind of a recasting of a eugenic argument that we tried to get rid of in the early 20th century but still sticks with us, and it discriminates against that person and puts them in a class, and now they become that class of what we treat. We forget about the individual and now we treat that class because we’ve labeled them. And what you’re really speaking to so beautifully is ways of modulating the expression of these characteristics by changing the environment, changing both the micro- and the macro-environment. That’s a different kind of medicine, by the way, I believe, philosophically, than the way that we grew up from our view that disease is caused by a vector that you treat with a molecule and you then have a self-limiting condition where the body gets well. These conditions that we’re speaking about that plague us in the 21st century are very complex situations that relate to pattern disturbance across multiple parts of our physiology, and no one magic bullet is going to treat it. It requires this much more sensitive orchestration that you’re speaking to so beautifully in the Gottfried Protocol. As I listen to you, I can just envision how you speak to your patients, and how it must be very empowering for them to go from the model that they’re flawed to the model that they’re in control; they have a locus of control. I bet you have a lot of “a-has” with your patients. How Will Medicine Make Genetic Testing Actionable? SG: Well, I believe that is true. I think so many of the women who land on my doorstep—you know, they first come to me because they want to get their hormones in balance, and of course that’s just the tip of the iceberg. But, you’re right that many of them have been dismissed, or they feel like they’re doing something wrong. You know, they feel like a stress case because they can’t get to yoga often enough, or they don’t want to sit on a meditation cushion every morning, and I think it is so important to do what you’re describing—to really validate their experience and to talk about, “Here’s the biology. Let’s address the biology and then figure out if there are any emotional/psychological components that need to be addressed once we have improved your biology.” I completely agree with that, and also I think you’re calling out something very important. I don’t think we’ve got good language around it, but this idea of new paradigm medicine, or personalized medicine, and the fact that I’ve heard some predictions—and maybe you can chime in here—what I understand from when I was at MIT and they were working on the Human Genome Project was that it cost about three billion dollars to sequence the first genome. And now, it costs about 10 grand—10 thousand dollars—to sequence your entire genome. But in 2015, it is predicted that it will cost about 100 dollars to sequence your entire DNA. So that’s an incredible opportunity, but I really believe that old school medicine has no idea how to make this actionable, so it’s an incredible opportunity for functional medicine, for the practitioners who are listening to us, to really understand, “Okay, how do we help people going forward? How do we message this? How do we help them with their short serotonin transporter gene, or the Amish gene (one of those thrifty genes that you’re talking about, where your tendency is to put on weight, and—if you’re like me and you’re trying to fit in your skinny jeans—you’re fighting it all the time? How do we help people make this information actionable, especially as the costs significantly decline in the next few years for sequencing your genome?” Do you have any thoughts about that, Jeff? Can I ask a question back to you? JB: Absolutely. This is a dialogue that’s really fun. Well, I think you’re right on point. I just went to a meeting, here, a month ago in Mountain View, California, that was the global personalized medicine symposium, and for three days there were speakers every 15 minutes that were, like, the head of the FDA, the head of Medicare, the head of Aetna, the head of Blue Cross, the head of NIH. I mean, this was a very esteemed panel of presenters and it was all focused on this question that you’re raising, and that is, “What are we going to do now that the cost of having a full sequence of your genome will be accessible to virtually every patient?” In fact, it is suggested that it will start with infants, and every infant will ultimately get their full genome screened, and then it will transfer from that into other members of our society, but eventually—within a period of probably 10 years—everybody will have on a smart card the full sequence of their genes, which is the ultimate lab test, by the way, because if you think about it, every lab test you ever want to do or will be done (developed in the future) has information that’s really encoded in your genome and your epigenome. These are major paradigm shifting, seismic changes in the way that we can enlist technology into understanding certain strengths and weaknesses of our uniqueness. The question is always—and that was the principal question out of the meeting—“Okay, what do we do with it? Is this all going to be doom and gloom that now you know how you’re going to die, or is it really how you figure out how to live, and how to live effectively to the limits of your biological potential, whatever that might be–a century-plus of good living, compressed morbidity, and you know, have natural death that James Fries talked about in 1980 in the New England Journal of Medicine?” This is a new medicine that’s going to emerge to support this technology. I mean, it’s not the old medicine. The old medicine is wait until it is broken and fix it, and we see how efficient that is with the rising cost of health care, so this new medicine will be prospective rather than retrospective. It will be functional-focused rather than pathology-focused, and it will change curricula, education, training, and reimbursement for health care and how it’s delivered. So we are at the front edge. One can argue how long it will take to occur and certainly I have been recently criticized that I am always the guy talking about how the change is right over the horizon and then the question is, how far away is the horizon? But this is an inevitable change, this is not a fad or a fancy, this is something of substance as important as was the discovery for infectious disease—that bugs can cause illness—and that’s where we are right now in society. The Difficult Part is Not Making a Plan, it is Implementing It: Daily Lifestyle Challenges SG: I completely agree, completely agree. And I think it’s so important for folks who are listening to understand that this is coming and to prepare for it—you know, to really invest in your knowledge, you know, whatever your niche is, however you want to start taking this on and helping people with understanding how you uplevel the expression of your DNA. You know, my particular niche is the neurohormonal dashboard. I’ve tried to make it astonishingly simple in The Hormone Cure, but I find that the challenge—even with all the science that we have, even with all the randomized trials that we have for how to work with your neurohormonal dashboard–what I find is the difficulty for folks is not how to make a plan, but rather how to implement it—like, some of those daily lifestyle challenges that keep people from being able to do the things that they know to do. When I start off a talk sometimes I’ll ask people to raise their hands if they know what to eat in order to lose weight, and all the hands go up. And then I ask them, “Okay, how many of you are doing it?” and the majority of the hands come down. So we know so much about how food, and exercise, and the right dose of mental retraining, and the right supplements, how they influence your DNA, and yet I still think there’s a big gap in terms of helping people implement and maintain. Do you have any thoughts about that piece, Jeff? I mean, I found that yoga was one of the best ways to do it, but I would say more often than not in my practice when I suggest yoga to people, they look at me bug-eyed, like that is the last thing they want to do. They don’t want to go sit in a yoga class. Do you have any thoughts about this particular piece, about the implementation and the maintenance? JB: Well, I think you are one of those leaders who is helping us to understand how to translate intention into action. That’s why books are important. That’s why books from leaders who know what they’re talking about are important. That’s why being mentors, and guides, and role models and walking the talk as well as talking the walk is very important, and I think that’s why your book is a substantial contribution, because I think “The Hormone Cure” gets down into some of the issues that you’re speaking to in a very sensible way that comes from your experience, both as a person—as mother and as a person walking the world as a woman—and as a professional who understands the intricacies of how physiology plays out. I think you’re part of the matrix of change. I’d like to think that we are, in some small way, as well. How many individuals does it take to change a lightbulb? I’m not sure, exactly, because we’re trying to change the light that lights up global society, but I think this is a movement that is enlisting all sorts of people from different backgrounds who are seeing the light and are becoming advocates for a transformative state of thinking, which has to happen because this old model of thinking…the proof of the results are already in. It wasn’t a controlled study, but enough data are there that we can pretty much understand what the strengths and weaknesses were of that study, so now what are we going to do? Are we just going to continue to do the same and hope for different results, which is the definition of insanity? I think that you’re absolutely—in your book—talking about the answer to your question of me. Cortisol, Thyroid, Estrogen: Charlie’s Angels SG: It’s true. I guess I’m always trying to ask that question and answer it because I want to reach as many people as possible with, “We need to make these changes—the upstream and the downstream changes—that aren’t painful and don’t feel like a gigantic project.” I’m always trying to find the small hinge that swings the big door. That happens to be yoga for me, and we know that yoga helps you with the mental retraining. It helps you with tendency towards cortisol resistance. It helps with limbic hijack, and then downstream we know that it reduces cortisol, it reduces IL-6 (one of those cytokines you talked about). It also raises melatonin. So I’m a big fan of making that list as long as possible. I really want to offer people an a’ la carte menu for working in this way, for both the upstream control systems, as well as that downstream place that I call altered Charlie’s Angels. I think about your hormonal Charlie’s Angels for women, which is your cortisol, your thyroid, and your estrogen; and in men I call it the Three Amigos, which is your cortisol, your testosterone, and your thyroid. I found that those three seem to be very important, especially for women. I also realize, for women who are reading my book, I wanted to offer the content in two ways. I wanted one option to be very streamlined, where you take a questionnaire, figure out the root cause of your symptoms—for why you feel like you’re rushing from one task to the next, or feel tired but wired, or have endometriosis or fibroids or painful breasts, and then to be able to go to the chapter that corresponds to that particular problem. I did quantitative surveys in my patients to figure out what the top 7 hormone imbalances are, and those are the chapters of my book. So I have this very streamlined way that you can do the book, where you figure out your root cause and then you go to the Gottfried Protocol, this functional medicine approach to solving the problem, starting off with filling nutritional gaps and lifestyle tweaks and moving on to step two, which is proven botanicals, and then step three, bioidentical hormones (but for the shortest duration and at the lowest doses). I did that because I had some friends who read my book, and they said to me, “Sara, I love the book, but clearly that whole Harvard/MIT geek is coming out. Like, there’s so much science here. You make it really interesting, but if you say ‘adrenals’ one more time, I’m going to smack you.” So I wrote the book in these two different ways, and I wrote it, honestly, also for practitioners, so that they could have the data consolidated around how to address these top 7 hormone imbalances that women face. Have it consolidated in one place, and especially in chapter 4, where I address cortisol. I wanted to have that science consolidated and ready to have conversations with conventional physicians. That was a really important piece for me. JB: I think that’s probably why I loved the book so much, is that it really spoke to hemispheres of my brain. Obviously, I like to think that it’s a male brain, but the female influence came through very strongly. I think that you did a really nice job of treading that balance between enough of the science to demonstrate the rigor of authenticity, but put in the context of a useable program that really addresses the uncertainty of life and the process by which we navigate through life. It’s really a useable program. I’m very, very impressed. I guess one of the last questions I really should ask you—we could go on and on, and I’d love to in this conversation, but I know you’ve got a life to lead and things to do here—let me ask you, in making this practice that you evolved over 20 years and defining your professional and personal identity, you’ve undoubtedly run up against individuals who maybe have questioned how you’ve approached this. Maybe they’ve said, “Well, gee, you should stay in ordinarily confined areas and do what I want you to do”—this whole control of the guild-type model. How, as a physician, have you been able to make this change in your professional life? How do you make a living at it? How do you go through the daily world of peer oversight? All those kinds of things that we live in that become part of the reality, as you were saying, of putting our legs in our pants every morning. How has this worked for you? The Devils We Know: Premarin and Provera SG: I would say it has worked fabulously well. Whenever I answer a question like that, my default, which I think is similar to yours, Jeff, is to go to the data. I go to the data. To me, I think the first part of your question is about the doubters or the people who maybe feel threatened about the way that I take on conventional medicine and address these gaps that I came up against myself when I was in my 30s, and I know millions of women come up against them, too. The first part of that is that I really feel it’s important to be rigorous about the data. What I’ve emphasized in my book is the randomized trials. A well-designed randomized trial, as you know, Jeff, and our listeners know, is the best quality of evidence that we have; it’s got the least amount of bias, as long as it’s done well. I really feel like we’ve got a shameful past, especially in women’s health where we were using synthetic hormones—not just recommending them—and you know the devils I’m talking about, here. The devils we know: Premarin and Provera. We were prescribing them for 57 years before we had a randomized trial showing that they are dangerous and provocative in 1999 with the HERS study, and then confirmed again with the Women’s Health Initiative in 2002. Now, of course there were many flaws in that study—I don’t really even want to get into that—but I just think it’s shameful that we had 57 years of prescribing these hormones to women in a vast, uncontrolled medical experiment. I was taught not just to suggest them but to really proselytize them in my training. So I feel that it’s very important that we keep women safe, and that we have randomized studies to support the recommendations that we make. So the data that I have, the recommendations that I have, the solutions in my book, are all supported by randomized trials. Getting back to that question of the haters…my daughter said to me the other day…someone called my publisher and complained—she said that I didn’t go to Harvard Medical School—and that’s because I had my maiden name when I was at Harvard Medical School, and she also said, “Dr. Gottfried is recommending estrogen without a prescription and I disagree with that.” And she didn’t understand that I’m talking about the way that you eat, move, think, and supplement as a way of changing the tango between estrogen and progesterone. Getting back to that bridge that I want to build with conventional medicine, I really feel like this us/them paradigm is not good; it doesn’t serve anyone. And so I want to meet the conventional physicians in the middle. I am fortunate to have gone through the same medical training. I know what it’s like. I’m not blaming them for these gaps that we have in what women want. But, I also feel like we need to work together to find the right solutions. The first part of your questions is really, “How do you deal with the haters?” and I would say start with the data because that’s a lot harder to argue and there’s less of an emotional tone to it. The second part of it is, “How is this working for me?” and I think dialing back to when I was in my 30s, when I was working in McMedicine and struggling so much with PMS, and low sex drive, and wanted a glass of cabernet pretty much every night as a way of dealing with it—which, oh, by the way, raises your cortisol, it’s not a good solution—what I found was that when I really stepped into my own authentic ideas about how to take care of people, everything downstream was better. So that made a huge shift for me, and now, you know, I wanted to go from the one-to-one conversation that I was having with clients in my office to the one-to-many conversation, and I really love that. I think there’s something very sacred about leverage, about teaching online, about doing what you’re doing, Jeff, with how you train practitioners. I’m super excited about that. That’s another reason why I’m so excited about the book, but the short answer is: it feels a lot more authentic to be working with people in this way. JB: I think that’s a powerful, powerful sound bite that really relates to the advocacy that probably all of us feel when we step a little bit out of what was considered the standard of thinking at the moment. It’s not that every different idea is always right. You can get into the Galilean dilemma—because Galileo said that the sun was in the center of the universe and he was excoriated—anybody that thinks differently is a Galileo. I don’t think that’s always true, but I think there is something very special about being authentic to your purpose and using the best of the information you have from your colleagues, your training, your peers, but not being bound by it. The brain is still there to create solutions that we probably didn’t even know were going to come about until time moves on, so I want to just compliment you not only for the writing of the book, which I think is brilliant, but really for your advocacy, for the way you language things, for the sensitivity you have within your practice and your world. I think it’s a model for what many of us in the functional medicine movement are aspiring to be known by and be imprinted with. Thank you so much. We’ve spent a lot of your time going through this discussion, but every moment for me has been very, very rewarding and I thank you for all your hard work and your advocacy for your patients. SG: Thank you so much, Jeff. It’s been such a pleasure to be with you. Every time I talk to you it raises my oxytocin, and we know how good that is. JB: That’s a good way to end. I think we both are on an oxytocin high. Thanks so much, Sara. We’ll be in touch, and good luck as the book moves forward. SG: Thanks, Jeff. Thanks, everybody.

Welcome to Functional Medicine Update for April 2013. You know, we’re having a virtual epidemic—what I call almost a silent epidemic—of an issue that’s very, very serious in our global healthcare community, and that’s blindness in the adult population. And it’s not congenital blindness. This is what I would call induced blindness through what has often been termed age-related macular degeneration. We’re very fortunate this month to have an expert in the area of ocular health and ophthalmological research guide us through this extraordinarily interesting and tortuous field of visual acuity, retinal pathology, and how it interrelates with this rising tide of blindness. This is a very, very serious issue. As you talk to older people, they’ll often say, “If the quality of my life is so depreciated that I’m not enjoying it, then it really marginally evaluates whether going forward is worth it.” And one of those things that affects life quality is sight, a virtuous and important function as we grow older (along with memory). As you talk with seniors in settings where there is common communication among people of geriatric age about concerns they have, vision and memory keep coming up as  important areas of concern. And these are the areas that are most often impacting older age people, particularly in institutional settings and in various community living situations in which there is a lot of sadness about the loss of vision and the loss of memory that is experienced by older age individuals who are still looking to have some great days ahead in their lives. Vision and Ocular Health: Connections to Glucose Management, Oxidative Stress, and Mitochondrial Bioenergetics So what’s the cause of this ever-increasing source of age-related macular degeneration and ocular injury that is so serious that vision is ultimately impaired? I call this collateral damage, and it interrelates with insulin resistance, and oxidative stress, and many other topics that we have discussed in Functional Medicine Update over the last 30-plus years. In fact, it might be considered the poster child for the outcome from what happens over the course of decades of living where insulin has not been able to properly manage glucose, oxidative stress and mitochondrial bioenergetics are uncoupled and enhanced, and glycation, which is the connection of glucose to various proteins and the activation of inflammatory response, has been occurring for long periods.   Eventually, the macula in the eye starts to undergo degeneration, the ophthalmologist predicts that this particular process will lead ultimately to blindness, and the best therapeutic tools we have in terms of pharmacology and surgery are not able to restrain the tide against these processes. This sounds like an opportunity for lifestyle medicine. It sounds like functional medicine. And it’s exactly—I think as I said—a poster child for this kind of intervention. And the collateral damage, which  is injury to the eyes, as you’re going to be hearing from our extraordinary researcher/clinician of the month, relates to these conditions.  Dr. Kaushal can provide both a biochemical perspective, with his PhD in biochemistry, and a medical perspective, with his medical degree and specialization in the fields of ophthalmological surgery and ophthalmology. Let’s—in preparation for this discussion with Dr. Kaushal—talk a little bit about what we have known and what we have learned. I think this is a very interesting topic that takes us back to a period that some of you might remember if you’ve been in this field for some time and following Functional Medicine Update, because it’s been part of our discussions that we’ve been having since the late 80s. But there was a very important paper that appeared in 1994 in the Journal of the American Medical Association, and it was titled “Dietary Carotenoids Vitamins A, C and E and Advanced age-Related Macular Degeneration: The Eye Disease Case Controlled Study Group.”[1] You might remember this study; it got quite a bit of press at the time. It was done at the epidemiology unit of the Massachusetts Eye and Ear Infirmary in Boston, and it was published in JAMA, as I mentioned, volume 272, page 1413, in 1994. What they were attempting to do is to evaluate the relationships between dietary intake of carotenoids in vitamins A, C, and E, and the risk of neovascular, age-related macular degeneration. This turns out to be an interesting study that probably begs the question: why would anyone want to know what the levels of intake of carotenoids would be relative to the appearance of this age-related macular degeneration? What’s the association? Why would you even be led to ask that question? To understand that, we need to go back to look at age-related macular degeneration as a leading cause of blindness in the elderly worldwide. In fact, it affects millions of individuals and the clinical hallmarks of age-related macular degeneration are observed in people in all industrialized countries. In fact, its global cost for management—and as I mentioned, we don’t have a good medical treatment really at this point—is over 340 billion dollars annually.[2] So it’s a very, very big problem and it’s rising in its prevalence. The majority of age-related macular degeneration patients in the United States are not eligible for clinical treatments, as I mentioned, because we don’t have really good late-stage treatments. Therefore, preventive interventions through dietary modulation have become  attractive, and strategies are now being designed to try to look at the relationships of specific nutrients and their role in the prevention of injury to the macula. Understanding the Physiology of the Macula and the Fulvia Now, it is really important for us to understand a little bit about the physiology of the macula and the fulvia—the center of the retinal area.  As you probably recognize, the fulvia is the only tissue in the body that has a color associated with it due to the selective concentration of specific nutrient-related carotenoids, or let’s call them xanthophylls, or pigments. The body doesn’t make those pigments. This is a very important point. The body concentrates specific pigments that come from our foods, and in this case, those pigments are found mainly in vegetable products So, individuals said, “Well, hold it. If macular degeneration is associated with a bleaching of the fulvia (meaning loss of the pigments), and those pigments are strictly due to the amount that you consume in your diet, and we think that maybe as people grow older they don’t eat a lot of these dark green vegetables, and red and orange fruits and vegetables, then maybe there is a correlation between the lower level of intake of these specific pigments in vegetable products and the increasing risk to age-related macular degeneration. That was the underlying hypothesis that led, ultimately, to this retrospective study looking at dietary carotenoids in the eye disease case-controlled study in Massachusetts. And by the way, there’s a very nice review of the molecular aspects of the pathophysiology of macular degeneration that appeared in Molecular Aspects of Medicine in 2012, in volume 33, page 318.[3] What did they find in the JAMA paper? They found that increasing the consumption of foods rich in the carotenoids, and particularly the dark green leafy vegetables that are rich in things like lutein and other xanthophylls, may decrease the risk of developing advanced or exudative age-related macular degeneration, which is the most visually disturbing and disabling form of macular degeneration among older people. So this sat in the literature in 1994 with a call for intervention trials. This was an association study—an epidemiological retrospective—but does that really mean, for sure, that people who ate more vegetables with these pigments in them would have decreasing risk of AMD? Over subsequent years, for nearly 20 years, clinical trials have started to appear that have been probing this particular retrospective epidemiological association. And it’s those trials that I think we want to speak to, because the results look very encouraging. Now, are they hard, iron-cast, we-know-absolutely-for-sure? I would say no, but directionally we have some very good information from human intervention trials that certainly point the direction towards the relative understanding of the role that certain nutritional components play in the prevention and maybe even the management of at least earlier stages of AMD. Let’s look at some of these studies, just in preparation for our discussion with Dr. Kaushal. Recently, in the Journal of Nutrition Health and Aging (this is a 2013 issue, volume 17, page 219), a very interesting paper was published looking at biomarkers of oxidative stress in patients with this wet age-related macular degeneration, the most problematic form of it.  The studies showed   that people with this condition have an increased oxidative stress condition going on within the eye, and this is a consequence of factors that activate inflammatory processes.[4]  Inflammation rears its ugly head once again, in this case with eye pathology. What they found is that these processes are triggered by the accumulation of various advanced glycosylated end products, or what is sometimes called “AGEs.” Where do these come from? They come from the connection of glucose with proteins that then damage proteins and make them into funny proteins. I call them “crusty” proteins because this is a little bit like when you bake bread. The sugar in the bread connects with the protein in the dough to then form this crust that occurs after baking, so if you think about crusty proteins in your eye that’s not so good. And that can activate this oxidative injury and inflammatory effect. Now it turns out that these ocular pigments I was speaking of, these xanthophylls that are concentrated in the fulvia of the eye, are antioxidants, and they help to protect the eye against oxidative injury. They are also photosynthetic, meaning they are photo-reducing pigments.  Because the eye is always exposed to sunlight, the eye enhances its own oxidative risk just as a consequence of light exposure. You probably know that’s why we recommend sunglasses if you’re going to be exposed to a lot of UV radiation, because these wavelengths of light can cause damage to proteins in the eye and induce retinal damage and changes in lens opacity that are associated with cataracts. So, here’s another example of multiple effects that could enhance or increase the relative risk to the eye over time.   One  day or one month or even maybe one year, or over several years or several decades of cumulative injury that then accelerates and becomes more problematic and eventually leads to the diagnosis of AMD, which, in the latter stages, as I mentioned, we don’t have really good treatment for, and so the person goes on to unfortunately become blind.   Personalized Approaches to AMD Prevention and Management Can we, then, use nutrients, at some level in this process, in supplementary form, or can we change the diet through personalized lifestyle intervention, to retard or maybe even turn back this trend towards injury to the eye? That’s the kind of work that’s being done now and published. One of the family of nutrients that’s been found for maintaining the structural integrity of the eye and resisting some of these changes that we associate with AMD are none other than our good old friends, the omega-3 fatty acids. So, you know, it’s not one nutrient.  It’s not just, “Oh, everybody take lutein because that’s going to be the savior to AMD.” No, it’s multiple factors that play roles, as I mentioned. If you have insulin resistance, and hyperinsulinemia, and poor glucose management, that can increase the risk. If you have photoexposure (excessively exposing your eyes to UV light), that’s another risk. If you smoke, that increases oxidative chemistry in the eye, that’s a risk; in fact smokers have a much higher incidence of AMD when they grow older than non-smokers. And then we talk about omega-3 fatty acid consumption. If you have a low omega-3/high omega-6 diet, which is the proinflammatory fat diet, then you have an increased risk to AMD as well. So, all of these things accumulate together. It’s not just like one factor is the panacea. In the Journal of Nutrition in 2013, a very interesting paper was published titled, “High Concentrations of Plasma Omega-3 Fatty Acids are Associated with Decreased Risk of Late-Age Macular Degeneration.” This appeared in volume 143 on page 505.[5] Again, they did some wonderful photography of the eye, looking at the effects of omega-3 polyunsaturated fatty acids on the prevention of late-age macular degeneration, highlighting the fact that it looks like omega-3 fats are very protective. Now, again, we don’t have what I would call definitive intervention trial data yet, and in fact, some of you probably know that there is a little bit of work that’s been done by Cochrane; the Cochrane database did do a systematic review of the strength of data on omega-3 fatty acids and AMD, and what they say is: “Evidence from animal models is strong and observational studies in humans looks very suggestive that increased omega-3 fatty acid intake is associated with lowered risk to injury with AMD, but we are still lacking a good definitive long-term intervention trial, so they’re saying it still is speculative and not completely proven.[6] But if you’re evaluating options, this might be an option at least that at worst does no harm, to at least make sure that you’ve got proper omega-3 fatty acid intake. Now what about the xanthophylls (these flavonoids) that are the pigments; do they play a role? Of course, here we’ve got some pretty good intervention trials in humans that have actually started to look at specific doses of intake, like low lutein intake (it would be something like 10 milligrams a day versus high lutein intake supplements, which are 20 milligrams a day, versus placebo), and asked: Can you increase the plasma level of these pigments? Can you increase the level in the eye of these pigments by supplementation? The answer is yes. There is a dose response, graded effect of serum levels of these pigments and ocular levels of these pigments, and you can measure these in the eye actually non-invasively using what’s called macular pigment optical density. I won’t go into the technical details, but this is a way you can look into the eye with a specific measuring device and you can measure the density of these pigments in the eye. What is found is that by increasing levels in the diet, either by supplement or by food, that there is increasing concentration in the eye. Remember, I said this is the only place in your body where a pigment is intentionally concentrated selectively, for a functional aspect of your physiology. So the body knows what to grab out of your diet and to put it, in that form, in your eye. That is, if you’re eating it. If you’re not eating it, you can’t grab it and put it there. So there is a good bit of data saying that intervention trials do show a dose response effect of lutein and also of zeaxanthine.[7] Some of you know zeaxanthine is the yellowish/golden pigment found in corn. It’s the principal colored pigment in corn, whereas lutein is the principal pigment found in orange/red vegetables and in your dark green vegetables as well. So omega-3 fatty acids and the visual pigment carotenoids/xanothophylls do appear to be very important. What about vitamin A?  Because we think of vitamin A, which is produced from beta-carotene by an enzyme in the body that splits beta-carotene into two vitamin A molecules. People have started to look at vitamin A’s relationship to macular degeneration, and it’s interesting that vitamin A seems to have some added value to that of carotenoids themselves. Rather than being a pigment, vitamin A is not colored, but it affects the expression of certain genes.  Vitamin A has a specific gene expression response effect through what is called the nuclear orphan receptor family. That’s a big term, but what it means is on the nucleus of cells you have these receptors that are bound to various activating substances, one of which is retinoic acid derived from vitamin A, which is retinol.  The retinoic acid receptor binding site on the surface of your nucleus of cells, like your ocular cells, is stimulated by retinoic acid (and by the way, this receptor co-hybridizes often with 1,25-dihydroxycholecalciferol, which is vitamin D3).  The  combination of vitamin D3 and vitamin A, as retinoic acid, on these receptors activates a family of genes that then regulate retinal health. So, vitamin A plays an important role beyond that just of beta-carotene. In fact, there are quite a few intervention trials performed under controlled conditions (in animals, I want to emphasize) showing that graded intakes of vitamin A can have a very positive effect on regulating the expression of genes that are associated with visual pigment activity.  For example, rhodopsin, a protein that is involved with visual acuity in the rod cells of the retina , orphotophosphodiesterase transduction and fatty acid elongases that are all regulated by vitamin A in the retina of the eye. So again, I want to emphasize vitamin A, carotenoids, xanthophylls, omega-3 fatty acids, staying away from high glycemic load diets which stimulate too much glucose and insulin activity.   In fact, there is a very interesting animal study that looked at the relationship between glycemic index and ocular health, which showed that high glycemic load diets increase the risk of what we would call the animal model for AMD.[8] So again, all these things speak together as to the importance of lifestyle in enhancing or modulating the function of the retina that then helps to prevent, in years of service—like 7 decades of living—the relative risk of AMD. Are there nice studies that have been done demonstrating intervention-positive outcomes? There’s a nice study that was published in the journal Ophthalmology in 2012, volume 119, that was an intervention trial with a graded dose of lutein and zeaxanthin (10 milligrams a day of lutein, 10 milligrams a day of zeaxanthin) versus placebo showing  a trend towards improved visual function and what looked like early-stage prevention of AMD.[9] Again, these are short-term trials. You really probably need a much longer-term outcome trial to fully nail this down, but you have to go off what you have, so an 8 to 12 week trial is generally the length of most of these studies at this point. There’s another paper that was published in the American Journal of Ophthalmology in 2012 that demonstrates improvement of retinal function in early age-related macular degeneration after lutein and zeaxanthin supplementation, and this was a randomized, double-blind, placebo-controlled trial in 108 subjects with early AMD, showing that the 10 milligram per day lutein and 10 milligram per day zeaxanthin combo was associated (versus placebo) with reducing the trend towards advancing AMD.[10] Again, I think this field is still in a state of interesting development of more support for the association between lifestyle, diet, and AMD, but it certainly looks very, very strongly associated, particularly now that we now have started to develop a mechanistic understanding of how these pigments work as antioxidants and photo-reducing agents that prevent these oxidative injuries to the eye. There’s a wonderful review paper in Free Radical Biology in Medicine in 2012 that talked about the mechanism by which these pigments reduce photo-oxidative injury and modulate the expression of inflammation-related genes in retinal cells.[11] As I mentioned, if we just look at the general trend of what’s going on right now, if we do nothing—if we just use the available drugs that are on the market today to try to treat this—it’s not looking too good. That was kind of a double entendre, wasn’t it? A play on words: Not looking too good. Diabetic retinopathy and age-related macular degeneration are increasing almost exponentially in our culture. We’re growing older, but we’re not necessarily growing older healthily, and blindness is becoming a very, very big problem. There was a paper that was published in 2012 in the American Journal of Preventive Medicine, volume 43, page 48, that talks about the high frequency of unawareness among older age people of diabetic retinopathy and its relationship to age-related macular degeneration and how that relates to lifestyle habits—that older age people just do not understand this.[12] It’s not been a topic of conversation. Their doctor has not discussed it with them, and so it’s almost like a firestorm burning uncontrolled. And so either foods that are rich in these pigments, or supplements, have been found to be valuable. There is a paper published in the British Journal of Nutrition in 2012, volume 108, page 334, that compared nutrient supplements containing lutein and zeoxanthine versus consuming foods that are rich in these pigments—natural foods (it could be spinach, for instance, or carrots)—and showed that there was value in either of them (either through the supplements or through the foods that are rich in these pigments).[13] Again, I want to emphasize the data says it is a whole-body, functional effect. If you’re a smoker, if you’re a high alcohol consumer, if you’re an individual who has a lot of proinflammatory dietary habits, you are at much higher incidence risk of AMD. And so it’s a full change. It’s a functional medicine, lifestyle, personalized change that really can turn the tide in the other direction, and it’s that that we’ll be talking about with our extraordinary clinician/researcher of the month, Dr. Kaushal, who will help take us through a better understanding of what’s occurring at the forefront in this very, very important area where drugs and surgery are not the answer. It appears as if a functional medicine approach using personalized lifestyle medicine is the preemptory approach that we available today. So with that, let’s turn our attention to speaking to a person in the know in this extraordinarily important area

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Shalesh Kaushal, MD, PhD Vitreoretinal Consultant, VRMI Gainesville, FL Here we are once again—that’s the moment I think you and I wonder, “Okay, who’s the next exciting person we’re going to explore some visions of the future with in medicine?” Boy, are you up for a real great treat today once again. We’ve been so fortunate to engage in conversation with a thought leader, an expert who has quite a remarkable background, Dr. Shalesh Kaushal, who is an MD/PhD. He was an associate professor at the University of Massachusetts Medical School. Ophthalmology is—I guess you would say, his “label,” although as you’ll find, he is far-ranging and broader in terms of his scope of interest and impact than maybe just one medical discipline because what he’s doing I think has a significant spreading effect into many other disciplines in medicine from a fundamental, heuristic, and I think didactic, and probably even philosophical perspective. Let me tell you just a couple of things about Dr. Kaushal that I think you’ll find interesting. The first point for me is some of you know I had my lineage kind of coming up through the ranks of organic chemistry and then into biochemistry and ultimately into clinical work, so he shares a little bit of an interest in that he’s got a PhD with a gentleman who I had very, very high respect for back in the 60s and 70s when I was doing a lot of my doctoral and postdoctoral work, Dr. Khorana, who was known for being one of the great organic/biological interface transition people that not only was an expert in organic chemistry but he was an expert in biological chemistry and biological systems thinking. So, Dr. Kaushal did work as it relates to some of the visual pigments, which he’ll be speaking more about, that enters into this whole concept of the outside environment—the photoenvironment—and interrelationship to neurology, neurochemistry, ophthalmology, and this gene/environment interaction model is obviously tied to these visual pigments. And then of course, he has a medical degree, and is the Chairman of the Department of Ophthalmology at the University of Massachusetts School of Medicine, and has worked across many different disciplines, both as a clinician and as a researcher, and also has a very rich publication record that we’re going to have a chance to talk about that relates to issues pertaining to some of the major risks that we are developing in the field of ophthalmology, like retinopathy. Some people call this a cratering—when you look at the retina of the eye of some patients they have these hemorrhagic problems and retinal injury that ultimately leads to the major cause of adult blindness in the United States, and how that interrelates with other age-related problems like macular degeneration. This concept of sight and vision is a big concern, as you know, as we start to see more and more cases of insulin resistance, hyperglycemia, and the effects of type 2 diabetes. I think we’re right on the edge of some of the most remarkable questions that will lead to solutions to these systems-related problems. It’s probably not just one drug for one disease; it’s more a systems approach. Dr. Kaushal, thank you so much for being available to Functional Medicine Update, and for the remarkable opportunity to get to know you and your work. You are truly a leader in the field. I guess my first question is: “How did your path take you down into the field of ophthalmology and this bridging of gaps across the disciplines?” SK: Yes, Jeff, thank you for having me on and taking the opportunity to share some of our thinking—my lab’s thinking and my own thinking—over the years. My own educational odyssey, as it were, or training odyssey, really began at first in college as an undergraduate, where I always knew I had a passion for math and science. Actually I wanted to—at one point—be a professional basketball player (being 6’5”), but that’s a rare event. But I really got turned on by a set of professors in my junior and senior year while I was an undergraduate at Yale University, and then went on to medical school, and really in medical school I vacillated between a couple of different specialties—neurosurgery was one—and my exposure, particularly during the third-year rotations in ophthalmology with Drs. Irene and Ed Maumenee at Johns Hopkins Wilmer Eye Institute, galvanized my excitement about ophthalmology, and really the opportunity in that field (the field that I’m in) to take on a career of being a clinician scientist. Their really wonderful, strong encouragement lead me to pursue—as you’ve mentioned already—PhD work with Dr. Har Gobind Khorana at MIT. I was absolutely absorbed in the world of research and I actually had entertained the thought of just pursuing a postdoctoral fellowship as a scientist, but I really missed taking care of people. And that passion to combine my sincere interest in science and eventually in clinical trials as well as so-called translational research, and in simultaneously taking care of people, led me to do my clinical training first in ophthalmology and then as a retina specialist. I did my ophthalmology training out in Los Angeles at the Doheny Eye Institute at USC Medical School, and then my surgical retina and medical retina training in St. Louis at Barnes Retina Institute. Because of that training, I felt I still wanted to spend a little bit more time learning about inherited retinal and macular diseases, and I was very fortunate to be a Fellow in London at Moorefields Eye Hospital with Professor Alan Bird and Professor Shomi Bhattacharya. Professor Bird is considered one of the international authorities in inherited retinal and macular diseases, as well as other medical retinal diseases. Dr. Bhattacharya is also a really outstanding internationally known basic scientist. It was there that I started really formulating how I might eventually pursue a career as a clinician scientist. JB: That path, drawing from so many academic and clinical disciplines, gives you a very interesting imprint, I’m sure, on how you look at patients, how you look at their disease. I have a suspicion that it may lend itself very nicely into this systems approach that you’ve been developing, which we’re going to talk more about. Has this been at all a challenge with some of your colleagues who don’t have this broad-based perspective that you’ve developed over your years? SK: Yes, there is a set of us that have been fortunate or blessed to follow this path, but from my own personal and professional perspective, once of the real beauties of being a retina specialist, or an ophthalmologist in general, is that we can actually observe the biology directly through the microscope and other non-invasive diagnostic testing that we can do (imaging that we can do) of the retina. I find it particularly satisfying, not only in terms of taking care of patients and helping them improve their vision, but also as an experimentalist, because you can directly visualize at least part of the biology of the disease. What I really enjoy is seeing patients and then trying to recast some of the biological problems related to the disease into experimentally tractable problems that can be attacked in the lab, or at least pursued in the lab, to try to better understand the disease and/or develop potential therapeutics. JB: So with that as a basis, help us understand what’s going on in disease epidemiology related to retinopathy and retinal diseases. We have these inborn diseases that remain maybe reasonably fixed, and then we’ve got these induced diseases which may be affected by the environment, so where are we in this whole…? Diabetic Retinopathy Incidence is on the Rise SK: Yes, yes. This is a great question. It’s a huge concern both in terms of clinicians taking care of patients with retinal diseases, but even more broadly as a public health problem. As it turns out, for example, diabetic retinopathy—as you are already pointing out, diabetes in general is rising essentially exponentially across the entire globe. And in addition, as you might imagine, so are the complications related to diabetes and in my own field there is clearly a worldwide shortage of retina specialists, because we simply can’t manage all of the patients that need to be evaluated and/or treated for diabetic retinopathy. Likewise, macular degeneration is quickly rising to be the number one cause of blindness in the world. Right now it’s the number one cause of blindness in the Western world for sure, but the incidence in the developing world is also rising quite dramatically. Between those two diseases, which is pretty remarkable in and of itself, it accounts typically for probably anywhere from 50 to 70 percent of a retina practice. In other words, the number of patients that a retina specialist will see are preponderantly patients with diabetic disease or macular degeneration. That’s just those two diseases alone, and remember there are so many other retinal diseases, some as you were already hinting which have a genetic component, and others which are clearly influenced by environment, nutrition, diet, and so on that are also rising for sure. For example, certain types of vascular occlusions, you can consider them as mini strokes or strokes of the eye. The numbers of those types of patients with those types of disorders is rising as well. We’re seeing a tremendous change in the patterns of referrals of patients or the incidence and prevalence of disease in a retina practice, but obviously in a larger sense in medicine as well. JB: One of the things that I’ve heard people say, which I don’t necessarily agree with but I’d like to get your much more well-informed opinion, is that these diseases of the eyes that we’re seeing, this increased prevalence, is a consequence of the aging of our society and so this is just a natural consequence of older populations who have older eyes. Is that strictly the answer? SK: That’s a wonderful comment, Jeff, and I would say no. I don’t think it’s purely an aging event. We know that there is an age-related change in the metabolism of the retina and the eye in general, but the actual manifestation of disease, which is the consequence of aberrant homeostasis, as it were, in the retina, there is clear and mounting evidence of the role of environmental influences and also nutritional influences, even in our own field (or in my field) as a retina specialist, the awareness and understanding of that has begun to emerge with lovely epidemiological work done not only here in the US but elsewhere around the world. So it’s clear that the profound effect of nutritional and environmental stressors, as it were, on the body in general and the eye as well, is increasing. I further say, even though I’m a retina specialist and primarily focused on addressing issues of the retina, these diseases that we see with retinal manifestations are really evidence of a systemic disequilibrium in many, many retinal diseases, and that understanding has started to emerge more clearly I would say over the last 10 to 15 years with both wonderful and epidemiological work, but also molecular and biochemical understandings of these disease processes where we see that even though we may directly visualize changes in the retina, we recognize that those types of changes are occurring elsewhere in the body as well. JB: That leads to a very, very interesting question. You talked about the disease processes and your work has helped really to explicate and break through with new understandings of these processes at the molecular and cellular level, and I know that you’ve been doing quite a bit of work on signal transduction in some of these pathways that get disturbed or modified in their expression. Could you tell us a little bit about things like your heat shock protein work, and how you see signal transduction influencing these disorders? SK: Let me step back and sort of set the stage—a conceptual framework—to understand some of this, for you listeners. So you might imagine, for example, in the rooms where we’re sitting, to feel comfortable we don’t turn the temperature widely ten degrees one way or the other on the thermostat, which is essentially a rheostat. We just turn it a couple degrees one way or the other to be comfortable in the room. Now, think about a cell or a tissue that is stressed either by some environmental influence—for example, cigarette smoke, or some nutritional imbalance, or some genetic (intrinsic) change within the cell. So you can think of that cell, which was previously in equilibrium, now it’s sort of off-kilter, just like a see-saw that’s out of balance. And the real goal of any therapeutic agent is really to allow the cell and the tissue to re-achieve equilibrium. In other words, bring that see-saw back into balance. That’s the fundamental idea around the therapeutic, as we conceive it and obviously many other folks as well. The other piece of this framework is that if you think of the cell as having a set of multiple pathways—for the moment you can think of them as these little points—and these pathways are connected to each other with springs. So you might imagine that if you touch on one spring—you know, one particular pathway that’s important for cell survival or cell functioning—that when you press on one spring, because all these other springs of these other pathways are connected, that all the other springs will also vibrate. Now, what does that mean in terms of a therapeutic? The way we think of it is instead of targeting a particular protein, what we’d like to do is target a particular pathway. For example, the heat shock protein pathway. There are other pathways that we’re interested in as well. You might imagine that if you have a therapeutic agent—in other words, a small molecule or a drug—that can affect one of those pathways, because there’s this intrinsic intelligence of a cell to rejigger itself back into homeostasis. If you affect one pathway rather than a single protein, now you have a chance for that cell to re-equilibrate. In other words, for that see-saw to come back into an equilibrium state, where it is straight (you know, parallel) with the ground again. The concept of these small molecules—I’ve nicknamed them molecular rheostats because they’re just like a temperature regulators, as it were, a thermostat. The idea is, again, to affect a pathway, because it is interconnected with other cellular pathways, that this would allow the cell to reestablish homeostasis. We’ve become very interested, as you’ve pointed out, in the heat shock protein pathway, as well as the role of certain drugs called histone deacetylase inhibitors, like valproic acid, like SAHA and Vorinostat, and others, because they allow us to target a pathway and sometimes even multiple cellular pathways, rather than a single protein. JB: This is extraordinarily interesting based on the way that functional medicine has evolved around a systems biology concept, because the way I’m interpreting what you’re saying is the imbalances in only a few basic cellular processes give rise to literally thousands of different diseases depending on how they flow through that person’s genotype into their phenotype. SK: That’s exactly right. JB: And then that leads into the question: “Okay, if there are only a few of these pathways that ultimately control and regulate multiple outcomes in the phenotype, then what are the determinants for the expression of those imbalances in those pathways or those networks? How do those genes interface with the environment to give rise to the expression that we call that family of diseases? This sounds to me like a general precept in medicine that you’re applying beautifully to retinal diseases, but it seems like it has a very broad-reaching implication. SK: Yes, absolutely. Jeff, if I may recast it in my own terms, that’s where I really find the approaches of functional medicine so resonant with what we think in terms of cellular therapeutics, what functional medicine thinks of in terms of overall patient well-being, For example, we know that for almost every human disease, there are at least three or four clearly associated biological changes. One is there is oxidative stress. It seems, from my own reading and then talking to experts in many areas of medicine and science, there is clear evidence of oxidative stress in almost every human disease. Second, the role of inflammation in human disease processes. And third is the role of the immune system, which is being better appreciated across many, many diseases, including retinal diseases). And then finally the fourth is the role of cell death. At least in science, there is a great interest in apoptosis, or so-called programmed cell death, but there are other forms of cell death as well: necrosis, inflammatory cell death, and then there is something even called necroptosis, where there is inflammatory programmed cell death. So those four or five canonical principles of disease, at a cellular level or at a tissue level, I think resonate very well with the concepts of functional medicine that, Jeff, you and others have developed and are now starting to be practiced across the country and elsewhere. JB: This is very, very exciting. So let’s take this, now, to your work, which I think has been pioneering work, to look at how this construct translates into searching out for a drug that will treat a specific ocular disease. How does that then guide your research and guide maybe therapeutics as we look downstream as to how we’re going to better manage this exploding prevalence of these conditions? SK: Yes, this is at the level of experimental science, that’s the real challenge of it all. Let me just, again, share with you some of the ideas we’ve developed. Obviously there are other folks who are thinking along similar lines as well. We’re just fortunate we have a model system that Mother Nature has gifted to humans and mouse models, eyes that are easily observable and easily quantifiable in terms of what may be happening at the level of the biology of the retinal tissue. Experimentally, what we had set up and completed was to use the power of robotic screening—in other words, high-throughput screening in multiple assays. We’re looking for molecules that have the properties of one, being antioxidants; two, that they are anti-inflammatory; third, they should have some ability to prevent cell death; and then fourth—like I was mentioning before—those canonical aspects of human disease—that they should have some ability to modulate the immune system. At first glance that may be a tall order if you look at it on the surface, but it turns out, quite interestingly, that nature solves many of these therapeutic problems with natural plant products and herbs as well. Many of them, as some of your listeners may be familiar, Jeff, and you may be familiar as well, are called adaptogens, and these types of natural small molecules (or “drugs” if you’d like to call them that) are produced by plants and herbs to allow them to survive in unusual climates (unusual cold or unusual heat). As it turns out, they have—very, very interestingly—these types of properties that I’ve just mentioned, that could be useful as therapeutics in human disease. Part of the attraction of all of this to me is because they’re natural, they can be consumed either as the native plant or herb, or in some instances the natural product has been isolated. In fact, that’s what we originally discovered. And as you might imagine, that since nature has developed these literally evolutionarily—over thousands and maybe even hundreds of thousands of years—that they must pass certain intrinsic biological safety tests, which turns out to be true, right? And without getting into the real nitty gritty specifics of it all, the excitement to me is that this interfaces directly with some of the concepts and approaches that functional medicine takes. In other words, using natural products, or if you want to recast it a slightly different way, one might imagine having these versatile small molecules that affect potentially—as I mention—multiple pathways, and thereby mitigating multiple aspects of disease manifestation, or, Jeff, as you were describing, the phenotype. This approach, to me, is conceptually very satisfying and we believe it may be the future of therapeutics in the not-so-distant-future. What I want to point out is how it contrasts with typical approaches in academia and the pharmaceutical industry. Typically, what happens is a target protein is identified to participate in some aspect of the disease process, and the idea is to develop a biological agent—it could be an antibody or a small molecule (a drug)—that binds to the target with extremely high affinity. Often the idea is to have something with nanomolar binding affinity for that protein target. Basically, you load up the cell, or the human being, with that drug in order to affect or change the cadence of the disease pattern. What we’re suggesting is slightly different, and that is, first of all, that you don’t need large concentrations of the drug, and thereby you limit the potential toxicity. And then secondly—and more importantly, as I’ve said before but repeat again—is the idea that you’re rejiggering the cell into homeostasis by affecting a pathway or other multiple pathways within the cell that allow it to then re-equilibrate or reacquire homeostasis. JB: I think this is an unbelievably interesting merging of what I guess some people would call traditional medical thinking from both traditional Chinese medicine and Ayurvedic medicine. It’s a very powerful mixing of models into a systems biology model that addresses pleiotropy, it addresses redundancy, it addresses complexity, and it’s less involved with single hits of single targets as it is modulating systems of disturbed function, so it’s a really powerful concept. In your models of retinal disease have you had any successes? SK: Yes, Jeff. We’ve been very fortunate to literally take things from cell culture, animal models, into humans. In fact, I’ve been very fortunate to present some of this work at national and international retina meetings. The first time I presented it a couple of years ago there was less interest, and then as you know, as there is more use and also additional work that is done in the area, there is greater interest and also greater scientific validation of the approach. My colleagues are now starting to use the therapeutics (or at least one therapeutic) we’ve identified, and we’re obviously keen to replicate that. So at least we have one proof of concept and now we’re seeking others—some natural products—to bring those to clinical use in retinal diseases and see that they also literally allow us to go from bench (again, from cell culture and animal models) into humans to affect the disease process itself. The other very tantalizing idea or possibility, and I think, Jeff, you already hinted at it earlier, is in part because these disease pathogenetic events are conserved by Mother Nature. In other words, when a cell or tissue—whatever it may be: heart, lung, liver, brain, eye, bone marrow, muscle—when that cell is stressed by environmental or genetic factors, Mother Nature only has a constrained set of options from which she tries to deal with that disease. And if it isn’t able to deal with that stressor, then that becomes manifest as a disease of, for example, the muscle, or the heart, the lungs, or liver. One might imagine these types of molecular rheostats…not only have we used the retina as a platform for discovery, but also they have potential utility in other diseases. Is that true? Well, at least in the mouse models we’ve explored of non-retinal diseases, like of the lung, of the pancreas (like diabetes), and also heart disease. Those same sets of molecules that are modulating and affecting retinal diseases, at least in our mouse model appear to be effective in these other diseases. And that would be consistent with our thinking of how a molecular rheostat should work. JB: Yes, I’m thinking of a compound like resveratrol, which has received a tremendous amount of attention over the last decade, which we know is a histone deacetylase modulator and has effects on the sirtuin gene families and the mammalian target of rapamycin (or mTOR), that would be kind of a candidate that we might think of, from peanut skins or from grape skins that could be such a candidate for this model that you’re describing. SK: Absolutely. In fact, maybe it was rather telepathic of you, but that is one of the molecules—we haven’t published that work yet, we’ve presented it as a poster—but we’ve identified it as a compound that clearly affects the cells of the retina in terms of protecting them. JB: This is taking my reading of some of your publications to maybe a level of abstraction so I apologize if I’m leaping too far, but I’m very interested in your work on Leiber’s optic neuropathy, because that’s a constituent of mitochondrial deletion disorder that’s genetically inherited through the maternal linkage, but it also has a very interesting model to bioenergetics and how that interrelates Leiber’s optic neuropathy to myopathies and to encephalopathies because these conditions kind of come in groups of families, to talk about your multi-target types of tissues. Have you had any experience in you molecular rheostat model looking at something that’s as constitutively intrinsic as Leiber’s optic neuropathy, which is a mitochondropathy? SK: Right, I think you’re thinking of our published work on Leiber’s congenital amarosis. That’s where we’ve had some degree of success with gene therapy, and that’s a disorder of the retina which affects photoreceptor function. But your thinking about Leiber’s optic neuropathy is correct in that it is a mitochondrial disorder. I don’t have direct experience with that disorder. JB: The reason I’m asking the question is it strikes me, from the extraordinary work you’ve done—the systems biology approach—that this may interface ultimately at a mechanistic level with bioenergetics at the mitochondrial level. Systems Biology and the Future of Retinal Therapeutics SK: Absolutely, Jeff. That’s a true statement for sure. In fact, in the midst of writing a prospectus on the future of retinal therapeutics, which also has implications, obviously, for other areas as well, but this whole concept of cellular homeostasis, which requires a systems biological approach to really embrace not only the complexity and nuance of disease, but also by embracing that complexity one can think about therapeutics like molecular rheostats. And again, I wouldn’t say that that’s the one approach, the one we’re taking; there may be other approaches as well. Coming back to your comment, it has to embrace the importance of energy metabolism, because in nearly every single disease process—at least in my own reading of the literature—there are clearly effects on the dysregulation of energy metabolism. In other words, the efficiency with which a cell may produce ATP, or the way that the cell may process or use that ATP in various energetic or biological machines that exist in the cell. JB: Let me, if I can, talk about one last area that I know you have much more depth of understanding than I, but I think it interrelates with everything you’re talking about, and that’s macular degeneration and its relationship to visual pigments in the fulvia, this lutein connection to diet. People are trying to understand these photo desensitizers, which are these pigments that are concentrated in the tissue and are unusual in that the body picks a certain chromaphore to concentrate. Could you tell us a little bit about how that fits into this model of molecular rheostats because it seems like it’s another example of your concept. SK: Yes, Jeff, that’s right. Macular degeneration, just in terms of a little bit of clinical medicine, is quite common in the Western world; it’s the number one cause of blindness in the West and it’s rising throughout the world. It comes in two basic forms. I think “forms” may be a less correct term. It comes on a spectrum of disease. You can think of it almost like an autism spectrum. There’s a so-called dry form, or non-exudative form, where there is an absence of abnormal new blood vessels that are growing underneath the retina, and then there is the so-call wet, or the exudative form, where there are examples where patients develop neoangiogenesis—new blood vessels that are growing within or underneath the retina. In that disease it is clear that there are multiple, critical, pathogenetic events that occur in that disease. Some of them I’ve already mentioned in the general context of human disease, but we know that, again, oxidative stress, clearly inflammation, and in the case of the eyes, photo oxidative stress—in other words, excessive light exposure—we know that there is also evidence of immune dysregulation that occurs in the retina and in the body that can participate in the disease process, to name at least a few of the critical pathogenetic events. The whole idea of molecular rheostats, frankly, was born out of trying to understand or embrace the complexity of the disease itself and some of the beautiful biology that has been understood by many groups around the world as well as our own group, in the context of this disease. And so this whole concept of molecular rheostat, I think, really was born out of trying to understand how one could potentially treat macular degeneration, and we’ve identified a set of natural compounds, and in fact also FDA-approved drugs like some of the histone deacetylase inhibitors that you were mentioning earlier, and heat shock inducers as well, which we believe could be used to help treat this systemic disease with eye manifestation. JB: I can tell you that I know we have just touched the tip of the iceberg with this discussion. The depth of your understanding and the way that you’re using these conditions of the eye to explore and probe a general thought about the origin of chronic degenerative diseases is absolutely, to me, at the forefront of moving from a pathology-based form of medicine to a mechanistic form of medicine. I want to thank you so much, both for your work and the way you describe it and for your advocacy. I know that this must be a very exciting time for you, but it probably is also very challenging because you’re trying to help people to understand—guide them to understand—this new model, which is kind of different than the model that many of us learn which was a memorization model of histopathology, and cytology, and histology, and now we’re really talking about mechanisms that underlie the appearance of these conditions that ultimately fan out to be thousands of diseases in our DRG book. I really want to applaud what you’re doing. I think every listener of this discussion with you has come away saying, “Wow, no matter where we look in the body, if you look at the expert who understands the mechanisms of disease, they all tend to converge on a single model, which is very, very exciting.” SK: Yes, yes, I think so. Again, Jeff, I’d like to thank you giving me the opportunity to share with you some of the ideas that have been percolating in our thinking over the last 3 to 5 years. JB: I’m looking forward for the opportunity to have a chance to meet you at the upcoming functional medicine annual international conference. I’m sure that you’re going to infect the IFM population with a lot of great new thoughts and bring this concept of eye-related diseases much more into the forefront of the thinking within the functional medicine community. Thank you so, so much, Dr. Kaushal, for sharing all this with us today.  

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Bibliography

[1] Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA. 1994;272(18):1413-1420.   [2] Bright Focus Foundation. Macular Degeneration Facts and Statistics. Accessed at http://www.brightfocus.org/macular/about/understanding/facts.html   [3] Jarrett SG, Boulton ME. Consequences of oxidative stress in age-related macular degeneration. Mol Aspects of Med. 2012;33(4):399-417.   [4] Zafrilla P, Losada M, Perez A, Caravaca G, Mulero J. Biomarkers of oxidative stress in patients with wet age related macular degeneration. J Nutr Health Aging. 2013;17(3):219-222.   [5] Merle BM, Delyfer MN, Korobelnik JF, Rougier MB, Malet F, et al. High concentrations of plasma n3 fatty acids are associated with decreased risk for late age-related macular degeneration. J Nutr. 2013;143(4):505-511.   [6] Lawrenson JG, Evans JR. Omega 3 fatty acids for preventing or slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. 2012;11:CD010015.   [7] Evans M, Beck M, Elliott J, Etheve S, Roberts R, Schalch W. Effects of formulation on the bioavailability of lutein and zeaxanthin: a randomized, double-blind, cross-over, comparative, single-dose study in healthy subjects. Eur J Nutr. 2012 Sept 30. [Epub ahead of print}   [8] Welkel KA, Fitzgerald P, Shang F, Caceres MA, Bian Q, et al. Natural history of age-related retinal lesions that precede AMD in mice fed high or low glycemic index diets. Invest Ophthalmol Vis Sci. 2012;53(2):622-632.   [9] Ma L, Yan SF, Huang YM, Lu XR, Qian F, et al. Effect of lutein and zeaxanthin on macular pigment and visual function in patients with early age-related macular degeneration. Ophthalmology. 2012;119(11):2290-2297.   [10] Ma L, Dou HL, Huang YM, Lu XR, Xu XR, et al. Improvement of retinal function in early age-related macular degeneration after lutein and zeaxanthin supplementation: a randomized, double-masked, placebo-controlled trial. Am J Ophthalmol. 2012;154(4):625-634.   [11] Bian Q, Gao S, Zhou J, Qin J, Taylor A, et al. Lutein and zeaxanthin supplementation reduces photooxidative damage and modulates the expression of inflammation-related genes in retinal pigment epithelial cells. Free Radic Biol Med. 2012;53(6):1298-1307.   [12] Gibson DM. Diabetic retinopathy and age-related macular degeneration in the US. Am J Prev Med. 2012;43(1):48-54.   [13] Graydon R, Hogg RE, Chakravarthy U, Young IS, Woodside JV. The effect of lutein- and zeaxanthin-rich foods v. supplements on macular pigment level and serological markers of endothelial activation, inflammation and oxidation: pilot studies in healthy volunteers. Br J Nutr. 2012;108(2):334-342.

Welcome to Functional Medicine Update for May 2013. We have a really extraordinary opportunity this issue to speak with and hear from a most remarkable person who will give us a perspective on what I would call lifestyle intervention, environmental modulation, and its relationship to mental health affect and overall physiological function. This is Dr. Joel Robertson. Dr. Robertson is quite a remarkable individual, having developed, over the years, many programs that are involved with facilitating improved mental health, physical health, and physiological health. He’s recorded tens of thousands of patient records and data points. You can hear from him directly as to his story, but I think you’ll find it fits beautifully within the matrix and concepts that we’ve been developing in Functional Medicine Update. Dr. Robertson also brings, I think, a very interesting point of perspective that has been a theme of ours, and that is, what is the role of lifestyle intervention utilizing the functional medicine matrix for improving function in areas where there’s not an acute disease, so we can’t fall into a tidy little diagnostic code, but there’s also not the presence of what we consider high-functioning health. It’s kind of this grey area that we’ve talked about in many issues of Functional Medicine Update. I think Dr. Robertson’s book, which talks about “Natural Prozac,” in other words, activating the body’s own reticular immune neurological system with multiple features of a healthy lifestyle, is a very, very powerful concept and certainly represents a treatment modality that may be most beneficial in terms of both safety and effectiveness in those conditions that fit in between optimal function and what we might call a very distinct pathological disease (a mental health problem).[1] In that grey area is where so many people reside in terms of their dysphoria, depression, lack of motivation low energy, fatigue—things that are interrelated to arousal. Dr. Robertson will tell you about the breakthroughs that he’s made in understanding these types and facilitating improved function. We are witnessing a very dramatic, continued theme, which I think most of us are seeing in the media every day, be it either the medical press or the general press, which is a rising tide of chronic illness and a reduced sense of overall health within our culture. This seems paradoxical to most of us because this is a time where we have more high tech medical therapies, and more clinical options, and more pharmaceutical intervention agents than ever before, yet the overall health of the country seems to be in peril. And when we look at why that is, we recognize it’s not just solely a consequence of our society growing older. In fact, the data would say that children born in the United States today are being found to have more atopic disorders than ever before: allergies, asthma, and various types of what we might consider cognitive affective disorders like attention deficit disorders. So we might raise the question: If these conditions that we call chronic illness conditions are not just reserved for the older population but are being seen in our younger population, what is the reason for it? Are our genes suddenly changing to be more prevalent to these conditions? Well, that’s not likely, at least not the genetic structure in and of itself. Our epigenetics might be changed in certain respects, but certainly not mutational changes occurring at the core of our genome. Therefore there must be other events that are influencing the expression of our genes that are creating the increased prevalence of these conditions that we consider to be chronic illnesses. Atopy and Asthma Rates Among Children Appear to Be Increasing, Especially in the United States In fact, it was very interesting that just recently a study which surveyed 80 thousand children in the United States was looking at the presence and prevalence of conditions like asthma and allergies.[2]According to Dr. Ruchi Gupta, who is at Northwestern University, Feinberg School of Medicine, in Chicago, there is definitely something clinically happening that is increasing the relative frequencies of these conditions, and it’s most likely something related to the environment in which these children are found. Then we say, “Well, what does that mean?” Does it mean environmental pollution? Does it mean environmental stress? Does it mean environmental nutritional changes with poor quality nutrition, or are there a myriad of other factors? Low grade radiation? I mean, one could conjure up many, many variables. Or could it be components of all of those that are working on the genetics of the individual that are creating the increased prevalence of these conditions? In fact, it’s interesting to note that when we compare children in the United States to that of children born outside the United States, that these atopic disorders of allergy and asthma are increasing much more rapidly in the United States than in other countries. It might suggest that there are certain environmental variables in the United States culture that seem to be more prevalent in producing the outcome called these conditions than in other places. So this is a medical detective story. How do we tease this apart? How do we understand it? It’s not just finding new drugs to treat allergies and asthma. It’s finding the causative agents. In fact, Dr. Sidney Baker, in a wonderful quote that he’s been credited with many times, when asked, “What is the treatment for chronic illness?” he said, “Well, it’s very simple.” Number one is you find out those things that the child is exposed to at too high a level and you take those away. And then you find out those things that the child is not getting enough of and you give them. So it’s taking away the bad things and it’s giving the good things. That’s the basic philosophy rather than just suppressing the symptoms by giving a medication that manages the outcome—the symptoms—without managing the cause and effect. So I think that’s an interesting watchword to what we’re going to hear from Dr. Robertson as it pertains to how the functional medicine model as an operating system can play a role. The same thing holds true, obviously, for other conditions like autistic spectrum disorders, where we’re seeing such a rising prevalence. One might say this rising prevalence is a consequence of just better diagnosis and it’s sensitivity in our culture to it now, so we’re suddenly recognizing it, but it’s probably more than just better diagnosis. There’s something else going on here that’s leading to a rising prevalence of these conditions, which is not just suddenly the genes of children started to be autistic. There is something in the environment—the complex nature of interaction with genes that probably are susceptible genes, that give rise to the outcome that we give a name to called autistic spectrum disorders. Recent Article on the Etiopathogenesis of Austistic Spectrum Disorders In fact, a very interesting paper was just published in the journal Medical Hypotheses talking about etiopathogenesis of autistic spectrum disorders, trying to fit the pieces of the puzzle together. This appeared in the April 24th issue in 2013. And the authors go on to say that when we look at this particular constellation of data that relates to autistic spectrum disorder, we’re led to understand that there’s something going on in the immune system of children that seems to trigger these neurocognitive behavioral problems.[3] The genes were always sitting there in wait of the information from the environment, and what their getting—probably starting in utero and going on in infancy—are messages that can trigger certain types of phenotypes that we call autistic spectrum disorders. I think it’s a very interesting observation, and in fact they conclude that to confirm this hypothesis we need new research approaches that look at these things from a different perspective: the interface between genetics and environment to chronic infections and nutritional deficiency like vitamin D, the presence of immune system dysregulation—all of these things become part of a broader footprint upon which we would rest our observations to determine whether a child has certain things that we can either take away or add to ameliorate their condition that we call autistic spectrum disorder, or ASD. So it’s another example, I think, of the fact that we cannot account for these rising prevalences of certain disorders strictly on the basis of a traditional model and say, “Well, they have the genes for the condition and that’s why they got it.” Now we have to say, “Well, the genes have always been there; why are more children experiencing this condition?” It’s Never Water Under the Bridge: Lifestyle Can Impact Health at All Ages That leads us into a question of lifestyle. If environment and lifestyle are intimately interrelated, which obviously they are, does lifestyle play any role in the amelioration, prevention, and/or management of these conditions? And does it cut across multiple ages? I often hear, when I speak to groups in which the people that are listening are principally seniors, they say, “I wish I would have known this information when I was younger. I might have been able to do something about it, but now, you know, it’s water under the bridge. I’m too old and I really can’t do much about it now. I mean, I’m 75 years old or 80 years old, and it’s too late.” But if we start looking at the data that’s been developed over the last couple of years we see that it’s never too late. Yes, it is true the earlier the better, however there is plasticity that appears in physiology throughout all of our lives, up to the last breath we take. So there is still functional capability that is untapped in individuals if they take away the things that are creating the problem and add the things back that are necessary for function. How do I know about that? Let’s take an example from a recent paper that appeared in the American Heart Journal. This was in May of 2013, page 785, in which the investigators were looking at the benefits and costs of an intensive lifestyle modification program.[4] These are in older age individuals with symptomatic coronary artery disease. These were all Medicare beneficiaries, so they fit into this category of people that I was talking about who are often attendees at lectures that I might give to seniors. What they showed in this multi-site demonstration project that was conducted between the years 2000 and 2008, that those individuals that were engaged and successfully participated in an intensive lifestyle modification program with activity, diet, and stress management were found to have a very significant reduction in need for medical services, a very significant improvement in cardiac function as well as overall physiological function, and that the cost per individual for medication and medical management was less than that of the people of the same age and the same condition who didn’t engage in the intensive lifestyle intervention. These are examples, I think, of how important these variables are that we’ve often relegated to a second tier in medicine because we said, “Well, that’s public health, and public health, that’s not medicine. That’s somebody else’s business.” But actually these concepts as applied through the lens of functional medicine and personalizing intervention through diet, lifestyle, and environment, are very, very powerful primary tools for ameliorating these conditions that we call diseases of the 21st century. What we often know is that these conditions first are seen as kind of diffuse symptomatologies. They don’t often present as acute illness, and so they are more difficult to get our arms around in medicine. They may be things like chronic pain, chronic fatigue, depression, low energy. I mean, these are like a constellation of symptoms that cut across almost every diagnosis and so people say, “Well, gee, that’s so confusing. Let’s just wait until they get sick enough that I can really get a better handle on what they’ve got, so I’ll just manage the symptoms with sleeping pills or anti-inflammatories, or anti-depressants until they get more serious.” However, what we’re starting to recognize is that by the use of arrays of various types of biomarkers we’re able to examine functional changes in individuals that precede the onset of disease that are associated with these altered states of physiology—what we might call disturbed physiology or disturbed metabolism—that are tracking a trajectory towards becoming acute disease. So it gives us the tools, for the first time, to start looking earlier at these types of things that will become later more significant and more pathologic. Earlier intervention not only saves years of declining function, but also it prevents what might be a much more costly, expensive, and difficult disease by putting it off into the future or maybe eliminating it entirely. This is Dr. James Fries’ concept of compressing morbidity and increasing functional capacity. And you might recall that that concern was raised all the way back since 1980 when we started talking about this compression of morbidity improving function throughout life.[5] Assessment Protocols: Diagnostic Markers versus Prognostic Evaluative Tools When we start looking at this from an assessment protocol, we’re not so much looking at diagnostic markers as we’re looking for prognostic evaluative tools. And what’s the difference between a diagnostic marker and a prognostic marker? A diagnostic marker is one that we would look for—something that you can taste, touch, feel, see—that is related to a pathology (an end-organ pathology). Where a cell, or a tissue, or an organ can be seen under a microscope, or with radiological examination, or with specific types of biochemical markers to be a specific indication of a disease, like you might have with troponin in a person who has suffered a heart attack. You would say, “Oh, that’s an indicator of a heart attack. It’s a pathological indicator.” There are, however, a myriad of other newer biomarkers that are being employed to try to look at trajectory of function, that map the domain of physiological function. Any one of those by themselves is probably not as valuable as when they are taken as a family of different assessment tools, like using data from an oral glucose tolerance test with fasting insulin, with glycosylated hemoglobin, CEF peptide, and glucose determinations all together to get a better understanding of the domain of insulin sensitivity and glucose tolerance. That’s why we often in research will use what’s called a compiled glucose determination that actually uses a variety of variables, including things like fasting glucose to our postprandial glucose, fasting insulin to our postprandial insulin, to start to look at insulin sensitivity well before one gets to a frank state of diabetes. Some people call this pre-diabetes, or insulin resistance, or metabolic syndrome, and it has its own sequelae of presentation symptoms and signs that give us early assessment opportunities to evaluate before the onset of frank diabetes. So these circulating biomarkers become very important for predicting overall trajectories towards later stage risk, and we can see virtually every organ system has its own unique defining biomarker portfolio. This raises a very interesting question, and that is: How many things do you need to test? That’s still open for a lot of debate. I think the first point is, if one starts without an exhaustive profile of tests, to do a good physical history on the patient and to really understand the antecedents and triggers that that patient has experienced that are giving rise to their signs and symptoms. As one starts to dig through the detective work using the functional medicine model, however, you may require certain extended types of evaluative tools—other biomarkers that help us to understand the nature of that individual’s own metabolic disturbance or physiological dysfunction. That’s where certain biomarkers become predictive and become prognostic in their evaluation. There’s a very nice paper that recently appeared in PLoS One Medicine in April of 2013 that really looked at various types of markers for disturbances that are associated with cardiometabolic disease.[6]—things like fibrinogen, which we might think of as a clotting factor but it’s also related to inflammatory potential; or apolipoprotein B, which is the nascent lipoprotein for low density lipoprotein’s atherogenic dense particles; or apolipoprotein A-1, which is a very important carrier for the HDL component that leads to cholesterol efflux and atherosclerotic regression. We recognize even inflammatory markers like C-reactive protein and Interleukin-6 become important assessment tools and we can even go into metabolic tools like uric acid, which tracks not just for gout, but also tracks for cardiovascular risk as well (cardiometabolic risk). So all of these become tools that are not focused on diagnosis of a specific disease, but looking at patterns of metabolic disturbance that drift toward, or has a trajectory towards, disease. We can tie these together, obviously, with specific types of genotypic analysis, and here’s where SNP analysis—so called single nucleotide polymorphism analysis—becomes useful as well. You can’t change your genes, but you can understand something about what you genes deliver to you in terms of potential, either strengths and/or susceptibilities. Let’s use an example: the apoE gene. That, as you know, exists in three polymorphs: the apoE 3, apoE 4, and apoE 2 polymorphs. These particular genotypes, knowing in a haplotype we might have one gene coming, obviously, from our mother that could be an apoE 2, and another from our father that could be apoE 3, but if you happen to have the apoE 4 from your mother and also from your father (the double apoE 4 allele), that is associated with a very high risk and incidence of cardiovascular disease and Alzheimer’s. So some people say, “Well, I don’t want to really know my apo genotype because, you know, there’s nothing I can do about it, and woe is me if I just got the bad luck of the draw and got an apoE 4.” But what we’re recognizing now is that actually you can do something about it. You can’t change your apoE genotype, but you can change the environment in which the apoE genotype is exposed to characteristics that might lead to the expression of an adverse outcome. So in the case of an apoE 4, what would that be? That would be an individual who probably needs to be very careful not to consume excessive amounts of saturated animal fat. They need to be very cautious to manage their oxidant-antioxidant balance, meaning proper antioxidant, high phytonutrient content foods (flavonoids and xanthophylls and polyphenols), because these are individuals that have a much higher oxidative stress risk, and individuals that are much more saturated fat sensitive. Rather than saying, “Well, I don’t really want to know my apoE genotype because there’s nothing I can do about it,” in this case what we’re really saying is we do want to know these characteristics because it helps us to modify our personalized environment in such a way as to create a more likely positive health outcome. By the way, this was discussed very nicely in another article that appeared in PLoS One Medicine in 2013 in the April 17 issue, in which the authors, at the Department of Genetics, at the University of Oslo Medical School and Hospital in Norway, and what they were looking at were apoE genotypes in relationship to cardiovascular disease and rheumatoid arthritis, and found that there were correlations between apoE 4 and both cardiovascular disease and rheumatoid arthritis that were associated with oxidative-prone (or let’s call it inflammatory-prone) phenotypes.[7] So in that case, these individuals need to obviously balance their lifestyle and their diet and their intake of substances very carefully to be on a low inflammatory program. Metabolic Flexibility: Multiple Pathways Lead to Plasticity and Health What we are really talking about is use of specific personalized lifestyle intervention based on sieving through the functional medicine model that would improve metabolic flexibility. I think this is a very interesting term when we talk about metabolic flexibility. You recall that years ago when we were designing the formalism of functional medicine, we talked about the importance of metabolic redundancy, or metabolic degrees of freedom, or making sure that there were multiple pathways in our network that were open and available for substances to move from starting materials to endpoints—that the more redundancy, the more sophisticated, the more plasticity, the more healthy the individual. So this is what we call metabolic flexibility. You see it with heart rhythm if you’re measuring what you might call chaotic flexibility in heart rhythm; we know that the healthier an individual is, the more flexibility they have in heart rhythms in the fine structure of their electrocardiogram, and so that’s a measure of these physiological degrees of freedom. I think that these are closely associated with decreased biological aging. There’s this inverse relationship between increased metabolic degrees of freedom and that of biological aging. Higher freedom, lower biological aging. This was actually talked about in a very nice commentary in the journal Nutrition and Metabolism, in which they were really looking at the interface or the interrelationship between genetic and environmentally determined function.[8] On the proper interface between an individual’s genome and their environment, you get maximum mitochondrial bioenergetics capability, maximum metabolic degrees of freedom, and decreased biological aging principles. This cuts across many animal studies and different species. The objective, obviously, in the approach that we’re describing and the implementation of a functional medicine intervention system into a personalized lifestyle management program is to match up these genotypes with the environment in such a way as to produce maximum metabolic flexibility, reduce biological aging, improve organ reserve, and reduce the risk to later stage disease.   Research Continues to Link Nutrition to Cognitive Function and Mental Health How does that relate to things like cognitive function and mental health? Well, there is tremendous work going on in this area that is very, very exciting. You’ll hear more about this from Dr. Robertson. But I’m reminded of a very interesting paper that appeared just recently in the Journal of Nutritional Biochemistry in 2013 titled “Nutritional Modulation of Cognitive Function and Mental Health” by investigators from the University of South Australia in Adelaide. In this particular paper they showed that the dietary risk factors for cognitive dysfunction and mental health are now becoming fairly clear.[9] Things that enhance insulin resistance. Things that increase inflammatory burden. Things that increase cellular mitotic activity. All of those types of principals in our diet are those principals that are associated with—over time—decreasing cognitive and increasing issues related to mental health. So there is a very important strong relationship that’s appearing from good research that ties diet and lifestyle intervention tightly together with the ever increasing prevalence in older age populations of cognitive dysfunction and of diseases like Alzheimer’s. In fact, there’s a very nice review paper that appeared just recently that describes the role of nutrition and diet in Alzheimer’s disease.[10] I think what we’re starting to see is a very, very science-based, supporting system for the sensibility that the lifestyle of the individual plays a very important role in experiencing the expression of their genes, which gives rise to their phenotype, which is their health and disease patterns. That model is a very powerful model from which the functional medicine operating system delivers, I think, the interventions that relate to personalization of cause rather than just amelioration of effects as is often the case with pharmaceutical intervention programs that are tied only to symptom amelioration. With that in mind as a prelude, let’s go to our Researcher/Clinician of the Month, Dr. Joel Roberson, who will really give us the news to use.

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INTERVIEW TRANSCRIPT

Researcher of the Month Joel Robertson, PharmD Robertson Health www.robertsonhealth.com We’re so excited, once again, to be at that portion of Functional Medicine Update where I’m introducing our researcher of the month. You know, we’ve been so privileged, haven’t we, over the last many years, to have some of the top opinion leaders in the world who have been sharing what I think will become the nature of the way medicine and health care evolves in the years to come. It’s kind of at that leading edge that we often get treated with, to hear what’s happening—no surprise—this month we have a similar circumstance with our clinician/researcher of the month, Dr. Joel Robertson, in Michigan. Dr. Robertson is a PharmD. He is chairman and CEO of a widely recognized leader in the area of brain chemistry. I think you’re going to find his work just fascinating. You probably know if you’ve been reading the literature over the last few years that he has a best-selling book called Natural Prozac, which we’ll let him tell us about. His background is that which has really developed, through the Robertson Research Institute, which is a nonprofit organization dedicated to enhancing lives and advancing the knowledge of healthcare professionals, this whole nature of the lifestyle/brain/environment/function interconnection, and he’s done it in a way that, as you’ll hear from him, is very novel, very unique, very innovative, and I think very pace-setting for 21st century medicine, because it’s really built on a systems biology approach, which, as we’ve talked about over the last few years, is where health care is really moving. It is moving away from disease as a single entity to moving to the interaction and understanding of the network of systems that interface with function and ultimately give rise to such complex things as high-order thinking and cognitive ability. Dr. Robertson, wonderful to have you as a leader for us here on Functional Medicine Update, and thank you very much for making yourself available and talking to us about global health solutions. Tell us a little bit about how a PharmD made this extraordinary transition and became the leader that you are in this field? JR: First of all, I appreciate the opportunity to share, and talk, and all the great work that you’ve been doing, and like you say, moving medicine to a different level. It’s kind of funny because I do a lot of speaking in front of pharmacists, and they say, “How did you make that transition?” And I say, “Well, I never really practiced as a pharmacist. When I came out of school, I actually contracted with taking over emergency room laboratory, pharmacy, and physical therapy departments (to run those), and in doing that of course pharmacology—and my specialty is neuropharmacology—I guess the best way to say it is, ‘Why would I do what I don’t want to do?’” Emergency Room Observations Lead to Theories of Neuropharmacology You know, I’d see people come in in the emergency rooms and they’d have a heart attack or something, and give them a new way of changing and they would come back and they hadn’t made changes. From my perspective, with all the observing of the addictions, and the compulsions, and the behavior, you know, it just began to start the theory of maybe it has something to do with neuropharmacology. So that PharmD aspect came in very handy when I started looking at pharmacology, how drugs interact, how they affect us, and how they affect behavior, and you could correlate it back into the whole main chemical make up. JB: One of the things that has struck me of the many that you’ve accomplished in your work is your ability to make your information very accessible to individuals that I think have impact on many others, like your work with General Motors, and Fuji, and Dow, and United Airlines, and the Department of Defense. You’ve really been able to make this news to use. Is this a gift that you’ve always had, or is this something that you worked at in developing systems that could translate this information into a way that would be user-friendly for a variety of different levels of organizations? Behavioral Emergencies: National Treatment Protocols Were Needed for ER Personnel JR: I was asked by the government to write the national treatment protocols for the emergency medical services when I was only 27. And when you’re talking about behavioral emergencies, and you’re talking about emergency room physicians, you have a disconnect. You have a lot of information with a lot of technical diagnostic training needed, and yet you have physicians who really don’t want to deal with them. So that whole ability to say, “How do I learn to take information to people who may not understand it, and yet make it useful for them?” So in many ways that challenge of taking to the emergency room physician how do you handle these difficult-to-handle patients, was a great stepping stone for me to say, only in a different fashion, “How do you take complex topics and complex interaction, make them something that is simple and yet useable and that I can verify and give immediate feedback to the effectiveness of what they are doing?” That’s probably one of those things where opportunity knocks. I was thrown into a situation, and had to learn how to do that, because I, like a lot research guys, love to write in the technical world, which isn’t very practical. JB: Yes. So when I read your book, which by the way is very, very well-written and very user-friendly, Natural Prozac, which has as a subtitle “Learning How to Release Your Body’s Own Anti-depressants.” I was taken back to all the work that’s been done over the last few decades about addiction and the serotonin receptor and how we have these genes for melancholy and how certain types of the serotonin 5 receptor polymorphisms lead certain individuals into higher risk of additive behavior. When I read your book, it sprung me free from this kind of determinism or our genes to there are things that we can do, and I think that’s a very empowering concept. I bet you’ve been confronted with people who say, “Oh, I’m sorry addiction and depression and so forth…it’s in our genes; there’s little we can do about it.” Can you tell us about what kinds of things you experience in getting this message out and giving people much more options for how they regulate these functions? Treating Before You Know What’s Broken JR: Absolutely. You know, I think what people fail to realize is when you think in terms of the nerves of the synapse, even researchers don’t stop and think, “I have this electrical energy that turns to chemical energy, and then it has to go back to electrical energy.” That’s essentially pre-synaptic, to synaptic, and then post-synaptic. So when someone says they have a genetic problem, it’s not all three areas. It might be pre-synaptic so that I don’t have enough, and then you say, “Well, let’s figure out how to create it.” And it might be, for example, serotonin—I don’t have enough of the enzyme (you know, tryptophan and dehydrogenase) to convert tryptophan into 5-HTP. Well then you say, “Let’s skip them, and let’s go right to 5-HTP.” Or maybe it’s a post-synaptic receptor gene transport issue. Great, we know how to do some things. I think the issue probably lies with our whole concept of how we diagnose behavioral medicine. When I look at depression, that’s a diagnosis, and yet I look at it and I’m going, “I could have low serotonin, I could have low dopamine, I could have low norepinephrine, I could have high GABA, or I could have a combination of all four.” And so we throw it in the one system, and treat it, and as I’ve always said, you’re treating before you know what’s broken. And that’s one of the difficult things that I see when we’re dealing with behavioral medicine. We can really pinpoint now as to where (if there is) a genetic issue, where (if there is) an environmental issue, and how do we reprogram the brain to work around it, or stimulate areas that might be able to stimulate it. So it all comes into recognizing what’s broken in order to fix it or enhance it. JB: One of the many things that you’ve done, I think, that makes this very useable is the way you’ve approached assessment. I’d like you to talk about how you develop your assessment instrument and tools, and what that does, because I think it really grounds the whole approach that you’ve got in a very measureable system. Neurohormonal Assessment: Arousal, Satiation, or Combination JR: Absolutely. For one of my first jobs I actually ran an alcohol and drug rehab center. One of the first things that I felt we needed was to answer a question: what will I do versus what should I do? The vast majority of medicine in which you’re asking people to change behavior, you tell them that they should do it, instead of asking what they will do. So one of the first things that we said is that we need to know three things about our brain, and the first one is what is our reward center? What will we do? Why is it that feels good for us? For example, if you want me to relax, I’m going to be one of these guys that climbs mountains, white water rafts. You know, I do things—I bike, I run. That relaxes me. You want to stress me then ask me to curl up by the fire and read a book. So essentially we’re taking this complicated brain, and we’re talking about our neurohormonal dynamic, but we made it kind of simple for people and we say either you are arousal, or you are satiation, or you are combination. So that was the first thing that we said we needed to assess, because then I can prescribe activity, diet, and using different things based upon what a person will do, so we can have compliance. The second thing is I had to look at what are the behaviors that I will tend to do when I get out of balance? So you take a guy like me, and I’m high dopamine, high gas pedal chemical, and the behaviors that I do and I personally consider these post-Pavlovian bell because it’s like when my dopamine goes up, I become impulsive, my listening skills go down, I want to make a decision even if I don’t have the information, and I’m not very patient. Probably I even get task oriented. These are behaviors that are done automatically when people’s brain chemistry changes. So I thought I need to figure out what behaviors are because if I’m doing excitatory behavior but I’m depressed I’m probably trying to treat myself with my behaviors, or if I’m doing depressing things, then I’m doing it in response to my brain chemistry. So the second one is very important for what behaviors are connected. And we know things such as cocaine addiction, sex addiction, risk taking—all the same neurotransmitter issue, they just show up in different behaviors, so it’s very helpful. The third thing, which was the biggest challenge, was how do you know what brain chemical is off. I think the greatest insight that we had as we did all the research by doing blood studies and CSF (cerebral spinal fluid studies), all that sort of stuff to try to find the correlation, and we couldn’t find the correlation. Then we finally decided that—and I think this is the key thing that people need to understand when they are talking about the brain—there is no normal serotonin, but there is an optimal for an individual. There is no normal dopamine, but there is an optimal. So in our particular case, now my pharmacology background came in and said, “Let’s look at what are the symptoms that we might have of low serotonin? What are the symptoms that we might have of high serotonin? And a lot of that is drug side effects. Drugs that enhance certain chemicals and drugs that reduce certain chemicals. And let’s ask physiological questions and try to correlate. And when you correlate, what you can do is really say, “Alright, I’ve got a series of symptoms that I can measure, and so might say I have five low serotonin symptoms, so that’s my hypothesis.” Now I can go in and say, “Well, I know, for example, if you put me on a treadmill (or a person on a treadmill) and do a short burst of exercise, and check their dopamine, you’re going to have tyrosine hydroxylase turnover and burn up the dopamine.” So you can prescribe it to those activities, diets, behaviors to your hypothesis, and what should happen? Symptoms get better and behavior changes. That’s how we did the research on over 25,000 people. JB: So when I look at how you’ve described that complexity in a very understandable way in your writings, you talk about, as you mentioned earlier, the satiation type and the arousal type, and then that directs into specific types of therapeutic interventions that then modulate those networks (those biological networks). I’m fascinated, looking at your blogosphere, at how people have talked about how they have responded and how their personalized approach that you’ve described out of this assessment have led them to have remediation of problems that they’ve had for some time; even on medication they weren’t successfully able to be balanced, but on the program that you’ve described, they are starting to get tremendously positive outcomes. It seems that this ability to take this complexity and to summarize it down into these categories has a very, very valuable outcome in terms of making it accessible to people who will get better outcomes. JR: That’s the key thing, I think, with a lot of medicine: how can somebody own it, measure it, feel it, understand it? We started out originally looking at the area of what we would say unhealthy brains trying to get them better, whether they were unhealthy because of compulsions, additions, depression, things of that nature. And then that’s an “ah-ha” into the area where it became performance enhancement, and so I’ve taken on professional sports—wrestling, NASCAR—and corporate executives and saying, how do we make you perform better by A) eliminating unwanted behaviors that are caused by your brain chemistry, and B) just teaching you to perform better because different brain chemicals are more effective when you want to be creative that they are when you are wanting to be detailed and budgetary, etc.? So really it’s a matter of when a person understands the symptoms that relate to their brain chemicals, and they understand they are already changed their brain chemistry, whether they had a cup of coffee, whether they had a piece of red meat, or whether they had pasta, they are changing their brain chemistry. Now it’s just a matter of teaching them enough to say, “How do I hit the behavior, the music, the things that change brain chemistry, and use them specifically to be able to enhance or inhibit the release of the brain chemicals that I need to do in my particular case?” People really grasp that. We have great compliance and great effectiveness, because like you said, I like to refer to it profoundly simple. Self Health: The Mobilization of the Individual JB: I think what you’ve done, and I really commend you for this, is you’ve made this system available so that a person can help themselves. There is a self health component here that’s very, very valuable so that it doesn’t build a dependency on a therapist for the solution, because this, in the end, is the person’s own life, and their own solution is inherent in the way they manage that life. I think you’ve done a very good job of balancing professional health with the mobilization of the individual to become the activist for themselves, to be involved with self health. JR: That’s one of the things, I think. I ran a behavioral medicine clinic, and our motto was “The less you see of us, the better off you are.” And I really believe that empowering people with knowledge so that they can do it on their own and , and then our mental health and our behavioral medicine systems are dealing with those that need more support but don’t have family support or systems, and can give them more time, more energy, and get more outcomes. So definitely that was a model of behavior that we began right out of the gate saying, “I need to equip people to be able to not see us, versus see us.” JB: To make this more understandable for our listeners because they don’t have the benefit of sitting with you here and talking this though, could you maybe give us a case history or two as to how this program works in people with, say, something like ADHD, or some kind of complex behavioral issue? JR: Yes, absolutely. The first thing that we do is of course we run through a series of tests like this, and then we teach them what I’m going to call the yellow flags. I believe this is the only behavioral medicine program that looks pre-Pavlovian, meaning once the bell rings you don’t have a choice. So if you do something—let’s say a bell rings that says, “I feel like I’m going to drink”—and that bell rings and a person may drink or they may go to AA, but the bell is still rung. Our goal is to say, “How do we know the bell’s going to ring?” Let’s use an example of ADHD. You take something like that and we teach the person to say, “Let’s define the yellow flag that says the bell is going to ring.” It might be with ADHD or with dopamine, you might say, “The ciliary muscle there in your eye begins to twitch. Your jaw begins to tighten up. Your heart rate goes up a little bit. Your palms get a little sweaty. You find yourself not able to focus.” Those are what we call yellow flags that say, “If you stay within that environment and don’t do anything, the bell’s going to ring and you’re out of control.” So we say to them and we teach them, so you realize in your case that everybody’s different, we might say to them, “We want you to use CBS—chicken, beans, and salad. Get off of the red meat, back down from caffeine, stop the Mountain Dews, stop the energy drinks, because those are all contributing to the high dopamine. If you can go out and go for a brisk walk or a run go do that. Take music—listen to slow, consistent beat music. And those are things all that are decreasing dopamine.” And what happens is immediately they can begin to feel the ciliary muscle stop twitching. They get immediate feedback that says, “I’m getting what I need to do because I know when it spikes I’m going to be impulsive, and all of these behaviors that we might have identified.” So, we really begin to teach them how to identify the yellow flags, and as you well know, one of the difficulties in medicine is teaching people how to listen to their body. And we just teach them techniques to listen to what’s going on in the brain chemistry so that they can make a response, do something, to correct before it gets to the point that they are out of control. JB: I think that is so amazingly consistent with the functional medicine model. It’s very exciting to hear how there’s a confluence or a convergence, really, of the way that you’ve approached this and the way functional medicine has talked about. We would call those early warning signs that are related to change in function like involuntary reactions in smooth muscle, and then we would say, “What triggers are related to the change in those mediators that associate with those functional changes?” So our language in functional medicine might be a little bit different, but it sounds very similar to what you are doing—moving back on the timeline of pathology towards functional changes that are associated with triggers and mediators that ultimately arrive at a pathology, but you want to get it much earlier than when you’re in the acute state. It sounds like you’ve done it in such a way that it really makes it understandable to the patient. They don’t have to be neurophysiologists to understand how they are traveling down that road of progression. JR: Yes, and you know, there are different types of people. We always take our assessment and we say, “We’re going into three categories.” The first one is some people, and I’m not going to be stereotypic, but some of my hockey players just say, “Tell me what to do. I just want to perform better.” So we give them that. And the next group will say, “Tell me what to do and tell me why you’re seeing things change”—like you said, the genetics, the developmental time of the brain when that might have been impacted. And then there’s the third group that says, “Give me the research.” So we like to hit all three categories, including those who say, “All I want to know is how to do it, fix it, and etc.” And a lot of times we have some really tough people and tough environments in South Africa. Some of these guys are working in 140 degree temperatures up on scaffolding in these electrical power plants, and we’re just teaching them how to learn the feedback and know what to do so that they don’t get out of control. That might be, “Just tell me what to do.” And then we’ll expand it out depending on the personality. And again, it’s always trying to say, “Where is that person at now? How do I get them to do what they need to do to get better, because once they get better they’re going to take it a next step to even begin to move into prevention?” So kind of like this transition of health is where you try to take people. An Epidemic of Sleep Disorders JB: Yes, I can see that. That’s really a positive feedback reward system, that a person is building confidence and they’re getting positive response, which then builds more activation and more commitment to the program. Let me shift over to another problem that I know is increasing prevalence in our society and one that you deal with as a constellation of issues within the behavioral medicine field, and that’s sleep and its association—or let’s call it sleep disturbance associated with apnea and what appears to be almost an epidemic of sleep disorders. Tell us a little bit about how your program interrelates with these sleep disturbances. JR: I think that’s really one of the key things, that you’ve got the cyclical nature. Sleep, of course, is necessary—especially REM sleep—for us to be able to balance our brain chemistry back end, and if we don’t get it, it kind of gets into a cycle, and then if you get out of balance then you don’t sleep. Just as we do in everything, we kind of think in terms of algorithms. When we look at sleep we’ll say, “Let’s define and figure out what is happening as to why we’re not sleeping.” And I’m going to give you an example of what I think is beginning to happen in our society, and why we’re starting to see so much sleep apnea. First of all, not to simplify, but I think that most studies are going to show that serotonin is related to compulsive disorders, and compulsive disorders can go anywhere from addiction (drinking alcohol, or it can be obesity, or it can be perfectionism, whatever), so many of them are not “pathological” in the medical field, but they are in lifestyle, and that appears to be a dominant characteristic. So you start into this whole cycle of thinking which then can create stress—stress in relationships, stress in your self-esteem, which can cause dopamine to go up. So now you have a double whammy happening: I have low serotonin because that’s what I was born with; I have high dopamine because of the way I’m thinking because of it, and then the brain kicks in and says, “I’m going to try to compensate with too much gas by pulling on GABA.” So you’ve got two dynamics going on. That is the most common issue—that combination—that I see with sleep disturbances. Because you have this thought process that is compulsive in thinking so a person can’t shut off their brain, they have their anxiety issues going so they can’t get to sleep, and then they have GABA there fighting it so when they go to sleep it goes quickly and they come back out. So basically when you look you have to say, “If that’s my pattern, I have to attack low serotonin/high dopamine, and I can’t cover it up with something hypnotic because that won’t do it. When you’re dealing with sleep, you’ve got to go back to the root cause, and there really are about 9 or 10 different combinations with sleep that are very different in how you approach them—different, even if there is medication, how you would use medication. Our main goal is to do it as natural as possible as much as possible. Because you’re absolutely right, you get into this cycle and the cycle just keeps extending and makes it worse, and then typically, tack on all the sedative hypnotics which interfere with the natural sleep rhythms. It’s just a bizarre sort of thing that happens and it needs to be attacked at the root cause. JB: Clearly, everyone that’s listening is saying, “Wow, I need to tap into Dr. Robertson’s program and become much more understanding of it. Where would you suggest a person start to become more familiar with your work and how it can be applied? JR: Go to the website, which is www.robertsonhealth.com and you’ll see three different categories there. The Robertson Global Health Solutions is our global diagnostics, so that’s not what we’ve been talking about. When you come into Robertson Wellness, that’s where you’ll come in and actually there are three different types of approaches that different listeners may want. If you’re a clinician and you’re looking at using this with your patients, we have what we call a Blaine Chemistry Optimization Program Certification. We teach them how to use it with their patients. The second one a consumer can tap in on, and that’s called the Behavioral Medicine Self Care. And then, of course, we have the corporate work where we work with our professional athletes and executives, and that often involves a medical person because it’s almost like a concierge medicine, but then we do have those that are based on coaches and people who have corporate clients. JB: I can say that what you have done over your many years of service and practice is just truly remarkable, Joel. It’s amazing to see the scope and the span of your activities. It also suggests to me that there couldn’t be a better time in our history than now for people to really take a hard look at what you’ve amassed in your 20,000-plus case history experiences, because to me this is one of the greatest needs that we have—this whole behavioral medicine and how it interrelates with personalized lifestyle medicine and how that interrelates with the functional approach towards neurocognitive behavioral outcomes. I really want to applaud and celebrate what you’ve accomplished. It’s quite amazing. JR: Jeff, I appreciate it. I just wanted my life to make a difference. As I began I said to my kids, “I don’t think what I do will ever be appreciated, but I believe that I’ll at least challenge people to think differently.” I feel really blessed that not only are people embracing it, but also my kids have gone into the field and joined me. So it’s kind of a great opportunity and exciting that as a family we pushed toward not really a new way of thinking but a new way of communicating. And it is exciting and making a difference in peoples’ lives is the most rewarding thing that you can do. JB: Thank you. That’s certainly very high advocacy and I think we share that goal between us. I want to thank you for sharing with our listeners this extraordinary work you’ve done over the many years. JR: I thank you so much, it’s always about people working together. Together we can make much more impact. JB: Dr. Joel Robertson, thank you so, so much, and I think you gave us some real great news to use, some places that people can get started. Thank you so much for being with you today. JR: Thank you. I appreciate it. JB: You take care,  

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[1] Robertson, Joel C. Natural Prozac: Learning to Release Your Body’s Own Anti-Depressants. San Francisco: HarperOne, 1998.   [2] JAMANetwork. (2013). Study suggests U.S. children born outside the United States have lower risk of allergic disease [Press Release]. Retrieved from http://media.jamanetwork.com/news-item/study-suggests-u-s-children-born-outside-the-united-states-have-lower-risk-of-allergic-disease/   [3] Gentile I, Zappulo E, Militerni R, Pascotto A, Borgia G, Bravaccio C. Etiopathogenesis of autism spectrum disorders: fitting the pieces of the puzzle together. Med Hypotheses. 2013 Apr 24.   [4] Zeng W, Stason WB, Fournier S, Razavi M, Ritter G, Strickler GK, Bhalotra SM, Shepard DS. Benefits and costs of intensive lifestyle modification programs for symptomatic coronary disease in Medicare beneficiaries. Am Heart J. 2013;165(5):785-792.   [5] Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980;303(3):130-135.   [6] van Holten TC, Waanders LF, de Groot PG, Vissers J, Hoefer IE, Pasterkamp G, Prins MW, Roest M. Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses. PLoS One. 2013;8(4):e62080.   [7] Maehlen MT, Provan SA, de Rooy DP, van der Helm-van Mil AH, Krabben A, et al. Associations between APOE genotypes and disease susceptibility, joint damage and lipid levels in patients with rheumatoid arthritis. PLoS One. 2013;8(4):e60970.   [8] Nunn, AV, Bell JD, Guy GW. Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe? Nutr Metab (Lond). 2009;6:16.   [9] Parletta N, Milte CM, Meyer BJ. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013;24(5):725-743.   [10] Shah R. The role of nutrition and diet in Alzheimer’s disease: a systematic review. J Am Med Dir Assoc. 2013 Feb 16.

Welcome to Functional Medicine Update, June 2013. You know this old statement you’ve heard many times from the movies, “Houston, we have a problem.”? Well, so it is in health care. As you know, we see this rising tide of chronic illness, and this model that we’ve been using, which is to treat each condition with a single drug to get a single outcome, doesn’t seem to be beating back the rising tide of chronic illness; it continues to grow in prevalence and severity. It’s been suggested that maybe we need a new model, and that’s where the functional medicine model can play a role. This month we’re going to be talking through the lens of this mind-body connection: the psychoneuroimmunology, the psychoneuroendocinology connection, through arguably one of the world’s great contributors to our understanding of this field, Dr. Bruce McEwen. Many of you know his extraordinary work as it relates to allostasis and his remarkable book, The End of Stress As We Know It.[1] Multiple Conditions in Single Patients: A Trend Identified in Medicare Patients Before we get to Dr. McEwen and the discussion with him, I’d like to just set the context as to why this area is so important for us to understand and to start implementing within clinical practice. As you recognize, we are seeing a very rapid increase in multiple chronic conditions people have, particularly older age individuals in our society. Medicare review of degree of concerns now indicates that most Medicare recipients have two or more different diseases that are being treated. Often these diseases are considered to be independent and isolated, so they end up with two sets of doctors with two sets of drugs, for two different sets of conditions, even though they may all be related to disturbances that are associated with altered gene-environment interactions, from a functional perspective. So rather than treating the cause we often end up treating the effect. There’s a wonderful paper that appeared recently in the journal Health and Quality of Life Outcomes that discusses this whole area of the increasing prevalence of multiple conditions in single patients in the Medicare population, tracking patients from 2006 on and looking at the increasing number of multiple conditions.[2] We recognize that this co-occurrence of diseases is really very strongly lifestyle-related. A data was assembled from 2002 to 2009 and was published in another very interesting paper that appeared in Prevention of Chronic Diseases in 2013 in the April issue.[3] In another paper where we looked at multiple institution quality improvement initiatives to transform chronic illness care, this is a pretty discouraging review of what’s really going on. According to this article that appeared in 2011 in the General Internal Medicine Journal, we still have very significant challenges as it relates to institutional delivery of programs that will transform chronic illness care, and we really need to start looking at other ways of evaluating or implementing strategies.[4] In fact, it’s interesting to note that this paper that appeared in 2011 was a consortium of different institutional groups, including the Oregon Health Sciences University, faculty of medicine of the University of New South Wales in Australia, the Feinberg School of Medicine at Northwestern University in Chicago, Stanford University School of Medicine, University of Texas, the Southwestern School of Medicine, and the MacColl Institute for Healthcare Innovation at Group Health in Seattle, Washington. All of these collaborated together to come to this data set that says there’s a long way to go in managing chronic illness and the model that we’re using doesn’t seem to be delivering the goods. What can we then take away from all of this that will lead into hopefully improved healthcare effectiveness, improved outcome, and reduced expenditures? That really has led us into the development of a new institute, the Personalized Lifestyle Medicine Institute, that really is a hopeful partner with the Institute for Functional Medicine in developing health conscious consumer education as it relates to alternatives and where we are going that will couple together with the healthcare provider education that is necessary to provide quality intervention and quality care. And there are some precepts of the Personalized Lifestyle Medicine Institute that I think are important as we move into the discussion with Dr. McEwen, for us to understand. Let me just talk a little bit about the precepts. The Personalized Lifestyle Medicine Institute: Coupling Together Consumer Information with Healthcare Provider Training First of all, it is believed that health care is in turmoil; I don’t think there is much debate about that. With all the money spent on disease care, we’re still globally witnessing an increase in lifestyle-related diseases. Number two, that new models for improving healthcare efficacy will arise out of new institutions that don’t have the vested interest in the old models, and so we kind of have to look for where innovation might arise, which may be in different places than where the status quo is now being practiced. Number three, the successful new models for healthcare delivery will be disruptive and incorporate characteristics of a disruptive, distributive healthcare system, where it is not top-down with a few people controlling the whole system; it will rather be cooperativism across many different areas of distributive function, with different skills working together collaboratively to improve, hopefully, integrated systems, biology-based health care.  Number four, decision-making for the incorporation of new models for health care will not rely solely on the double-blind, placebo-controlled trial, but will incorporate clinical case histories and other evidence in decision-making, and this has to happen if we are dealing with a personalized medicine model because each person is their own control and you can’t do a study with randomized controls when each person is little bit different than everybody else, so you need new models for evaluating how to assess outcome in that kind of a personalized regime. Number five, the evaluation of new therapeutics will be contextualized through a personalized medical perspective, and the concept of disease emerging from the interaction of genes with environment will be a dominant paradigm in the new medical era. That is, obviously, an emerging thought which we are getting more and more reinforcement from with the literature that is being published as we speak. Prevention will be a public health issue and prospective medicine will become the new medical strategy, and reimbursement for medical services will become more outcome- rather than procedure-focused, and I think that’s a really interesting trend that we’re seeing right now. The internet, smart technologies, and social media will frame much of how the new medicine will be executed, so the person will be measuring their own body function using smart technologies and interfacing with healthcare providers in ways that were never imagined even five years ago. We’ll  be witnessing a bifurcation in medicine, with training and credentialing in crisis care that will continue, but also a training and credentialing in chronic care, using this distributive healthcare system. Enlightened healthcare consumers will demand and support a two-tiered system of medicine that will deliver high-quality crisis care, hospital-based medicine, and chronic-illness-focused community clinic-based health care, so there will be excellence at both levels, but you can’t be a master of all disciplines; you’ll have to find out where you want your specialty to be, be it either the chronic care management at the community-based level, or more of a crisis-focused, hospital-based medicine in institutional settings. Medicine will become more participatory and require higher health consumer advocacy and knowledge—much more is being pushed back to the consumer and they’ll have to be responsible for a lot more of their health, and therefore advocacy around health knowledge will become very important. Fortunately we have the internet to deliver information but we have to separate the wheat from the chaff in terms of internet; we can’t be delivering information that is not well-grounded and reproducible, evidence-based application. And then lastly, the largest financial growth engine in health care, I think, in the future will come from the wellness healthcare innovations and not from the traditional economic drivers of drugs and surgery. So that’s a new business model that will really fuel a lot of this innovation. So those are pretty important standards of change. Those are write-them-on-the-wall-and come-back-and-review-a-few-years-in-the-future and see if we really were pretty good predictors of what the future may look like. But they circumscribe a very dramatic change in the way people think about health, the way professionals are trained, how reimbursement is delivered, and how a person will ultimately be managed as part of their own healthcare continuum. BRCA1 and BRCA2: Questions about Genes and Environment Through the Lens of Breast Cancer Now, you might say, “But, Jeff, our genes are not going to change. Maybe the way we see this whole thing will change, but if we’ve got these genes that encode for disease, how is this going to really make any difference?” Let me look at that genes and disease question for a second. And I look at it through the lens of a very remarkable investigator, a woman who I have a tremendous amount of respect for, Dr. Mary Claire King. Some of you know her as the discoverer of the BRCA1 and BRCA2 genes that code for significant increased incidence of breast cancer in women that carry the homozygous recessive double allele for these characteristics. This has been such a remarkable discovery that now, as you probably know, there’s a whole medical ethical procedure that a woman would through to evaluate whether she’d be a candidate for prophylactic double mastectomy as preventive medicine. This is probably the most aggressive form of preventive medicine that you can imagine, taking off breasts. And there are people making this decision, like the celebrity, Angelina Jolie, who recently had this procedure done and sent a message to many women across the world, probably. So when Angelina Jolie does this and we found out later her aunt has just recently died of breast cancer, which probably was part of her decision-making, it brings this concept of genes up very strongly (genes and disease). But I want to go back and review Mary Claire King’s work with you for a second, because I think it’s very insightful relative this question that we’re talking about in terms of decision-making, consumer participation in health care, and taking charge of one’s health. I’m going to go back with you to 2003 in Science magazine in a paper that was authored by Dr. King and her colleagues, the New York Breast Cancer Study Group, that was entitled, “Breast and Ovarian Cancer Risk Due to Inherited Mutations in the BRCA1 and BRCA2.”[5] These are the genes that we are talking about that give rise, when they are mutated, into this very high incidence of breast cancer. I think you’ll find this interesting if you haven’t been familiar with this work in the past because she goes on to say the following. I think this says it all so I’m going to quote directly: “Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, similar to risk in families with many cases.” Now here’s where it gets interesting: Risk appeared to be increasing with time. Breast cancer risk, with women who had this BRCA1/BRCA2 mutational characteristic at age 50, among these carriers born before 1940, was 24{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. But among those born after 1940, these same genetic characteristics, it was 67{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. And women born after 1960, it’s 82{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. You get where I’m going with this, I’m sure. The genes have not changed. These are the same cancer genes. But we have seen the cancer penetrance in the phenotype go from 24{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of women born before 1940 to 82{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in women born after 1960. So, what’s going on here? What it says—I think—is it’s more than genes. There’s another variable called environment. That even in these very severe cases where women would say, “This is so concerning to me that I will have my breasts removed for prevention,” that in these very severe linkages between a genetic determinant and a disease, in this case breast cancer, there is wobble related to modifiers of the environment. And we don’t know exactly what those modifying factors are in the environment. I wish I could tell you exactly what a woman would have to do, but in this article they go to say, “Physical exercise and obesity seem to be related to delayed breast cancer onset.” So, there are variables that are modifiable if you ask the right questions or you have broader perspective on how the genes influence the outcome called breast cancer. I don’t want to leave you with the impression that what I’m saying is no woman should ever have a radical preventive double mastectomy, because this is a very personal question and it depends on all sorts of variables and relative penetrance, and if your mother and your sister and your aunt had breast cancer then probably you’re going to be very concerned as well, so I don’t want to say this is never a good decision. But what I want to say is that there are modifying factors in these outcome that we call disease from genes that we might say, “Oh, I inherited a gene for cancer, or for heart disease, or for diabetes.” Most of these are not single gene conditions; there are modifiers of multiple genes that modify the penetrance into the phenotype and those factors are influenced by environment. That leads, then, to what do we really mean by modifying the penetrance into the phenotype? Well, that in part relates to something above the genome, right? Above the genome, which is epigenetics: things that occur that regulate how the genes are expressed. If you think of the genes as the hardware of your system, then what’s the software that runs it and tells how it’s going to produce the printout or the calculations of your body? And the software is your epigenetics, which are these marks that are put on your genes that either say “Read this gene” or “Don’t read this gene” or “Read this family of genes,” altering promoter region stories, the so-called methylation of the promoter regions of genes, then, can cause the stop reading of a certain, like stop reading an oncogene for  instance; that might be a desirable thing. Breakthrough: Epigenetics is Relevant Far Beyond Fetal Development These effects that we call epigenetic, we used think were only important in the early stage of development, like embryogenesis, after the sperm and the egg met as the cells would divide. Clearly, from the single cell you’re going to have to have it differentiate into the skin, and the brain, and the heart, and the bones, and so that same cell type is going to have to differentiate its message or you would end up with just one cell type. We know that epigenetics occurs embryologically to shut down certain messages, so because all cells have the message to make any other cell, but you don’t want your liver cell making a brain cell, so how do you stop that message? You do so by translating only certain messages in your book of life: the liver messages in the liver cell, and only the brain messages in the brain cell, hopefully. So that’s epigenetics. But what is more recently, I think, a breakthrough, is the recognition that this epigenetics is not just solely seen in the differentiation process of embryogenesis (fetal development). That it goes on, certainly much more slowly, as you are born than it did when you were the first few cell divisions are forming a new embryo, but it is still there, present, to reconstruct yourself based on your environment throughout the course of your whole life. You might say, “Well, how about stem cells, because aren’t stem cells constantly getting epigenetic messages to create different types of cell types to rejuvenate your body?” Yes, they certainly are, and so some cells are much more influenced by the environment than others, and some genes within those cells are more influenced by the environment, that then can be epigenetically marked to translate one message versus another message into your phenotype, like the BRCA1 BRCA2 genes that get expressed into breast cancer. So it’s not just the gene in and of itself that causes breast cancer; it’s the expression pattern in the presence of other genes that are functioning simultaneously, which are influenced in their expression by the environment of the host, right? What they are doing in their life, what they are eating, thinking, living, exposed to—all of things play roles in modulating the orchestration of those genes. So epigenetics is a new, I guess you would call it, back-to-the-future concept. It’s been around for a lot of years in explaining developmental biology, but only more recently has it been talked about more in the adult or the post-embryo state as influencing things that might relate to increasing risk. Think of the increasing prevalence of autistic spectrum disorder or autism. Now many people are thinking there’s an epigenetic link there that’s being discussed that might be related to methylation patterns or phosphorylation patterns of the genes from some kind of environmental factors that women and their embryos have been exposed to that would then translate into these neurological/neurodevelopmental alterations. The question is, are there implications for personalized health and personalized nutrition based on this epigenetic new discovery? The answer appears to be yes. There are a number of really nice review papers on this, advances indicating that epigenetic variation is an important influence in the interaction between nutrients in the genome, which can modify disease risk, and that there are certain genes that are called metastable epialleles. Now there’s a new term that you can throw into your lexicon: metastable epialleles.[6] Metastable Epialleles: Genes that Can Modify Disease Risk Now, what does that mean? It means that in people that are not embryos or infants, that there are still genetic characteristics, so let’s call it genes or regulators of genes, that are sensitive to epigenetic modulation by environmental factors, and therefor they are metastable, meaning they don’t just stay fixed throughout your whole life; they can be modified by what your environment might be. So a certain message can be wiped off, and another message can be added over the course of living so that you can get a different expression of their function. So that metastable epiallele concept is a fairly interesting concept because it doesn’t say all twenty five thousand genes are going to be constantly exposed to epigenetic change or we’d probably be a mess with all the changing stuff in our environment, but certain genes may be very susceptible or sensitive to this regulatory effect of epigenetics, and those are the ones that then ultimately give rise to different disease patterns in a population based upon a changing environment. So, that’s one big interesting new concept. Another big interesting concept is how these epigenetic effects influence metabolism. We think of the chronic, age-related diseases as being disorders that are associated with disturbed metabolism. They’re not single allele diseases. Like you can’t say that type 2 diabetes came from a single, or you can’t say heart disease came from a single gene, or arthritis came from a single gene, or really we could go down virtually the list of the whole family of chronic illnesses and not a single of them are monoallelic or monogenetic. They are poly genetic. They have multiple families of genes that work together to give rise the expression of these factors. So you might say the name of that disease could be the same from Mary Smith and Paul Jones, but the genetic modulation that gives rise to that disease could be very different between the two of them, because multiple genes are involved. The question is, does epigenetic alteration then influence the expression of genes to disturb the metabolic outcome that can be expressed in these diseases of chronic illness, and the answer is yes. There is ever-increasing support for this model that we might call a disease a single thing, but it actually comes from multiple different potential sources through complex interaction of genes with the environment to alter genetic expression through these epigenetic factors that ultimately gives rise to what call that disease. Although we might give it one disease code for reimbursement, it probably had multiple sources upon which it was experienced at the physiological level. We call this disturbed metabolism that occurs from modulation of this gene-environment interaction. There’s a very beautiful review paper that discusses this in Cellular Molecular Life Sciencesthat appeared in March of 2013 that really goes through the detail of how these transcriptional factors that modulate gene expression can be regulated and modified in their activity on the basis of epigenetic environmental changes.[7] So it could be toxins, it could be stress, it could be poor quality diet, it could be chronic infection. All of these factors play roles, then, in modulating how a genetic predisposition, or a genetic uniqueness, would be expressed into the phenotype that’s called the health and disease pattern of the individual. What this says to me is that there is really no disease of the chronic disease family that comes from a single gene that is caused by, “Oh my word, the bad luck of the draw. I just got that gene.” What you get are genes that are uniquely responsive to your environment, which can undergo metastable alterations through epigenetics to express their function in a different way that ultimately becomes what we call a disease. I hope you understand the difference between those two models because I think it’s very important in that this model is much more susceptible, or let’s call it sensitive, to plasticity, rather than the determinism that these chronic diseases come from genes alone. So this really leads us into this concept of systems biology and aging in linking, then, systems network effects that tie to diseases of aging. There’s a wonderful paper in Current Genomicsin 2012 that really describes how these factors regulate the system of function, not just a single step in this network of biology.[8] That they disturb metabolism so you get a network effect, and that’s why you see multiple biomarkers often changing. It’s not just like one variable like cholesterol changes all by itself. You get a disturbance that might show changes in inflammatory mediators. It might show changes in cell regulator neurotransmitters. It might show changes in sex steroid hormones. There is this web of changing architecture from the disturbance of multiple genes that give rise to that disease. How Can Intervention be Measured in Systems Biology? Pattern Recognition: The Patient Becomes Their Own Control Now what does that mean about, then, testing intervention? If we’re looking at a traditional model of a double-blind, placebo-controlled trial, which is you have one agent against one outcome, that’s great for a drug, in which you’re looking at the effect of, say, a molecule on blood pressure. You take the drug against a placebo. Maybe you look at it against one end point, which is blood pressure. And you see, does it work or doesn’t it work? Well, that’s great if you want to validate a drug on the model of one agent against one outcome, but I’ve just told you there are many agents against complex genes that gives multiple effects on expression, so it could be multiple outcome determinants. How do you do that in an individualized population? How do you study it? Well, these particular models require an alternative strategy and there are a number of methodologists who have really been working on that, and it would be a little bit presumptuous of me, in five words of less, that I could say that there is one path to understanding, but they basically come down to a different methodology that is related to pattern recognition, and to nearest neighbor analysis, and what’s called dendritic analysis clustering, and starting to look at how certain genetic characteristics cluster with certain outcomes, and how these relate to certain environmental perturbance. There’s a wonderful paper on methodological developments that appeared years ago that looks at this alternative strategy for clinical trials that’s based upon randomization of intervention, but looking at the pattern recognition within patient indicators.[9] So the patient becomes their own control. Rather than everything being Gaussian and statistically analyzed around some kind of a parametric analysis with standard deviations from the mean, you’re looking at individual variations of patient against him- or herself, and then you’re grouping them as it relates to different status evaluations of their lifestyle and their genes against their outcome. So, patient individualized intervention, standardizing the patient against themselves as a control. It’s a different way of doing these types of studies. The Unique Issue of Evaluating Stress Response Now, how then do you evaluate, going back to Hans Selye’s stress model of disease, the complexity of something you can’t smell, taste, or touch, like stress, and its effect on chronic illness, based on this model. Here’s where we start to get in the correlation of stress signals in the environment producing altered cellular genetic response that then changes the phenotype and changes the pattern by metabolic disturbance that measure, then, of the patient against him- or herself. It’s a way of utilizing this particular model versus the double-blind placebo-controlled trial of an agent against the endpoint, which is the drug model. And there are a variety of wonderful papers that have been discussing this, like stress response and how it relates to alteration in metabolic patterns, particularly related to changing in energy patterns or cell regulatory patterns, things like the mitochondria, the energy powerhouse of the cells, how it can alter mitochondrial bioenergetics and change intracellular function. So we now recognize that this concept of moving towards a personalized medicine requires different methodologies, and the stress response and how it signals into the genome through these epigenetic effects can cause disturbed metabolism that then shows patterns of change: different regulatory mediators, different inflammatory cytokines, different growth hormone-related substances, different cytotoxic agents, alterations in detoxification mechanisms, changing in neurochemicals/neurotransmitters. This pattern becomes a very, very important way of evaluating the influence in that individual of how their lifestyle and lifestyle behaviors influence their genomic signaling and ultimately give rise to their phenotype. It’s that model that we’re going to be discussing with our extraordinary clinician of the month, Dr. Bruce McEwen, and I think you’ll see how this weaves itself into a very, very important model for the future of what I would call functional medicine and managing through both experimentation and research these very hard to quantify connections of environment and lifestyle to outcome called health.

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INTERVIEW TRANSCRIPT

Researcher of the Month Bruce McEwen, PhD The Rockefeller University Alfred E. Mirsky Professor Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology New York, NY So here we are again at that point in Functional Medicine Update that I know you, as I, always look forward to with great anticipation. I’d have to say that for me personally, and I think as you will find out for yourself as well, this will turn out—the next half an hour or so—to be one of the most important, clinically relevant discussions that we’ve had the privilege of having on Functional Medicine Update over the last 30 years. The person you’re going to be hearing from who is an expert in the field is Dr. Bruce McEwen. The name, alone, probably you already know where we’re going with the concept of allostasis. You know, we’ve been very privileged over the years. I had the chance to meet Hans Selye prior to his death, up at McGill. We interviewed Robert Sapolsky at Stanford a number of years ago. But Dr. McEwen, who is the Alfred E. Mirsky Professor of the Harold and Margaret Millken Hatch Laboratory of Neuroendocrinology at Rockefeller University, I think, is at the peak of this understanding, and discovery, and innovation in the area of neuroendocrinology, and really what I might even call neuroimmunoendocrinology, because there is a portion of the immune system obviously involved here as well. Dr. McEwen was the past president of the Society for Neuroscience, a member of the National Academy of Sciences and the Institute of Medicine, and has received numerous awards. Just a few to kind of highlight his accomplishments: In 2011, he was the recipient of the Edward M. Scolnick Prize in Neuroscience; in 2009, the Gold Medal Award from the Society of Biological Psychiatry; and in 2005, the Pasarow Award in Neuropsychiatry. I first really got clued in to Dr. McEwen’s work when I had the chance to read his book The End of Stress As We Know It, which was in 2002, I recall. From that moment on, I kind of stepped over into the McEwen camp and have followed his work very carefully since. He has collaborated with a number of very well-renowned investigators, one of whom I had the privilege of meeting at a recent meeting that Dr. McEwen and I both attended, Dr. Teresa Seeman, who is at the David Geffen School of Medicine at UCLA, at a conference that we were involved in related to the concept of resilience in returning service veterans from war (men and women). Dr. McEwen and Dr. Seeman had considerable to contribute to that group that hopefully will weave its way into new programs that the military will be introducing (the Veteran’s Administration) for returning service people. Those of you not familiar with The End of Stress As We Know It (the book), when you read the editorials that follow the book, one of the things that will be said is, “There’s a whole new way to think about stress that comes from this book. Sure, some stress is inevitable, but some stressed out and being stressed out isn’t. In fact, we can learn to re-channel the powerful stress activators in our lives to make us even more effective. The good news is that there are definite things that can be done to prevent the process of being stressed out from ultimately taking the wrong turn. New research in brain functioning from the Dr. McEwen laboratory allows us to understand and harness the energy stored within us and to channel it in positive ways. The End of Stress As We Know It leads us to a new appreciation of the mind-body connection so that we can learn how to reduce stress and increase our overall sense of health and well-being, and even turn aside the slings and arrows of life.” That’s a pretty strong endorsement for the book, and I have say that’s how I felt in having read it myself. I think it was a very powerful manifesto of taking stress as kind of a negative connotation in physiology (in common parlance), and turning it into an operative term that allows something to be done to harness it. Dr. McEwen, it’s a great privilege to have you as a clinician/researcher of the month for Functional Medicine Update and thank you for spending the time with us. BE: Thank you very much. It’s great to be here, and I might mention, by the way, that The End of Stress As We Know It was out of print as a print book but is now available as an e-book, costing very little money. It is accessible on Kindle, and Barnes and Noble, and so on. JB: Well, I recommend it as kind of mandatory reading for all of our long-standing Functional Medicine Update subscribers. It’s really a seminal work. Let’s start down the road, here. We could obviously go back and start from square one with your chemistry undergraduate degree and work up, but let’s start a little bit more contemporary and talk about how you came on to the concept of allostasis and allostatic load. What is it, and how does it play a role in our better understanding of the stress that we’re experiencing today in our society? Early Research on the Concept of Allostatic Load BE: Okay. Well, go back to when I, as a young faculty member, came back to Rockefeller University, where I got my PhD, to join the laboratory of the late Neal Miller, who was a very famous psychologist, the father of behavioral medicine. I also, at the same time, was influenced by my mentor, Alfred Mirsky, to think about how genes are regulated in the brain and the body, and hormones (steroid hormones) were the new candidates, and still are important regulators of gene expression. So I began to study how hormones (sex hormones and stress hormones)—how and where they affected brain function, and made the discovery that an area of the brain called the hippocampus, which is very important in memory and also, now we know, mood regulation, is a major target for these stress hormones (for cortisol and the like). This sort of clued me in to the importance of not just the hypothalamus but higher cognitive centers, so for a number a years we worked on (and continue to work on) these very specific questions of how stress hormones and also sex hormones affect brain function, especially higher cognitive functions, mood regulation, and so on. But in the late 1980s I was asked to join the MacArthur Network on Health and Behavior headed by a woman named Judy Rodin and another man I consider my other mentor besides Neal Miller and Alfred Mirsky, the late Eliot Stellar from the University of Pennsylvania, a famous physiological psychologist. And it was there I was introduced to two people, Peter Sterling and Joe Eyer, who had introduced a concept they called allostasis, which literally means achieving stability or homeostasis by an active process of responding to a challenge. This fit perfectly because the term homeostasis really implies stability. People have used reactive homeostasis and other things, but allostasis, like producing adrenaline, raising your blood pressure, producing cortisol, which is important for adapting to stressful experiences—that process of allostasis leads to adaptation, but then we thought a little bit, and as I became more and more familiar with issues pertaining to human beings in relation to stress and health, and I certainly had help ultimately from people like Teresa Seeman and Eliot Stellar, we thought that there was a price that the body and brain pays for being under a lot of stress or not being able to handle it very well, and so we coined the term allostatic load to refer to this wear and tear. Over time, that term has begun to take hold, and I think more and more people appreciate what it is telling us. JB: You know, we had the privilege a number of years ago, at the Institute for Functional Medicine, in having one of your ex-post-doctoral students, Dr. Sonia Lupien, from Canada. BM: Oh, yes. JB: She is such a great advocate and ambassador for your work because she has done some really great in-the-trenches evaluation in clinic of applying your principles. Her results look absolutely superb, and I know you’ve done not only the exquisite laboratory work (animal models and others), but you’ve also translated this over into clinical application. Has this been well received by your colleagues, or how do they see a translational individual in this field, bringing these concepts into practice? Allostatic Load Concept Helps to Simplify How the Body Reacts and Adapts BM: Well, I think that initially the people who really caught on to allostasis and allostatic load were people in epidemiology and public health, people in psychology (some in health psychology, some in sociology), because I think the concepts of allostasis an allostatic load help to simplify or organize the great complexity that is how the body responds in many ways and adapts; I mean, through the immune system, the cardiovascular system, the metabolic system. It helps people understand it. I think just the notion of the metabolic syndrome is itself a recognition that it is more than just a single system of the body or a hormonal system that’s responding, but a series of interacting mediators that operate in a nonlinear manner. And so I think as we appreciate the complexity of the body’s adaptive responses and also of what leads to and exacerbates and causes disease. I think these concepts that are intrinsic to the terms allostasis and allostatic load, of nonlinearity, are beginning to be appreciated more and more, and whether you call it allostatic load or not, the fact that when something happens you’ve got your autonomic nervous system, your HPA axis, your metabolic hormones, your inflammatory pro- and anti-inflammatory cytokines, and on and on, all changing and changing each other. And so what it comes down to is, of course, the question of: Given this complexity, what should we do about it? And this brings up, of course, the more what I call top-down interventions like physical activity, things that we do that actually help the body help itself to do the right thing. JB: I’d like to come back in just a moment to this metabolic syndrome question because I think that’s a very interesting part of the spectrum of the clinical manifestations of the disorder, or of the influence of allostatic load. And I’d like to stop for a second in a weigh station and talk a little bit, if you would, about the difference between where Hand Selye took us, recruiting the term “stress” out of physics into physiology, which has now, I think, become the number one English word in medicine that is used. Interestingly I did a search on that and found that it trumps every other word in physiology and medicine right now. You and your colleagues have advanced this concept. Where did the Selye model leave off and where did your work take on? Explaining Exhaustion: The Hormonal Response and How the Body Adapts BM: Good question. I think it’s amazing that Selye had such insightful ideas when there was so little specific information about—and ability to measure—these different adaptive systems in the body. One of his concepts was the concept of exhaustion when the body has undergone a lot of stress. Exhaustion sort of implies the failure of hormonal and other systems to respond, and while that may be the case in maybe something like burnout, when there is, for example, low level of cortisol and a lack of responsiveness, the general idea of the imbalance of these adaptive systems that are counterbalancing each other, what Selye referred to as exhaustion I think is really what we would call the development of allostatic load, and the manifestation in different ways. If you have too much cortisol and become glucocorticoid resistant and have inflammatory processes and metabolic syndrome and so on, that’s one thing. If you don’t have enough cortisol and you have more, say, autoimmunity and various things of that sort, that’s another. And these things manifest themselves in different ways in different disorders. That’s sort of what I think he meant, but as I said, he did not have the knowledge that we have. JB: Yes, I think that it’s really, to me, so fascinating to read your work, and that’s again another of my ah-has in reading The End of Stress As We Know It, is that when you start using this network biology or systems biology approach, that you’re advocating to look at the interface between immune-related mediators, endocrine-related mediators, and nervous-system-related mediators. So you start, as you said, with neurotransmitters, neuroexcitatories like glutamate NMDA, and neurotrophic factors like BANF and you put it into a systems biology way of thinking, it really helps you to understand why so many symptoms can be manifest. It’s not like a pneumococcus bacteria produces one disease called pneumonia. You get all these vastly diverse symptoms that derive out of the tissue-specific activities of this web. It’s a very powerful concept for a different model of disease, really. BM: Yes, we talk about comorbidities and realize that often with, say, depression there are comorbidities in terms of cardiovascular disease, metabolic syndrome, and so forth. And it’s rare in the modern world to have one disorder without some others to some degree lurking as well. Allostatic Load and Research on Metabolic Syndrome and Cardiovascular Disease JB: Let’s, if we can, move that over into the topic that you introduced briefly here a minute ago, which was metabolic syndrome. Fortunately we’ve had Gerald Reaven as one of our clinician/researchers of the month on a previous issue of Functional Medicine Update as well, talking about his Syndrome X and insulin resistance phenomenon. The confluence, or let’s call it the connection, between what you’ve been doing with allostatic load and what he’s been doing coming from the endocrinology side with diabetes seems quite amazing when you start looking at these putative biomarkers. Could you tell us a little bit about that, because it’s fascinating? BM: Yes. Actually, maybe you can remind me of some of the biomarkers for metabolic syndrome, but basically I can start out by saying that what the allostatic load battery that Teresa Seeman now uses as an adjunct to the cardio study, is a battery that taps into autonomic (both sympathetic and parasympathetic); it taps into metabolic, looking, for example, at glycosylated hemoglobin; it taps into immune/inflammatory, looking at CRP and I think, possibly, IL-6. Now it’s possible to look at a whole panel of pro- and anti-inflammatory cytokines, and so it’s really tapping into the major systems that are struggling with each other, shall we say, and I think that’s the idea behind the metabolic syndrome measure, and the more and more people that are looking at metabolic syndrome and then at all of the diseases of modern life, the more we realize that a common denominator is a pro-inflammatory tone. That, of course, doesn’t exclude all of these other mediators, because when you have inflammation the body is also to trying to produce cortisol to calm it down, and this also then interacts with the metabolic system, in which the regulators that have to do with insulin resistance and control of appetite, like leptin, are distantly related to the cytokine family. JB: Yes, I think that you have hit exactly, from a different perspective, what Dr. Reaven was talking about. He started with things like elevated triglycerides, low HDL, decreased apoA1, increased apoB, increased hs-CRP, increased blood pressure, with an increased PIE1 plasminogen activator inhibitor one level, and increased waist-to-hip ratio with central adiposity. These track right across, it seems, with what you and Dr. Seeman have been looking at in allostatic load. BM: Yes, it’s very close to what I have just now in front of me, her list of markers for the allostatic load battery that she’s using in this cardio study. So we’re really talking about the same kind of thing: this multi-systems, nonlinear type of thing. Of course, then you think what the interventions are, and we have to also think about the role of the brain in all of this, but with what the interventions are, any kind of drug is going to perhaps help calm down or elevate one system, but it’s going to cause compensatory reactions in others, and that’s not necessarily going to help the body put itself right. Drugs can help with too much or too little as long as they don’t push it too far, but ultimately we have to have these top-down, more holistic interventions that will actually help the body help itself. Allostatic Load and the Obesity Epidemic JB: So that relates a little bit—and I don’t want to put you on the spot, here, but just get your opinion—about this obesity epidemic, because we seem to focus all of our attention on what I would call the thermogenic of the calorie; it’s that we have a calorie consumption problem is the singular in an exercise in efficiency, or an activity in efficiency or inactivity component, and in between we have this thing called metabolism, which is regulated by all these factors that you’ve been describing. Do you feel that what from what you’ve observed that some of this obesity epidemic is related to the biobehavioral response to our psychosocial environment? It’s not just calories in and of themselves? BM: For sure. I mean, I think we know that, for example, people on the average are sleeping less, often because they’re getting up early or getting or getting home late and commuting long distances. We live in this go-go atmosphere in which people are rarely sitting down as a family unit, or at least with other people and having a slow and deliberate meal. It’s the fast food, cram it down. And then, of course, it’s the kind of food—the energy-dense foods—which immediately may be satisfied. And then it’s the overconsumption of calories, and, of course, based upon, for example, Robert Lustig’s new book Fat Chance, the recognition of how much sugar we have in our diets, and how some sugars, like fructose, are more likely to lead to the generation of obesity because of the way they are metabolized.[10] All of these things are almost like a perfect storm. And then if you add to that the fact that there is increasing evidence of epigenetic factors, even transmission in modified DNA in the sperm of the father and possibly changes in the mother which will pass on a propensity towards obesity. The notion of starvation, as in the Dutch hunger winter, where the pregnant woman (and the fetus) is somewhat starved, or overnourished, and the consequences there may be very similar in that the offspring will then have this propensity towards metabolic syndrome, obesity, and diabetes.[11],[12] JB: Those are really powerful game-changing concepts that you’re bringing up because they really relate to how we design large societal intervention programs to reduce this rising burden of obesity-related diseases. We had the privilege also of interviewing Dr. Moshe Szyf, from McGill, on his behavioral epigenetics and the work that he is doing there, and that seems also to fit very nicely into your model as well because it’s one way that these epigenetic marks are put under conditions of adaptation. We have different kinds of regulators on gene expression. Some are long term. BM: Absolutely. JB: Have you done any collaborative work or had any discussions with the group that is involved with this behavioral epigenetics? BM: Well, Michael Meaney, for one thing, is a former postdoctoral fellow, and also the research mentor for Sonia Lupien, so we are interrelated—an expanded family of science. And I know Moshe; I like him very much. Actually my PhD thesis was with Alfred E. Mirsky. They were the ones who really pioneered what we now call epigenetics, the modification of histones, which affect the folding and unfolding of DNA and its ability to be expressed, and so I’ve lived with the notion of epigenetics (whatever it was called then). It’s a way of talking about how the environment regulates the genome, and we are actually presently doing studies on how stress changes the epigenome of brain regions like the hippocampus, and how that is related to the action of certain antidepressant drugs, the action of stress hormones, and also just related to what happens when an animal experiences something different that is perhaps somewhat stressful or enriching, and so on. It’s a fascinating topic and it’s now gotten to the point where we recognize that there are parts of the DNA that are not coding for proteins but are coding for RNAs that have a regulatory function, so that’s another aspect of epigenetics, and then there are DNAs that rearrange themselves. There is Barbara McClintock who studied corn maize and how it got the variegated color; it’s because DNA is being rearranged so that different things can be expressed or not expressed, and this is happening also in our genomes and may contribute to something called genomic instability that may actually make the brain or cells of the body more vulnerable to cancer, to degeneration, and so on. JB: Wow, what you just said was gold. There was a lot of density in the information you just shared with us. Barbara McClintock, to me, is such a remarkable figure in genetics and I was pleased that she finally was recognized for her extraordinary work on transposons, and how this jumping genes concept is not really not just found in Indian corn; that it’s a really very powerful concept that helps us to understand a little bit about genetic variability and also, as you said, genetic instability.[13] So it seems like there’s a lot of confluence among multi-disciplinary fields to start to understand the fabric of human function and how it interfaces with the environment. I guess that then begs a question. You, being at the leadership in the wheelhouse of this field, so to speak, do you feel that there is getting more traction about this way of thinking? That people are starting to understand it and incorporate it? That it’s part of training and taken seriously? What’s your assessment? BM: I think it is. I’m aware of the fact that a number of medical schools there is an interest and also even a demand on the part of students, but an interest on the part of the faculty in traducing more these problems that we face that have to do with our social environment and the concepts of integrative medicine and the importance of looking beyond drugs and the development of pharmaceutical agents to think about these kind of top-down interventions. And this is particularly so since, as the progress with the healthcare reform goes forward, there will be—as I understand it—more of an emphasis on producing results rather than just doing procedures, and this puts medical groups into the pressure of actually showing that their patients—their subjects, the people they cover—are actually improving in their health. That then makes us think about all things are fair game in terms of treatment. It’s not just giving a drug perhaps; it’s getting people involved in watching their diet, exercise, sleep, their commuting patterns, the kind of stresses in their lives, need to be brought under control. JB: So when you are out there teaching, lecturing, communicating do you find that people are asking questions of how to do this, or are they still at the level of what is it all about? Where are they, generally, in their readiness to change model? Physical Exercise and Stress Reduction Can Affect Brain Structure, Studies Show BM: I think the thing that I find and I often will bring it up, is that they find most amazing the notion that, for example, as was shown by a group at the University of Illinois led by Arthur Kramer, if you get sedentary elderly adults to walk 60 minutes a day, five out of seven days a week, and they can sustain this on a regular basis over six months to a year, their hippocampus gets larger because of (probably) the generation of new nerve cells, and also some of these plastic changes that we’ve seen in the brain, and their memory gets better, and also their prefrontal cortex shows improved function, blood flow, and peoples’ ability to make decisions—their executive function—is improved by something as simple as this very modest level of physical activity.[14] And if this works, there are studies that are being done on mindfulness-based stress reduction, for example, that show that if you can successfully treat an anxiety disorder there are actual physical changes in size of the amygdala, which is involved in fear and anxiety.[15] So behavior can change the brain, and I think the more people see that this is possible—that you don’t simply just need drugs although of course they could be helpful—and begins to empower people to think that relatively simple things can help yes, but we have to get the word out. JB: That’s a marvelous proactive statement for every one of us to listen to. One of the questions that I ask all of our luminaries is, in the bibliography of articles and papers that you’ve been a principal author of (of which there are many), are there some that stand out in your mind as seminal? I asked Linus Pauling this question, actually, about 30 years ago. Out of his some thousand papers I thought there probably would be one or two, but he was able to pick out a paper that he felt was the most important of his work. I remember reading your New England Journal of Medicine paper, I think it was, on protective and damaging effects of stress mediators.[16] Are there articles within your publications? BM: Well, I think that that paper was the…you know, has certainly been very highly cited and was the thing which really turned things around. There was a previous paper that I did with Eliot Stellar in 1993 in Archives of General Medicine that sort of started it off, but it was the New England Journal paper that was very important.[17] I think more recently I wrote with Richie Davidson, a professor at Wisconsin, a paper in Nature Journal on the impact of the social environment.[18] There are others in between, but it’s the New England Journal article that I think really got people thinking about this, and there have been a lot of filling in of the details since, and certainly Teresa Seeman’s operative rationalization of allostatic load has been extraordinarily important.[19] JB: My last question—and by the way, you’ve been very gracious to give us this amount of time—I’d like just to get a sense from your vision on high about what you see on the horizon as it relates to this field and its incorporation, both in terms of the research and clinical applications in the body politic of medicine. Do you have some thoughts as to where you see the trajectory taking us? Research is Now Focusing on Mental Health of Children BM: Well, one thing that I’ll be doing next week with some of my colleagues from the National Scientific Council on the Developing Child—this is headed by Jack Shonkoff, a pediatrician at Harvard—is to focus on those early life adverse experiences and the importance of trying to improve parent/child relationships because adverse childhood experiences, as was documented by Felitti and Anda in the California Kaiser Permanente middle class population, has a huge impact on lifelong physical and mental health, and contributes disproportionately to the woes that we see around us, and so that aspect is important.[20] There is a new realization that the brain is more plastic than we have given credit for, and there are attempts to change the brain. There was a Sackler Symposium published a year ago as a special issue of the Proceedings of the National Academy of Sciences on biological embedding—I think it is from fruit flies to kindergarteners; it has some marvelous articles there on this plasticity issue and some of the future-looking steps.[21] The social environment the MacArthur Network on Socioeconomic Status and Health, and people simply look on macses.ucsf.edu—I think it is UCSF—website. They will get two publications that they can download, one on reaching for a better life, which is a lay sort of view of the social environment and health, and the other is a New York Academy symposium on the social environment and its impact.[22] I think that’s where we are going. We have to deal with what the social environment is doing to our brain functions and our physical and mental health, and maybe the hope is that the brain and body are more plastic than we’ve given it credit for if we can get people to do these things that we know are good for us but don’t often find time to do. JB: Thank you, Dr. McEwen. That was a very uplifting and I thought very expansive review of many, many years of extraordinary work. By the way, one of the articles that I know you’ve published that I really appreciate—a recent article—appeared in Annual Review of Medicine in 2011 titled “Stress and Allostasis-induced Brain Plasticity.”[23] I think this brain plasticity concept that you are alluding to is very encouraging because it doesn’t suggest determinism, it suggests opportunity. BM: That’s right, and I’m glad you mentioned that because this was one of the first, more or less, official recognitions by the medical community that this is something worth paying attention to. JB: Well, you’ve made many contributions that have gotten our attention, so thank you very much and we appreciate everything you’ve done and spending the time with us. We look forward to following your work very closely. BM: Thank you very, very much. I’ve enjoyed talking with you. JB: Thank you. Best to you.  

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1. McEwen, Bruce S. and Elizabeth Laskey. The End of Stress As We Know It. New York: Dana Press, 2002.
2. Schneider KM, O’Donnell BE, Dean D. Prevalence of multiple chronic conditions in the United States’ Medicare population. Health Qual Life Outcomes. 2009;7:82.
3. Ford ES, Croft JB, Posner SF, Goodman RA, Giles WH. Co-occurrence of leading lifestyle-related chronic conditions among adults in the United States, 2002-2009. Prev Chronic Dis. 2013;10:E60.
4. Stevens DP, Bowen JL, Johnson JK, Woods DM, Provost LP, et al. A multi-institutional quality improvement initiative to transform education for chronic illness care in resident continuity practices. J Gen Intern Med. 2010;25 Suppl 4:S574-580.
5. King MC, Marks JH, Mandell JB, New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643-646.
6. Dolinoy DC, Das R, Weidman JR, Jirtle RL. Metastable epialleles, imprinting, and the fetal origins of adult duseases. Pediatr Res. 2007;61(5 Pt 2):30R-37R.
7. Cosentino C, Mostoslavsky R. Metabolism, longevity and epigenetics. Cell Mol Life Sci. 2013;70(9):1525-1541.
8. Hou L, Huang J, Green CD, Boyd-Kirkup J, Zhang W, et al. Systems biology in aging: linking the old and the young. Curr Genomics. 2012;13(7):558-565.
9. Bagne CA, Lewis RF. Evaluating the effects of drugs on behavior and quality of life: an alternative strategy for clinical trials. J Consult Clin Psychol. 1992;60(2):225-239.
10. Lustig, Robert H. Fat Chance: Beating the Odds Against Sugar, Processed Food, Obesity, and Disease. New York: Hudson Street Press, 2012.
11. Edwards MJ. Genetic selection of embryos that later develop the metabolic syndrome. Med Hypothesis. 2012;78(5):621-625.
12. Gonzalez-Bulnes A, Ovilo C. Genetic basis, nutritional challenges and adaptive responses in the prenatal origin of obesity and type-2 diabetes. Curr Diabetes Rev. 2012; 8(2):144-154.
13. Barahona A. Barbara McClintock and the transposition concept. Arch Int Hist Sci(Paris). 1997;46(137):309-329.
14. Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, et al. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006;61(11):1166-1170.
15. Desbordes G, Negi LT, Pace TW, Wallace BA, Raison CL, Schwartz EL. Effects of mindful-attention and compassionate meditation training on amygdala response to emotional stimuli in an ordinary non-meditative state. Front Hum Neurosci. 2012;6:292.
16. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338(3):171-179.
17. McEwen BS, Stellar E. Stress and the individual. Mechanisms leading to disease. Arch Intern Med. 1993;153(18):2093-2102.
18. Davidson RJ, McEwen BS. Social influences on neuroplasticity: stress and interventions to promote well-being. Nat Neurosci. 2012;15(5):689-695.
19. Chen E, Miller GE, Lachman ME, Gruenwald TL, Seeman TE. Protective factors for adults from low-childhood socioeconomic circumstances: the benefits of shift-and-persist for allostatic load. Psychosom Med. 2012;74(2):178-186.
20. Anda RF, Butchart A, Felitti, VJ, Brown DW. Building a framework for global surveillance of the public health implications of adverse childhood experiences. Am J Prev Med. 2010;39(1):93-98.
21. Bagot RC, Zhang TY, Wen X, Nguyen TTT, Nguyen HB, et al. Biological embedding of early social adversity: from fruit flies to kindergarteners Sackler Colloquium. PNAS 2012 109 (Supplement 2) 17200-17207.
22. http://www.macses.ucsf.edu/
23. McEwen BS, Gianaros PJ. Stress- and allostasis-induced brain plasticity. Annu Rev Med. 2011;62:431-445.

Welcome to Functional Medicine Update for July 2013. Gastrointestinal health. How many times have we talked about that over the 31 years that we’re been doing Functional Medicine Update repartee? Well, it’s an important fundamental process, isn’t it? In the Institute for Functional Medicine algorithm, it’s one of those core principles. We recognize that it plays a significant role beyond that just of the fact that it’s a digestive conduit that breaks large molecules into small and makes them bioavailable for absorption. We recognize that the gastrointestinal tract has multiple personalities, meaning it is pleiotrophic in its functions. One of the major parts of its function, as we’ve examined and discussed at length is its role as part of the immune system. In fact, we recognize that the mucosal associated lymphoid tissue and the gastrointestinal associated lymphoid tissue constitute, collectively, more than 50 percent of the body’s total immune system and secrete more than 70 percent of the antibodies that ultimately arrive at systemic circulation to provide defense against foreigners. So the GI tract is very, very important, and we recognize that beyond its immunological effects, it also has a very intimate relationship with the nervous system, because as Dr. Michael Gershon pointed out in his book The Second Brain, there is this density of nervous system connection to the GI tract.[1] And in fact, in a recent discussion with Dr. Alessio Fasano from Harvard Medical School, who is arguably one of the world’s experts on celiac disease and gluten enteropathy, he suggested—in a discussion I had with him—that maybe we should actually say the gut is the first brain—that there are actually more plexus of nerves in higher density of neurological connections in the gut than there is even in the brain. So these are interesting concepts. The neurotransmitters produced in the brain have an effect upon gut function, and the gut hormones, and gut modulators influence the nervous system, both peripherally and centrally, so there is this crosstalk which really is centered around the GI system to both the nervous and immunological system. So we might consider the gastrointestinal system to be the seat of the neurological immunoendocrine system—that they are all interconnected and tightly wired to the function of the GI system. This is very kind of contextually interesting view of the gastrointestinal system that has impact across many subspecialties of medicine. We probably would start, wouldn’t we, with a gastroenterologist who is supposedly the person who knows the most about the gastrointestinal system and ask the question, “How many of these practicing, board-certified gastroenterologists think of their organ of interest—of specialty—as being the center of the neuroimmunoendocrine system, and manage its function and dysfunction with that context in mind?” I haven’t done a survey of all the gastroenterologists, but I have talked to quite a few of them and I would say that this is more the exception than the rule that they would think of their own organ as having that centrally important function across these different subspecialties of medicine. In fact, as you probably recognize, a gastroenterologist that might think that way about the broad impact of the GI system on other organs that cut across other medical specialties do so at some peril because now they start crossing over and transecting into other people’s country clubs (other medical specialties) and they start interfering with the sanctity of these independent, siloed divisions of medicine as if each organ is owned by a different specialty and don’t ever cross over those boundaries because you’re liable to get yourself censured. So I think that the medicine of the future—this functional medicine model, this systems biology model—is going to witness the breakdown of these synthetic barriers among organs, and we’ll start looking at the body as a network biological/physiological, real-time, responsive holograph, where all parts are reflected in all other parts in real time. The GI Tract and Its Relationship to Chronic Diseases So what does that have to do, then, with the emerging new thoughts about gastrointestinal function? You know, we could say that there are major breakthroughs being made in the basic sciences of virtually every organ or organ system today, and we’ve tried our best in Functional Medicine Update to bring that out as we go through our various issues to look at how breaking news in the world of biosciences and medicine is changing our perspective from a histopathology-based model to a functional-based model, but certainly as we focus this issue on gastrointestinal function, we’re amazed at the extraordinary number of new discoveries that are being made virtually every month and being published in the world’s primary scientific and medical literature that are redefining the important role that the GI tract has in its relationship to the prevalent diseases of the day, beyond that of gastrointestinal diseases. Diseases such as type 2 diabetes, cancer, inflammatory arthritis, neurological disorders including dementia; there is an emerging GI link to every one of those. That’s a pretty exciting evolution, but it also then begs the question, what do you do with this information? How does it filter down into clinical practice and what are the clinical takeaways and payoffs from these discoveries? Let’s, if we can, set the context before we have the privilege of moving into our discussion with our clinician/educator/researcher of the month, who fulfills all those criteria, by the way, Dr. Patrick Hanaway. You’ll have the pleasure of what I think is a most remarkable discussion that Dr. Hanaway and I had just recently at the Institute for Functional Medicine Annual International Conference that was held in Dallas, Texas in late May/early June, in which Dr. Hanaway and I had a chance to really, as they say, “get real.” Before we get to that discussion with Dr. Hanaway, let’s set some of the context as to the nature of the changing playing field. Reviewing Facts about the Gut Let’s review quickly some of the things that are happening in this area of discovery in the gastrointestinal system. As you know, we recognize that the gut is one of those places that comes into direct contact with the outside environment through the food that we eat and the fluids that we consume, so the gut mucosa samples our environment, so to speak, just as our sense of touch samples the environment when we touch things, or our sense of smell when we smell things, or our vision when we look at things, or when we hear sound waves hitting in the tympanic membranes of our ears we get a sense of auditory stimulation. Similarly, the gut is bringing information to the body through the nervous and immune system, and also through the endocrine system that’s altering its function. So the food that we eat is very, very important in its translation of its message through the gastrointestinal tract as kind of a sense to pattern the body’s function. It’s more than just eating calories, it’s more than just eating nutrients; it’s consuming information that could be either positive information that helps orchestrate appropriate immune function, nervous system function, and endocrine function, or it could be disinformation, just like a noxious smell, or hitting your head with a hammer, or a loud noise, or, you know, glaring lights can create disturbance of your physiology, so can information coming in through the GI tract cause disinformation to produce “dis”-ease. That’s a very interesting way of looking at this broad perspective of gastrointestinal function and its interrelationship with gut function. Now there’s another part of the gut that is important to recall as well, and that is that it’s not living as an organ in absence of a community relationship, and the community relationship it has is represented by what is called the microbiota (the gut enteric bacteria). We now recognize that those bacteria, they have dietary preferences as well. They have different personalities. So they pick up nutrients that comes from the same source that nourishes the gut mucosa itself; that’s the food we eat. Some of those bacteria like certain foods that we consume better than others, so they flourish and they are selected for under certain dietary principles, and other bacteria are less selected for. I mean, there’s no magic barrier that keeps these bacteria out of our guts. The only thing that kind of determines the…I guess you would call it the population of our community of bacteria is the food they are eating and our gut immune defense that kind of tells us who are the campers that are camping on our GI mucosa, particularly in our large intestine. So certain diets encourage certain types of microbiological communities, and certain other diets alter these dietary communities. Now, why is that important? Recall that you can have upwards of 2 kilograms of bacteria (almost 4 to 5 lbs of bacteria) in your gut. It is a substantial organ. The only difference is that this organ is not connected to your body by the blood stream; it’s connected by the absorption of its metabolites, through the GI mucosa, and filtered through the immune system. So think of these campers all eating food, and producing waste products, and some of them camping so long that they die and have to get resorbed. All that information is picked up by the immune system of your intestinal tract and it’s sent out to the rest of the body as either: Yes, you’ve got a group of happy campers, or, no, you’ve got a group of not-so-happy campers, and that produces these dysfunctional messages. So, nutrition, gut microbiota, gut mucosal integrity, gut immune defense, and systemic messaging. That’s kind of the sequence of events that we’re talking about. What we do know is that this degradation of food that we call digestion also is associated with aspects that we call fermentation, because these gut microbial inhabitants can ferment by the way that they metabolize foodstuff into metabolic byproducts, some of which can be considered endotoxic, meaning they are not friendly molecules. They are nitrosated intermediates. They are deconjugated bile acids. They are modified steroids. They are twisted molecules, basically, that come as a consequence of the microbial metabolism of food and gut contents. Different bacteria have different personalities in how they form those metabolites, so we then breakdown some of these characteristics into three types of bacteria in our gut. We call the best our symbionts. Those are doing work for us and making vitamins, and they are making short-chain fatty acids that our gut mucosa can use, they are producing trophic factors that stimulate our immune system. This sounds like good work, so these are symbiotic bacteria. Then there are what we call commensals. Commensals are bacteria that take up space. They like the warm environment of our GI tract. They don’t necessarily do a lot of good work, but they don’t do bad work either. They kind of just live in cohabitation and they provide part of the occupying real estate in our gut, and we would say, “Good on them” for bringing social structure to our community of microbiota. And then there are the last ones that are the disruptors—we call those the parasites. They are very small in number, but they might have a fairly loud voice, so they could still do some mischief. As those number of parasitic bacteria increase at the expense of decreasing your friendly bacteria, then you kind of get more and more of these unfriendly voices being spoken, and you get the release of things like a bacterial lipopolysaccharides, cell wall debris from the bacteria that are proinflammatory. You get these funny transformed chemicals being released by them, and this produces a stress on the physiological system (on the immune system of the gut). All of this is interrelated to the diet and lifestyle of the individual, so it’s a very complex matrix. It’s a community. It’s an ecology that we’re talking about. You probably have heard that recently the genetics of these bacteria that live in our gut is starting to be analyzed—this is called the gut microbiome—using gene sequencing data, and it turns out that there is much more diversity of DNA present in our gut bacteria than there are in human eukaryotic DNA, so there are all sorts of messages that are being communicated in our gut from the gut microbiome that then influences our function. These are, I think, very, very interesting advances in our understanding of the complex role that food, gut function, and immune and neurologic interrelationships have on overall health and vitality. Now as it relates to that, we would then say, “Can we modulate, then, this environment in such a way as to promote a healthy balance of the symbionts, commensals, and parasitic bacteria, and change the personality and characteristics of our gut microflora so that it becomes friendly and supports health?” And the answer is yes, it does appear that these are modifiable factors. They can be changed through environmental circumstances like high sugar diets, high stress, alcohol, certain drugs and medications, certain types of dietary persuasions, lack of fiber in the diet—all of these things can influence the nature of the population of our microbiota in our gut and change the balance between the symbionts, the commensals, and the parasites. One of those big things that we all do commonly is that we consume food. We know that food is a factor that influences the speciation of our microbiota. If you eat a low fiber diet, you then do not have as many of the bacteria that are there that are fermenting fiber into these favorable secondary byproducts, like short-chain fatty acids, like butyric acid. So we know that certain dietary characteristics play an important role in establishing the GI environment and influencing the GI immune system.[2] Firmicutes and Bacteroidetes We know that there are two families of bacteria that have been studied quite extensively for their different personalities on this relationship to health. One are called the firmicutes, and the other are called the bacteroidetes. There’s an interesting balance between the two. When the firmicutes family of bacteria in our gut tends to become greater in prevalence, it is more associated with a tipping of the balance towards what we might call endotoxic effects within our GI tract, which are associated with such things as insulin resistance and type 2 diabetes, obesity, and dyslipidemia. When, however, we have a balance that’s more predominant with the bacteroidetes and lower in the firmicutes, then we have greater probability of insulin stability, and proper weight control, and proper lipid management.[3] This might seem to be a pretty remarkable change in our thinking that somehow our gut bacteria can influence weight gain, and can influence things like insulin signaling, and can influence the level of triglycerides and cholesterol and the packaging of them into lipoproteins within our blood. How in the world can that happen? That is the question of the hour. There are literally hundreds of studies now being published over the last few years in explicating this relationship. It’s still a work in progress. All of the evidence is not in. But it certainly is directionally important to recognize that, yes, gut microbiota does influence things like obesity, diabetes, and heart disease. We also know that because of the neurological connection to the gut that it can influence things like dementia through influence on the microglia of the brain and its function (the brain’s immune system), which is interconnected to the gut’s immune system. These are, again, examples of this network biology/systems biology emerging conceptualization where we can’t think of health and disease just one organ at a time—kind of siloed and isolated from any other organ. In fact, there’s probably no such thing as an independent disease that doesn’t have interrelationship with function of other organs. You Can’t Have a Sick Gut and a Healthy Body When we start examining the literature we say, “Well, gee whiz, that opens up for us a different way of interpreting papers like those that have the title ‘Nutrition Influence on Gut Microbiota and the Consequences for Gastrointestinal Health’.”[4] Because now we recognize that gastrointestinal health is associated with systemic health. And in fact, it might be so bold to say, “You can’t have a sick gut and a healthy body. They are interrelated.” This sounds like it goes back to Metchnikoff hypothesis in his book The Prolongation of Life. You’ll recall that Elie Metchnikoff won the Nobel Prize in medicine back at the turn of the last century for his discovery of cell-mediated immunity, and then later authored this book when he the director of the Pasteur Institute on the important role of Lactobaccillus vulgaricusyogurt for treatment of various types of health problems and prolongation of healthy life. So he was already speaking about the gut as the seat of good health or of disease back at the turn of the last century, and the recognition that various foods that contain both what we call prebiotics and probiotics can be helpful in establishing proper gut function. In fact, Dr. Marcel Roberfroid, who now is Professor Emeritus from Catholique Universite Louvain in Belgium, was one of the first people to coin the term called “symbiotics.” Symbiotics is the interrelationship between prebiotics and probiotics that work to establish a proper GI milieu of microbiological organisms, and that by the consumption of appropriate symbiotics (prebiotics and probiotics) you stimulate the appropriate activity of the GI microbiome, which then interrelates with the GI immune defense system in such a way as to promote favorable outcome. One might ask, “Well, what are symbiotics?” Symbiotics would be giving appropriate prebiotic selected food for the friendly bacteroides bacteria—things like fructans or arabinogalactans. These are prebiotic substances for which they form substrates for the friendly bacteroides. And then of course the addition of the probiotics, the friendly strains of bacteria that may have condition-specific activities on augmenting certain functions or supporting certain functions within the gut-associated or systemic immune system. One of the most principally important components of this has emerged to be that of maintenance of gastrointestinal mucosal integrity, because we now recognize that as you get a break down of the gastrointestinal mucosal barrier, you get what has been euphemistically called the Leaky Gut Syndrome. And it’s interesting to note that that term was first employed in Functional Medicine Update more than 20 years ago when it was considered, in traditional medicine, to be heretical to good thought; there was no such thing as “Leaky Gut Syndrome.” People almost made fun of that term in traditional gastroenterology. Now it’s very interesting in 2012 and 13 you’re starting to see article being published using the term “leaky gut” in the title of articles. It’s amazing how things can change with increasing information availability. What do we mean by “leaky gut”? We mean that the intercellular junctions that exist between gastrointestinal mucosal cells become impaired, losing their integrity, opening up then a portal of entry between those cells of larger substances. It could be larger molecular weight substances or even bacteria themselves that can translocate this juncture, and now can have access to the immune system that sits on the other side of the mucosal barrier and thereby activating the mucosal associated lymphoid tissue or the gastrointestinal associated lymphoid tissue so that it feels that foreigners are onboard and it needs to call out the guards. Metabolic Endotoxemia One of the ways that this is well known to occur has been titled metabolic endotoxemia, or post-prandial endotoxemia, meaning after-eating endotoxemia. This is a consequence of a diet that might be high in fat and sugar, maybe even a single meal, by the way, because these studies have been done in humans administering a single high fat high sugar meal to people and then examining gut mucosal integrity after the meal and finding post prandially that lo and behold that one meal tends to break down their intercellular junctions and makes their mucosa more leaky so that what happens is you start getting bacterial lipopolysaccharides, the cell wall debris from gram negative bacteria start swimming across (or leaking across) the gut mucosa into the access to the immune system, and these are proinflammatory mediators.[5] They activate the release of inflammatory cytokines like tumor necrosis factor alpha, interleukin-6, interleukin-1, which then stimulates the inflammatory cascade ultimately downstream releasing inflammatory prostanoids and leukotrienes. What we are starting to see is a very, very interesting supportable story emerging as it relates to how diet can adversely affect or positively affect gut mucosal integrity and ultimately either releasing, to systemic circulation, proinflammatory mediators that can actually be measured in the blood, by the way. There are many studies that have been published showing that these inflammatory mediators like lipopolysaccharides can be seen in the blood post prandially and are correlated with increasing systemic levels of cytokines, like TNFalpha and interleukin-1.[6] I think this is more than just theory and just conjecture. There are now very strong associations between diet, microbiological function of the gut, gut mucosal integrity, and ultimately leakage of these immune active molecules into systemic circulation that can induce action at a distance. The distance can be joint space problems that we call arthritis, or it could be liver inflammation that we call fatty liver infiltration, or it could be cardiometabolic effects at the endothelial cell that we call atherogenesis, or it could be influences that occur at the blood-brain barrier with the microglia that we call dementia. All of these, then, are mechanistically interrelated to this sequence of events of breakdown of gut mucosal integrity, release of toxic metabolites, and activation of the immune system. Intervention in Creating a Proper Microbiological Gut Community This opens the door, obviously, for intervention, so what do we intervene with? We intervene with agents that would reduce the burden of irritants that cause breakdown of gut mucosal integrity. We would intervene with friendly bacteria and prebiotics to develop symbiotics so we get the proper microbiological community in the gut, and we’d intervene with nutrients that are necessary for restoration of gut mucosal integrity, things like the amino acid l-glutamine, for instance, or l-arginine, or nutrients like zinc in a non-irritating form, or pantothenic acid, or essential fatty acids or the the omega-3 fatty acid family, all of which have been shown to help improve the integrity of the gut mucosal junctures. [7],[8] This, as translated through the lens of functional medicine, becomes part of what has been called the “multiple R” program—the Remove, Replace, Reinoculate, Repair type program—where you’re actually doing gut restoration through selective delivery of a different environment that nourishes both the friendly bacteria, establishes the right gut microbiota, and establishes proper gut mucosal integrity. Now, what we have learned recently as this work has proceeded is that there are certain substances in our diet that can really be serious irritants to gut mucosal integrity, and that these irritants can be individualized based upon the genetics of the person. The one that rises very tall in this list, obviously, is gluten and gluten-containing grains, where in people with specific genetic propensities or sensitivities this molecule which is found in food protein in grains can induce, through its partial breakdown into various what are called proteoic fragments, that these fragments can create an irritant effect on mucosal integrity leading to leaky gut and to inflammatory responses, not just local, alone, that we associate with things like celiac disease, but also systemic that we start seeing, like arthritis. So autoimmune disorders are identified with the etiology of these gluten immunological-mediated problems. We used to think that these only existed as a consequence of histologically identified injury to the mucosa that you could do and find under biopsy. But now we recognize that you can have biopsy negative sensitivity but have systemic sensitivity to these food proteins. So this wouldn’t be a typical sprue-like patient (a typical celiac patient). This would be a patient that has gluten-related sensitivities—intolerance, might be the better word—for which they fall outside the bounds of what we would call a classic celiac patient. The links, then, between these dietary principles and leaky gut syndrome is becoming much more well understood, and we recognize that gluten is not the only family of potential GI irritants, that based on different individuals’ genetics that there may be many different families of irritants that are not allergic substances but hypersensitizing substances that also contribute to the depreciated integrity of the gastrointestinal mucosa. We also recognize that as food becomes more highly processed and you heat treat food in processing where you have sugars and protein together and therefore you get this chemical connection between sugar and protein that we call glycosylation, that these glycosylated proteins that we eat in foods, particularly in highly foods, can also become irritants to the GI mucosal system and activate the immune system. So, overprocessing of foods and the production by the heat processing of these secondary glycoproteins that cause immunological reactions can also induce these difficulties. You probably recall that these glycoproteins activate what are called the receptors for advanced glycosylation end products. That’s R-A-G-E: receptors for advanced glycosylation end products. So we might say that these food materials en-RAGE the gut immune system, right? They bind to these receptors and they activate this inflammatory cascade, so I just used, euphemistically, the term they en-RAGE them—they cause amplification of the inflammatory response. What this really says to a clinician is if a patient has systemic inflammatory conditions or local GI inflammation they need to be very cognizant that multiple offenders could be involved in activating this system, causing gastrointestinal permeability to occur and enhancing mucosal immune function in producing systemic inflammatory mediators. Therefore it’s a little bit of a trial and error empirical approach that’s why elimination diets can be so helpful, why gastrointestinal restoration approaches can be so helpful. It may require a very rigorous and aggressive intervention to try to determine exactly what the offending foods and substances are that are intimated in this breakdown of gut mucosal integrity. It’s not just one-size-fits all. It’s not just one agent. Obviously gluten is getting a lot of press recently, but it’s not the only family of substances within foods that can cause this difficulty. Certainly we know that dysbiosis itself, unfriendly bacteria, can induce this difficulty producing post-prandial metabolic endotoxemia as well. So our colonic flora, probiotics, obesity, diabetes, cardiovascular disease, dementia—it has a tremendously rich influence across a wide range of clinical effect and that’s why many people say when you’ve got a chronically ill patient, start with the gut first. Look at their digestive function. Look at their diet. Look at their microflora. Try to understand whether that may be a principal seat for some of these difficulties. With that in mind, I think this is a good context to move to this extraordinary discussion we’ve had with Dr. Patrick Hanaway, who, as you know, was the Medical Director for Genova Diagnostic Labs for a number of years. He’s an extraordinary family doc, wide-ranging in his skills and background, and most recently—I’m very excited to say—has taken on a new role, a very important role, as Director of Medical Education for the Institute for Functional Medicine. Dr. Hanaway is kind of almost the archetype of the type of person you would want in charge of education under the Institute for Functional Medicine banner. He’s a lifelong learner. He’s a person who is working very, very hard, always, to know more, to take this news and make it news-to-use in the clinical arena. He’s an articulate communicator. He’s a passionate doctor who is an advocate for his patients. And I think, above all, he is a person who is conscious and present always for the best intention of his work for setting up a healing environment. As you probably recognize, Dr. Hanaway takes on a big responsibility as the new Director of Education for the Institute for Functional Medicine. We might say they are big shoes to fill, but I think he has the capability of not only filling those shoes but growing the impact globally of the functional medicine model as he steps into this new role. The discussion I’m having with him you’ll notice is done live at the recent Annual International Conference of the Institute for Functional Medicine. It was, for me, a very intimate conversation, a very warm and extraordinary example of the deep humanist that is present in those people who are within the Institute for Functional Medicine community, what I call a very special tribe of individuals dedicated to patient management. So with that in mind, let’s move to our very, very interesting discussion with Dr. Patrick Hanaway.

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INTERVIEW TRANSCRIPT

Clinician of the Month Patrick Hanaway, MD Director of Medical Education The Institute for Functional Medicine 505 S. 336th Street, Suite 500 Federal Way, WA 98003 www.functionalmedicine.org You know, we’re very privileged to have with the Institute for Functional Medicine Movement, some extraordinary spirits, souls, intellects—dedicated people, courageous, tireless workers. There are so many attributes and adjectives I could use that characterize the energy that goes into this institution that it would be hard to pick out one feature set of characteristics that defines those that are meritorious in the organization. But, with that said, I’m very pleased that we are going to be talking with one of those people who has those characteristics that define why IFM has grown up over the last 20-plus years to be an agent of change of great significance, and that’s Dr. Patrick Hanaway. Patrick, thanks so much for being here. Dr. Hanaway and I go back a few years. I’m not going to disclose how many because it would once again contribute to my aging process, but let’s suffice it to say I first met him and his wife in Asheville, North Carolina, where we shared the same dinner establishment. I got introduced to him as the most esteemed family doc in Asheville, North Carolina, and I’ve come to recognize that that was an understatement of Patrick’s skill, and also his wife who is a physician. Patrick, your depth of your vision as to how medicine travels is built on your experiences both as a child growing up in obviously a very, very interesting family with interesting mentoring and role modeling, and then secondly with your experiences that you chose as to how to use your medical training and some of the after-medical-school experiences. Maybe you could just tell us a little bit about that journey because it’s very much part of your texture. PH: Well, if we’re going to go back to the beginning on that, my dad was a lawyer, my mom was a nurse, and I knew by the time I was five years old that I wanted to be a doctor. I had the microscope and the little microscopic man for Christmas gifts, and that was all I ever planned on being. When I went to college at the University of Wisconsin and studied biochemistry and molecular biology it was all planning to go to medical school, and frankly it wasn’t until I got accepted to medical school and took some time off when I was 21 and I thought, “Is this what I want to do? I don’t even know if that’s what I want to do.” I had a chance to travel and was very interested in public policy and health policy, and I considered and made application to not go to med school but to go to public policy school. Then something happened and I said, “No, I want to help people.” I grew up in a political family and I kind of was like, “I’m not really sure that politics is going to be all that helpful.” So I went to med school at Washington University—and I think you’ve heard me say this—but when I started medical school I thought it was going to be about how to help people, and how to learn how to care, how to promote health and well-being. It was sort of surprising to me that it wasn’t. It was all about pathology, and memorization, and we started a nutrition course in our medical school that first year. We asked the Dean for $400 and he gave it to us, and he thought we would go have the RDs teach us about nitrogen balance. We talked about many different things. We spent the money to go buy fresh fruits and vegetables to give free to the medical students so they’d come to our lectures and they came because there was free food and it wasn’t donuts and they still came. We had Nathan Pritikin come. That was 1983, and Washington University was not exactly a place for Nathan Pritikin at that point in time (low fat diet). You know, I was working in the Lipid Research Center, adamant that cholesterol was the worst thing that could ever happen in the body and that we should have a cholesterol of 100 plus your age and went through all that. Of course, got depressed. Imagine that, with that low of a cholesterol. My cholesterol was 102 (total cholesterol, I’m talking). And, you know, I learned and went through the training and decided that the best way to be of value was to be a family doc. I went through medical school, I studied traditional Chinese medicine, I learned acupuncture for a couple hundred hours, I learned chiropractic, I learned nutrition, I learned the things that I wasn’t getting in medical school that helped me to think more broadly, and I think that there are not very many people who choose to go through medical school and say, “This is one aspect.” A quick, brief story. Jeff Gordon. You know who Jeff Gordon is. JB: Yes. PH: Jeff Gordon taught our pathology class our second year, and I’d been studying that summer Hans Selye, and understanding this and traditional Chinese medicine, and we started off the first day of class, 8 o’clock in the morning, first day of the second year of medical school, pathology, and he starts off and he says, “Well, you know there are many different views of health and disease, and we can look at it from a model of Chinese medicine, or Ayurvedic medicine, or stress models of Selye. We’re going to look at the model of pathology and that’s what we’re going to focus on here. It’s just one of many models.” That was like the big liberation. It’s like, “Oh, okay. I can learn this model well, but it’s not the whole thing.” And all my life, since medical school, it’s like, “I’m interested in the whole thing. I’m interested in, how do the pieces fit together?” And that’s what I’ve done, so my career—learning each additional aspect—is, how do the pieces of the puzzle fit together? Really, that’s what functional medicine is: how do the pieces of the puzzle fit together? This is the first and only operating system that I’ve seen that allows us to put those pieces of the puzzle together. So I give thanks—homage—to you and David for the work that you’ve done to help build this and bring it together. And it’s evolving. It’s deepening. It’s not even so much like evolving; it’s more like the depth is being mined as we move through the process of applying it. JB: So let me just throw out a couple of words and do a Rorshach test. Soldatna, Bethel, King salmon. Tell us a little bit about how those words relate to your experiential inventory. Building a Foundation for a Medical Career Focused on Communities PH: I did my residency training, and studied herbology with Tieraona Low Dog during residency, before she went to medical school, and learned that, and then worked for the Albuquerque Indian Hospital and took care of the native people, the Jemez and Isleta pueblos, but I was very fortunate because there were 15 doctors there, all who had on average 15 years of experience of working in the bush, and I was the only young pup. And they learned some things from me. I didn’t imagine that I could teach them anything, but they thought I could, so I taught them some new techniques, and they taught me how to care for people and they kept saying, “You need to go to the bush because that’s where this comes in. You need to go to the bush.” We looked around, and it was a sort of fateful series of circumstances where, there we were, on a plane to Bethel, Alaska, or I should say four planes to Bethel, Alaska, which is 500 miles west of Anchorage on the Bering Sea. There was an article in the New York Times just on Sunday about the doctors in Bethel, and we took care of 28,000 people in an area as big as Oregon (10 doctors). I did that for two years and I learned really the value of western medicine, deeply. And I learned to trust my ability to think through a problem and work to solve it in a pretty stressful setting. JB: So that was like double-time, emergency room, do-everything, be the Jack of all trades and maybe the master of none. My roommate in college was one of my best friends in high school, and he and I went on, ultimately, to medical school together. He went to USC; I went on to UCLA, then ultimately to Oregon. He, after he got out of USC, went into the Bureau of Indian Affairs to become a public health service physician on the Navajo reservation with another one of his friends. They were going to give him a car, and he said, “No, I really can’t develop the relationship by driving in in a four-wheel-drive; I’ve got to go by horseback. So they gave him a horse. He would do go by foot and by horseback on trips out to the various villages. And he was very aghast at the way that the Native American was being treated as it relates to not just medicine but culturally. He and his partner both railed very heavily against what was going on in these pretty strained circumstances. You know, very, very high stress. They were able to get some policies pushed through the government that changed the way that medicine was delivered to Native Americans on the reservation. Right after this bill was passed, which he had worked for for three years (his kind of part-time job was this advocacy), his partner, who was his partner in advocacy and also in medicine (traveling around on horseback) committed suicide. It was such an unbelievable stressor that he ended up wanting to get as far away that he could, so he ended up going to Maui to the Kula Hospital on the side of Haleakala. It was, I guess, a hospital that was in kind of catastrophe. They were having a lot of ethnic problems because of the cultural diversity and so he came to the conclusion very quickly that the only way that he was going to be able to do anything there was to learn how to heal through food, because they all had their own way of cuisine. So he took some of the grounds of the hospital and made them into gardens, so there was a Korean garden, a Japanese garden, a traditional Hawaiian garden, and a Chinese garden. And then the people from the community that were of those ethnic origins would then raise those products that were used in the hospital cafeteria and then they had to learn how to prepare meals together. It actually transformed not only the hospital but the whole community, and then that led into dancing, and all sorts or other cultural things where people mixed together, and then he taught himself Chinese and Japanese during that period because he felt that he had to really communicate with the group in their native languages. So that ultimately got him to be recognized by Governor Waihee that he was a pretty interesting guy, although he was a Howli (Caucasian), that he was pretty interesting in the way that he was embracing cultural diversity. So he got appointed to be the Secretary of Health for the State of Hawaii. And then he ran later, when Waihee was retiring, for governor of the state of Hawaii around this whole concept of health as his principal platform. He lost by 325 votes, the governorship, only to end up in California as the president of the California Medical Association, where he tried to do the same thing in California unsuccessfully. But I think his path of enlightenment was one that reflects that there are certain people like you and your wife that somehow seek a road less traveled, and it’s always been a question to me as to what are those things? It’s not just intelligence. There is something else that is going on that motivates a person to take the road less traveled, and what is not only more complicated, but maybe also not as favored if you’re thinking about, “Oh, where is my next appointment going to be, and how do I get the proper kind of pedigree?” What was it in your life that you think kind of defined that you would take this road less traveled? New Role at the Institute for Functional Medicine PH: It’s about helping people, and it’s about finding out where the suffering is, and seeing that. I, in my life, have been so blessed, and I view that as a gift that I’ve been given, but also a duty that I have to be able to offer those gifts for the benefit of other people. That’s what my life is about. So, when we go to look at where there is need, that’s a driving force, to be able to apply it. And for me, thinking that medicine would be the way to help the suffering and then realizing, “Oh, this particular paradigm doesn’t actually help to relieve suffering a whole lot.” It suppresses symptoms, which has its value. When people are extremely sick, the antibiotics in the acute care, or the emergency room, or the hospital room—they’re important. But that’s not where the bulk of suffering is happening right now. So how do we do that? How do we take care of that? I think that’s always been a driving force, so there are many different roads to consider in the conversation. I was working with a project through the medical student association on health promotion and disease prevention in a federally funded health center in inner-city St. Louis (in North St. Louis). Lisa was working in a project doing reproductive health work with a migrant clinic in the Skagit Valley. The two of us were asked to communicate about that to the federal government and to the National Association of Community Health Centers. That’s how we met. So that’s always been important. So today, when Oscar from Peru comes up and says, “Hey, I’m a family doc here, and I want to understand how to apply functional medicine in federally qualified health centers and be able to help people of need, I’m like ‘Yeah, that’s where the opportunity is’.” These tools work, and they have been promoted or pejoratively cast aside as being an elite or a creaming-the-crop kind of approach to taking care of the worried well. And it’s not the worried well who are coming into my office. People have a lot of suffering and they haven’t received benefit from the healthcare system. And that has the opportunity to be applied much more broadly, and I feel like it works in any setting. And we see it. People will sometimes say, “What’s this thing about why functional medicine?” And I say, “You know, there’s really only one reason: It works. It’s helping people.” And that’s what brought me here. You told me you’d take me to this spot. That’s it is and that’s what the vision is. It’s like how do we standardize this and create it in a reproducible way so that it can move across and that the teachers…everyone’s on the same page? We’re all very close, but let’s work to create some clear standards so that it can be leveraged, and what we’ve taught to 1200 people here can be taught to 12,000 doctors two years from now, and 120,000 doctors twelve years from now. It’s totally doable. JB: So you’ve walked the talk, or put your money where your mouth is by changing your life significantly from a family practice doc of great repute to a medical director of a diagnostic laboratory that’s involved with support of functional approaches to health care, to now becoming the Director of Medical Education for the Institute for Functional Medicine. These are kind of sweeping changes, maybe, in how people would see their professional life, and maybe even consider it three career changes. And you’ve done it by maintaining what I would call a very high level of scholarship. Maybe, to be a little bit cute about it, “eggheadedness,” as you’ve approached this heart-felt need to help people. In those kind of major career transitions, what was your moral compass that led you to make these changes, because you could have been very comfortable just staying a well-esteemed family doc. PH: I’m going to touch on the eggheadedness first because I find that within western medicine the science is the coin of the realm, and that it’s important to be able to meet a high standard. One of the things in my medical training at Washington University is they taught us to be critical, to learn how to read a paper and understand what it is. Now, I saw both sides of that equation where a favorite paper I remember reading was this paper on looking at—this was 1983—trans fats and their effect on lipoprotein lipase and HMG-coA-reductase. I’m reading this paper, and we’re having our journal club on it, and I’m talking to Oliver Lowry of Lowry assay. This guy is like one of the most referenced authors ever, and I said, “You know, what’s fascinating about this is these guys are from the Hormel Institute and this is SPAM they’re talking about, and SPAM has this effect on lipid metabolism.” And he said, “Well, you can’t take it that far.” And I said, “Look, it’s in the methods.” I’m going, “This is what’s happening.” It was kind of like he argued with me, but then he’s like, “Okay, it is right there in the methods section.” It’s like learning how to use science in a way that’s teaching us. You know, in business we have agreements upon which we work so that we can do business together. In science, we have agreements upon looking at data so that we can have a conversation about it. There can be different interpretations of it, but we have a language. That’s important. So the eggheadedness comes from there. Now in terms of the moral compass, it’s almost like there’s nothing else to do, that each of these decisions have that have occurred…you know, I looked at being in practice and I actually went into what some might call a vision quest when I was looking at a change, considering a change in direction. I came away and there was no question. It was like, “Oh, this is the path to follow.” Because I had set a clear intention that what I wanted to do was help be—as you said—an agent of change to transform medicine. That’s what I’ve been interested in since I was in medical school, and I feel, again, just incredibly blessed that I get that opportunity. It’s like, “Wow, it’s happening in my life.” And so as it came time to know that I was done working for this diagnostic laboratory, it had been 10 years, it had been successful, everything that I worked to do had worked out well, and quite frankly I had problems with being seen in the business setting as being someone who was just trying to promote a business or a product. Anyone who knew me knew that wasn’t the case. In fact, they often would say, “Actually you kind of go over backwards to not do that.” Because integrity is important, but it was time to change. So I stepped away, creating space purposely in doing that, and the opportunity here with IFM just seemed to be perfectly aligned with what my life interests are, which is about the transformation of medicine. It says that on one of the posters somewhere. So at a time where the inflection point for change has taken off, again, what a great opportunity. JB: So, carpe diem, you’ve obviously done that in your life, you’ve made decisions that would be considered major decisions very decisively, you and your wife have supported those and made a transition successfully, and now you stand at a threshold with the IFM or the functional medicine model development in which it has probably passed through the first two stages of an evolving concept. Stage one is: Is there anyone more than the founders that would be interested in it? So that’s stage one, because generally, you know, there might be five people in the family that think that the idea of a founder is interesting and then it falls off the edge and dissolves into the universe. So we passed first level a few years ago. Now it has passed the second level. The second level is: Gee whiz, it’s recruited people from a broad array of different backgrounds who have credentialed expertise in areas of medicine and have demonstrated their capability of implementing those concepts that they learned successfully in their own practice with their patients, and now those people are becoming affiliated as, let’s call it, early-adopters but not first-level adopters, so we start to get a little bit more stickiness to the concept, so that’s like the next level of “we will survive as a concept” phase. And then it’s the next phase, which is where you get into the potential knee of the hockey stick, where it really starts to have a a replicative action across people that may not have even considered it at all until they heard it in a different way and suddenly they became an affiliate. So in this particular phase, one of the dominant themes that we’ve heard time and time again is, “Well, this is a really great model, this functional medicine model. It really seems to address issues in the ways that are consistent with why I went to medical school to begin with.” And then we have a “but.” And we never put a “but” in the sentence and that means that everything after the “but” is probably the most important thing, which is “How do I make a living doing this?” How do I actually make this work within the scope of seeing 35 to 50 patients a day in managed care, and the reimbursement coding, and the oversight of uninvited guests in the exam room called the insurance company and Medicare? So this is going to be your challenge. Are you having any thoughts about how you’re going to approach those questions? From Learning about Functional Medicine to Experiencing Results PH: Yes, certainly. To me, the answer is simple; the execution to get there will be what it’s all about. And that ends up, from my perspective, focusing on outcomes, and doing the systems-based research, and having the codification that allows us to be able to demonstrate what we who are using it know to be true. You know what it’s like to be in practice and using these tools. You may recall when I first met you I was of the questions, “Well, you’re talking about all these complex things that I don’t understand. I don’t think I’m stupid, but I’m not following this. It’s way too complex. How do I do this in practice?” I got taught how to use that, and lo and behold it worked. But I have to say, in those days I thought that a large part of the reason why it worked was because I was special or different. I had the right stuff to do it. And what it meant when I went out and started teaching it, and people would say, “I applied what you said and I have my son back, or my father is now healed, or these patients, it worked,” I sort of honestly looked like, “Really? It’s not just me? There’s value in this?” And I found that, and I find that over and over again, and we’re finding it here. As I said earlier, it works. So I have no doubt that as we do the systems-based research that focuses on outcomes, which is what? The stages of the Affordable Care Act and working towards accountable care organizations, and the development is going to be focusing on. Reimbursement will be based upon outcome and effect, and so we’ve got two or three legs up on everybody else because we continue to hear from everyone who comes through the training and does it and applies what we’ve been talking about that it works. And I think that our hit rate on being able to simplify it enough to bring people along as David Jones has said “to help to make that on ramp easier.” We find that what we’re talking about now in relationship to nutrition as a single common avenue that people can jump on that onramp and be able to get on to it and see, “Oh, nutrition isn’t about nutrition for IBD, or IBS, or asthma. Nutrition is for health, and that we have changed the overall structure of what’s going on.” And we use that and apply that in clinical practice, it’s going to work. So now it’s our job twofold: 1) to codify and ease the training so that people can clearly see the path and they can move to a place where they are applying it in practice; and the other is to be able to do the systems-based outcomes research, and it sounds like it’s a couple of simple words, but it’s such a different paradigm that understanding how to set up systems to be able to do that, it’s going to be three five years, but I think that in three to five years we’ll have the outcomes data that is there that will lay the framework. We wanted to do this three or four years ago, but we weren’t mature enough as an organization and a set of practitioners to be able to all be on the same page to do it. We are there now. So those are the steps that are going to help, and I think, frankly, working with various individuals of what are business models that work? There are several different kinds of approaches, and frankly, I think that there’s value across a lot of different models, but I see subscription models (even low-income subscription models) where someone is paying $75 bucks a month to be able to get rudimentary care from a functional medicine model. That, if I’m a doc and I’ve got a thousand patients and they are paying $75 bucks a month, that’s nine hundred thousand dollars right there. Then I’m taken care of. I’ve pretty much got my practice covered, and I should be able to do this for that. Seventy-five bucks a month is a cup of coffee a day. Do you care enough about your health? So I think there’s ways to be able to do this and we’ll need to investigate those, but my primary focus is on simplifying the onramp relative to teaching and working to develop a structure to allow for outcomes-based research. JB: That’s really beautiful and I totally agree with your assessment. So let me ask one last question, which I learned this from a very sage gentlemen that had traveled through three different careers and had been successful in three entirely different fields of activity, the last one which was medicine, actually. I was asking him what characteristics that he felt would define an area that had really great opportunities for providing social good, for providing a livelihood, and for being something that would be considered high social value? In other words, a place you’d want to put your life, because we know we can work, but work which occupies a lot of our life should also be a fulfilling part of our social enterprise. And he said, “Well, it’s very simple. There’s one rule that he’s learned, and that is it would have to be something that fulfilled the litmus test of encouraging your own children to go into it. If you can’t be confident enough that you would want your children to go into it, it’s probably not something you should be involved in as an individual.” And right now in medicine I hear from so many docs saying, “I wouldn’t want my children to go into medicine.” Just like I wouldn’t want them to go into investment banking—you know, you hear that too for other reasons. Give me your litmus test. How do you look at medicine and the future? As your boys come to you, what would you say about the future? PH: It’s a great and timely question. My younger son is starting college. We had an entire conversation from a family trip we did last weekend about intermittent fasting, glycogenolysis, and how to be able to optimize energy output. He’s 18 and he’s a high-level athlete who plans to continue to do that collegiately, and he cares about his body and he had looked at business, and sports medicine, and being an agent, and doing this kind of thing. We’ve been having the conversation recently like, “You know, doing sports medicine, and working with athletes, and working to help optimize health and well-being as I’m trying to do would be great. What do you think about that?” “That’s perfect. That’s a great synthesis of what you know and who you are.” He cares and this is what he’s watched us do, and the fact that he’s been able to see us finding joy. We work hard. We take care of many different people, but we love what we do. So, that’s a great litmus test. And for me, the other litmus test that is fundamentally important for me is about service. Being of service to other people. That is what brings me joy in my life. It makes me feel that there is incredible worth in doing that. JB: I have to say having had the privilege of knowing you now for the better part of going on two decades that you radiate service. You embody service. You don’t even need to say the word; it comes across, it’s on your countenance, it’s part of your aura, your energy, it’s authentic it’s deep, it’s behind the screen—if you look behind the screen you see more than you see up front. That’s what really establishes the authenticity of any field, is there’s a core group of people who, when you dig deep below the surface, what you find no matter what level that you want to engage, no matter what stress that person’s under, that you’ll find that that core principle—whatever that principle is—is all the way through to the roots, and it is in you. And I think the future of the Institute for Functional Medicine and its educational curriculum, and its heuristics, and epistemology is in tremendously good hands with Patrick Hanaway. It’s really a privilege to know you and have a chance to watch how your energy, and wisdom, and experience, and knowledge permeates into the evolution of this model. Thanks. PH: Thank you. And, as you know, Newton said, “We can see farther because we stand on the shoulders of giants,” so thank you for bringing us along on that journey as the initial pioneer and scout. JB: Thank you.

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Welcome to Functional Medicine Update for August 2013. You’re in for a treat this month with our Clinician of the Month. I know I say that every month, but you haven’t been disappointed and you certainly won’t be this month either. Well as you know, historically Functional Medicine Update has breathed its life from that of its core contributors. We call them clinicians and researchers of the month, and I would say as I review the last 31 years, the individuals who have made contribution to the texture and tapestry of Functional Medicine Update have really chronicled the evolution of this emerging 21st century medical discipline, which seems to be catching and getting tracking. We recently had the 22nd International Conference for the Institute for Functional Medicine and much to our surprise—and pleasure, I would have to say—there were over 1200 practitioners there, in excess of, I think, 800 medical doctors from 30-plus countries around the world. It’s not too long ago that we were able to meet in a phone booth and still have room for other people to get in, so it’s quite amazing to watch the change, and the change is occurring on the shoulders of many pioneers who have really paved the way and helped to understand how this form of health care can actually deliver better outcome or cost-effective service levels, and one of those major contributors (for me, a great pleasure) is our Clinician of the Month, Dr. Woodson Merrell.

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INTERVIEW TRANSCRIPT

Clinician of the Month Woodson Merrell, MD Executive Director, The Continuum Center for Health & Healing Chair, Department of Integrative Medicine Beth Israel Medical Center 245 Fifth Avenue New York, NY 10016 www.healthandhealingny.org I have had the privilege of knowing Woody now for the better part of 30 years (certainly 25-plus years). His work has just been, I think, extraordinary as a clinician, as an innovator, as a conceptualizer, and as a person who has done something that many might consider the impossible and that is to put together a commercially successful center in the heart of Manhattan in New York City, the Continuum Center for Health and Healing, which is part of the Beth Israel Medical Center Outreach Program. I’ve had the privilege of watching it evolve over the years, now expanding to a whole additional floor in the facility, over 13,000 square feet with multiple practitioners. You might say, “Well this was just plunked down into the world easily and fully formed and fully matured,” but we know that’s not the case. It came as an evolving process, going back to Dr. Merrell’s conceptualization as to what he wanted to be as a doctor. So it’s a great pleasure to have you, Woody, as our Functional Medicine Update Clinician of the Month, professionally, personally, and vision-questing, to have your voice and your experience to be shared with our listeners. Welcome to Functional Medicine Update. WM: Oh, it’s exciting to be on. Thanks for having me. I feel honored and I look forward to our conversation today. JB: Maybe a great place to start is that juncture in your career, after completing your medical training. We all stand as kind of early novitiates saying, “Okay, where am I going to go? What’s my path going to be? And gee whiz, I’ve fulfilled certain hurdles of accreditation and licensure and credentialing, now where am I going to take it?” Take us back to that time and kind of help us understand your transition as you’ve moved through this process. Looking for East Meets West, and Finding No Common Ground WM: Mine was interesting. I actually was fortunate. I was raised very holistically. My parents were, in the era of the 50s when they’ve got the vegetable man, and the produce man, and the milkman, and the bread man coming to the home with incredibly fresh products, and a grandfather in the Sierra Club, so amazingly I was raised with homeopathy as a kid. So early on I saw the connection between a really healthy lifestyle as well as some gentle remedies that were outside the realm of conventional medicine. In the late 60s when I was in college I actually very much was interested in the practices of yoga and meditation, even being a real science jock at the time. I actually went to medical school really not to be a physician but actually to see if I could marry what were considered at the time metaphysical practices, or the Asian disciplines, with western science. I quickly found out that there was really—at that time, in the early 70s—no east-meets-west. There were a few pioneering studies by Herb Benson on the relaxation response and that was basically it. So for the rest of medical school I pretty much poured myself into medicine and my residency, learning all I could about conventional medicine. I realized at the end of my training that I had put my original quest on hold, and when I got out into practice found that most of the information I had garnered wasn’t helpful in a general practice where you are actually seeing people who are in, what I call, the gray area—they aren’t sick, but they aren’t well, and many of them are desperately working on getting sick (kind of the “worried well”), and I needed new tools. They didn’t have these incredibly esoteric diseases that I was so well trained to treat at Columbia in my residency medicine. Acupuncture Paved the Way to Balancing Science with Medical Training: The Research of JS Han So I began, really, as a scientist looking for what evidence base existed at that point. It was amazing. One of my first “ah-ha” moments was I went to a lecture in New York by JS Han, who was the Chairman of the Department of Physiology at Beijing Medical School. It was founded by Rockefeller in the early 20th century, and even during the depths of the cultural revolution it was still allowed to train doctors using Harrison’s Textbook of Internal Medicine. JS Han came, and I figured out at that point that acupuncture was, you know, basically kind of metaphysical five elements, yin/yang. JS Han had done hundreds of research studies of core basic science.[1],[2],[3] He literally mapped out every neurotransmitter known to find out how it was affected by acupuncture, and this was exactly what I was looking for: the science, evidenced-based conjuncture of western and eastern so-called practices at the time. So I threw myself into acupuncture training, and realized that there were a number of other places to go for training. There weren’t very many in the 1980s, believe me. I ended up going to a small town north of Montreal to take a course on homeopathy and herbal medicine from George Lewis. Really it was a smattering of trainings that existed back in the late 80s to really help me become knowledgeable in all the different modalities that one could use as an integrative physician. By the late 1980s, I would say I was fairly well trained in most of the integrative modalities: hypnosis, biofeedback, acupuncture, homeopathy, herbs, and understanding the place of that within conventional medicine. I have to say that it was just about that time, around 1990, when I came to my first lecture that you gave, Jeff, when you used to go around the nation doing one-day talks. That was another major “ah-ha” moment that showed me that there was an unbelievable scientific base to the practice of medicine, and most of the things we spend learning in the first year of medical school had been thrown out the window—the arachidonic acid cascade, the Krebs cycle, the things we learned (and hated), the things we learned and memorized and that’s the last we ever thought of it in our career. And all the information of an entire day-and-a-half lecture on the synthesis of vitamins, which was our entire nutritional counseling, suddenly putting into dead center, and understanding so much better at a profound, deeper level how the body works with the principles of functional medicine, I’d say by the early 90s I felt that really filled in the final piece, and I think the great thing is now we’ll talk about maybe a little bit more in depth how doctors can start with functional medicine, which really should be a foundational learning experience that really students should have as the way to guide them through understanding how the body works physiologically and biochemically, really the first year of medical school. JB: I’ve never had the opportunity or the privilege, actually, to thank you, and I want to take this moment both between the two of us and publicly to the Functional Medicine Update audience, to thank you as one of the original Board members of the Institute for Functional Medicine. You know, we started with humble beginnings like all organizations do, and we were very, very fortunate to have people like yourself guiding our thought as to how we were going to evolve this model, and I think it’s quite amazing to see what happens when you get good people that are very thoughtful, and conscious, and committed to their ideas, and willing to share and cooperate, what can happen. It started, actually, with a very small group of people, of which you were a core person, so thank you very, very much for all your contributions, both in the inception of the idea and how we constructed the organization, and how it’s evolved with leaders such as yourself at the helm. For the listeners who are new to the field, you would be considered actually one of our very important pioneering leaders in construction of the model. The interesting thing that I see in this field, which you reflect beautifully, is that when you get pulled into this field it’s a little bit like having a virus that you can’t get out of your nervous system that infects you, and it infects the whole family. I’ve had the privilege of meeting your wife, Kathleen, and I know the two of you co-authored a really great book called Power Up: Unleash Your Natural Energy and Revitalize Your Health.[4] Tell us a little bit about how this journey you’ve been on has affected your relationship, your family, how you see yourself in the world, how the world sees you, how your peers see you. This is all part of what we wear as we travel through life, other than just our initials at the end of our name. From Disbeliever to Skeptic to Someone who is Intrigued: Integrative Medicine is a Process for Many Doctors WM: Well, I feel fortunate, again, that I was raised in a very healthy environment, which was really what you are doing with your Preventive Lifestyle Medicine Institute. We were raised with a preventive lifestyle. It’s just a natural thing, what we did: eating healthy, exercising, trying to handle stress properly, getting enough rest—all these key factors, the fundamentals of health, is something I’ve tried to inculcate in my kids, who—God bless them—even love broccoli as teens. And I think they may go in and out of healthy practices, but I think they know. I even taught a meditation class for one of my kids when they were in kindergarten. I feel very fortunate to have a wife who is also very like-minded, as do you, who has been a really incredible life partner, so I think the inner-family journey has been amazing. Our friends and other members of the family who may not be into this eventually will call with some health challenge and see if there is anything that I know about that could be helpful to them, and often—as so often happens in medicine—there is, because these gentler remedies are sometimes quite powerful as adjuncts, or even sometimes instead of, some of the other conventional remedies that may or may not be efficacious. So I think in terms of the family it has been a tradition that I feel blessed to have inherited—being able to transmit to my family. It’s a little harder to do institutionally with my colleagues. I remember going to a meeting back in 1989 or 1990. I was doing a preceptorship with medical students at Columbia every year, and I went with a preceptor leader, Dr. Garvey, and I remember one year, after doing it for 2 or 3 years, I decided to broach the subject. Even with acupuncture, I was in the closet at that time. She asked how I was doing, what I was up to. Nobody knew that I was doing all these other modalities. I didn’t really advertise it because at the time the Quackbusters—the National Council Against Health Fraud—were actually quite active. I felt a little protected because I was in a teaching position at a medical school, but they were really going after people. It’s like the IRS; once you get on their radar screen it’s brutal. You know, you become bankrupt just with legal fees. We were all a little bit anxious about hanging up the shingle that was saying we were doing all these—at the time—alternative practices. One day I mentioned to her in our prep session that, “Glenda, I’m actually doing acupuncture.” She froze. I mean, literally froze. She wanted to shake it off like she actually hadn’t heard me say those words, and then quickly moved on to what we were going to be doing with the medicine that I was supposed to be teaching the medical students. In the course of a year, the next year I went back and she actually asked me how the acupuncture was going voluntarily, without being mortified, and then the third year she said to me, “You know, I was a little bit (very) skeptical a couple of years ago, but the more I’ve read about acupuncture, it sounds pretty interesting. I think I may actually try it for my back pain.” And that kind of shows you, in the span of two years, how it went from disbeliever to skeptic to someone who is intrigued to actually someone who comes to become a bit knowledgeable and then almost embracing of it. That kind of parallels what’s been happening in the field of integrative medicine as it began being seen as often practiced by renegades without significant evidence bases to the point now where it’s become most of the practices, even energy medicine, considered if not mainstream, something that is no longer thought of as quackery but as something that might possibly be at the very least an adjunct to conventional practice. And I think the evolution of functional medicine that you thought up and developed brilliantly—I mean, genius visionary, talk about something visionary in the 80s that had this groundswell that began slowly but now is at the point where it is really exploding amazingly with doctors realizing how important it is to have this knowledge base that they didn’t acquire in medical school that they really need to know so that they can actually help so many of the patients for whom conventional medicine falls a little bit short, particular for chronic diseases and prevention. Science: Intellectual Permission to Try Different Approaches JB: You know, I’ve had the privilege of meeting a number of your colleagues and friends that you’ve brought into the field who have impeccable academic medical credentials and are top of the line specialty practitioners. I think—as my mother used to say—birds of a feather flock together. You’ve really pulled in, through your example of excellence and rigor, an amazing group of individuals that you’ve infected with this irreversible virus, who are maybe not doing all this in their practice, but they are pretty supportive, and pretty interested, and willing to venture a little bit out of the lines now to try things because they’ve gotten some intellectual permission based upon the recognition that there is some science underlying this that gives them some confidence they can do it without getting into trouble. I think this is how movements grow and you’ve certainly done a wonderful job of introducing all sorts of people very non-confrontationally. That’s something I’ve observed in your style which might be a watchword to a lot of individuals. You’ve got some political savvy as to how you communicate with your colleagues and how you interrelate so that you don’t look inflexible. You take it to the level of the receptivity, the readiness to change model, I think, and you’ve done a very nice job in that. WM: Well, the non-confrontational aspect I think is huge. I think early on that 30 years ago a lot of the docs who were doing this kind of work were outside the mainstream and they kind of figured that if they even brought it up there was no point in them even talking to conventional physicians because they would be dismissive and they were probably correct. One of the things that was amazing was that when Beth Israel agree to create some services of integrative medicine is that a number of physicians who had been really outside the mainstream but who very much valued the evidence basis of what they were doing, flocked to the opportunity to work within a conventional system that embraced, finally, this approach to care. Establishing the Continuum Center for Health and Healing Just quickly, the story of the Continuum Center for Health and Healing. Back in 1997, one of the main trustees, Bill Sarnoff, offered to put in, with a couple of his buddies who were on the Board, three million dollars to set up some sort of program that would provide integrative medical services (at the time called “alternative” or CAM services), not knowing what they would be, but just realizing through coming to a couple meetings I had with a bunch of like-minded practitioners in New York, that the miserable death that his wife experienced from breast cancer, where she received no support…“There must be a better way,” as he put it. The hospital held a think-tank in the summer of 1997 with all the major thought leaders, the CEO, COO, members of the Board of Trustees, Chair of Medicine of Medicine, and Surgery, and Nursing, and amazingly, at the end of this two-day think-tank in 1997, the group decided that integrative medicine was the future of medicine and a lot of patients were using it but seeing who knows what credentials. They knew from the Eisenberg studies that there was a significant interest, and they felt that this is something that they should actually be providing to their patients, so they went on a search to find someone they could trust who would understand the evidence basis and weigh what was credible and what wasn’t for the patients, and I was fortunate that they offered me the position and I took it, and I think you can’t do this anymore, but they basically said, “Here’s five million dollars. Create your dream center.” So I said, “Yeah, I think I would like to do that.” I took, basically, eight practitioners in New York City who had been doing the work with me in various fields—pediatrician, Larry Pulaski; OB/GYN, Alan Warshowsky; family medicine practitioner, Ben Kliegler; internist, Robbie Lee; acupuncturist, Ari Nielson; nutritionist, Mary Beth Augustine—and brought them in to the practice and said, “Would you like to join and create something together?” and they said, “Yes.” So, it took us about two years to build it, and in 2000 we opened with the nine of us in practice, we opened with a full practice because these were practitioners at the peak of their practice—all fee-for-service—and we opened in to essentially a full practice. This is something that is very hard to do even now—to find that number of people to create it. In fact, I wouldn’t recommend most people build a 13,000 square foot center and populate it with 8 providers, but we were well funded, and we were in New York, and we had a very supportive clientele and 8 providers, and I think one of the things we’re proud of is over the evolution of the last 13 years that we’ve been open is we’ve actually brought in junior practitioners who actually began to take insurance, and now about 70 percent of our practice is managed care, where it began 100 percent fee for service. Right now we’ve grown from 13,000 to 26,000 square feet, and from 9 providers to 24, with a staff of 80 providing pretty global comprehensive services—primary care medicine where about 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the 5 family physicians practice pediatrics, 2 gynecologists, 3 internists, an ear, nose, and throat specialist, 2 psychiatrists, and 7 physical therapists and sports trainers, podiatry, chiropractic, a nurse practitioner doing only homeopathy. We have a new integrative cardiologist, Vivian Cominos, who is about start a Dean Ornish program at our center as well. We also have acupuncture, two nutritionists. We have an incredible…I mean, I could go on and on about the providers. Once you start naming them you don’t want to leave people out. The key is that we have probably the most comprehensive outpatient services that exist. We were fortunate five years ago the president of the hospital, after our being very successful for eight years—no complaints, only praise and incredible PR for the hospital—said, “I think it’s time to create a department. The good news is we’re going to have a Department of Integrative Medicine on the same level of the Department of Medicine and Surgery. You’ve been coming to the Chairs meeting for seven years and we all know and appreciate what you’re doing. The good news is there is a department and you’re the Chair. The bad news is your operating budget is zero, so anything you can do, you can do, but you have to provide self-funding.” This is one of the issues I wanted to get into in our discussion—about institutionally how you can actually bring this in when there is no way the CEO, or COO, or CFO would want to spend a penny for this stuff, and how you can possibly bring it in without always having to have it be grant funded. JB: I’ll tell you what, you just gave in that last 5 to 10 minutes was so concentrated news-to-use, exciting, goosebump history. I mean, if that’s not motivational to people listening I don’t know what is. And that list of your original collaborators is like a who’s who of the founders for some of the implementation programs (successful implementation) of this integrative and functional model. So that was really a great history. I’m glad we captured that. Remarkable. I don’t know how many times you’ve told that story but that was beautiful. Let me, if I can, just for the listener who may not have been around since 1997 in this field, go back with you just for a sec because you said something that I think is very important historically, and that’s David Eisenberg at Harvard and the study he did in JAMA, and his finding from this survey that, when extrapolated to the whole of the United States, the out-of-pocket expenditures for these services that we would consider now to be integrative, holistic, functional are somewhere in the range of that of out-of-pocket expenses for hospital care in the United States.[5] They were very substantial, and there were more visits to these providers of alternative care based on that article, than there were to primary care providers. It’s a paradigm-shifting concept, and a lot of people wanted to fight that data back and say, “No, no.” They wanted to marginalize it or say that it wasn’t statistically significant, or he didn’t do the study correctly, but I think it was a frame-shifting reality check on the whole of the field, and it seems like it must have had also an impact in Beth Israel that kind of softened peoples’ views and helped you to incubate your program. Three Events that Changed Thinking on Integrative Medicine WM: I think we’re fortunate at Beth Israel because it has always been kind of an outlier in medical centers as a hospital in the city where there are more elite hospitals and to compete they actually have offered services that the other hospitals would eschew as being unfounded or unnecessary for real medicine. We’re very fortunate to be in a culture—and you have to have good fortune in life, too—I feel very blessed that I’ve kind of been in the right place at the right time to help facilitate all this. I think that the hospital had an understanding that some of these therapies might be successful, but pre-dating the 1997 think tank were the Eisenberg studies, and actually I’ve always looked back in the field of what used to be called alternative medicine, and there were three events that actually kind of came together more or less at the same time that made even the most conservative physicians stand up and think that there might possibly be alternatives. One was David’s study for sure, showing that 40 percent of patients were using this. Another was Bill Moyer’s series, Healing and the Mind, that showed the incredible power that we have to actually transform our health with our own mind. And the third was AIDS, actually, interestingly enough. At that time, back in the late 80s, there was no treatment before HAART came out. Conventional medicine—these hematologists and infectious disease specialists—literally had nothing to offer their patients, so often their patients said, “Look, I did therapy or this herb or that IV drip or whatever, and I seem to feeling better.” Before this medication, these formerly very conservative docs who would never let patients do anything “alternative” were kind of open: “Well, why don’t you try it and let’s see if it works.” And, of course, most of them didn’t, but it made them knowledgeable that there might be something out there. I think the rap in the 90s was that there was no evidence base, and really there wasn’t a lot of evidence base as published clinical studies, although in functional medicine there was. You had the evidence and the science. It was grounded in the conventional medicine textbooks that they were telling students that this is what they needed to do but then they weren’t making it clinically available, so functional medicine was the earliest progenitor of the evidence base of what really already existed. You didn’t need more studies to inform doctors in terms of how to practice, but then over the next 10 or 15 years, really there has been in the last decade, an explosion of good quality, evidence-based studies on acupuncture, and mind/body practices, and botanical medicine, etc. to help guide us. So early on, even the president of the hospital, when he founded the center, said, “You know, evidence-based is really important, but it also can be a bit tyrannical.” In the case of Chinese medicine, for example, if you’re not taking any drugs where there may be a drug/herb interaction, this is a 2500-year empirical trial that seems to have been pretty successful, so your level of evidence depends upon what the risks are and how severe the illness is, so some of these very gentle remedies like homeopathy, you’re not going to give it for multiple myeloma, but you can do it early on, particularly to help ameliorate some processes, or to be adjunctive to processes. I think we’ve been fortunate that now, for the young practitioner wondering what they should do, there is so much evidence and data out there to back up what we are using in our practices that it is a much better place. When I was doing it in the late 80s there were almost no quality courses and now there are so many CME-level courses. I mean, functional medicine alone, the AFMCP week-long intensive course, and the weekend courses, and the annual symposium, and the FMU, and all the materials you have, as well as courses in botanical medicine and mind/body practices, and food as medicine, and places such as Scripps, and the Center for Mind/Body Medicine in Georgetown, and the Integrative Healthcare Symposium we have in New York, providing an incredible smorgasbord of opportunities for even the most hard-lined, evidence-based doctors to see how much there is that can be incorporated into conventional practice. Establishment of the Bravewell Collaborative and the Consortium of Academic Health Centers for Integrative Medicine JB: Let’s talk a little bit, on that stream of thought, about the Bravewell Collaborative, because I think the Bravewell Collaborative and the Consortium are two very interesting evolving parts of the story that you’re describing of the frontier of accreditation and respectability of the field. You’ve been actively involved in both Bravewell and the Consortium. Tell us a little bit about how those came about and their impact. WM: The Fetzer Institute brought together five senators back about 12 years ago to do a study to see what they thought would be possible, if there is anything to this field at the time called CAM medicine, and the outcome of that was that there was, but it was unclear what to do about it. I wasn’t a part of that. We were in the second year at Beth Israel. There was one other institution—I think it was Thomas Jefferson—that was allowed in by vote of the group of five. Each of these seven academic centers had an existing center that utilized integrative medicine, and at the time, the schools, including Arizona, Duke, Harvard, UCSF, Thomas Jefferson, Beth Israel, Maryland, and one or two others, decided how to best help the field of integrative medicine to evolve forward. We decided that there were two tracks. One was philanthropists: Bill Sarnoff, Penny George, and John and Christie Mack setting up the Bravewell philanthropic collaborative for integrative medicine to go out to other philanthropists who were wanting to contribute, but they were not sure where to give their money and they wanted their money to be well spent and not just get them down some sinkhole on some study that didn’t show much and then their money was gone. They wanted to see how they could actually use the money. And also some of them, once the word got out that a particular donor was giving money, then they were besieged by requests, so they wanted to set up kind of like a Ford Foundation, almost, of a philanthropic collaborative. And while they were doing that we decided that there should be a consortium of medical schools that actually would get together and would support each other and help to expand this within academic medicine, and so that was the birth of the Consortium of Academic Health Centers for Integrative Medicine. It originally started with the five investors, and with the seven at this think tank in Miraval, and to the point now where 40 percent of the nation’s medical schools are members of this consortium, so when young docs are looking for support in most every major city in the US and in 40 percent of the medical schools, these centers exist. The ticket of admission is three things: you have to have an existing center that provides integrative medical services in two of the key three areas of research, education, and clinical care; you have to have been in existence for three years; and, most importantly, the dean of the medical school has to sign a letter attesting to the fact that integrative medicine needs to be an integral part of undergraduate and graduate medical education and training in their school. This is huge. I mean, the fact that deans of the medicals schools would actually say integrative medicine should be incorporated into conventional medical training, ten years ago was an enormous statement. It still happens, every once in a while a reporter will say to me, “Well, people say there is not much of an evidence basis to this and this still really shouldn’t be mainstreamed.” And I say, “Well, I don’t know who your sources are, but if they think they know more than the dean of the medical schools of Harvard, Yale, Stanford, UCSF, Einstein, Georgetown, and Duke, I’m curious to have that debate.” Like functional medicine, I think that the incorporation of a range of integrative services into academic medicine is a good idea whose time has come and it’s here. It’s not just the future of medicine, but it is the current practice in many places. I will say that there are considerable challenges. The fact that the dean says it should be done, it’s a big leap to then actually providing the education and training to the medical students as residents and the equivocal care to patients. JB: Let’s move—I think that’s a very good segue—into where we probably should go from this extraordinary and robust history that you reviewed for us, and talk a little bit about the clinical approach, the funding, and some of the barriers, and some of the things that might—from your experience—help some newer people coming into the field to be knowledgeable about that might help them as they make their transition forward. Time: The Greatest Challenge for Providers in Providing Personalized Lifestyle Medicine WM: Well, I think if you’re looking to be a student, obviously, my opinion of where you go—the best college and medical school—is where you get in, so it’s not like you have the choice of every place you’re going to go to, but to try to find a medical school, if you can and you get accepted to, that actually provides some training in integrative medicine, and the same thing with a residency. There are almost no residency programs except for a couple, including Beth Israel’s going back 15 years, that provide training in integrative medicine. As a matter of fact, at Beth Israel, Red Schiller, who is the Chairman of the Department of Family Medicine and Chairman of the Credentials Committee, to show you how deeply ingrained this is, has required a rotation in integrative medicine for 15 years in the 3-year family medicine programs. These programs and trainings exist for people, but these academic centers also exist that have many CAM courses where doctors can actually find quality information, and even if they can’t do it within their medical schooling and residency training, there are probably evidence-based/science-based information that they need to incorporate into their practice. Once they get out into practice it can become more difficult because of insurance systems. One thing that integrative medicine requires is that you understand your patient at a deep level and you spend time with a personal social history to really get into what’s going on in their lifestyle. I know something, Jeff, that you’ve championed for such a long time and you’ve now set up an institute for it, PLMI. Without understanding the background of where patients are, it is very difficult to treat one or two symptoms of a problem and never really make an effective change for most of the people. I think that doctors need to really focus and have the time to do this, and they often don’t, so that’s a real challenge. Another challenge is actually within the hospital itself—making these practices available to patients in the hospital where it is desperately needed. I’ve been going to Chairs meetings at my hospital for nearly 12 years now. About 4 years ago one of the surgical division chiefs—I won’t say the name—very conservative, editor in chief of his journal, actually decided after hearing me talk about this for years that he would hire a half-time Reiki provider, of all people to bring in. It wasn’t even acupuncture or nutrition; he started way out there with Reiki. He brought in a Reiki practitioner half-time in the recovery room, offering it to patients coming out of surgery. And he said a month after bringing this person on board that not only from his perspective were the outcomes improved by having this person, but it changed the entire culture of the department. This is profound, but you have to be lucky and get somebody who is kind of a champion within the medical center who believes in this and helps you to get it going. The Importance of Cost-Effectiveness Studies: Can You Afford to Save a Million Dollars? One of the things that people are working in institutions where they are dragging their feet about doing it that I think is really important is there are a lot of studies on clinical outcomes. Beginning 15 years ago we began to understand how a lot of these things worked and if they worked. I think in terms of nutraceuticals and botanicals, the studies are just beginning to come out now in terms of the downside of using too many antioxidants and other things, so they are beginning to see that there are negatives; it’s not all positives, so we need to put that in balance. The thing that particularly hospital administrators are having a hard time with—and the same thing with insurers–is, “Okay, so this works, but how do I know this is not going to cost four times what I’m paying now with the same outcome. Why should I do this?” So you really need cost-effectiveness studies and there are cost-effectiveness studies people can point to. There are studies going back 10 years by Citibank, of all places, showing there was a 10-to-1 return on investment for bringing in and actually just counseling on basically lifestyle practices for their employees.[6],[7],[8] So many companies have found that bringing in preventive lifestyle practices significantly reduces healthcare costs. Within our hospital we did a study—a wonderful study that was funded by the Urban Zen Foundation and Donna Karan—where we transformed the entire cancer floor of Beth Israel into an optimum healing environment, and we provided patients with self-care. We empowered the patient to engage in their own healing process rather than being victims and passively waiting for the nurse to come with yet another pill for their symptoms, to engage their mind in the healing process. What we tracked is that over the course of four months of the study amortized over a year, by bringing in the person who would be an advocate for them and doing yoga therapy and teaching them mind-body practices, just tracking three medications for pain, anxiety, and nausea, we—amortized over a year—saved a million dollars in medication cost from having that one person.[9] So you go to the administrator—which I did—and you say, “You know, I think this is good evidence that we should bring in a yoga therapist onto the floors because we’ve shown in our study that we published in the American Journal of Managed Care [not exactly a radical journal] that amortized over a year you could save a million dollars just in medication costs alone. Patients would hit their pain button with their mind rather than asking for the pain medication.” He said, “Well we can’t afford that.” I said, “Can’t afford what? To save a million dollars?” Mount Sinai did another great study by Guy Montgomery showing that if nurses just went up to patients in the gurney in the hallway waiting for the most commonly done surgical procedure, which is breast biopsies and lumpectomies, and you asked them if they wanted to learn a hypnosis technique to help them through the procedure, they found that they saved an average of $772 per patient with less anesthesia, less procedure time, and less medications in recovery.[10] So basically after the first 100 patients, providing a full-time nurse, the rest is gravy in terms of savings. I think for those people who are working within an institution, there is now evidence they have to take to the administrators and say, “You not only can improve outcomes, by the way, you can improve the patient satisfaction, which is going to end up being 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of Medicare reimbursement. You can actually save money.” JB: You know, you have just…there are so many pearls that you just dropped and so many little tidbits of news to use that are applicable in every practitioner’s—actually every person’s—life. That was just very, very beautiful, dense information. One of the things that struck me coming out of the most recent Institute for Functional Medicine International Conference on energy medicine, that what you really beautifully described is kind of an energy field—that you change the context of healing, which is really a state of energy. It’s hard to quantize. It’s invisible. You can’t taste, touch it, or feel it, but it’s very real, so it’s almost like an electromagnetic field state that interfaces with physiology to produce different outcomes that are probably measureable with different mediator molecules of emotion and things of that nature that ultimately affects end-stage physiology. It’s a remarkable example of distant effects, action at a distance, through energy fields that sometimes we marginalize or we don’t take seriously. That was a beautiful, beautiful explanation. The Case for Positive Energy Fields WM: I’m a big fan of the work of Larry Dossey and other people who have talked about energy fields. Even if you just look at it more conservatively, just the intentionality that is brought into the room of a nurse or a doctor who are actually going in to be the patient’s advocate rather than being ticked off that they’ve got to go in and give another medication or change the IV, can make a huge difference. When we have trained these people at the hospital with the Urban Zen training from the Urban Zen program to be therapists, we train the nurses and some of the Chairs say, “Well, that’s great but the nurses have no time. They can’t sit for 10 minutes and teach the patient a healing technique. They barely can get the medications charted.” I point out, “You know, once you understand from self-care what it takes to be whole, the nurse or caregiver, in the 30 seconds they are taking to change an IV, they can just say to the patient, ‘This is an opportunity. Why don’t we just sit here and do some breath work together. It will help you and it will help me. Let’s just close our eyes and do that technique you just learned together.’ While they are doing their work.” That energy that surrounds that experience is profound and powerful and it stays with someone for a very long time. It’s just like when you hear a tune—Dean Ornish was just saying this the other day—when you hear a tune on the radio in the morning and you find yourself like three or four hours later humming the tune, it’s like as you do these meditative practices, they actually begin to stay with you even at a subconscious level, and not only stay with you but begin to radiate out into your field. It’s kind of like that study that showed that the circuit of obesity that actually went through three or four contacts of people, if you were around people who were obese you were much more prone to be obese just from your contacts, even three or four removed.[11] JB: Yes, I think that’s a beautiful example. We’ve taken a tremendous amount of your time, but I’d like to give you a chance to do a little forward looking, vision thinking with us. Where do you see the field going? What’s your prognosis? Is this something that if you were recommending to one of your children or loved ones to go into medicine that you’d be optimistic about the future? What’s your state of the vision of the future? WM: I think you have go into medicine loving the opportunity, the blessing you’re given, the great privilege to be able to engage in a healing encounter with patients. It’s a gift, and I think you have to be motivated for that. Who knows, really, in the current healthcare environment with the reimbursement model? You certainly can make more money doing some other fields, perhaps in finance rather than medicine (unless you’re a plastic surgeon). You have to go into it loving the opportunity to actually help people, and you need to be able to, perhaps sometimes on your own, learn those modalities in your own life, for your own self, that balance you, and that you bring that into the workplace, and when you do that, you will be satisfied. You need to make sure you love the field because there will be many challenges ahead. Even though there are a lot of kinks in the armor and it’s almost like there is a very soft armor now at a lot of the institutions that are allowing these to take place, but they are still often only available where they are grant-funded. They aren’t institutional priorities. Even the teaching and training is not yet an institutional priority. You go from the Dean saying these things should be taught, to training the hundred and fifty-odd faculty to be knowledgeable, to train the students is a definite leap. I think this is the future of medicine. It’s here. I think that the ability to train and become knowledgeable with functional medicine as the foundation, and mind/body practices, and then adding in other things that you want to put in your practice are there, or at least knowing who in the community is someone great to refer to. It’s an incredibly exciting time. It’s kind of like the best of times and the worst of times. I don’t see the worst of times now. I think, really, even though they didn’t make a huge leap with Obamacare, you are providing care to tens of millions of people who didn’t have it before, and I think that we are in a state where increasingly integrative medicine is going to become the standard of medical practice. Because I’m a glass half-full guy, I’m very, very positive about it. Where we’ve come in the last 15 years…it’s unimaginable that we’d be this far with these formerly considered kind of wacko alternative medicine therapies now becoming mainstream. The Need for Integrative Medicine is Patient-Driven I feel very fortunate. I think that the next generation—it’s only going to get better for being able to really be truly holistic in your practice of medicine and in your own lifestyle. One of the shifts that has occurred is we are much less doctor-centric. I think that this began, again, back 20 years ago with the Moyers and the Eisenberg work, the fact that this is a patient-driven movement. This isn’t because doctors wanted this to happen with alternative practices being incorporated. They were almost led kicking and screaming into it. As part of that I think we’ve now realized that some of the other professions have profound benefits to offer, not just as an adjunct where you send someone out to them, but incorporated with conventional medicine and really making it patient- and relationship-centered. Utilizing doctors where you need to, but also thinking about naturopathic medicine, which has at its core the scientific understanding of the use of nutrition and many other modalities. Acupuncture, Chinese medicine, holistic nursing—all of these professions working together as John Weeks and many other have been trying to get going for a very long time. I think we’re in an era now where conventional medicine is beginning to lose its grip on having all the power and recognizing that they can’t help all their patients and there are many other providers who are extremely well-trained and knowledgeable about conventional medicine and about the evidence basis of their own field that actually can dramatically improve overall healthcare outcomes. JB: Thank you. I think that’s a really great way to end this discussion. That’s one of the reasons that I’ve been advocating with my colleagues the formation of this Personalized Lifestyle Medicine Institute, because it is a consumer-driven movement that we’re witnessing, and we need consumers to be well informed and have access to quality information across where genes meet environment meets lifestyle to create the right outcome, and then that has to be interfaced with health professionals that are credentialed and properly trained to deliver services to people that have chronic illness. I think that interface will then drive the change that we’ve all been looking forward to. I believe that your comments around various ways of approaching this problem is the definition of a distributive healthcare system versus a top-down linear reductionistic healthcare system, where you get to know more and more about less and less until you know everything about nothing. I think that we’re seeing this distributive system start to emerge where different skills can be woven together to create a better outcome. So, I thank you. You do this beautifully, by the way, in your oversight of the integrative health meeting in New York City each year. I think that’s a wonderful meeting that embodies multiple disciplines showing how this cooperativism can emerge. Dr. Merrell, to say this has been inspirational would be a great understatement. This has been an incredible word journey we’ve taken with you here. It’s ironic. I’m sitting here, as I’m interviewing and listening to you, looking out over the Seattle, Washington skyline at Providence, Swedish, Harborview, our medical centers in Seattle that are all associated with the University of Washington School of Medicine, and I’m just thinking of my 40 years here in the Pacific Northwest, and kind of morphing, or doing holography of what you’re saying into this community here and recognizing that every one of those medical centers, when I first came here, would be considered right down the center of the line. Now each has their own integrated medical facilities within those centers, and they have affiliations with Bastyr University—many of these—through the naturopathic medicine that is licensed in the state of Washington. As you just said, who would have thunk that 40 years ago? It didn’t sound possible. I think that we really are seeing a paradigm shift and it’s going to be built on authenticity, and competency, and on the shoulders of people that have done the really heavy lifting like yourself in creating an environment that will deliver improved outcomes and more cost-effective care. I can’t tell you how much, both on a personal level, I’ve appreciated our friendship and your guidance over the years (the decades, actually) in developing my model, but also on behalf of all the listeners for the extraordinary contributions you’ve made to the field. It’s just quite remarkable. WM: Thank you so much for having me on. It was a pleasure and honor to be on FMU and to get a chance to speak with you and share a little bit of the history of where we’ve come from and the excitement that holds for the future. JB: Again, all of our thanks for your years of work and efforts and we look forward to continuing and following closely what’s going on there at Beth Israel and all of your activities  

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Bibliography

[1] Han JS, Tang J, Ren MF, Zhou ZF, Fan SG, Qiu. Central neurotransmitters and acupuncture analgesia. Am J Chin Med. 1980;8(4):331-348.   [2] Han JS, Terenius L. Neurochemical basis of acupuncture analgesia. Annu Rev Pharmacol Toxicol. 1982;22:193-220.   [3] Han JS. Acupuncture analgesia. Pain. 1985;21(3):307-310.   [4] Merrell, Woodson and Kathleen Merrell. Power Up. Unleash Your Natural Energy, Revitalize Your Health, and Feel 10 Years Younger. New York: Free Press, 2009.   [5] Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280(18):1569-1575.   [6] Reiff MG, Sperling KL. Measuring the savings from managed care: experience at Citibank. Benefits Q. 1995;11(2):9-15.   [7] Ozminkowski RJ, Dunn RL, Goetzel RZ, Cantor RI, Murname J, Harrison M. A return on investment evaluation of the Citibank, N.A., health management program. Am J Health Promot. 1999;14(1):31-43.   [8] Ozminkowski RJ, Goetzel RZ, Smith MW, Cantor RI, Shaughnessy A, Harrison M. The impact of the Citibank, NA, health management program on changes in employee health risks over time. J Occup Environ Med. 2000;42(5):502-511.   [9] Kligler B, Homel P, Harrison LB, Levenson HD, Kenney JB, Merrell W. Cost savings in patient oncology through an integrative medicine approach. Am J Manag Care. 2011;17(12):779-784.   [10] Montgomery GH, Hallquist MN, Schnur JB, David D, Silverstein JH, Bovbjerg DH. Mediators of a brief hypnosis intervention to control side effects in breast surgery patients: response expectancies and emotional distress. J Consult Clin Psychol. 2010;78(1):80-88.   [11] Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. N Engl J Med. 2007;357(4):370-379.

Welcome to Functional Medicine Update for September 2013. You’re in for a real pleasure, and a surprise, and an “ah-ha” moment this month. Let me set the context as to why I would be so bullish about the content of this issue. As you recognize, over the last 25 years there have been some very substantial changes in the way that health is viewed in our country–the dominant disease patterns, the changing dynamics within the industry that we call the health and disease industries, changing in agriculture, changing in commerce as it relates to foods and nutrition products, rapidly continued rise in the prevalence of obesity, increased use of various medications to manage lifestyle disease symptoms and signs. I mean this is a pretty panoramic cultural transformation and transition that’s been occurring that surrounds health. In fact, it is interesting to note that some individuals have defined this era of our go-forward history as being the age of health—that this will be the biggest singular issue as we have aging baby boomers, as we have more burden of chronic illness, as we start to see disorders that were at one time relegated to older age now being seen in younger people,  like we’re starting to see diabetes in teenagers that was called adult-onset diabetes 20 years ago, but now we have to call it type 2 because it is being seen in children. All of these trends are pointing us in the direction that new solutions to problems need to be developed, and this is one of the reasons that we felt that functional medicine, as an operating system for the new healthcare challenges, new healthcare advocacy, could be so important.   To Understand Our Future, It Is Important to First Understand Our Past But in order to understand our future sometimes it is important to understand our past. Where did we come from? How did we get here? We’ve tried very hard in the three-plus decades of Functional Medicine Update to give a historical perspective to what’s going on in the now and how that might influence what is going to happen in the future. I’m very proud when I go back and think of the topics that we’ve discussed over the years in Functional Medicine Update, many of which at the time seemed to be maybe at the bleeding edge were actually found to be at the leading edge and became dominant new concepts. Five to seven years later people were talking about this as if it were a great new discovery and was changing our view of certain aspects of health and medicine, and yet if we go back to root origins we were talking about these concepts in Functional Medicine Update almost a decade previously. So it’s important, I think, sometimes to understand where we have come from to understand where we are going. That’s really what you’re going to be enriched by in this issue of Functional Medicine Update. We have the privilege of talking with an architect of one of great transformations in health care that has occurred within the last 50 years, and that’s the transformation that occurred with the outcome of things like organic agriculture, things like the range of botanical medicine products that are now available to the healthcare consumer. Things that relate to the wider array of what Linus Pauling called orthomolecular substances—things that were natural to the human body that would correct certain kinds of metabolic disturbances that were previously not allowed for commerce, and then under the new law of the land passed in 1994 called the Dietary Supplement Health Education Act became available. Think back, if you would to the rising tide of general understanding of the role that omega-3 fatty acids have in promoting appropriate health, and go back, if you have been in this field for a few decades, and remember the era of the Pritikin regime that said all fats were bad and that the best approach was to cut all fat out of our diet, and now we’ve come to where we recognize there are certain fats that are good, and in fact we haven’t been getting enough of them. Witness the literally thousands of scientific studies that have been published on the clinical benefit of omega-3 fatty acid intake and supplementation. Research and science that has actually transformed the industry, leading to a small sidebar in nutritional supplement family that started off as MaxEPA, an RP Shearer product first sold in the United States as a fish oil supplement in the early 1980s, to where now it is Lovasa sold by GlaxoSmithKline, that has sales of greater than 1.5 billion dollars annually for that product, meaning it is a blockbuster drug in the parlance of traditional pharma. So these are major transition conceptual things that are occurring, not to mention the sweeping change in the view of medicine, personalized lifestyle medicine, functional medicine, integrative medicine, which are now finding their ways into the curricula of medical schools, and into advanced training and fellowships, and ultimately into new reimbursable programs for intervention, as seen with the Ornish program through Medicare for individuals that have cardiovascular disease. So I think we’re in an extraordinarily robust and rich time of transition, and to understand where this transition might take us and the responsibilities we have for stewarding it in the right direction so it really will produce societal benefit and reduce the burden of reducible disease and enhance quality of life for hopefully hundreds of millions of people over the years to come, we have to know a little bit about where this concept was born in the culture of today, and what some of its strengths and limitations are based upon this history. I went back and said, “Who in my nearly 40 years of involvement in this field would I think would be the best chronicler of this history? A person who has really been at the moments of great change, both an architect and an historian and communicator that relates to these major epic transitions that occurred?” And of course, the name that comes immediately to my mind is a friend and colleague, Loren Israelsen, who is an attorney and is the executive director and founder of the United Natural Products Association. Loren and I have had the privilege (for me, at least) of spending many, many hours together over the last nearly 30 years, both talking about where the future of this industry and this field might be going, and also talking about responsibilities, and conduct, and standards of identity, and professionality, and what defines excellence so that this will stick and really become a significant contributor to reducing the burden of disease. I’d have to say that Loren has made extraordinary contributions across this wide-ranging platform of both industries and consumer activism and delivery systems that is seen in many different areas of impact. So we’re very privileged this month, in our September issue of Functional Medicine Update, to do something we’ve never done in the history of FMU, and that’s to have a discussion—I would call it a fireside chat, an intimate conversation—with an architect of this great social change who has been a principal player in manifesting this change in our culture, and kind of understanding, from his perspective, how we got to where we are today, what are some of the things that we are very proud of that open the door for future opportunities for improvement, and what are some of the things that we still have work to do, that are still areas that require our vigilance, our diligence, and our commitment to honor these traditions, and to hold them sacred, and to make sure that they are properly applied so that they really will deliver the benefit to society that they have the opportunity to do. With that in mind, let’s move into our extraordinary verbal journey, conducted tour, with Loren Israelsen

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INTERVIEW TRANSCRIPT

Guest of the Month Loren Israelsen, Esq. Executive Director, United Natural Products Alliance www.UNPA.com Here we are once again at that portion of our Functional Medicine Update series that I think is, for each one of us, kind of a discovery process, because we’ve had the chance to talk with some of the world’s great luminaries as it pertains to the way that health care is emerging and evolving, and how personalized lifestyle medicine and functional medicine are playing roles in this emergent global healthcare system. One of the things that I noted as I went back and reviewed the luminaries that we’ve had the privilege of interviewing is that there was a notable absence of one of the individuals that has had the most significant impact on my understanding and my asking the right questions—or hopefully asking the right questions—about the landscape under which all of this form of health care is delivered, which is the regulatory and legislative landscape. Of course I’m speaking about my friendship and my professional relationship with Loren Israelsen that goes back now more than two-plus decades. Loren, as probably you know, is an iconic figure in our industry. He’s a lawyer by background, working with Senator Orrin Hatch. Later he was very, very important in the guidance of the development of the nutritional supplement and dietary supplement industry first as a senior leader in companies that played significant roles in carving out a legitimacy in this space, and then later as a very important figure, and probably in my estimation the most important figure in working with Senator Hatch, and then later Senator Kennedy and Senator Harkin, in what became the passage of a bill that I think most of us felt, in the 1990s, was very unlikely to be passed, called the Dietary Supplement and Health Education Act. Loren worked with a number of his colleagues and associates tirelessly through the midnight hours, drafting and redrafting, and discussing and modifying the language in the bill that eventually led it to be the law of the land, which has an international global implication as it relates to the use of nutritional supplements, claims that can be made for them, and how it impacts ultimately the healthcare system and individuals’ ability to get these products and to use them as part of their health programs. Through all of this Loren has maintained an extraordinary high-level professional relationship with leaders in congress, with leaders within the industry, with raw materials suppliers, and breeding suppliers, finished product suppliers, and the myriad of different hoops that have to be jumped through, including relationships with the Food and Drug Administration as they started to better understand what their future might look like as it relates to the regulation of this category. We know that the United States becomes a lightning rod for much of the rest of the world as it relates to its regulatory standards and procedures, and therefore Loren certainly has had a global impact in Europe, Asia, and even in our discussions with our colleagues in Australia as to how things work their way through the regulatory framework as it pertains to nutritional products. So with that fairly lengthy introduction, I guess the last thing I should I should say is that Loren Israelsen is also one of the great human beings. He’s a humanist. He’s a broad-ranging thinker, and brings perspectives to our discussions, always, that cause me to have to stop and learn new things. Loren, thank you for being part of Functional Medicine Update, and welcome as a key opinion leader to help us understand a little bit more about this complexity of the regulatory environment of nutritional supplements. LI: Thank you, Jeff. It’s my pleasure. JB: For those who are not maybe as familiar as you and I are with the history of how we’ve gotten to where we are today, could you take us back to how Loren Israelsen started down this path as an extraordinarily talented law school graduate—a guy that had spent some time in Japan and learned Japanese who comes back and is on this path now for 30 years. How did this all begin and what were some of the critical steps along your path? The Nutritional Supplement Industry Had No Roadmap or Guidebook LI: Like so many things, it was serendipitous. I was finishing law school. I had no idea what I wanted to do, and went to a birthday party. I was living with nine guys in kind of an Animal House set up. We were always ranging around for a meal, and ended up at somebody’s birthday party, and the birthday boy was the general manager of Nature’s Way Products. We were introduced. He said, “Listen, I could use some help down here,” and offered me a part-time job, which I took. That became a summer job, and in turn that became a full-time offer of employment. In 1981, I dove off that cliff and took the position as general counsel of Nature’s Way at a time when, to the best of my knowledge, this was the first time a lawyer had gone inside the health food industry to work for a company selling supplements or natural products. The beauty was there was no roadmap, there was no guidebook, we pretty much made the whole thing up as we went, and that was the beginning of what is now a 34-year career in this industry. JB: Well it’s to our advantage, obviously that that transition occurred because I recall meeting you for the first time at the Nature’s Way facility in Utah and was very, very impressed with the way that you were thinking on a much more broad base about the future of the industry, and as I recall, were already in discussions as it relates to some of the things that were going on in Europe as it relates to botanical medicines, Schwabbe and Medhaus companies, and kind of thinking about how one could lift the professionalism of the industry and the reproducible quality assurance of products to make sure that what people were buying and using was delivering the goods. Tell us a little bit about how that ultimately evolved for you. LI: Good questions, Jeff. Yes, as I was involved with the company, I was new to the industry. My family, we had no history or experience using botanicals, dietary supplements, really nothing in the natural products arena at all, so this was all new to me. I was fascinated by everything. As I got to know the culture and the traditions of the industry I was really struck by what a powerful belief system this is, and that consumers of our products hold a really strong and centered view about how we as humans coexist with plants, animals, biosystems—that this underlying belief was very attractive to me. Today I would consider myself among the believers that have been for decades. But I was as impressed by…I guess coming out of law school, there was a lack of scientific rigor of investigation of research. That is understandable because of the belief system the industry really was nurtured in for so many decades. As I looked at our company, there were several things that I thought we needed to do: go find the world’s best researched products, bring them into our portfolio, and introduce those, such as from Germany, Italy, France. So I spent about two-and-a-half years combing Europe, traveling high and low and side to side, trying to figure out best-of-class products, introducing myself, our company, and went from the early days when I was not taken seriously because everybody in Europe knew that you couldn’t take a scientifically researched product to the United States and make a success of it. Two reasons: a very hostile FDA, and an uninformed consumer that didn’t have an appreciation for science. So we made a deal that if I could help solve the FDA problem, will you help us solve the science problem? That was a handshake deal. A number of companies in Europe agreed to come over under the Nature’s Way banner, and that was so successful that those companies today are the owners of Nature’s Way. At the same time, we were very interested in organic agriculture. I believe it was in 1985 I made a trip to Trout Lake Farms in Washington state, and we developed the first major company program with an organic grower—in this case Trout Lake Farms—to supply against an annual contract requirement—to bring stability to the farmer a strong commercial relationship, and an advertising campaign to begin teaching the rest of the industry that you could grow and produce beautiful, high quality, organic botanicals, which was a new thing. We were also interested in quality systems, and this is where you and I, Jeff, got together along the way as we were fighting the battles of DSHEA, was the need to quantify and qualify the various quality standards that existed for the various categories of dietary supplements, which turned out to be a monumental task that was really the beginning of beginning to sort out in a coherent way, how can consumers understand something about the quality of the products they are buying? It was through that project that a number of wonderful people that who have remained good friends and colleagues I would say now for 22 to 23 years, so those were some of the projects that we were really interested in that I was particularly hopeful that we could develop and make a difference with. JB: I think you are, as always, understated in your advocacy of the past, because that role that you played in introducing these European pharmaceutical botanical medicine providers to what was going on in the states and then reciprocally understanding what might be needed in the United States to bring these higher quality materials with a different standard of evidentiary support to the states, and then working as an advocate to form the regulatory framework to allow that to occur is no small undertaking; it’s huge. Of course, eventually then things like the commission e-monographs being translated and becoming available in the United States, and all sorts of things then happened after that in the concept of organic agriculture, of which there were, many, many other participants and players, but it always takes a few people to lead the division and I think that you did an extraordinary job in kind of having a vision as to what a legitimate industry that was really providing high quality service and products might look like, which then leads me to the next question. Now, how did you first meet or get involved with Senator Hatch and later with Senator Harkin? Early 1990s: Darkening Skies and Growing Rhetoric from the FDA LI: I first met Senator Hatch in 1978 when I worked in his office for a short time and was introduced to the unique world of Capitol Hill, Washington DC, and from that beginning, built and maintained great relationships with him and with his office. He always said, from the very beginning: “I am an advocate for Utah.” He is a personal believer in natural health and wellness—a very deep believer. After my tenure at Nature’s Way—this is rolling forward now to 1990, 1991—I had seen Senator Hatch at an event, told him that we were gravely concerned about the darkening skies and the growing rhetoric coming from FDA that there confrontations that were very explicit indicators that FDA was going to essentially scope down the range of claims, ingredients, and motion that the supplement industry could operate in to the point that after my tenure at Nature’s Way, I contacted a number of my colleagues in Utah. We began sit-down meetings and for probably six months we would get together at least once a month and literally on a white board try and figure out what could we do as an industry to protect ourselves against what felt like a certain attack from FDA. We concluded that nothing short of legislation would really solve the problem. We were not naïve, in that we understood that the chances of that happening were so remote that it was unlikely we could interest anyone in Congress to introduce a bill that would rectify the problems we had identified, nor did we think the industry would be supportive of that sort of effort. We were not organized politically to do it. We were certainly not funded to do it. But we thought, “You know what, there is really no other option.” We put together a draft of ideas. I flew to Washington, DC and sat down with Senator Hatch, and the meeting was remarkably short. I basically said, “Senator, we’ve got some deep concerns. We’ve got some ideas.” At about that point he said, “Count me in.” He said, “I’ll need details and I’ll need to get my staff involved, and you will need to go get yourself a good democrat in the House of Representatives to co-sponsor the bill in the house, but if you’ll take it that far, let’s get this thing going.” So in June of 1992, Senator Hatch and Congressman Bill Richardson from New Mexico jointly introduced the bill called The Health Freedom Act, which was the original name of the bill that finally passed in 1994 as the Dietary Supplement Health and Education Act. So literally, it was a simple start—beginning with Senator Hatch—simply saying, “I’m in. I understand the problem, and I will do all I can to help create an environment that provides stability, opportunity, consumer access, to products and information, and where we need to reel back FDA, we’ll do it.” And sure enough, that’s what happened. The Dietary Supplement and Health Education Act: So Much More than Labeling JB: You know, these are easy stories to be told in retrospect, but very complicated stories in the real time of the moment. I’d like to take a couple of steps again with you through this process to give our listeners a sense of the spar and parry and the dynamics that occur in these kind of cultural transitions, because this is fairly big impact on society, on commerce, on decision-making, on even health care and even in the broad sense with the passage of DSHEA. I think it is very interesting when I just hear you rename the Dietary Supplement and Health Education Act to remind myself that it was not just dietary supplements, it was health education, the combination of those. It’s a very important, I think, positioning, and often I believe that people, when they say DSHEA, just think of it as somehow regulating dietary supplements with a structure/function claim opportunity, but there is much more below the surface that has significant spreading implication coming out of the McGovern Committee reports on diet and health in the country that preceded this, and talking more and more about people aspiring to take charge of their health through implementation of different strategic approaches toward diet, exercise, lifestyle, environment. This was a movement that had broad spreading implications, not just pills in a bottle or powder in a can, that you were spearheading and I think the concept of dietary supplement and health education is much broader in its implications than probably some people, upon reflection, thinking. Who did you go after on the democratic side to be your advocate? I know the answer to this, but some of our listeners may not. LI: It was an interesting battle that required bipartisan support in the Senate, in particular. We had heard—there were rumors—that Senator Tom Harkin from Iowa was a very interested senior member, and that if we could gain his support it would make all the difference. Indeed we met with him a number of times. In one of the great stories of DSHEA, he said, “I will be there when you need me.” Curiously, he did not come on and cosign the bill early on. There was a strategic wisdom in doing that—that at the critical moment when there a big Senate hearing about DSHEA, and if the bill had not been as it is called “marked up” out of that committee, this would have been the end of the bill. The vote was going to be very, very close. Senator Harkin had not yet publicly declared his support. We believed that he would do that. What we did not know was that he would reveal himself not just as a supporter, but as an extraordinary champion, and he gave a statement during that committee hearing that is still one of the great statements of all time with respect to this industry. He made it abundantly clear that he not only supported the bill, he would provide any necessary means of support he could. He told his personal story of being a lifetime allergy sufferer, who had been cured, literally overnight, by using a natural product recommended by a very curious little old man that sought out Senator Harkin, almost as if he intended to appear before Senator Harkin to give him this news personally. It’s really quite a mystical story in many ways. But the Senator was indeed cured for life of these allergies, and his support from that moment in 1993 to this moment in 2013 has been unabated, unqualified support for natural health and for dietary supplements. It was a wonder to behold to see him play his cards so carefully, and by his skill was able to save that hearing from defeat, bring two other democrats on to join the bill, and, by a very narrow vote, we survived that critical Senate committee hearing to live another day, and ultimately to win the battle of DSHEA. JB: So, personalities, people, improbable events…somehow the universe has a warp and weft to it that creates the unexpected, all of which was happening during this interesting period. One of the things that I recall you were confronting was, as you mentioned earlier, could the industry police itself? Would it have the intention of quality that would justify these remarkable steps to redefine legislatively, in the regulatory framework, the scope of practice of the industry. It was that, then, that led you and I to form the Natural Product Quality Assurance Alliance, which I thought was quite an interesting chapter in the industry’s evolution. Can you kind of reflect back to that period in the early 90s? The Political Landscape Has Changed and DSHEA is Under Review LI: Indeed. What we learned very quickly as we were advocating on Capitol Hill for the right of consumers to have access to supplements and information about supplements, we were being asked the same question over and again: You’re asking for a lot. Can you demonstrate to us your worthiness to have these liberties and freedoms, which are unusual in a regulated market environment? In other words, are you capable of self-policing and assuring us that product quality claims substantiation will be adequately respected? We honestly did not have any convincing materials to answer the question, which was the moment of creation of the Natural Products Quality Assurance Alliance, that you and I and others were involved in, to create a compendium of standards, but that required us to scour the industry, have numerous and robust discussions about how do we do these things? We did develop a compendium, which we did present to most members of Congress. It was a critical tool in helping us assure the membership that we understood the concern and that we would address it. However, one thing you learn with great victories is that there tends to be a great period of relaxation and the adoption of triumphant behavior, which means that the hard work of governance often goes neglected. It’s my greatest regret, with the victory of DSHEA, that the dual responsibility to continue the hard work of administration of that law, of developing quality standards, of self-policing our practices and behaviors within the industry, did not match the promise of the bill itself. We continue to struggle with that today. To speak freely, it is the greatest threat to the continued existence of DSHEA. If consumers lose confidence in the quality and integrity of our products, if health professionals are uncertain of their therapeutic and medical benefit, or of their safety, that the erosion of that confidence will ultimately lead to a review on Capitol Hill. As we know, Senator Hatch is in his final term. Senator Harkin is retiring next year. Our historic political leadership is in transition, and this is the critical moment now where we will see whether the industry can bring together a clear and focused agenda to maintain quality, close ranks, protect standards and practices, otherwise that we will be back on Capitol Hill, revisiting the very issues that we thought we had resolved in 1994. JB: I want to proceed a little bit with that in more detail, but I’d like to go back and pick up a couple of very important things that you mentioned and emphasize them. The importance of single individuals can never be, I think, diminished as it relates to these great cultural changes, and of course your contributions stand very high. And Senator Harkin, who you mentioned, also, along with Senator Hatch, have made remarkable contributions to changing the landscape for health care, so when I think of this period, I’m thinking not only about what Senator Harkin and Hatch did as it relates to the advocacy of the ultimate passage of the DSHEA, but also of the pressure put on the National Institutes of Health to change research and medical training in the area of these products and concepts that was found through the funding of the Office of Complementary and Alternative Medicine, a new division of NIH that didn’t exist before, kind of a step-child division at first, but it’s gotten a little bit more muscle over the last 15 to 20 years, and that was born, really, out of this whole zeitgeist—this whole similar intellectual endeavor that was being spearheaded had broad-ranging, sweeping effects on not just consumer understanding and availability of these products, but health education and later even medical understanding of these products and how they play a role in health care. It sometimes may be difficult for people to see how these points of the curve are all interconnected to form a new functional status, but I think as you look back you must take great pleasure in seeing the spreading effect of these concepts in terms of cultural transitions and recognition of the viability of this model for disease prevention and health promotion. LI: Oh, there is great pride and a sense of “We really did something useful and important with DSHEA.” We went into that very narrowly focused battle around what we now call dietary supplements, but have to remember that until this law passed, we didn’t even have a legal definition of what it is we were fighting for. That was one of our problems. We just had no framework to deal with. Perhaps the most striking lesson is the enormous power of the grass roots that rose up to support DSHEA from 92 to 94. It was far greater than anything we realized existed. And for me it was a revelation in understanding that within the American cultural tradition there is a very deeply held sense of health populism, that consumers here, unlike any other country that I’m familiar with—and I’ve done a lot of traveling—have a sense of a right and entitlement to knowledge, to access to products, unlike any other country. That creates a populism when these issues end up being politicized, and this has happened in the 1950s, the 1970s, in the mid 80s, and again in the mid 90s; the same thing has happened over and again. And in fact, the roots of this goes back to the 1830s and 40s with a guy named Samuel Thompson that was going door to door selling small, medicinal herb seed packets and little booklets to housewives, encouraging them to grow medicinal herb gardens. His books provided medical advice and so on. He was routinely hounded by physicians and doctors of the day, told that he was a quack and practicing medicine, and that this was their exclusive domain. Samuel Thompson was to a large degree protected by a cadre of housewives that were thrilled at the prospect of growing their own plants, having their own medicine, which they made with their hands. That tradition is unchanged to this day. This is what we have learned. So that other industries—the pharmaceutical industry, the packaged foods industry, the information industry, practitioners of all sorts—sat up and paid attention in 1994, realizing that something big had happened here, that there was a tremendous consumer base for these products. And the post-DSHEA world was immediately all about, how can we get into this? And that was Big Food, Big Pharma, Big Medicine all trying to figure out, what the magic here? There is lightning in this bottle and we don’t understand what it is, but it’s big, it’s powerful, and they spent a great deal of time and money—and still do—trying to figure out how can they create legitimacy with natural health shoppers. So we had no idea, Jeff, going into the post-DSHEA period, that we would change not just the regulation of dietary supplements, but entire categories of other products and classes of service that are fundamentally changed because of what happened with this one category of dietary supplements. JB: That was beautifully stated and I was reminded, I think it was 2010 when I attended, as did you, the meeting on complementary and alternative medicine sponsored by the Institute of Medicine. I think this was the first time ever that the National Academy of Sciences, with its outreach to the IOM, sponsored, in their Washington, DC, headquarters, a cooperative meeting among different representatives of this field called complementary and alternative medicine that was really born out of that same period as we’re discussing of DHSEA. This all kind of came together, and Tom Harkin (Senator Harkin) played a role in the formation of the CAM division, or the Office of Complementary and Alternative Medicine within NIH, so one can see the spreading effect ultimately rising up to what might be arguably considered the high standard of scientific evidence, which is the National Academy of Sciences and the Institute of Medicine, where these topics were seriously discussed, and as I recall Senator Harkin, who gave a keynote speech at that meeting, became one of the great advocates for broadening our perspective of health care, broadening our perspective of medical services to include these concepts that were born out many of the discussions that happened in the early 90s that led to the passage of DSHEA. It’s a remarkable example of cultural transformation, I think, that occurred during that period. LI: It was very formative, and only now—with the benefit of 20 years of look back—can we begin to piece together the real effect that this has had, just as you have described. That the concepts of health and wellness, the emerging understanding of personalized medicine and personalized health care in many respects find their roots that were manifested through DSHEA, but we also could look at DSHEA at those beginning points and look back again in time and realize that the foundations on which that success in the mid-90s was based on was truly predicated on other foundational transitions and transformations, but it’s the same pattern; it’s a repetition of the same theme. But generationally it’s all new to us, and no doubt there will be another generation following us that will rediscover the very same powerful current of populism, self-determination that Americans specifically, based from the political point of view, profoundly want to understand how to hold and retain the ability with knowledge and products to stay healthy and well, and are far less interested in institutionalized answers. Our task going forward is to meet that new challenge. As information now flows so quickly, as the power of individualized knowledge about our personal genetic history will become so accessible, is to understand once again, how do we understand this new science? Not be afraid of it. Not reject it. Flow with it, so that we can be a part of the DNA of this evolutionary process going on right now. JB: That’s really, really beautifully insightful, and I think it codifies so much of what we’ve been trying to do in Functional Medicine Update over these 30-plus years in continually raising the bar of understanding and allowing people to get what I call this virus of knowledge in their nervous system that becomes infective, so that they can see that there is substance, and value, and reproducibility/authenticity to these concepts that deliver improved patient outcome and improved health outcomes. There is one little vignette I’d like you to share, which is just an anecdote, but you tell the story so well and I think people that are not familiar with it will enjoy hearing it, and that is the seminal moment in the passage of DSHEA and the interrelationship with Senator Ted Kennedy. I think that that might be an interesting little part of how sometimes the magic that occurs in the moment is totally unexpected. Tense Moments as the Clock Ticked Down: How Last-Minute Negotiations Passed DSHEA LI: There were a couple of moments of truth. There were three that I’ll do very quickly. The first was another hearing in the Senate, that Senator Kennedy was chairing, and he and Senator Hatch had an extremely close personal relationship, but on this issue they profoundly disagreed. This was another critical hearing, and it was our understanding that Senator Kennedy wanted to postpone the hearing to collect a few more votes to vote down the bill going through committee. Senator Hatch insisted on the vote. We were in the gallery and we were terrified that a big mistake was about to be made, that the bill was going to be lost right before our eyes. What we did not know is that Senator Hatch had rounded up enough votes to win, and Senator Kennedy looked directly at Senator Hatch and said, “Orrin are you sure you want to do this?” And he said, “Yes, Mr. Chairman. Let’s count the votes.” The room was electric with energy. Sure enough, we won by, I believe it was, two votes. The room erupted into cheering, and that is bad protocol in the Senate. Senator Kennedy took his gavel and hit it so hard on the table calling for order the head of the gavel broke off and flew off into the middle of the room. It was a fantastic moment. There was a second meeting at the very end, which was an intense negotiation between all of the principals. It was Waxman, Dingell, Kennedy, Hatch, Harkin, Richardson, all gathered in a little closet room on Capitol Hill, trying to come up with a very last minute agreement. At one point Senator Kennedy pulled Senator Harkin aside. They had a private chat and he said, “I will support this, but I need your personal promise that you will help see this thing through and that the industry, who I really don’t trust, will behave itself, and that you, my fellow democrat, need to make sure that happens. Do I have your assurance?” And Senator Harkin said, “You have it.” The final moment was literally probably five or four minutes before the end of the 1994 congressional session, and our bill was up for unanimous consent, which was the only way it could pass. We were told the bill should come up at about 9 pm. Nine came and went, 9:30, 10, 10:30 came and went, and our bill was nowhere to be seen. We were very concerned about foul play at this point, and sure enough had found that another senator had put a hold on our bill, and all they had to do was wait it out, the bill would die, and would never be seen again. We thought that Senator Kennedy had done this, but couldn’t believe it because he was really a man of his word. Senator Hatch found Senator Kennedy on the floor of the Senate with about four minutes to go. This was about 11:23 pm. The clock is literally counting down below five minutes, and there was a very heated exchange between these two old friends on the Senate floor. Senator Kennedy said to Senator Hatch, “I promise you it’s not me. It’s not me.” And we found out, within about 30 seconds, who it was, and one of the great standoffs in congressional history occurred. The other senator, who was retiring that night, had secretly put a hold on our bill, but he had federal judges that required senate confirmation. So I won’t finish the story because you can fill in the blanks, but at the very last minute there was both the passage of DSHEA and the confirmation of federal judges from one state. JB: It’s so rich. I so appreciate your sharing this. This is a legacy that—on so many levels—is a teaching moment for all of us, about perseverance, about serendipity, about, you know, sometimes things are right even against what appears all odds and they happen against all probability, so very remarkable. And it also reminds us how important and sacred this bill became in changing the architecture of health care in the country, but also the responsibility that it places on all of our shoulders to preserve its integrity and to stand up to that commitment that Senator Harkin made to Senator Kennedy to guard the implementation of this in ways that would maintain the proper intention of it. Which then relates to you and your professional evolution because you turned around and formed this organization that has become a standard bearer for quality, and integrity, and kind of a watchdog of the industry (a participatory watchdog, I would say), which is really engaged in a form of information, self-regulation, and that’s the United Natural Products Alliance, which is just celebrating its 20th anniversary. Congratulations. I can’t believe it’s been 20 years. Tell us a little bit now, as the UNPA—your organization that you founded and are executive director of—has come to the 2013 threshold and we’ve got this new emboldened FDA that is relooking at DSHEA and looking at the provision under what is called new dietary ingredients, which is a look-back now as to what’s been going on in the industry, and what’s good news and what’s not-so-good news. What’s your view of where we are and how this interrelates to some of the opportunities going forward? Work on Refining and Enforcing DSHEA Continues in a World that has Changed Since 1994 LI: Yes, UNPA was formed in 1992 with the express purpose of advancing what became DSHEA. When the bill passed, we saw a mandate to work towards a full implementation of the bill. We’re here nineteen-and-a-half years later still working on it. Much has yet to be done, as it turns out. A major bill very often takes roughly a generation—20 years—to see whether it will be truly and fully implemented. It’s surprising to me that here we are still working on some fundamentals, unfortunately. Organizationally we’re really focused on safety, science, and quality. Within that, we’re looking at DSHEA implementation. That really focuses on good manufacturing practices. The industry has not yet fully adopted the common standard of GMPs that is adequate. There is too much variability in quality. That’s a great concern to us. That the world has changed since ’94, that we live in a highly globalized supply chain. It is extremely difficult to track and trace the source of your ingredients in that global supply chain. We’re doing a lot of work trying to create systems and mechanisms so that companies will have a much better idea of their ingredient pedigree, so that we really have confidence in the global supply chain, which is not going to go away; it will just become more so. FDA has proposed a guidance regarding new versus old dietary ingredients. That’s important because DSHEA created a grandfather date of October 1994, that old ingredients that were on the market at that time would not need to undergo additional or new safety reviews unless there was some evidence of a problem. However, going forward, new ingredients—and this is the question: what is a new ingredient?—need to go through an FDA review process. We agreed to this and think that’s appropriate. The problem is that FDA’s definition of that process is at odds with ours as an industry, so we are trying to work out a compromise to be able to move forward. I anticipate some problems and some disagreements yet on that. Another area of great interest is adverse event reporting. This was created by a separate law from DSHEA, but is bolted onto DSHEA in so far as dietary supplement companies have to surveil and report to FDA if there was a serious adverse event. That helps us understand if there is a trend either that is cause by ingredients, where the safety in the broader population tends to be unpredictably unsure, or if there is a blip in the supply chain with an unsafe ingredient that gets into the supply chain. This is an important measure. It’s critical that companies have good systems to implement it. We’re big supporters of trying to make sure that that is being done correctly. We’re also very interested—you and I have talked about this a lot, frequently—the role of information as it flows to consumers. What we have to always remember is, when we look at important moments in history it is to try and remember what was life was like at that time, and in 1994 this was just the beginning of the internet and the worldwide web, and for many email was still new. Cell phones were very crude and not particularly useful. As we look back on how people were able or not able to get information, we had no way of imagining that the problem would be too much information that is undifferentiated, and the source and origin of that information would be so plentiful that the trick was not how to be able to protect people’s access to information, but now it is how do we filter and qualify high-quality sources of information. That’s what consumers really need. We’re still, like everyone else, trying to figure out how to do that. Our law was built around the idea that the government would try and prevent the flow of information, but the government didn’t understand either that they would not be able to stop what has become a globalized information network. So that’s a real point of interesting concern to us, is how do we manage information, because was a very critical part of DSHEA (protecting the ride and flow of information). Those are among the things that we’re really focused on right now. We have other issues of great interest that we’re working on, but DSHEA-related, those continue to be our high-activity focus points. JB: Loren, I think what you just provided us in these last minutes is truly epic; it’s seminal. I’m sure you’ve told the story many, many times to many different groups, but I think this may be the first time that this has been codified for a medical audience globally that are functional medicine devotees. I think it gives every one of these listeners a much clearer perspective as to the landscape of this extraordinary changing environment that was really borne and germinated out of the early 90s and the response that ultimately became DSHEA and how that affected NIH with the formation of the Complementary and Alternative Medicine office there, and how that led to increased funding and now a well-over 150 million dollars annual budget of the NIH for funding of research into this area with raising the bar for science-based information, and how that led to the formation of the GMPs for dietary supplements that are changing manufacturing policies and procedures, and how that led, then, to changing communications through the support of structure/function claims. All of this has a global impact on health care. I think that a lot of this goes back to the advocacy, the vision, and the tireless work that you’ve put into this field over these many 30 years. I want to thank you for this narrative, but more thank you for what you’ve done. Anyone that is not familiar with UNPA should go to the website UNPA.com. It’s interesting that you’ve still got on your team Peter Rieneke and Patricia Knight, who were working with you through Senator Hatch in DSHEA way back when. This is a body politic of knowledge that is second to none in the universe. I think that this next step forward for not just the industry, but the interrelationship with health care at large is going to be of critical importance in this time of rising burden of chronic disease globally and the fact that drugs don’t seem to solve these problems and that we have to find new solutions and have to draw from a legacy of experience that a lot is rooted in—historical healing methods and a healing environment—which is in this industry and the things that you’ve advocated. The test is upon all of our shoulders as we go forward to make this really stand up and be meaningful in reducing the burden of illness and improving people’s capability to live long healthy lives. Thank you so, so much for all that you’ve done and for sharing this with us. This will be an epic discussion. LI: Jeff, it’s my pleasure. A real honor to spend the last hour with you, and I salute you for everything you did in the critical moments of DSHEA. I think without your steady hand and deep insights I don’t know if we would be having this conversation today. JB: Thank you and we’ll keep in close touch with you and UNPA. More yet to be seen. Thanks so much. LI: Thank you, Jeff.

Welcome to Functional Medicine Update for October 2013. Boy, do we have something in store for you this month. You know, we’ve been talking a lot about what I call the trilogy of ‘omics: genomics, proteomics, and metabolomics, which then regulates phenomics (or the phenotype of the individual). We’ve spoken around this. We’ve had many investigators and researchers and people who are very much specialists in this area talk through the landscape that defines the ‘omics revolution that we’re now engaged in. But never before—until this issue, October 2013—have we had someone that has the background of Dr. Michael Snyder, Chairman of the Genetics Department at Stanford University, who I think is going to open up this topic of personalized health care, personalized medicine, personalized lifestyle medicine and functional medicine in ways that may blow your mind, to use a vernacular. I think you’re going to find this an extraordinary journey that we’ll be taking with Dr. Snyder over the next 30 minutes. So without further ado let’s jump right into out adventure with Dr. Michael Snyder.

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INTERVIEW TRANSCRIPT

Researcher of the Month Michael Snyder, PhD Professor and Chair of Genetics Director, Stanford Center for Genomics and Personalized Medicine Stanford University Palo Alto, CA http://snyderlab.stanford.edu/home.html This month again we’re so privileged to have an individual who frames the epitome of what we’re trying to get to in this clinician/researcher of the month component, which is someone really doing cutting edge work, changing the knowledge base, pushing our understanding of disease prevalence and maybe ways to modify disease expression at the genomic level at that frontier, and that’s Dr. Michael Snyder. Dr. Snyder is the Chair of the Department of Genetics at Stanford University School of Medicine. He’s also the Director of the Center for Genomics and Personalized Medicine at Stanford. He came from Yale, where he was in the Department of Biology there (now, Molecular and Cellular Developmental Biology at Yale), and made the transfer over to the west to Stanford. He’s a chemist by training (both a biologist and a chemist). I would have to say he’s probably a master of many things, doing his PhD work at Cal Tech in the Department of Biology. Again, we all find ourselves having some intellectual consanguinity; my work with Linus Pauling over the last few years of his life as a Research Director at his Institute and my vicarious connection to Cal Tech always reminds me Cal Tech graduates are individuals who have special training in translational science and Dr. Snyder has certainly brought that to his work at Stanford. His topic is one that clearly is on all of our minds, and that is how does this genomic explosion of revolutionary information impact medicine and health care, and how is it going to find a way to converge with all the other things that are happening in information science and big data to really create a frame shift in how we understand the origin of disease, how it can be prevented, and how it can be personalized in its treatment. He gave a presentation at a meeting that I went to in Mountain View earlier in 2013, which was on personalized medicine. His talk was very, very interesting because it was a little bit of a personal history as to how genomic data could be used actually by him, himself, in constructing his own trajectory as it pertains to health and health outcome. So it was all the way from the very precise research-based information to where we start personalizing it and understanding how this can be applied in a translational way. Dr. Snyder, we’re so privileged to have you as our guest for Functional Medicine Update. I guess the first question I might ask you just to get started is, as you have made this transition from Yale over to Stanford and you’ve watched how the genomic discoveries of the turn of the century have started to translate into medicine, how is it seen by you? How has this directed your career and your focus as a leader in the field? Genome Sequencing Technology Has Driven the Personalized Medicine Field MS: Well, I’ve always been interested in understanding things at a more global level. I should say, first of all, thank you very much for having me on the show. The way it has affected me most is I think that we’ve been very interested in understanding things on a much more comprehensive level, and the genomic revolution has really made that possible. So, I think this had been happening with micro-arrays, initially, and such for being able to follow gene expression, but what has really driven the field forward I’d say in the last 10 years or so is the new high-throughput sequencing technologies that have emerged, making it now possible to characterize whole genomes at an accuracy that can be useful for clinical purposes in the so-called personalized medicine field. It’s really the genome sequencing technology that has driven a lot of this, although other technologies have advanced the field as well and some of those we’re now bringing to bear, as I can talk about a little bit later. JB: I’d like to have you describe a little bit for our listeners this concept that seems to have emerged over the last 20 years where we went from discussing certain things within the genome that were not coding, which we called “junk” DNA, to where we’re now talking about them as having regulatory and functional value, and how this has to do with things that regulate gene expression. It seems like this is a pretty interesting part of the development of our knowledge base. Explaining DNA Coding Within the Genome MS: Sure. Basically your DNA, if you will, is a giant ocean. It has six billion bases (that is, six billion letters) that define the genetic code for all of your genes and producing, basically, what you are. What we do know is that the gene part of it—the part that actually winds up encoding for RNAs and later encode for proteins—is really only a few percent, probably on the order of about one-and-a-half percent of the genome encodes genes that make proteins, and a little bit more encodes RNAs that don’t make proteins. It’s still a very small fraction of the giant ocean of DNA that’s in our genome. One of the things that has become clear over the last, I’d say, probably 10 years or so as people started looking at this DNA that was not coding proteins, people have come to realize that it does have a lot of other things. It has, first of all, a lot of regulatory RNAs, so genes that encode regulatory RNAs. But perhaps most surprising is it has a lot of the control elements—the regulatory sequences, or switches, if you will—that control the expression of our genes. I think what is kind of fascinating about this whole part is that the amount of information that controls your gene is probably more than the gene itself. So the switches that decide when genes are turned on or turned off or how much of a gene is expressed in each tissue are really just getting mapped out now, although there is a long ways to go. I would argue we’re just getting started at it. But these switches are very, very important because a lot of the things that make people different…it’s not the genes themselves, but it’s the control sequences for the genes and it’s something we really need to understand in order to be able to understand why people are different from one another, and actually why we’re even different from our most closely related species. We think the difference between chimpanzees and humans, in fact, is mostly due to gene regulation more than to the genes themselves. JB: You know, I just had the chance to read in the last few days, this really wonderful paper that you and your colleagues authored that appeared in the Proceedings of the National Academy of Sciences this year titled, “Systematic Functional Regulatory Assessment of Disease-Associated Variance.”[1] This kind of ties together the SNPs—the Single Nucleotide Polymorphism variations—from person to person together with regulatory assessment, and I like the term “functional,” how they actually function in translating into disease patterns. Could you tell us a little bit about that paper, because I think it is a very powerful story? How Does Regulatory Information in the Genome Relate to Human Disease? MS: Sure. One of the things that our lab is very keen on is trying to understand how this regulatory information is related to human disease. These days you can sequence a person’s genome, it’s not so expensive, it’s about $3000 US dollars to get a human genome sequenced, although the interpretation of that sequence does cost quite a bit more; it’s probably on the order of about $15,000 US dollars. Even when people do this interpretation they spend virtually all of the time on the protein coding sequence of that few percent that I mentioned before, and they ignore the regulatory sequences because they just don’t know how to look at them properly from a disease standpoint and from a functional standpoint. And so with the various efforts going on to map these regulatory sequences outside genes, there are these maps. In a sense they are almost like Google maps people are trying to set up, where you’ll be able to have these landmark sites, and what we’re trying to do is map disease phenotypes on top of those. So, with each of these elements, can they be associated with human disease? So we have been making hundreds, if not thousands, of these associations between particular diseases like cardiovascular disease or diabetes, and trying to map these onto regulatory elements—these regulatory switches. And so at the end of the day, imagine you are a clinician in an office and someday someone comes up to you with their genome sequence, we’ll not only be looking at the coding sequences but we would be looking at these regulatory sequences and seeing how they might map onto disease risk, and then ultimately make some predictions about what a person should watch out for, and maybe what they should eat or not eat, based on knowing something about, again, not just the coding sequences but the regulatory sequences in their genome. JB: I really like another one of your recent papers that you authored, which is titled “Overview of High Throughput Sequencing Technologies to Elucidate Molecular Pathways in Cardiovascular Disease” that appeared in Circulation Research in June of this year.[2] To me that’s a really interesting application of what you’re speaking to in a specific disease-focused area. It sounds to me like this model will cut across all the subspecialties of medicine. It’s a generalized model once it is better understood for defining functional disturbances at the phenotypic level that translate back into expression patterns that are caused by altered regulation of gene expression, which then may translate back to the environment in which the genes are being expressed—what they’re being bathed in and how that influences these expression patterns. MS: That certainly is our hope that by gaining more comprehensive understanding of these control switches—how they intersect with disease associations and then expression differences—that we will be able to make better predictions. I mean at some level this relates to my particular story, which I know you’re familiar with, which is by sequencing my genome we were able to make predictions about my disease risk, and in my case one of the highest disease risks turned out to be type 2 diabetes, which in fact I did get, and we were able to catch because we had sequenced my genome. It told me I was at risk, so I was following this and actually many other molecules as well (we were following all my proteins, and RNA, and metabolites). I can envision a future like that where based on your genome sequence you’ll be trying to map out these regulatory sequences, which, again, are largely ignored right now, and then the variants that lie in those (that is, your personal variants, or your personal changes that lie in regulatory sequences), and see how they associate with human disease and the expression of the genes they control, and make predictions about disease risk that would be useful clinically. That certainly is our goal. In a sense it’s really very similar to the vision that was espoused in this movie Gattaca, where people were—based on their genome sequence—predicted what they’re at risk for and what their fate in life should be. I’m sure many of your listeners have seen that movie. It’s a very fascinating movie, and I believe that at some level this is true. One of the big pushes we’re making is, again, not just to look in the coding sequences for the genes but to look in the regulatory sequences where there is probably 10 times more information than the coding sequences themselves. JB: I’d like to go back if I could and pick up on this fascinating story on, I guess you would call it, the quantified human, which was you. You’re like the n of 1 of the start of this quantified human movement with the way that you did the ‘omics evaluation, going through the metabolomics, and proteomics, and genomics, and expressomics. Maybe if you could tell our listeners a little bit more about that? I thought it was a really fascinating story as to how you assembled that information and what it led you into, knowing that you had pretty good health habits and were health proactive to begin with. I thought it was fascinating. Dr. Snyder Volunteers to Become the Quantified Human MS: Sure. So the rationale of this project is to essentially see how you might be able to use genomics and other sorts of ‘omics information and bring it into health care and personalized medicine. I think the key feature for this is we’re thinking very hard about how to do this for healthy people, not just in cases of disease, so it’s pretty clear—to back up a little—that genome sequencing has huge impact in cancer. Cancer is a genetic disease and if you sequence cancer material versus normal material from the same patient you can try and find the underlying genetic mutations. It’s not routine yet, but it will be routine, in my opinion, in just a few years, and it will have an enormous impact; it already is. There will be other cases, too—trying to solve mysterious genetic diseases by genome sequencing, but one thing that really motivated us is, to what extent can getting your genome sequenced now have some impact on your health care? Our lab was one of the few labs that does quite a bit of genomics and also does other ‘omics. Cardiomics is the study of all the proteins, transcriptomics is the study of all the RNAs and metabolics. We had worked in all these different areas. We could see with the cost of sequencing dropping that it made a lot of sense to see if we could actually start sequencing genomes and incorporate this into health care for a healthy individual. And the other thing that I think struck me that was going on at the same time is that I was always perplexed that when you went into a doctor’s office and they took blood from you and they gave you back a report, they gave you back a report on about 15 different things, and knowing that with today’s technology you can measure thousands, if not tens of thousands, of molecules from a blood sample, I always felt this was woefully inadequate—that is, we’re measuring so few things in a doctor’s office when, if you were to measure ten thousand things, presumably you could learn a lot more. We had been talking a little bit about this when I was at Yale, but the motivation was when I came out to Stanford that we should really see if we could explore this bringing genome sequencing and other ‘omics technologies into profiling a person’s health. And so just as a pilot study we actually chose me just because of the availability of being able to draw blood, and also the fact that at the time it was a bit controversial. A lot of people were kind of scared of genome sequencing. Some people still are. They’re afraid that if you get your genome sequenced you may learn things you’re not really able to handle psychologically; that is, you may discover you’re at risk for a disease that you can’t cure and that would be devastating to a lot of people, and there was a lot of discussion when I first showed up at Stanford—this was in 2009—about whether genome sequencing can and should be used for normal healthy people because, again, they may learn devastating news that they’re not prepared to handle. So, for a variety of reasons we thought it was just easiest to start with me, and it was really a proof of principle study. We sequenced my genome and then made various disease predictions, many of which actually correlated with my family history; things like higher incidence of coronary artery disease was one of the things that was predicted, we knew that from my family history, lower rates of obesity, we also knew that from my family history. But there were some surprises, and certainly the biggest surprise was this high risk for type 2 diabetes that popped up that I was not aware of from my family history, and that did show up early. At the same time we did these blood draws for sequencing my genome we actually decided to look at all the proteins we could out of my blood (meaning out of my blood cells; they are called peripheral blood monocyte cells), also out of my plasma and serum. So we were profiling proteins, metabolites, and RNA out of the peripheral blood monocyte cells, and we also looked at my antibody profiles because they are a pretty good marker for certain kinds of human disease, and we actually profiled my reactivity to 9000 human proteins and we also profiled viruses. And most recently; we’ve added on DNA methylation patterns, which lets us follow epigenetic changes, and we also profile my microbiome, meaning my stool, urine, skin, nasal, and tongue microbiomes, so five different microbiomes we’re now profiling. The idea is to collect all this information and actually see how it changes across time when I’m healthy and times when I have infections. We’ve now been doing this for almost three and a half years, and we draw samples quite frequently when I have a respiratory virus infection. Believe it or not, I’ve also had six of those over these three and a half years because I have two little kids and they seem to pass their germs onto me periodically. So I’ve had six viral infections, three rhinovirus infections, one respiratory syncytial virus infection, and two adenovirus infections during this time. What we do is we do dense sampling when I have these viral infections, meaning we take blood as soon as I start getting some symptoms of being sick, and then we take it the next day, and two days later, and so on. We do dense sampling over three weeks, and then we do it every two to three months when I’m healthy, so fairly infrequently when I’m healthy, but quite frequently when I’m sick. In total we’ve now collected over sixty samples from me across these three and a half years, and then we profile for all these different “oms” that I mentioned before: the transcriptome, the proteome, the autoantibodyome, and the metabolites, and we also profile some very specific proteins as well—cytokines, which are great markers of your immune response, and such. And then we try and follow how all my molecules changed. Initially, we were following about forty thousand molecules in my blood, and now we make literally billions of measurements with the DNA methylation and the microbiome. We’re trying to see how these change over time. What we discovered was, first of all, that I was predicted to be at risk for diabetes, and much to my surprise, I guess scientifically it was quite interesting, personally it wasn’t what I was expecting, I did in fact get diabetes during this time that we were profiling. It turns out, actually, it came up right after a very nasty viral infection—the respiratory syncytial virus is when my sugar shot through the roof. And we caught it because we were doing all these other profiles, all these other “oms,” and we actually caught it fairly quickly, and it didn’t just shoot up for a few days; it was actually up for several months and we were doing all these subsequent tests, like hemoglobin A1c, and sure enough my blood sugar was very, very much up there, to the point where I was classified as diabetic. Once I saw this it took several months to see that it was there and it wasn’t going away—it seemed reproducible—that I actually dramatically changed my diet, which was not a very good diet, I have to admit, in the first place. I used to eat lots of desserts, lots of sweets, because I didn’t know I was at risk for diabetes, or at least I didn’t have it running in my family. Once my sugar did shoot up high I cut out all that and I increased my exercise (increased my biking and started running), and it took about six months but gradually I could bring the sugar levels down to normal range. When I was diabetic, my hemoglobin A1c was up at 6.7. Once I brought it down to normal it was below 5. It was all managed without drugs. It has generally stayed pretty low ever since. The thing that was quite interesting was that also by doing all these other “omes” (meaning the transcriptome and proteome), we could see at a level no one has ever seen before all the different pathways and things that were changing, both during the time I got diabetes and also during the various times I was getting these viral infections. And actually we’ve discovered some new patterns, even since that first paper was published. We’ve seen very interesting cytokine fluctuations that occur after getting certain of the viral infections. It’s really quite fascinating. The bottom line is we can see the physiological changes that are going on at a level no one has ever looked at before, and as one person liked to phrase it, it’s like we’re now getting an IMAX view, if you will, of a person’s molecular state and, in a sense, their physiological and their health state, by following all these molecules, whereas before it would be something akin to looking at a very low resolution, maybe noisy radio, is how I would classify the way we look at things today. It’s just very low level, very crude, compared to what we’re capable of doing. This is the direction I’d like to see medicine go. Right now, everything I’ve told you is very much a research project; that is, it’s like we’re making billions of these measurements. We don’t know which ones are the most meaningful just yet, but by actually doing this on large numbers of people—we’re now trying to study 50 pre-diabetics to see what molecular changes occur when they get diabetes and when they see other periods of stress, like viral infections or other things that might be going on in terms of lifestyle stresses. So we’re actually trying to follow all this, and we’ll see what kinds of molecular changes occur, and ultimately I think we’ll see a new kind of blood test come out where instead of measuring just 15 things as is routinely done, we’ll probably be measuring hopefully thousands of things. And the other thing, I would say, is we would measure them much more frequently than we currently do as well. I’m not sure about all the listeners out there, but as a healthy person I used to go to the doctor I’d say about every 2 to 3 years. If I had done that during the time I got diabetes, I probably wouldn’t have discovered it for another 20 months, so I think we’ll need much more frequent measurements. This will be a bit controversial, but I’d like to see them set up as home tests, where you can actually do self measurements, or you might mail off a little blood spot and get back a detailed report. You’d get these measurements much more frequently, and then if you saw something that looked a bit aberrant you’d go in and get more detailed follow-up tests. The bottom line is I think we’ll be able to see human physiology at a much, much higher resolution than we’re currently doing with these various ‘omics technologies, and ultimately this should have the power of driving medicine, which is now very much symptom-based—as people get sick we treat that. We’ve got to get away from that to a much more preventative and early diagnostics phase where you could predict someone’s disease, try and avoid it, or minimally catch disease early when you can do something about it, like in my case for diabetes. You catch it early and you can manage it. If you catch it late, for most diseases it is very hard to reverse course, but you can manage it somewhat. So that’s my story and some of my thoughts, there. I don’t know if you have some questions for me. Examining Inflammatory Regulatory Pathways in Diabetes Pattern Recognition Work JB: First of all, that’s just a revolutionary story and it’s so inspiring. It’s like having a window into the future. It’s one of those looking glass opportunities. You know, as I looked at your PNAS article recently on the systematic functional regulatory assessment, I recognized that you talk a little bit in that paper about the nuclear factor kappa beta binding regions enriched in disease-associated SNPs. I’m wondering, in your diabetes pattern recognition work with the ‘omics, did you see a confluence between the inflammatory regulatory pathways and the insulin resistance and prediabetes? MS: That’s a great question. We definitely saw the inflammation pathways go up during the time I got infected, and it was after that was when a series of pathways also changed that were related to the glucose metabolism and insulin signaling pathways. So, they were phased a bit. We don’t know whether there is a direct cause or not yet, but of course it’s very attractive to think there is some linkage there, certainly between the viral infection and its associated inflammation response and the glucose dysregulation. We certainly like to think that’s the case. I think this is where we need to study a lot more people to see how often this happens. One other comment I could make on this is that diabetes is a very heterogeneous disease. In fact, we like to think it is probably a hundred different diseases and not one simple disease. It may be that some people do get diabetes and it is linked through things like inflammation, and for other people it may be linked in other ways; it may come out in a different manifestation. The one thing they all have in common is high glucose, but there may be many ways to get there. So that remains to be seen and I think the ‘omics technology will be very useful for dissecting that out to see how many different diseases are there, and that may actually affect the way in which we treat these diseases; we may treat them all a bit differently. JB: I think you just crossed a really important bridge for us in the functional medicine community. You’re probably not familiar with what our definition of functional medicine is about, but it is basically focusing on mechanisms that underlie disturbances in physiology that produce what we later call—for convenience of nomenclature—diseases. We think diseases are kind of the manifestations of resting grounds before we understand mechanisms. As you’ve talked about with diabetes, being multiple different conditions that arise with the same phenotypic outcome called hyperglycemia, you can use that same model across a range of other diseases from the autoimmune family or from the cardiovascular family. That you may have a pathophysiological determinant at the histology level that you call a disease, but the mechanism by which you got there could vary significantly from patient to patient. The future, we believe in functional medicine, is you treat the cause rather than the effect; you understand the origin of the disturbance in the physiology and you find how to treat that rather than what we call “naming and blaming,” putting all your eggs in the basket of the disease. You’ve just spoken eloquently about the whole concept that we, in 1991, formed the Institute for Functional Medicine around. MS: I would agree with everything you just said. I think this can be true of so many different complex diseases. Even cancer, you probably appreciate now, as being stratified by either the genetic underpinnings of the disease and that’s how it’s being treated, and as people look more and more at, for example, breast cancer, they see more and more different subcategories; same with colon cancer. I think this will be true of virtually every disease people look at. There will be different underpinnings, and I think that’s ultimately how it has to be addressed, so I agree 100 percent with you, Jeffrey. JB: Thank you. Since 1991, the Institute for Functional Medicine, which provides approved CME courses for physicians has had about, I think, nearly one hundred thousand physicians have gone through its courses worldwide since 1991. We’ve published a medical textbook in 2005 that was revised in 2010. The concept, then, led us to believe that this is a systems biology operating system for medicine. It’s still in the early stages. It’s a little bit like what Leroy Hood has been talking about with P4 medicine, trying to find a clinical algorithm that will be the top of the funnel into which we pour all this extraordinary information that we’re developing that you’ve described to help the clinician be more precise in how they’re going to manage that patient and their problems and hopefully get to a quantified prevention—a personalized prevention—which then leads me, lastly, to where that has taken us. We recognize that there was probably a rallying round of many different viewpoints and language systems and pedigrees and backgrounds, which is this concept that we call personalized lifestyle medicine. Everyone has a lifestyle, and we know that it’s a wildcard—it’s a variable—that modulates or modifies whatever therapy a patient may be put on. It can affect cytochrome P450 activities and drug detoxification. It can affect immune function…well, it can affect all functions of the body. We said, this seems to be the outlier in medicine because we often think of lifestyle as being soft and all this other being hard science, but yet when we really bring genomics into it, lifestyle—the gene-environment interaction—may become one of the most important modifiers of the phenotype over decades of living, particularly now that we get into understanding more about epigenetics. So we formed the Personalized Lifestyle Medicine Institute in January of this year (of 2013) to try to raise the bar and encourage discussion so that members of this community with divergent backgrounds and expertise might find this a common place for a quantifiable approach towards prevention and early disease management by looking at lifestyle through the same lens that we look at disease. We’re up now with a website. It’s quite remarkable, actually, the kind of response we’re getting. I didn’t realize it until we published an article in the medical press here two months ago that we were the first people to use the term, at least according to PubMed in this personalized lifestyle medicine concept as a word, or as a theme.[3] But it seems to me it ties together many of the things that we’re discussing. It’s early in its infancy, but it may be a place that is a meeting ground for people like yourself and others with different disciplines to really discuss how this gene-environment interaction really influences health and disease patterns. Lifestyle is Multivariable and Hard to Quantify MS: Sure. I mean, I agree again a lot with what you just said. I think one reason it is avoided is the lifestyle part. It’s the hardest thing to quantify, and it is so multivariable—there are so many different variables—that people often don’t know where to start. I think people are digging into this now. You’ve seen the simple devices people wear to measure all the steps they take, the Jawbone and the Fitbit and other things that you can put in as apps on your iPhone, so people are starting to quantify other sorts of parameters. There’s a long ways to go; measuring your food intake and all the various things that do basically integrate into lifestyle. I think there’s a lot to be done here, and I agree with you that it is completely in its infancy. I think the other comment I would make and I think you alluded to, but to be more explicit, is I think things like the DNA methylation and transcriptomics that gives you information, we think, about your epigenomic state, and it’s an indirect measure of some of these lifestyle impacts, I would say. So we’re hopeful that some of these other ‘omics will be a bit of a readout; an indirect readout of some of the lifestyle things that are occurring, that they will help us be more predictive about what sorts of possibilities might be happening with regards to your health. That is, if you get a viral infection does it leave a permanent mark or a semi-permanent mark on your DNA methylation pattern, which in turn could lead to acquisition of a disease, like diabetes or what have you. We do want to get more ‘omics measurements to get these readouts, and I think also quantifying more of the things that you just talked about—the various toxins that people get exposed to in the food they eat, all the sorts of things I think will ultimately be very, very powerful not only in understanding human physiology, but being able to make predictions. Ultimately, it comes back to that Gattaca movie; we want to be very predictive about both the combination of our genetics and our environmental lifestyles that will make things very predictive about possible outcomes, and that way we’ll be able to manage health care much, much better. JB: I can’t tell you how much I appreciate both your insight and time. I would call this discussion, for me, comparable to two other epic discussions I’ve had the privilege of having on Functional Medicine Update, one was with Moshe Szyf at McGill University, who is in the labs of Hans Selye. He and his coworkers have been looking at epigenetic imprinting by psychobehavioral changes in the animals’ environment. You might be familiar with some of this work—how they show that methylation patterns change with nurturing and with stress patterns in the animals’ environment that then alter expression patterns of cassettes of genes that are associated with alarm genes. So they talk about things like posttraumatic stress syndrome and how they get locked in by epigenetic programming, basically. And then I also had the privilege of interviewing on a couple of occasions Randy Jirtle at Duke, who has done some really wonderful work on nutritional epigenomics. I think you’re probably familiar with his work with Bob Waterland where they looked at the methylating nutrients—folate, B12, and B6—in pregnant animals (in the Agouti mouse, actually), and showed how they could modify the fur coat and form these pseudo-Agoutis that don’t get fat, and they don’t get diabetes, which are conditions that their parents with the same genes, are predisposed to getting.[4] I think there is a tremendous frontier that is opening up thanks to work of people like yourself to really change the complexion of medicine from being a deterministic medicine to being a very modifiable form of health care. If you know the answers to the right questions you can get entirely different answers. MS: I agree. It all sounds great. JB: Thank you very, very much. We’re going to follow your work very closely, and I can’t tell you once again how much we appreciate your sharing what you’ve done. MS: Sure, thanks again for having me  

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Welcome to Functional Medicine Update for November 2013. One of the topics that we have discussed at some length throughout the course of the last nearly 30-plus years has been the research methods that underlie a proof of hypothesis or a proof of concept. We’ve talked a little bit about how complicated it is in the area of systems biology to use a univariate type of hypothesis to prove a point. In other words, if you are trying to use a model, which is one agent against one outcome, and you’re really trying to look at a systemic or systems-wide effect, it’s very difficult to design a study that would be appropriate to test that hypothesis using an univariate model or let’s call it a double-blind, randomized, placebo-controlled, single-agent-against-single-type of approach when trying to prove a systems effect. It’s not impossible, but it’s certainly very challenging in terms of design. We’re going to have the opportunity in this issue of Functional Medicine Update of talking to an expert, Dr. Jay Udani, who is an internist who is overseeing as the director of a CRO—contract research organization—that’s really focused on looking at some of these systems biology approaches and issues in the field of medicine, and particularly focused on some of the natural products areas and these biological response modifiers that are pleiotropic in their mechanism of action, meaning they have multiple hits in physiology—that they are weak interactors, but they have multiple effects on different physiological functions. So the question is how do you design studies to prove efficacy and safety? That’s something we’ll be discussing at length with Dr. Udani. Beyond that, however, is something else that has come to light. It really comes as a consequence of the experiences that I’ve had over the last 30 years, but amplified over the last couple of months, where I’ve had the opportunity to travel extensively and speak with researchers and clinicians around the world. Let me just tell you how I have derived this thought.   Traveling the World, Seeing the Need for Global Changes in Thinking During the course of the summer of 2013, I had the opportunity to be in Canada for a meeting where I was presenting before the Canadian Naturopathic  Association, and so I met some of the leaders in natural medicine in Canada. Then later in the summer I had the chance to go to Taipei, Taiwan to meet with many leaders in the traditional medical circle within the Taiwanese medical community who are venturing out as early adopters into this concept of systems biology and functional medicine. I’ve had the privilege of going there several years in a row now. This group has grown quite large with over 200 different medical doctors from major medical institutions who are asking questions about the proof of concept within this functional medicine/systems biology model. From there, then, I had the chance to be involved with several medical school engagements, looking at collaborative research projects with what we might consider traditional, institutional-based medicine, and where the interest really is looking at systems biology in medicine and how you actually start to define proof of effectiveness in these broad functional medicine models  versus pill-for-an-ill-single-hit-type model. And then from that I had the chance most recently to travel to London to engage in a collaborative discussion with over 400 health practitioners, many of them from the traditional Royal Society of Medicine model, and asking questions about new ways of proving success and efficacy in this new biology of the 21st century. And then lastly, a very interesting visit in Milano, Italy with a group of about 165 medical providers who are, again, heads of their medical school departments, and leaders of clinical wisdom within their communities who are again asking the same question: What do we do to prove some of these broader issues within the area of systems biology and medicine? So it seems like, from my own personal experience, this is almost like the hundredth monkey; how many people have to think about this before we start producing global change, or, you know, the butterfly’s wings in China producing a weather change in North America—that kind of concept. As I came back through all of these trips and spent some time on the plane reflecting on these conversations, I came to recognize that some of these beliefs that we’ve had about the single agents having single effects to produce single outcomes are fallacious; they’re really not true. When we start examining with a broader lens the effects of what we think are single actions—independent actions—like a drug that hits a specific target to influence a specific biomarker, an endpoint that has a specific disease implication, we find that those are really, when we dig deeper, not actually correct. These drugs are hitting multiple things, of which one we look at. You know, if you don’t ask the question, you don’t get answers; you see only what you see. Statins: The Classic Example of a Therapeutic Agent with Pleiotropic Effects I think if you use, as an example of this, statins, which I find is probably the most predominant story, because when we first all were told about statins and the way they were discovered is through their ability to block these monocholines that were found in fungal metabolites of certain species of fungus. These monocholines were able to block or inhibit an enzyme called hydroymethylglutaryl Coenzyme-A-reductase, which basically is an enzyme that is involved with the rate-limiting production of cholesterol. So we were told that these drugs worked by blocking the synthesis of cholesterol. And by the way, they do that, so that’s not to be corrected. However, with more, now, 30 years of experience with these statins, both the original Lovastatin and then the later developments of other derivatives, like the more potent statins of today, we find that they have pleitropic effects. They have biological effects other than just the inhibition of this enzyme HMG-coA-reductase. In fact, these other effects may be as or more important in their efficacy than was the singular belief that they worked solely by blocking HMG-CoA-reductase. These are the effects that they have on things like the immune system. Now we say, these statins are anti-inflammatories and they work by blocking immune reactions at the arterial endothelium, and therefore they prevent, somehow, the atherogenic process, not just by their mitigation of cholesterol biosynthesis, but also by these pleiotropic influences on the complex interaction of monocytes and macrophages with the vascular endothelium and how that relates to lesions that ultimately become sclerosed that we call atherosclerosis. If we use that as just a single example of where we believe that something was a single agent against a single endpoint and now we find it is a single agent against multiple endpoints, and the more we look the more we find, we can probably extend that into virtually every class of therapeutic agents, and so in some ways everything is working in a systems biology fashion; we just didn’t ask the question. You can use the same logic for things like angiotensin-converting enzymes, or angiotensin-receptor blocking agents that are involved with hypertension management. We look at those and we find that these are pleiotropic molecules as well. They don’t just hit angiotensin receptors or angiotensin-converting enzyme activity. They have other effects that influence multiple things such as inflammation, insulin signaling, cell proliferation, as well as hypertension.   Connecting Obesity and Diabetes: Understanding Mechanisms and Therapeutic Approaches Where am I going with this? I’m going to shine a light on the emperor in the corner who is not well dressed, in fact maybe even a little bit naked, and doesn’t look that good in the bright light of our present view because we recognize we’ve missed a lot of that emperor’s anatomy. That there are things that are probably more important than we previously understood. Let me take an example now of how this fans out into the complex question of how you prove something in a systems biology model. Let’s take what we all know about, or at least we think we know about, the connection between obesity and diabetes. That seems like a fairly simple question. Shouldn’t we be able to just make studies in which we’re looking at people with elevated BMI (body mass indices) and show that these individuals have a high prevalence of diabetes, which would then “prove” the hypothesis that obesity causes diabetes?  It seems like a reasonable concept, and in fact, if you look at literally hundreds and maybe even more like thousands of papers, the assumption has been made that obesity causes type 2 diabetes. Okay, good. Thirty years of understanding, and so to treat diabetes by putting people on weight loss diets, meaning you restrict calories by some mechanism so that they will lose weight, or you increase their activity levels by having them suddenly take up going to fitness clubs or something so they will no longer be diabetic. Now, what’s wrong with this? Just as I was examining or using as an example with the statins and heart disease, it’s that that model that I’ve just described for obesity and diabetes is not totally wrong. We know that there is a very high correlation between elevated BMI and diabetes. But an association does not prove causality. Just because two things are associated doesn’t mean that one is caused by the other. They may be both caused by something else—by some other disturbance in the system—in a systems way, just as we said the reduction in heart disease incidence with males taking statins may not solely be a result of lowering cholesterol biosynthesis. It may be a result of other effects of this pleiotropic mechanism of action of statins across vascular endothelial health and immune function and inflammation. I hope I’m not losing you all here. I know I’m getting a little bit alliterative, but I believe you kind of get the drift of where I’m going. So let’s look in a little bit more detail at this obesity-diabetes connection, because I think it’s not only insightful in terms of helping us to understand the complexity of developing an understanding of mechanism and therapeutic approach, but it also leads us into what might be a much better way of approaching diabetes than just to think we’re going to put people on weight loss diets and they’re going to get better.   Fitness and Fatness: A New Study Illustrates the Complexity of Pre-Diabetes Let’s now look at this. A recent study in this area has been published that bears light on this particular question. This is, again, like shining light in the corner on the emperor over there with no clothes. The study was collaborative work, including the department of human performance and sports science from Winston-Salem State University, and the Department of Exercise Science and the Arnold School of Public Health at the South Carolina School of Medicine.  They recently published a paper titled “Fitness, Fatness, and Survival in Adults with Pre-diabetes.”[1] Now, why is this paper one that I’m citing? Because I think it illustrates the complexity of this topic. Because what they found in this particular study in which they screened for individuals with metabolic syndrome, insulin resistance, pre-diabetes, whatever you want to call it—so they screened a very large number of individuals that fulfilled this criteria. In fact, over the course of the study 17,044 responded, so it’s a fairly large study. This group of people had pre-diabetes, meaning they had fasting blood sugar somewhere between 105 and 126 milligrams per deciliter, so they weren’t frankly diabetic, but they weren’t normal glycemic; they were in that grey area. So they then asked the question, what was the mortality of these individuals who had this pre-diabetic condition? What was seen is those individuals with elevated BMIs who had high cardiovascular fitness, meaning on a standard submaximal cardiac stress tested they tested to be reasonably fit (so these were reasonably fit, overweight people, who were pre-diabetic), there was no difference in their health outcomes than lean, fit individuals. In fact, what they found is that thin, unfit individuals had a similar adverse effect as heavy unfit individuals, which was entirely different and more advanced promotion of disease than in either overweight fit individuals or normal weight fit individuals. I hope you understand what I’m saying here. This is a fairly important study because we know from previous work that has been published that in frankly diabetic patients, people that have fasting blood sugars above 126 milligram per deciliter, that the same thing is found to be true—that there is no correlation between diabetes and elevated body mass unless you also look at fitness. level.[2] We also know, to confound this even more fully, and we’ve discussed this at length in previous editions of Functional Medicine Update, that in individuals who are overweight but have low normal GGT (gammaglutamyl transpesidase) levels in their blood, that they do not have elevatedrisk of diabetes. It’s only in those people that are overweight and have upper-level normal or above normal GGT levels in their blood plasma, and who are unfit, that have the highest risk of diabetes.[3] So can we say that fatness causes diabetes? No, we can’t. We say it is associated, but there are other factors that we have to take into account as part of the system disturbance to really understand personally how that individual has a risk of diabetes. From this fans out all the secondary conditions of disease that are associated with diabetes. Not just diabetes itself, but nephropathy, ocular injury (cataract, for instance), neuropathy, dementia, cardiovascular disease—these are all attendant covariables associated with diabetes. Clearly, our simple-minded univariate association between fatness and diabetes is incorrect, so that would mean that we would put a huge number of people on weight loss diets, assuming that that was the cause of their diabetes, only to find that they didn’t respond very effectively. And other people, who are reasonably thin, we would say, “Well, they certainly don’t have any problem with their body weight so I won’t have to do anything with them,” when actually maybe the cause is below both of those, and we should be looking more deeply for the personal contribution to their system disturbance we call metabolic disease or diabetes. What this means, in fact, is if we took a hundred type 2 diabetics or a hundred pre-diabetics at random and asked what is the characteristic that defines them, what I think we would say is, we have a hundred pre-diabetics or diabetics, each one is different from the other. You cannot form one general rule, saying this produces that. You have to look at each individual patient or each individual person and ask, what’s the contributor in their specific situation to lead to this metabolic disturbance? In other words, it is the interrelationship of their genetic uniqueness with their environment that produces this outcome. Now you’re going to say, “But, Jeff, there are literally tens of thousands of people who kind of get the generic treatment of diabetes and they seem to be doing just fine. Their blood sugars are normalized and they don’t seem to be getting kidney failure and we’re using a formulaic approach, so aren’t you exaggerating your story?” I don’t think I’m exaggerating my story for the following reason. If you go back and you review where people were studied whose blood sugars were tightly controlled by pharmacological mechanisms using a standard recipe, so they were rigorously controlled, their A1cs were controlled, and their blood sugars were controlled by precise use of the pharmacology of the day, you will find, on outcome-based levels—not just measuring the numbers, but how did they do over years—you’ll find that their outcomes were not as good as you want them to be. These are studies that were published in top-level journals, like JAMA and the New England Journal of Medicine.[4],[5],[6] So, how does that work? Well, it says that the rule of the averages is pretty good if you’re in the average. If you’re in the middle of a Gaussian curve, probably a formulaic approach will work. Good for you. But all those people on the side of the curve, the bell-shaped curve of life, those formulaic approaches for them may not work as well. In fact, they may even produce an untoward outcome. But medicine has been developed for the averages, not for the individual, so what the heck do we do? We change medicine. We can’t change the individuals; their genes are what they are. We have to change the medicine to get a better outcome. This study that I was describing about fitness and diabetics and pre-diabetics I think is a very telling study because it suggests that the way we should start doing research is to cohort stratify. We don’t just throw everybody in a big lump and call them 70-kilogram humans and assume they’re going to respond the same. We have to look at cohorts of individual susceptibilities or individual responses to environments and ask, what’s best for that group? You’re going to say, how thinly do we need to cut the cohorts? Like, is everybody a patient unto himself, so everyone is an individual study? Maybe that’s a little too ambitious at this point in our technology, although I think in the future that’s the way we will go. We’ll have the data from Big Data on each individual that will allow their programs to be very personalized to their need, but in the absence of having all of that information available today, which may be available more quickly than we think, but today maybe we don’t have it, so we have to use the best information we have available to stratify. Let’s start asking how we would stratify, in a study, to evaluate the influence of body fatness to diabetes and its secondary side effects. I’ve described a couple of ways we might stratify. One way would be to stratify on fitness levels, because maybe those individuals who are unfit, their primary therapy should be improving their fitness levels. Maybe more so than drugs. Maybe more so than anything, that’s what they need. Their prescription should be principally a fitness prescription. Maybe that is a takeaway that is more important than any pharmacological or nutraceutical intervention that a person can get if they have  that status. Or, let’s assume that these are individuals that have elevated gammaglutamyl transpepsidase, which is a surrogate marker for what? Toxicity. That these people have accumulated in their bodies a burden of toxins that their glutathione pathway is trying to detoxify and they are at constant risk to this mitochondrial interruption from toxic burden of their energy powerhouse in the cells, including their pancreatic beta cells, the insulin-secreting cells, so maybe for those people the first important thing is to put them on a detoxification program, to liberate from their body the burden of these toxins that are inducing mitochondrial inhibition and causing insulin resistance. Well that’s an interesting concept. So, who, then are those people? Well, we need a different set of screening tools to know who those people are who have the principal problem of toxicity, and that’s where GGT levels in the blood might be useful as a first-level screening tool. Well, what about another one? How about endotoxemia? Oh my word, now we really get into the netherworld. Endotoxemia, meaning maybe some peoples’ origin of their diabetes starts in their intestinal tract because they have a gut inflammatory condition going on as a consequence of funny bugs in their microbiome that are releasing cell wall debris, which we call lipopolysaccharides, that are powerful proinflammatoriy substances produced in their gut, and punch holes in their gut epithelial lining, which leads to what? A portal of entry for other toxic molecules that then activate their immune system and triggers  insulin resistance induced by systemic inflammation. And that systemic inflammation, I might add, is principally delivered through the relay race of macrophages and monocytes—these white blood cells that are sitting around in the liver getting information from the liver’s immune system, which is called the Kupffer cells. So the Kupffer cells are saying to the circulating white blood cells, “You know, I just got a message upstream from the portal blood coming from the intestinal tract that we’ve got trouble on board and you ought to be really alarmed, so take that message out to the rest of the body.” So these macrophages and monocytes circulate out into the blood, and where do they end up? In part, they end up in the fat mass, which is called the adipocyte mass, particularly the central adipocytes, the intra-abdominal adipocytes, the big waist-to-hip ratio adipocytes, right? And what do those adipocytes do? They are also derived from the same family lineage as are the white blood cells, the Kupffer cells, and the intestinal mucosal immune cells. They are all from the same family line, so they get the information from these macrophages that are embedded now in the fat mass that are saying, “You know, the intestinal tract tells us that it’s pretty upset with the way it’s being treated. You ought to be upset, too. And the way I say it is, it’s as if the fat cells say, “I’m fed up and I’m not going to take it anymore.” Right? Using kind of a double entendre. And so what do those cells do? Those fat cells, they have the ability to upregulate their genes to express a message called adipocytokines. And what are those adipocytokines? They are alarm molecules. They have names like TNFalpha, tumor necrosis factor alpha. Just the name alone kind of suggests what its activity is. Or interleukin-6, one of these proinflammatory cytokines. So they circulate out in the blood and where do they end up? They go everywhere. They go into the vascular endothelium. They go into the brain. They go into the muscle. They induce lipotoxicity. And they can even activate, in the brain, the embedded immune system, which is part of their relatives, and what are those cells called? Microglia. So if the microglia pick up an alarm message in the blood that has come from the fat cells, which has come from the liver, which has come from the intestinal tract, what do you think the brain immune system says? It says to the neurons—its adjacent cell type—“You ought to be upset, because everybody else is upset.” That’s called neuroinflammation. That leads to dementia. Is there a connection between insulin resistance, diabetes, and dementia? Yes.[7] So we start understanding a mechanism here that cannot be identified by one agent against one outcome. I hope you see what I’m saying. You’ve got a pattern of disturbance, here. You’ve got a system of disturbance. In that case, if a person has endotoxemia, where do you want to focus your attention? You want to focus your attention on normalizing gut immune function. You know, if might seem in a traditional medical model like, what? You’re now in gastroenterology trying to treat diabetes? That sounds like crossing the barrier between two different medical disciplines that are independent of each other. They are not independent. They are all part of the system of communication that relates to insulin and glucose regulation. If you take the most recent issue of Nature Medicine, in a very, very nice little article titled “Microbes, Metabolism, and Medications,” what they talk about is the key role of intestinal flora, known as the gut microbiome that we’ve discussed for years—in fact, from the dawn of creation of Functional Medicine Update we’ve been talking about the microbiome.[8] It seems like I’ve been living and talking about this as long as Ilya Metchnikov at the turn of the last century. This article goes on to say that this gut microbiome, or the intestinal flora, is a very, very important component in establishing the integrity of the mucosal barrier in the intestinal tract and it contributes to immune function and epithelial growth and differentiation. We call this leaky gut. Now the term leaky gut is gaining traction and in fact what used to be considered like the grounds for disbarment if you brought up leaky gut in a traditional group of medical physicians, now leaky gut is quite fashionable and everybody is talking about it. In fact, the head of the Italian gastroenterological society has made his claim-to-fame in Italy by being the chief researcher on what he calls leaky gut. We are seeing a frame shift, a real paradigm shift in understanding the gut is the central therapeutic focus for improving insulin sensitivity and treating type 2 diabetes. So if you have a person who has gut endotoxemia, or let’s call it postprandial dietary endotoxemia, then you would want those patients—the individual—to have their primary focus not on fitness maybe, or not on systemic tissue insulin sensitivity or beta cell insulin secretion, but on improving integrity of the gut mucosa to prevent leaky gut and transference of potential immune activating substances across the gut mucosal barrier and activating the gut immune system, the so-called gastrointestinal-associated lymphoid tissue. This again shows you the nature of thinking from a systems biology approach, that you need to get beyond thinking of one agent for one outcome. Your agents may have multiple effects. Particularly when you start talking about lifestyle intervention or diet intervention, you’re not just hitting one target. You’re hitting many, many different targets, so you wouldn’t just put a person on a program solely for their gut mucosal effects. You would put a person on a good nutrition program that would re-nourish the gut mucosa, but it would also simultaneously have positive effect upon multiple other factors, systemically, really, that relate to physiology.   Dr. James A. Levine and the Concept of Non-Exercise Activity Thermogenesis Let’s go back for a moment and just look at this fitness part of the equation. Because whenever I say fitness, in the mindset of many that conjures up this view of joining some kind of marathon training group or something, like it’s a boot camp. You’re going to have to go to cruel and unusual levels of commitment to improve strength, endurance, and flexibility in order to get a positive benefit. I had the privilege of hearing a lecture and then speaking personally with Dr. James A. Levine at the Mayo Clinic, who is a world leader in development of a concept called non-exercise activity thermogenesis. Non-exercise activity thermogenesis. By the way, for those of you who are interested in learning more about this, there’s a wonderful review paper that he has authored with his colleagues at Mayo that appeared in the journal Arteriosclerosis, Thrombosis, and Vascular Biology. This was actually back in 2006, volume 26, page 729.[9] It outlines this concept, which he abbreviates as NEAT—it’s a NEAT concept—that stands for non-exercise activity thermogenesis (NEAT). The subtitle of this article I think you’ll find interesting. It’s “The Crouching Tiger Hidden Dragon of Societal Weight Gain.” That’s kind of an interesting metaphor. And what he is saying is that you don’t have to be out running around the world training for marathons and involved with extreme athletics, or pushing the envelope into the area of aerobic/anaerobic debt of the wall to get extraordinary benefits. The way that this group proved this—you might be familiar with this—is really tremendously innovative work. They developed a set of underwear for men and women that then contain, in regions around the underwear—this would fit around the torso, all the way up to the chest and down through the buttocks, sensors (piezoelectric sensors). Let’s call it accelerometers, so to speak, that would measure XYZ coordinate movement. So these were able to measure in real time and transmit data to a collecting device that would then be able to model exactly how a person was moving throughout their day. So that would be like moving in sleep, moving at rest, at work, moving whatever—24-hour movement profile. What was found was this component of calorie expenditure that was not very well understood until their work, which is called non-exercise activity thermogenesis, meaning there is about a six-to-eight hundred calorie difference among people who move around. Some people call this fidgeting, but it’s not really fidgeting. It’s getting up and moving your body, not just sitting in the same position in front of a computer screen for like eight-to-ten hours a day, not moving. This can contribute up to 800 calories of energy expenditure. It would be like running eight miles additionally per day if you were jogging at eight minutes per mile. It would be like that level of energy expenditure. And that’s the difference in these people that maintain leanness and those people that don’t. It is this non-exercise activity thermogenesis. From those studies, what they found is, okay, how do we induce it? How do we make it easy? This is where the whole concept of walking became so important because they found that if a person would just walk after every meal for 20 minutes—after every meal they would go out for a short walk (15 to 20 minutes)—that it blunts the postprandial blood sugar.[10] They developed all sorts of ways in schools for kids to move and stand up in classroom orientation so they weren’t just sitting for long periods of time without movement. They took this to the workplace. They developed standing workstations—you’ve probably seen them—and even treadmills, where you can work on your computer standing up and you can walk slowly while you’re working. They have these workstations in many companies where you can go and plug in your chip and you can work for a half hour or an hour at that workstation while you’re slowly walking. When they looked at the group overall aggregate body composition, they found unbelievable improvements. So what I’m trying to say is simple things that come out of complex thinking through systems thinking produces extraordinary breakthroughs in therapeutics, rather than just if all you have is a hammer everything’s a nail, kind of one univariate thinking. With that in mind, we’re going to be talking to Dr. Udani about how do you actually address these things in experimental methods to prove them and to actually move this ball forward so we’re not stuck in this old model of one agent against one outcome, and we can actually propel medicine forward based on a systems biology approach?

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jay Udani, MD, CPI, FACN CEO and Medical Director, Medicus Research CEO, SysteMedicus, Inc. Medical Director, Northridge Hospital Integrative Medicine Program www.medicusresearch.com November 2013 Well here, once again, we’re at that place in Functional Medicine Update that I think really defines the topic, defines the focus of each of our issues, and that’s our clinician/researcher of the month, and we’re very fortunate this month to have a person who really fulfills both of those criteria. I’m speaking about Dr. Jay Udani, a medical internist, who is founder and CEO of Medicus Research, which is a contract research organization working within the natural products and natural health product regime and really looking at the clinical safety and effectiveness of things like botanical drugs, dietary supplements, and functional foods. As you probably know, Dr. Udani, whose reputation precedes him, is from Cedar Sinai (was a resident there) and then moved over into a program, which he has been very, very principally responsible for, which is this innovative clinical research program at Northridge Hospital in the San Fernando Valley. He works at the Geffen Institute at UCLA, in the medical school, and has been very actively involved as a clinical associate there as well. And he is certainly seen as one of the bright lights in the whole field of clinical research in the natural products area. An eloquent speaker, a very clear speaker, and a person who has really started to help us understand how clinical research will play a bigger role in defining proof of concept and proof of principle as it pertains to the safety and effectiveness of natural products in managing chronic illness. Dr. Udani, it’s a great privilege to have you as a Functional Medicine Update clinician of the month and thank you for your time with us today. JU: Thank you, Jeff. You’re a great inspiration to me and one of my mentors, so it’s my pleasure to be here. JB: Let’s start right down the trail, here, Jay, as I often do with individuals, and ask them how they got on their path, on their journey to this point. You probably didn’t just start by saying, “Hey, I’m going to start a contract research organization to do clinical research in the area of natural products.” How did this arrive in your career and your focus? Establishing a Contract Research Organization to Conduct Studies of All Sizes JU: Well, you know, it’s a confluence of many things. I’ve been doing human clinical trials since working at a local hospital in Chicago, where I was running a clinical trial for a neonatology unit, and so I had been doing research all along in undergrad, med school, and residency. A couple of things happened in my residency, which was very traditional internal medicine, and I had planned to go into one of the internal medicine subspecialties and be firmly on the allopathic track. The first was my fiancée, now wife, Amy, had mentioned just off-handedly one day that she was having a bit of an acne breakout and was going to go to her Chinese medical physician in downtown LA and get some herbs and some other treatment— possibly acupuncture. Being chief resident of internal medicine at the time, I very calmly responded, “What are you talking about?! When you’re engaged to the chief resident of internal medicine at Cedars Sinai you do not go see some quack downtown.” She, of course, being right, as she always is, said, “Why don’t you open your eyes to what’s going on out there?” And this was in the mid-90s where this really hadn’t broken the surface, at least within the medical community, about what was going on. And I did. I started looking around and I said, “Holy cow, people are using dietary supplements and alternative medicine. They really had no—from my standpoint—authoritative medical guidance at that time about what they should use or not use, and what was safe and not safe. Serendipitously, at the same time, Eisenberg came to Cedars Sinai to deliver ground rounds on his groundbreaking research, looking at the number of people in this country using alternative medicine.[11] And I sort of figured out this is something that is going to be big and also in conjunction with all that our chief of medicine announced that they were going to be starting an integrative medicine program at Cedars Sinai. So I volunteered and said, “Look, if you’re starting a program you’re going to need a fellowship. I’ll be your first Fellow. I’ll write the curriculum. I’ll put all this together.” I had an opportunity to work with Dr. Mary Hardy in starting that up, and really while finishing up a health services research outcomes fellowship, focused on research methodology and design for alternative medicine. Not just for dietary supplements, but for how you research alternative medicine paradigms, like traditional Chinese medicine or chiropractic, in the context of only looking at the reductionist model of pharmaceutical drug development. How do you effectively document and track and compare efficacy of whole systems versus with standard-of-care approaches. That really was the genesis of it, and when I came to Northridge Hospital to start their integrative program, I began doing some clinical trials there and eventually spun off what is now Medicus Research, which is a independent contract research organization doing, as you said, clinical trials for natural health products, but in the context of always knowing that these products have a certain risk-benefit ratio, which is that the benefit may not be as immediate or abrupt as pharmaceutical, but the risk profile is—in my opinion—so far superior that it is worth doing. And then along the last 12 years now, you’ve seen yourself the evolution of the industry. The first clinical trials were a pastime in that very few companies would support them. If you didn’t have academic or government support, there really were no clinical trials to be done. But as regulatory pressures have been changing, as enforcement has stepped up, especially in the last four years, the demand for this work as a solid business, if you will, has really taken off, and so we’ve been preparing for all these years—again, the last 12 years we’ve been doing nothing but this—and now have the ability to help these dozens and dozens of companies in designing and running their clinical trials. JB: I really want to compliment you. I think your prescience in being able to look forward to what is going to be needed in the way of designing appropriate trials to do proof of principle or proof of concept I think was really, really very forward thinking. I think it might be useful for our listeners just to go back. You know, you have over 20 publications on different ingredients and different products in different human clinical trials. Maybe we can review a few of those just to kind of give people an idea of what we’re talking about. Let’s start back, if we can, with a trial that you were involved in, which I think is very interesting, looking at the interface of psyllium and plant sterols in hypercholesterolemic individuals. This was published back in the Journal of Nutrition in 2006.[12] A Study on Psyllium Delivered Via Chocolate Chip Cookie JU: Sure, and that’s an excellent study to talk about because we deal with companies of all sizes and shapes, from the largest of large to this study, which was, in fact, funded by two registered dietitians. I mean it was literally an in-the-garage type of thing. They had a very unique delivery vehicle, which was a chocolate chip cookie. They put the sterols and the fiber into the cookie and found a way to make it taste good, so we were looking at what it was going to take to design and run that study. The main challenge was the placebo cookie. The psyllium and sterols do add and change some of the mouth feel. It’s a lot easier when you are taking something in a capsule to blind people to the intervention, so we had to look for certain ingredients and certain baking processes that would at least make the two cookies roughly equivalent, and that’s an important part—when we’re looking at blinding, again, to contrast and compare pharmaceutical studies with natural health products. In pharma you have a pill, tablet, capsule, whatever and it’s manufactured and you simply manufacture a placebo that looks identical. In what we deal with, you have foods and other things that have flavors, that have mouth feel, that have taste, that have smell. If you open up a bottle containing fish oil, for example, it’s going to have a certain smell. If you open up a bottle containing turmeric, it’s going to have a certain smell. So we had to learn over the years how to mask, how to add additional smells and flavors, and try to make our blinding as good as possible, and the concept there is sensory equivalent if not sensory identical, meaning that in some cases it may be impossible to replicate a certain smell—let’s go to fish oil or turmeric—but you can add another smell that is as strong and doesn’t carry connotations that are so different, so that when a clinician or a patient is taking it, they can’t tell, “Oh, this one doesn’t smell at all. It must be placebo. My friend has the one that smells. He must be on the real thing.” Anyway, to go back to that particular paper, we did see statistically significant differences in a reasonable time period for the endpoints we were looking at in cholesterol and also especially we were looking at LDL subfractions. It’s been well known that psyllium and sterols have this impact, but it is the combination of the two together and it was the unique delivery vehicle of the chocolate chip cookie that I think made that article most interesting. JB: Yes, very interesting. Thank you. Another example is the really interesting study you did on adding to white bread a white bean extract to study the effect it had on glycemic index. That was a 2009 paper in Nutrition journal.[13] Tell us a little bit about that. That’s another interesting study. JU: It’s an alpha-amylase inhibitor—a proprietary one—called Phase 2, and it binds competitively to alpha-amylase in the gut (alpha-amylase is a pancreatic enzyme). They bind to the carbohydrate itself, or in this case they are binding to the primary enzyme responsible for digestion of long-chain complex carbohydrates into shorter chain sugars, which are more easily absorbed. What we found in this case is there does appear to be a dose-response curve, and possibly even a threshold effect, meaning that you have to give enough of the product to overwhelm and bind to all of the alpha-amylase in the gut that is released in response to a meal in order to adequately reduce the effect of glycemic index of the bread and allow the long-chain polysaccharides to move into the small intestine rather than being broken down and absorbed quickly. I think the overall absorption rate will probably not be dissimilar in terms of total caloric intake, but if you can reduce the rate of that absorption and have a more slow and steady digestion and absorption of the carbohydrates, you lower the effect of glycemic index. It’s not turning Wonder bread into wheat bread, but it’s making the bread perhaps not so harsh on the insulin axis and allowing the body to deal with the amount of carbohydrates that are being delivered in a more time-sensitive fashion (over time, that is). So, we found that interesting, and again, one of the things we have talked about is that a lot of times when we do clinical trials or if you review third-party literature, there are doses that are very, very important, and it’s also important when correlating your ingredients that you are using in practice, that you’re using the doses that were used in the clinical trials because there may be these differences. It may not be that 50 percent dose will give 50 percent response. It may be that there is a certain threshold below which the dose will give no response. JB: Yes, I found that that study design was very, very interesting in that paper, in that it was really a dose-ranging study. I think you looked at 1500, 2000, and 3000 milligram doses. I think that’s a very nice way of kind of getting a bead on kind of where is the therapeutic threshold. I compliment you. I think that’s taking some of the good stuff from pharmaceutical science and applying it to the natural products clinical review area, so good work. Let me move to another one, which is this area that we are at least semi-familiar with, and that’s these prebiotics that are known to be non-digestible carbohydrate sources. One of which that has gotten a lot of attention is larch-derived arabinogalactans. You’ve been a principal on a really interesting study, again published in Nutrition Journal back in 2010, looking at an arabinoglactan extract from larch and its effect on antibody response to pneumonia vaccine, which I thought was a very interesting study design.[14] The Challenges of Designing a Study on Immune Health JU: You know, immune health is such a challenge to study because what does a healthy immune system mean? In my reading it means immunomodulation, the ability to respond to an outside threat. Raise the alarms, activate the immune system as appropriate, take care of the threat and then bring itself back down to proper levels. I don’t think that necessarily I would want to have increased levels of circulating cells at all times. I think that the “upregulation” may not be healthy in the long run, but immunomodulation is a better response. The challenge there, in an in vivo setting, is how do you standardize the antigenic challenge? How do you take a group of individuals and ensure that they are all exposed to the same antigen in a way that is precise and you can measure the benefits or changes? We were looking for standardized antigenic challenges. I thought about the vaccine model and said, “Okay, pneumococcal vaccine is a bacterial vaccine. The good news is that most of the population under the age of 50 has not been exposed to this vaccine, which is different than, for example, tetanus or influenza, because it is generally given to the 50-plus population, and so we were able to identify a group of individuals who had not previously received a vaccine. We primed their immune systems with 30 days of the larch arabinogalactan or placebo, and then gave them the vaccine and watched the antibody responses to that. It was, I think, a 22- or 23-valent vaccine, and what we found was that there were subtypes of the antibodies in response that we looked at, and we found that there were statistically significant improvements compared to placebo, meaning that the subjects who had received the larch arabinogalactans for 30 days prior to vaccine showed higher antibody response rates than those who had not. So in some ways it could be considered a vaccine adjunct, especially as we look at an aging population with a senescent immune system that simply doesn’t respond—doesn’t pick up and respond as well—to antigens and vaccines. But I think, moreover, it was really meant to show that this product helps the body respond appropriately to this particular antigen and not generically to, you know, cause a response by multiple arms of the immune system. In fact, we had measured other arms of the immune system—not just the adaptive, but the innate, looking at white blood cell counts and other things—and did not find elevations in those because there was no reason for those to be elevated. But within this adaptive arm, within the specific antibodies that we looked at, we did see this. I hypothesize these long-chain polysaccharides activate the gut-associated lymphoid tissue as they traverse through the gut, and that these arabinogalactans may mimic in some way the bacterial capsule in some of their structure, which may have been priming the immune system. So it’s a very interesting study and a good model for testing the immune system. JB: Yes, I absolutely agree. I think it was a very novel design. I think this concept of challenge testing, where we start looking at a body’s response to a challenge, just like we do with, say, stress testing for cardiovascular function, or oral glucose tolerance testing for glycemic insulin response. I think these are really very powerful tools for evaluating function versus pathology. I believe the model that you’ve used here really is a very novel way of looking at immune system reserve and function and, as you call it, adaptation to a challenge. Great design and great study. You’ve published recently—in 2013—another very interesting paper that opens up another chapter in the types of studies that can be done with a different study design in the natural products area, and this is what sometimes would be called a screening trial, or an open label trial, or a participation trial, in which you’ve looked at fish oils and their relationship to health outcomes over a period of time in kind of an open label trial. So this is a different, not the controlled placebo-type trial, but it’s more something you can do in a population-based study. Could you tell us a little bit about that? I think it’s an interesting approach. You published this in the Journal of Nutrition in 2013.[15] JU: Several challenges face the industry and validating response and sample size is one of them. In a well-controlled setting where you can stress the body as we did with the vaccine or some of the other things that we do, like joint health studies—running people on stepmills—you can define the magnitude of effect and have a power calculation that helps you see, within a relatively smaller sample size (maybe 50 people, maybe 100 people), that you can see a response in a placebo-controlled setting. Generally, though, for some of these softer outcomes—patient-reported outcomes, quality-of-life outcomes—the sample size required can be quite large. One of the challenges of that is that there is simply a cost associated with seeing patients in the clinic, recruiting them and getting them in. We have designed, and are running several now, what we call remote studies, in which we have online screening tools, so they go through an online informed consent, go through the screening process (the inclusion/exclusion criteria), and go through a telephonic review with one of our clinical staff. If they meet the criteria we ship them study product and have them track their endpoints using electronic means, whether they are iPods, iPhones, or computers, and track things like SF-12 or satiety, or this and that. In this particular case we looked at the SF-12, and we did a large population of individuals that were given the omega-3 supplementation for a period of time, and demonstrated after 120 days that we saw statistically significant improvement. The idea is that you can get several hundred individuals and you can do it in a cost effective manner for sponsors of natural health products, and see statistically significant results in this sort of setting. Now this could be done in a placebo-controlled manner as well, but these type of data become part of the totality of the evidence, and even though the randomized, double-blind, placebo-controlled trial is the “gold standard,” there are other legitimate study methodologies and designs which are appropriate and can be very helpful in, as I said, in substantiating claims and adding to the overall claim substantiation file. JB: Yes, I think that’s beautifully stated. Again, a very creative and novel approach towards getting your numbers up so your power increases. You lose a little specificity, but you get a return in terms of the power, and ultimately if you get enough people the statistics can be your guide. So I compliment you. I think that’s a very astute alternative way of approaching some of these problems, as you say, with softer endpoints. Jay, after looking at this research and listening to your, I think, highly introspective review of the different methodologies that one can use to examine the weaker effects that natural products have, meaning you’ve got some challenges in the way these studies have to be designed in order to look at outcome against a control, and you need to do it in a systems environment. How does one manage the data in this particular type of approach? Because it would appear that you might have to use different kinds of algorithms or different types of statistical methods for evaluating these systems effects than you would in a strong effect in a single outcome univariate type experiment where you have one variable and one placebo and it’s one endpoint. Are there other ways that one goes about looking in a systems model at the data? JU: Sure. We have a team of biostatisticians who look at this and we try to come up with our statistical plans in advance. One thing we do is we try to stratify enrollment and we do secondary variance, meaning when we’re looking at our inclusion and exclusion criteria we’re going to eliminate anybody who has a condition or some sort of variable that would potentially affect the primary endpoint. Also we would stratify. Again with a smaller n, you don’t want to find that certain effects like gender or age end up skewing your data on one side or the other, so we’ll try to ensure that both groups have equal representation of male/female—not that it’s 50-50, but if there are, for example, 20 percent men in a study, at least half of those men are in one arm and half of them are in another arm, so that we don’t find out later on that it was the gender effect which skewed the data one way or the other. We tend to apply stressors, as we talked about, in clinic—with the vaccine or this and that—so that we can control for the time and date upon which the body is most responsive to the effects of the product. In an ideal world we would have metabolic wards where we could lock people up for 30 days, control diet and exposure to other things. I’ll give one quick example. We were running an antioxidant study, and the data didn’t look quite right, and when we started pulling it apart we found that there was a time interval effect on the data in that there was a certain two-week period in August where everybody’s variables had gone in a certain direction. It turns out that it was because there were extensive fires in southern California during that time, so the particulate matter that was in the air was reducing everybody’s oxidative stress capacity regardless of which treatment they were on. So then you have to go back and decide what you’re going to do with that data. We used a modified protocol, including anybody who had had at least one post-treatment exposure visit. In some cases we’ll do intent to treat with last observation carried forward to look at things. You know, all those traditional statistical methodologies, but really in a more academic style of looking at the data and saying, “What does it actually mean?” Take a look at the whole data set. Look at trends. Look at deeper dives. Look at subgroups. So, for example, responders analysis. It’s not realistic to think that 100 percent of people are going to respond to anything. You, leading the torch of personalized medicine, are showing that that’s clearly the case, and so a more blunt form of personalized medicine is to simply say a certain percentage of individuals will respond to this treatment, and a certain percentage will not. Now, within those people who did respond, what did their data look like, and how is that different than, perhaps, case control matched on the placebo side? These are all things that are very interesting and tend to really show what does the product do, and not just fill out a box and a checklist of how to design and run a study and say, “Well, it worked or didn’t work.” There’s a lot nuances here that are often missed in a more traditional setting. JB: Yes, I think you really said, in that array of different alternatives, a beautiful description of the landscape of the difference between really understanding how to design and manage a study versus just doing some rote project where you just recruit people with a certain set of characteristics and give them something versus a placebo after randomizing them and look at the results in kind of a statistical T-test. I think that the way you’ve described this is much more compatible with these weaker effects that have been seen with natural products. In fact, there’s a very interesting thing that I’ve observed—I’d like your comment on it—and that is we have two confounding variables. When you have weaker effects, then some of the things that occur as it relates to the biological variability you were talking about, or so-called single nucleotide polymorphism differences among individuals, become more problematic in your response. When you are using a very strong acting substance, something that has a very tight binding of the molecule that you’re using to its ligand, it kind of overwhelms the subtle differences among SNPs, and so you wash that out. But when you’re dealing with a weaker interaction, these SNPs then start to become more problematic, which then gives you the possibility that cohort analysis, as you mentioned, or stratification of the data set becomes more important. And of course that then creates the difficulty of the numbers needed to get power in any single arm of that stratification. As you’ve indicated, all of these things have to be taken into account as you’re doing studies on these weaker, longer-term acting substances in natural products. Does that seem reasonable, from what you were describing? JU: It does. It’s very interesting. There is still an art to this. It’s not just purely the science, and the art is to really start connecting the dots from the very beginning about what are the claims? What are the mechanisms of actions? And where might those two connect? Within that, then, we look at what are the other influencers of that particular mechanism? And, ask you say, would they be overwhelmed by somebody’s genetics or other outside variables. Your talks on diet really are important, here. It is possible that people with different types of diets may respond differently, or if somebody changes their diet, or takes a certain type of food. Even that, itself, could overwhelm the more subtle effects of the supplement. We also use a methodology called adaptive design, in which if the calculations are difficult to understand because that substance in that extraction, for example, has never been tested in this population for this endpoint, then taking third-party literature and making power estimates is of marginal benefit. I don’t know if I can rely upon that, and if you do rely entirely upon that third-party power calculation you could be way off. So in our adaptive design methodologies we may institute an interim analysis in which data are still collected in a blinded manner and one member of the statistical team may, after the interim analysis is completed, unblind them and take a look and see where are we in terms of achieving differences in the primary endpoints, and it may require additional power added to the study in the middle of the study, and this is a methodology used extensively by Big Pharma because as you can imagine you’ve got ten million, fifty million, 100 million dollars on the line for a clinical trial. They don’t necessarily want to wait until the very end to find out that it didn’t work. JB: I have one last question and that may be a difficult one to focus in on a specific answer, but I’d love to get your opinion, and that’s the regulatory environment of the Food and Drug Administration, and also how this is being seen in terms of changing regulatory environments in Europe and Asia and Australia and New Zealand as well, as it pertains in the States, of things like the Draft Guidance Document on the New Dietary Ingredients of the FDA, and the mandates as it relates to different research proof of claims that are being required, and the new medical foods guidance document that came out that becomes very much more restrictive and sounding much more pharmaceutical-based for genetic metabolism diseases, and how all of this is, in your perspective, going to influence the necessity for companies that are producing, marketing, and selling natural products to be prepared for doing business under these new regulatory environmental conditions? JU: The evolving regulatory state is something that I have foreseen and been watching over time with great interest. A lot of it is not actual changes, per se, in the regulation but enforcement or interpretation of the guidance documents. It’s becoming clear that yes, first of all, primary substantiation is becoming an expectation, so reliance upon third-party literature is less viable because there is a big concern about matrix assessment—what about everything else you put in there, and doesn’t that potentially impact the effect of the ingredient. There is a much more pharmaceutical approach at one end of that spectrum that appears to be, in many ways, overly restrictive and does not allow certain things that are fairly common knowledge. In other areas, you don’t design studies that allow or restrict a certain regulatory area but are meant for all of the regulatory environments, and the main challenges there are if you run a study on disease subjects or not, and everybody says, “No, they can’t be diseased individuals.” So then how do you make that effect be seen and so that goes back to all the other conversations we’ve been having. It’s very clear that if you expect to be selling, going forward you have to have clinical trials. I had one distributor tell me you can sell a small amount of anything but if you expect to get the type of distribution that you really want to make a big splash in the market, you have to have clinical trials because now it’s being demanded by the distributors at all levels, and not only from the regulatory side, but unfortunately from the class action lawsuit side. Those lawsuits have as large an impact on the necessity for clinical trial as the evolving regulations do. JB: That’s very, very insightful. I want to thank you, both for this commentary that you’ve given us, but also for the years of service that you’ve provided in raising the bar and giving us all a foundation and footprint for what is really truly authentic in terms of these bioactive components that are found in food and spices and herbs. We know that they have physiological effects, but sometimes quantifying them and having the proof of concept at hand has been the missing link, and I think what you’re doing is really helping to raise the bar and provide the tools that are necessary to close that gap. Thank you so much for all you’re doing and we’ll look forward to keeping up with you. This is obviously a changing domain on a daily basis, so keep up the great work. We really appreciate it. JU: Jeff, thank you. It’s been a pleasure and an honor.

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Welcome to Functional Medicine Update for December 2013. It’s been quite a year, hasn’t it? Quite a year in terms of the extraordinary advances that are being made in understanding about the origin of chronic disorders and actually what to do about them, based on their now putative mechanisms of action and understanding the cellular pathology—things that we didn’t even begin to know anything about 30 years ago when we started this series, so it’s quite remarkable just from an intellectual evolution perspective to see what’s changed and how functional medicine is gaining an underpinning of really strong both basic science and clinical science support. This month is certainly another good example of this. I’ll call this the month of neuroinflammation. It’s a very powerful topic and one that we have addressed multiple times. This will be another kind of facet on the diamond of this topic. We had an extraordinary interview in 2012 with Dr. Dale Bredesen, from the Buck Institute and from the UCSF Medical School, talking about Alzheimer’s disease and its etiology and the complexity of the condition—how it’s not just one condition, it’s multiple conditions. It’s going to require a complex intervention for a complex disorder to get improved clinical outcomes. Dr. Bredesen shared with us this whole evolving understanding of the origin of Alzheimer’s disease as a neuroinflammatory condition. We have the past history of extraordinary discussions with Dr. David Perlmutter, a neurologist in Florida who has shared with us his brilliant insight as it relates to the neuroinflammatory processes, it pertains to Parkinson’s and other neurodegenerative disorders, and the management of these conditions—at least the progression of their symptoms—using intervention that is focused on rising of antioxidant potential. He talked to us about his work on intravenous glutathione. Although it is a transient effect in these patients, it is aremarkable transient improvement they have in function as you raise their redox potential and improve their ability to manage both the toxic burden and the oxidative stress reactions associated with the disorder. And then we’ve had previous discussions that have come through the brains and verbal elocution of clinicians talking about gluten-related enteropathy and gluten-related neurological dysfunctions and how that interconnects the gut-immune system to the nervous system, and how we have to look at a much broader perspective at the etiology of neurotoxicity and neuroinflammatory disorders to even talk about dietary components. Just so we don’t forget about the 2014 year coming up, that topic will be much more fully developed as we move into January of 2014, where you’ll have the pleasure to hear the interview that I did with Dr. Alessio Fasano at Massachusetts General Hospital, and arguably one of the world’s leading experts in the area of gluten and its association to inflammatory disorders. He’ll be talking about neuroinflammation. So this month, what is going to be our major focus? This month we will be through the lens of a clinician who is a brilliant seeker, searcher, discoverer, thought-provoker, a synthesizer of information who had no better reason for motivation than her own specific declining health as it relates to progressive multiple sclerosis (MS). Often we put names and labels on conditions for lack of a better understanding of the mechanism, and in this case the diagnostic criteria was MS, a member of the autoimmune disease family associated with neuroinflammation. You’re going to hear from Dr. Terry Wahls—as a medical professor at a very reputable medical school, and as a very highly motivated seeker of information, and as a convert to the functional medicine model—about how she has applied this model successfully, in her own case, with progressive MS, and now is spreading out with a clinical trial to work for—hopefully—the improvement of many thousands of people to come who share a common health challenge. Neuroinflammation and Oxidative Stress To set the context for this story, I want to go back for a moment and just talk a little bit about what is happening at the frontier of research pertaining to modulation of nervous system inflammation using what we might consider non-drug interventions. This would be things like nutrition, and lifestyle, and oxygen interventions. These have historically been parts of every indigenous culture in their arsenal of therapeutics. They may be called different things, like yoga, or tantric breathing, or dance, or physical therapy, but there are various types of techniques that have been found empirically to help people who we would now call having conditions associated with neuroinflammation, either the peripheral or the central nervous system. We know that the biggest threat to the nervous system is oxygen deprivation, which seems paradoxical when we think of neuroinflammation as being associated with hyperoxygenation, or in other words, peroxidation (oxidative stress). Yet, paradoxically, the times of greatest oxidative stress in the nervous systems occur at times of oxygen deprivation, called hypoxia, so I want you to be reminded of a very simple thing: a person can live for literally weeks to months without eating; they can live for days to a week without taking in water; but they can live for only minutes without oxygen. It’s the most critical nutrient of any of our nutrients in terms of its temporal effect on physiology, because we are oxidative organisms. We all know that. Aerobic metabolism is the way we primarily produce our energy by breaking down glucose into energy. The effect of low oxygen (hypoxia), or in the worst case, complete absence of oxygen (anoxia) is that then the physiology of the nervous system shifts over from oxidative chemistry to what I would call anaerobic chemistry. Anaerobic chemistry produces a variety of secondary metabolites of cellular cytoplasmic metabolism that are acids—we know of lactic acid but there are many other intermediate substances that are acids that are not completely broken down. These change intercellular pH, and they change metabolic function—they poison cells, basically, and the organism, then, because it can’t participate in the efficiency of oxidative metabolism, dies of internal toxicity that we call anoxia. So high oxidative stress is associated with these conditions. You see the most significant levels of oxidants and peroxidized lipids, and proteins, and nucleic acids occurring during times of low oxygen tension in the nervous system. That’s why, for instance, in the days of the heart-lung machine and its development, it was so important when you took the heart out of the system and you mechanically transported blood through the machine and back to the body that you had proper oxygenation. That’s also why we have things like reperfusion ischemia as a major problem in this procedure because you get a bolus of oxidants that are produced if you’re not oxygenating the blood correctly and that can then put a huge challenge of oxidants on the body when you turn the heart back on (you restart the heart). I think that all of these are parts of our increasing understanding of this balance between proper oxidation or oxygenation and absence of proper level of oxygen that we associate with oxidative stress. Oxygen and the processing of the oxygen by mitochondria in cells is so important, particularly neuronal cells that, as you know, are generating most all of their energy by the metabolism of glucose (blood sugar). Although the brain represents only three to four percent of the total weight of the organism it consumes 20 to 25 percent of blood sugar and a disproportionate amount of oxygen to power up that oxidative chemistry in the neuron. So as we start to see absence of appropriate oxygen and increasing oxidation—or let’s call it inefficiency of mitochondrial oxidative phosphorylation occurring within neurons, we then start to get spin off of intermediary compounds and substances that we call the oxidative stress compounds. So now we get mitochondrial oxidative stress, neuronal oxidative injury, and ultimately this leads to triggering of gene expression of the death genes, so to speak, the caspase genes, and we get apoptosis or neuronal death, and that’s what happens in Parkinson’s or in Alzheimer’s. In different regions of the brain we start getting cell suicide occurring as a consequence of these altered metabolic pathways. That would then beg the question: In these times of great oxidative stress, what do you have resident (what reserve is resident)? When I say reserve I really am talking about organ reserve, going back to James Fries’ concept of organ reserve that healthy individuals have reserves, multiple fold, greater for function of an organ, greater than what’s required for homeostasis, and the problem with aging and biological function is we often lose organ reserve so that we don’t have the ability to mobilize the reserve when we need it. How does the nervous system maintain this reserve? It does so by what’s called redox buffering. I know that’s a big chemical term, but what it really refers to is a reservoir of available redox-active substances and processes—enzymatically activated substances or things that can be upregulated as needed, like superoxide dismutase, catalase peroxidase, glutathione reductase, and so forth—that then are capable of accommodating this increased oxidative load, or oxidative stress, in the nervous system. So the body has those built-in mechanisms. Genes, Environment, and Oxidative Stress Now as you know, because we are unique each one of us, our genes code for different abilities to accommodate that level of oxidative stress, meaning we have different levels of neuronal reserve, or oxidative capacity to manage these challenges. This has been found in animal studies and in insect studies, even using Drosophila melanogaster (the fruit fly). We recognize that these processes are partly genetically determined, but they are also sensitive to environmental factors. I’ve already talked about oxygen itself, and the absence of oxygen is like the greatest promoter of oxidative stress. So you might say, “Well, gee whiz, that would mean that anemia might have a detrimental effect on delivering oxygen, so maybe there’s an association between anemias and neuronal injury.” And, yes, there are some, certainly, examples of that.[3] Cutting off blood supply, like the carotid arteries, doesn’t do your brain any good, does it? You start to get neuronal oxidative stress and dementia. We also recognize that heavy metals like mercury, or cadmium, or lead, or excess iron, like you see with various hemoglobinopathies. These also will increase oxidative stress in the nervous system. We see that various types of petrochemicals, the so-called xenobiotics, will activate the monooxygenases associated with cytochrome P450 that can increase oxidative stress, because we know that cytochrome P450 splits the oxygen molecule, which is a diatomic, O2, into individual atoms of oxygen. That’s why we call it a monooxygenase. It’s used in oxidizing petrochemicals through the cytochrome P450 pathway, but what happens to the other half of the oxygen molecule? It can become a nascent contributor to oxidative stress. That’s why we often think of toxicity associated with hepatic oxidative injury, because during the process of detoxification if there is not adequate protection of the liver, you get increased oxidative injury. The nervous system—particularly the brain—is unfortunately exquisitely sensitive to these oxidants, because it has…I don’t want to call it primitive, but let’s call it lower-level antioxidant protection to that of other tissues, like the liver, the hepatocyte. And therefore the brain, when exposed to oxidants, has the potential for greater oxidative sensitivity, and injury, and apoptotic death. Where does that reserve come from? Well, here is the emerging, exciting story, and you’re going to hear more about this as we get into the discussion with Dr. Wahls, and that is it has been found that the diet contains a rich array of phytochemicals that play roles in helping to maintain this neuronal reserve against oxidative stress. You might say, “Well, this sounds maybe like a bunch of hand-waving speculation.” But actually there are an extraordinary number of good papers that being published recently. For instance, out of the laboratories of Dr. Mark Mattson at the National Institutes of Health, who has been publishing a number of papers looking at how phytochemicals are hormetic in protecting against neuronal oxidative injury, and that people who don’t eat diets that are rich in these hormetic dietary phytochemicals, meaning they don’t get plant food and they don’t get a lot of color in their diet from natural plants, have a decreasing reserve of these important modulators of oxidative injury, neuronal oxidative stress, and at higher risk, then, to injury from neuronal oxidation. A wonderful review paper appeared in Neuromolecular Medicine in 2008, volume 10, page 236—this is Mattson and his group at NIH—titled “Hormetic Dietary Phytochemicals,” in which they review this whole interesting signaling pathway that these phytochemicals play a role in, the so-called FOXO-NFκB pathway that relates to neuronal oxidative injury.[4]   Phytochemicals and Redox Potentiation And then we start examining different families of phytochemicals, like the flavonoids, and the polyphenols, and the glucosinolates found in cruciferous vegetables, and we find that each one of those has a different role in influencing potential processes associated with what we used to call antioxidation, but now we call it redox potentiation. For instance, there is a very interesting paper that appeared in Oxidative Medicine and Cellular Longevity in 2013 talking about sulforaphane, which you know is in broccoli, Brussels sprouts, and cauliflower, as a potential protective phytochemical against neurogenerative tissues in which the mechanism has been fairly well, now, developed and explicated.[5]  So this field of literature is really developing very, very strong support. I’m also interested in work that has been done by a variety of neurology investigators about dietary polyphenols; you know, these interesting compounds that we find in berries, and in various fruits, and to some extent certain vegetables that are extraordinary modulators of brain function. They have biological actions that underpin their action as a redox-active substance and buffer against oxidative stress in the brain. And then we’ve got some of these intermediaries, as I’ve talked about: glutathione and its precursor N-acetyl cysteine, and N-acetyl carnitine, and essential fatty acids of the omega-3 family, docosahexaenoic and eicosapentaenoic (or DHA and EPA), and then alpha-tocopherol and tocotrienols from the vitamin E family, and the rich array of colored flavonoids and carotenoids like astaxanthin. All of these have been examined as potential contributors to providing neuronal reserve against oxidative stress. So I think we are witnessing a very, very dramatic increase in the overall important role that diet and lifestyle play in protecting against neuronal injury. Taking that from a theoretic umbrella of understanding down to the clinical, where-the-tire-meets-the-road, there is probably no better story that we could use to exemplify that than that of Dr. Terry Wahls, internal medicine, OB-GYN physician, whose own journey across this frontier I think symbolizes the extraordinary increasing understanding we have about mitochondrial function, neuronal activity, neuronal death, and the reversibility of many of these conditions by utilizing the appropriate lifestyle/diet to increase neuronal oxidative stress reserve, or what we call redox potential. With that, let’s move to this extraordinary story through the lens of Dr. Wahls personally.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Terry Wahls, MD, MBA, FACP Clinical Professor of Medicine University of Iowa, College of Medicine Iowa City, IA www.terrywahlsmd.com I have to say this month we’re fortunate to not only have an extraordinary clinician, but also an extraordinary thought leader—a person who has really embodied the spirit of what I call research at the fundamental level. This is a very interesting theme that we’ve had in functional medicine throughout the last 30 years in that research really starts with good observation, and good observation starts with clinicians who understand how to put associations together to form hypotheses, and then from hypotheses how to develop them into models that can be tested and ultimately hopefully lead to outcomes that result in clinical improvement. I would say there is no better example of that model than Dr. Terry Wahls, who we’ll be speaking to this month. We’re very privileged. You probably already know of Dr. Wahls, her experience and her teachings and her extraordinary lesson for all of us. In fact, I think her YouTube video may be one of the most highly watched medical videos on YouTube. It’s absolutely a fascinating journey with her through her own situation with—as she will describe—some her own health challenges. Just to bring you up to speed, quickly, about Terry Lynn Wahls, who is a medical doctor and an MBA. She graduated from Drake University with her BA, went on to get her MD at the University of Iowa, and has been a very extraordinary contributing member to medicine through her training and certification in internal medicine. She has published highly, nearly 40 publications. She’s a renowned lecturer. She is a renowned clinical professor of medicine. And she’s a renowned patient as well, having fought her own illness successfully; she’ll be telling you her story. I think that her work in OB/GYN and internal medicine probably put her into a very unique position to look at herself and at disease from a systems biology approach, and it’s that perspective that she captures so beautifully in her work, and of course in her most recent book, which I think should be mandatory reading—The Wahls Protocol: How I Beat Progressive Multiple Sclerosis Using Paleo Principles and Functional Medicine.[6] It’s an extraordinary read. You’re going to hear more about that from Dr. Wahls, now. Terry, thanks so much for being part of our Functional Medicine Update series. I guess my first question should be, what brought you into medicine, some—nearly—35 years ago? TW: Well, I started, actually, with a Bachelor of Fine Arts in studio art painting, and then decided no, I was not going to go into graduate school in painting, and went back to science—biology—and that took me around to medicine. I got into medical school not quite understanding just how long my training period was going to be, so I had a little bit of a shock there. It really has been very gratifying, and over time I came to appreciate that my fine arts background (the painting background) gave me a much greater ability to observe the patient and a more thoughtful application of listening than most of my colleagues who had gone through the usual science background to get into medical school. JB: So as you applied that very, very—I would call it—remarkably broad-based perspective and you started to have experience in the practice of medicine and doing some extraordinary work, when were the first signs that you found in yourself that indicated things weren’t going in the right direction? Multiple Sclerosis Diagnosis Leads to Research on Mitochondria and Bioenergetics TW: I was diagnosed with MS in 2000, and elected to do the usual conventional medicine route. So I found the best center in the country at the Cleveland Clinic and saw terrific people, took the latest newest drugs, including tizanidine, and I didn’t have more acute lesions, but I had this very steady relentless decline. I was told that I had secondary progressive MS. I took Novantrone, I took tizanidine, and continued to decline. The reality that I saw ahead of me was that I was likely to become bedridden by my illness. I was having a lot of brain fog, and so I knew that cognitive decline was likely. That’s when I decided I needed to take more personal responsibility, and so I started at first doing searches with the health science librarians, but as I got more comfortable and faster I started doing my own searches through PubMed.gov. I worked very hard to relearn some basic sciences. I started reading the animal models for MS, for Parkinson’s, Lou Gehrig’s disease (ALS), and Alzheimer’s. From that, I started zeroing in on mitochondria and the bioenergetics and what I could do to resuscitate my mitochondria. That was sort of fun. I would see some interesting mouse studies and I would translate these mouse doses of various vitamins and supplements to human-size doses, and then check that against my med list for drug interactions, and start. I tinkered that way for about, I suppose, six months and then decided I was wasting my money and I just quit my vitamins and supplements. And the next day I was too exhausted to get out of bed. So I spent two or three days basically in bed, and then my spouse came to me with my supplements and said, “You know, honey, I think you ought to take these again.” So I took them, and then the next morning I felt better. I was able to get up again and go to work. That was a very exciting, empowering moment; like, “Okay, my vitamins and supplements really are doing something here. Maybe they aren’t making me recover, but they are clearly helping me in some fundamental way.” And so I thought I could at least—with careful attention to the literature—maybe find a way to slow down the speed of my decline. And I did that for the next four years. But by 2007 I was pretty much in a zero-gravity chair or in bed, so I was declining. I could walk short distances with two canes. That’s when I discovered functional medicine. I took their neuroprotection course and had a much longer list of nutrients. I incorporated that into the Paleo diet that I had been following already for a few years, and when I had reorganized my food to maximize the nutrients that I had learned from functional medicine, that’s when the magic really began to happen. In the next year, I went from a tilt-recline wheelchair, to walking throughout the hospital without a cane, and even doing an 18-mile bicycle tour with my family. It completely changed how I thought about health and disease, and of course it changed how I practiced, it changed my approach to all clinical disease, and I became this big advocate for this more integrative approach (functional medicine, therapeutic lifestyle approach) to treating disease by creating health. Origins of the Term “Mitochondrial Resuscitation” JB: I just want to take a moment of pause to let everybody who is not familiar with your story to have this sink in because I think it has a deep and profound important message that hopefully gets beyond the first layer of the cerebral cortex of our listeners. It’s a profound example of why I believe network physiology and systems biology is the way to be thinking about complex chronic illnesses, and your journey, and your pursuit of an understanding is a model for what I believe needs to happen throughout all sectors of our healthcare system so that we start really looking at some new truths that are emerging from discoveries that have been made over the last 15 to 20 years. I was very intrigued and pleased to hear you use the term “resuscitation of mitochondria.” That was a term that was really born out of Functional Medicine Update in an interview we did with Paul Cheney back in the 1980s. It really started to resonate much more in the 90s when we founded the Institute for Functional Medicine, and one of our core principles was mitochondrial bioenergetics. We chose the Paul Cheney concept of mitochondrial resuscitation as kind of a thematic buzzword for what we were trying to achieve. I think that this construct that you’ve come up with of food, lifestyle, and supplements patterned to the individual need is a profound paradigm-shifting concept. It’s born out of obviously many people’s work previously, so it’s certainly not a de novo new discovery, but I think the way you’ve applied it is a truly remarkable revolution in thinking in medicine, so I hope everyone just had a chance to allow your very easy way you present this to sink in deeply beyond the first layer of their cerebral cortex because it’s a profound statement. If I can ask a follow-on question, as you got into this—and I actually remember our first meeting, I think you were still in a wheelchair at that point, coming to some of the education events of functional medicine and were probably on your path to recovery or improvement—what were the steps along your road of recovery that gave you a sense that you were on the proper path, and how did you kind of make your own iterative adjustments as you moved down the path? How Dietary Choices Influenced Multiple Sclerosis Symptoms TW: Historically, in about 2002, I quit gluten and dairy and began a Paleo diet (so vegetables, meat, fish, eggs). That’s what I consumed, but I continued to decline. In 2004 through 2007, I’m doing literature searches and adding vitamin supplements as I’m learning about them, so I’m adding more B vitamins, CoQ, lipoic acid, carnitine, creatine, omega-3s, and it certainly slows the speed of my decline, but I’m definitely still declining. Then when I had the neuroprotection course, it really deepened my understanding of molecular mimicry, gut resuscitation. I did some basic food sensitivity testing and found out I have a severe sensitivity, also, to eggs, so I took eggs out of my diet. I had a list of about 20 compounds from my research and the functional medicine neuroprotection course, so I added those. Really the magic happened when I did some more investigation on where these compounds were in the food supply and reorganized my diet so it was focused entirely on creating the most nutrient density I could for the nutrients that were key for brain health. And it was really quite dramatic. I mean, my diet was really very good beforehand, but I took it to a new level, and within weeks my energy was steadily improving. My mental clarity was steadily improving. I also have to say that parallel at the same time, I was doing sort of a radical new treatment with neuromuscular electrical stimulation to my muscles while I was exercising. For the first time in many years I was able to sustain an exercise program, which also, of course, is very helpful for my brain as well. I got to experience intellectually what I thought was going on biochemically. Early on I would occasionally think, “Well, I could have a dietary indiscretion occasionally,” and, at least for me, within 48 hours I would have a severe flare of my occipital neuralgia, which is horrifically painful. I learned early on that I was not going to stray from my dietary regimen because my energy dropped, and I had horrific pain that would take a course of Solu-Medrol to stop. Pilot Study on 20 Patients with Progressive Multiple Sclerosis The other thing that I, of course, wanted to do was test if this protocol could be adopted by others and what would it do for them. We wrote up the protocol. I went out and secured one hundred thousand dollars of funding for this pilot study, which we have now been doing for just a little over three years. I’ve got 20 other individuals with primary progressive/secondary progressive MS who have done my protocol. The last person is going to finish up in December. What I can tell you is people can adopt this very complicated regimen; they are willing to do it. The inconvenience is if you are overweight you’ll lose weight, and there will be some dietary adjustments that will happen, so you have some GI distress initially. Some detox certainly happens to pretty much everyone, but there are no serious problems in terms of any kind of kidney damage, liver damage, heart damage. People’s health indices all improve—their CRPs, their lipids, their cholesterol profile, their insulin sensitivity, homocysteines, all of that improved. Fatigue markedly improved. Gait is sort of variable. The reasons we can’t walk with MS, of course, are quite varied, so not everyone improved their gait. But we do have some people who went from needing a cane to jogging within 12 months. There were some people who were able to experience really radical transformation of their health status, and others who experienced a more modest transformation of their health status. JB: I think you’re describing beautifully why I’m advocating so strongly that people read your book The Wahls Protocol. I think it really helps to provide the substance for people really starting to get started with this program. It’s wonderfully done. The Wahls Protocol: New Book Can Be Used as a Guide for Transforming Your Diet TW: Yes, it’s really quite remarkable. In The Wahls Protocol I lay out the science behind why we designed the protocol the way we did. We give people a very detailed step-by-step plan for how you would begin to implement and how you can transition from the standard American diet to a progressively more nutrient-dense, mitochondrial resuscitation-oriented diet and lifestyle plan. And we applied a lot of information for clinicians who are going to want to take this information and use it to transform how they think about creating health, and anyone with any type of chronic disease, whether it’s an autoimmune or a disease that we don’t yet think of so much as autoimmune, such as obesity, diabetes, or even heart disease. JB: I want to make sure everyone understands its W-A-H-L-S—Wahls—protocol. I highly recommend it as required reading. Let me ask you a follow on question. You’re a professor—a clinical professor of medicine—at the University of Iowa College of Medicine, so you have peers that obviously knew about your illness, and were undoubtedly supportive in providing council and so forth. And then you made this decision as to how you were going to manage your trajectory and your journey with this illness. What kind of support/inquiry/interest/intellectual curiosity…whatever you might say the Zeitgeist of your environment…what was the kind of response that you were getting from your colleagues? TW: As I declined, the university and the VA were extraordinarily generous in redesigning my job multiple times so I could continue to work. One of the things they did was they put me on the Institutional Review Board, so I was reading research and I asked, “Give me all the protocols having to do with the brain.” That accelerated my understanding of brain physiology greatly. As I recovered, that was the summer that I was up for promotion, and yes, we have a promotion talk. You normally give a talk about your active research, but I decided instead to do a case report on myself detailing what happened to me, what my intervention was, and reviewing what I thought were the likely mechanisms behind my recovery. Then I added a proposed clinical trial to test whether or not these interventions would work in others. The promotions committee thought that was so interesting they suggested I give it in Grand Rounds to the entire department, which I did a couple of months later. That, of course, generated quite a buzz. I’d say about half the audience thought this was the most brilliant and most engaging Ground Rounds they’d ever seen, and the other half thought I was a nut and should be thrown out of the College of Medicine. That Ground Rounds let me attract a few more senior scientists to help me craft my study design and get it through our Institutional Review Board. They helped give me some suggestions on my grant writing and I got off a grant and came back with the funding so we could start the study. And then, twice a year we have Research Day, so we can have a poster up that presents the status of our research findings, and so people are seeing that, in fact, people can comply with this complicated regimen, that we are able to create this radical improvement in dietary intake in terms of the nutritional quality, and this very striking improvement in fatigue and cognitive performance in these individuals. And now that I can show these videos of how people’s gaits were are the beginning and what their gait looks like at 12 months, I’m getting more and more recognition by the university. In fact, I’ve been nominated by the university as the University of Iowa’s nominee for the 2013 Women of Innovation Awards in the state of Iowa. That organization asked me to be the plenary speaker. I think more and more people at the university and here at the state are recognizing the incredible brilliance of this very complicated, very messy, whole-systems biology approach that I’m doing, and that instead of this little tiny incremental improvement, I’m showing this radical improvement in health, which is probably the best way to treat, frankly, any of our chronic diseases that I treat in my primary care clinics, or in my traumatic brain injury clinic. JB: What a remarkable story. Talk about motivating. Congratulations on every level, first to you personally and then second how you’ve been able to leverage this and make it available as a broad-based opportunity for many others who I think will follow in the wake and hopefully as more is done in this area we’re going to get more “proof of concept” and more validation and those people that thought you were a nut either will retire out of medicine or be transformed and say they always believed that this was the best thing that could happen. That seems like the nature of the history of what we’ve observed over the years. Tell me a little bit about your support group, because obviously these are some fairly major changes in lifestyle and how you divvy up your time on a daily basis in terms of food preparation and thoughtful construction of your program. What would you say about people who are heading down this path as it relates to the development of their support group? Wahls Protocol Study Design TW: We have some tools that were very helpful in our study. We created a daily log so people would know precisely what food groups to eat and how to hit the nutritional goals every day. We also had them log every day their stress-reducing activities and their exercise and ESTIM. In the first two months, I had a coach for the exercise call them (the study participants) every week, and the nutrition support called them every week. We saw them at month one, month two, month three, then month six, nine, and twelve, and I would saw generally by three months people really understood the diet and the lifestyle. We had them complete the medical symptoms questionnaire monthly, so we could see that those numbers were continuing to improve, and whenever they had a bump, that was a sign for us to really explore with the study subject what was going on—where there was unresolved conflict. Was there a new infection issue? Or had they been feeling so well they thought they could begin to have a few splurge foods that created some nutritional compromise? I think the daily logs are very important. I think doing this as a whole family…and we explain that when people enroll—that it’s a family commitment and if the whole family is not ready then they are not ready to be part of our trial. Actually it’s really been pretty fun. So we watched the transformation of the subject, and then we also see this transformation of the other members of the family as they, too, adopt this very nutrient-dense diet, and their lives are transformed as well. Emotional support is very, very important to be successful here. Paleo Principles and Nutrient Density JB: Let me, if I can, follow on also on your really insightful comments as it pertained to the difference between taking, say, purified nutrients as pharmacological adjuncts or as tailored nutrients versus delivery of a high-nutrient density diet, where you saw your improvement markedly enhanced. Do you feel that this has to do with—and I’m probably asking it for some speculation, so I apologize—do you think it has to do with bioavailability, do you think it has to do with the complex nature of food versus individual supplements used as therapeutics, what’s your view as to the benefit of the food versus the supplements alone? TW: I think when we look at, for example, hunter-gatherer societies around the globe, they all have very different actual food stuffs, so what you do is a nutritional analysis. There are always one-half to ten times the RDA depending on which nutrient you’re looking at. Ideally we want to have the most nutrient density we can per calorie, but since we are using agricultural foods instead of wild foods it becomes a lot more complex to figure out how to best organize the food to get the maximal nutrient density. And when I get the maximal nutrient density from food—we’ll take some of the B vitamins, for example, or the antioxidants—in food there are thousands of other related compounds that will also interact with my cells, and I’m more likely to get nutrients in appropriate ratios, so I don’t accidentally create an imbalance, say, of zinc because I get too much copper, or an imbalance of vitamin K because I get too much vitamin A. I think food provides additional compounds that are related, and it puts the nutrients in the balance that’s more optimal, so you don’t accidentally create compromise because you’ve got things out of range. Multiple Sclerosis Research and Mitochondrial Function Linked in the Medical Literature JB: I think that’s a beautiful way of describing it. I’d like to do a little fun thing with you, here, if you wouldn’t mind, and just take you through a couple of recent 2013 publications in this area of MS and mechanism and its relationship to mitochondrial function, and get your comments. I know you’ve become an expert in this and I thought just giving a couple of parenthetical comments might be interesting. There was a model study just done in primates published in Frontiers in Physiology. This was work done at the Oregon Health Sciences group in Portland, Oregon. What they have demonstrated is this redox model for mitochondrial dysfunction appears to relate very closely in a primate model for MS, and they actually in this publication which appeared in the July 25th issue of 2013, have a very nice figure in which they talk about the MS disease process related to cellular endoplasmic stress, and the release of reactive oxygen species and how that activates certain kinds of intercellular signal transduction processes that ultimately influences mitochondrial complex I/complex II activities and becomes almost like a dog chasing its tail.[7] The person gets locked in to a self-perpetuating mitochondrial neuronal death spiral. Tell us a little bit about how your review of the literature tracks with that model and how it relates to your program. TW: Well, I think mitochondria are absolutely key. When I was looking at this back in 2004, I saw that apoptosis/mitochondrial strain/excessive oxidative stress was being talked a lot about in diseases of neurodegeneration. People were not yet relating that—at least that I could find in the literature—in MS, but since you had steady indication of atrophy of the brain tissue and spinal cord in MS, it just seemed logical to me that apoptosis and oxidative stress were likely a big factor in MS. That’s why I got into trying to understand what I could do to provide for the support of the mitochondria. I was doing it kind of piecemeal by piecemeal until I discovered functional medicine and really had, I’d say, a much more comprehensive toolkit for the mitochondrial resuscitation at that point. JB: So that then leads us to the next question and that is, okay, if mitochondria are a potential target organelle that relate to the etiology of MS, then we might say why do some people get it? Is it a genetic sensitivity of mitochondria, or is it induced somehow by events that occur throughout the life of the individual? There are a couple of papers that have appeared recently that suggest that maybe both those models that I just suggested are present. One is a paper in Genetic Molecular Research in 2013, September issue, looking at mitochondrial nuclear genes as a cause of complex I deficiency in MS, and found there are some genetic sensitivities apparently to complex I activities, meaning there are different genotypes that reflect the phenotype of complex I activity.[8] And then another paper that I think follows along with that is in the International Journal of Molecular Science in October of 2013 looking at the pathogenesis of complex I/complex II problems in MS pertaining to petrochemical byproduct exposures, things like acrolein, and things that could initiate interruption of mitochondrial complex function and induce oxidative stress, so it would appear, from my reading, that there is evidence of both genetic susceptibilities coupled with environmental triggers. [9] Does that seem consistent with what you’ve read? TW: Correct. And in my book what I talk about is there are about 100 genes that have been identified that slightly increase your risk of developing MS, and so it’s your total burden of genetic SNPs that have increased your risk, plus your total burden of environmental exposures as your diet, toxins, stress level, exercise level, etc. So if you have a smaller number of genetic risk factors, it’s going to take a higher dose of environmental problems to create a syndrome that will be diagnosed as MS. If you have more genes that increase your risk, it will take a smaller dose of environmental factors. And I also talk about there are probably an infinite number of ways to develop the damage that will be diagnosed as MS. This could come through a predominance of genetic risk factors, or it could come from infective factors, or mostly toxin factors, or a combination of all of that. There’s never going to be just one path that explains all of MS. That’s never going to happen. This is a syndrome of many kinds of diseases that have many different ways of acquiring this symptomology and structural change that is diagnosed as MS. So a broad-based supporting of the environmental factors is a great way to start, and then if you don’t get the full response that you’re hoping for, then absolutely the person is going to need to have more detailed functional medicine testing to tease out what the burden of infection is, or the burden of toxins, or that there may be some truly exceptional nutritional needs to bypass some of the SNPs. JB: I think that was a brilliant summary of so much information. I really appreciate the clarity. You know, it’s interesting when we think back—again I’m thinking of the evolution of the functional medicine model to what I call the three Hs, or H-cubed, that was Heaney, Holick, and Hayes, who were our vitamin D triad that really set, I think, the tone of vitamin D as more than a nutrient for bone as a very important immune modulating nutrient. We’re very fortunate. This was probably 15 years ago when we had the three of them present at our IFM symposium. Of course, Elizabeth Hayes was talking about her role in animal models—the EAE model of MS—with vitamin D deficiency, and providing a putative mechanism as to how vitamin D deficiency could result in MS-like symptoms and animal models and how that may connect together with the etiology seen in humans, and latitudes, and so forth. As you’re pointing out, there are probably many paths that a person could be on that would lead to a diagnosis of what appears to be a singular disease coming from multiple etiological contributors, of which maybe vitamin D would be another thing in the laundry list of factors to evaluate. TW: Yes, absolutely. JB: There’s another interesting paper, which I think is so wonderful because many times a hypothesis—and I’m using that term guardedly here as it relates to your observations and your program—would be valued when a person says, “Well, there’s a respected animal model that’s been able to demonstrate the proof of concept in reproducible controlled studies.” Of course, this EAE model is the one that has often been used as the animal model in MS. That’s the Experimental Autoimmune Encephalitis in mice. So there’s a very nice paper that was just published in September of 2013 in what I consider one of the premier biochemistry journals, Biochemical Biophysical Acta, in which they actually report, using this EAE model of MS, on a mitochondrial resuscitation program using the nutrients that you’ve described against placebo controls and showing very dramatic improvement in function in these animals that go on and get these spontaneous MS-like symptoms.[10] It appears, now, we have a pretty good animal model that shows mitochondrially targeted therapy actually delays the progression and alleviates pathogenesis of MS. I think this type of work you must feel very good about. TW: Yes, yes. I’ll have to go find that paper. That sounds perfect. JB: It’s page 2322 of volume 1832, September of 2013. This work actually was also done at the division of neurosciences at the Neurogenetics Laboratory, Oregon Primate Center, in Portland. I think it is a very nice study design showing really remarkable (in that animal model) proof of concept. TW: We have a lot of frozen blood. We’re waiting until the last person gets through December, and then we’ll begin to discuss a plan for what type of analyses we’ll be doing in terms of monitoring how things have changed biochemically. I’ve got the head of the immunology department, and the head of our anti-aging department on the study team and we’re having those conversations now about what further analyses we are planning, so we can go write the grants to get the money to do that as well. It’s very exciting stuff. JB: It’s more than very exciting; it’s revolutionary. Again, I want to tell you how much we appreciate you sharing this journey with us. I think, you know, you’re very courageous, not only in the way that you’ve approached your own health, but the way that you’ve been willing to share what I know has been at times probably extraordinarily frustrating and challenging for you, and opening yourself up to your journey so that other people can learn from it, and helping us to understand what it takes in terms of a support team and lifestyle changes and a dramatic re-patterning of our thinking in order to make this paradigm-shifting outcome. You’re a model for us all, Dr. Wahls, and we can’t thank you enough for sharing your experience with us. TW: Thank you. Thank you very much. JB: We wish you well. Is there anything you’d like to saw to our listeners, most of whom are obviously clinicians who are probably being very inspired by what they are hearing from you? Anything that you would give them as juice to move forward? TW: I’d encourage them to get to my website—explore that—so they can share that information with their patients to help them get fired up and excited and see the initial steps and all of the stories from other people that have had their health transformations. We could, in theory, train an army of what I affectionately call the “Wahls Warriors” that are out there learning that food, and nutrition, and lifestyle is the real key to creating health and eliminating disease. JB: You’re the model—the quintessential model—as to why we started the Institute for Functional Medicine in 1991, and we hope that we can replicate your experience in millions of people over the years. Thank you very, very much and the best to you in all that you are doing. TW: Great. Thank you so much.

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Bibliography

[1] Mehdi SH, Qamar A. Paraquat-induced ultrastructural changes and DNA damage in the nervous system is mediated via oxidative stress-induced cytoxicity in Drosophila melanogaster. Toxicol Sci. 2913 Aug;134(2):355-365.   [2] Shen LR, Xiao F, Yuan P, Chen Y, Gao QK, et al. Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age (Dordr). 2013 Aug;35(4):1133-1142.   [3] Hare GM. Anaemia and the brain. Curr Opin Ananesthesiol. 2004 Oct;17(5):363-369.   [4] Son TG, Camandola S, Mattson MP. Hormetic dietary phytochemicals. Neuromolecular Med. 2008;10(4):236-246.   [5] Tarozzi A, Angeloni C, Malaquti M, Morroni F, Hrelia S, Hrelia P. Sulforaphane as a potential protective phytochemical against neurodegenerative disease. Oxid Med Cell Longev. 2013;2013:415078.   [6] Wahls, Terry and Eve Adamson. The Wahls Protocol: How I Beat Progressive MS Using Paleo Principles and Functional Medicine. New York: Avery, 2014.   [7] Su K, Bourdette D, Forte M. Mitochondrial dysfunction and neurodegeneration in multiple sclerosis. Front Physiol. 2013 Jul;4:169.   [8] Rezaee AR, Azadi A, Houshmand M, Makmoodi F, Purpak Z, et al. Mitochondrial and nuclear genes as the cause of complex I deficiency. Genet Mol Res. 2013 Sep 12;12(3):3551-3554.   [9] Tully M, Shi R. New insights in the pathogenesis of multiple sclerosis—role of acrolein in neuronal and myelin damage. Int J Mol Sci. 2013 Oct 9;14(10):20037-20047.   [10] Mao P, Manczak M, Shirendeb UP, Reddy PH. MitoQ, a mitochondria-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Biochim Biophys Acta. 2013 Sep 19;1832(12):2322-2331.

Welcome to Functional Medicine Update for January 2012. Can you believe it, another new year for Functional Medicine Update? I have to say, of all the things that I’ve done over the years, one of the things that rises to the surface is Functional Medicine Update. To think that we’re now at more than three decades of our activity with regard to this audio magazine. What I would say to all of you is that this has been an extraordinary run of learning. Cardiovascular Extended Risk Factor Assessment This month my introduction is on cardiovascular extended risk factor assessment. The reason that cardiovascular seems noteworthy is, as you know, it’s the number one cause of death (still) in much of the world, certainly in the developed world it’s true (developed countries). Secondly, it’s because this area of extended risk factors, or biomarkers, really relates to the very fundamental question of function, because rather than looking at overt pathology, these evaluative tools that we call biomarkers are really looking at aspects of disturbed physiological function or disturbed pathology. One might really view a biomarker in two respective ways. One is you might look at a biomarker that is analyzing the primary agencies that cause a specific dysfunction and urge, then, or contribute to, the development of an ultimate disease. And the second is a biomarker that looks at secondary effects of that disease process; it’s kind of the smoke that comes from the fire that tells us how severe the insipient disturbed metabolism or pathology is at that state in the patient’s life cycle. Cholesterol is a Biomarker, Not the Cause of Disease So you can really look at two different kinds of biomarkers. Let’s use cholesterol as an example. I don’t think that we believe that the elevation of blood cholesterol isn’t, of itself, the necessary pathognomic agent that causes disease, but it’s a marker for a state of disturbed metabolism that is associated with disease, and therefore we would call this kind of the precedent landscape that sets the tone for a disease called atheroma. We would look at things like phospholipase A2 (PLA2), which is a measurement of the inflammatory burden from a disturbed plaque: here we’re looking at the smoke that comes from a fire, and how it interrelates, then, to the progression of a particular pathology that will become a disease. As we examine different biomarkers, we can ask where they fit into this sequential series of events moving from optimal states of function into complete loss of function, which in the extreme, obviously, is death. I couldn’t be more pleased to have as expert guests this month people who really represent this whole concept beautifully and really, I believe, reflect the nature of the evolution of the functional medicine concept. These are founders and individuals associated with Cleveland HeartLab, which grew of the Cleveland Clinic, certainly—arguably—considered one of the centers of excellence in the world with regard to cardiovascular research.   Inflammatory Biomarkers are Indicators of Progressive Risk We’ll be hearing from Dr. Marc Penn and Jake Orville from the Cleveland HeartLab a little bit later in this issue of Functional Medicine Update. To set the tone I want to remind you that over the last decade, within the recognized etiology of cardiovascular disease it has become more and more well-respected that inflammatory biomarkers and processes are indicators of a progressive risk. Certainly we saw this in the JUPITER trial with Paul Ridker’s studies at Harvard looking at individuals who had fairly low (what might be considered non-risk) LDL cholesterols, but who had elevated high-sensitivity C-reactive proteins (CRP), which is a surrogate marker for inflammation, and found that when those individuals were put on a statin that their relative risk to heart disease went down, even though their LDL cholesterols were considered already to be fairly low risk.[1] What it did is it resulted in a lowering of the hs-CRP level, so above 2 milligrams per liter hs-CRPs were associated, in the chronic state, with relative increasing risk regardless of the LDL cholesterol level. It suggests that there is this independent series of events that relates to cardiovascular risk that is associated with inflammation. There is a very interesting recent paper that was published in the Journal of Clinical Lipidology titled “The Clinical Utility of Inflammatory Biomarkers and Advanced Lipoprotein Testing.”[2] This is from an expert panel of lipid specialists—actually nearly 20 different experts in the field—that commented on the importance of doing relative risk analysis using an extended panel of biomarkers that incorporated inflammatory assessments. Their broadened panel included CRP; lipoprotein phospholipase A2 (or what’s called Lp-PLA2, or some people call this the PLAX test)—it’s really a measurement of this inflammatory biomarker that is produced by resident plaque in the arterial system; apolipoprotein B100 (apo B), which relates to the carrying of lipid associated with LDL, the atherogenic-dense LDL particle; lipoprotein a (most of us are familiar with this as another atherogenic risk factor associated with inflammation); and then lastly are the HDL and LDL subfractions (the particle number and particle count types of data that are now available from a number of laboratories to take us beyond just the gross numbers of LDL, HDL, and VLDL). Don’t Discount the Framingham Risk Factors These are extended risk factors that really reflect more the inflammatory milieu than the traditional Framingham cardiovascular risk factors. Now, do these replace the traditional Framingham risk factors? No, the Framingham risk factors are still very viable and very valuable as gross determinants. These get down into a slightly deeper level of looking at inflammatory connections to atherogenesis and how that interrelates to the concepts of stickiness of white cells to the vascular endothelium, transluminal migration of LDL particles, LDL oxidation, foam cell formation, ultimately, then, setting up the potential for monoclonal hyperplasia of the arterial tissue and atherosclerosis. That ultimately leads to an atheroma that can have a fibrous cap and be unstable. Unstable plaque ultimately can give rise to a much higher risk to a cardiovascular accident than stable plaque. Unstable plaque relates to inflammatory mediators. You’ll hear more about this from Jake Orville and Dr. Marc Penn in the interview. I just want to set the tone: we have moved from kind of a steady-state view of atherosclerosis and its origin into this dynamic model of progression and activity that is associated with the release of inflammatory markers and the interrelationship of inflammation to atherogenesis. I have to say that as I’m listening to myself, I’m reflecting back to nearly 150 years ago to Rudolf Virchow. He is credited in many textbooks as being the father of pathology, and he talked about atherosclerosis, which was very uncommon back in his day during the middle-to-late 19th century. In patients he did necropsy on, he found that their atherosclerosis (what we call atherosclerosis today) looked like a wound, so he developed this wound (or injury) theory of atherosclerosis. As we get into this inflammatory sequelae in the 21st century, and now we start talking about the interrelationship of inflammation, atherogenesis, and unstable plaque, it starts looking like a wound or an injury and having some of these inflammatory mediators that are associated with injury to tissue. So, the Virchow model, revisited in the lens of the 21st century, doesn’t look so preposterous. In fact, it looks like it has a very important contribution to make in our understanding, both in the late-stage understanding of disease and in its early progenitor stages as a functional disturbance at the arterial endothelial level, that one-cell-thick lining of the artery wall, where integrity of the vascular endothelium is very, very important for maintaining the integrity of what goes on inside the artery wall. These concepts I’m describing are related a little to perspective or vision: What are we trying to ask, and what are the questions that really are on the table when you see a patient in your office? As has been often said during the training programs from the Institute for Functional Medicine, including the Applying Functional Medicine in Clinical Practice course, the lens that we view information through can determine exactly what we focus on and ultimately our conclusions. If you’re really looking at pathology as your ultimate endpoint and trying to diagnose a disease, you may be looking at different markers and analyzing them in different ways than if you’re looking at the trajectory towards disease, meaning the functional alterations that ultimately lead to a disturbed state of physiology in those cells that ultimately would give rise to pathology. Does the Availability of More Tests Equal an Overuse of Technology? What are we asking? What questions are we asking and how are we focusing the information from those questions through what lens to give rise to a specific understanding of an endpoint? That relates to this question concerning particle number and particle count in lipid assessment. There would be some individuals who might say, “Well, this is an overuse of technology. You really don’t get much more definitive information by measuring particle count and particle number than you get if you just do a gross, fairly simple, cholesterol HDL, LDL, and triglyceride measurement. Why would you want to go to the difficulty of doing this more exhaustive evaluation?” It is true that within the mean of people that go on to get heart disease that lipid particle number and particle count probably is…I don’t want to call it superfluous, but maybe the next step beyond that what you need for really picking at pathology. But in kind of the mid-range, where people have reasonably normal total cholesterol and they only have marginally elevated (maybe even normal) LDL levels, but die of heart disease as a consequence of having none of the traditional risk factors, should we have asked different questions? Should we have looked at their particle number/particle count to try to differentiate them from the midline of the mean? This is what some people call the “Ghost of Gauss” (Friedrich Gauss, the German statistician who talked about the midline, bell-shaped curve distribution of populations). Start saying, “What happens at the outlier side of these curves?” If you’re one of those people, you’d like to know it. You’d like to know what to know what to do about it. So here’s where some of this extended risk factor analysis that relates to function helps us to better understand individual personalized risk versus kind of general population risk. There Are Different Ways of Interpreting Tests for Different Individuals That’s what many people have argued as it relates to where we’re going with assessment protocols for functional intervention. Again, it depends on what we’re focusing our information through—what lens and what questions we’re trying to answer that really determines the kinds of things that we might be studying or evaluating in a patient. This even relates to things in the standard blood screen, like the analyte gamma-glutamyl transferase (or GGT).   As you know, historically that’s been considered a liver enzyme, along with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a serology, and individuals have thought of this as a way of testing for drug and alcohol abuse to monitor the success of therapy. When people have elevated GGT, one follows their abstinence by looking at this enzyme in the blood to see if it is coming down into normal range. So people have really identified GGT as kind of a toxicity from drug and alcohol surrogate measure. But there is a new interpretation on the use of GGT from Dr. David Jacobs at the University of Minnesota, who we interviewed on FMU a year ago, and his colleague, Dr. Duk-Hee Lee from Korea. What they have started to recognize, from evaluation of the Health and Nutrition Examination Survey (NHANES) data that has been compiled over the last couple of decades on American individuals and then looking at other countries as well, is that marginally elevated GGT (within the highest quintile of the normal range) is associated with increased incidence of diabetes and other cardiovascular disorders that has nothing to do directly with drug and alcohol toxicity, but really indirectly is a surrogate measure for glutathione status and oxidative stress.[3],[4] In fact, there is a very nice paper that was recently published in the journal Atherosclerosis which really describes the role of serum glutamyl transferase and its relationship to mortality in people undergoing coronary angiography.[5] This is a study actually done in Germany as part of the Cardiovascular Health Study. What they found in this particular study was that individuals whose serum levels in the upper quintile of GGT in the normal range had a significantly increased predictive all cause in cardiovascular mortality versus those who had the lower normal levels of GGT. And they again tie this to other risk factor markers other than alcohol and drug toxicity that are associated with cardiovascular disease origin, or the etiology of atherosclerosis. What would this be? Well, that takes us into a functional model rather than a pathological model in which we say the GGT may be a surrogate marker for oxidative injury, for mitochondrial uncoupling, for oxidative stress , and on toxicity and therefore we might start looking in a different place to answer the question as to atherosclerosis in that patient other than the traditional cholesterol risk factors. HDL is a functional protein that is made up of apolipoprotein A-1 (apo A-1) and 40-plus other different proteins that give the HDL particle a personality that’s very different than the LDL or the VLDL particles, or the IDL particles. The HDL is a functional protein: it has antioxidant capability, it has anti-inflammatory capability, depending upon the personality of the various proteins that are found within the HDL particle. The differentiation of composition of the HDL is more than just the number, so we can’t really say the HDL number, let’s say 50 or 45 milligrams per deciliter, isn’t the whole story. In fact we know there are people in Italy–in the Limone Sul Garda region–who have very, very low levels of HDL, but yet have very low incidence of cardiovascular disease, and it is found out that their HDL, even though it is low, is functionally very capable based on the protein composition of their HDL particle of engaging in cholesterol efflux and pulling cholesterol out the artery wall and lowering serum cholesterol effectively. It’s a measurement of HDL function as well as HDL number that becomes very important for determining relative risk. We’re going to hear much more about functional tests for HDL. This was a big discussion by Jay Heineckein the New England Journal of Medicine recently in the January 2011 issue, in an article he authored that discussed the role of functional HDL in cardiovascular disease protection versus just looking at the HDL number.[6] I think this is a wonderful segue into what we are going to hear from the experts from Cleveland HeartLab, Jake Orville and Marc Penn, in which we’ll be discussing how we use biomarkers in the laboratory to more effectively evaluate relative risk as it is associated with dysfunction of the cardiovascular system, as contrasted to just looking for cardiovascular pathology. So we moved the sequence of our insight back maybe decades to an earlier time where intervention can occur much more mildly and we can follow much better the trajectory in that patient’s health to avert a later stage necessity for intervention with stenting or surgery. With that, let’s move to our discussion with our clinician/researchers of the month.  

INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jake Orville, President & CEO Marc Penn, MD, PhD, Chief Medical Officer Cleveland HeartLab 6701 Carnegie Avenue, Suite 500 Cleveland, OH 44103 www.clevelandheartlab.com Here we are once again at that point I look forward to with great anticipation and that’s our Clinician or Researcher of the Month. I’m very fortunate this month. Actually in my office sitting with me are two luminaries that are really doing things that I would say are on the cornerstone of what we’ve been talking about in functional medicine for the better part now of 30 years: Jake Orville, who is the President and CEO of Cleveland HeartLab, and Dr. Marc Penn, who is an MD/PhD in cardiology and also an expert on the whole field of stem cell research as well. So, some very interesting basic science as well as clinical background. We’ve been talking today about what’s going on in the theranostics area, the early stage assessment area, how one looks at function prior to the onset of pathology. What are the rising tides in this field that can be more capable of uncovering occult trajectory towards disease to both lower the expense of disease management and of course, humanistically, to improve quality of life and quality of care? Both Jake and Marc, thanks a million for being with me here this afternoon. Let me throw out the first question. What took you two down this road with Cleveland Hear Lab to start moving away from maybe the more traditional cardiovascular Framingham risk assessment markers into some of these more esoteric or functional-based markers? Establishment of Cleveland HeartLab JO: Sure. Jeff, thank you for having us. I think it all started with our idea that we could do better, and the traditional methods—at least we were being told by physicians—maybe weren’t good enough. So we got together, Marc and I, and really thought about innovative novel testing that is additive to the traditional methods of testing to see if we could really help practitioners identify those that were really at risk for disease. JB: Marc, you have a very interesting joint background: basic science as well as clinical work. How did it pull your interest into the field? MP: I think what I recognize is that we have made tremendous strides in treating lipids in patients and decreasing the risk for heart disease, but now that about 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the patients who present with heart attacks have normal lipids, either treated to or naturally, I think it became clear that we needed to look under a different rock, if you will, in order to define who still has residual risk even though you’ve treated them to what the guidelines state for lipid management. A Brief Chronology of Establishing Cardiovascular Risk Factors JB: I’d like to go back with the two of you and do a little bit of a quick chronology. I want to go back first to Framingham, and then from Framingham I’d like to go to Brown and Goldstein, and then from Brown and Goldstein I’d like to go to Paul Ridker, just to kind of get a connector of beads on a string that makes a necklace. If we go back to Framingham and look at the work that was done in Massachusetts, it set the tone for risk factors and how that would be woven eventually into medical management, and then how that tied with blood cholesterol. Boehringer, I think, was the first company to develop a finger-stick cholesterol test that made it accessible at health fairs and suddenly the cholesterol number became a person’s number because they could get it at their shopping mall. That technology, then, ultimately drove probably the largest singular drug family in the pharmacopeia today, the statin drugs. From your perspective as a cardiologist, Marc, give us a little bit of your lens as to how you have seen the evolution of this field. MP: Yes, and I think you’re exactly right. Framingham set the tone for risk factors, recognizing that certain patients will be at a higher risk of developing disease. The other milestone I would put in your list is Russell Ross’s response-to-injury hypothesis in ’76, which really set the tone for studying lipids and how they induce injury, and then studying inflammation and how they propagate the disease. Brown and Goldstein, in their seminal work, recognized the lipid portion as inducing that injury, and perhaps driving the propagation. And then Ridker coming back and recognizing the inflammatory part of the pedestal, and recognizing that even in patients whose lipids are okay, if they have arterial inflammation they are still at risk. I think you’ve laid it out very nicely and I think that really is an amazing history in the era of medicine that had tremendous effects on changing the disease process. JB: Why do you think that there has been such a push back in medicine? I heard Paul Ridker speak not too long ago and his work seems quite impeccable on the inflammatory connection to atherogenesis, yet there are some very vehement members of the cardiology community that are totally resisting these extended factors. Why do you think that is? Resistance to Acceptance of Extended Risk Factors MP: I’m not certain why. Cardiologists are a challenging group to change our mind. I’m a cardiologist and I feel that way, I guess, too. I often wonder if the reason CRP is not well accepted is because we were all trained on the classic CRP, and these values are all within the normal range of the tests we were all taught. So there is always a resistance to changing something we learned, and if it were a new test called something else maybe people would be more accepting of it. But I agree, I think Paul’s work is impeccable. I think it’s revolutionary and he’s really moved the field forward in many important ways. I personally use it and I think it is an important strategy in anybody’s armamentarium who is truly going to try and push prevention, either primary or secondary. JB: I often hear some docs say, “Well, you know I tried measuring CRP in my patients, but it seemed to jump all around because maybe they had a cold, or maybe they went out for a long run.” As a clinician, how do you respond to those comments? MP: I can only go by my own personal experience and I think the test behaves fairly well. If somebody comes in sniffling and sneezing it is not the time to measure CRP. I think, you know, one of the debates I’ve heard is, “Well, my patients have rheumatoid arthritis and their CRP is high.” Well, if a patient has rheumatoid arthritis they have a five-fold increase of MI anyway, so we should be treating aggressively and that CRP is, in fact, reflecting that. Part of it is an education piece, part of it is an open-minded piece, but again I think the data are pretty strong. Personally I think I’ve had good success with it. JB: So now let’s go to the JUPITER trial. What’s wonderful about the field that we share is it never suffers for lack of controversy and back and forth. People take the same study and they get polar opposite, diametrically different opinions about it. Tell us—from the view of an expert—about the JUPITER trial. MP: What I find interesting about the JUPITER trial is that really the breakdown of those who’ve got a CRP under 2 and those with an LDL under 70. Obviously if both an LDL was high and a CRP was high in patients, they didn’t have any benefit compared with controls. If either the CRP or the LDL were below that cut-off they did better. What I find really interesting is if the LDL and the CRP were lower, they did yet better, which really does suggest that if one chooses to just measure lipids, they are choosing to miss half the story. And while certainly I think in a lot of people’s minds the lipids drive the inflammation and if you know where your lipids are you can figure out where your inflammation is or vice versa, but reality is the data repeatedly, in multiple studies, would suggest knowing where your patient achieves a lipid status and what their inflammatory status is are actually additive information, they are not redundant, and it truly helps us fully describe the risk of that patient in front of you. Biology versus Anatomy of Vascular Disease JB: So I’ve heard you eloquently talk about the biology and the anatomy of vascular disease and how one can see it progressing both anatomically and also physiologically, and different markers provide different types of insight into that process. Could you talk a little bit about this lipid versus inflammation connection in that context? MP: Sure, so you know there are repeated studies that have either looked in the coronary tree using calcium scoring and then looking at plaque activity with myeloperoxidase, or with the Lp-PLA2 test (the PLAC test), showing that if you have good anatomy but you have bad biology (a high myeloperoxidase) you have risk. If you have bad anatomy and bad biology you have even more risk. So clearly, again, this concept of if you choose to pick one or the other, cardiologists are very good at the anatomy side with cardiac catheterization and computed tomography angiogram (CTA), and you’re limiting, really, fully describing the risk of that given patient. JB: I’m going to put my little spin on this and you can correct me if you feel I’ve over interpreted, but I would put the spin from the functional medicine perspective that the biology refers to function and the anatomy refers to pathology, right? MP: Yes, I think that’s very fair. JB: Okay. So what we would say in the functional medicine model is that dysfunction precedes pathology. MP: Yes, and certainly if you look at our offering of F2-isoprostane as a general marker of oxidation, that precedes pathology, but if we have that abnormal function, the studies will tell us that the pathology will follow. F2-Isoprostane as an Analyte JB: So let’s talk about the F2-isoprostane. I think that’s a really interesting analyte. Early on, as I recall, when that was first in the literature, people were talking about it as an oxidative stress marker—as a kind of an interesting prostanoid-like molecule that came from reactive oxygen hitting an eicosanoid structure to form this. Do we interpret it differently today as we’ve learned more about it? MP: No, I think we recognize it possibly as the gold standard measure of oxidative stress and how much oxidation is going on. When we look at deconditioned patients and recognize that they have high F2-isoprostanes, and we recognize that as they begin to exercise that actually goes up because they’re burning more fuel, but as they become physically fit, it goes down because they are burning less fuel per unit of work. We recognize that it really does reflect the functional physiology that’s going on, and if we allow it to maintain a high state in a deconditioned patient, we’re working our way towards the pathology. JB: Let’s now then go back and review because we’re going pretty quickly, probably, for the listener who is trying to keep track of this. We have the F2-isoprostane. We have the CRP. We’ve got the myeloperoxidase and we’ve got the Lp-PLA2 (the PLAC-type analysis). How do they fit together, then, in a schematic representation? MP: What we would suggest is that F2-isoprostane is really defining the patient who has a lifestyle risk: they are deconditioned, they smoke, they have a bad diet. That leads to increased oxidative state, increased risk long-term of not only cardiovascular disease but also cancer. If we’re now looking for presence of marker of disease, we’re really looking at CRP, which based on our studies would really be a measure of atheroma burden, and then albumin/creatinine ratio, which is really a measure of endothelial dysfunction. Working our way from lifestyle to presence of disease to activity of disease, now we’re looking at the myeloperoxidase (MPO) and the Lp-PLA2 (or the PLAC test), which are really looking at vulnerable plaque formation from really two different points of view. The Lp-PLA2 (or the PLAC test) really looking at it from the vessel wall point of view or “inside the house,” if you will—looking at the activity in the necrotic core, macrophage activation, things of that nature. And the myeloperoxidase test is really looking at it from the lumen side—what the white cells are saying—“outside the house,” if you will: fissures, erosions, hot atheroma that is starting to come through a collagen cap. Together, this really not only helps us to find whether a given patient has risk, but where they are on a risk spectrum: Are we really focusing on lifestyle? Are we trying to modulate disease? Or are we really trying to quiesce the function that is going on in the vessel wall that is risking a clinical event? JB: I have often heard docs worry about “over utilization” or “over testing.” They’ll say, “Gee, I wonder if that’s a standard of care? I wonder if I’m doing too much testing?” It sounds like when we have a portfolio of tests it gives us different ways to look into the lens of the progression of cardiovascular disease. What would you say to a doctor who says, “Am I using too many tests?” MP: The reason we focused on a panel approach at Cleveland HeartLab is the studies have demonstrated that these tests offer additive information. There is an elegant study by Heslop and colleagues out of Canada last year that showed that if you had a high MPO level your ten-year risk of mortality was significantly increased.[7] But what they also ended up showing was that if you had a low MPO and a low CRP, you did well. If either were high, you didn’t do so well. If both were high you did yet worse. So it is hard to say that defining a MPO and a CRP are redundant or over testing. Similarly, we’ve looked at data in over 2000 patients from executive health programs and preventive cardiology clinics where about five-and-a-half percent of the patients will be at risk based on high MPO, and about four to four-and-a-half percent will at risk based on a high Lp-PLA2, but yet despite having well over 2000 patients, only six patients had both markers up. So it is hard to argue that those tests are redundant when you have such high discriminatory values. By random chance you would think you’d have more than six patients up in that kind of population, yet we did it. What we say—and it is consistent with the biology and consistent with our understanding of the pathology and the function—is that if you have a hot vessel wall, and you have white cells responding to that, you’re not in an executive health physical. You probably have acute coronary syndrome if it is in the coronaries. So I don’t see—and we’ve developed this panel very specifically—not to have redundant testing, not to be over-testing, but really to, in a very logical and rational way, taking pathology and function into consideration, a panel of tests that allows us to define where our patient is. JB: That was a brilliant explanation—very succinct—but you also used a term, there, which I think is a very interesting term, and that was in the context of a “syndrome” (acute coronary syndrome). Why don’t we call that acute coronary disease? What’s the difference, there, in the languaging of that as a syndrome? MP: I think the reason it is a syndrome is it can be caused by multiple different effectors. You can have a hot vessel wall that ruptures. You can have fissures and erosions that allow platelet activation. You can have a flu-like syndrome that causes active plaque. You know, it is just not a single event. It ends at the same place: you have plaque rupture, the growth of lesions, and/or thrombosis. But there are multiple avenues to get into that state. JB: I’ve heard Dr. Mark Houston say something like, “There are an infinite number of causes with a discrete number of biological responses.” Does that make sense that the body has a discrete number of biological responses to a whole set of offending precipitators or initiators? MP: Yes, I hadn’t heard that, but I think that’s excellent, actually. We clot, we attack infection, we don’t do that many different things. JB: So Jake, from the perspective of getting to docs and helping them understand this emerging new biology of vascular disease and how these analytes can be useful in helping them be more specific in managing patients, what are your challenges and how do you overcome these in getting people to understand, people who may be trained in a different perspective and this is all new to them. JO: The biggest challenge is education, and education starts with: What are these tests and what do they mean? Then it goes to: What are the results and how to interpret? And beyond that, which is really a focus of our company: What do you do next, and what do you do with the patient, and when should you see them? So after that patient leaves the office, that practitioner has a good understanding of what they have just gone through, an explanation to the patient of what they should do, and then a clear expectation of what they should do after they leave, and when they should come back. I think that’s one of the biggest hurdles. You don’t necessarily take that educational piece and put it on your back as a service laboratory, but we really believe strongly that that is where we should focus the most. JB: It seems interesting to me, as I just—from one step removed—watch what’s going on in the specialty lab area in cardiology, you’ve got Berkeley Heart Labs recently (not real recently, but reasonably recently) acquired by Celera, which sounds like a very interesting jewel to put on their crown, and you see others, like Atherotech and LipoScience being acquired as investments from companies that you normally might not think would be focused on functional cardiovascular diagnostics. What does this say? What does it say about the field? What does it say about the trend? JO: To me, I think people are trying to go as far upstream as possible to get the information, to understand what’s happening, so they can design therapeutics, design supplementation—nutraceuticals, foods, what have you—that attack what is happening in the body and I think it all starts with a test. If it was as easy as us just looking around and saying “You’re at risk and you’re not” we wouldn’t need this, but we need a lot more information than that. I think it has been a great effort by a lot of the labs you mentioned, which are the great groups that are out there really doing innovative things, and I think we’re all working together to show that getting a diagnosis or getting a prognosis will help the downstream efforts of not just the physician, but the companies that are then going to help support the physician afterwards. JB: And I think part of it drives what you said earlier about patient education: tools that the patient can use to kind of understand their body at a different level so they become more invested. If it is somebody else’s body you just drop it off in the exam room and walk away, you don’t maybe have the same investment as to owning and understanding what’s going on. JO: That’s right. How Important are Particle Number and Particle Count? JB: Marc, one of the things that strikes me as interesting about the evolution of this field is you’ve got debate going on around lipid particle number and particle count and whether this is really going to be helpful in personalizing therapy or it is just another window dressing. What’s your perspective on that? MP: Well, I think the concept of particle number is interesting and important in, clearly, a subset of patients whose particle numbers do not track with the classic lipid panel. Their apo Bs are high. You really do identify an insight into that patient that you wouldn’t otherwise get. The same is likely true for HDL and HDL particle numbers. So, again, I think in this era of specialty testing, if you identify patients who have a risk, I think you can better describe what that risk is and more importantly what your therapeutic response should be based on those kinds of tests. JB: Tell me a little bit about this interesting particle, the HDL. When we learned about apolipoproteins and lipoproteins, I think we all had this thought that maybe they only differed in density and size. But now we have learned that this HDL is this very complex particle with 40 or so proteins that make it up. Tell me a little bit about how the HDL differs from the LDL, the VLDL, and the IDL. MP: I think what’s interesting about HDL or what is becoming clearer is it’s not about how much HDL you have, it’s how functional your HDL is, right? Folks with apo A1-milano have relatively low HDL levels, but what is clear is their HDL is relatively oxidant resistant. It stays functional longer. It fluxes through the body better, so it can pick up lipids from the vessel wall and return them to the liver through LDL in a more efficient manner. I think we learned a tremendous amount through the Torcetrapib experience with the cholesterol ester transfer protein (CTEP) inhibition and the fact that, you know, if you do a mass balance on CTEP inhibition you might argue that you’re not sure it’s going to work, but I don’t think anyone expected it would be hazardous. And clearly an accumulation of dysfunctional HDL particles appears to be proinflammatory, and certainly (in that study) seemed to have negative consequences. Given the degree of blood pressure changes, it doesn’t seem to many, including myself, that the adrenal effects were really where the negative effects were. Now it may be that other CTEP inhibitors that are not irreversible, that are partial inhibitors, maybe they will be successful. I know they are certainly going forward in clinical trials and it will be exciting to see. And then what we have learned is that even in the absence of CTEP inhibition, apo A1 can become oxidized. There is some very beautiful work by Jay Heineke that has demonstrated that oxidized apoA1 cannot participate in reverse cholesterol transport.[8] So we are learning that these folks who have inflammation may have low HDLs, but it may be functionally much lower than we think it is because in fact a lot of the HDL they have may not be functional. I think we’re learning. We’re working diligently on dysfunctional HDL assays. And I think as physicians we’re going to finally learn not only what percent of our patients have dysfunctional HDL, but which one of our therapies improves that. Because right now it’s a black box: Is it fibric acid derivatives? Is it stains? Is it niacin? We just don’t know, and I think it’s going to be a very exciting time when we have a dysfunctional assay out to not only define who’s really at risk, but also who responds and what the right therapeutic target should be. JB: That was really very, very insightful. For the listener—just to kind of fill in a little bit of the lexicon—CTEP transfers the cholesterol out of a lipoprotein to another site. The Torcetrapib trial had Pfizer ready to roll out to market this new drug that was going to extend the patentability of the atorvastatin via combo HDL-elevating molecule coupled with LDL cholesterol lowering molecule. That 800 million dollar risk adventure failed, for the reasons Marc was just describing. That begs a question on this whole news about niacin, because niacin was also one of these pharmacological agents (the therapeutic dose) that was an HDL elevator. Do we see the same thing going on there as with Torcetrapib? MP: Well, Torcetrapib raised HDLs for sure, but where CTEP inhibition came into play is that HDL can pick up the cholesterol from the artery wall. It ultimately transfers that cholesterol from the HDL to LDL in the bloodstream. The LDL actually completes the circuit by returning the cholesterol to the liver. There was hope that if you block cholesterol ester transport protein, you raised HDL levels and in fact you raised HDL levels very well. The question was: Could the scavenger receptor B1 (SR-B1) in the liver take up all that HDL? Would it go there, and would it be efficacious? Even on the patients with Torcetrapib who raised their HDLs 60, 70, 80 percent, they actually had an increase in mortality because there was a lot of this HDL around that could not return their cholesterol. As near as we can understand, that HDL became dysfunctional, and actually was then probably proinflammatory and caused vascular events. With niacin we’re not seeing that. Niacin is driving more HDL to be made. It is not inhibiting the flux; it is hopefully enhancing the flux. The vast majority of trials with niacin have been positive. Recent carotid intimal medial thickness (CIMT) trials were not positive. There is a debate as to whether they were the right patient populations which truly had risk. And they were also well-treated going into the trial, so there wasn’t a lot of atheroma to try and reduce. But niacin is certainly safe, and seems to be efficacious in the majority of trials. JB: One last question which I think bears on this mosaic of confusion, and that is statins. We have this concept of a class effect. The more one gets into pharmacology, the more a person starts saying, “Is there really such a thing as a class effect? Is that just kind of a marketing language?” Because each of these molecules that are within a class, if they have a different structure they have a different function. So we think, is Crestor the same as Lipitor (or whatever—choose your statin of the day)? Could you tell us a little bit about how you see things evolving as it relates to the difference among the class of statins. What Do Statin Trials Tell Us About Class Effect? MP: I think if you take the field as a whole and you look at outcomes, you have trials like the ASCOT trial that looked at 10 milligrams of atorvastatin and you compare that to the Scandinavian Simvastatin Survival (4S trial) which looked at twenty milligrams of simvastatin. Simvastatin 4S reached a mortality end point; ASCOT did not. They had about the same level of LDL lowering, so you start to wonder why. Well, simvastatin tends to be a better HDL-raising statin than atorvastatin, so maybe it’s that. You then look at ASTEROID, which was 40 milligrams of rosuvastatin, which was an intravascular ultrasound study, and you compare that to the REVERSAL trial, which was 80 milligrams of atorvastatin. Well, 40 milligrams of rosuvastatin has roughly the same LDL-lowering effect as 80 milligrams of atorvastatin, and you say, “Well, why did ASTEROID see regression and REVERSAL didn’t see any regression?” Well, rosuvastatin is a pretty good HDL-raising statin and atorvastatin is not a particularly good HDL raising statin, particularly at 80 milligrams. So you start seeing themes around the biology (the picture, the anatomy) and then the function, or the pathophysiology, between ASCOT and 4S. Steve Nicholls, who was a colleague of mine when I was at the clinic, published a very nice study several years ago, now, that looked at intravascular ultrasound studies and what changes in lipid parameters predicted regression.[9] What Steve found was that if you got the LDL under 87.5 milligrams per deciliter, there was evidence of regression. But what he also showed, which was very interesting, was if you raised HDL, it’s 7-and-a-half percent, so that’s 40 from 43. It’s not a big change. There was also significant benefit. So again, if you take 4S and ASCOT, REVERSAL and ASTEROID, and you say, “Well, maybe the HDL effect is real,” and then you say, “Well, how do you get 7-and-a-half percent rise in HDL?” Almost any dose of simvastatin will get you above 7-and-a-half percent. Any dose of Vytorin will get you above 7-and-a-half percent. Five milligrams and above of rosuvastatin will get you 7-and-a-half percent. Almost no dose of atorvastatin will get you 7-and-a-half-rise in HDL. It becomes a very interesting concept of: Is it the HDL effect of the statin and therefore, then, it is not a class effect? And, again, when we have a dysfunctional HDL assay and we can say, “Not only did we raise HDL, but actually 20 percent more of it was good,” we’ll be able to make better conclusions along these lines. Because it does appear that the HDL effect of a statin, as modest as it really is, seems to predict the biologic and functional response. JB: That’s really insightful—very, very interesting. I guess it is a theme that would play, also, with other interventions—lifestyle interventions or anything that is going to influence your lipid number, particle size, and distribution, you could use that same logic, it would seem. I said that was the last question, but I actually have one more follow on. We’ve always thought of this as the “Lipid Hypothesis.” But I recall an article that was written back in the mid-to-late 70s called the “Lipoprotein Cascade.”[10] I think it was by Eaton. He was proposing that atherogenesis is also an apolipoprotein issue as well as a lipid issue, and that there are many things that influence the biosynthesis of apolipoproteins: it could be stress, it could be hormones, it could be insulin (a hormone, I guess, but I was thinking of steroid hormones versus peptide hormones). And so we ought to be looking at it from the apolipoprotein perspective as well as the lipid, because the lipid is carried, obviously, by apolipoprotein. Do you have any comment about that kind of duality—lipid versus apolipoprotein? MP: Yes. Part of it is the dysfunctional part of HDL and apo B certainly is all about the apoprotein (the oxidation). It’s the protein; it certainly is the part. We also have some interesting data that will be coming out soon that apo A-1 may play a significant role in the uptake of Coenzyme Q10 (CoQ10). We’ve now looked at mice that cannot make apoA-1, and in a gene-dose dependence, it actually regulates how much CoQ10 is actually taken up in the heart. And if you actually induce a heart attack in these mice, their infarcts are huge—much greater than normal mice. But if you supplement them with CoQ10, you actually normalize their infarct size, and we’ve now mapped this to a very specific deficiency in the mitochondria. It’s quite clear to us now that apo A-1, the apoprotein, does have quite a significant role in CoQ10 absorption. If that turns out to be clinically valid, which I think there is evidence it is, you almost have to reinterpret Framingham to recognize low HDL may not just cause more heart attacks, but it may actually cause bigger heart attacks, and we may be raising HDLs for all of the reasons we don’t understand, which is to actually improve the absorption of CoQ10, replete the mitochondria in the body so that if they have an infarct, their infarct is smaller. JB: That’s fascinating. So Jake, I’m going to give you the last word. You’ve got the responsibility as president/CEO of Cleveland HeartLab of kind of directing the future implementation of this wonderful new science that is becoming available. What do you see on the landscape, in front of you and your group? JO: I think you two have discussed where we want to focus, which is the function. I think we see a lot of novel markers that predict risk and I think there are a lot of those that are out there. I think we’re trying to decide: Does it have a good risk? Can it give insight on what to do? And what is the function of it? That’s where we are at. Clearly there has been a strong interest in the educational side of things and complement the biomarkers, and if we can continue to focus our areas on functionality and the additive nature of risk and what happens next I think we’ll do very well. I think we will continue to be adopted and embraced out there in the physician community. JB: Are you seeing much push back or receptivity to these panels being included within various insurance reimbursement diagnostic code programs? JO: Just to clarify the definition of a panel: When Marc suggests a panel, that’s for educational purposes. We don’t sell panels. We provide testing and we provide education. It’s really up to the physician to kind of form their own panel. Marc provides a lot of education on panels that may be insightful. From an insurance company standpoint, obviously we want to make sure that they are aware of this testing, that they are aware of the value and the benefit, and I think it’s a question you asked several questions back, which is: Is too much testing a problem? I think our answer is “yes,” which is why we go right to the root, which is what we believe to be inflammation, and then follow the risk backwards. Let’s find out where this patient is—if they are at risk—and I think we have seen a good embracement of that from the insurance companies, to understand what it is to go right to the heart of the risk, first in an affordable manner and then decide where to go from there. JB: Very well said. I want to thank you both. I think this has been really a lot of news-to-use in a very concise fashion. Thanks a million, and we’re going to be checking back. This is actually the pulse point of where functional medicine and functional cardiology is going. Thank you both. JO and MP: Thank you  

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Bibliography

[1] Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207. [2] Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol. 2011;5:338-367. [3] Lee DH, Steffes MW, Jacobs DR Jr. Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes? Diabetologia. 2008;51(3):402-407. [4] Ha MH, Lee DH, Jacobs DR. Association between serum concentrations of persistent organic pollutants and self-reported cardiovascular disease prevalence: results from the National Health and Nutrition Examination Survey, 1999-2002. Environ Health Perspect. 2007;115(8):1204-1209. [5] Stojakovic T, Scharnagl H, Trauner M, et al. Serum gamma-glutamyl transferase and mortality in persons undergoing coronary angiography—the Ludwigshafen Risk and Cardiovascular Health Study. Atherosclerosis. 2010;208(2):564-571. [6] Heinecke J. HDL and cardiovascular-disease risk—time for a new approach? N Engl J Med. 364;2:170-171. [7] Heslop CL, Frohlich JJ, Hill JS. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J Am Coll Cardiol. 2010;55(11):1102-1109. [8] Shao B, Cavigiolio G, Brot N, Oda MN, Heinecke JW. Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I. Proc Natl Acad Sci U S A. 2008;105(34):12224-12229. [9] Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297(5):499-508.   [10] Eaton RP. The lipoprotein cascade: clinical implications of hyperlipemia. Continuing education for the family physician. 1977:42-49.

Welcome to Functional Medicine Update, February 2012. Can you believe that we’re into the second month of the year already? Things just are moving, I think, at almost light-speed. It’s suggestive of the nature of change that the whole world culture is undergoing right now. There are these convergences of very remarkable, paradigm-shifting perspective s, including not only biological sciences/medical sciences, but also information sciences and social sciences. These are all on a converging course to really create—I would call it—an amplified motivation for change. New Clinical Tools are Making a Difference in the Practice of Personalized Lifestyle Medicine This month we’re going to be focusing on the area that is near and dear to my heart and that is the concept of personalized lifestyle medicine, built upon the principles of Roger Williams and biochemical individuality, Linus Pauling and orthomolecular medicine, and the view that each of us are genomically unique and that our requirements for optimal function are  our own and not that of the average. In fact, Roger Williams said years ago—in 1974 actually, when I was at one of the early meetings of the then-American Academy of Preventive Medicine—“Nutrition is for real people, statistical humans are of little interest.” I remember that—it is just kind of emblazoned in my memory from all those years ago—because it’s a sound bite that so captures this concept of uniqueness and personalization.   The unfortunate thing is from 1974 to 2012, we often didn’t have the tools to really make this concept stand up, we weren’t able to find effective ways to personalize, but I think those limitations are changing rapidly in the post-genomic era in which we’re now living. Now we are able to define certain specific subsets of the whole, and define unique clan genomics (as it is called) that connect us together with people with similar types of patterns of genomic pluripotential. Clan genomics would determine response to an environment like low gluten, or changing the protein-to-carbohydrate ratio, or changing the specific levels of certain nutrients. That’s really what we mean by personalized lifestyle medicine.   How are we going to approach this discussion in this issue of Functional Medicine Update? We’re going to look through the lens, the eyes, the experience of one of the master clinicians in personalized lifestyle medicine. That would be our Clinician of the Month this month, Dr. Kristi Hughes, who is a marvelous clinician, also a fantastic educator, and a seeker, like all of us, looking for better ways of managing individual presentations of complex chronic illness.   How Hard is it to Reverse Established Medical Practices? What’s the field in general starting to look like? What’s the domain saying about the whole nature of medicine? This leads me to  a short article in the Journal of the American Medical Association in the January 2012 issue titled “Reversals of Established Medical Practice: Evidence to Abandon Ship.”[1] It’s quite an interesting title, isn’t it? What’s the theme of this particular short article? I think the theme is that many of the things that we thought were truth, that were facts, that were prima fascia, peer-supported, and standard of practice, when we have better information and stronger data, we find that they were, in some cases, not just partially incorrect in their assumptions, but the whole paradigm was incorrect, and there was a factual misconnection with what we have found is more likely the truth. I think the introductory paragraph of this article sets the context: “Ideally, good medical practices are replaced by better ones, based on robust comparative trials in which new interventions outperform older ones and establish new standards of care. Often, however, established standards must be abandoned not because a better replacement has been identified but simply because what was thought to be beneficial was not.” So then it goes on to discuss same examples of this, things like the story related to the use of equine estrogen replacement therapy in women, or the story that relates to the emerging understanding of percutaneous coronary intervention for stable coronary artery disease, and goes on to really talk about the more detailed intervention trials that have been done in these areas, or retrospective studies that have demonstrated that many of these therapies that we’ve taken as fact, as standards of care, as the best available, were actually not delivering the goods, even though they may have been used by board-certified trained individuals that had been examined on these and part of their licensure renewal was dependent upon understanding and reciting on demand the value of these particular therapies, that, in actual fact, when they were exposed to more rigorous evaluation, proved to be either incorrect or even—in some cases—had some adverse effects associated with them in terms of outcome.   So that’s one interesting, as I call it, fifty-thousand-foot perspective. The other one that I think is interesting also comes from JAMA. This is an article that appeared a few years ago, but I think in the context of what we are talking about now with revisiting the importance of personalized lifestyle medicine and the management of chronic age-related diseases, this becomes a more interesting article. The title of this article is “The Conflict Between Complex Systems and Reductionism.”[2] Again, let me emphasize: “The Conflict Between Complex Systems and Reductionism.” This appeared in JAMA as well in 2008. This particular article is about the way many of us have been trained—this reductionistic Cartesian approach: taking big and breaking it down to smaller fractions until we understand the piece parts, and then assuming that the assembly of the piece parts makes us able to understand the whole. This is the one-pill-for-one-ill mentality that leads us to believe that blocking enzymes downstream in complex physiological processes in a system actually can lead to remediation of long-term disease. We have a whole series of drugs that are involved with blocking, or anti-this, or basically inhibiting specific types of downstream metabolic functions. What this article talks about is that the emerging science recognizes that we are a complex adaptive system. That’s what the human is. It’s modifying its function in real time, all the time, on the basis of environmental inputs (information coming from the environment) that are translated through our unique genes to give rise to our genetic expression into our phenotype that then regulates how we act, feel, look, and perform, and determines our health and disease over time, and that this is individually unique to all systems built around our exposure to the environmental inputs and how that’s focused through the lens called our genome.   The Systems Approach: Networks not Pathways The systems approach is to look at the interactions of networks rather than pathways, and to start to put together the complexity of this adaptive system that we call the human body and its response to the environment and things that are going on around us all the time. These things include infectious disease, psychological stress, exposures to chemicals, altered nutritional intake, sedentary lifestyles, or dysfunctional signals that might come from allergens or toxins. All of these are part of a different view of what ultimately leads into a complex approach towards managing patients rather than a pill for an ill. This perspective is: What’s the mosaic of inputs that will create a positive outcome through altered lifestyle, which is multivariate, not univariate? We know that lifestyle has a huge number of different variables: what we breathe, what we drink, what we eat, how we think, how we move, interactions of the social network, where we work, what we are exposed to in terms of radiation. All of these variables play a role in modulating our function over time.   Some people say, “Well, that’s too complex, and that’s outside the bounds of medicine because it doesn’t really address pathology in the way that we need to look for a causative agent or a remediating agent.” But other individuals say, “We now have the information systems, and we have the capability with our social science systems, to actually start addressing these broader issues, which are really the Rosetta Stone for understanding the origin of chronic disease.” Chronic disease is complex. Chronic disease is unique to the individual. And chronic disease is a result of these interactions of the genome and the epigenome with the environment.   So this article, “The Conflict Between Complex Systems and Reductionism,” I think is a very, very powerful conceptual framework, particularly when we put it within this bailiwick of “Reversals of Established Medical Practices: Evidence to Abandon Ship.” I don’t think we need to abandon ship. What we need to do is move our perspective up a notch or three (meaning, to a higher elevation)so we can start to see the forest for the trees, or we can get out of the dust storm that’s close to the ground that relates to individual symptom evaluation and the drive for the sine qua non called diagnosis, and move us up to the landscape of understanding of the system that this patient is interacting with that gives rise to the expression of their multi-symptom dysfunctions that we call chronic illness. Of course, I’m really speaking now to the functional medicine model. This is the whole basis of the model: patient-centered, built on the concept of systems biology, it deals with biochemical individuality, and this genome/environment interaction giving rise to the expression of function.   One Size Does Not Fit All When it Comes to Pharmaceuticals: Women, Statins, & Type 2 Diabetes Can we think of a recent example—a prominent recent example, even–where the concept of a pill-for-an-ill seems to have led us into somewhat of an uncharted blind alley? I think there are probably many examples, but one that has certainly stuck out prominently in the last month or two is discussed in this Archives of Internal Medicine paper from 2012 titled “Statin Use and the Risk of Diabetes Mellitus in Postmenopausal Women.”[3] These women were part of the the Women’s Health Initiative (WHI) studies, This is a very alarming epidemiological, statistical, restrospective analysis of some 161,808 postmenopausal women, so certainly a fairly large number of individuals. These were women 50 to 79 years of age that were recruited at 40 clinical centers as part of the WHI across the United States from 1993 to 1998 and have been followed since. The data that were reported in this paper was through 2005. Statin use was captured at enrollment and year 3. In this particular work, the incidence of diabetes type 2 was determined annually from the date of enrollment and then statistical methods were applied to see if there was any kind of connection between statin use and, in this case, type 2 diabetes. There was an adjustment for propensity score and other potential confounding factors, such as race, ethnicity, obesity, and age, to see if there was any effect of the relationship (at least statistically) between taking statins and the appearance of type 2 diabetes in these postmenopausal women. The results reflected increase in the incidence of diabetes in women who had been taking statins in their postemenopausal years.   Now, the mechanisms of action or the origin of this is not known. This is, again, an associative study; it’s not a clinical controlled trial, prospectively, so it always raises all sorts of questions. How important are statistics? If you don’t have a relative understanding of a mechanism is it just an outlier, is it circumstantial? But there was a very high association and the odds ratio was pretty well clustered with statin-taking women across all classes of statins interestingly enough, not just one statin, which means is there something interesting in the pharmacology of statins that could be associated with the onset of type 2 diabetes in a unique cohort of individuals, in this case postmenopausal women? With that as a question, let me diverge for a just second and illustrate how a functional medicine-trained practitioner might think about this. I’m doing this to characterize and maybe contrast how functional medicine training is really about a thought process, not about specific therapies. The therapies drive out of the process. Rather than an algorithm, where we drive to a specific formulaic approach towards the management of that patient (meaning a clinical protocol), what it drives to is a thought process that allows us to understand the variables through the matrix of the functional medicine model that might contribute, in that individual patient, to their situation (their clinical signs and symptoms). With that as a precept, let me talk a little bit about what this means in terms of the statin connection to diabetes—how, as functional medicine-trained individuals, our brains are patterned to review this. Here’s one way of thinking about it. I don’t want to say this is THE way. It’s certainly not the only way, but it illustrates a way of thinking. So we go back to the literature and we ask, from our history of experience: What do we know about statins as a class? And depending upon the specific statin, with differing degrees of relative risk, we are historically reminded that statins have one common reported adverse effect, which is muscle pain and its interrelationship to the more extreme example of it, which is called rhabdomyolysis, a situation where you get muscle necrosis and muscle tissue cell myocyte breakdown, and it can become very, very serious (the extreme edge of this adverse side effect). What’s the origin of that myocyte problem? Recall, if you would, that these statins are fungal byproducts. They are manufactured, initially, in the environment (these monacolins off the genome) of a fungus, of a proteus, basically. They are manufactured by these organisms as a defensive substance that is a toxin to other organisms. We also know that these are enzyme inhibitors. We are well aware that whether you are talking about red yeast rice monacolins, or you’re talking about Lovastatin, or Atorvastatin, or whatever the statin of the moment is, that these have influences on specific enzymes, the most prominent of which we know is the hydroxymethylglutaryl Coenzyme A reductase (HMG-CoA reductase), which is the rate limiting step in cholesterol biosynthesis. We’re all told that the role of these molecules is to selectively block HMG-CoA reductase and to lower cholesterol de novo biosynthesis. As a consequence, we also recognize that it lowers the synthesis of other downstream molecules that are involved with a mevalonate pathway, including things like coenzyme Q10. That is one of the reasons we often supplement with coenzyme Q10 in statin-consuming individuals. This is all kind of historically understood. What may be less understood is that these molecules that are members of the statin family have other effects such as enzyme inhibitors within the electron transport chain. The electron transport chain, as you probably recall, is found within the mitochondria. It’s the biochemical pathways that are involved with energy production/energy regulation within cells. One of the problems that occurs in specific individuals with certain statins is mitochondrial bioenergetics is impaired. These fungal toxins that we call statins and their chemical derivatives that have been modified by synthesis to be improved examples of these monacolin molecules, in certain genetically susceptible individuals and maybe even in individuals of a certain age, hormonal balance, and gender, might influence adversely these functions. If you start injuring, let’s say chronically, mitochondrial oxidative phosphorylation and bioenergetics, we know that that is directly related to the appearance clinically of insulin resistance. This is well documented that there is a connection between mitochondrial interruption—let’s call it mitochondrial toxicity—and insulin desensitization, meaning insulin resistance, and that ties ultimately to the etiology of type 2 diabetes. So could it be—and again, this is the way a functional medicine practitioner might think—that part of what we’re observing in the statistical connection in this study of 161,808 postmenopausal women (the connection between statin use and type 2 diabetes) is looking at a certain susceptibility in cohorts of postmenopausal women to the effects of these molecules on mitochondrial bioenergetics that affect certain cell types (or cell lines) within their bodies, that influences then insulin regulation/insulin sensitivity and ultimately what we call type 2 diabetes? Could it be the interruption in the downstream production of the mevalonate molecules—things like lanosterol and farnesyl and ultimately on into squalene and finally into the sterol molecules that regulate function and immune response—that these are influenced adversely? Even things like coenzyme Q10, which then shows up, in these women who have undergone hormonal changes with menopause, as altered insulin sensitivity and increased risk to type 2 diabetes? So I think these are all very, very interesting questions that derive out of functional medicine thinking as it relates to taking a broad statistical evaluation and funneling it down to look at an individual patient, let’s say a postmenopausal woman who has been on statins who starts to develop type 2 diabetes, or insulin resistance, or metabolic syndrome. For that woman, we start asking: What’s the evidence that she might have mitochondrial bioenergetic problems, or oxidative stress, or that she’s got hormonal imbalances that are creating different signaling of insulin, or that she’s got a coenzyme Q10 insufficiency that creates alterations in mitochondrial function then presenting as type 2 diabetes? And then what do we do about it in that specific person? If she is going to remain on statins, do we augment her with coenzyme Q10? Do we give her essential fatty acid supplements? Do we give her different vitamins and minerals to promote proper function? Do we give her higher levels of detoxifying nutrients in order to lower risk of toxicity? These are all, I think, very interesting types of approaches that would only derive out of the thinking of a trained functional medicine practitioner. I think you’re going to see how this example weaves its way into personalized lifestyle medicine with this extraordinary discussion with the Clinician of the Month, Dr. Kristi Hughes, and how this ultimately relates to the connection between functional medicine and personalized lifestyle medicine.

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INTERVIEW TRANSCRIPT

Clinician of the Month Kristi Hughes, ND The Healing Center 819 30th Avenue South, Suite 206 Moorehead, MN 56560 www.thehealingctr.com The Institute for Functional Medicine 1-800-228-0622 www.functionalmedicine.org Each month in Functional Medicine Update I have the privilege of doing an interview that takes us down the road of what we call news to use—some of the most recent things that I think are happening that help us to better understand some of the tools that are becoming available within the field of functional medicine. We’re certainly fortunate this month to have a clinician’s clinician: a teacher, a clinician, a business manager, a thought leader, a person who has stepped up and been recognized as an authority in the field. I think her history really is symbolic of how we all, in this field, are in the pursuit of excellence and moving towards higher level of understanding and application to patients in need. I’m speaking to Dr. Kristi Hughes, who is our clinician of the month this month. Kristi has been a colleague and friend now for nearly 15 years. She graduated from the National College of Naturopathic Medicine in 1997 in Portland, Oregon after having earned her undergraduate degree at the University of Minnesota in Duluth. From there she has just taken off over the last 14 years. She is symbolic of what it takes to really be a successful practitioner/leader in the area of functional medicine. I think her experience really nicely reflects the rising importance of naturopathic medicine, which I’m very proud to see emerge so brilliantly over the last 25 years. I recall when Joe Pizzorno, Les Griffith, Sheila Quinn, and Bill Mitchell, were starting Bastyr University back in the late 70s and early 80s. At that time I was teaching nutrition at the National College of Naturopathic Medicine. We always wondered in the late 70s if would we be able to see the emergence of a field of natural medicine/naturopathic medicine that would be licensed nationally that would really fill the unmet need for credentialed professionals in the area of natural medicine. Certainly that has been seen in spades over the last 25 years, and Dr. Hughes is really, I think, reflective of the quality of graduates that come out of those programs. Kristi, it’s wonderful to have you as one of our leaders in Functional Medicine Update. Let me start with the trivially obvious question. When you started down this road with earning your naturopathic degree, did you have in mind where you were heading, or did you just take each step along the road in your own laying process? What was your motive? KH: You know, the interesting thing is, Jeff, where I grew up in the midwest, I had actually never even heard of a naturopathic physician before. I grew up with a wonderful family base. My mother was very interested in eating right, and looking at vitamins and minerals when I was a child. She went out on a limb to hide and breastfeed me as a baby when it just wasn’t accepted in those days. I was raised going to the chiropractor, so my very first directional push to move into this field was really looking at and pursuing chiropractic. I went off to Oregon to attend college in that location, and as soon as I started hearing about naturopathic medicine there, Jeff, I realized that I was close but I wasn’t completely aligned with the exact right training for me. So it was through my exposure to being raised very naturally with a hands-on approach that I found naturopathic medicine and that is an absolute blessing for me because that was really the place I belonged all along. Literally, even during my undergraduate training, I had no idea that naturopathic medicine even existed as a career option. JB: As you then decided how to embellish and fortify your undergraduate and finally your naturopathic degree training, you ended up doing some very, very interesting things, one of which is working with another one of our dearly loved colleagues in functional medicine, Dr. Carolyn McMakin in Portland, who has been an FMU interviewee a number of years ago. Tell us a little bit about that experience, this mentorship program concept. There are not some formal postgraduate courses for many of the people coming out of schools. How did you select Dr. McMakin and what was your experience there? KH: It was through a personal experience. I had an injury while in medical school and no one could really help me. Carolyn was at the school that I was attending. She was in her last year. She is the one that took me to the student clinic and transformed me, in a couple of visits, with her work with microcurrent. So as I left the chiropractic profession and headed toward the naturopathic, I realized that she had something special that she was doing. As I got into that third and fourth year in naturopathic school, I asked her if I could please come in and work with her, and I would spend up to 20 hours a week. I would go to school all day and then I would go work in her clinic as many hours as I could fit in. It was very informal at that point. It was because I knew she was doing something that was so special and so remarkable with patients and I just wasn’t seeing it anywhere else. One of the interesting and, I think, wonderful things that she set into motion for me was she had the expectation that miracles do happen, and if not then you just haven’t found the right stones to turn or the right buttons to push yet. In her office, it was just patient after patient, and the books were full, and it was always a waiting list. I came out of naturopathic medical school with the mindset that that’s just the way it is, and I think my intention was such that when you go to work, you’ve got waiting lists. It was within a six week window from graduating from NCNM back in 1997 that I had full books. JB: That really raises a very, very important question. For a lot of people who are in this field who are very mission-driven and philosophically aligned with functional medicine, when they move to put it in their practice they find they have a difficult time making a business out of it. It becomes a challenge for them to see how they are going to actually keep the lights on and the doors open from a financial perspective. Somehow you moved back to Minnesota. Reminiscent of the Mayo brothers, you moved back to a portion of Minnesota that might be considered quite rural and out of the mainstream (unlike the Minneapolis/St. Paul metropolitan area), and you became very, very successful in building not one but several clinics, almost immediately being successful as a young initial practitioner. What do you attribute that to? KH: I think I attribute it back to community. Having grown up in these smaller towns where you’ve got 20,000 people, not a million people, the one thing that I really learned early on is the sense of community. Communities can heal. You have, I think, a better foot in the door when you go into these regions and areas and you start moving your first couple hundred patients towards healing and success because they don’t stop talking about it. Word of mouth is by far the most powerful advertisement piece when you are in your new private practice. I was having patients driving from all over Minnesota, Wisconsin, North Dakota, South Dakota. Do you remember, Jeff, back in 1997—you and I talked about this in 2000—there was the great flood that wiped out parts of northern Minnesota and the Dakotas, and Grand Forks, North Dakota? This had unbelievable turnover in that community, where a third of the homes and the businesses were flooded. Do you remember us talking about that? JB: Absolutely. KH: That was a turning point for me because after that community became so sick, from not only the mold, the mycotoxins, the environmental pollutants that came about from that horrible environmental exposure, I started treating and managing some of the key professors at the university. They were driving five hours to come down and see me, and they actually talked me into coming up to North Dakota—all the way up to Grand Forks, North Dakota—to start seeing them in large groups. I remember telling you this story, Jeff, when I met you at AFMCP in 2000. The year before that there were so many people literally coming out of woods in those areas with fatigue, and pain syndromes, and GI distress, I would go up and manage education groups. I would rent teaching facilities at the hotel. I took literally 80 people through a weekend workshop learning about their GI system, their detoxification mechanisms. I sent everybody off with stool culture and food sensitivity testing and they all came back six weeks later. I ended up having to teach the whole entire group of them what the results meant because I couldn’t see people one-on-one anymore at that point. And that for me, Jeff, was the shift, I would say. It put me in a whole different playing field. I was just coming off of that year—that unbelievable growth experience. I had solutions through naturopathy, through natural applications, and through the functional medicine principles at getting to the underlying cause of disease, and when people heal they talk about it. JB: Just listening to you, what comes across so strongly are two things, I think. Number one is your personal advocacy and your mission is very, very clear, and secondly is your pursuit of lifelong learning and your undaunted courageous spirit. How do those things get manifest in a practitioner? Does this come through courses? Does this come from going to the right meetings? Does this come by seeking out the right mentors? Does this come by being in the right societies/institutions? What might you provide as guidance for people who feel a little bit lost and are trying to find that focus that resonates from your advocacy? KH: I am really impressed that you pulled that out because I sat back last year when I was thinking about rebranding and launching new websites, and I realized that I have grown into a patient advocate. I’m trained as a clinician, but I spend the majority of my time helping patients navigate the healthcare system. I would say that piece has really come about because of the need of the community, the needs of the patients, those who just need guidance. They’re looking for a roadmap: Who do I see and what labs should I consider? I’m not always the one managing their care as their primary. I find myself playing this very important advanced triage liaison role, where I advocate back to their primaries and their principals about their best needs and interests, and then I tend to step back and manage all the pieces that surround the lifestyle and functional medicine aspects of that patient’s life. I really believe that the way to transform health care is to empower the other practitioners that have been working with these patients versus take the patient away from that practice. I am forever encouraging growth within the system. I love it when I have patients I’ve worked with who go back to their physicians and say, “You know, this is what I’ve been doing for the last year. I have transformed my diet. I have made adjustments with my food choices. The labs that you and I ordered last year—I’ve really been working on these underlying causes of disease. It’s time for us to repeat these parameters and see how I’m doing.” And then for those physicians to see that their own patients that they’ve known sometimes for 10, 20, or 30 years are going through such incredible improvements with metabolic dysfunctions, and blood sugar management, and dyslipidemias, and hypertension concerns. You know what I’m talking about, Jeff. The list goes on and on. I think the really exciting piece is empowering the patient and empowering the clinician. I would say it is almost a Trojan horse approach or a very grassroots approach to really get into the clinician’s mind (the other physician’s mind): what’s possible by educating them through their own patients. For me, it’s a journey, it’s exciting. I love it myself, so when you bring up the piece of this lifelong learning aspect—there’s no question. That, I think, is really the key. If I really step back and I say, “What set up me becoming that type of advocate, and what set up this goal and desire for lifelong learning?” I really would honestly have to say it truly goes back to the way I was parented. The space that was created where I was allowed to grow, I was allowed to explore, and really I was always encouraged that the most important aspect is education, and that with education you can believe that literally you can conquer the world. JB: That leads to really two kinds of questions that I hear very frequently being asked. They can be asked in many ways, but I think they boil down to the following two things. Number one is: “I didn’t learn this in school, and so how can I develop a path to competency? What sequence of events in my self-learning experience will get me to feel competent? I don’t want to go in there and look foolish with my patients. I don’t want to look like I’m underprepared.” That’s question number one. And then question number two, which we’ll come to, is: “Once I start feeling competent, how do I actually get reimbursed for this? What’s the business structure, because there has to be an infrastructure for this to be able to be practical?” Let’s start with question one. What, would you say from your experience, is kind of a path to competency for someone coming out of school that is affiliated with this concept philosophically? KH: I have to say my answer is really biased because it’s how I got there. Coming out of naturopathy training, you’ve got this depth, you’ve got this breadth of knowledge. What I found was that I didn’t really know how to apply it. I knew there was so much that could be done. I knew about the solutions. I knew about therapeutics. I knew about the interventions. But I didn’t necessarily really get this: How do you treat the underlying cause of disease? When I found the Institute for Functional Medicine (IFM) programs (I found AFMCP first in 2000), that for me was the game-changing piece, because all of a sudden what I had now was a new architecture. When I found the functional medicine matrix for the first time, really looking at the concepts of the matrix, understanding the principles of why we’re trying to uncover the antecedents, the triggers, and the mediators, or those perpetuating factors. Those two pieces really transformed me as a clinician more than anything I can say ever before or since. So really it is the fundamentals of functional medicine. It’s the ability to really look at what’s the underlying cause of the cause, and what’s the cause of the causes? And to keep going deeper and deeper and deeper. And then as you’re starting to understand the pathophysiology of disease, now I think it gives you a place to apply the knowledge of those therapeutic interventions. We’ve got the brand new release of the functional medicine matrix coming out this year through the IFM—and the new matrix, to me, really truly just embodies, symbolizes, I think what hundreds of years of these advanced clinicians have brought together—their clinical experience—and that there really are three principal legs of the stool that set you up for great clinical success and competency. One is you need to be willing to go into a dialogue with the patient and really hear their story and go far beyond just the disease to get a sense of how thatt patient has arrived at that diagnosis. As we hear over and over, there are so many different underlying associations with the development of a particular disease, so getting to know the patient’s story, finding those very important predisposing factors, looking closely at their genes, their genetic predisposition, and their familial trends, and then taking the time to find the triggers. What are the points in time in which the patient says, “I’ve never been well since this happened.” Finding either the triggering events or those moments, and then getting clearer with those perpetuating mediators and those factors that drive cycles forward. So really getting antecedents, triggers, and mediators (ATMs) for me was very important, and now being able to position that on the new matrix. First is the patient’s story, where we discover and uncover the ATMs. Two, and this is where I think I have really grown the most, is understanding the foundation of the matrix. That’s what we call the personalized lifestyle factors—really getting how critical it is that we move beyond just public health, and we move into personalized lifestyle care, where we look so closely at the diet, exercise, resilience, and ability to find balance in their stress parameters. And then the third is systems biology—really organizing your thoughts for each and every patient’s history in that systems approach, where we have the opportunity to think about how all of the organs are orchestrating and working on the patient’s ultimate function on a much higher plain. So the third leg of the stool is this organization capability: How is it that the body functions, so when dysfunctions begin to manifest, where is it that we’re going to go first? These three “legs of the stool” have really truly moved me down that path to competency. I think of it, very closely, Jeff, as an architect would build a facility. You have this vision of where you want to go, but you need somebody to come beyond just that rendering and help you. You need help with the blueprint and really putting up that first frame, and for me the framework is the fundamentals of functional medicine, and once I had that framework in place, now it allowed for me to fill in those places and those spaces and it gave me the architecture to hang all that information that had come previously for me on that journey. JB: That was beautiful and eloquently stated and I think really is a great blueprint for the listener who may be aspiring to move to the next level. They might ask, however, a follow-on question. They might say: “Well, as I start to understand this landscape better and I start to develop my blueprint it seems like there are so many doors I could go through with my patients. What tools are most important? Where do I start?” If you were to guide people through this overwhelm, what would be your guidance on where to start and what tools might be most important? KH: I think the number one tool that clinicians should become comfortable with–and they will almost be freed up once they learn how to master it–is the timeline. This really goes back to the work of Dr. Sidney Baker, and how he says the patient’s story is so critical. Taking the time to plot things out on a timeline and look for the patterns to emerge, I think that is by far one of the most important things. The new emergence functional medicine timeline was brought forth by all of the principal faculty over the last couple of years at the institute. That timeline is the place to begin to understand what’s happening: pre-birth, the impact of the metabolic imprinting that takes place through that pre-natal exposure, understanding pre-conception the uniqueness of pre-conception health from mom and dad and really what does the familial patter lead to? Then you lay things out on a timeline, where you are looking at this chronological pattern for that patient as things emerge. There is just power that happens when you look at things in a different way, and so if you can begin with the timeline, layout the timeline, look at the patterns and see the overlap and very unique triggers that have set into motion new manifestations of signs, or symptoms, or diseases themselves. That’s the first place to begin. Beyond mastering this new way of taking the medical history, I would get very familiar with the concepts of lifestyle medicine, and feel comfortable knowing that, yes, there is this huge contribution that food plays, and stress, and movement or lack of movement. Get comfortable identifying and moving patients along the healing pathway by transforming their lifestyle. And then third move into the complexity of understanding systems biology. I’d put money on the table, Jeff, that if you ask the masters, “Where do you begin?” almost everyone says you begin in the gut. You start with assimilation. The majority of your naturopaths, and your really successful functional medicine practitioners, they would say, “We start in the gut. We look at assimilation. What are the foods and the ability to bring things from the outside to the inside world?” Get specific with the diet. Get particular with changing and transforming immune response patterns. And so I would get very comfortable with all the aspects that have been brought forward through the process of like the 4R Program. JB: As I listen to you, one of the things that just beams through loud and clear is your extraordinarily well-refined communication skills. We can think of a doctor as a teacher, and this teaching that goes on in that intimate relationship that a practitioner has with their patient in the exam or treatment room is really a model of some kind of high-level communication, probably both verbal and nonverbal. What have you done to really hone your skills as a communicator, which obviously are very highly refined? KH: I think that’s one of the biggest challenges. I am so in love with the biochemistry and the pathophysiology. I love the pathways and I love the understanding of the science. But patients don’t relate. I think it was drowning in the deep end of the pool in the first years of practice, forcing me to learn: How do you take something so complex, with such a high level of detail, and then bring it into the story in a way that the patient understands where you’re at and where you want to go? It’s a whole new language. How you think about the patient, and then what you eventually end up saying to the patient, that’s a huge jump, that’s a big leap. I don’t think anybody really trains the clinician to break things down in a way that is really appropriate for their needs. So, gosh, no one has ever asked that question, Jeff, and I’m not exactly sure where that comes from, but having been guilty of overeducating and always speaking to the highest denominator, it’s taken me years to learn that when it comes to patient education, it’s best to break things down to that level. You’ve heard it before: If you’re going to teach the public and you’re going to train patients, take the time and explain it to someone as though they were literally in junior high or high school. I really think: How would I teach this to somebody that was in high school? Putting it into perspective for them, using those safe, soft words, so they can guide the conversation and bring it up to as high a level as they are comfortable with. For me, honestly it’s been through trial and tribulation, and that’s what’s driven me to really build out my business model, because I personally find I talk too fast. My responsibility is so high. I have so many patients to see in a day. And the needs that the patients have at times I wasn’t able to deliver on, which drew me in this direction of really truly needing to build out a business model that worked. I have brought in additional training teams. I have lifestyle educators on staff. I have built support teams around me that have included other naturopaths. Our new expanding residency program extended my nursing and my lifestyle education tier. And so I put myself in the role of making the most important decisions, and laying out the path, and creating the programs for the patients. Then they really need to sit down and spend an hour learning, what does this really mean when I have an intestinal permeability problem, and it extends fromof a small intestinal bacterial overgrowth (SIBO), and there’s good bacteria and there’s bad bacteria and we need to change the diet? What I have really found works the best for me, Jeff, is to bring in a tier of support staff that really can take the time, they can slow down with the patient, and create the space for the patients to truly understand what is going on in their health care, where we need to go, and then to open up and create the space for them to ask the questions and truly be heard. That, for me, has been my clinical success. JB: I think you’re being very understated with regard to how you’ve pursued–as you have in all things I’ve observed in your life over the last 11 years–a level of excellence. You’ve gone out and gotten professional coaching in presentations. You’ve given, literally, hundreds of presentations to different audiences all around the world. There’s nothing like being a teacher to learn things and to test different communication styles. You’ve put in thousands of hours on this whole concept of: What does it require to become an expert? It requires 30,000 hours, and you’ve paid the dues. So I think there is something there that relates to how someone pursues their craft, their expertise, their discipline, and really becomes competent as an expert. Education doesn’t happen just by osmosis, and becoming a world-class communicator doesn’t happen just as a God-gift alone. So I think those are all parts of what has exemplified your path over the last 14 years that characterizes your expertise. KH: And Jeff, as you say that, there is a book that really stands out in my mind. You’re right, I’ve got an amazing coach that I work with, and I have been working with now for six years. He’s transformed my whole entire life, not only what happens when I’m on the podium teaching other clinicians and physicians, he’s changed the way I speak to patients, and he’s actually transformed the way I read books to my kids at home. What I love about my speaking coach is his premise: How can you be as authentically you as possible? It’s you on your best day. How can you be you every day when you get up and do “you” to the best of your capability? Not trying to be someone else, but being you to this high level of authenticity. He has given me permission to fall into myself in a way that no one else has, and one of, I think, the pivotal books for me—it’s a short, simple, easy read—is called Real Leaders Don’t Do Powerpoint.[4] The title always makes me laugh because I live in Powerpoint. I spend so much of my life in Powerpoint slides. But that book was beautiful for me in my journey because it really helped me understand that to teach and to give a presentation you have to master the knowledge, you have to be able to have your Powerpoint deck and your computer crash and still be able to give the same talk, and yet at the same time that book has done such a beautiful job creating frameworks for how you will communicate and you go in with such a high level of intention, and with the majority of the lectures that I give surrounding functional medicine, I actually use one of the techniques that they talk about in that book. It’s a speech—it’s a form of lecture—called the I-You-We format. How you give that lecture–not what are you going to say, but how are you going to say it—comes through making sure it’s clear that you establish: I have learned to do this and this is my own experience, you can do this, let me show you how you can do this as well, let me help you on your journey, and then won’t it be great when we can change the world and we can do it together. So the I-You-We principle I think is really one of the strongest that I use from the podium, and that book is so simple—it’s such an easy read—and I’ve probably read it a half a dozen time now the last five years, and there is always something more inside that helps me. I think it’s more about really leading a movement. I’ve really connected with the vision, as you’ve said. My passion is that I really honestly want to change the world. I want to bring functional medicine around the world. With my last breaths, I’m going to think about my family, I’m going to think about my husband and my kids, and I’m going to think about functional medicine. That is going to be, for me, those last moments of feeling the sense of joy, love, and completion. Truly, I believe that every single patient needs to have access to a doctor that is trained in functional medicine. I really believe that is how we’re going to heal the planet. JB: That’s so inspiring I almost hesitate to want to say anything else, and just let the beauty of the power of silence be the teacher. But I am, I guess, obligated, given that I said that there were going to be two questions, to finish with a kind of pedantic, but also a real-world, question, and that is about reimbursement: How do we make all this work in the practice? Are there any kinds of guides, or tools, or things you’ve learned over the years that help us to provide information to a novitiate—a person who is just moving into this—as to how they could construct their practice to be financially viable given that we are on a mission here? KH: I think the first thing is to give yourself permission to grow out of yourself, or beyond yourself. There are so many practitioners, I know, in solo practice who feel that they can’t afford to hire anyone, and I think that’s the rate-limiting enzyme in the equation. I truly feel that you want to grow beyond yourself and identify what you’re really good at and then build your team to support you to be who you are on your best day. Early-on, I acknowledged that one of my weakest links is stress management, so one of the first things I did was bring in a team of people that can work helping patients with their stress management. I tend to talk fast. Some patients need to have it slowed down. I brought in a team that could sit down, and take time, and really hold their hand and march the patient forward until the patient is at point where they really understand where they need to go next. I had to understand for myself that I cannot do the same thing over, and over, and over again. I mean, even when it is a lecture and you’re giving a 12-city tour, there is no time in which the last seminar is ever the same as the first seminar, and so I’ve really taken that on in my own practice. There are pieces that I’m good at and there are things that I love to do, and the things that require redundancy, like sitting down to explain the low glycemic modified Mediterranean diet, or sitting down to go through the comprehensive elimination diet, or, you know, when there are just real standard things I need many patients to be educated in, that’s where I have brought in the back-up support. So, the business model, for me, that has emerged is that I still hold the position as the primary principal medical director of the clinic. I’m in a state—Minnesota—that was just recently granted a new registration bill for naturopathy, and increased and improved the scope of practice here, but because I chose to come back to a state to try to work with the politics and move naturopathic and functional medicine into this particular part of the country, it has forced me to begin my practice in a cash-based model, and we’ve been so successful in a cash-based model that at this point I don’t know that I would want to transform to open up for insurance reimbursement directly. Our patients are not rich—they don’t have deep pockets, they are teachers, they are farmers, they are local providers from these small rural communities—so I’ve had to build out my financial business structure so that they spend enough time with me, but not too much time with me that they can’t afford me, and they are able to go on and work with one of my middle or lower level providers that bill out at a different rate. So we use me to my highest expertise and they pay for my services, and then they pay for their education at a different pay rate, and then I work with their provider—their principal primary care physician—and if they are uncomfortable or unhappy with their provider, I help connect the dots to get them to someone that can help them within the insurance model. So for the naturopathic profession, I think this, Jeff, will become one of my deepest passions in my next decade, I really want to bring the naturopathic provider to functional medicine because the business model is so incredibly effective, and so many NDs that I’ve met over the last…more than a decade, since graduating 14 years ago…so many of my colleagues come out and I wish there was a better term, but the only one that really sticks with me is it’s almost like a poverty mentality: that they shouldn’t make money, that they should be afraid to make money, because it’s natural. You know, they’re talking about natural things. They’re talking about the diet. I would really love to empower my own profession and encourage them. Step back and look at how much we pay for our education: $140,000 for our naturopathic medical school training alone. The knowledge doesn’t come free. The continuing education doesn’t come free. And, therefore, don’t be afraid to charge for that which you know. JB: That’s really, really inspiring, Kristi. You know, as I’m listening to you talk about naturopathic licensure in Minnesota, I’m reminded that one of the graduates of my 1978 class at the National College of Naturopathic Medicine in Portland went home, back to Minnesota, and was the first guy in the state to proclaim a naturopathic license and work in the state legislature to try to get naturopathy licensed. So, progress is made, and things do happen positively, and it’s very exciting to hear about licensure status in the state and people of your quality being there to serve what were certainly underserved individuals with this form of healthcare delivery. We’ve really enjoyed walking down this path with you, and I’ve personally enjoyed this journey, knowing you for the last 11 years and watching the extraordinary talents you have come into maturity and be delivered so effectively to thousands of people, globally through your education and even through the development of your residency program, which is, I think, one of the first in naturopathic medicine. You might mention what you’ve done in your residency program, which I think is very innovative. KH: The naturopathic medical school—three years ago—talked about wanting to support the movement of the registration bill, and they identified our clinic and our location because of the high volume and the high exposure that we do have, and asked me if I would be willing to consider creating the very first Minnesota-based residency to help bring more financial support and increase the movement of students into this region. And at that point, I have to say, I really wasn’t looking for another project. I wasn’t thinking, “Oh, I’m bored, I have all this extra space, that sounds like a great plan!” But, it just resonated with my heart and soul, that absolutely I would love to bring in more properly trained naturopathic providers into this area of the country and the world, really. I would say our residency program is built upon a platform of three fundamentals. One is that my resident applicants and my residents need to understand naturopathic health care. Second, they need to be trained formally in functional medicine; they must go through the AFMCP program and then begin the certification program because I really truly myself have experienced such phenomenal education through IFM and therefore that is one of the areas I really have insisted my residents also are trained in.The third, which is just so near and dear to my heart I almost feel like it is another one of the children in my life that I have birthed, is the ongoing development work around the FirstLine Therapy program. I truly believe and I have seen that the FirstLine Therapy principles have been able to move naturopathic practices forward by creating a very unique system—a very nice business organization system—for the application of nutritional therapeutics, medical foods, and really creates a business model for the naturopathic provider to manage and work with patients with the metabolic syndrome and various cardiometabolic risks. So our program is really built off of those three fundamentals, and then we are also encouraging our residents to go on with their training with Frequency Specific Microcurrent (FSM). So it’s a very unique residency that’s out there, Jeff, because those are some of the absolute fundamentals in training. It’s been learning functional medicine, really understanding the architecture and hanging everything there, coming to terms with understanding what can you do with FSM, when you really empower the healing down deep at that level of mitochondrial ATP production and frequency specificity, and then these very organized and very methodical ways of applying lifestyle medicine principles and unique applications of food. So it is those three things that I feel really bring the naturopathic provider to a whole new level of understanding and creates this depth where I feel the naturopaths can apply their own philosophy of treating the cause of disease by learning how to treat the cause of the cause of the disease. JB: This was one of the most content-dense and rich, robust reviews of the how-tos of delivery of quality care that we’ve had the fortune of exploring in Functional Medicine Update. Dr. Kristi Hughes, you are certainly—at every level—representative par excellence of what this field is emerging to become. I’m also reminded of the impact you’ve had in South Africa and developing the program there—in Europe, in Asia, in Mexico. It’s quite remarkable where you have gone and touched over the last 11 years. Continue on this path and journey, and bring with you all these individuals who have this latent capability of being really seen as healers in their community. We wish you the very best in really taking functional medicine to the next level. Thanks for sharing. KH: Thank you, Jeff, for the opportunity.

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Bibliography

[1] Prasad V, Cifu A, Ioannidis JP. Reversals of established medical practices: evidence to abandon ship. JAMA. 2012;307(1):37-38. [2] Heng HH. The conflict between complex systems and reductionism. JAMA. 2008;300(13):1580-1581. [3] Culver AL, Okene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med. 2012;172(2):144-152.   [4] Witt, Christopher and Dale Featherling. Real Leaders Don’t Do Powerpoint. New York: Crown Business, 2009

Welcome to Functional Medicine Update for March 2012. This month we’re very privileged to have as our clinician/researcher of the month an individual who I think will speak to this long-standing discussion we’ve had within Functional Medicine Update  that I call the food/supplement conundrum: How important is the composition of the overall diet in modulating metabolic function in such a way as to increase or decrease the relative risk of age-related chronic illness in comparison to the benefit or value of nutritional supplements that would augment specific nutrients? This is a very interesting dialectic to engage in because it’s not an easy question. There are so many different variables at play that to try to make this overly simplistic and say food versus supplements would be to do a reductio adabsurdum—to really try to reduce things to first principles and lose the meaning. Food versus Supplements: A Reductio Ad AbsurdumOversimplification The reason I say that is we now recognize within the field that as we are examining these associations and trying to demonstrate causality between a substance or an intervention and an outcome, or a principle and a causation of disease, then we have to take into account things like genotropic and genetic variability. We have to take into account the variety of environmental modifying factors that can serve as triggers. We have to look at specific temporal effects within circadian rhythms that can influence outcome that may, if we take a snapshot of data at the wrong time of the day or at a different time of day we might end up having a different picture of the physiological status of the patient. A simple example would be this: What happens if we were measuring random blood glucose levels in populations and we just happened to choose populations right after they had eaten (within two hours after eating a big meal) and we made that our assumption as it relates to the average blood glucose level in the population rather than taking fasted samples? I think questions like these become a very important part of how we piece together this complex puzzle, which ultimately leads us into decision-making in the chronic disease area. That is part of the broad topic that we’re going to be discussing with Dr. Deanna Minich today–this interrelationship of personalized lifestyle medicine and nutritional intervention to both the prevention and management of chronic illness. Before we get into this discussion and the specifics, let’s look at some general principles. Defining Biological Response Modifiers Does our food contain substances that are beyond that which we would call protein, carbohydrate, fat, vitamins, minerals, essential amino acids, essential fatty acids, water, that serve as biological response modifiers? Now, what do I mean by a biological response modifier? The term really refers to substances that have molecular interactions with specific characteristics of our metabolic web in such a way as to modulate function and to create different phenotypic outcome. That’s a long-winded sentence. What does it really mean? It means: Do we have biologically active substances within our foods, beyond that of the traditional “fabulous 50” essential nutrients, that regulate in some way the expression of our genes (i.e., nutrigenomics) to then alter metabolic function in response to environmental stresses? That’s what’s known as a biological response modifier.   Since the dawn of the science of nutrition, I believe we have recognized that food has multiple effects on human function at the whole-organism level. But for many years we didn’t have the tools to be able to really evaluate specific components of the food, when broken down and isolated into their component parts, on how they mechanistically influence various aspects of function on the whole organism. Over the last 10 to 20 years the tools of molecular biology and molecular genetics, cell biology, and biochemistry have become more sophisticated, more refined, and more available for general applications outside of the specialized research labs of a few major academic centers. We are starting to really see an opportunity to evaluate some of these characteristics of foods from a different perspective: What are the natures of various substances within the food that may serve as biological response modifiers, and do different foods have different personalities as it relates to their biological response-modifying capability? Food is Your Best Medicine, and Now We Have the Tools to Explain Why This obviously traces its lineage way back to Hippocrates, if you think about it—food is your medicine, and medicine is your food. Also Dr. Bieler’s book, Food is Your Best Medicine.[1]What was not understood during those periods of time was exactly how substances within foods would regulate function and serve “medicines.” That’s, I think, a part of what is emerging now in this more recent age of nutritional research (nutrigenomics research), the mechanisms by which these particular substances that reside within various foods that we now call biological response modifiers and how they influence specific cellular function and specific tissue types to create specific cellular outcomes or functions. Red Yeast Rice as an Example of a Biological Response Modifier Let’s look at a traditional Chinese medicine (TCM) as an example. It’s a culinary nutritional substance used in traditional Chinese medicaments and cooking called red yeast rice. This is an interesting concept if you start looking at it from a whole-organism level. This is rice that has become moldy, basically, with a specific type of fungus that produces a red-colored metabolite, and so it colors the surface of the rice a moldy red. It’s a specific strain of fungus, and it has a specific set of genes that encode a specific metabolic biosynthetic pathway that results in this series of compounds that are within red yeast rice (within the actual fungus itself), which have been found by phytochemists and medicinal chemists to be a member of a class of compounds called monocolins. So, monocolins are an interesting class of bioactive substances that have been synthesized specifically by this form of fungus that grows on rice and produces this red color. What do we know historically about red yeast rice from a TCM perspective? First of all we know that in TCM the view of anatomy and physiology of the human organism differs from that of western medicine, and so the circulatory system, the vascular system, has kind of a different configuration, or at least let’s call it a different symbology or representation, than it does in the western medicine. It doesn’t mean that the heart and blood vessels are in different places; it means that they play different roles. With that said, what we can say is that within the scope of a western analogy to Chinese medicine, red yeast rice historically has been found to be useful for conditions on a whole-organism level (functional conditions) that would tie to what we call (in the west) cardiovascular-related issues. For thousands of years, this empirical observational connection was known between red rice yeast and the nature of outcome of health in individuals, so it became part of this empirical pharmacopeia. Only recently, as I’ve indicated, have the constituents—the chemical constituents within red yeast rice—started to be understood as being these monocolins. And as individuals have studied monocolins in much greater detail, they found that they have unique biological response modifying characteristics. In the west, one of the individuals who has taken this on as a focus of study is a colleague, and that’s Dr. David Heber, Professor of Medicine, Chief of the Division of Clinical Nutrition and Director of the Center for Human Nutrition at the University of California, Los Angeles. Dr. Heber has done work with his group on trying to understand the nature of the monocolins that are present in red yeast rice and their influence on human health and function. If you go back and look at his publications, what you’ll find is back in the 1990s he started publishing a series of papers that started to evaluate the role of red yeast rice as a blood cholesterol-lowering substance in humans. He’s done very detailed work correlating the monocolin content and the various constituents within the monocolin family (in other words, the specific chemical principles, like monocolin , for instance) and their relationship in consumption to the effects on blood cholesterol in humans. One of the interesting papers in this series was published in the American Journal of Clinical Nutrition in 1999 and titled “Cholesterol Lowering Effects of a Proprietary Chinese Red Yeast Rice Dietary Supplement.”[2] In this particular paper—it’s a clinical intervention trial in humans—Dr. Heber demonstrates that when an individual consumes a set amount of red yeast rice that contains a certain percentage of these monocolins, it significantly reduced total cholesterol and LDL cholesterol and triglycerides as contrasted to placebo, and actually did so in a way that was comparable to some of the first generation statin drugs, which–as we know–were themselves first derived as fungal metabolites and were found to be cholesterol lowering as a consequence of what was proposed to be the ability of these statin molecules to block 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA-reductase), the rate-limiting enzyme step in cholesterol de novo biosynthesis. So we were told that the cholesterol-lowering effects of statins (like, Mevacor/Lovastatin—the first statin that Merck brought to market), was a consequence of inhibition of cholesterol biosynthesis at the hepatic level. And it turns out, as Heber and others now have defined, that the red yeast rice monocolins have a similar effect on lowering the biosynthesis of cholesterol, and in fact these monocolins are chemically identical (some of them) to the first generation statins (the Mevacor/Lovastatin-type molecule).[3] And that led, as you may know, to a very, very big point in law, where Merck took exception to nutrition supplement companies that were selling red yeast rice as a cholesterol-lowering nutritional substance because they said that some of these bioactive molecules were identical in chemical structure to the patented structure of the statin drug (Mevacor). The history of this is quite interesting because you probably recognize that at first this was upheld (the Merck contention) and therefore there was going to be a prohibition of the availability of red yeast rice to be sold as a nutritional agent. And then that was contested in federal court by a manufacturer of a red yeast rice dietary supplement and the Merck judgment was overturned, and that was kind of a vindication for nutritional substances being able to be used as bioactives derived from food and spice sources. And then, to make the story even more confusing, there was subsequently another intervention at the court level, which once again went back and reconfirmed Merck’s supremacy in this area. So this became a very cloudy area: When is something a drug and when is something a food? That was back in the early 2000s.   Since then, what has come to be recognized is that the Chinese red yeast rice story (the bioactives of monocolins) is really just the tip of the iceberg. There may be thousands of molecules that are biosynthesized by plants and proteus that are biological active and have been used historically as foods or spices or condiments, and have tissue-specific effects, just as we saw with the monocolins in red yeast rice. A whole array of papers have been published, such as “Anti-inflammatory Properties of Culinary Herbs and Spices that Ameliorate the Effects of Metabolic Syndrome.”[4] This was a recently published paper in the journal Maturitas that demonstrated that there are many, many different types of foods and spices and herbs that modulate inflammatory mediators, such as nuclear factor kappa B (NF-kB) and peroxisome proliferator activated receptor gamma (PPARγ), ultimately signal to the genes inflammatory signals and up-regulate the expression of cyclooxygenase genes and all those kinds of factors we’re well aware of in the arachidonic acid cascade. They serve as anti-inflammatory modulators of the gene expression of these inflammatory downstream mediators. From Single Ingredients to Whole Diets We also recognize that there is a whole array of papers and studies that have been done looking at diets rich in fruits and vegetables, and how these diets are known to suppress blood biomarkers of metabolic stress in relationship to insulin resistance, metabolic syndrome, and Type 2 diabetes. An interesting paper on this was recently published in Preventive Medicine in 2011, about outcome of biomarkers as it relates to the consumption of diets that are rich in fruits and vegetables and have these bioactive components.[5] An  extraordinary review paper appeared in Nutrition Research Reviews in 2012 titled “Health Protective Mechanisms of Whole Grain Cereals: What is Beyond Fibre?”[6] This paper looked at not just the vitamins and minerals that are in whole grains, but also the different bioactive compounds that are able to modulate cell signaling and gene regulation, including things like sulfuric compounds such as glucosinolates, lignan, phytic acid, polyphenols, the whole family of what you might call the lignan-related or hydroxylated flavone families that all serve as very important regulators of function of how genes are expressed. Then we can look at things like chronic kidney disease.I If you look at fruit and vegetable diets it is an alkalizing diet, it contains very high levels of various nutrients, including essential fatty acids, minerals, and vitamins that help to improve kidney function, and it contains a whole array of these bioactive phytochemicals that are in certain plants that help to reduce inflammatory conditions and improve function at the kidney level. If you want to look at a good review of this, Kidney International in 2012 published a nice review of this work.[7] This article is about how the key to halting progression of chronic kidney disease might not be in the pharmacy but rather in the way that we eat in the marketplace (foods). So there is something very dramatically valuable about foods and the array of these bioactive ingredients they have which may differ from that of just single vitamins, single minerals, or single ingredient nutritional supplements. It certainly doesn’t mean that nutritional supplements are without value. What it means, however, is that they play a role within the context of the full diet and the genetic uniqueness of that individual, and how that expresses itself, then, into function. We’re now going to move to a discussion with Dr. Deanna Minich, who I think is an expert in this whole area, to kind of explore this in greater detail, and look at this personalized lifestyle medicine/bioactive ingredient in food relationship—this symphonic relationship that people share with their food that orchestrates the function and ultimately their health and disease patterns.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Deanna Minich, PhD, CN, RYT Vice President, Research & Development Communications Metagenics, Inc. 9770 44th Avenue NW, Suite 100 Gig Harbor, WA 98332 1-800-843-9660 www.metagenics.com www.foodandspirit.com This discussion is with someone I would consider to be one of the world’s experts in the application of personalized lifestyle medicine through the lens of nutritional therapeutics and diet therapy. I’m speaking of my colleague and friend Dr. Deanna Minich. Dr. Minich, for those of you not familiar with her background, is a trained nutritional scientist. She has an undergraduate degree, a Master’s, and a PhD all in the area of nutritional science. She then worked in one of the major food companies as a nutrition professional. She went on to become certified as a Fellow of the American College of Nutrition and a Certified Nutrition Specialist. She brings, then, a body of knowledge both practical, from the commercial side, but probably most importantly, practical from the food nutrition side into the development of successful programs to implement personalized lifestyle medicine. She is really a world’s leader in the whole area of phytonutrients and how they are applied, and the role that they have in therapeutic nutrition intervention. She has been an author of reviews as well as research articles on the development of food plans, and is really one of the architects, along with Dr. Kristi Hughes and Lyra Heller, in the FirstLine Therapy food management program at Metagenics. Deanna it is wonderful to have you as an expert on Functional Medicine Update. I’ve looked forward to this for years. I think it is the perfect time to bring your expertise into this field because lifestyle medicine is getting, finally, the marquee publication visibility I think it deserves in attempts to combat this rising tide of chronic disease. Maybe you could start by telling us a little bit about how your personal journey took you into the area of nutritional therapeutics and food plan management and development. DM: I’d be glad to do so. And I just want to say, Jeff, it’s such an honor to be on Functional Medicine Update. I follow you very closely, as you know, listening in my car on the way to work, and it’s just amazing to have this opportunity at this time, so thanks for having me on the program. My personal journey with food and eating I would say started when I was very young. I often tell people that I became a nutritionist at the age of nine. That was partly because of my mother and my upbringing. When my mother was pregnant with my brother, her third child, she really became invested in what the whole family was eating. She really started to read labels. She started to make her own food from scratch, everything from yogurt to bread to just really unique dishes. I remember this was a very traumatic thing for me growing up because I would be bringing strange lunches into school. I remember being on Girl Scout trips where I had to bring my own food all packaged up. I couldn’t partake in kind of the campfire s’mores and all of the other fun activities there. Food and eating was a little bit of a jolting experience for me when I was very young. I wasn’t able to see outside of the bubble that my mother was doing something really good for us. So as I evolved into my teenage years kind of continuing on this track of really healthful eating and getting into my own issues, I would say, as it relates to more emotional eating and really struggling with eating certain foods and having lots of guilt. As I went into college, what I noticed was that I was really gravitating towards the area of medicine and science, so really thinking about the body from a physiological perspective and really dismissing the food aspects that my mother had brought us all up with. By the time I was in my junior year of undergrad I was ready to take the MCAT. I had taken all my pre-med courses and I was working every single summer during my breaks at different medical offices. I was a candy striper in a hospital when I was a teenager, so I really had more than just a theoretical perspective as to what medicine might be about, because I had experienced it in every opportunity I could take. And also, in our family we had lots of different health issues. At the age of twelve I watched my mother and father really nursing my grandmother to health in the best way that they could; she was dying of cancer, of breast and bone cancer. So I was all set to go to medical school, but after this one summer working for a cardiologist in Chicago, I had this revelation: “I can’t do it. I can’t go to medical school.” Because what I was seeing is that it is really an all-or-nothing path, and it was really a path that was directed down this trajectory of writing prescriptions. I remember being in there with the doctor, with the cardiologist, and him not even really looking at the patient, writing a script within probably about five minutes of the conversation, and I just felt: “That’s not me. I can’t do it.” I’m an all-or-nothing person and I felt: “I can’t go down this path of doing this kind of cookbook way of working with people and treating them.” Medical School was Not the Right Path So, at this point, I really had to make a decision: Is it medical school or is it graduate school? I started exploring a little bit more and I realized I wanted to do something more preventative rather than treatment-oriented, so I decided to go to graduate school, and I went to the University of Illinois at Chicago. Postgraduate Work and Research in The Netherlands I signed up for a program in human nutrition and metabolism, working with Dr. Phyllis Bowen, who is, in my opinion, really a leader in the whole area of carotenoids. I was not only a teaching assistant, but I was also a research assistant and I got to do some fun studies with lycopene and beta carotene. That was very stimulating. At that point it wasn’t as much clinical as it was research-oriented. After three years, I finished my Master’s degree and it was really a revelation for me and I decided I needed to go on. I was thirsty, I was hungry for more of this information. I decided to embark upon a PhD program, and went to The Netherlands for this. I went to the University of Groningen, which is up in the north of Holland, a small town. What many people don’t realize about The Netherlands is that really their science is impeccable, so they’ve got many different universities, one of which is Wageningen. It’s very well known in their agricultural sciences. I joined a group that was focused on human nutrition and metabolism specific to pediatrics and also specific to fat metabolism in the body. My PhD mentor was HenkJan Verkade. He’s a medical doctor (a pediatrician) and also a PhD. He’s brilliant. He’s just like you, Jeff. He’s really an integrative thinker. He synthesizes the literature. He’s always asking the tough questions. I had the privilege of working with him for four years between 1995 and 1999, working on animal models up into really full-fledged clinical trials with babies with cholestatic-type of conditions, and also children with cystic fibrosis. We were trying to find optimal nutritional regimens for these children because their absorption of fat was impaired. So this is where I started to see the phytonutrient aspect during my Master’s degree training and then I started to see this whole evolution of essential fatty acids and what that could do for the body on many levels. Work in the Food Industry As you mentioned, after that I went into the food industry—first the medical food industry working with Dr. John Cooke, who is a cardiologist. He had a wonderful product called the HeartBar(R) for peripheral vascular disease. As many people may or may not realize, a medical food is a specific nutritional product that is designated for a particular clinical condition. So in this case it was really looking at peripheral vascular disease and we had a number of different nutritional agents in that product. From there I thought: “Well, wouldn’t it be interesting to move my way into a larger food industry to see what I can do to change eating on not just my own community level because I was really starting to get into this, but also from an industry perspective?” I joined a large food manufacturer in April of 2000, and I have to say it was pretty tough. It was enjoyable because I really got into the guts of the food industry to see what they are about, and as I always tell patients, food companies are going to make what you buy, so really the power is in your hands if you want to make a change. So that was a great experience. I was a nutritional expert for many of the different brand groups and I got to work on organic food brands as well as mainstream brands, and I even was active in doing clinical work. From there, I really started to get into the clinical aspects. I was also working in private practice at that point, and I had started to use a number of Metagenics products, actually, and really found that they were intriguing, that they were working in patients, and this opened my perception into a whole new view of nutritional medicine, and I was really looking at nutraceuticals and medical foods much more closely. JB: I think that is a model for the perfect background of a professional qualified to deal with the broad-based issues that surround personalized lifestyle medicine—everything from the genomic side, the biochemical side, metabolic side, and human behavior side, because that is, in the end, where the tire meets the road: what people will do and whether they’ll comply and adhere with certain programs. Your role now is the Vice President of Scientific Affairs for Metagenics and you are really one of the key people in developing the clinical applications of much of what we’re working on in discovery and interfacing that with the FirstLine Therapy (FLT) personalized lifestyle medicine program. it sounds like you couldn’t have found a better match to your background, talents, and expertise with your present professional challenges, which leads me then to the question of what you have learned and now kind of taking many of these things gained through your training, your background, your experience and taking them out into the field with patients and practitioners who have different backgrounds, different expertise, and different needs, and different responses. What have you seen through the multiple clinical trials and the interactions you’ve had with people over the last nearly 10 years? Teaching Personalized Lifestyle Medicine Around the World DM: Yes, it’s been a fabulous experience. As you alluded to, in my role what I am able to do is to talk with doctors and practitioners worldwide. Just this year I was in South Africa, Mexico, Australia, Taiwan, and London talking with thousands of practitioners and really getting to not only educate them on clinical protocols, but also to hear about their challenges and their different approaches, because with functional medicine the way I see it is there are really many paths up the mountain. Every patient that comes in is very unique, and you can have as many unique approaches as there are practitioners probably. So I’ve really learned a lot, and what I’m also able to do is not just speak from clinical experience from working at the Functional Medicine Research Center, but also from doing clinical trials and being involved with the research aspects, which really brings me back to my graduate school days of looking at nutritional medicine in a very structured way, and then having publications so that we can create more credibility as it relates to these nutritional medicine protocols. I think that’s really important to get the word out. So I’ve learned a lot, and what I can say from working with Metagenics over these last ten years is I’m starting to see a percolation of interest in many different circles, and I do think the paradigm is changing under our feet. I’m excited, because as we have seen in the New England Journal of Medicine, we’re starting to see in JAMA now, there is discussion about lifestyle medicine: What is lifestyle medicine? How do we educate physicians on lifestyle medicine approaches?[8],[9] So I feel like we are really in the sweet spot of really catapulting forward into this change. Word Choice is Important: Diet versus Food Plan JB: One of the many things that I think is of note that you have accomplished over the last years is the incredible development of this low glycemic load modified Mediterranean food plan. Through your education of me I’ve learned not to talk about this as a diet but as a food plan. I think it is important for you to help us understand the distinction between a diet, which is a four-letter word, and a food plan, and also, what is this low glycemic load modified Mediterranean diet that you and Barb Schiltz have developed and have published ?[10] DM: The “D” word—diet, the four-letter word—and I’m glad that you’ve been consistent about using the food plan language rather than diet. I think much of how we effect change in patients comes through how we language things. We could say to a patient: “You have metabolic syndrome” or “you have a precursor condition that will lead you in the direction of type 2 diabetes (something like ‘pre-diabetes’).” So I think language is really important, and I think when we think “diet,” as Brian Wansink has said in his book Mindless Eating, it’s like “die with a ‘t’ on the end.”[11] People think of deprivation, they think of something temporary, and so they can’t wait to get off the diet. And when they are off the diet, their way of eating can be radically different than when they were on the diet. So then you have these huge extremes that happen, and that can really change us not just physiologically but also psychologically. I think it is good to go into a lifestyle change program with the idea that this is really for your lifespan, and we’re making small incremental changes, whether we’re moving like a snail or we’re moving like a grasshopper (kind of jumping forward), these are changes that are meant to stay. So, yes, whenever we’re working with patients, what we like to say is “food plan” rather than the diet word. Making the Mediterranean Diet Even Better Actually I really give lots of credit to my mentor, Barb Schiltz, who worked in the clinic for 10-plus years and together with Dr. Dan Lukaczer came up with the FirstLine Therapy food plan. And the FirstLine Therapy food plan really has lots of different elements. At the heart of it, it is really based on a low glycemic way of eating, which is really important for many different chronic conditions. We focus a lot on cardiometabolic syndrome within FirstLine Therapy, but really it’s so good for whether it is cardiovascular disease, cancer, or developing signs of insulin resistance, so it really fits a whole spectrum of different conditions. And then as an adjunct to that, as we went on in our research we started to look at all of the publications coming out on the Mediterranean diet. In my review of the literature, I would say that the Mediterranean diet is probably the most studied diet. If you go PubMed and you just type in “Mediterranean diet” with quotes, you’ll come up with thousands of articles. In fact, there was a study—I think it was published in the Journal of the American College of Cardiology—looking at a meta-analysis of all of these studies in thousands of different individuals following this way of eating and showing that it is very compelling for metabolic syndrome, cardiovascular disease, and even mortality.[12] As Barb and I were going through the creation and evolution of this FLT food plan, what we noticed was that the Mediterranean diet really, in our eyes, wasn’t perfect because it was too high in carbohydrate and in a lot of the grain-containing carbohydrate. What we decided to do was to modify the program to incorporate a lot of the phytonutrient density aspects of the Mediterranean diet, but then to take out a lot of the high gluten/high carbohydrate aspects. So really the FLT food plan is more of a Mediterranean diet “style” rather than being a pure Mediterranean diet. We’d like to think that we made the Mediterranean diet even better. And also there have been publications talking about how certain foods on the classic Mediterranean diet—things like pizza and other carbohydrates—may be higher glycemic, so we had that concern as well. The modified diet is really low glycemic, it’s Mediterranean-style, high in phytonutrients, and what Barb would tell you if you were talking with her right now is that it is very low in sugar. She feels very strongly about the sugar aspect—that we get too much sugar in our foods—and so it is really about having the patient become aware of all of the hidden sources of sugar in the food supply, and teaching them to read labels, and really to become aware of that. JB: I think that’s a magnificent description, but there might still be—in the minds of our listeners—some confusion as to how they differentiate a diet from a food plan. I know you’ve done some studies on weight loss and calorie control and so forth that maybe would help our listeners to understand the difference between a food plan and a diet. Mixing Art with Science DM: Yes. I would say, in my experience, the way that we use a food plan in the clinic if we are not doing a clinical trial but we are doing more of a case study, where it is more of an individualized approach to working with a patient, is they are really not on this program for any set duration of time. What we really want to do is change their eating. Maybe a patient is not ready to make the leap into working with the full-on FLT food plan as we have it, so we will kind of inch into working with them. I remember many times just working on this: How do we get more vegetables? And then finding creative clever ways to do that and we would also look at food diaries. What I think is really important is food color. We are really moving away from the “analysis paralysis” aspects of eating and looking at calories, looking at grams of protein, carbohydrate, and fat, really moving them into this line of thinking: How do they feel when they eat certain foods? What are the colors they’re getting? And instead of taking their diet diaries and analyzing them, looking at the grams of all of the macronutrients and all of the vitamins and minerals, what I think is one of the best ways to promote patient compliance is to take a package of colored markers and to circle all the different colors in their foods, in what they are eating (and that would be natural colors—that wouldn’t be things like M & Ms or other things that are artificially colored). We can see from the get-go what they are getting. Are they getting the rainbow variety? One of my other favorite tools when doing a food log is to fold the page in half, and on the left, be writing the foods they are eating, and then on the right, how they’re feeling—what types of things are going on for them throughout the day, are there certain stressors, and if there are certain stressors, how does that change their eating? That really gives me a great palette to work with as we have the therapeutic encounter because really then it is not just about the dietary aspects, right? It’s really more about how do they feel, what do they notice in their bodies, what’s changing, how’s their energy level? They start to develop an awareness of how their mood and food work together. JB: It sounds to me like you use a lot of terms that interrelate to the concept of the art of living. It is very interesting—knowing you—that you are this interesting bicameral mind that’s really got the reductionism on one side of science and the synthesis of art on the other. You are an artist. I’ve seen your art and it’s beautiful and you bring that into your work and into how you language things (the use of a word like “palette” for instance, and use of marker pens with colors to indicate the diversity of the rainbow of food). When you distill it down, how does that all relate to communicating change in ways that people understand, so you’re an effective guide/counsel in personalized lifestyle medicine transitions, and secondly how does that relate to ingredients, or let’s call it density, of phytochemicals in food to ultimately what a person is eating? DM: That’s a great question. Yes, I think it’s important to bring art into the science and to really create this hybrid. When you see patients, you’ve got lots of different personalities and certain people will resonate with certain things. Some patients are clearly more structured than others. For those who aren’t as structured, what I think is really fun is to go down the path that’s a little bit more artistic and to talk more about the relationship with food and eating rather than get bogged down in the details of all the different nutrients that they may not be getting because they may not be hearing that information. In my opinion, I don’t think the patient needs to know all the intricacy of what all those color compounds do, but I do think it’s important for practitioners to be aware. It’s really interesting because there have been lots of different reports on what colors people are getting too little of, or how much we are consuming in the way of produce, things like fruits and vegetable. Many, many people are not meeting their requirements for the different colors, especially for green, and blue, and purple. How does that translate into the body in terms of the effects that these colors are associated with? I think if you were to ask me this question 15 years ago, probably the simplistic answer would be something along the lines of just talking about antioxidants, and how we need these colored compounds because they work like antioxidants in the body, and we’ve got all this oxidative stress and we have to somehow quell these free radicals. That is what we knew at that time and that is what I knew this during my graduate days working with carotenoids–that these were very potent antioxidants, so I might have given you that answer then. But really in the past 5 to 7 years, we’ve been seeing a whole flurry of articles coming out talking about the pleiotropic effects of these different phytochemicals and what they are doing in the body. What I often say to patients is that these colored compounds are not just antioxidants, but they are physiologically being routed to certain parts of the body for certain functions. What we know from Dr. James Joseph’s work at Tufts is that—as an example—blueberry compounds find their way into certain parts of the brain that are responsible for learning and memory.[13] We also know that things like curcumin can also be very protective in the brain, preventing the build-up of things like beta-amyloid.[14] I think that’s pretty interesting, because why does the body shuffle these different phytochemicals to certain parts of the body? What are the functions they are serving, and what are their roles on a cellular level? And what we see, if you start to scratch the surface of this research, is that these nutrients, or really these phytochemicals, are having very specific effects at the level of the cellular communication. This would be things like protein kinase transmission, and really conducting a signal throughout the cell. Jeff, I really like it, because for many years you’ve been talking about how food is information and it is really true because if you look at the literature, and even in our own research at Metagenics, we’re seeing that a lot of these compounds within food—these colored compounds—are changing the cellular communication, and they are changing it in a beneficial way, so almost getting that cell back into balance so that this becomes more like a system-wide effect: we move from the cell into kind of a ripple effect of restoring function throughout the body. JB: When we look at the interesting epidemiological evidence around fruits and vegetables, what you’re saying really starts to have some fundamental “a-ha” understanding at a mechanistic level because we have known for years, without a really good explanation, that cultures or groups of people who eat higher levels of fruits and vegetables in their diets have a much lower incidence of virtually every chronic disease, even down to the Seventh Day Adventists living in Loma Linda, California. They are neighbors of people in the Los Angeles area–they all share the same water and air and freeways–but yet they have a much lower incidence of all sorts of chronic diseases, including diabetes and heart disease. People have associated that with that group’s increased consumption of fruits and vegetables, like we see in other studies (epidemiological studies) around the world, but no one has ever really been able to provide an effective mechanistic link between cellular physiology and those epidemiological observations. I think the article you authored in Nutrition Reviews, which was “Beyond Macronutrients,” talking about the nature of phytochemicals as it relates to insulin sensitivity, that model—to me—is a remarkable opening up of a new paradigm in nutritional science taking us beyond the age of vitamins.[15] That’s how I abstract what you’ve said. Can you take us down that road a little bit? Phytonutrients and Insulin Pathways DM: Sure. Especially even within my nutritional research training there was so much emphasis placed upon the macronutrients, and I think it is really starting to emerge that the phytonutrients—even though we really only get such a small amount—are really having a huge impact. In that article, which was in Nutrition Reviews in 2008, what we did was essentially look into a number of the different phytochemicals and how they impact insulin pathway targets. We looked at everything from resveratrol, to quercetin, cinnamon, and green tea. These are a lot of the things that are already used in traditional medicine, but we wanted to understand the molecular biology as to how they work at the level of the cell. In this review article, we essentially put together a lot of the research that showed that many of these different actives tickled and modulated in some way the insulin targets, things like insulin receptor substrate 1, PI3-kinase, PKC, glycogen synthase kinase—all of these aspects of communication within the cell that are all related to the effect of insulin coming into the cell receptor. If we look at how these agents can beneficially impact things like metabolic syndrome and insulin resistance, it seems to be a likely link. And even in our own research at Metagenics, we have tested a number of these different plant compounds, and there have been a couple of stars that have risen to the top. What is really interesting is that we were able to show, in a kinase model in addition to a cellular model, that these plant actives can change up the cellular physiology, and then we took that knowledge and moved that into a clinical trial in which we saw dramatic effects in the group that was given the targeted phytonutrients. We looked specifically at individuals with metabolic syndrome. We leveraged the research from our cell animal work, and we put those actives into a medical food, and essentially saw a 43 to 44{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction in markers related to metabolic syndrome, which is really phenomenal. You don’t typically see that in the literature with different dietary approaches. JB: So when I look at this, what I’m starting to recognize is when you marry the food plan concept together with specific foods that are low glycemic load with a variety of colors, meaning rich in vegetable and fruit products, and then you start to tie that with the emergence of our understanding of nutrigenomics, molecular-based nutrition, and ultimately even nutriepigenetics, that what we’re really starting to see is a whole new paradigm that’s emerging in how to personalize food plans for individual needs, which then takes us into functional nutrition and its application to functional medicine. Have you ever thought of yourself as the inventor of this concept, because it’s a pretty powerful evolving model? DM: It is a very powerful model, functional nutrition is. And it’s not that one food plan fits all, by any means. My experience has been specifically in the area of cardiometabolic syndrome, but we’re starting to extend our research into other patient groups as well, so looking specifically at groups that are relatively healthy—maybe have some metabolic disturbance—but they are overweight, and what kind of program would be suited for them? I do think that looking at the whole lifestyle and really starting with the bedrock of food…the way I think about it is really food first, and correcting of signals on a very large level. If you think about what the average American eats in a year, it is something in the neighborhood of 2000 to 2500 lbs of food, so that’s a lot of information running through us. It is really important, I think, to focus on the food first and to correct the signals at the level of the cell, which you’ll start to see in the physiology and in the expression of the patient’s symptoms. With the FLT food plan, which is what we’ve worked a lot with in the clinic over these past years, we’ve seen incredible effects, and in fact the effects have been so dramatic and so pronounced that as we went further into studying our different targeted phytonutrients, we didn’t really think we could do much better than the FLT food plan for individuals with the metabolic syndrome. But to our surprise, adding in these targeted phytonutrients, things like hops, rho iso alpha acids, things like proanthocyanidins from a tree that grows in Africa and Asia by the name of Acacia nilotica, what we’ve found is that we can really get those signals corrected. Of course, we did have exercise built into one of these studies as well because that’s going to help to improve insulin sensitivity. So it is really a lifestyle—a programmatic—approach to chronic disease and, in this case, metabolic syndrome. Functional nutrition is really like a kaleidoscope: we’re not just focused on one aspect, one condition, although one condition like metabolic syndrome really does radiate out into many other chronic disease conditions. In our clinic, we’ve just completed a study over the course of 12 weeks in which we were looking at overweight individuals. We tried out a different food plan program, and we’re right now in the midst of looking at the results, but preliminarily they look just fabulous. Can we keep these effects alive in the patient over a longer term? I think that is really a point of interest as well, because in a lot of these different studies, we see in everything from the Atkins program to Weight Watchers to Jenny Craig, all of these different types of diets, which are—again—short term, patients can lose weight, but then the questions are: 1) Do they keep the weight off?; and 2) Do we see an improvement in these biomarkers over the long term? Many times we get so focused on numbers like weight and weight loss that we really need to look at the shifting sands of the different physiological biomarkers within the body. JB: I think you have led us to a really great place to kind finish our conversation because for many individuals it is not just the treatment of a disease (that’s the negative, fear-based model), but rather it’s the promotion of successful aging, and that’s more of your positive, outcome-based expectation. What we’re looking for is how do we achieve, in an individual, the rectangularization of their survival curve, compression of morbidity, and letting them live with good health out to the limits of their biologically determined lifespan? When we start asking that question it leads us to others: Do these types of dietary or lifestyle changes do things that epigenetically, or at the molecular level, modulate the aging process? Is there something that goes on that really can help promote successful aging? Are we protecting the most valuable legacy we own, which is our book of life in our genome? I know you’ve been engaged in some work in those areas as well, as it relates to genomic stability and to successful aging. How does this concept lap over from a disease focus into a successful aging focus? First Wellness, then Graceful Aging DM: I’m so glad you asked that question because that’s definitely something I feel really passionate about. As a practitioner, I think we definitely do look at biomarkers and we’re trying to move patients from chronic disease back into a state of wellness. What I also think is interesting along that spectrum is to move the patient into optimal health and then ask the question: How do we help them to age gracefully? It’s not that we can anti-age or prevent aging from happening, but how can we get them a better quality of life? This conversation actually brings to mind a patient I recently had in the clinic. Dr. Lamb and I had been seeing this patient for I think about a year. When he first came in I remember he was a little bit worried. He had just been diagnosed with type 2 diabetes, and at the time he was 61. He was feeling kind of depressed about it, and, just kind of thought this was the end. I clearly remember saying to him: “You know, you’ve got 30-plus years of your life. We really need to embark upon a whole new lifestyle medicine way for you.” And he said: “Deanna, 30 years? That’s a long time.” He said: “I’ve never thought of myself living so long. Once I knew that I had type 2 diabetes there was no way that I would ever think that I could live another three decades.” And I said: “Absolutely. We’re going to work on this. We’re going to work on how you feel and really get you back.” Just recently we had a visit with him—I think about a month ago—and he said to me: “Deanna, I think I got my 10 years back.” He feels much more vital. He feels energized. I think it’s exciting because even though I don’t talk about things like genomic stability, or heart rate variability, or a lot of these different aspects of aging, what we clearly see is that his body is changing. His mind is changing. His attitude is changing. And this is just so uplifting for me because within one year’s time for him to say that he got 10 years on his life, that he really feels like he’s made an impact, his body composition has changed, his way of eating—he’s been so motivated and now even his wife, his family, has seen the change in him and is wanting to adopt more of what he’s doing. And they were all very reticent in the beginning. You know, things like this, I’m sure your listeners see many times when they start to follow this type of program, but when I think of aging on a more scientific level, as I’ve been working with patients and reviewing the literature, at the end of the day what I really have seen is that it is all about flow and fluidity. If we’re talking more in the artistic realm and more metaphorically, then it’s about keeping the body moving and fluid and flexible. There are common things in the literature, things like neuronal plasticity (the flexibility of neurons). How do we keep things moving in the brain and have complexity of the synapses all communicating? And then there’s heart rate variability. The more your heart can be variable in its heart rate pattern, the better the chances are for things like reducing cardiovascular disease risk and also reducing mortality. And then also the gut and thinking of the whole aspect of metabolic inflexibility, which is what metabolic syndrome and all of these metabolic disturbances are. How do we create more metabolic flexibility? These three things—just thinking of brain, heart, and gut—and weaving them together, creating more flow, and I think we can do that with lifestyle changes. I think we can do that with food, with activity patterns, with stress management. I’ve seen it with patients, and with this one particular patient just recently really brightening my day. Hearing him say that he got his 10 years back was a testament to everything we’ve been doing. JB: I think that’s a beautiful way of bringing this discussion to a close. I want to give you one other attribution. We had the fortune, just recently last week, of having one of these spontaneous moments of “a-ha-ism” that really comes out of your work and the work that you’ve been doing at the Functional Medicine Research Center and the advocacy that you and Barb Schiltz and others have had in the food plan (the low glycemic load modified Mediterranean food plan). It turns out that at a meeting the audio technology group was taping, there was an individual who had taped this meeting a year previously and had heard you speaking and this had motivated him in his own life. Unbeknownst to me he had gone back home, sought out some care from a functional medicine practitioner, had gone onto the food plan that you have pioneered and described, and this year at the meeting he was willing to stand up in front of an audience of several hundred and talk about the flexibility that it gave back to him. As a type 2 diabetic who was the father of a 1-year-old at the time, he was 39-years-old and was very worried about his future. He couldn’t bend down to really play with his daughter on the ground because he had so much musculoskeletal pain, and this year all of his parameters have normalized. He’s off all of his medications. He lost, I think it was, 62 lbs on the food plan and through lifestyle changes. And then his wife brings his now 2-year-old up to the podium and he bends down comfortably and picks her up off the floor as a testament to his range of motion and his function. This is better than real, right? This is what we’re all here to do. I think what you’ve said is actually the aspiration we’re all trying to work toward. These signals really do create the outcome that we call our lives, our phenotype, and our function. Thank you for sharing this. It’s been a very powerful journey with you over the last 45 minutes in the milieu of the changing architecture of food and its relationship to function. DM: Thanks for having me, Jeff.  

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Bibliography

[1]Bieler, Henry B. Food is Your Best Medicine. Ballantine Books: New York, 1987.   [2] Heber D, Yip I, Ashley JM, Elashoff DA, Go VL. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr. 1999;69(2):231-236.   [3] Li Z, Seeram NP, Lee R, Thames G, Minutti C, Wang HJ, Heber D. Plasma clearance of lovastatin versus Chinese red yeast rice in healthy volunteers. J Altern Complement Med. 2005;11(6):1031-1038. [4] Jungbauer A, Medjakovic S. Anti-inflammatory properties of culinary herbs and spices that ameliorate the effects of metabolic syndrome. Maturitas. 2012;71(3):227-239. [5] Yeon JY, Kim HS, Sung MK. Diets rich in fruits and vegetables suppress blood biomarkers of metabolic stress in overweight women. Prev Med. 2011 Dec 20. [Epub ahead of print] [6] Fardet A. New hypotheses for the health-protective mechanisms of whole-grain cereals: what is beyond fibre? Nutr Res Rev. 2010;23(1):65-134. [7] Uribarri J, Oh MS. The key to halting progression of CKD might be in the produce market, not in the pharmacy. Kidney Int. 2012;81(1):7-9. [8] Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med. 2011;364(25):2392-2404. [9] Chiuve SE, Fung TT, Rexrode KM, Spiegelman D, Manson JE, Stampfer MJ, Albert CM. Adherence to a low-risk, healthy lifestyle and risk of sudden cardiac death among women. JAMA. 2011;306(1):62-69. [10] Schiltz B, Minich DM, Lerman RH, Lamb JJ, Bland JS. A science-based, clinically tested dietary approach for the metabolic syndrome. Metab Syndr Relat Disord. 2009;7(3):187-192. [11] Wansink, Brian. Mindless Eating. Bantam: New York, 2006. [12] Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol. 2011;57(11):1299-1313. [13] Joseph JA, Shukitt-Hale B, Brewer GJ, Weikel KA, Kalt W, Fisher DR. Differential protection among fractionated blueberry polyphenolic families against DA-, Aβ42- and LPS-induced decrements in Ca(2+) buffering in primary hippocampal cells. J Agric Food Chem. 2010;58(14):8196-8204. [14] Gagliardi S, Ghirmai S, Abel KJ, Lanier M, Gardai SJ, Lee C, Cashman JR. Evaluation in vitro of synthetic curcumins as agents promoting monocytic gene expression related to β-amyloid clearance. Chem Res Toxicol. 2012;25(1):101-112.   [15] Minich DM, Bland JS. Dietary management of the metabolic syndrome beyond macronutrients. Nutr Rev. 2008;66(8):429-444.

Welcome to Functional Medicine Update for April 2012. The brain, neuronal function, diet, and genes. For some people those might sound as if they are really completely separate, independent, and unconnected topics. But from a functional medicine model, these are highly interconnected in a web-like series of cross communications, and it is that which we’ll be talking about in this issue of Functional Medicine Update. Hormetic Connections: Neuronal Function, Diet, & Genes Dr. Mark Mattson, a senior research investigator at the National Institutes of Health (NIH), has been writing recently on the research they’ve been doing in his laboratory on what he calls neurohormetic phytochemicals.[1],[2],[3] Now, what are neurohormetic phytochemicals? First we have to know what “hormetic” means. It is derived from the word “hormesis,” and those of you that have been following Functional Medicine Update for some time know that “hormesis” is a term that refers to small things having much larger influence on function than we would have predicted. Hormesis works by different mechanisms than the traditional pharmacological mechanisms of dose response (increasing dose, increasing response). Rather, sometimes lower dose has bigger effects with hormetic substances. The reason for that is they have unique receptor interactions to—I’m going to call it “tickle”—specific receptors in such a way as to modulate their function, or send a signal through those receptors that are different than a hard-hitting, high-activity signal. This would be like thinking of different effects of aspirin, for instance. You might think of aspirin taken at the baby aspirin level to prevent heart attack, or you might think of aspirin taken at a higher level to treat a headache, and then you might think of aspirin taken at a much higher level to treat the pain of rheumatoid arthritis; different activities at different concentrations of therapeutic dose. Now, I would say the baby aspirin analogy is not quite hormetic, because the level that I am speaking of related to hormesis may be even much lower than that of a baby aspirin (exposure to certain bioactive ingredients). What Dr. Mattson has pointed out is that our nervous system and our neuronal function may be very sensitive to certain types of hormetic phytochemicals, meaning substances that are found within the diet, like epigallocatechin galate (EGCG)  that is found in green tea (Camellia sinensis). Or he talks about the effects that resveratrol, which is found in peanut skins and in grape skins and may serve as a neurohormetic phytochemical. Or he talks about curcumin from the spice turmeric, which has been demonstrated to have the potential to serve as a neurohormetic phytochemical. So these are fairly interesting new developments in how the brain may be influenced by substances that come through our diet that plants make as anti-stress compounds that become influential on neuronal functioning even though they are at very low concentrations within the body, working by different kinds of structure/function relationships. Homocysteine as a Biomarker for Alzheimer’s Disease I think this concept is interesting if we go back and examine a biomarker to Alzheimer’s disease and its relationship to neural hormesis and nutrition, and that biomarker I’m talking to is homocysteine. Elevated homocysteine has been statistically associated with both increased incidence of Alzheimer’s dementia and of coronary heart disease.[4] It has been suggested the reason for this is that homocysteine is either a cause or an effect of inflammatory processes in specific tissues. In actual fact, when we start looking at homocysteine, it often comes as a biomarker in conjunction with a couple of other biomarkers that are elevated, and those are high sensitivity C-reactive protein (CRP) and also uric acid, which we often associate with gout, but also is another marker that is associated with increased upregulation of oxidative inflammatory stress.[5] So the combination of elevated homocysteine in conjunction with elevation of high sensitivity CRP and uric acid reflects a certain kind of metabolic disturbance that has a statistical association with Alzheimer’s disease, with type 2 diabetes, and with coronary heart disease. It’s interesting that it cuts across those very different disease entities and specialties of medicine. One might ask: Are these, then, solely a consequence of the poor metabolism of homocysteine because it somehow is blocked in the tetrahydrofolate cycle in its ability to be appropriately metabolized and recycled? If so, does that mean it will be ameliorated solely by administering supplements of folic acid, and vitamin B12, and maybe betaine hydrochloride as the cofactors that are necessary—the nutritional cofactors—for stimulating the metabolism of homocysteine?  There is the ability to lower homocysteine levels by supplementation by vitamin B12. This is seen even recently in population-based studies.[6] We’ve started to fortify grains with folate. [7],[8] However, if you look at very detailed meta-analysis of tens of thousands of peoples’ data, we don’t find a very significant correlation with a reduction in incidence of either Alzheimer’s disease or heart disease as the general trend of homocysteine has gone down.[9],[10] Is the answer that homocysteine elevation is a biomarker for putative or occult B vitamin deficiency, or are there other things going on here in which homocysteine elevations, particularly in conjunction with elevations of uric acid and high sensitivity CRP, represents a disturbance in metabolism that reflects inflammatory oxidative stress in specific tissues that then demands other review, other than just supplementation with folic acid and/or vitamin B12?   A Recent Meta-Analysis of Modest Homocysteine Elevation A recent paper published in 2012 in the February issue of PLoS Medicine looks at a meta-analysis across these thousands of case studies that have been published and tries to tease out whether homocysteine in modest elevation is, in and of itself, the cause or the effect of some of these problems.[11] The authors of this paper concluded that in a large population, you do not find a statistically significant correlation between moderate homocysteine elevations in the blood and coronary heart disease incidence, and that although B vitamins will lower homocysteine, there is no statistically significant reduction in overall population-based coronary heart disease or Alzheimer’s incidence. They then went on and asked the question: What about those individuals that carry a methylene tetrahydrofolate reductase polymorphism that makes their folate more challenging in terms of metabolism? They’ve got a block in conversion of folate to 5-methyl tetrahydrofolate (5-MTHF; the active form)? And even by segmenting it to that 5-methylenetetrahydrofolate reductase (5-MTHR) TT677 polymorphism, which is the genotype that has, in about 10 to 15 percent of the population, the greatest resistance to the proper metabolism of folic acid—that even in that genotypic segmentation of the data, you don’t find a strong correlation between elevated homocysteine and coronary heart disease. Could it be, then, that homocysteine is more a marker for overall disturbance in metabolism that goes to only a part of its relationship directly to the cofactors that activate the enzymes in the folate cycle, and that is the folic acid, the vitamin B12, and betaine, and also deals with other factors that may serve as modulators of this inflammatory personality? We go back again to what we learned from Dr. Mattson, and that is that within foods there are neurohormetic substances that modulate the expression of genes in the nervous system and in the vascular system that can influence inflammatory response and oxidative response that then changes homocysteine, uric acid, and hs-CRP levels. It may be a much more complex topic than just supplementing alone with 5-methyl tetrahydrofolate, and methylcobalamin, and betaine. If a patient doesn’t have a lowering of their homocysteine and a lowering of their hs-CRP as a consequence of B vitamin supplementation alone, then you need to look more broadly at the phytochemical families that might influence inflammatory potential. That’s what we’re going to be speaking to today as it relates to this genotropic relationship to neurological disorders and how that interrelates, then, with specific complexity within the diet and lifestyle. In our own research laboratories, we have recently been screening families of various types of phytochemicals that are derived from foods for their abilities to modulate the intercellular regulating system called kinases. There are over 500 kinase enzymes found in different cells. These influence the signaling of environmental messages ultimately to the genome, which then causes transcription of various proteins and alters the function of the cell. And so as we start to use various cell models, like neuronal cell models, and we screen against various kinds of botanical extracts from foods and spices. What we find is that there are very differential effects in the ability of these phytochemicals found in various foods to serve as neurohormetic phytochemicals and modulate function of the cells. In fact, as we screen those various chemicals, we find they are involved with selectivity of modulating things like brain-derived neurotropic factor and how that interrelates with kinases like the MLK-3 family, which is associated with expression of neuronal function. We see the same things with regard to kinases that modulate neurogenesis, and modulate anti-inflammatory processes within the neurons. I could go on at some length in this, but suffice it to say that what we are starting to recognize is that beyond that of just the B vitamins, this homocysteine/high sensitivity CRP/uric acid elevation profile is in fact related to something beyond B vitamin deficiency. It is related to the complexity of genotropic uniqueness interfacing with the environment and the signals that are being seen and picked up by different cell types, like neuronal cells, and transmitted, then, into gene expression functions and ultimately into either cells that are at peace or cells that are in a state of unrest that we call alarm or inflammation. Inflammatory Mediators Seen in Many Disease Types   I think this is very interesting when you start examining, then, how that interconnects disease etiologies across multiple disease types. As I said, not just Alzheimer’s disease and heart disease, but also type 2 diabetes and autoimmune disease. Recently there have been papers demonstrating that some of these inflammatory mediators I’ve been describing are seen not only in insulin resistance and type 2 diabetes patients, but also in patients with systemic lupus erythematosus (SLE), and seen in patients who have Alzheimer’s disease.[12],[13] Does that mean individual patients have all these diseases simultaneously, or does that mean there is a metabolic disturbance that occurs in that person that happens to cut across these different disease entities as a consequence of disturbed gene expression patterns in different tissues and different cell types? In fact, if you look at an autoimmune disease like systemic lupus erythematosus, you’ll find that it has very similar kind of alteration in kinase signaling to other diseases. Alterations in AKT, SX-kinase, mTOR, in the adenosine monophosphate kinase family are the same disturbances of these kinases that are seen in Alzheimer’s disease, and seen in type 2 diabetes, and seen also in coronary heart disease. We also see mitochondrial oxidative stress and reduced function in SLE, just as we see in type 2 diabetes and Alzheimer’s. We see elevated expression of gamma glutamyl transpeptidase (or GGT) and how that relates to altered glutathione physiology across those different conditions. We see increased autoantibodies obviously in SLE, but we also see increased autoantibodies in Alzheimer’s disease and in type 2 diabetes. And we see increased inflammatory biomarkers, as I suggested, not just hs-CRP but also cytokines and prostanoids. The point I’m trying to make here is that Mattson’s concept of neurohormetic phytochemicals, the gene-environment interaction, how we look at neurological disorders and behavioral neurology may connect itself in a functional way beautifully to what might appear to be very divergent diseases that share common lineage in terms of metabolic disturbances, such as type 2 diabetes, heart disease, and autoimmune disease. With that in mind, let’s move to an expert who  I believe is at the cutting edge of this gene-neuronal revolutionary breakthrough, and that’s Dr. Jay Lombard.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jay Lombard, DO Genomind Co-Founder, Chief Scientific and Medical Officer Genomind, LLC 100 Highpoint Drive, Suite 102 Chalfont, PA 18914 www.genomind.com April 2012 Can you hear the excitement in my voice? I hope you can because I’m really feeling a state of exalted energy in this opportunity to interview our clinician/researcher of the month. This is one of those privileged times that I have each month when I select a personality that I think is doing something quite remarkable in the field that we should all be aware of. Someone who is doing pace-setting work that helps us to understand what the landscape of medicine of the future might look like. We certainly are fortunate to have one of those individuals with us in the studio today, Dr. Jay Lombard. Now, some of you probably know the name Jay Lombard. He is certainly a well-recognized personality in our field of functional medicine. You may not know some things about Jay Lombard, however, that I know. There are no secrets here; it’s all very above-board information. Dr. Lombard is one of those quite remarkable seekers. I value people who are seekers: What level of inquiry do they bring to their life? What level of commitment to excellence do they bring? How do they view their discipline in the broader context of the social milieu, and humanity, and time/history? Jay is one of those individuals. He is board-certified both in neurology and psychiatry. I first met him in 1984, when I was teaching at the Omega Institute in Rhinebeck, New York, and Jay was just finishing up his medical school training. Since that time I’ve gained a brother-at-arms, both intellectually and professionally, in the interaction that Dr. Lombard and I have had over the years. Behavioral Neurology: Where Psychiatry and Neurology Meet What I really want to do is talk with Jay in this interview about the nature of a field that I think he has really been the father of. I think he might not give himself credit for this, but I believe those of us who have observed his contributions over the years would certainly give him credit for the coining of the term “behavioral neurology.” The concept ties together his psychiatric background and his neurologic background in a very unique way—really a translational way of taking science and understanding of neurologic function and translating it into understanding behavior and some of the issues that we are confronting, both individually and socially, as it relates to behavior patterns and what we might consider aberrant behavior, or antisocial behavior, or even DSM-related diagnostic behavior. It’s with that context that I’m so privileged to have Jay in the studio today, all the way from his home on the east coast here to the west coast. Jay, welcome to Functional Medicine Update. Let me start with a question which I think you addressed in our last interview, but might be useful for some of our listeners to hear to contextualize your path. How did you come to focus on behavioral neurology, which I think is so timely and important? JL: Well, thank you, Jeff. You know, it’s interesting. I think that many neurologists don’t regard behavior as a brain-based function, and nothing could be further from the truth. Obviously both normal behavior and abnormal behavior have roots in how our brains are operating, and I think understanding the brain as best as we can–because it is still pretty much a black box but it is one the most important pursuits of our society as scientists–to realize what produces brain health and also what things are at risk to produce brain disorders. JB: So taking that and looking at your career as I have seen it, which probably is at the 30,000-foot level (there’s a lot more at the cornfield-level that has gone on that you know about in your life than I), it seems that your career has almost mapped against the evolution of this field. You’ve been very interested in molecular genetics. You’ve been very interested in metabolism. You were one of the first people to speak intelligently about the use of nutrients to modulate various neurologic functions, and later looking at various bioactive ingredients from plant products and how that interrelates itself mechanistically with the drugs that are commonly used for psychiatric and behavioral symptomatologies. How did you actually start to put these things together? It seems like there must have been kind of a grand design for you, making what might have been appearing to be two separate worlds come together. JL: I’m not sure. My wife thinks I’m an idiot savant. Maybe just the idiot part, I’m not sure. To answer your question, quite frankly, for anybody who practices in the field of neurology and psychiatry, if you have at all any sensitivity to humanity, it is quite a profound experience to be in front of people who are experiencing Alzheimer’s disease, or a parent with an autistic child, or someone with intractable depression, or an adolescent who develops prodromal schizophrenia. These are disorders that affect us existentially. Other areas in medicine, with all due respect to my colleagues, you know, a dermatologist who is treating some skin disease, or a gastroenterologist who is treating gastrointestinal dysfunction—those are all important, obviously, to our overall health and well-being, but when someone is affected by a behavioral neurological problem, the implications of this really affect us at our core. And I think that has been my motivation all along in my life: to really be able to add some value to understanding how these disorders come to be and how we can best understand ways of potentially diagnosing and treating them. JB: So with that as a really great context, I think it’s important for our listeners to recognize that this is much more than just theory for you. You’re a great thinker, you’re a great innovator, but you’ve also done the heavy lifting. You’ve worked at Bronx Hospital, and you’ve been at Cornell Medical Center. You’ve overseen patients who are in every degree of jeopardy. Maybe you could tell us a little bit about what you learned through the kind of hard knocks of dealing with fairly significant problems in patients. JL: Well, I think that neurology, from my training back in the late 80s/early 90s, was a “diagnose-and-adios” field. I’ll never forget a particular experience that really affected me profoundly, which was being with the chairman of neurology back during my residency program, and we saw a man who had developed weakness in his arms and had difficulty breathing. After an examination he was told he had amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease). The family, when they understood what that meant, the doctor told them to just go ahead and get your life in order and get ready to die, which was true. I mean, there was really nothing to offer. But it was astonishing to me how we could be in a profession to heal and to improve lives, and be left with such a poor understanding about what things to offer a patient with that disease, or Alzheimer’s, or other diseases. The good news is that we are much further along in terms of understanding the pathophysiology of these disorders and what risk factors there are, but we’re also still in the dark regarding how to translate some of these discoveries into clinical practice and I think that’s what we always need to keep our mind on whether we are clinicians or researchers: what the practical implications and ramifications of our discoveries are and how best suited to apply them to people who are suffering from these disorders. Mental Health is Expected to Be Largest Category of Healthcare Expense Over Next 20 Years JB: That’s a fantastic next step. It’s like we practiced this ahead of time. I’d like to segue from that to a little factoid that I learned recently. One of the most significant risks that we have in the United States as it relates to financial, economic, and maybe social peril, is the Medicare overhang for medical services to be offered to baby boomers over the next 20 years.[14] That overhang has been projected to be 37 trillion dollars, which is some seven times greater than the present national debt. Not only is this enough of a burden to bring the economy to its knees (which means society to its knees), we don’t have a solution to the problem. If you were to categorize those expenses that lie under that 37 trillion dollar overhang, the largest single category is in the mental health area, with Alzheimer’s rising up. So, you are, I think, one of the beacons of white light in helping us to understand some aspects of how we might at least address—conceptually, on the front edge—this overhang. Tell us a little bit about where you are heading in your discoveries/exploration in the understanding of the etiology and maybe prevention of Alzheimer’s. JL: First of all, I agree with you a hundred percent that this is a public health crisis, bar none, and we are in a collective state of denial about this disorder, and one of the reasons is that Alzheimer’s doesn’t clinically manifest until there is significant underlying pathology. The reality is that people are experiencing the degenerative properties of Alzheimer’s many years before clinical symptoms actually set in, and our ability to treat Alzheimer’s properly really requires us to identify the disease in prodromal, or preclinical, stages of the disorder. This is where a lot of my own personal efforts are right now. This is where a lot of the research in Alzheimer’s is being applied, including both genetic detection of the disorder, which we can talk about a little bit in more detail if you like, and other things like looking for protein biomarkers that actually indicate the active expression of Alzheimer’s disease, and also imaging, which is important, but still unresolved about what type of imaging (brain imaging, particularly) is most sensitive and specific to pick up the degenerative changes associated with Alzheimer’s disease. These are all important efforts because if we are able to create a healthcare system that is able to pick up the problem earlier on, then our chances of success in reversing these trends is significantly higher than if we bury our heads in the sand and don’t worry about the problem until it is fully expressed and we will have no chance of success. And the implications of this, as you mentioned, are truly catastrophic both at an economic level, but more importantly at a human level, because someone losing their cognition really strips from them the core of their identity. Our memory is in many ways our identity, and without our memory we have no identity. This is a very tragic consequence of Alzheimer’s disease. Alzheimer’s Disease: The Search for Early Biomarkers JB: Tell us a little bit about these biomarkers, because it seems the term “biomarkers” often has been applied to later stage diagnoses of disease versus what you are alluding to, which is maybe an earlier trajectory/understanding towards ultimate Alzheimer’s disease. JL: Absolutely. You know, the first biomarker really, in many ways, for clinicians to be aware about is to frankly acknowledge the elephant in the room and to ask patients a very simple question: Are you concerned about your memory? If the answer is yes, people should take that seriously. The reason people don’t ask that question is because they don’t know to do with the answer. If someone says, “Yes, I’m concerned about my memory,” okay, well, now what? Don’t worry about it? So we really need to create better algorithms to take next steps after asking this question. Predicting Risk is Not Predicting Actual Disease In my opinion, there are genetic tests that are useful that predict risk of dementia. One of the things that is important to understand is that predicting risk is not predicting actual disease, so if we say a patient who has a genetic test for any particular neuropsychiatric condition and they are at higher or lower risk, it does not mean that this is a fait accompli and they are actually going to develop a particular disease, which is one of the reasons that most clinicians have now adopted preclinical gene testing for Alzheimer’s disease. We have not established what steps to take once a risk is identified. This is, I think, a big misguided assumption, because we do know that clearly there is strong evidence for prevention strategies. We should be taking those identifications and recommending preventative steps in patients who are identified with higher risk of Alzheimer’s disease. JB: So before we get to the gene test, which I really want to get into in a little bit more detail, I’d like to ask a clinical first-level question. I’ve been reading recently and hearing a number of people report that one of the early markers for Alzheimer’s could be a rapid change in smell and taste. Is this at all a clinical part of the profile from your experience? JL: Absolutely. This is not new news; this is old news that loss of olfaction may be a particularly sensitive biomarker—a clinical biomarker—which should be part of the routine cranial nerve examination. Never is. We always test cranial nerves 2 through 12. We skip cranial nerve number 1. But yes, loss of olfaction may be a very early warning sign of developing degenerative changes associated with Alzheimer’s disease.[15] JB: So now let’s move from that to gene testing. This whole area of genotyping has become really a major area of both interest and controversy. In the cancer area now we get into tumor typing with specific genotype maps that leads to differential chemotherapy that are designed for the individual patient’s tumor type. We’re starting to see the same strategy spread out into other fields. How does this relate specifically to what we are learning in the area of Alzheimer’s and other neurodegenerative diseases? Many Disorders of the Brain are Protein Aggregation Disorders JL: Great question. First of all, one of the opportunities to study genetics and psychologies and neurologies is really, in my opinion, for understanding the pathophysiology of a disorder as opposed to a diagnostic biomarker in its own right. So the opportunity here, if we listen carefully to what genes tell us, is a better appreciation of the fundamental mechanisms that produce degeneration of the brain. So for instance, some of the more commonly established genes which have been associated with Alzheimer’s disease include the apo E gene, which has a lot of very important roles in brain physiology and particularly in lipid metabolism in the brain. We know that the E4 allele, although it is the minority allele in terms of its prevalence in the population, is substantially overrepresented in terms of risk for dementia. We need to understand how the E4 allele, particularly, leads to an increased risk compared to the E2 alleles. There are other genes also that are highly relevant and important to Alzheimer’s disease. Another gene is called the apo J gene, which is associated with a protein called cholesterin, and cholesterin indicates protein aggregation. Many of the disorders of the brain, including Alzheimer’s, are really protein aggregation disorders, and we think of proteins as being two dimensional. The reality is that proteins are three dimensional, and when we lose the conformational structure of that protein, like amyloid, this is what produces the pathophysiological changes. So these genes are telling us—they are really providing us—with clues into the underlying steps that are leading to brain loss in these disorders. JB: So we’ve heard a lot about beta amyloid and its connection with Alzheimer’s. We’ve also kind of got an association that it’s connected to the apoE4 allele. We recognize that this amyloid form. We realize that this amyloid forms rope-like structure, as we can see it in hippocampal degeneration under cytology and fluorescence microscopy. Tell us a little bit about this amyloid story, because it sounds to me like this connects molecular genetics to cellular biology to ultimate pathophysiology. JL: Amyloid—especially amyloid precursor protein—is a normal molecule in our brains. What happens is it is processed abnormally. Either we have increased deposition of amyloid, or we have decreased degradation of amyloid, or we have a combination of increased production and decreased degradation of amyloid. The other important pathophysiological protein involved here is something called tau, which is associated with microtubules. Microtubules are the pillars, if you will, of cellular function, regulating things like synaptic efficiency, neurotransmission, transport of intercellular machinery, mitosis, and clearly when microtubule dysfunction occurs as a result of either aging or head injury, which is one of the major causes of microtubule dysfunction, this also produces pathophysiological changes in the brain associated with dementia. So both of these aspects, the amyloid story and the production or abnormal phosphorylation of tau protein, are implicated in dementia. JB: Tell us a little bit about this tau protein. When we talk about these kinase pathways that regulate phosphorylation of tau, that has a branching out into other physiological distortions, such as insulin resistance and insulin sensitivity, which then helps us to understand what we talked about some years ago as it relates to the influence that pre-diabetes and hyperinsulinemia might have to Alzheimer’s. Tell us a little bit how that all connects together. Studying Epothilones: Natural Compounds that Regulate Microtubules JL: Well, I wish I knew. I can tell you, though, that tau dysfunction, or microtubule dysfunction in particular, is not only associated with Alzheimer’s disease, but also has been implicated in other neuropsychiatric disorders, including schizophrenia and autism. And why wouldn’t it? I mean, you’d think something with such a ubiquitous and required cellular functionality, when you disrupt those processes would lead to neurological dysfunction. Really the key things in my mind are: A) How do we identify microtubule dysfunction; and B) What do we do about it once we do identify it? Interestingly—and this relates probably to insulin resistance as well—is that the phosphorylation/dephosphorylation of microtubule-associated proteins is what really essentially regulates the microtubule and determines its activity. This is actually an opportunity for us to understand—because it is a variety or a family of compounds that regulate microtubules—very interestingly, one of the compounds that is found in the soil is called epothilones. Epothilones are a product of bacteria that exist in soil; they are like sort of a probiotic material, that are microtubule stabilizing agents. One of the theories of the increased risk of disorders that we are seeing in the brain is that we’ve moved away from eating farmed foods, which may have high amounts of these soil-based compounds in them that are actually preserving our brain function: these epothilones, which have been looked at in cancer as well. JB: So when we start looking at this as a system of biology–you’re raising all sorts of extraordinary little points on the landscape for us that are interconnected–we start talking about things like the ecology of the human being that sets up the state of function that we later diagnose as Alzheimer’s disease. I know one of the things you’ve written about and talked about has to do with the ecology of our mouth and how that interrelates with the overall immunochemical competency or function of our body that has some aspect of relationship to the brain. Tell us a little bit about that. One Theory of Alzheimer’s Disease: Low Grade Infection and Antimicrobial Peptides JL: This is work that really comes from Rudy Tanzi’s lab at Mass General. We were discussing this a little bit earlier today. His lab identified that antimicrobial peptides, which are endogenous peptides involved in scavenging any kind of immune challenges, whether it is bacterial, viral, or even head injury, there’s activation of these antimicrobial peptides. What is so interesting about antimicrobial peptide, which abbreviated as AMP, is that the conformational structure, the molecular makeup of antimicrobial peptide, very closely resembles amyloid. So the theory is—and, again, this is still a theory but there are lots of leading witnesses that point to this being a significant culprit in Alzheimer’s disease—is that low grade infectious processes, in particular bacterium in the oral cavity, lead to increased expression of antimicrobial peptides. These antimicrobial peptides induce amyloid-like properties in the brain, and this is what’s causing us to have an increased amyloid burden: an immune driven response to low grade infectious processes. This is also supported by the fact that there are higher rates of Porphyromonas gingivalis (P. gingivalis) in dementia patients, and other antibodies indicating an immune response. The implications of this, of course, are quite profound. Because if we truly can establish a link between high levels of persistent “benign” bacteria (chronic low grade inflammatory processes like gingivitis or periodontal disease), this may be a call to action to give people: A) much better vigorous oral hygiene; but B) consider a low dose of antimicrobial agents like doxocycline or something else to reduce the infectious process in people who are at risk of developing dementia as a result of that process.[16] JB: So you spoke earlier about the higher prevalence of Alzheimer’s dementia in people that carry the apo E4 allele. Is there a connection, then, between apo E4 and this antimicrobial peptide story? The Role of the Blood-Brain Barrier in Neurological Diseases JL: Well, one of the areas that Genomind, a company I work for, is interested in is looking at the blood-brain barrier. This is something that is very important not just to the nutraceutical industry, but also to the pharmaceutical industry, for a couple of reasons. One is that many neurological diseases, including stroke, primary hypertensive hemorrhage, multiple sclerosis, autism, schizophrenia, and Alzheimer’s disease are associated in some way with perturbations of the blood-brain barrier. But in Alzheimer’s disease, why is this important? Because these abnormalities in the blood-brain barrier may actually adversely affect the ability to degrade and remove amyloid. So in many ways, Alzheimer’s disease may in fact, in some types of the disorder, be due to a reduced efficiency of efflux of these pathological proteins, as opposed to what we commonly think of as being an abnormality where there is too much influx of bad stuff going into the brain. Perhaps in Alzheimer’s it is the opposite, where there is a reduced sort of kicking out and departing of these abnormal proteins from the blood-brain barrier. JB: So let’s go back and pick up this extraordinary work that you’re doing at Genomind because it seems to couple together so many of the things that we’ve talked about in this landscape: an assessment using biomarkers, genetic susceptibility, factors that then guide us towards individualized personalized preventive strategies, maybe the use of specific types of interventions. Tell us about Genomind. Testing Profiles Being Developed by Genomind JL: Thank you. We are in the process of looking at clinical application both in psychiatry and neurology. Our first test is a test that is primarily used by psychopharmacologists in treatment-resistant depression, in which we know that trial and error is the lay of the land in people who have been exposed to a series of antidepressants without clinical response. We believe that using genetic biomarkers will help to sub-endophenotype (that’s a mouthful of a word, there) different subtypes of depression that will lead to more specific antidepressant interventions as opposed to continuing the trial and error approach. We are currently getting tremendous feedback from our psychopharmacological colleagues who have had the chance to use the test. We have a number of clinical trials right now looking at whether these patients, which are a difficult population of patients to treat to begin with, whether having the Genecept assay, which is part of the Genomind testing profile, is helping to reach a faster antidepressant response than they would have without the use of that tool. The second effort of Genomind is, as we discussed, looking at how biomarkers play into Alzheimer’s disease. Again, preclinical diagnosis is our mantra. We do believe that testing early and testing as many people as possible will ultimately be the way that we can reduce risk by preventing and applying preventative strategies. But we can’t prevent unless we know there is a problem there. So therefore, preclinical testing of Alzheimer’s disease becomes, in my mind, really a public health policy. It’s not just a Genomind policy or philosophy; it’s really a philosophy which I believe the neurological community needs to adopt, and the reason we’ve not adopted it is because we don’t have clear establishment that preventive strategies do in fact reduce the onset of Alzheimer’s disease or prevent progression. Treatment of Nonresponsive Depression JB: Wow. Really important stuff there. So there are three follow-ons that I would like to take from that that we can break out. Number one, let’s talk about treatment of nonresponsive depression. There is some evidence suggesting that at least some forms of treatment resistant depression could respond to an adjunctive use of therapeutic 5-MTHF. Do you have any experience or thoughts about whether that looks, from you experience, to be realistic? JL: Oh, absolutely. I think a lot of the credit for this really is due Mauricio Fava at Mass General, who is the vice chairman of psychiatry at Harvard Medical School. He has been sort of the granddaddy of methylation hypotheses and psychiatry, particularly in depression, for over 20 years. Finally I think that we are seeing the fruits of his insights, particularly in patients who have variance of the folic acid pathway in which they are unable to convert folic acid to the active form of methyl folic acid due to a genetic polymorphism called the MTHFR gene. This particular gene is responsible for activating methyl folate from folic acid. A common allele called the MTHFTT allele is essentially reducing the efficiency of this conversion process. We know patients with this particular allele have higher rates of depression and may be more likely to respond to methyl folic acid. There is lots of good evidence that this actually is indeed true. JB: What doses are generally used, Jay, in those kinds of applications? JL: Pretty high doses, Jeff. The doses in clinical trials are between 7.5 and 15 milligrams, which probably is not the dose that people need who either don’t have this genetic variant or don’t have a syndrome associated with folic acid abnormalities. But it is not only potentially looking at depression, there is also a higher risk of other abnormalities associated with the folic acid pathway, including metabolic syndrome and also including vasculopathies, particularly venous vasculopathies, but also arterial vasculopathies as well. JB: So when we look at 7.5 milligrams, just to make sure we’re all on the same page here, that’s 7500 micrograms to 15,000 micrograms we’re calling it. The RDI is somewhere in the range of 400 micrograms. These are what we call nutritional pharmacological doses, and so the question might be asked: Could you do better by going upstream from 5-methyltetrahydrofolate and use S-adenosylmethionine (SAM-e), which is the principal methylating agent? I recall actually ten years ago or so you and I both spoke at a symposium in Aspen where I think you spoke about SAM. What’s your thought on SAM versus 5-MTHF? JL: Well, I love SAM. In fact, my best friend’s name is Sam. That’s not why I love SAM, though. S-adenosylmethionine is also a very interesting nutraceutical or pharmaceutical, if you will, also involved in methylation pathways. It has unique properties which are different than methyl folic acid. Particularly its activity on an enzyme called catechol-o-methyltransferase, which regulates dopamine metabolism in the brain. SAM-e (I guess we can call it SAM-e, or just SAM? I’m not sure what the proper way of calling it is), but there is very good evidence that as an antidepressant, which is either equally effective or even more effective than may standard antidepressants that are on the market today, and may even have a more rapid onset of antidepressant response.[17] My belief is that SAM-e (or SAM), like methylfolate, has a unique niche in terms of who is more likely to respond to it. Here again is where I think biomarkers become helpful, because perhaps polymorphisms in the catechol-o-methyltransferase pathway may indicate preferential response to this as an antidepressant as well. DSM Disease Diagnosis JB: Let’s move from that to the second of my three takeaways from your previous discussions and talk about the Diagnostic and Statistical Manual of Mental Disorders (DSM) and disease diagnosis. One of the things that you’ve really helped me to understand is when you cohort stratify for various genotypic uniquenesses underneath a specific “DSM Disease Diagnosis,” you may end up with several subvariants, some of which are sensitive and others of which are insensitive to specific interventions, which means our whole medical model of disease as independent, isolated independent kind of paradigm seems somewhat questionable in light of the age of genomics. Tell us a little bit about that. JL: Jeff, what you just said is something that I wish I could duplicate and reproduce for all listeners on my side of the table because that is exactly correct. What Genomind’s philosophy is, particularly as it applies to psychiatry, is that psychiatric disorders, and probably this is true not just for psychiatry but is true for all of medicine, that these are dimensional, not categorical disorders. We need to change the paradigm of how we understand psychiatric disorders in particular. There is not autism as a single disorder. Autism probably represents many different types of disorders. This is true for dementia. It’s true for schizophrenia. It’s true for depression. Until we are able to move away from a categorical diagnosis to a dimensional diagnosis, and what I mean by that is understanding the fundamental pathophysiological processes that are implicated in the manifestation of these disorders, we are going to be unsatisfactory in terms of how we treat them. We’ll be basically putting Band-aids on these disorders, as opposed to addressing them from their principal pathophysiological processes. For example, schizophrenia. My belief is that schizophrenia may be related particularly to the adverse effects of reduced (or lack of) glutathione on D2 receptors. There is very , very compelling work that this is true, and that an inability to properly protect these D2 receptors from oxidation, particularly in vulnerable periods of neurodevelopment, may lead to the structural changes that result in what we call schizophrenia[18],[19]. Schizophrenia is not a neuroleptic deficiency. Right now, in the last 40 years, all we have done is basically provide symptomatic treatment through drugs which block dopamine or modulate dopamine. We’re never addressing the fundamental etiology of the disorder, which in my opinion may be due to a redox imbalance of D2 receptors in the brain. B: Well, that’s kind of fascinating just to speculate (if you take this as speculation). If you look at Abram Hoffer’s work with niacin treatment, or nicotinic acid treatment, of schizophrenia, which we know is not applicable to every schizophrenic , but in certain individuals seems to have a remarkable effectiveness. High dose niacin (pharmacological dose of niacin) has an effect on glutathione biosynthesis by mass action, so one might speculate—at least it would be an operative hypothesis—that nutritional intervention at a pharmacological level in those subtypes could have a very interesting positive effect on regulating this redox potential as you are suggesting. This model opens up all sorts of differing ways of approaching hypotheses, that in the absence of what you are talking about (core stratification, gene interaction with the environment of the individual), you wouldn’t even be able to generate these hypotheses. JL: Or take any kind of actionable steps, so again the biomarker, in my mind, what it does is provide insight into the molecular abnormalities associated with a neuropsychiatric disorder, and therefore gives us a chance to intervene not just on a hypothesis but on sort of an evidence-based platform that we know there is this pathophysiological effect, which we can see either through a gene biomarker or a protein biomarker. JB: You know, it’s extraordinarily interesting, isn’t it, as we see this evolving, how the term “functional medicine” really looks prescient? I think when we chose it over 20 years ago we kind of had a rudimentary feeling that it had a little trajectory into the future, but as we are talking, all of these are really functional disturbances in the individual between how their environment and genes interact to give rise to their expression of function. It seems like it cuts across all these disciplines. Once again, what Genomind is doing is forming a certain mosaic pattern of gene markers that help us to understand the unique way that that person’s environment is influencing their—in this case—psychoneurological function. JL: It seems so obvious now, doesn’t it, Jeff? JB: Yes. It’s amazing. JL: I always laugh at the expression of how the word du jour is “personalized” medicine, something Dr. Bland, the interviewer extraordinaire, has been the godfather for at least 30 years, so it is quite rewarding. What are the Preventive Strategies? JB: Well, as long as we can make some good of it. We’re at that very interesting place in our discussion where there’s going to be a pay off, which I want to come back to and you’ve alluded to it, and that is once you’ve done the Genomind assessment and you’ve gotten some interesting insight into some genetic markers that may relate to the high degrees of susceptibility, now what are the preventive strategies that come out of that? Maybe you can tell us a little bit about what travels from the information? JL: Yes, well I think that has to be on a particular case-by-case basis. That’s a loaded question, by the way. But if you want to ask maybe for particular examples of that, because there’s really a whole library of potentially effective agents which can be used dependent upon one’s personal genotype or phenotype. JB: Let’s take maybe the more obvious example that we’ve alluded to, and that’s apoE4 double hit allele Alzheimer’s relative risk. JL: Right. Well, the short answer is no one knows for sure. The particular hypothesis that we’re looking at Genomind right now is that apoE4 represents, rather than a proinflammatory state, a defective immunological state in which the normal endogenous processes that are responsible for removal of amyloid are impaired. And this normal physiological process relates to something called heat shock proteins. Heat shock proteins are chaperone proteins that the immune system actually induces to carry defective or senescent proteins sort of out of the war zone, taking them back to the recycling plant of the cell and using that material for resynthesis of other proteins. The senescent protein has to recognize it is currently senescent, which is a complicated molecular process, but these heat shock proteins sort of chaperone or identify the defective protein and chaperone it back to the endoplasmic reticulum. These heat shock proteins are up regulated by a variety of nutraceutical compounds; they are many of the things that plants use for resilience against extreme temperatures that are plant-based and possess high levels of these heat shock proteins. One certainly could speculate that this may be a novel intervention for patients with apoE4 subtypes who are at risk of developing dementia. JB: So when we talk about plants that have developed this adaptive response to their environment, transference of that over into humans, where it has an impact in the human, that’s kind of a xenohormesis concept. You start thinking of how plant interconnection/co-evolution with humans relates to these adaptive molecules and anti-stress molecules. Can you give us some of the things in the plant kingdom that are at least interesting from a speculative process as it relates to the regulation of these functions? JL: Sure. I have to think particularly about which of the plant compounds are leading candidates in this regard. A lot of the ginseng-based molecules have effects in up regulating heat shock proteins particularly. Rhodiola, and some other plant-based extracts. But I think this needs to be looked at in a more systematic way in which you start with sort of cell-based cultures to see which of these natural compounds that exist in nature are able to increase heat shock proteins, and then apply those to animal models of Alzheimer’s. The problem, quite frankly, is that these are expensive trials and if the drug companies don’t recognize that these are potentially patentable processes that are worth their while, these will never get from pre-discovery to translational research. That’s my concern: that we’re never really going to be able address this question properly in the absence of adequate funding to demonstrate their potential efficacy in patients with risk of dementia. JB: I know one of your colleagues at NIH, Dr. Mark Mattson, who I know you’re familiar with, has written a series of wonderful articles. He is in the area of Alzheimer’s research and neurology research and has been looking at hormetic phytochemicals and published a whole series of papers. He talks about the role on cellular regulatory functions in the neurological systems of green tea (epigallocatechin gallate), and resveratrol, curcumin, these are compounds that actually seem to be hormetic neuroregulators. Certainly what you are saying seems like it’s getting—at least at the fundamental research levels—some traction now. JL: Yes. JB: Now how we can take that into clinical proof of concept and tie that together with the Genomind portfolio of evaluative biomarker gene tests that open up the dawn of a whole new era it seems in behavioral neurology? JL: One hopes so. Absolutely. JB: So as we bring this discussion to a close, knowing that it could go on for hours (and between the two of us, it has, with hopefully more hours to come), what’s your outlook? How do you look at the landscape? Because there is certainly room for pessimism as it pertains to standard of care, kind of following lock-step into a guild-like mentality. And then there are opportunities for optimism, looking at the opening of new discoveries that really change the whole perspective as to the plasticity of the nervous system and how the environment influences its function. What’s your take on this overall mosaic of the future? JL: Well, first of all, it’s my life mission. This is very important to me personally, again because of my direct experiences with literally thousands of people who have suffered from neurological psychiatric disorders. I take these problems personally. I ruminate over them, much to my wife’s dismay. I’m optimistic because I think that we do now have the tools, we’ve been given the insight through our explosion of genetic information about the biology of schizophrenia, bipolar disease, and Alzheimer’s, and depression. Now the opportunity and the responsibility is ours to take this basic science and to move from basic science discovery to translational genomics and translational research, and certainly functional medicine and the recognition of how we are each individually different and it is now one-size-fits-all in terms of how we address these problems. It’s just a matter of connecting the dots, and I think we are closer now than we have ever been before. There are still lots of battles to fight, but we at least have our gloves on and are in the ring. JB: Well, Dr. Lombard, I want to say, as I have said in our previous interviews, you’re a model on many, many levels. You’re a seeker. You’re courageous. You’re an individual who has taken personal risk in your profession for stepping out and not being in a box of constraint. You’re willing to paint on the whiteboard knowing that sometimes you’re not sure if you put the exact right mark on the board, so you might have to come back and erase it and put a new mark. As I look at your track record over the last 30 years, I’d say you’re a model to the functional aspect of neuronal plasticity, and to creative, innovative, absolute, dedicated patient management. Your dedication to patients both your individual patients and the collective patient (the collective brain and the collective nervous system of our society) is evident in the moment that someone meets you. I want to thank you very much for your courageous dedication and I continue to applaud you as you move forward. We’re all chopping the wood and carrying the water to try to create a better healthcare system, and this, as I said in the opening, is really the gorilla in the corner, this burgeoning problem—this burden—of mental health and neurological difficulties in our society. Thank you very, very much for all of your hard work. JL: It was my pleasure. Thank you for inviting me

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Bibliography

[1] Son TG, Camandola S, Mattson MP. Hormetic dietary phytochemicals. Neuromolecular Med. 2008;10(4):236-246. [2] Mattson MP, Son TG, Camandola S. Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals. Dose Response. 2007;5(3)174-186. [3] Mattson MP. Dietary factors, hormesis and health. Ageing Res Rev. 2008;7(1):43-48. [4] Hoffman M, Hypothesis: hyperhomocysteinemia is an indicator of oxidant stress. Med Hypotheses. 2011;77(6):1088-1093. [5] Pasalic D, Marinkovic N, Feher-Turkovic L. Uric acid as one of the important factors in multifactorial disorders—facts and controversies. Biochem Med (Zagreb). 2012;22(1):63-75. [6] Deshmukh US, Joglekar CV, Lubree HG, et al. Effect of physiological doses of oral vitamin B12 on plasma homocysteine: a randomized, placebo-controlled, double-bland trial in India. Eur J Clin Nutr. 2010;64(5):495-502. [7] Nagele P, Meissner K, Francis A, Fodinger M, Saccone NL. Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification. Pharmacogenet Genomics. 2011;21(7):426-431. [8] Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr. 2005;82(2):442-450. [9] Van Dam F, Van Gool WA. Hyperhomocysteinemia and Alzheimer’s disease: a systematic review. Arch Gerontol Geriatr. 2009;48(3):425-430. [10] Marti-Carvajal AJ, Sola I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2009;4:CD006612. [11] Clarke R, Bennett DA, Parish S, et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med. 2012;9(2):e1001177. [12] Lozovoy MA, Simao AN, Hohmann MS, et al. Inflammatory biomarkers and oxidative stress measurements in patients with systemic lupus erythematosus with or without metabolic syndrome. Lupus. 2011;20(13):1356-1364. [13] Jefferson AL, Massaro JM, Beiser AS, et al. Inflammatory markers and neuropsychological functioning: the Framingham Heart Study. Neuroepidemiology. 2011;37(1):21-30.   [14] The World Health Forum and the Harvard School of Public Health. “The Global Economic Burden of Non-communicable Diseases.” September 2011. http://www3.weforum.org/docs/WEF_   Harvard_HE_GlobalEconomicBurdenNonCommunicableDiseases_2011.pdf (November 15, 2011) [15] Li W, Howard JD, Gottfried JA. Disruption of odour quality coding in piriform cortex mediates olfactory deficits in Alzheimer’s disease. Brain. 2012;133(9):2714-2726   [16] Holmes C, Cunningham C, Zotova E, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73(10):768-774. [17] Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010;167(8):942-948. [18] Steullet P, Lavoie S, Kraftsik R, Guidi R, Gysin R, Cuenod M, Do KQ. A glutathione deficit alters dopamine modulation of L-type calcium channels via D2 and ryanodine receptors in neurons. Free Radic Biol Med. 2008;44(6):1042-1054.   [19] Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M. Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol. 2009;19(2):220-230.

Welcome to Functional Medicine Update, May 2012. Glutathione. Long word. A lot of implications. The most important intracellular antioxidant known in human physiology. An enigma in some respects, because we recognize that glutathione has multiple functions within physiology and therefore, as such, might be considered a pleiotropic molecule, meaning that it participates in multiple functions. We know it as a principal antioxidant, but we also recognize that it is involved in detoxification, to form mercapturic acids that detoxify biotransformed set intermediates that can be excreted in the bile or urine. We also recognize that it can conjugate itself with various substances like arachidonic acid metabolites to form lipoxins and other types of interesting compounds that come as a consequence of the enzyme lipoxygenase. When we start looking at the multiple roles of glutathione in modulating leukotrienes, or modulating the oxidative stress and the redox potential of cells, or participating in detoxification, we recognize that it has a central important role as a cellular agent of cellular direction. It’s a director of function. We also recognize that glutathione is biosynthesized as a consequence of functions within certain cell types where it is needed in high levels, like hepatic cells, by the construction of three amino acids: glutamic acid, and cysteine (itself or containing an amino acid), and the simplest amino acid of all, glycine. This gamma glutamyl cysteinyl glycine becomes a tripeptide that we know as glutathione. We recognize that gamma glutamic acid is not the normal way that the amino acid glutamic acid that is stuck together with other amino acids to make proteins. Normally they are acid amino acid linked, but in this case it is a gamma linkage, which is unique to the glutathione use of glutamic acid in the construction of glutathione as gamma glutamyl cysteinyl glycine.   We recognize that oxidative stress is a fundamental property of aerobic metabolism. All oxygen-breathing organisms, by the nature of their function, oxidize substrates with oxygen into secondary metabolites, ultimately going to carbon dioxide and water in humans. But along the road they may produce free radicals that are oxygen- or nitrogen- or sulfur-containing that could have damaging effects on cellular function. It’s the regulation—it’s keeping what I call the electrons on the wire and preventing them from jumping off the wire and burning the curtains, which we call the cellular membranes and the various materials that make up cells. This burning, or this singeing, or this combustion is known as oxidative stress and is credited with producing free radical pathology. And glutathione, in the centers of oxidative chemistry within cells like the mitochondria, is very, very important for maintaining proper control of these electrons that flow down the wire and don’t jump off onto the curtains and create combustion in the house.   Glutathione is oxidized to its byproduct, glutathione disulfide, and glutathione disulfide is subsequently regenerated into glutathione with the enzyme glutathione reductase, which requires a reduced form of riboflavin, adenine dinucleotide. We recognize that the oxidation of glutathione to its disulfide doesn’t occur just at random but occurs in the presence of a facilitator called glutathione peroxidase, and that is a selenium-containing enzyme. So this shuttle of glutathione’s regulation back and forth between glutathione and its disulfide is a tightly controlled, energy dependent function that keeps the electrons on the wire. It’s a very, very important switching point for the maintenance of what I call the voltage in the battery of our cells, our so-called redox potential. Where our car batteries need to be about twelve volts in order to start our motor more efficiently in the car, so does our electromotive force, or our voltage in cells, have to be maintained properly by the regulation of the redox potential that’s generated out of the mitochondrial oxidative phosphorylation, and that is in part regulated through the personality and the function of glutathione in conjunction with many other cellular components of this redox engine. With that in mind, we start saying: What have we learned about glutathione? It’s to that that we’re going to have this extraordinary discussion with our clinician/researcher of the month this month, who I think has done a fantastic job, Dr. Tim Guilford.  He has really been at the cornerstone of really starting to understand the glutathione story in clinical medicine. So with that in mind, let’s move over to our clinician of the month.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Frederick Timothy (Tim) Guilford, MD 5050 El Camino Real, Suite 110 Los Altos, CA 94022 (650) 964-6700 www.guilfordmd.com www.readisorb.com I had the good fortune, at the recent College for the Advancement of Medicine meeting, to have a personal discussion with a physician/researcher in our field that I think is really doing something very, very interesting that I believe all of you will be interested to find out about, and that’s the work of Dr. Frederick Timothy Guilford. I’m going to say “Tim’; that’s the name that he goes by. Tim did his undergraduate work at Johns Hopkins and then his medical doctor work at the University of Texas Medical Branch at Galveston, a very good institution. One of our previous FMU interviews, Dr. Victor Sierpina, is on the faculty at the University of Texas Galveston and is in charge of the family practice residency program there, so we have a good kinship with that institution. Tim presently is in practice in Los Altos, California and I also have a kinship to Los Altos, having spent a couple of years at the Pauling Institute. I moved down with my family to Los Altos Hills, a beautiful part of the world there in northern California. Tim has been engaged in a variety of different clinical intervention-type programs, particularly focused on things like heavy metal detoxification related to mercury and other heavy metals. But through that work he has also become very, very much the expert in a nutrient, or a conditionally essential nutrient, that we are all very familiar with and one that we can never learn enough about because of its central importance in human physiology, and that is glutathione. Certainly if we were to do a search of the times that I’ve mentioned glutathione over the 30 years of doing Functional Medicine Update the result would be a laundry list of discussions about this very important substance that is, as you know, a shuttle in the electron transport chain in mitochondria. It plays a very important role in a whole series of functions related to redox potential of cells. And it is also a very strong chelator as a consequence of its sulfhydryl moiety that is one of the three amino acids that makes up glutathione, the cysteine residue. With that as an introduction, Tim, welcome to Functional Medicine Update and thanks so much for being with us at a time where the discussion of glutathione couldn’t be, I think, more important. Welcome. FTG: Thank you very much, Jeff. It’s really a pleasure to be here. JB: Tell us a little bit, if you could, about your practice and what led you into this whole area of heavy metal concern, detoxification, and ultimately into this focus on glutathione? Glutathione and Heavy Metals FTG: I’ve had a lot of fun in my clinical practice. I started in practice around 30 years ago, and had the experience of not only practicing as an ear, nose, and throat surgeon, but became the director of an allergy and immunology lab. That introduced me to a wide variety of individuals and medical approaches, and one of them was dealing with chelation, or heavy metal detoxification, and in the mid-90s some of the lab testing came out with improved mercury testing. So I went to the library to find out what made mercury toxic, and the first article that I ran across was an article by a fellow named Stohs, who had written about heavy metals depleting glutathione.[1] This was about 1996. At that time I had only a superficial knowledge about glutathione, and as I started reading about it I realized that it played a critical role in both immune function and also in detoxification, and that led me into glutathione research. I became addicted to reading about glutathione, if you will. There are almost one hundred thousand articles out there with the key word “glutathione” now, so that’s what started me on the path of research in glutathione. JB: I find it really interesting when I look at your resume and talk to your colleagues about what separates certain people that have an intellectual curiosity that move on to where it becomes just a burning part of their pursuit of understanding and other people who may just kind of move on and say, “Well that was an interesting thing for the day but it’s not worthy of my attention at the deep level of pursuit.” In your case, obviously, this has become a very, very important part of your continued pursuit and understanding, and really becoming, I think, arguably one of the most significant experts in this area. In fact, as I recall, you won the Norman Clark award for your work in this mercury detoxification area, and I share that years ago I was a recipient of the Norman Clark Award as well, which I take with great pride. So that illustrates, I think, a very strong leadership. Tell me how, since that 1996-97 period, you’ve kind of pursued this to the level that most people don’t. Because you’ve ended with a technology, with an understanding of some of the difficulties of glutathione as a therapeutic, and maybe how to overcome some of those therapeutic difficulties with different technologies. A Liposomal Delivery System Allows for Oral Ingestion of Glutathione FTG: Early in the days of my research into glutathione we were using, basically, the building blocks of glutathione. You mentioned earlier the three amino acids that form the tripeptide—glutamine, glycine, and cysteine—and at the same time as using the building blocks, especially materials like n-acetyl-l-cysteine, we were also able to give glutathione intravenously for a number of conditions that are associated with low glutathione, and occasionally we’d see very dramatic improvements, especially in older people with Parkinson’s disease and occasionally in children with autism, and it became clear to me that we needed to have some way to get the reduced form of glutathione into the body on a regular basis. About seven—almost eight—years ago now, I was very fortunate to find a manufacturer who understood the delicacy of putting glutathione into a liposome. A liposome both keeps the glutathione stable in the reduced (that is, the active) state, and also allows some improved absorption so that we’re able to get glutathione into the system, for the first time, orally. Having the opportunity to get glutathione into the system clinically began to show some real value, so I started on a path where I was fortunate to be able to develop the product first and then I have been pursuing research to demonstrate its various properties since that time. JB: I think that’s a great segue. Let’s back up and make sure everyone is coming down this road with us together. So you talked about reduced versus oxidized glutathione. Let’s start there. What’s the chemical difference between those two and are they both bioactive, and how do you know what form of glutathione you have, reduced or oxidized? Difference Between Reduced and Oxidized Glutathione FTG: Basically, the difference between reduced and oxidized is the availability of that hydrogen atom on the sulfur (prominent sulfur) that makes up glutathione. The molecule glutathione creates a platform with the cysteine portion containing sulfur sticking up out of it. In its active state it is able to donate the electron and the proton, the sulfur, to various chemical reactions and that’s what allows it to have what’s called a very strong reducing action, meaning it can donate this electron. The platform of glutathione is what makes it unique. It’s very stable inside the cell, where other peptides are degenerated, and it allows it to interact with enzymes such as glutathione peroxidase, and another one called transferase. These are the key components of its antioxidant and detoxifying function. When it is oxidized (that is, it gives off the proton hydrogen and the electron), it has a preference to bind with another glutathione, so the molecules are still available, they’re just not as biologically or biochemically active, and they can be returned to this active state by interaction with other antioxidants like vitamin C, or through an enzyme mechanism through glutathione reductase, which will separate the two oxidized molecules and create the two molecules of reduced glutathione. As far as telling which ones you have, it would require some biochemical testing, for example with our ReadiSorbTM Glutathione we test each batch and we have followed it along chronologically to be sure it is indeed staying in the reduced state. We’ve been very pleased to find that it is very stable. The Two Primary Roles of Glutathione JB: I think, again, you are doing a marvelous job of helping fill in some of the gaps for us. Let’s talk about these two kind of schizophrenic or pleomorphic roles that glutathione has that you mentioned. One is, in its redox capabilities, maintaining redox potential in the cell, which sometimes we call its antioxidant properties, and the other is its detoxifying properties. So the enzyme that you mentioned relative to its detoxifying capability, glutathione s-transferase, that enzyme as I recall is highly polymorphic, meaning it has a lot of genetic variability, and I think there are certain states of that, certain single-nucleotide polymorphisms (SNPs), that make it what’s called the null mutant, that it doesn’t work very well, and therefore those people may be slow detoxifiers relative to the ability to conjugate glutathione with biotransformed intermediates to form these mercapturate byproducts. Is there any way, by increasing the cellular concentration of glutathione, that you can kind of force that sluggish reaction in a person who has a slow glutathione s-transferase activity? FTG: I think you can. I like to refer to glutathione s-transferase as the matchmaker. This means that the matchmaker is introducing glutathione to a toxin. That way it facilitates glutathione sticking to that toxin, which allows it to be excreted out of the cell, through the blood, to the liver, and out through the gastrointestinal tract. That’s the mechanism for removal for a lot of toxins and mercury a prototype of that, for example. As you mentioned, there are several different forms of glutathione s-transferase, and we can refer to this as GST (that’s the usual abbreviation that you’ll see in print). There are several forms of the GSTs, and up to 40 percent of the population can be deficient in the ability to make some of these different forms (scientists call them isoforms). When this happens, glutathione is still able to interact with a large number of the majority of the toxins that it needs to work with, but in my opinion you need an increased number of molecules of glutathione to allow this interaction to occur. Again, back to the matchmaker: you need more encounters to find the right match (to continue that analogy). We have seen individuals with documented GST SNPs in which they don’t make the isoforms as efficiently. Many of them feel better by having an increased number of glutathione molecules available using the oral liposomal glutathione. But those are anecdotal observations at this point, but it has been very gratifying to be able to help many of these people. JB: So let’s now look at the other side of the equation, which is the antioxidant or redox capability of glutathione. So you talked about glutathione reductase and glutathione peroxidase being enzymes involved with that shuttle. Are there situations where there has been a compromise in glutathione status, knowing that it is the principally most important intercellular antioxidant, and I think, as I recall, the ratio of the reduced-to-the-oxidized glutathione in healthy cells is something like 100-to-1 (100 of the reduced to one of the oxidized), so if you start getting a shift in redox and you get less of the reduced and more of the oxidized that means the kind of voltage of the battery of your cell is running down. Can you improve that, then? Just as we talked about detoxification improvement with glutathione addition can you improve the redox potential of a cell with glutathione addition or support? FTG: I think you can. It’s a little more difficult to demonstrate the electrical side of that, but we have a published study showing that cells exposed to materials like maneb and paraquat, which cause oxidation stress inside cells—these are materials that have been used as pesticides in the past; happily they’re not being used as much now, but there is still some usage. Neuro-researchers, for example, use this to cause oxidation stress inside of cells. We have an article showing that the oxidation stress can be limited and diminished significantly by adding the liposomal glutathione.[2] And I should also point out that the use of any antioxidants in general, ranging from vitamin C and vitamin E, and including N-acetylcysteine, which help build the tripeptide glutathione and these other materials, the antioxidants help maintain the reduced state, these are all critical components of maintaining reduced glutathione in the cell. We have some information coming out from our research that shows that there are certain situations where it is difficult for cells to make the tripeptide glutathione, and in these cases there is some advantage to adding the intact molecule of reduced glutathione to the cell in the liposomal glutathione. JB: So let me, if I can, now ask the question which is probably on the minds of many of our listeners, and that is: “Okay, well you’ve certainly done a good job with your explanation in demonstrating why conditionally essential glutathione might be beneficial to supplement. Why can’t we just give glutathione itself? What’s the problem with just administering high doses, orally, of glutathione?” FTG: It turns out that most of our cells have an enzyme on the outside of the cell called gamma glutamyl transferase. You have to remember that most of these enzymes and biochemical molecules were named when they were found and their full usage became apparent later. The glutamyl transferase, often abbreviated GGT, and incidentally is available on your routine chemistry panel now, plays a role in breaking down glutathione. It sits on the outside of every cell, and particularly in the gastrointestinal tract of humans, and it breaks down glutathione into these three amino acid component parts. Then the cell can take up the materials and reassemble them inside the cell, which sounds useful, but it turns out to be not very practical, and doesn’t really replenish the levels of glutathione as efficiently as we would like. You have to remember that reassembling these molecules, especially in a stressed cell, requires energy and various interactions like that can become compromised in a very stressed cell. The enzymes need to work very efficiently. There are two enzymes that piece these three amino acids together, and if you don’t have the right amount of energy, and the right amount of the enzymes, you don’t get the glutathione reduced as efficiently. So, that’s the major problem with taking plain, non-formulated (as we sometimes refer to it) glutathione orally. JB: So let’s, Tim, go from there, then, to talk about what I consider a very remarkable and laudatory step that you’ve taken. You know, most clinicians who have the level of inquiry that you have, which is, in itself, quite remarkable, get to this point of understanding and then might put up their hands and say, “Well, I just don’t know how to solve the problem. There’s a block here, but I’m not sure what the solution is.” But somehow you took it to the next level. You worked on this formulation, and you’ve actually been involved now, as you mentioned, in work that has ultimately led to publication. This recent paper in Neurochemical Research that has your name and your co-colleagues on it from the department of neurology at the Robert Johnson Medical School in New Jersey is an illustration of going to the next level. Tell me how you did that, why you did it, and what the outcome was, because I think this paper titled “Liposomal Glutathione Provides Maintenance of Intracellular Glutathione and Neuroprotection in Mesencephalic Neuronal Cells” is a very interesting advance from hypothesis to proof. FTG: Well, thank you very much. I appreciate it. At first I was just slow in terms of understanding biochemistry, meaning I had to read it a lot to hold the information. As an aside, I went through various detoxification procedures myself to lessen the mercury load in my brain, and I think it allowed me to understand this a little better, perhaps from the practical side. I became really interested in the mechanism, and there were so many interactions it became fun for me. It was a bit like relearning medicine, being able to follow the roles that glutathione plays. I spent six months in a lab over at Stanford that’s known for its work in glutathione, the Herzenberg Lab, and then I began pursuing some more research, and the paper you mentioned by Gail Zeevalk in regard to the intercellular glutathione and neuroprotection was started by a chance interaction after I read Dr. Zeevalk’s 2008 paper, in which she was writing about Parkinson’s disease. The title of her paper was “In the Discussion of Parkinson’s Disease, Is Glutathione the Elephant in the Room?”[3] Meaning, it is really difficult to talk about Parkinson’s without talking about the fact that glutathione is depleted in the specific brain cells, the substantia nigra cells, which are responsible for the production of a continuous supply of dopamine to maintain movement. Dr. Zeevalk had set up a cell culture model in which she was able to demonstrate that cells depleted of glutathione, using a binder material that would remove glutathione, could be repleted with plain glutathione at a about a concentration of 500 micromolar (if you put 500 micromoles in the cell culture you could replete these cells efficiently). They call that “to the effective concentration.” I sent her emails and eventually we had a phone conversation and she said, “If you think your product works send it out and we’ll test it in the cell culture model.” It turns out that where plain glutathione took 500 micromolar, it took only 5 micromolar of the liposomal glutathione to replenish these cells. Dr. Zeevalk went on to do a series of studies demonstrating that the glutathione is contained in the liposomes, doesn’t leak in the cell culture, and the whole liposome molecule is absorbed right into these brain cells. Incidentally, the mesencephalic cells are made up of astrocytes and neurons, and it is primarily the astrocytes that are engulfing the liposomal glutathione. That also points out the roles of neurons, as Jeff knows, are very specialized in their function and they actually are fed glutathione from the astrocytes in the anatomic situation, so being able to get glutathione into the astrocytes in an efficient fashion using the liposomal glutathione may have some real advantages. JB: Tim, you’ve really opened up a very interesting journey with us that I’d like to follow up on, so let me go back, if I can, to pick up your first discussion about paraquat as a chemical that can stress cells and deplete glutathione. I’m reminded of my own experience in 1982 when I was at the Pauling Institute. That was a time when there had been reports that individuals in the San Francisco bay area who had been using a certain form of marijuana were coming down with a high frequency of Parkinson’s symptoms, and then they ultimately traced this back, as I recall, to the fact that the source of the botanic marijuana were fields that had been sprayed with paraquat and that they were actually being exposed to this substance that was inducing in them, through the administration of marijuana, this Parkinsonian syndrome, and they ultimately used that actually as a way of assessing this oxidative stress component of the disease. It is interesting how things run kind of full circle, because then we segue fast-forward to Dr. David Perlmutter, who we both know as a colleague in our field and who has been a Functional Medicine Update interviewee a couple of times over the last 30 years, and his observations in clinical practice as a neurologist by intravenous administration of glutathione, the remarkable improvement in symptoms he’s had in patients. Unfortunately it doesn’t seem to last; it has a short-term duration. But it certainly does open up, as you said, the question as to what role does glutathione play at a supraphysiological level in individuals that have undergone maybe significant oxidative injury at the nigra striatum and who have high oxidative stress and depleted redox. Then you come back to this wonderful work you’ve done in culture with Dr. Zeevalk and demonstrate actually in a cell model that you can, by increasing in the medium the appropriate absorbable form of glutathione, that you can actually produce outcome in the cells that are reflective of what we see physiologically in the whole animal and maybe even coupling it back to the 1980s observation of the use of this paraquat-tainted marijuana and Parkinson’s. It sounds to me like there is a very fascinating clinical story here that probably moves on, then, into your interest in other neurodegenerative conditions like, say, autism, and probably a variety of other toxic situations that lead to the depletion of glutathione. Am I making sense here at all with the way I’m describing the story? FTG: It does to me. What has been most interesting to me is how exciting it is to explore these various pathways and various applications. A friend of mine, Professor Ben Lucchesi at the University of Michigan, has mentioned the fact that when you are exploring these pharmacologic and biochemical interactions it’s a lot like puzzle solving and being able to see the solutions for some of these problems has been the real motivator for me. One other note on the paraquat plus maneb, it turns out that these SNPs that you were mentioning earlier in regard to the GSTs can also be at play in regard to some of these pesticide problems because maneb, for example, is broken down by certain hydrolases, which there can be varying levels of their representation in people, and if you don’t have as much of these enzymes available you may be at greater risk, but then you need that heavy environmental exposure to increase the chance of problems like Parkinson’s developing. It points out the interaction between environmental exposures and the individual’s ability to detoxify that may play a role in a number of conditions, and you mentioned autism. The exploration of that problem was a real stimulator for me. A researcher named Jill James published a paper in 2004 which described for the first time the fact that children with autism are poor methylators, meaning they don’t methylate or stick a carbon onto the important biochemical involved in a cycle called the methionine cycle.[4] That’s the one that takes methionine around in a circle, creating homocysteine, and returns the homocysteine back to methionine. That cycle is important for glutathione research as that cycle will produce the cysteine that’s the rate-limiting factor in the production of glutathione. I should mention that those two enzymes that are involved in the production of glutathione. When you have cysteine, there is one called glutamyl cysteine ligase, which will combine cysteine and glutamine, so you have two portions. And then the next one, glutathione synthase, will stick the third amino acid on there to create the tripeptide. It turns out there are certain conditions and situations, especially heavy oxidation stress, which can compromise these enzymes as well as the transcription factors controlling these enzymes. So all of a sudden this world of information is kind of blooming up on the horizon that is going to help better explain why certain children with autism and certain individuals who develop Parkinson’s are more at risk than others. JB: I think that was brilliantly summarized. That’s a very complicated area, but you’ve done a marvelous job of summarizing it. In fact, we did interview, for Functional Medicine Update, Dr. Jill James in the wake of her publication. Her continued work in this area is, I think, really kind of pioneering. It seems to me, once again, as I introduce the topic of glutathione that there is a thousand points of contact of this very important intermediary, and the concept that it could be a conditionally essential substance or nutrient in some cases is a very, I think, powerful concept. What is a Liposome? Let’s now go to the story of the liposomal delivery system. The term “liposome” for some may be not such a familiar term, so I would like you to describe what a liposome is. And secondly, there might be a variety of different kinds of liposomes that have different characteristics and so why is the liposome that you have pioneered the superior delivery form? Why this specific one? Those are my two questions. FTG: As I said earlier, I was fortunate to find a manufacturer that has experience in encapsulating materials in a liposome. You can think of a liposome as a small fatty bubble. The ones we use are, on average, around half the size of a human hair (500 nanometers). The process that is used actually in this case uses a very unique liposome and process that allows it to encapsulate the water soluble glutathione inside, usually in a single layer, but sometimes multiple layers of these very thin layers of liposome, and it creates this little fatty bubble. The big advantage was the fact that you could take these liposomes orally. We’ve known for a long time that the glutathione itself was not utilized if taken orally as efficiently as we’d like. There was an assumption—and I think a correct assumption—that most of the liposomes you take orally are not well absorbed. It is clear from our research we’ve documented in other studies absorption and tissue function in animal studies, and incidentally we have some ongoing research in that area that demonstrates increases in both heart and brain tissue, for example, but being able to take orally the liposome and demonstrate an action in distant tissue has been the real advantage with this material. And it begins to open up investigation into a range of conditions that are associated with low glutathione. JB: When I look at this really interesting paper that was recently published in 2012 (January) it talks about the difference between a liposomal (your ReadiSorb Glutathione delivery) and a kind of normal glutathione preparation, and shows, using a cobalt isotope assay in the rodent, superior intracellular incorporation.[5] Is this the kind of assay system that can be useful, from your experience, in actually evaluating how these comparative delivery systems might work in humans? FTG: I think it would be very useful. I guess the disadvantage of doing it in humans would be getting them to take the radioactive material. In the rats, they were given an intravenous infusion with radioactive cobalt. Cobalt is known to be bound by glutathione. In this particular study that was done by Dr. Levitskaia at the Pacific Northwest National Lab, where they specialize in radiation and radiation remediation techniques, they showed that the oral ReadiSorb liposomal glutathione has about 75 percent of the function of the intravenous-administered glutathione, while the plain glutathione which we were discussing earlier (the difficulties in getting plain glutathione to be absorbed), the plain glutathione in the rat had minimal function in terms of removing the radiotag cobalt from the liver of these animals. So we were very gratified to see that the orally administered liposomal glutathione can be absorbed and have a similar function to IV glutathione. Of course the advantage in that situation is that you can take the glutathione daily or several times a day depending on the situation that you’re dealing with. That, again, is both illustrating the utility of the material, and then as you have pointed out, opening up a variety of lines of research that are really quite exciting in terms of solving these different puzzles. JB: Let’s close with probably what a lot of people at this point are asking and that is: “Okay, we’ve talked through the importance of glutathione, we’ve talked about comparative delivery systems, we’ve talked about the advantage of this particular liposomal delivery system that seems to promote cellular uptake, so now what is your experience, or anecdote, or experimental experience with the human administration with this liposomal system? What doses are effective and what kind of things have you seen as it relates to its application?” Anecdotal Results of Clinical Use of Liposomal Glutathione FTG: Well, I’d like to remind everybody that we don’t make any claims for treatment. This is a dietary supplement, and by the same token we have demonstrated that it has an ability to support and maintain glutathione, so it can be used in a wide range of conditions that have low glutathione associated with them. We have a generic website that we maintain that has just descriptions and some research information on these various conditions. My practical experience in the clinic, for example in some individuals with Parkinson’s, has been gratifying. If we have a couple of minutes I will tell you a very interesting anecdote about two children with cystic fibrosis. Early in the development of this product these two parents contacted me about their children who were then 18 months and two-and-a-half years. Both of them had documented gene defects causing cystic fibrosis, which means that their cells in the lung and in the GI tract are not able to move glutathione, in the lung, for example, to the extracellular lung fluid layer, which is important for the macrophages in the lung to take up glutathione. So they have a block in the ability to use glutathione across tissues. This gave me one of the first real clues that this product had a real potential because both the children improved, one in the lung function (this child had the typical thick mucus that is seen with CF) and improved over a month’s period of time, and this child has remained stable. She unfortunately needs to take the liposomal glutathione on a regular basis (meaning daily), but this has been keeping her lungs clear for over seven years now. And the other child had GI tract presentation, and her growth pattern returned to normal and has continued. So that was a real stimulating factor for me. But as far as observation in the clinic, recently I have seen a few individuals with Parkinson’s disease that have responded very nicely. Incidentally, there is some very interesting research showing that you can monitor homocysteine levels in people with Parkinson’s disease. What we use in adults for dosing is I always suggest people start low and go slow. My target for support is usually one teaspoon twice a day for the initial phases of support, but I always start low and if they have any kind of chronic condition I may use a serving as low as one quarter teaspoon for a few days and then move up to twice a day, with a progression up to one teaspoon twice a day. There are numerous reasons for this, but if you think of restarting the system, it’s kind of like an old car that has been sitting aside for a while. If you go in and turn the key, if the engine starts it may push out a lot of junk, if you will. The same thing can happen as you restore glutathione to a system. You can start pulling toxins from one area and perhaps the liver still needs some time to catch up to all this, so by starting low and going slow you can allow all of these systems to come online simultaneously. With children we use lower dosing, usually about a quarter of a teaspoon (100 milligrams) for every 30 lbs., once or twice a day, again starting with a little lower dose initially and moving up slowly. We’ve had many gratifying anecdotal observations. JB: Well, Tim, I really want to applaud you. I think there are several takeaways for me in listening to you. I was very impressed when I had the chance to meet you, and even more impressed in having the chance to have this conversation. First of all, I’m very impressed with the scholarship that you take into your observations and in your practice. Obviously your patients benefit greatly from that level of intellectual inquiry and the way you commit yourself. Secondly, I think the pursuit of this interesting path over the last—I guess it would be since ’96 to 2012, now—of your own intellectual inquiry into this field of glutathione and how that translates into improved patient management is just really remarkable. And then, of course, lastly to actually translate that into a technology and proof of concept with your research that you have collaborated on with these investigators is quite unique in our field. I really want to applaud that. I think if we had more of our field taking this level of commitment of their interest into innovation and discovery we would move this whole field ahead much more rapidly. Thank you, and by the way, what you have shared with us clearly has some significant potential clinical benefit in these multitude of conditions that are associated with altered redox and altered detoxification. My very best of thanks to you, and my strong admiration for what you’ve accomplished. FTG: Jeff, you’ve been an inspiration for me in my research over the years and I really appreciate being able to interact with you and your comments are appreciated a great deal. Thank you. JB: Thank you, and I wish you the best in 2012 and I’m sure we’ll all be checking in as this field moves forward because this is kind of at the cutting edge, I think, of where chronic-related illnesses lie: this inflammation/oxidative stress/toxicity connection. You’ve given us another point of light into the understanding of it and what to do about it. Thanks a million.  

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Bibliography

[1]Bagchi D, Bagchi M, Hassoun EA, Stohs SJ. Cadmium-induced excretion of urinary lipid metabolites, DNA damage, glutathione depletion, and hepatic lipid peroxidation in Sprague-Dawley rats. Biol Trace Elem Res. 1996;52(2):143-154.   [2] Zeevalk GD, Bernard LP, Guilford FT. Liposomal-glutathione provides maintenance of intracellular glutathione and neuroprotection in mesencephalic neuronal cells. Neurochem Res. 2010;35(10):1575-1587.   [3] Zeevalk GD, Razmpour R, Bernard LP. Glutathione and Parkinson’s disease: is this the elephant in the room? Biomed Pharmacother. 2008;62(4):236-249. [4] James SJ, Cutler P, Melnyk S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80(6):1611-1617. [5] Levitskaia TG, Morris JE, Creim JA, et al. Aminothiol receptors for decorporation of intravenously administered 60Co in the rat. Health Phys. 2010;98(1):53-60. [6] Lim JS, Lee DH, Park JY, Jin SH, Jacobs DR Jr. A strong interaction between serum gamma-glutamyltransferase and obesity on the risk of prevalent type 2 diabetes: results from the Third National Health and Nutrition Examination Survey. Clin Chem. 2007;53(6):1092-1098. [7] Unproven methods of cancer management. Livingston-Wheeler therapy. CA Cancer J Clin. 1991;41(3):A7-12. [8] Guri AJ, Evans NP, Hontecillas R, Bassaganya-Riera J. T cell PPARγ is required for the anti-inflammatory efficacy of abscisic acid against experimental IBD. J Nutr Biochem. 2011;22(9):812-819. [9] Bassaganya-Riera J, Guri AJ, Lu P, et al. Abscisic acid regulates inflammation via ligand-binding domain-independent activation of peroxisome proliferator-activated receptor gamma. J Biol Chem. 2011;286(4):2504-2516. [10] Guri AJ, Hontecillas R, Bassaganya-Riera J. Abscisic acid synergizes with rosiglitazone to improve glucose tolerance and down-modulate macrophage accumulation in adipose tissue: possible action of the cAMP/PKA/PPAR γ axis. Clin Nutr. 2010;29(5):646-653.   [11] Corkey BE. Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes. 2012;61(1):4-13.

Well here we are. I consider this a watershed moment in the history of Functional Medicine Update. I don’t want to make this overly dramatic, but I have to say that a 30th anniversary—three decades of production of this educational series—to me is a pretty interesting accomplishment. This is the 30th anniversary of Functional Medicine Update.  I’ve had the privilege of interviewing, over that 30 years, some of the most remarkable opinion-leading, kind of innovative thinking, new-medicine-creating individuals. And of course, we must then have selected a notable example of all of those extraordinary people for our 30th anniversary edition, and we did. Ten years ago we were very pleased to have an interview with Dr. Mark Houston. Mark set a standard of excellence during that discussion of an explanation of something that is very complicated, vascular biology and how it applies to medicine Dr. Houston has agreed to come back after this 10-year period to once again rejoin us as our as our clinician/researcher of the month 30th anniversary edition

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Mark Houston, MD, MS Director Medical Director of Clinical Research Section Chief of Nutrition Division Hypertension Institute St. Thomas Medical Group 4230 Harding Road, Suite 400 Nashville, TN 37205 www.hypertensioninstitute.com June 2012 In case you are not familiar with Dr. Houston, which I would find hard to believe if you are in this field—Dr. Houston is a graduate of Vanderbilt University Medical School. He’s the president of the Hypertension Institute in Nashville, Tennessee. He’s a practicing specialist in the area of vascular biology and cardiovascular/cardiometabolic medicine. He is very, very noteworthy. He has been voted by USA Today as one of the most influential doctors in the United States, selected as a top physician in both hypertension and hyperlipidemia in both 2008 and 2009. He was included the Consumer Research Council of America’s list of America’s top physicians in 2008 through 2011. I think that probably gives you the landscape of the notoriety of Dr. Houston, who is not only a clinician’s clinician, but a life-long learner, a teacher, and educator, a researcher, and truly a leader in our field. So with that, Dr. Houston, wonderful to have you once again here on our 30th anniversary, and also the 10th anniversary since we last had a chance to speak with you on Functional Medicine Update. MH: Jeff, it’s an absolute honor and delight to be with you and celebrate your 30 years. Congratulations on an incredible achievement. JB: Well, thank you. We were both at the Institute for Functional Medicine meeting, which was the most successful meeting in the history of the Institute for Functional Medicine, with over 900 attendees at the meeting. You were a central bright light at that meeting, which was on functional medicine approaches to cardiometabolic disorders. I think there are a couple of things that we’re going to talk about, one of which is your view of vascular biology related to hypertension and what it is teaching us about ways to manage this complex condition that is seen so frequently in our population in the western world, and secondly talk about hyperlipidemia’s risk factors and some of the emerging new ways of looking at extended biomarkers. But as we do that, I know both of us are very fast talkers and fast thinkers, so for our listeners there may be times that they say, “Whoa, this is going pretty fast. I’m going to have to listen to this several times,” so I want to give a reference to your website because it is very rich and robust site of information that people can come to later, and that’s www.hypertensioninstitute.com, and we’ll clearly be putting that on our information for the listeners. Also, I’ve had a chance to read your most recent book, What Your Doctor May Not Tell You About Heart Disease, which is just a fact-filled, news-to-to-use information guide that I would highly recommend as another source to follow up from this conversation.[1] We’ll talk about those here, I’m sure, during the course of our interview, but I just wanted to make sure for people who think we’re moving awfully quickly and they’re not keeping up that there are these extraordinary sites and resources they can come back to. So with that, Mark, let’s move into the discussion. First of all, you have a very interesting academic background, not only in medicine, but also having graduated summa cum laude in chemistry and then later going on and getting your MS in human nutrition. Tell us a little bit about what led you into this journey and how it prepared you for the 21st century medicine. MH: Jeff, as you pointed out, I was trained traditionally as an MD and in 1992 my father developed prostate cancer, and I went into the functional medicine literature trying to help him become healthier beyond the traditional treatments he was getting. So I learned about oncology and cancer in functional medicine initially, which was totally out of my field of expertise. We got him really back on track and he lived for another 5 or 6 years despite very bad prognostic signs, and I attribute a lot of that to the lifestyle changes we made in a functional medicine approach, so I realized if it is available in oncology it is available in cardiovascular disease. So about 1995 I really started looking into functional medicine, nutritional medicine, and totally changed my practice. Of course, as you know, when you are out there in an academic setting as an MD, there are a lot tomatoes coming out of the audience, and darts on your board and in your back, so you have to become credible in your field, so I decided, “I’m going to go back and get a nutrition degree,” which I did from the University of Bridgeport. That really was the impetus, along with being at IFM in 2000 with you and other tremendous speakers during that setting, “The Heart on Fire,” to really catapult me into a totally different way of practice, which is what I do now, which is really an integrative cardiovascular medicine practice. JB: You know, in those 12 years since you were a keynote speaker at the IFM Symposium, many of the things that you discussed back then have now become kind of like the “new news.” It is very fascinating to me how certain people can forecast and see the future and then they become reality to everyone else. Tell us a little bit, if you would, about what you think some of the major shifting understandings of vascular biology are and how they are getting integrated into medicine. Inflammation, Oxidative Stress, Autoimmune Dysfunction : The Three Finite Responses MH: Jeff, I really believe if you have a great understanding of vascular biology you can apply the concepts to every other biological system. The body is very smart, and it replicates the way it responds to injury in other systems in the same way that the blood vessel responds. One of the mantras that I continue to say—you’ve heard me say this over and over again, and you’ve been saying this for years as well—is that the blood vessel really has only three finite responses to an infinite number of insults: inflammation, oxidative stress, and autoimmune responses. So if you throw the millions of insults that we’re faced with every day on top of our genetics and our epigenetics, and you look at a systems biology approach to the person, vascular biology becomes the root of really understanding of how to apply those concepts to neurodegenerative disease, to gut health, and to anything else within the functional medicine matrix that you want to look at. We’re doing a sort of different approach now. We take the finite responses and look at those to do markers, and then backtrack and say, “Okay, we’re inflamed. Why are we inflamed? Let’s go back and find those insults that caused the inflammation.” As opposed to going the other way, which is what we’ve been doing for years in traditional medicine. JB: To me, that’s very interesting from a historical perspective, going back to, Rudolf Virchow back in the 19th century, who is arguably considered the father of modern pathology, and who had a pretty interesting debate going about the etiology of what we call cardiovascular disease today. He was talking about the injury theory, and about the fact that the atheroma looks like a wound. Although he was clearly a genius and made so many contributions to the pathology, his views weren’t widely held. And then, of course, at the turn of the 20th century, the Anichkov concept of the lipid hypothesis kind of overrode the Virchow injury model. But it looks like we’re coming back to revisit this injury/insult model related to vascular biology and pathogenesis of atherosclerosis, and it seems to tie so closely to that marker tissue or marker cell type called the vascular endothelium, which was neglected for so long as just this one-cell-thick lining of the vessels. Maybe you can tell us a little bit about how you see that emerging understanding applying to both the origin of and treatment of vascular disease. Endothelial Dysfunction (ED) as a Marker for Predicting Vascular Problems MH: I think one of the major breakthroughs, Jeff, in cardiovascular medicine is this: When the blood vessel responds to one of these insults or one of these injuries, it is doing what it is supposed to do. It is an acute response that is the correct response. It is basically applying a defense mechanism against an invader. Now, when we do that acutely everything is fine. You take care of the problem, whether it is a microbe, or it’s a toxin, or it has oxidized the LDL cholesterol, or whatever. But when you continue to respond to that insult you continuing to insult the endothelium, and then it becomes what I call the innocent bystander of a chronic, dysregulated response, and it’s the same three responses: inflammation, oxidative stress, and immune dysfunction. Over time, the body’s normal response to injury becomes actually a dysfunctional problem, and later, as we progress, becomes a disease and we can put a name on it. But in that intervening period, which can be decades before we can actually define the disease, you will have endothelial dysfunction (ED), which becomes the best marker for predicting stroke, heart attack, coronary heart disease, congestive heart failure, renal disease, and a lot of other vascular problems. So the new movement in cardiovascular medicine is to be able to identify the insults, to identify ED with non-invasive basic testing, and start prevention and aggressive treatment before the patient develops a known disease related to cardiovascular illness. JB: That’s extraordinarily powerful information. I hope everyone who is listening got the “a-ha” there. That, to me, is really setting a tone for a whole different view of both the etiology end and the potential prevention and treatment of vascular disease. Let’s move to a level of kind of clinical granularity here for a second, and that is: How do you measure vascular endothelial function? Are there ways that one can do that in the clinic? EndoPAT: A Non-Invasive Test to Identify Endothelial Dysfunction MH: Absolutely, and this brings up the second concept which I really want to talk about, and that is what I call the vascular risk factor disconnect. What I mean by that is you may have 400 risk factors out there, but not everyone responds the same way for obvious reasons (genetics, epigenetics, and so forth). But just because you have a risk factor doesn’t necessarily mean you get vascular disease or ED. And the reverse is true: Just because you don’t identify a risk factor doesn’t mean you won’t get ED. So the vascular insult hypothesis has to be what’s called vascular translational medicine. What we are doing now is we look at people and we do these wonderful scores—Framingham score, INDANA score (INdividual Data ANalysis of Antihypertensive Intervention Trials), PROCAM Score (Munster Heart Study)—and we give them to people: “Okay, your score is 15. That puts you at a moderate risk for coronary heart disease.” The problem is that’s a number that doesn’t necessarily translate into a functional or a structural problem in the blood vessel. So what we’re doing now at the Institute, which is I think is where cardiovascular medicine is moving, is we now have non-invasive tests which actually will identify ED very early. One of the best ones is called EndoPAT. It’s a commercially available product. It takes a probe on your finger, a blood pressure cuff, and in about 15 minutes you have one of the most accurate assessments of ED presently available. There are other tests out there, but this one, in my feeling, is probably the single best one right now, and the correlations with outcomes for CV disease are better than anything we have. They trump any sort of risk scoring we have available, and actually trump looking at risk factors by themselves. So this is the key to translational vascular medicine, I think. JB: I’m really excited to hear of your support of EndoPAT. We, in our research setting in Gig Harbor, have been working with EndoPAT over the last eight months now, in several hundred patients that have come through the clinic. Our clinical view of the procedure (it’s non-invasive) is very similar to what you’re saying and we’re very excited about it. It seems to be a very sensitive indicator because you can demonstrate in a month or so positive changes in the EndoPAT valuation, so it’s a way of not only assessing but also a way of following the response to therapy. Has that been your experience? MH: It is, Jeff, and the other thing that is really interesting–and I didn’t realize this until I started doing it—we’ve done probably about 1500 EndoPATs in the last couple of years, so our data is very good now, and there’s a couple of things I want to say that will help, I think, our audience understand how valuable this tool is. First of all, when you do the EndoPAT in someone who looks like they are very healthy and they have no risk factors but their EndoPAT shows that it’s abnormal, what it does is it takes you to a whole different direction of looking at tests, and diagnoses, and treatment: What am I missing, here? Something’s not right. So you are going to go and do a better search for a missing risk factor, or a missing mediator. I can’t tell you how many times I’ve found something just because the ED was abnormal on the test despite the fact that the risk factors were totally normal. And then at the other end of the spectrum is someone who comes in, they are about a year out from a coronary bypass graft, they have horrible vascular disease, but you’ve done everything in your power to improve their endothelial function with nutrients, lifestyle changes, weight loss, medications, etc., and guess what? Their EndoPAT is normal. Now, what that says to me is that even though you have bad vascular disease you can stabilize it and even reverse it if you know what you’re doing and have the appropriate test to monitor and track it. JB: You said something just in passing there that I wanted to pick up on as a sidebar. You used the term, or the abbreviation for, endothelial dysfunction (ED). That also obviously is an abbreviation that is used in the parlance in the common language for erectile dysfunction, and there is some data suggesting that ED correlates with erectile dysfunction. Have you clinically observed any of those things in your practice? MH: That’s absolutely correct, Jeff: ED equals ED. One of the key questions to male patients when they come in your office is you ask him about erectile dysfunction, and if they have it, you’re almost guaranteed they are going have endothelial dysfunction as well. JB: I think that’s a very interesting part of your systems biology discussion, that things are connected together in these networks and these webs. I don’t want to bear too much on the erectile dysfunction connection, but I think mechanistically if we think about how sildenafil (Viagra) works, it works by modulating cyclic GMP activity and how that relates, then, to the release of various mediators or molecules that regulate vascular tone, and one that comes up in mind as it relates to endothelial function in general is nitric oxide and endothelial nitric oxide synthase (eNOS). There must be a connection here somewhere. Can you help us understand that? Nitric Oxide is the Key to Understanding Endothelial Dysfunction and Vascular Health MH: Absolutely. As you know, the nitric oxide story was one of the reasons for winning the Nobel Prize. Nitric oxide (NO) is really the key to understanding endothelial function and vascular health. It has numerous functions. It’s not just a vasodilator, but it’s an anti-inflammatory, an anti-atherosclerotic, it reduces cell adhesion molecules, it reduces growth hypertrophy, oxidative stress, and even autoimmune dysfunction. So if you have a normal nitric oxide level (or bioavailability, I should say—that’s a much better term), if your NO bioavailability is good then that’s a good signal that you’re going to have good endothelial function. There are so many things that decrease nitric oxide in your system. A lot of these insults we talked about have direct effects on reducing nitric oxide bioavailability. And there are indirect ways of measuring nitric oxide. There is not any great way to measure it directly, but one of the things we use clinically is asymmetric dimethylarginine (or ADMA). If that is high it is considered an inhibitor for eNOS, which is the enzyme that forms nitric oxide, so that’s a great way to get a handle on whether someone might have low NO bioavailability in a study of ED. JB: I think, again, there are so many levels in this discussion that we could take it, but let me just go one level more down. We won’t go too far down, here, to lose everybody. This ADMA story is also a very interesting story because it has something obviously to do with methylation. The ADMA is an arginine that has been methylated and it is part of the catabolism of protein in arginine-containing proteins. As it builds up as a consequence of, say, insulin resistance, which then inhibits the enzyme that is used to clear or detoxify ADMA, then what happens is you start, as you said, interfering with eNOS activity and vascular compliance. So here is another example, I think, of the web, where insulin resistance/hyperinsulinemia is tied to a metabolic distortion which then has a downstream effect on vascular endothelial function. Am I saying this correctly? MH: Absolutely, you’re right on track. There are so many co-factors in the activity of the eNOS enzyme that have tremendous therapeutic effects that we can do clinically to up regulate the eNOS enzyme and therefore increase the conversion of arginine to nitric oxide and citrulline. JB: So I know one of those interesting co-factors is tetrahydrobiopterin, which has a precursor—it has a number of precursors, but one of those precursors is 5-methyltetrahydrofolate, a derivative of folic acid, which then seems to tie back to people with methylenetetrahydrofolate reductase (MTHFR) polymorphisms that are slow methylators of folic acid may be more at risk. Is there a place for genotyping MTHFR in looking at relative risk? MTHFR Should be a Routine Test MH: I think that should probably be a fairly routine test now because it is so easily available and inexpensive because the methylation story, not just through detoxification and vascular biology but a lot of other things which everyone’s aware of, is extremely important. And certainly you can give activated folic acid. You can also give tetrahydrobiopterin orally as well. It may be a bit more expensive, but the idea is to try to identify factors that are affecting the production of NO and then backtrack. I tell all of my students: “If I ever ask you a question and you don’t know the answer, if you come back with the following answer you are always going to be correct, which is ‘What could be messing up the eNOS enzyme?’” And you say: “Oh, it could be inflammation, oxidative stress, or autoimmune dysfunction.” Everything ties back to those three basics when you start looking at enzyme function and also production of a lot of different compounds. JB: A number of years ago we were very fortunate to have a discussion on Functional Medicine Update with Lou Ignarro, who is one of the three people who received the Nobel Prize in medicine/physiology for the discovery of the NO connection in physiology. Lou made the comment that this NO pathway that is consistent with what you’ve just said about inflammation, oxidative stress, and autoimmunity is very dependent on redox potential within the cellular milieu and therefore specific types of antioxidants or complex networks of antioxidants may be very helpful in restoring eNOS activity and NO production in the vascular endothelium. I think that’s kind of a recapitulation of what you’ve already stated, but have you had some clinical experience and benefit to patients who get kind of complex cocktails of antioxidants in improving their NO production? MH: Absolutely. One of the things we’ve looked at, and you probably do the same thing with your EndoPAT, is we’ll take a patient and we’ll do a baseline EndoPAT, and then we’ll do something: either give them a donut, or we’ll give them some antioxidants, and then we recheck their EndoPAT a few hours later and see what happens. And it is amazing. You probably remember the old McDonald’s study, where they gave a McDonald’s hamburger with one group, and a McDonald’s hamburger with vitamin C and E and some other things, and showed that endothelial dysfunction was blunted when you took some antioxidants despite the fact you were doing the hamburger.[2] Well, we’ve done the same thing in showing that you give what I call a bad food or a good food, or a bad food with some antioxidants, and do the same thing and blunt. We’re trying to go through systematically and identify which antioxidants or which foods are most likely to blunt that ED. One of the things that I have learned—I say this kind of jokingly—is if you are going to go out and have a Krispy Kreme donut and a cup of coffee, have a little broccoli and red wine with it at the same time. JB: That’s an interesting combination. There’s a new cookbook. Atherosclerosis is a Post-Prandial Disease MH: But the point I’m making is atherosclerosis and ED is a post-prandial disease with endotoxemia, bacterial microbes, and other nutritional toxins that get through leaky guts, and that sets up an inflammatory response in your arteries, along with the other two things that are the finite response. And if you can mediate some of that receptor inflammatory response with different types of nutrients and antioxidants, you can blunt even a very bad diet and a very leaky gut through some preventative techniques. JB: Well now you’ve crossed over into a very interesting area that I was going to hold for later, but this is a great segue into it,that is this connection between gut function and vascular function, which might appear to be very distant in the minds of some. That connection is not so distant at all if you look at the more contemporary literature you’re describing. We were just involved, actually, in a collaborative study with Patrice Cani and Nathalie Delzenne from Louvain Catholic University Medical Center in Belgium. Arguably their lab is one of the world’s experts in endotoxemia and this so-called leaky gut area. They just published a wonderful study that is a result of looking at, in a mouse model, the effect on vascular function in that animal who is fed a high-fat diet and then given specific types of phytochemicals to see if, on the same diet intervention, they can neutralize the adverse effect on dysinsulinism, hyperglycemia, and dyslipidemia.[3] Interestingly enough, they were able to demonstrate that there are a number of phytochemicals, including modified hop extracts, that are very useful in kind of neutralizing adverse effect, in this animal model, of a high fat diet on vascular function and insulin resistance. I think the gut connection—and this term “leaky gut” that we started using in functional medicine 20 years ago, which at the time was considered kind of antithetical to good language, has now started to rise up in prominence. Give us your thought about the trajectory in this whole field. MH: Yes. You know, as a preventive cardiology person, I tell everyone that if you do not clean up your gut, you will not clean up your cardiovascular system. It’s that simple. And that’s because the relationship between the brain, the heart, and the gut are really absolutely key for neurodegenerative disease as well as all the things related to gut health and cardiovascular ED. One of the things you mentioned, Jeff, which I think is fascinating, and this is a new factoid—here’s a new concept for our listening audience: 75 to 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the people who walk into your office with dyslipidemia, the cause for it is nutritional and microbial endotoxemia. JB: Wow. That’s a very powerful statement of the new medicine. Wow. Most of the Time Dyslipidemia is an Environmental Issue MH: And I couldn’t have said that about three or four years ago, but I’ve really researched it and looked into it now and I feel pretty comfortable that I could back all this up with a lot of data. The concept is this: there is only about probably 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the population that really has a genetic dyslipidemia. For most of us it is clearly environmental, and the two environmental causes are intestinal absorption of what I call inflammatory nutrients or dyslipidemic nutrients, and the endotoxemic microbes. So now we’ve tied together infectious vascular disease and bad micronutrient vascular disease, and these two have exactly the same pathogenesis. The blood vessel doesn’t care which of those two is coming in as its insult. The pattern recognition receptors, the Toll-like receptors, the Nucleotide Oligomerization Domain (NOD) receptors, the caveolae, the whatever you’ve got sitting on your endothelium as a receptor to transmit signals into the cell from its inflammatory signals or whatever, the endothelium is going to respond the same way. So if you realize that dyslipidemia is most of the time an environmental issue, then instead of saying, “Okay, I’m just going to treat your lipids,” instead say, “Let’s track back why you have dyslipidemia, fix that problem, and guess what? Then your lipids will be normal and you don’t have to take anything for your lipids, specifically not a statin.” JB: This is so fun, this conversation. I’m looking at this paper that just appeared in the March 2012 issue of PLoS One titled “Tetrahydro Iso-alpha Acids from Hops Improve Glucose Homeostasis, Hyperlipidemia, and Reduce Body Weight Gain and Metabolic Endotoxemia in High Fat Fed Mice.” [4] I think it relates directly, in a controlled study, to what you’re speaking to. Recent evidence suggests that many different phytochemicals impact adipocyte metabolism and glucose tolerance in obese and diabetic animals. In this study they found that administration of this phytochemical, tetrahydro iso-alpha acid, to high fat fed, obese and diabetic mice for eight weeks reduced body weight gain, the development of fat mass, glucose intolerance, fasted hyperinsulinemia, and normalized insulin sensitivity, and reduced hyperlipidemia. This was associated with reduced portal plasma lipopolysaccharide (LPS) levels, meaning the actual leaky gut component that leads to bacterial endotoxemia was reduced in the blood—kind of like chronic sepsis, basically. It reduced gut permeability and led to higher intestinal tight junction proteins Zonula occludens-1 and occludin. It also increased the cytokine granulocyte colony-stimulating factor, and reduced the proinflammatory cytokines, and increased the anti-inflammatory cytokine interleukin-10, showing—according to these researchers—a novel mechanism that allows us to decipher the connection of the gut to insulin resistance, obesity, and vascular dysfunction. So this sounds to me like it’s an emerging, extraordinary new chapter in our lexicon of etiology of vascular disease. MH: That’s fascinating, and it’s consistent with we’re seeing and what I’ve read. If you want to make this really simple for people now, you can say that hypertension is an inflammatory, autoimmune, oxidative stress disease, and so are cardiovascular disease, and coronary heart disease, and congestive heart failure. If we can start to block those three responses, we’re going to have a good chance in reducing all of those outcomes. There are so many phytochemicals out there that we know about now that block the toll-like receptors and have a lot of anti-inflammatory effects. They are more of a shotgun approach as opposed to our typical pistol approach that we take with pharmacology. The Cholesterol Conundrum and Statins JB: So you mentioned something else previously that I want to come back to pick up because it’s a big one. It’s on everybody’s mind. It’s the dominant theme in the whole kind of dogma as it relates to the etiology of coronary heart disease, and that’s the cholesterol conundrum and how that relates to statins, and what the story is that’s emerging. Tell us a little bit about the JUPITER trial, because it appears the JUPITER trial with Dr. Ridker changed some of the conceptions and maybe also how we’re looking at statins. MH: Basically, as you know, Jeff, statins were developed primarily to reduce LDL cholesterol. In the process of defining how they really worked we realized that they have other pathways, some of which are beneficial and some of which are very detrimental. One of the pleiotropic facts is that they reduce inflammation. And so the JUPITER trial was a hypothesis: Let’s give a statin and see if we can see which of these two markers is more important–is it the LDL, is it the inflammation, or is it both? The bottom line was if you lowered the C-reactive protein (CRP), you still had an independent reduction in cardiovascular risk regardless of what you did to the LDL. Then you say, “LDL is important.” Well, yes, it’s important, but it’s way beyond LDL levels now. It’s the size of the LDL. It’s the particle number. It’s whether it’s modified. And then there are another 38 different mechanisms that we talked about during the symposium that really change your whole approach to dyslipidemia now. The bottom line here is that inflammation is sort of evidence by CRP, and JUPITER was your typical double-blind, placebo-controlled trial that said: “Inflammation is really important in cardiovascular disease so we need to start looking at it.” That’s something that we didn’t already recognize, but now it’s got validity at least through the JUPITER trial related to statins. JB: I know in your book What Your Doctor May Not Tell You About Heart Disease you have a very—I think—lucid and understandable explanation of this whole cholesterol concept: where it developed, how it became a dominant theme, some of its strengths and limitations, and how not to get high centered by it when you are looking at true overall relative risk. I want to compliment you because I think that is a very complex area with a lot of—I guess you call it—legs on it, and I think you’ve done a really good job of simplifying it and making it understandable, and also in a status that it can be used clinically. I think the information is there to use. I want to compliment the way you’ve handled that difficult topic. MH: Thank you, Jeff. One of the things I do want to say that maybe will help people understand this connection a bit better is this. Your native LDL for the most part is not an atherogenic molecule. It’s part of your normal body’s production so it’s not recognized as foreign. It is only when it becomes modified, and that modification can be oxidation, acetylation, glycation, or a combination of the above. When that happens, the body recognizes it as a neo-antigen; it is now a foreign particle. So then it mounts the response that it’s supposed to, which is to get rid of the oxidized modified LDL. And we all know the downstream responses after that, with macrophages, and foam cells, and cytokines and all that. The idea is not just to lower LDL burden, but also to prevent its modification, and prevent some of those other steps that go from the time it becomes modified to the time it goes all the way through the endothelium and becomes a foam cell in the plaque and then it ruptures and you have, of course, myocardial infarction. Apolipoprotein A1 and the HDL Particle JB: That is a beautiful segue into another chapter in this very multi-chaptered book on vascular biology and vascular disease, and that has to do with the particle in the blood, or the apolipoprotein that’s associated with cholesterol efflux and transport of some of these modified cholesterol forms out of the body so they don’t sit in residence and create havoc. I’m speaking about Apolipoprotein A1 (ApoA1) and its interrelationship with one of the most complex…I don’t think it is one of, I think it is the most complex lipid particle, which is the HDL that has over 40 proteins in its composition, and HDL associated with cholesterol efflux and how that relates to the functional HDL, and of course how that relates to the niacin story. Can you tell us a little bit about your position on HDL, niacin, and its function? MH: Yes. Let me give you a clinical study that will totally change your thinking about HDL. We have found, through the IDEAL trial and several others, that if you’re HDL is around 85 milligram percent, it is most likely to be dysfunctional, and offers no cardiovascular protection.[5] So, in traditional office practices now, where people measure only your standard lipid profile, and they say to you, “Oh your HDL/LDL ratio is fine. You don’t have anything to worry about,” particularly if they have a high HDL they are getting the wrong message. Starting around 70 milligram percent, as HDL starts to go up there is a higher and higher chance it’s dysfunctional HDL because it is inflamed, and all these proteins are disorganized. They just don’t work. So HDL and ApoA1 don’t do reverse cholesterol transport among about 20 or 30 other things that HDL is supposed to do to prevent atherosclerosis. But if you take all the risk factors and risk markers out there that we have available, reverse cholesterol transport is one of the greatest predictors of cardiovascular disease. And one of the best ways to indirectly look at reverse cholesterol transport right is through myeloperoxidase (MPO). We don’t have good clinical assays yet, but that one is available because it tells you you’re inflamed, and MPO basically makes ApoA1 become dysfunctional. JB: I understand there are a number of clinical laboratories that are now providing MPO serological analysis, so it can be actually measured by the clinician. MH: Yes, it can. Absolutely. And I would highly recommend it in people who have these sort of high-end HDLs, because you’ll find that if you do MPO, the MPO is high. You get a very false sense of security in people who have high HDLs if you don’t check their MPO levels and realize that they’re really at high risk because their HDL is not functioning correctly. JB: Is there any clinical correlation that you’ve seen between elevation of MPO and phospholipase A2 serology (a positive PLAC test)? MH: They do. They run in very high correlation because they are both very good oxidative stress markers, and they are also very good markers for plaque rupture. If you have a plaque that has a very thin fibrous cap and a lot of inflammatory mediators within the plaque that are trying to eat through that cap and erode into the artery, then you’re going to have a high risk for a thrombus and a myocardial infarction. Both of those are good markers predicting that risk. The Niacin Controversy JB: So let me come back to the niacin question because this has been a big recent controversy given the study that was published two years ago in the New England Journal of Medicine suggesting an increased relative incidence of vascular disease on niacin-supplemented patients.[6] What’s your opinion on that in comparison to the other literature that exists on niacin? MH: That was one of the studies I took apart and dissected and read through, and I’m satisfied, Jeff, it was a terribly designed study—bad methodology, asked the wrong question. There were a lot of issues, but I think that study stands out as contrary to all the other great clinical data on niacin, and it has not dissuaded me in one way or another to not use niacin. I still use a lot of it. Niacin is one of the best agents we have to not only increase the size of HDL to a 2B, but also increase the HDL particle number, to improve its functionality, and then it has other great effects that are independent of HDL and other lipid parameters and other vascular markers. So the HDL story, the niacin story, I think got miscommunicated with that study, and if you really look at it and you’re honest with yourself you would say that study is probably a fairly bad study. JB: Let me loop back now to the previous discussion we were having concerning statins. At one time—not too long ago—there was a very strong advocacy that children should be started on statins if they have any degree of dyslipidemia. In England, statins were put over-the-counter for more regular consumer use. There is this trend to think that statins are benign, safe–the safest drugs that have ever been developed–and that everybody who has a problem should be on statins. But yet, then we see this most recent meta-analysis study on the prevalence of type 2 diabetes in postmenopausal women who are on statins showing increase in the incidence of diabetes in women taking statins versus age-matched cohort of women not taking statins postmenopausally.[7] Where do you weigh in on this very, very controversial area? MH: It is very controversial. The key issue is the risk/benefit story. There are clearly patients who are going to have benefit from taking statins, and that’s primarily in your secondary prevention patients who have already had an MI, or who have significant CHD. But on the other hand, it has started to come out that for primary prevention in anyone, whether it is a child or adult, it gets very questionable then, and the benefits really don’t outweigh the risk. To me, the real risk of a statin is it is a mitochondrial toxin. If you look at studies, most of the things that happen related to statins are related to the slow destruction of your mitochondria in your skeletal muscle and other areas. And I think actually the diabetic issue is partly related to mitochondrial dysfunction and loss of lean muscle mass. But all the nutrient deficiencies, as well, contribute: CoQ10, carnitine, vitamin E, omega-3 fatty acids, selenium, the protein pathway, thyroid dysfunction, anemia, the list goes on, and on, and on with the statins. I’m beginning not to use nearly as many statins as I used to in the past. I’m very, very selective about who I give them to. I usually don’t go to higher doses. I’ll do interrupted therapy. I’ll monitor things carefully. If I start seeing any problems—and I do a lot of tests to monitor–then I go to alternative therapy, and we’ve actually published now, Jeff, several articles that show that by using some very powerful nutraceuticals I can get exactly the same LDL reduction, same reduction of CRP, that you can get using some of the statins on the market, and I’m talking about 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} decreases in LDL cholesterol with nutraceuticals.[8],[9] JB: That’s very, very exciting. Talk about really giving a broad spectrum of options to the clinician. Lastly, I know this is a big topic and I’m asking something that is impossible to answer in a short summary, but I guess I’m going to challenge you a little bit and say maybe you can give us a top line, and that has to do with hypertension and the way we’re approaching it, knowing that the guidelines for hypertension have been established to be lower now in terms of systolic and diastolic pressures. More and more people—a percentage of the population—are diagnosed as being either pre-hypertensive or hypertensive. The treatments of choice are drugs that were really designed, initially, to manage more overt hypertension, so one questions the risk/reward sometimes, or the risk/benefit in treating marginal hypertension with things like beta-blockers, diuretics, calcium channel blockers; maybe not so much with ACE inhibitors or angiotensin receptor blockers (ARB). It seems to me this concept that came out of the Dietary Approaches to Stop Hypertension (DASH) report, that before you get into pharmacotherapy you ought to do a lifestyle medicine intervention, is prudent in this area.[10] You are one of the world’s experts in hypertension management. Can you give us your opinion, which probably is the most educated opinion I could ask for? Disconnect Between Blood Pressure and Vascular Pathology MH: Here’s what I’m doing right now, Jeff, and I think I’ve got pretty good data to back up what I’m going to say. There is a disconnect between blood pressure, and vascular pathology, and ED. It’s the same concept that I mentioned earlier with translational vascular medicine. What I mean by that is if someone has an elevated blood pressure, let’s say of 140 over 90, and you were to put them on a diuretic or beta blocker and you dropped them to 120 over 80, at the end of two years, would you get the same results on endothelial function, vascular smooth muscle hypertrophy, structural and functional changes if you had done either nutritional therapy or picked a different drug, like an ACE inhibitor or an ARB? We have clear data now both in surrogate studies looking at actual gluteal muscle biopsies from Ernesto Schiffrin in Canada, we have outcome studies with the ACCOMPLISH trial and the BPLA study out of Scandinavia.[11], [12], [13] The bottom line is this: lowering the blood pressure is not necessarily going to reduce target organ damage because how you get there is as important as getting there. So diuretics and beta blockers in general—and there’s a few exceptions within those classes—are inferior drugs to reduce all the things we’re trying to do with cardiovascular outcomes compared to lifestyle, nutritional changes, nutraceuticals, and specific pharmacologic agents, like dihydropyridine calcium blockers, ACE inhibitors, and ARBs. JB: That was an unbelievable concise and fantastic summary of a huge body of work. Thank you very much. Obviously you’ve been asked that question before. That was remarkable. MH: Thank you. JB: In the close—and, again, we so appreciate you giving us this amount of time on our celebratory 30th anniversary edition—I’d like to use your forecasting and your clairvoyance to look out at the horizon for a moment, knowing that there is some risk for any of us to try to be predictors of the future. From your position, which is a pretty lofty position, where do you see medicine going, say over the next 10 to 20 years? MH: I think we’re on a precipice of a revolution, not only in cardiovascular medicine but in medicine in general. We’re one of the best countries in the world if it comes to an acute problem. That’s where I want to be if I have a heart attack. But we’re one of the worst countries in the world when it comes to prevention. So we’re not doing things correctly and it’s time that we looked at what we’re doing and started to change it. I see us moving into a systems biology approach to medicine, looking at all the interconnections in a functional medicine way, trying to get to the basic reason why people have symptoms, trying to get away from the concept of let’s just label somebody with the disease and think we’ve done a great job. Robert Rountree, MD—I love this—he says, “If you come into my office and you don’t have all the criteria for multiple sclerosis, I’m not going to give you a jersey for my team so you can’t play ball with me.” The idea is, in traditional medicine, we have an ICD-9 code, we give a diagnosis, and we’re good, we just pop a drug. That’s not the way we’re heading. We’ve got to start looking at the patient in a much more complex systems biology approach with the nutrigenomics, metabolomics, and all of the things you know so well and teach so well before we’re really going to be able to really have an impact on disease management worldwide. JB: Well, Dr. Houston, as advertised, you are the perfect guest for our 30th anniversary. I think not only did you give the news-to-use down at the level of stuff on the street for clinical outcome improvement, but you’ve given us the vision as to where we are heading in a way that I think is an aspiration that is realizable through continued commitment to the evolution of medicine. It’s really a privilege to share this field with you. When we first met back in 2000 I was immediately impressed, as people are when they meet you. I think your authenticity and your commitment to excellence really is a watchword for where this field is going and how it’s going to pull itself up and be a catalyst for the transformation of medicine as a whole. I want to thank you as a leader, I want to thank you also as a guide, and as a colleague, and as a friend. I think this has been really a wonderful run this last 12 years, and I think the next 10 years are going to be very robust in seeing medicine mature. Thank you so much. MH: Jeff, I want to thank you for allowing me to be on your 30th anniversary. It’s really an honor to do this for you. As you know, I’ve respected you for years and we’ve become great friends over the years. I always learn so much when we have conversations. It’s like you set off all the neurons in my brain and synapses start flying. When we start talking, we go into a different arena of biochemistry and medical technology. Thanks again for your expertise and all the work you’ve done, and congratulations again on this wonderful achievement of 30 years of FMU. JB: Thank you, and once again I want to remind the listeners because we’ve spoken fast across a wide platform of different conversations here. For following up in more detail, Dr. Houston’s website is www.hypertensioninstitute.com, and of course, his recent book is a wonderful treasure trove of good news-to-use: What Your Doctor May Not Tell You About Heart Disease. Mark, once again, best to you and I look forward to many more years of collaboration. MH: I do too, Jeff. Thanks so much.

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Bibliography

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Welcome to Functional Medicine Update for July 2012. Well, I’m very excited about this month in that it is a little bit like back to the future. We have the opportunity to visit with a clinician of the month who—I would say arguably—is at the head of his game, top of the class, and has done an incredible job in implementing functional medicine in his practice. I take some vicarious pride in that it was a little over 10 years ago that we had the opportunity to visit with this same clinician as he was moving his practice more and more into the functional medicine milieu, and over those 10 years Dr. Mark Hyman has become a leader in this field and has guided literally hundreds of other clinicians in the successful implementation of the functional medicine concept. Dr. Mark Hyman: Ten Years of Leadership I’m very, very pleased that in this ten-year span not only has Dr. Hyman had his career and his impact on patient management grow by exponential bounds, but also his impact on changing health care has started to become much more impactful as well through his work at the level of the executive and congressional  branches of our government, and in the area of our armed services and some of the programs that are going to be applied over the years to come with our veterans. In these experiences, Dr. Hyman has started to understand the burden of chronic disease that’s rising every day, the challenges that this family of diseases presents to our healthcare system, and some of the resistance there is to change within the system as a consequence of patterns of behavior and systems reimbursement policies. This resistance has retarded the integration of new concepts that would make chronic disease management more effective and efficient. You’re going to hear from Dr. Hyman about his personal journey, which we’ve all kind of shared in over this last 10 years within the growing and expanding domain of functional medicine, both at the individual practice level and at the societal level as it relates to the changing medical paradigm.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Mark Hyman, MD The UltraWellness Center 45 Walker Street Lenox, MA 01240 (413) 637-9991 www.drhyman.com www.functionalmedicine.org July 2012 Here we are again. I feel like we’re all in the living room, sitting in comfortable chairs and we’re going to have a fireside chat with him in our Functional Medicine Update Clinician/Researcher/Educator of the Month interview. It’s one of my great friends and colleagues. A person who has been a leader in our field for a number of years and continues to provide vision and guidance. I would call him a clinician’s clinician: Dr. Mark Hyman. Mark is a medical doctor who presently is in practice in Lenox, Massachusetts, with a very, very remarkable clinic that serves people with chronic illness across a wide range and spectrum of concerns using the functional medicine model. He’s one of the aficionados and primary experts in the functional medicine model. Mark has broad-based interests, talents, and resources. He was a Chinese studies major in undergraduate school at Cornell. He went to China. He learned Chinese. He is involved in all sorts of different disciplines within the healing arts and brought them into primary care and family medicine. He and I met in an early stage of the evolution of the Institute for Functional Medicine. Mark went from student to teacher very rapidly. He integrated these concepts very successfully into his practice, and pioneered new ways of actually applying functional medicine. He was involved in the development of the Textbook of Functional Medicine, and the early days of teaching as faculty within the Applying Functional Medicine in Clinical Practice training program. From there, history has been written. Mark now is the Chairman of the Institute for Functional Medicine. He is a luminary/consultant/resource for all sorts of people who are looking for high-level understanding of the model, and has a list of patients that are extraordinarily grateful for the services that he has provided. We were very appreciative at the Institute for Functional Medicine annual symposium in Scottsdale in late May/early June, that the introduction to the symposium was provided by President Bill Clinton, who happens to be one of Mark’s patients. Former President Clinton gave a wonderful salutation to the 850-plus delegates at the symposium, welcoming them and saying how much functional medicine meant to him and his family. Mark also has had a very strong relationship with Secretary of State Hillary Clinton. And he has recently been featured along with Mehmet Oz and Daniel Amen through this extraordinary project they’ve done at Saddleback Church in Orange County, California, called “The Daniel Plan.”[1] So Mark has really been a leader and advocate for changing medicine, both how we do it and what we do in medicine. Dr. Hyman, welcome to Functional Medicine Update. This is a re-visit for you, having graced us previously as a clinician of the month, but clearly a lot has been happening. You just got back from the Clinton Global Initiative, and lecturing for the second time at the TEDMED conference, and now this Daniel Plan and making it more well-recognized. Tell us how this all swirls about, plus your media tour on your book, and your public television educational series. I mean, that sounds like about four lives right there. Tell us a little bit about how it’s going. Functional Medicine in the National Spotlight: TEDMED, the Clinton Global Initiative, the Daniel Plan MH: Yes, it is a lot, isn’t it? Especially when you put it all together like that! I think: Wow, I don’t have time for anything else. But actually right now I’m sitting out on my deck enjoying the sun. It’s a beautiful summer day in the Berkshires, and I’m feeling really happy because at this moment in time there is this huge shift that is happening, and we can see it happening all over, where functional medicine is reaching prime time. It’s getting recognition by President Clinton and Secretary Clinton; at the Clinton Global Initiative I spoke about it. It’s been put into a mega-church in California with 30,000 members and we’re seeking to expand.. People are looking at this as a mainstream solution to our chronic disease epidemic. My book became number one on the New York Times Bestseller List and the PBS show that went with it has been hugely successful because this message is the right message at the right time, and God knows we need a solution because we’re in trouble.[2] Awareness Happens: The Functional Medicine Movement We look at this whole diabesity issue and the study that came out in Pediatrics a few weeks ago that showed teenagers went from nine to twenty-three percent pre-diabetes or type 2 diabetes from 2000 to 2008, which is frightening. And now we see even 37{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of kids (teenagers) have one or more metabolic syndrome risk factors like dyslipidemia, high blood sugar, and hypertension, and they are metabolically obese even though they are thin because they are eating industrial toxic food.[3] This culture, this society, this shift happening—there is an awareness happening—and I think there is a movement starting to brew. We’re getting sick and tired of the status quo. When I was at the Clinton Global Initiative, I met with Michelle Obama’s director of the Let’s Move program and another person who worked for the bipartisan policy center who were very knowledgeable about functional medicine. They were wanting to talk to me about how they can help support the growth of functional medicine, and they want to support the Institute for Functional Medicine’s building of a nutrition curriculum for medical schools because that’s one of the policy recommendations they made to change this conversation, so it is very, very exciting. JB: Tell us a little bit…I mean, we all read the extraordinary article that reviewed the experience that you had with Dr. Oz and Dr. Amen with The Daniel Plan. Tell us a little bit about that, because I think there are some deeply embedded truths that are very important as it relates to how we can modify the healthcare system. How the Daniel Plan Came to Be MH: Yes. You know, when I think of the tagline for IFM–We Have to Change the Medicine We Do and the Way We Do Medicine–I think the medicine we do has to be germinated off of systems biology in medicine and functional medicine, but the way we do medicine has to change as well, and that’s the delivery model. So we couldn’t keep doing it in the way we were doing it, and I realized when I went to Haiti that Paul Farmer solved TB and AIDS not by finding medications, or better applications of surgery or interventions, but by using the community as a level to create behavior change, and that the social, economic, and political conditions were driving infectious disease in these countries. I realized that there was a parallel for this in the developed world, which was that the social, economic, and political conditions that exist in America and increasingly even in developing worlds are leading to obesity, and diabetes, and heart disease, and lifestyle-driven diseases, and that we have to deal with that through community-based intervention. I began to noodle on this, and I read a book Chelsea Clinton recommended, a book called Turning the World Upside Down by Nigel Crisp, the former head of the National Health Service.[4] It was basically saying that we have to shift our thinking and put patients and communities at the center of health care, not doctors and hospitals, and that really changing the conversation around chronic disease must be done in order for us to solve this, that’s it’s not going to happen one-by-one-by-one in the doctor’s office but by the tens of millions in communities where people live, and work, and eat, and learn. That’s where change happens. And I realized that that’s really what could be done in this country. If we could take the functional medicine model and we could deliver it through small groups and communities, that just maybe something could happen that would show us a different way. I met Rick Warren and I had this idea and I presented it to him over dinner one night. He said: Yes, let’s do it. Because he had baptized 800 people one day, and they were all fat, and after the 500th one he thinks: Man, we’re a fat church, and I’m fat, and we need to do something about this. So he was ready for it. We launched the Daniel Plan in January 2011. We had 15,000 people sign up the first week. The plan was basically a functional medicine lifestyle plan delivered through small groups in the community, and we also changed the culture of the church: we changed what was served, we changed the menus and the recipes, we got people active and exercising, so we changed the culture as well. Using that strategy–the small groups, changing the defaults in the community, and driving the right concepts through functional medicine–over the course of a year the church lost about 260,000 lbs. It was remarkable. People got rid of all sorts of chronic illnesses, because as we know in functional medicine, if you deal with the root causes, all of the other diseases go away downstream. People got rid of asthma, and migraines, and autoimmune disease, and irritable bowel, and reflux, as well as obvious things like diabetes and hypertension. People got off insulin (diabetes medication). We really saw that there was this potential for shifting the healthcare system through a wellness model in the faith-based communities. It’s sort of bizarre for me because I’m a Jewish guy from New York so what do I know about evangelical churches, but it was really clear to me that the community had to be the cure and that the group was the medicine. That was the insight that led me to move this forward. As I’ve been talking about this around the country, it’s sort of a lightning rod. People are very excited about it. President Clinton asked me to speak about it at a conference called Health Matters in January and at the Clinton Global Initiative. I gave a talk at TEDMED about it. I think it is really an idea whose time has come—in fact, has to come because we can’t solve this on a one-by-one level in the doctor’s office. There are just too many patients. Community-Based Programs May Be the Future of Treating Chronic Illness JB: It’s very interesting. I think you’ve done such a tremendous job of assembling a wide body of data information across many different disciplines into a very sensible kind of—as my father used to say—“rule of reasonableness” model. It just fulfills a rule of reasonableness. I reflect back to the interview I did a number of years ago on FMU with Dr. Halsted Holman. I know you know him by name if not the person. He’s now at Stanford. He’s 90-years-young. Still practicing. He is the guy who developed this concept of a community-based program for chronic illness that engaged patients in self-care. He authored that article “The Need for a New Clinical Education” that appeared in JAMA.[5] When I interviewed him on FMU, he talked about the power of small groups, and that people become their own teachers. And they are more effective when they are speaking to one another and guided by a professional than kind of getting lectured to by a professional in the absence of the group. I think you’ve hit on so many different points of connection: using the neural net as a behavior mod tool in the group process. It almost sounds like the psychobiology of this could be studied as it relates to this social networking approach that you use in the Daniel Plan. MH: Absolutely. I think we all have a desire to be part of a tribe and a group. EO Wilson talked about this in his new book, The Social Conquest of the Earth.[6] There is a process called group selection. We’re hard-wired to connect and link to each other for our survival. I just met a gentleman who is the head of the Center for Compassion Studies at Stanford, which is kind of surprising—he’s a neurosurgeon—but really talking about the biology of compassion, and connection, and this is an underestimated medicine, I would say. Food is medicine, but community is also medicine. Leveraging those two things together is a combination that is uniquely suited to lifestyle disease. What is striking to me is when I review the literature on this (and there is a fair bit of literature), these interventions do work and they work better than conventional care, and they work both in developed and developing worlds. For example, there was a study recently in Health Affairs looking at comparison of lay interventions (lay groups) versus healthcare-professional-led groups for the diabetes prevention program, and there was no difference in outcomes; they both worked equally well.[7] So you don’t have to be an expert to even do this. Peer support is adequate. . Even in developing worlds…Peers for Progress is an intervention that has been developed by the American Academy of Family Practice to look at peer-support models in the developing world. They looked at Thailand, Uganda, Cameroon, and South Africa, where diabetes is rampant. They taught villagers simple skills and knowledge, and then they helped them support each other, and through that self support and peer support (not led by a health profession but each other), they had dramatic reductions in their biomarkers: their hemoglobin A1C went from 9 to 6, and they had had better outcomes than any medical intervention, and there was a ten-fold reduction in healthcare costs.[8] So this is a very cost effective and actually more medically effective treatment. It’s something that just has not been integrated in any way into medical care, and it’s sort of surprising to me. It’s like this big “a-ha.” JB: I think it’s absolutely fantastic what you are kind of creating here. If we think of functional medicine as built on a systems biology framework or architecture, and that that systems biology has something to do with signals that come in and are translated by the individual into operative functions, which could be things like neuromuscular function, or gastrointestinal function, or cardiac function, that that signal systems biology matrix has never taken into account to the extent that you’re having us recognize the signals that come from the social environment, from the social interaction. Yet we know, because there are many published papers that have demonstrated that the singular largest risk factor to cardiovascular disease is a feeling of being impoverished: low attribution, low sense of recognition, low sense of self-esteem, and low locus of control.[9],[10],[11] I think you are codifying, in a systems biology way, how social interaction is a signal so important in health. It’s really quite remarkable, Mark—the way you are doing this. Sociogenomics: How Our Social Connections Influence Gene Expression in Health and Disease MH: Thank you. Well, you know, some of the insight I have—I’ve been following you and functional medicine, and I’ve been sort of focused for so many years on biological networks and really understanding at a very detailed molecular and genomic level what is going on with our biological networks. That’s what functional medicine is: an understanding of how those biological networks are the determinants of illness. But I realize that there is another kind of network out there: our social networks. And, in fact, those networks and the social trends that connect us in the end may be more important than the genetic threads. I call this sociogenomics, which is how our social connections influence our gene expression in health and disease. The whole idea of sociogenomics is a very interesting insight for me because it has sort of been a natural flow for me from biological networks to social networks. I have always been involved in groups of different sorts and it is sort of how I live in my own life, but I never applied it to medicine, and now I realize that it actually may be the missing piece that can help really move this whole epidemic along. JB: With that in mind, let’s kind of just take a point/counterpoint view for a second. There is this sense of importance of individualization, or personalization, or what Roger Williams called biochemical individuality back in the late 40s/early 50s. A person might say: “Well, this sociogenomic model is great except doesn’t it focus on the individual. Doesn’t it tend to regress to the mean of the group and you lose personalization?” How would you respond to that? MH: I think that’s a fair statement and I think, you know, if you were to look at the basic principles of functional medicine, it’s really the science of creating health. If you understand how to modulate those biological networks to create health, it works for most of the people, most of the time. It will—basically, without treating disease directly—ameliorate or improve or even resolve many conditions, as we found when we did this with 15,000 people in the church. However, there is probably going to be about 20 percent of people who still need extra help. In those cases, you can customize the program. I think you can even customize functional medicine using self-care models. I think this is the next step for functional medicine: creating models of self-care that can be decentralized and democratized, taking the veil back on the sort of secrecy of medicine and guiding people through self-diagnostics, questionnaires, and even self-testing—how they can adjust and modify their own lifestyle and diet and various interventions to help personalize the program. We actually have that as part of the Daniel Plan, so it’s done as a self-care model. And then, of course, if people get stuck, then they have to go see a functional medicine doctor and get that extra level of intervention. It is sort of like if you reboot and restart the system a lot of problems will go away and then you see what you’re left with. I once talked to my friend and he said he has people and he can’t see them because his practice is so busy, and he takes his nurse practitioner and they put them on sort of an elimination diet and sort of basic supplementation, and then 30 days later they check in with them and they do an MSQ and most of their problems are gone and they haven’t even seen a practitioner. And then those who still are stuck, you know, that’s when they need expertise and the skillset of an experienced functional medicine doctor. I would say right now I do tertiary functional medicine. That’s what I do, and it’s people who really have complex chronic diseases and aren’t amenable to simple changes, and that’s fine—I mean, we’ll always have a need for that—but most of the time we can actually create a basic plan and also a customized, personalized model that can be done through self-care. JB: I know I’m getting into thorny questions but these are the kinds of things that I’m asked very frequently and I’m kind of going to the expert now to re-ask them to you. A person might say: “This is great. I spent 10 years getting training in medicine. I feel like I’m pretty skilled in the art. And now you’re telling me that really I don’t have much use because I can use a paraprofessional and I don’t really need to see these people, so what good is my training and how can I make service?” Doctors are Trained in Acute Care Rather than Basic Care of People with Everyday Problems MH: I think, like most doctors who are listening, I went through my training in the hospital and became very skilled at acute care medicine, and was dealing with things in the extreme. And when I went into clinical medicine, it was a big jump. It wasn’t actually what I was trained in. I wasn’t trained in basic simple care of people with everyday problems. So our training is very sophisticated and very skilled and I think that’s always going to be needed, but a lot of what we do is not at the level of our skillset, or training, or knowledge. That’s unfortunate, and I think that can change. And I think doctors should be the ones who are dealing with things that are more complex and require more thinking and more evaluation and diagnostics. There will always be a need for that, but I think a lot of what we do, and particularly in primary care—even in a lot of specialty care—is just not up to what we were trained in, and I think that has to shift. What we are doing, and part of the reason our healthcare costs are so high, is we’re using all these acute care interventions and diagnostics that we were trained in, and we’re using them on things that aren’t acute; we’re using them on chronic illnesses. That’s where the problem is. JB: Yes, I think that’s very well said. You said a couple of other things, there, that I believe are very important—like hot buttons—and that’s diagnosis and disease, which we know are two words that really relate to the sine qua non of how docs are trained: to drive to the diagnosis, to get the definitive disease, and treat the disease as if it were a battle that is going to be won by medical therapeutics. Tell us a little bit of how your model fits into this disease diagnosis frame of reference paradigm. MH: Your question is how does the diagnostic paradigm fit into this model? JB: Or kind of juxtapose maybe the two, the way you have described, which I think is a beautiful way of describing a systems biology approach versus this kind of conceptual framework that most of us learn, memorize, and recite on demand, which is this diagnosis/disease model. MH: We’re mixing—or we are confusing—our approach, because we still need sort of a western diagnostic model that we’re all trained in, but it’s not sufficient to deal with multi-system, complex, multi-genome disorders that are being treated as if they are, you know, sort of the infectious disease, bug/drug model. For example, I had a patient the other day who has hyperaldosteronism. This is because of hypertrophy of her adrenal gland increasing the mineralocorticoids. To me, as a functional medicine doctor, I’m wondering why she’s got this. I asked if she’s having liquor issues, is she doing other things to trigger this, is this a hyperplasia of the adrenal gland or is it a tumor (an ectopic tumor)? Some things just happen that we don’t completely understand that may not be completely amenable to the functional medicine approach. It may need to be cut out—she might have a tumor that needs surgery, she might need some medication to help shut down the aldosterone receptors, like Spironolactone. I think we have to be open to looking at people in the full spectrum of what’s going on with them and understand how to distinguish between someone who just needs a hip replacement because her hip is destroyed and someone who needs a retuning of their systems biology. JB: Yes, I think that’s a beautiful model. You’ve kind of segued over into a very interesting point. I think a lot of our listeners would like to know: what is your practice like? What kind of patients do you have? What are the range of issues that you have to deal with? You’ve always called you’re a “resort doctor”—the doctor of last resort. Tell us a little bit about that. MH: I’m very excited because we’ve just moved into a brand new UltraWellness Center. We’re 5000 square feet. We’ve got four doctors, a nurse practitioner, four nutritionists, two nurses (probably three soon), and we do a whole range of care that is everything from optimal health and aging and wellness care, to dealing with very complex chronic illnesses, along the age spectrum from autism to Alzheimer’s, from diabetes to depression, from reflux to hormonal disorders and menopause. We do a lot of different chronic illnesses. It’s pretty interesting. You never know what’s going to walk in the door, but if you just stick your head down and you ask a lot of questions, you can use the matrix and come up with a roadmap even if you’ve never seen a problem before and begin to understand how to apply this model. That’s what is so exciting about it. It doesn’t matter what the condition is. My staff often gets asked: Do you treat this, or do you treat that? Yes, I treat everything. If it is something I don’t know how to do, like a hip replacement, I’ll refer them, but essentially most of the problems will be amenable to functional medicine, and you can know how to start by using the matrix. That’s what we do, and it’s very, very effective. JB: Tell us a little bit about the matrix, for those who may be either new to the functional medicine model or just in early in kind of gaining of mastery of it. Tell us what the matrix is and how you find it useful. Using the Functional Medicine Matrix MH: This is something that has been evolved over the last 15 years by the faculty and by you and others in functional medicine. It’s essentially a one-page sheet that we’ve summarized the model of functional medicine into, which is understanding how lifestyle factors and how predisposing both genetic and environmental factors influence your biological networks: your genetics, your early childhood influences, your prenatal environment, your early childhood development, stresses, traumas, various things, can trigger imbalances in your biological networks. And so can change in lifestyle, so what you eat, and what you think, and your social relationships and connections, how much you move—all of these things influence your biological networks. So when I see a patient, I want to know how do these factors influence their networks and how are those networks out of balance? There are nodes in your biological network, and those nodes really are the things that make up the matrix, which is your assimilation system, or we used to call it digestion, and how you assimilate and absorb nutrients; your defense and repair, which is how you manage your immune system and inflammation; how you make energy in your mitochondria, and the metabolism of energy in your body and your mitochondrial function; and then how that influences detoxification and biotransformation. And then we have transportation and circulation: how you move around blood and lymph fluid; and then communication, which involves all the cell signaling, and hormones, and our transmitter function; and then finally your structural integrity, which is all the way down from the cell membrane level and even nuclear receptors, all the way up to your biomechanical structure. All those are dynamically interacting all the time. Chronic disease is really a sign of imbalance in these basic nodes in your network, so my job as a doctor is to find out what are the things that triggered these imbalances? As Sidney Baker says: Is there too much of something or not enough of something? Is there too much of a toxin allergen, microbe, stress, poor diet, and not enough of something like good food, and rest, and movement, and sleep, and connection, and love, and meaning, and purpose? All of these things are really the raw materials for creating health. Where we work, mostly, is to restore those systems into balance through using lifestyle, and using nutrients, and using hormones, or sometimes even medication, but it is done with the understanding that we have to work to reset and restore these nodes in the network. When those are working, health happens. It’s pretty extraordinary. JB: I think you said so many extraordinary pearls, there. It’s like a string of pearls, basically (a necklace). I want to go back and pick up a couple of them because I think they are very…you say them so easily because you’re familiar with them and you are working with them successfully, but for the person that is kind of moving and gaining mastery maybe they need to stop a moment and just kind of take a deep breath—a cerebral oxygenation event—and say: Wow, that’s a powerful concept. Let’s go to the term “nodes.” I think nodes are really interesting as it relates to the clustering of events, and how there is convergence to certain regulatory command centers in our physiology, and how that relates to things like promoter regions of genes, and regulating assembly and expression of families of genes. It has now become fairly well-recognized that genes don’t express themselves one at a time but rather as families that are regulated by these promoter regions that control a cassette of genes that are all interrelated. When you talk about nodes, you’re really looking at where the convergence of these lay lines of metabolic control reside. How does a doc do that? Is it from experience and just asking the right questions and being a good listener, listening to the patient’s story? Tell us how you gain this mastery. Remodel Your Medical Paradigm MH: It’s sort of like building a house. It’s like remodeling your paradigm (your medical paradigm). Instead of the IC9 codes and specialties, which is the original house structure, we have to remodel into different rooms, which are these basic core nodes in your biological networks that I just mentioned. And everything that happens to a patient in the course of their life gets sort of dumped into one of these areas. It’s either an antecedent, a trigger, a mediator, a lifestyle factor, or it’s some disturbance in one of these nodes. If someone, for example, has dysbiosis, or Lyme disease, or has mitochondrial dysfunction, or diabetes, these fall into different areas of those nodes, and often they cross over, right? Because diabetes is a mitochondrial dysfunction, it’s an inflammatory issue, it’s a hormonal problem, it can be related to microbes in the gut and micro-obesity. It can be related to structural integrity related to membrane function and receptors for essential fatty acid composition. So there’s a whole series of different things in each node that can relate to any condition, but you can kind of categorize things in a rough way in these areas of the matrix, and then you can begin to see where the patterns lie—where in any particular person their story will sort of highlight. It will come up in bold relief. You don’t even have to know what you’re doing. I’ve been doing this for 15 years. I do this with every single patient. I have a detailed questionnaire which ferrets out a lot of these issues that are different than most medical questionnaires, and it’s available for free on my website. People can download it. There is a practitioner button and they can get all these forms. Basically it’s a way for me to collect data, and then once I collect that data then I categorize the data in these areas, and I can see on this one sheet of paper what things jump into relief. So if there is an immune/gut issue, well that’s really clear. If it is more hormonal or toxic or nutritional factors, I can really identify what these are very quickly. And then based on that, I can begin to see: Where do I start? Where do we start with a patient? And you just sort of start to reset those systems. It’s something that does take some training, and the Applying Functional Medicine in Clinical Practice and the certification program through IFM are really the pathways to understanding this new paradigm and to remodeling your medical house, so to speak. JB: Let’s first make sure our listeners can find your website: www.drhyman.com. Is that where you would direct them to? MH: That’s right. Yes. JB: When you kind of boil this down to some of the big things that stick out from your experience, is there a short list of things that you have found that often are “a-has” related to the etiology of these chronic illnesses that produce these disturbances? Are there some things you say: “Wow, I never learned about these in medical school but these appear fairly frequently in the patients that I’m seeing? Significant Lifestyle Changes Yield Better Results Than Incremental Changes MH: I think there are a few things that I learned in functional medicine that work a lot. Nothing is going to work all the time for all the patients I have, but there are some few basic homeruns that if you follow these principles you’re going to get great results with their patients. One is to work on the gut, and that’s understanding it, how it becomes imbalanced, what things can go wrong, and what triggers it. Learning how to identify problems with the gut through a good history, through use of antibiotics, hormones, acid blockers, so forth, anti-inflammatories which can cause gut disturbance, early introduction of foods, for example (dairy, gluten, early antibiotics, early history of allergic or inflammatory disorders). We’ll often pick up gut issues. And that’s an important area to learn how to fix. And second is food. Elimination diets are very powerful, and often a hidden cause of many inflammatory and chronic diseases, even obesity, and gluten and dairy are probably the biggest factors. So those things can be enormously impactful when you change diets and see how they impact your patients. And then thirdly, just food as medicine in general. If you do incremental changes you’ll often not see much. But if you do significant changes where you get people on a whole real-food diet that is gluten- and dairy-free, low glycemic load with dense phytonutrients, in a week or two you will see dramatic changes in a patient’s health. They will see it in themselves and they will know that: “Boy, maybe diet does have something to do with how I feel.” And they’ll be willing to make those changes. If you do incremental changes, you might not get the results. In fact, I think that has been the key to my success. I build a close relationship with the patient quickly. I get them to engage and be willing to try something. I don’t promise them that this is the answer to everything, but I say, “Look, this is something that is easy to do, is short term, the outcomes can be dramatic, and you have nothing to lose.” If they buy into that, very quickly they can see that there are significant, significant changes in their health, and that clicks on with them very closely. The other thing—I think, the big homerun—is really understanding metabolic syndrome, and understanding how to deal with that. It’s really truly critical. If we do that, then we can really treat a lot of patients. There are other things like environmental toxins, and mercury, and chronic infections, but those are often the big homeruns in functional medicine. JB: Let me, if I can, take that down to kind of a retrospective of the last few years of the focus of the Institute for Functional Medicine as indicated at its annual symposia. A couple of years ago at La Costa, the focus was on integrative functional approaches towards oncogenic conditions in the cancer realm. We’ve seen a focus on a functional medicine approach to autoimmune problems. And most recently (in 2012, now), a fantastic symposium focused on cardiometabolic syndromes. It seems that it’s very interesting how this model, as you’ve described it, can cut across many different disciplines—what we might call medical siloes or areas of specialty. If you were to kind of get into your wonderful Mark Hyman philosophical chair and talk, at 50,000 feet, how is it this model can apply to such divergent states of pathology as cancer, autoimmune disease, and cardiometabolic disease? It seems like these are very different disease families, with different drugs to treat them, and different specialists who know them. How does that work? MH: It works because at the very heart of systems biology medicine is the idea that most of the diseases that we see are rooted in the same fundamental imbalances, and that if we look at an individual they might manifest as a migraine, or as asthma, or as irritable bowel, or as cancer, or as diabetes, but in the end if you look really down to the root of it, there are disturbances in just a very few key systems. Those are the things we work on: immune system, digestive system, detoxification, energy, hormones, so forth. So these are the things that we really focus on, and if you focus on the root, then the branches take care of themselves. That was sort of the surprise at Saddleback when we did this. You know, it wasn’t even with intervention. We just literally created a healthy living program and within a very short time people had dramatic changes in their health that were surprising even to me because we didn’t really see them as patients, and as we just got them healthy, diseases went away as a side effect. JB: I would call this a shifting huge paradigm in this time of great economic challenge to health care. You know, we’re still trying to figure out a healthcare system out of a disease-care model, and we’re still worrying about reimbursement and universal access, it seems, rather than talking about the type of system that we’re going to put money into and provide access to. As you look forward, probably being in a very unique position having gone to the White House and been in discussion with policy makers about the future of health care, tell us what you see in your crystal ball. Where are we heading and what might we look forward to? Change in Healthcare Will Come from the Bottom Up MH: I think it’s going to be a tough slog in terms of changing health care from the top down. I think we have to do it because it has to be done and I’ll continue to work at it. Maybe we’ll come up with some exciting new interventions, for example next week I’m going to New Orleans to work with the VA to create a functional medicine model within the VA in New Orleans because they have decimated their healthcare system, so it’s an opportunity to create something from scratch, and using the group model with functional medicine. If we can create a pilot program like that, that shows dramatically increased improvement in outcomes and decreased costs, then maybe we’ll catch on. But, it ultimately has to change reimbursement, otherwise things won’t change. One of the other things I’m working on is changing the exams in medical education as required to provide teaching to the exams, like the national boards, and if you can change what’s on those exams and make it more functional medicine, then the schools will have to change. So those kinds of interventions…there may be a few ninja interventions that could sort of shift the system from the top down. I believe it’s got to happen from a grassroots model, and that’s why I started at the church. If we create a huge change in the culture—if we change the way people think about their health and we help them understand what functional medicine is for themselves, then they will demand it, then doctors will be asked about it, then schools will want it, and it will shift. That’s what I’m hoping we’ll do, and so it is really moving multiple levers: education, reimbursement, demonstration projects, and grassroots movements around changing consumers’ demands and values. JB: I think that probably relates to the last question that I will burden you with. You’re the leader of the functional medicine movement through the chairmanship of the Institute and being such a celebrated practitioner of this form of systems biology and health care. How do you see functional medicine as both a discipline and as an institute, changing or morphing to address this global increasing burden of chronic disease and trying to make a contribution to it? MH: Well, the Institute has a five-year strategic plan that’s to raise 20 million dollars to expand our educational platform, and to engage in pilot projects and research programs, as well as collaborate with other organizations that can help extend this model, and we’re active in all those areas. I’m most excited about building a scalable e-learning platform, which we raised almost $300,000 dollars for at the last functional medicine conference, from our own community, in order to actually get this out there into a medical curriculum that can be used, and a nutrition curriculum, in medical schools and residency and postgraduate education, and it can be scaled internationally. IFM is increasingly being recognized as the leader in that field. Washington policy makers are coming to me saying, “We want to make functional medicine education part of the change that’s got to happen in medicine.” It’s not us going out to try to recruit people to our way of thinking; it’s people who have come to it and have now seen the light, and seen the value of it, and see how this needs to be what medicine is, and I’m very encouraged by that. JB: Well, Mark, I want to tell you how privileged we are to have had this chance to visit with you and how really impressed and truly congratulatory I feel for what you’ve accomplished and how you have been a lightning rod for the functional medicine concept and the Institute for Functional Medicine. I’m so impressed by its faculty, by the quality of the people, the dedication, the intelligence, the wisdom, and the tireless work that goes into the Institute from its faculty and staff. I think what you are doing is leading a movement that cuts across a lot of boundaries. It really becomes a system in and of itself that exemplifies systems biology and medicine, so it’s living its own model. I want to thank you on behalf of all of our listeners, and all I can say is keep the energy, take good care of yourself, we need leaders like you. I think the 21st century is going to have its challenges, which hopefully this model will provide some assistance in keeping a healthy population available to address the issues that we’re going to deal with on a global basis in the environment, social structure, poverty, and others that I think we’re going to have to find solutions to. Thank you very, very much. MH: Thank you, Jeff. It’s such a pleasure to be able to do this with you. In fact, how I learned functional medicine was by listening to every single Functional Medicine Update over the years. It has been a huge way for me to stay current and stay engaged and I’ve probably listened to thousands of hours of you. At first I had to keep hitting rewind until I finally started understanding the language. JB: Well, I think you not only understand the language, you’re creating the language now. That’s the sign of a movement when you have really bright, capable, dedicated people picking up the flame. Thanks a million, and we’re going to be traveling with you through your next journey. Be well. MH: Thank you, Jeff. Thank you so much for what you do for all of us.  

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Bibliography

[1] Kluger, Jeffrey and Elizabeth Dias. Does God Want You To Be Thin? Time. June 11, 2012.   [2] Hyman, Mark. The Blood Sugar Solution: The UltraHealthy Program for Losing Weight, Preventing Disease, and Feeling Great Now! New York: Little, Brown and Company, 2012.   [3] May AL, Kuklina EV, Yoon PW. Prevalence of cardiovascular disease risk factors among US adolescents, 1999-2008. Pediatrics. 2012;129(6):1035-1041.   [4] Crisp, Nigel. Turning the World Upside Down: The Search for Global Health in the 21st Century. London: Hodder Arnold Publishers, 2010.   [5] Holman H. Chronic disease—the need for a new clinical education. JAMA. 2004;292(9):1057-1059. [6] Wilson Edward O. The Social Conquest of the Earth. New York: Liveright, 2012. [7] Ali MK, Echouffo-Tcheugui J, Williamson DF. How effective were lifestyle interventions in real-world settings that were modeled on the Diabetes Prevention Program? Health Aff (Millwood). 2012;31(1):67-75. [8] Fisher EB, Boothroyd RI, Coufal MM, et al. Peer support for self-management of diabetes improved outcomes in international settings. Health Aff (Millwood). 2012;31(1):130-139. [9] Lantz PM, House JS, Lepkowski JM, Williams DR, Mero RP, Chen J. Socioeconomic factors, health behaviors, and mortality: results from a nationally representative prospective study of US adults. JAMA 1998;279(21):1703-1708. [10] Abeyta IM, Tuitt NR, Byers TE, Sauaia A. Effect of community affluence on the association between individual socioeconomic status and cardiovascular disease risk factors, colorade, 2007-2008. Prev Chronic Dis. 2012;9:E115. Epub 2012 Jun 21. [11] Alves L, Azevedo A, Silva S, Barros H. Socioeconomic inequalities in the prevalence of nine established cardiovascular risk factors in a southern European population. PLoS One. 2012;7(5):e37158. Epub 2012 May 29. [12] Loscalzo J, Barabasi AL. Systems biology and the future of medicine. Wiley Interdiscip Rev Syst Biol Med. 2011;3(6):619-627. [13] Liu YY, Slotine JJ, Barabasi AL. Controllability of complex networks. Nature. 2011;473(7346):167-173. [14] Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373(9670):1175-1182. [15] Gierman LM, van der Ham F, Koudijs A, et al. Metabolic stress-induced inflammation plays a major role in the development of osteoarthritis in mice. Arthritis Rheum. 2012;64(4):1172-1181. [16] Aktas E, Sener E, Gocum PU. Mechanically induced experimental knee osteoarthritis benefits from anti-inflammatory and immunomodulatory properties of simvastatin via inhibition of matrix metalloproteinase-3. J Orthopaed Traumatol. 2011;12:145-151. [17] Clockaerts S, Van Osch GJVM, Bastiaansen-Jenniskens YM, et al. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study. Ann Rheum Dis. 2012;71:642-647. [18] Conaghan PG. The effects of statins on osteoarthritis structural progression: another glimpse of the Holy Grail? Ann Rheum Dis. 2012;71(5):633-634. [19] Keiler AM, Papke A, Kretzschmar G, Zierau O, Vollmer G. Long-term effects of the rhapontic rhubarb extract ERr731® on estrogen-regulated targets in the uterus and on the bone in ovariectomized rats. J Steroid Biochem Mol Biol. 2012;128(1-2):62-68.   [20] Qin X, Xu M, Zhang Y, et al. Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012;222:307-313.

Welcome to Functional Medicine Update for August 2012. This issue is going to deal what I think is a very interesting topic, and that is how do we get the right database, and the right clinical support, and the right trials to demonstrate the effectiveness of functional medicine in clinical practice? That has been a standing discussion that I’m sure you’ve all been involved with when someone asks you: “Well, give me the references.” Or, “Cite the double blind, placebo-controlled, intervention trials.” Or, “How do you know what you’re saying is true based upon randomized, unbiased evaluations?” Of course, often a clinician working everyday with their patients doesn’t have the time to really be dredging the literature and to spend the time that is necessary to surf through all the various databases to pick out those articles and those studies that really adequately document, to a critic’s capability, the nature of how this form of medicine really provides an effective, safe, and improved patient outcome basis for care.   As we look at this in a broader sense, we recognize that a number of years ago, thanks to Senator Tom Harkin and his advocacy, and then his mobilization of other colleagues such as Senator Orrin Hatch from Utah, the National Institutes of Health was funded to set up the National Center of Complementary and Alternative Medicine (or NCCAM), which was focused on support of appropriate studies and interventions that relate to complementary and alternative medicine. A component of that obviously relates to functional medicine and nutritional interventions. This month we’re very fortunate to have as our clinician/researcher of the month an individual who has been actively involved in the NCCAM-funded studies, and the grant proposal process, and the outcome-based publication of these studies, which helps to build a rich and much more dense body of supporting literature for the safety and effectiveness of some of these therapies that have previously been considered non-scientific only because they were not subjected to the rigors of a good scientific study.   Joel Wallach, DVM, ND Receives Klaus Schwarz Medal When I think of this, I’m reminded of a colleague that I’ve known now since the late 1980s. In fact, when I was a professor of nutrition for the National College of Naturopathic Medicine in Portland, Oregon in the late 1970s, he came in to take over my position as the lecturer in nutrition. His name is Joel Wallach. He’s a naturopath. He’s also a veterinary medicine doctor. He was in experimental work, working at one time for the National Institutes of Health, and he had made an observation back during his time at the NIH that I think is a very interesting observation that was considered artifactual. It didn’t seem to fit into the standard body of logic.   This was not appreciated nor held. You know, there’s quite a distance in time between 2012 and the late 1970s. But over these years, a considerable body of literature has been developed and started to be much more well-appreciated that these relationships between trace mineral deficiencies and insufficiencies and problems as it relates to mysterious symptoms, including that of neurodegenerative-like symptoms, are not totally artifactual.   I was very pleased to see that in 2011 Dr. Wallach was awarded what is arguably considered the most prestigious award in the trace mineral nutrition area, the Klaus Schwarz Award.[1]Many of you know Dr. Schwarz, who was born in 1914 and died in 1978, was an investigator at the University of California, Los Angeles, and was a leading trace metal/trace element researcher and was certainly known for his discovery of the nutritional essentiality of the trace mineral selenium. So for Dr. Wallach to receive the Klaus Schwarz Award is no small compliment to the discoveries that he made early on when he was a post-doc at NIH.   I think we’ve started to recognize that there are all sorts of interesting associations that occur from insufficiencies of various nutrients that are hard to pin down as to the cause and effect, and even more difficult to define a specific mechanism by which those deficiencies result in certain pathologies. I’m reminded, when I think of this, that the origin of most chronic diseases from a mechanistic perspective were not known well at all, and only recently—in the last 10 to 15 years—have we started to see the emergence of pathophysiology at the molecular/cellular level start to be understood for a number of the major chronic age-related, degenerative diseases.   When we start looking at nutrient deficiencies or insufficiencies, many of these have what are called long-latency effects, meaning that the deficiency or insufficiency does not result in an immediate disease like you might have with an infectious organism (a virus or a bacterium), but rather relates to a long-term declining function, which later then produces a disease that has a long latency period, and that this disease may be very difficult to tie cause-and-effect to the deficiency of that particular nutritional element because of this long latency period. It may be sometimes many decades before something like osteoporosis with calcium insufficiency results in the adult.   I think this is one of the complicating factors when we deal with the area of nutrition and pathology, that the origin of these diseases often is masked over this long latent period. But I do want to acknowledge Dr. Joel Wallach’s interesting and very, I think, important discovery that he made as it relates to selenium in primates, now going on 40 years ago, that allowed him to be the 2011 Klaus Schwarz medalist.   Physiological Distress and the Origins of Chronic Disease And that, of course, then relates to a whole series of other interrelated questions about the origin of dominant, chronic, age-related diseases, such conditions like metabolic syndrome, type 2 diabetes, cardiometabolic syndrome, atherosclerosis, that are associated not just with dyslipidemia but with dysinsulinism. What is the specific mechanism of action or the origin of these particular diseases? I think it is easy to say, “Well, there must be a single gene that somehow is impaired or mutated, or there is a SNP that causes these conditions to occur, or there is a specific variable like an infectious organism or a toxic exposure that causes these diseases. But rather as we examine them in the light of 2012, what we recognize is that these diseases—their origins—fall into the same category that Hans Selye was talking about with stress-related diseases in the 1950s and 60s.   You recall, if you followed Dr. Selye’s stress model, that he indicated that physiological distress, as responded to by an animal in response to a changing environment, disturbs the web of metabolism and physiology in such a way that multiple outcomes in terms of pathophysiology can be seen. In his animal studies he showed it could be wasting disorders and what you might call metabolic sarcopenia or muscle wasting. Or it could be such things as cardiac conditions. Or it could be such things as ulcers. Or it could be such things as diabetes. Or it could be even such things as increased risk to a carcinogenesis. So the outcome of the condition is variable. The input that causes this disturbance in physiology is the individual organism’s response to their environment, seeing their environment as a hostile, threatening environment in which they mobilize, against this perceived threat, a disturbed metabolism.   Disturbed Metabolism is Normal Metabolism—Up to a Point Now we call it disturbed metabolism, but maybe a different way of actually contextualizing this is to say it’s a metabolism that is actually responding as it should based on the genetic messages that are preprogrammed from the lineage of that organism’s history (that person’s history). And so what we call a disease is really the appropriate response to a foreign exposure, or let’s call it a hostile exposure, that somehow gets locked in the “on” position, so that what was the normal adaptive response to a changing environment (a hostile changing environment) now becomes harmful to the organism itself, and we call that a disease.   So the disturbance of metabolism may, in the first stages, actually be the appropriate response to that perceived hostile environmental change. It’s only when it gets aggravated in response or locked in the “on” position that over time it then starts to produce its own untoward effect on the structure and function of the organism that we call later a disease.   That model holds very nicely for conditions like metabolic syndrome, syndrome X, hyperinsulinemia, and cardiometabolic disorders, which we know are very closely related to this gene-environment interaction. In fact, there are a number of very nice papers that have been published over the past few years that have really tried to explore this study of genes and their relationship to environment, that then signals to the organism a change in physiological status that later we diagnose as hyperinsulinemia, glucose impairment, and metabolic syndrome.[2]   So you think of genes like, for instance, the peroxisome proliferated activated receptor genes (the so-called PPARs). This could be PPARα, or it could be PPARγ, the one that has received so much attention with the thiazolidinedione drugs for the treatment of diabetes, which we know these drugs have been labeled as PPARγ agonist drugs. We recognize that there is PPARγ-Δ, and all of these have differential effects on modulating gene expression as orphan nuclear receptor signaling substances. We also know that genes like apolipoprotein E, and we know apolipoprotein E2, E3, and E4 have influences on lipid dynamics, on glucose dynamics, oxidative stress, and redox potential. Similarly, genes like glutathione s-transferase, both T1 and M1, have been identified to be very important in modulating insulin sensitivity, oxidative chemistry, mitochondrial oxidative phosphorylation and its relationship to type 2 diabetes.   We could go on and talk about literally hundreds of genes that have been implicated in different configurations and different expression patterns to be associated with the disturbed metabolism that we later label as type 2 diabetes. Now we might ask the question: Does that mean that type 2 diabetes is a singular disease? Or is it really just the manifestation of what we would call dysinsulinism and dysglycemia, of which the origin of it could have come from myriad different factors that are genetically unique to that person, based upon their gene environment interaction, and how that over a period of time (the so-called long latency period) leads to decreasing insulin sensitivity, increasing dysglycemia, and later crosses that magic boundary of a fasting blood sugar >100, which we will diagnose as diabetes and later elevated hemoglobin A1C.   The Events Associated With Disturbed Physiology These are, I think, important philosophical questions, but more importantly I think that they are really important clinical questions, because they start asking us to look earlier in the sequelae of events that are associated with disturbed metabolism/disturbed physiology, that are reflective; kind of like Plato’s “Myth of the Cave”—we’re looking at the reflections rather than the fire. We’re looking at the shadows on the wall of the cave when we start looking at the transition in these biomarkers, things like postprandial insulin, postprandial glucose that we see with an oral glucose tolerance test; drifting towards higher levels of hemoglobin A1C, going from 5.2 to .3 to .4 to .5 to .6 and moving up towards 6, where we see increasing levels of high sensitivity CRP (hs-CRP), knowing that there is a connection between chronic inflammation and dysinsulinism in type 2 diabetes; things like uric acid that start to drift up. All of these are indicators of a disturbance in metabolism that is resulting from altered cellular physiology from a change in the gene/environment interaction. The earlier we can understand that, in the functional medicine/systems biology model, the better off we will be able to intervene with less aggressive—less  invasive—therapies to modulate that disturbance by taking away the precipitating events we call the initiators that alter this gene expression pattern into that that we later associate then with this condition of metabolic syndrome.   Metabolic Memory: A Response Pattern of the Genes There is another kind of wild card at play here that I think, again, argues strongly for why we would want to intervene earlier with the functional medicine model. And that is it has been recognized, and you’ve seen this if you’ve been following Functional Medicine Update for the past few years, that the emerging understanding of epigenetics is starting to help us to recognize that certain environmental features that the organism is exposed to ultimately may lock in, or let’s call it “label” with these epigenetic marks, the genome in such a way that it changes gene expression patterns. I don’t want to call it adaptation to the environment. What I would call it is that genome becomes conditioned by the environment, and in so doing it becomes more difficult, then, to change the expression patterns once you’ve put these marks on the genome—these methylated promoter regions of genes, or change the histone acetylation patterns, or change the ubiquitination patterns, or the phosphorylation patterns that are all associated with epigenetic modulation of gene expression. Once those are locked in you then develop what might be called metabolic memory. And metabolic memory is a more difficult thing to break because now we’ve kind of hard-wired that organism into a certain response pattern of their genes, and it becomes more difficult, and maybe more necessary for aggressive therapy, to wipe off those marks and put on new epigenetic marks that would allow a metabolism to result that is less disturbed, less distorted.   Large randomized studies have established that early intensive glycemic control in the diabetic reduces the risk of complications, both in terms of micro- and macro-vascular disease. Epidemiological and prospective data support a long-term influence of early metabolic control in clinical outcomes.[3] This phenomenon has been defined, as I said, as metabolic memory, which I think is now starting to be recognized mechanistically as tied to epigenetic alteration over time. The genes get conditioned to that environment. By the way, this same thing seems to hold true for pharmacology—that long-term administration of specific medications have been found to alter the methylome or the epigenome, so that you’ve actually changed, on a kind of metabolic memory basis, the way that specific genes are expressed by long-term exposure to specific types of pharmacological agents.   This mechanism for propagating this memory is the production of species that ultimately alter the way the genes and way the proteins are going to modulate metabolic function, things—as I mentioned—like methylation patterns, acetylation patterns of the genome, even things like protein glycation, like advanced glycosylation end products, which modify the way proteins actually do their work.   Metabolic Memory May Require More Aggressive Intervention The reason I am going into some detail on this is that as you intervene with a patient that has this kind of stuck metabolism, this metabolic memory, you have to recall that you may be working uphill a little bit against epigenetic conditioning that may require some more aggressive intervention. That’s why sometimes very dramatic nutrition programs are used that dramatically alter dietary habit patterns and create kind of a frame shift in the way that the genome is receiving signals from the environment. So it could be things like detoxification programs. It could be—in the chemically sensitive patient, like those who have multiple chemical sensitivity (MCS)—a completely pristine environment for a while, just to completely alter the signals the genome is getting.   A Meta-Analysis of Metformin Efficacy The alternative of this, obviously, is polypharmacy, and we do know that polypharmacy has been used in medicine for the management of complex disorders associated with metabolic disturbances. One of the principal drugs, as you know, that is used in the management of type 2 diabetes is metformin. It’s the first line of therapy. Metformin has a history of safe use, reasonably. It has a history of efficacy. But I found it very interesting that recently there was a reappraisal of metformin efficacy in the treatment of type 2 diabetes, doing a large meta-analysis of the published randomized controlled trials.[4] I want to be very cautious. I don’t throw the baby out with the bathwater when I go through this because you might take away that I’m a nihilist around pharmacotherapy. That’s not the point I’m trying to make. The point I’m trying to make is the nature of the heterogeneity of these conditions and how in one patient something might work very well but in other patients not. Because when you do a meta-analysis of the large-scale randomized controlled trials on metformin in the treatment of type 2 diabetes—this is 13 randomized trials with 13,110 patients—what you find is that the metformin, although considered the gold standard, its benefit-to-risk ratio remains uncertain when we look at it from a meta-analysis large perspective. There is a potential, obviously, of a statistical reduction in all-cause mortality, but this is a range of effects, all the way from that which has been proven to reduce all-cause mortality to that which has been shown to increase all-cause mortality, with the same medication. So, wide standard deviation of variation, marginal improvement when you look at the averages of these kinds of trials on the average patient, so then you start asking: Is the drug a good drug? In the right patient under the right conditions, the answer is yes.   Gut Microbiota Correlates to Type 2 Diabetes and Insulin Resistance The point I’m trying to make is there is no one panacea for these complex disorders of chronic disease. They are heterogeneous in their origin: multiple genes influenced by multiple environmental changes. We even learned recently that environmental change called our gut microbiome is a big factor that modifies insulin sensitivity. In fact, there are now  papers that are being published, one by our colleague at the Universite Catholique de Louvain in Belgium that looked at the gut microbiome in the development of low-grade inflammation and type 2 diabetes that is associated with obesity, finding that there is a very close correlation between specific types of microbiota, the interrelationship with the diet, gut permeability, and inflammatory connection ultimately to type 2 diabetes and insulin resistance.[5]   So we need to keep our field of vision wide open when we’re in the functional medicine model. We need to move it to earlier understanding of trajectories towards changing metabolism. And we need to recognize that these diseases don’t have a single origin. They have multiple origins from complex interactions of genes with environment that require personalization of therapy for maximum effectiveness. Whether drugs are used, or lifestyle interventions are used, or the combination, one needs to be very aware of this complexity of interaction between the environment and the genes of the patient, so that the program becomes personalized.     With that said, I think now we’re ready to really talk with our clinician/researcher of the month, Dr. Chris D’Adamo, who is going to tell us a little bit about how all this plays out in the medical school environment, in the NCCAM-funded studies, and how we’re starting to build a rich body of literature and clinical support for what I consider to be the medicine of the 21stcentury.

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INTERVIEW TRANSCRIPT

Researcher of the Month Christopher D’Adamo, PhD Center for Integrative Medicine University of Maryland School of Medicine 655 W. Baltimore Street Baltimore, MD 21201 cdadamo@compmed.umm.edu August 2012 Here we are at that place in Functional Medicine Update that all of us look forward to with great anticipation. For you it’s probably a little bit of a surprise: Who will Jeff Bland choose for the interview of the month? It’s not an easy thing to make these decisions. As you know, we’re so fortunate in our field of functional medicine to have so many remarkable contributors—clinicians, researchers, educators, people who really bring tremendous breadth of talents and experience to the field and are really germinating the field, causing it to evolve at a very rapid rate. But I am always very impressed as we start seeing new energy come into the field, individuals who have diverse training and background. I don’t want to say they are in the first part of their career, but let’s say in the earlier part of their career, and they start to affiliate with the functional medicine model and bring to the field some new talent, new energy, new capabilities that I think are going to make the field even more robust and more effective. That is, of course, a longwinded introduction into this month’s researcher/clinician/educator on Functional Medicine Update. Let me say a little bit about him. I had the opportunity to meet Christopher D’Adamo a number of years ago, and more recently we spent some time together at the integrative medical conference hosted by the University of Maryland integrative medical program. Chris is just a remarkable guy. He was not only involved with the organization of the meeting which went well—very well attended and very smoothly run—but he also was one of the keynote lecturers and was giving multiple presentations on multiple topics and connecting with the majority of the attendees on a personal level as an ambassador to what we’re all about. He just struck me as the exact right energy, right enthusiasm, and right knowledge base. As I got to know Chris a little bit better I recognized that not only is he quite remarkably talented, but his background also reflects a very interesting and diverse set of experiences, going all the way from a certified personal fitness trainer to a nutrition consultant (certified) to an assistant professor at the University of Maryland School of Medicine, with a primary appointment in the Department of Family and Community Medicine and a secondary appointment in the Department of Epidemiology and Public Health. He has his Bachelor’s from the College of Holy Cross in mathematics and pre-med, but then went on and got his PhD in epidemiology. He is an Epidemiology of Aging Fellow at the University of Maryland in the Department of Epidemiology and Preventive Medicine. Obviously I could go on and on, but I think what you’ll learn as we have a chance to talk with Chris is that he has brought this wide range of diverse experiences into really the same mission that all of us are aligned to, and that is finding more effective ways to both prevent and manage chronic disease. He background and experience I think provides a very unique way of looking at what I call personalized lifestyle medicine and how that interfaces with functional and integrative medicine. With that, Chris, we can’t tell you how much we are very pleased and privileged to have you as our clinician/researcher/educator of the month, and welcome to Functional Medicine Update. CD: Thank you. It’s my pleasure. That’s a very flattering introduction and I’m looking forward to the discussion today. JB: Let’s start like I do with all of our invitees/interviewees, and that is with the question about how your path of life took the tributary or took the juncture into the University of Maryland, the integrative medical area, and ultimately into the position that you find yourself as a faculty. It must have been a very interesting journey. Tell us a little bit about how you got there. Lifestyle Issues Did Not Play a Role in Hospital Care CD: It has been an interesting journey with a lot of different stops along the way. You know, you trace some of it in your introduction. I was math/pre-med in undergrad. I had always wanted to be a physician and had followed that track. I was fortunate to have won a fellowship at Johns Hopkins Hospital going into my senior year of undergrad in medicine. The experience was eye-opening and enlightening in a number of ways. During that experience it became clear to me that I was interested in a different style of medicine. I had always been a lifestyle enthusiast. I was an athlete, so I believe in the virtues of exercise and eating right and I had been learning a little bit about stress management, and I came to witness that didn’t play a very big role in what I was seeing in the hospital. To me, I was a little more interested in proactive prevention of disease and promotion of health and a less reactive approach. It kind of threw me a little bit. I had taken the MCATs, I had done all the steps, and I decided not to go into medicine and I took a divergence into healthcare management consulting, which was also a pretty enlightening experience in many ways, just to see how the business of medicine and health care worked. But at the end of the day, I was still very interested in the science and helping people and the lifestyle component, which again wasn’t really there. So I decided to take up personal training in my spare time on weekends and got some certifications in that and nutrition as well. I worked with clients and was really just blown away with the results I saw from basic lifestyle interventions. Getting people off their blood pressure meds, losing weight and so on, which you’d expect and I think that is very important, and then the ability to kind of ameliorate autoimmune disorders that people were having, digestive problems, and I really saw how this lifestyle stuff is pretty powerful. I wanted to kind of “up” the level of education I had in that and study it more formally, so I chose to get a doctorate in epidemiology at the University of Maryland School of Medicine to apply rigorous methods to the study of lifestyle medicine, mainly exercise and nutrition. That’s what got me started on this path, and I can say that functional medicine principles—reading the blue textbook several years ago—was very formative for me. I was very fortunate to get hooked up with Dr. Brian Berman at the Center for Integrative Medicine and it’s just been a real blast so far. University of Maryland has Support from Key Government Officials JB: Let’s talk a little bit about that connection with Dr. Berman. Those of us in the field recognize both he and his wife as really fundamental pioneers in this whole integration of these concepts that fall under integrative and functional medicine into a medical school teaching environment and clinical environment. It’s quite an ambitious project that the two of them undertook and were successful. I was very impressed at the conference when I saw the number of influential people in the government within the state of Maryland who are supporters of the center and who have been very actively involved in making sure that it has adequate funding and support for its go-forward future. Tell us a little bit about how the center is disposed, how it interfaces with the medical school, and your role and your present position would kind of juxtapose between those two. Education, Research, Clinical: A Three-Pronged Approach CD: Absolutely. We’ve been around for 20 years. We celebrated our 20th anniversary last year. It’s essentially a three-pronged approach to what we do. We’ve got a robust education program for medical students. The bread and butter has probably been the research, where we have really led the way in terms of bringing rigorous methods to the study of integrative medicine, acupuncture, mind/body medicine, nutrition, and so on. And then we’ve got a clinical presence as well, where we see patients. We have physicians, many of whom have followed the functional medicine model. So it’s three-pronged and I can tell you it is very exciting to see how integrated we’ve become in the school of medicine. We have an elective course, which I can talk about in more detail, for fourth-year medical students, but we have exposure at all levels. Everybody in the second year is taught some principles of integrative approaches to pain management, which is a big problem that mainstream medicine doesn’t have all the answers for, as well as stress management. We’re working with shock trauma quite closely, as you recall from the conference, and we were very happy to have you there. Dr. Tom Scalea is the head of our shock trauma center and has welcomed us with open arms and an integral part of what they are doing there is bringing these modalities into the trauma center. We’re forming collaborations in different departments. I’ve got an appointment in epidemiology and public health, so we bring our perspective there. We’ve got people in psychiatry. The ideal goal is almost to lose the label “integrative medicine” and just become ultimately “good medicine.” I think the way to do that is to get assimilated into all the other departments and reach them with evidence, and that’s one of the main things we’ve done: the modalities we talk about, and treat patients in the clinic, and teach and research are backed by evidence. JB: I want to really compliment you and the whole team there with Brian (Dr. Berman). I think that you have really accomplished that—being the image of integrating your concepts into the body of medicine at the larger scale, and I think that takes a lot of skill to bring something that’s different into a form that can be created or assimilated into peoples’ other systems of learning or systems of observation, and sometimes they don’t even know it’s happening. It’s almost like the Trojan horse model. I think you have done this very, very effectively. I also was very impressed, at the meeting, with the advocacy of Senator Mikulski from Maryland, who clearly has a tremendous amount of respect, and admiration, and support for the program that you are engaged in there, and being a person of extraordinary importance in the Senate—being on the committee that relates to health care, being one of the senior members in tenure—it seems that that relationship has been very vital. Can you tell us a little bit about how you handle things like government relations? It sounds like you’re doing a good job. Some Law-Makers Understand the Need to Change the Healthcare System CD: Sure. Senator Mikulski’s one of our biggest supporters. She spoke at the health and wellness conference this year, and she spoke at our 20th anniversary last year. It is critical to have that backing. I think she and many others understand that the current healthcare system can’t continue on the way it is. It’s not financially sustainable. The modalities that we’re talking about, and self care, and lifestyle medicine, it’s unquestionably more cost effective to prevent disease than treat it, and if we get to these biological underpinnings then it just makes sense that that’s how we’re going to quell the bleeding in the healthcare system. She has been a great supporter and I think it has been very helpful for us to have her support and the support of others in the federal government. That includes the National Center for Complementary and Alternative Medicine, which has funded quite a bit of our work over the years. We’re an NIH Center of Excellence, which helps get buy-in within our own school of medicine, but the greater model, as well, is to have credibility in a sense from doing good research and having the backing of people like Senator Mikulski. JB: I think that’s a great segue, Chris, to the next question. You talked about the three-prongs that you are involved in. Let’s start with prong one, which you’ve already segued to, and that’s the NCCAM sponsorship of research and how you focus your research, the kind of projects you’re engaged in. Could you tell us a little bit about that, because you’re really doing some very interesting things across a wide range of topic areas? NCCAM-Funded Research CD: Right. The center in general has done an incredible amount of work in acupuncture. They’ve published studies in the Archives of Internal Medicine and other high-impact journals.[6],[7] They’ve done quite a bit of work with stress reduction and so on. My personal interests are in nutrition and exercise. I’ve done work in the past—published some papers—looking at the carotenoids and vitamin E and how those predictors function in older adults.[8],[9] I’ve looked at those same micronutrients and showed they are associated with lower levels of inflammatory cytokines. We know that inflammation is an underlying cause of many diseases. I know this is an interest of yours as well. Nutrigenomics—I’ve started to get into that a little bit more and we’re looking at those same micronutrients. We’re interested in vitamin E and the carotenoids because they’ve been associated with lower risk of a host of diseases, and we’re looking at variance on SNPs that predict higher and lower concentrations of those. We’ve seen that two people can eat a tomato and you’ll have very different levels of lycopene and so on. Apo B and apo E seem to have some impact on serum levels of these micronutrients. I really think getting to the biological individuality of people, I think this is one way to kind of really say it’s not one-size-fits-all, both when it comes to nutrition but also to these other modalities. Those are some projects. I’ve got a real interest in nutraceuticals. We’ve got a couple of studies. One with a mushroom blend of shiitake and maitake mushrooms, looking at how that prevents the common cold. We know these particular mushrooms and the alpha and beta glucans contained within them stimulate the immune system, and lots have been traditionally used for cancer and many other conditions. That’s a really interesting study we’ve got going on now. Another is a probiotic formulation to improve symptoms of acid reflux. People are very quick to reach for the proton pump inhibitors. We’re starting to see now that they can deplete B12 and inhibit vitamin B12 absorption, which can lead to H. pylori infection and perhaps some risk of bone fractures. We’re really looking at some nutritional solutions to problems that are affecting many. That’s some things I’ve got going on at the moment. Is Nutrigenomics Dead? JB: Let’s go back and pick up a little more detail. You’ve given us a pretty good smorgasbord there to select among. Let’s talk first about this nutrigenomics issue. I had a very interesting conversation last week with the woman who is the senior professor in charge of the nutrigenomics efforts in New Zealand at the University of New Zealand in Auckland (and at the medical school). She had made the point in a discussion that we had that it is now thought by people in the New Zealand power structure (in terms of the government) that the concept of nutrigenomics is dead. Its day has come and gone. It never really achieved its highly touted importance, and it was just a fad of the moment. What’s your thought about that? By the way, I can go into more detail about why some people are saying that. She doesn’t clearly believe that, but I’m wondering what your thoughts are. CD: That’s the first I’ve heard of that notion. I think it’s alive and well. In my eyes, I feel like we’ve just scratched the surface. The study that we’re doing is looking at predictors—these SNPs or variance on SNPs to predict concentrations. But I think if you look at some of the other literature on the way that certain foods impact genetic expression—if you look at NFκB and curcumin—a lot of good research there. One of the studies I really like was looking at broccoli, sprouts, and sulforaphane and its potent HDAC-inhibiting properties. I think it’s pretty clear that foods, and food components, and nutraceuticals can have an impact on genetic expression. As far as it being a dead area that has come and gone, I personally don’t view it that way. JB: Yes, I think that your point is well taken. The individuals who are criticizing, I believe are taking a very monotonic view of it. What they are saying is that these SNPs don’t really tell us exactly what the phenotype for the individual is. They just really tell us about the landscape of potential, and therefore they are really kind of useless because you really need to know more the phenotype in order to understand how an individual will get sick or be well. I think they are missing the point that the landscape is in part determined by the potentiality of the genes and their susceptibilities and strengths. And the environment interacting with those genes is what gives rise to the expression, which gives rise to the phenotype. You don’t want to throw the baby out with the bathwater and say that the genes and their uniqueness are not important. Mendel is still alive and well in terms of understanding aspects of inherited characteristics. How would you respond to someone that says: “Well, the genes are just there. It’s really how it is expressed and we don’t really care about the genes.” How would you respond? JB: I think I would agree with the points you made. It may be not seeing the forest for the trees. I think we’ve really only scratched the surface and as the methods continue to evolve we’ll be able to answer the questions perhaps more directly and with a little bit more precision. I think it is kind of missing the point in many ways, so I would agree with your retort. CD: You made another very interesting point about your research, which I think almost supports what we’re talking about, and that is the apo E and apo B genotypes. Often people feel, I think, that the absorption of nutrients just occurs passively. So you just increase the concentration of a nutrient in the intestines and somehow it pushes its way, through passive diffusion, into the blood so it improves bioavailability. But as you pointed out, there are—for many, many nutrients—transport proteins and very conducted-tour-type of absorption processes that are not so simple as just mass action. They actually have pumps that pump things in and pump things out, and these are controlled very tightly by regulatory proteins, and those are then obviously intimately connected to the genes of the individuals. So if you had an apo E4 individual, they have a very different absorption for specific types of fatty substances than does an apo E2 or 3. I think you have already, through your research, started to confirm it’s a combination of these genetic archetypes with their environment. In fact, maybe you can tell us a little bit about what you’re seeing in terms of bioavailability and apolipoprotein genotypes. Teaching Medical Students About Popular Diets CD: Our results have not yet come in, but looking at the literature that is there now, I think it is pretty clear that these things have an impact. Where I would really like to go with this is to a macro level. There is some evidence, looking at the macronutrient composition of diets, that some people respond more favorably, based on SNPs, to lower carbohydrate diets versus higher carbohydrate/lower fat diets. At this juncture we’re looking at the micronutrients, but I’d like to see it applied to whole diets. It’s one our educational endeavors—actually teaching popular diets and getting into what’s really practical. Ultimately it is what can a physician tell his or her patients? What’s the right diet for them? I think it goes beyond the absorption of particular micronutrients, but I think this work that we’re doing now will build towards looking at diets on a grander scheme and seeing genetic predictors of response to diets. There have been some studies. I’m not sure if you’ve read the one, but I think there was one that showed certain variants people responded better to a lower carbohydrate diet and others responded better to a lower fat diet. I think that is where I would like to take this on a grander scheme ultimately. JB: I think that’s really well said. In fact, I think just recently in the American Journal of Clinical Nutrition, the DIOGENES study was published that is evaluating exactly what you are talking about: looking at genetic patterns in SNPs that associate themselves with better response to certain types of diets, which once again reconfirms what you said—that there is no such thing as the perfect diet for everyone.[10] There are individual responses based upon these metabolic characteristics. I think where you’re heading is exactly where the field is heading. CD: That was the study I was referring to. And this applies even beyond diets. I think that this could provide a mechanism for the fact that it’s not one-size-fits-all for a lot of things. That applies to certain exercise modalities, and that would apply to mind/body approaches, or meditative approaches work better than others for certain people. You see certain federal dietary guidelines trying to make it one-size-fits-all for everyone. I just feel like it’s not as simple as that and we’d be better served to really personalize our approaches with lifestyle based on both personal preference and perhaps informed genetic associations as well. Throughout our education, research, and clinical efforts, none of our approaches are one-size-fits-all. We have to really look at personal preference.I In my practice as a personal trainer and nutritionist I saw that too. Some people respond and really enjoy resistance training. Others don’t. Others might prefer yoga. Me, if I try to do yoga I end up getting stressed because I’m so bad at it, but I love doing resistance training. So I think we need to take that approach across the board, and really remembering it’s not one-size-fits-all across all the modalities that we recommend to patients and that we work into our own lives. Recent Controversy About Curcumin Efficacy JB: I’d like to go back and pick up another interesting thing you had mentioned earlier, and that’s this curcumin story. If we were to look at the phytonutrients that have a reasonable amount of science based on their effect on cellular physiology, I think curcumin would rank right up in the top few, and maybe licorice would be up there too, and a couple of others. But certainly we would see curcumin. There has been a pretty significant controversy that has bubbled up here the last few months, unfortunately around one of the principal investigators in the curcumin area. That’s Professor Aggarwall. And it’s kind of put a little bit of a color on the curcumin literature. Do you have any opinions about curcurmin, or about this literature, or about this controversy? CD: Yes, well, it is a little unfortunate because I think there is a kind of potential there. We hosted a CME training in Ayurvedic medicine this past weekend for physicians. Turmeric has played such a role in Ayurvedic medicine for thousands and thousands of years. And the turmeric, from which curcumin is derived, to me is something that I think does have quite a bit of potential. It’s unfortunate what’s happened there, but I still think it holds great potential. There’s a lot of talk—I’m not sure how relevant this really is—about the absorption. There have been studies that have shown that when you administer curcumin with pepper the absorption is increased.[11] We have now looked at some fat delivery vehicles also. I think people would be well-served to at the very least include turmeric in their diet. If you look back at the traditional ways it was consumed, it was typically consumed with ghee, so there you get your fat to enhance the absorption of lipid soluble curcuminoids, and a lot of times with pepper. So I think it is an interesting example of how if you look back at history and traditional usage of many of these herbs, the science is now corroborating what had been practiced for thousands of years. I think curcumin holds some real promise. There is some evidence with autoimmune conditions, and certainly with inflammation it’s powerful. I think it is something to consider. JB: I think you are hitting on some really important points. I had the pleasure of meeting, and actually spending a couple of days at a meeting with Dr. AJ Goel. Dr. Goel is a gastroenterology researcher at Baylor School of Medicine in Dallas, and has published many papers that are really quite dramatically precise about gastrointestinal function, and carcinogenesis, and colon cancer (this is his specialty research area).[12] But he has also done a reasonable amount of very good work—published work—in the curcumin area (curcuminoids and GI function).[13] One of the things that we talked about is that it is always assumed that these phytonutrients must be absorbed into the blood like a drug in order to be effective. But as he points out, the curcuminoids have a very powerful effect on receptors that reside within the gastrointestinal lumen (on the cells of the gastrointestinal lumen). And these mucosal cells pick up information and they can be signaling cells to the rest of the body through the information that is translated through the curcuminoids on their membrane-bound surfaces, and therefore you may not require a high level of absorption to actually have a physiological effect. The effect may be mediated through signaling that occurs at the GI mucosal level. I think that these questions are still open, and I believe that the pharmacological models that we’ve used—you look at pharmacokinetics absorption and then you try to track that to physiological effects or potency—may be somewhat limiting as it relates to some of these nutrients that are signaling through the gastrointestinal immune system. So, just a thought as we see this field opening up that maybe absorption is not the full answer to the question. CD: I couldn’t agree more. I think we’re trying to fit a square peg into a round hole, so to speak, and trying to make it fit the current pharmacological model. Take turmeric, for example. The curcuminoids are part of it, but there are other beneficial components there as well. It may not be a story of maximum absorption to get maximum benefit. I think we’re focusing on something that may not be of utmost importance, and so I agree. JB: Let me ask you a question about the NCCAM research award process. Have you been…I don’t want to say pleased because anybody that’s involved with grants can’t always be pleased because it’s a very competitive process, but let’s say have you felt satisfied that the NCCAM grant process for complementary and alternative medical research is still robust, or do you feel like it’s a dying breed? Where are we right now? NCCAM Funding Reflects Choices Consumers are Making CD: That’s a good point. I mean, it’s challenging, and it’s becoming more challenging as time goes on as the budgets are not being increased. These are important research questions. There was a relatively scathing commentary recently about someone saying that NCCAM funding—I think it was in the New England Journal of Medicine as an editorial—should be reduced, because of some claims that they weren’t finding positive results.[14] But the fact is, these are important research questions.Dietary supplements is one of my big areas, and you’ve got half the population taking a dietary supplement, and many people taking several dietary supplements. We need to find out how well these work, and that’s where NCCAM comes in, so the criticism, to me, was missing the point. These are important research questions. People are using integrative medicine modalities—70 percent, actually, according to a National Health Interview Survey—at least in some form.[15] Mind/body techniques, nutritional therapies, yoga or movement, so we need to find answers to these questions. I think the criticism is really missing the point, and it is challenging. We’re very thankful that NCCAM is there. I mean, we feel the funding needs to continue to really bring evidence one way or another, so we can determine the modalities that are effective and distinguish those from those that aren’t. JB: When you set up research designs, sometimes the way we might approach an NCCAM research hypothesis or question might be very different than using a double-blind randomized placebo-controlled trial, which is often that methodology of research that is very suited for single agents against single endpoints. How do you deal with some of these complexity issues in setting up your research designs? The Importance of Comparative Effectiveness Research CD: If we look at the acupuncture research history that would be indicative and convey the point well. Again, it doesn’t fit the reductionist single molecule paradigm of RCT (double-blinded, randomized, controlled trial), because what they’ve done with acupuncture is they have had more and more elegant ways to do a sham control, where there is no actual insertion of the needle, it just touches the skin, and it is a very elegant method to respond to a criticism that this is placebo. But the issue is that that experience in and of itself has some therapeutic benefit, just the interaction with the practitioner, the touching of the skin, and so on. It’s not a single molecule. The RCTs work very well for studying drugs or single molecules, but it doesn’t work very well for something like acupuncture, or whole diets in my opinion either. It’s a challenge, and as we get more into comparative effectiveness research I think we can look at whole medical systems—a functional medicine approach, an integrative medicine approach, Ayurvedic medicine, traditional Chinese medicine—where we are comparing the entire practice as opposed to very standardized single modality-type approach that just doesn’t work very well for non-pharmacological interventions, to be quite honest. JB: I think you, again, did a very nice job of describing that. This concept of comparable effectiveness versus biomarker modulation as an endpoint is a very interesting philosophical difference of how you approach. And seems to tie also to the increasing concerns that some people are having about what appears to be research misdirection, research that comes back positive that doesn’t actually prove to be correct later. People are now saying: “You really need longer term outcome studies. You need to look at endpoints that are not just a number of a biomarker, but how did the person do?” You might change the biomarker and they died at the same level or maybe even sooner. I think what you are raising about comparable effectiveness is a very important point. I’m sure it is something you have to do a little education on to people who are very imbued or imprinted with the RCT model. CD: You’re right. We believe in individualized medicine, and I think there is great recognition that that is the approach we need take. By definition, in an RCT you want to have as standardized an approach as possible and that’s sort of in conflict with the practice of medicine—the individualized practice—that we are all starting to recognize (or many of us, at least) is most beneficial. Comparative effectiveness study—in research you’ve got your paradigm of efficacy, which is an ideal control situation. Everyone gets the same thing and the same control situations versus effectiveness, which is sort of a real-world, how-does-this-thing-work type of approach. Comparative effectiveness research is much closer on that spectrum on the effectiveness side. Let’s take someone with back pain, for instance. That involves different etiologies, and if we apply the same approach to everybody with that, chances are you’re not going to find out from a result, whereas if we really get to: is it someone’s stress, is it a highly inflammatory diet, or is it lack of movement? In an individualized approach you could distinguish that with a discriminating eye, and then you can study this on the whole-system level. That’s what comparative effectiveness allows you to do. It’s not as controlled. It’s more of a real-world environment. And there is a movement towards this. We heard a little bit about it with comparative effectiveness in the sense of comparing drugs. There was some talk about it a year or two ago and it didn’t really pan out, but as far as studying whole medical systems and practice styles, I think comparative effectiveness is really the future. Recently there was the Patient-Centered Outcomes Research Institute (PCORI), a federal agency that is going to fund comparative effectiveness research. This is really the way it needs to go to reduce healthcare costs and to improve patient care. Introducing Integrative Medicine to Medical Students JB: Let’s move from this kind of focus on the research base to prong number two, or platform number two, that you discussed, which is education. You had alluded to earlier the fact that you’ve got this very interesting elective course on integrative medicine for fourth year medical students. Tell us a little bit about how that has been picked up. Is something medical students look forward to? It is good it is in the later year; it is not in the basic science first two years where they are just totally overwhelmed. Tell us a little bit about this experience. CD: I’ve got to tell you, it’s an incredible experience, simply put. We have about 15 students per year. We keep it that way. It is highly competitive to get a spot because it is an experiential course. It focuses really on self-care, lifestyle medicine, all the modalities. So some of the things we do: they learn about acupuncture, they learn about TCM, they learn about mind/body medicine, meditative techniques. My focus in the class is on nutrition and exercise, so I look at dietary supplements, and I lead a popular diets whole day where we look at the Mediterranean diet, Atkins diet. I talk about alternative laboratory testing, so the functional medicine practitioners—what’s of interest to them. We do Metametrix, Genova, all those tests that are out there. We do integrative oncology. And I do an exercise session, so I actually lead the students in a home-based exercise session because they’re so busy. That’s one of the things we see with exercise—people say they don’t have time. But I can teach them a 15-20 minute exercise program that they can do from home and they can recommend to their patients. It’s just highly experiential, and the feedback that we get on the class is not only has this expanded their tool set with modalities that they can bring to their patients, but they themselves reduce their stress because they’re doing guided imagery, they’re getting to do healing touch, they experience all these things. We even have equine therapy where they go out and interact with animals. So it is something to really broaden their horizons beyond kind of the standard pharmacological approach that they get during the first three years of medical school. We like it because they’re going to be out practicing the next year and they’ve just really enhanced their skill set. It is really a fun experience for those of us that lead the course, and the students have given incredibly positive feedback on it. JB: Do you have ways of measuring any degree of competency as people go through this course, or is it not really directed towards developing competency, more developing understanding, and you would recommend then someone go on, say, to the Andy Weil fellowship program after, or the functional medicine certification? What place does it play in their education and development, I guess would be my question? CD: We consider it kind of an introduction to these therapies. Some people have pursued further functional medicine training. It has opened peoples’ eyes. It’s designed to give the students a sense of, at least, to whom they should refer: “You know, you’ve got this problem. Perhaps you should consider guided imagery. Here’s a resource for it.” Or, “You might want to consider movement.” But we have found that it has enlightened people and they’ve decided to pursue it. That is very gratifying. They are somewhat self-selected because they’ve enrolled in the course, but it gives them confidence that this is something they can do for a career, they can practice this style of medicine as a career. JB: Let’s move to the third prong, which is the clinical side. I know you see patients on consult. I know the program there within the center sees people. Tell us a little bit about how the people find the center or the clinic, what kinds of patients you have, what your methodologies are for managing through complexity. CD: It operates as a primary care model, actually. People find us in a variety of ways. Many times it is word of mouth. A lot of times they are frustrated with their current medical treatment. I think the things that we see people for most often are chronic pain, chronic digestive disorders, and stress and the many repercussions and correlates of that, such as depression and other conditions for which conventional medicine doesn’t always have the right answers. We see people and they get a full experience. Our primary clinic physician, Dr. Lauren Richter, is a functional medicine doctor; that’s what she practices as. So we run a lot of nutritional tests, do the stool tests, salivary, adrenal, hormones, urinary, neurotransmitters—looking for the real underlying causes of these multifactorial problems. It’s something that people have really found benefit from. JB: It’s interesting. When I hear you talk, there seems like such an interesting consanguinity of thinking, and probably even the way that the clinical experience seems to the patient between what you all are doing and what Mimi Guarneri and Robert Bonakdar and their team are doing over on the other side of the country over in Scripps in La Jolla. They have the integrative cardiology, but it really deals with similar types of patients: chronic pain, stress, depression, digestive individuals and how that interfaces with things like dyslipidemia and cardiometabolic syndrome. Have you all exchanged information or have you done any collaboration because it sounds like you’ve got similar ways you are approaching these issues. Relationship between the University of Maryland and Scripps Center for Integrative Medicine CD: It’s funny you mention that. We think very highly of the integrative Scripps program and in fact we had an Ayurvedic medicine training that Scripps had had the previous weekend, so we are developing a relationship with them. Brian and Mimi have been friends and colleagues for a very long time. It is similar. They sort of have a focus over there—it’s my understanding—on cardiovascular disease, and they’ve done a great job improving peoples’ lives. We have a primary care model, and also this relationship with shock trauma is growing, so I think that’s going to be another way that we kind of focus our efforts: bringing integrative medicine to the shock trauma setting. They’ve got their cardiovascular focus. That’s an area of focus we’re actively pursuing. JB: That obviously leads to a follow-on question. In medicine we have what are called the resistant syndromes, things like insulin resistance, leptin resistance, and so forth. In the sociopolitical word, we have intellectual resistance. I’m wondering if you have observed or have seen a great degree of resistance to what you are trying to do within the broader politic of medicine there in the center or in the medical school or the local environment, and then how you treat intellectual resistance? CD: When I first came on to the center, I anticipated more resistance. But we’ve had much less than you might think when it comes to these kinds of things, because we approach with evidence. We speak the common language of: Here’s the evidence supporting whatever we’re hoping to do. I think a lot of this stuff resonates on an intuitive level. I mean, again, when you talk about metabolic syndrome and insulin resistance, lifestyle is really the solution to that. Getting to get people to cut down on sugars, and refined carbohydrates, and other bad dietary components; moving a little bit more; managing their stress. It hits on an intuitive level. There is good evidence as well. Those are the kind of things, and we’ve hit much less resistance than, again, I would have thought. There are detractors out there, but I have found them to be much fewer and farther in between than we anticipated. Again, the clinical results speak for themselves, and the research we are doing just provides stronger support, I think, among those who might initially be skeptical. I can tell you one of the great things about the elective course is that the students are incredibly receptive to the stuff we’re doing. The state of nutrition education is, as you know, quite poor in a medical environment. I think there was a study that showed that only 27 percent of US medical schools met the 25 hours required of nutrition education: three days over the course of four years, which is just in my eyes abhorrent.[16] But the medical students want this stuff. I mean, they are so engaged and receptive to it, so I think as we go forward and as we increase our educational reach there is going to be even less resistance. As we go forward people are going to say: “Hey, this is the stuff that works, this is what is going to help my patients.” The resistance is not as bad as I thought it would be, and I think it is only going to be less as we go forward. JB: Chris, you’ve really done a tremendous job of painting a very broad landscape for us in the research, education, and clinical areas. I guess my last question is: As a very up-and-coming, highly capable individual in this field, how do you view the future? What’s your view? I look at it maybe with eyes over the last 35 to 40 years, you’re looking at it with eyes going forward into the 21st century. Tell us about your perspective going forward. CD: I love the term lifestyle medicine. We were, at one time, called alternative medicine, where it was an alternative to what was being practiced. That sort of evolved into complementary and alternative medicine, and now we’re integrative medicine. What I would love to see is that it is just ultimately good medicine, getting a doctor to reach not just for the prescription pad but to say, “Hey, these are some dietary things you might want to try. These are some exercise modalities.” I think just really having the healthy lifestyle tenets that underlie functional medicine and what we all believe in—have that become medicine, have that become conventional medicine. You know, there will be resistance, but I feel like it just makes such intuitive sense, and as the evidence evolves, what I would love to see is that this is what medicine is: It’s no longer integrative medicine, it’s just medicine. JB: I think that’s an absolutely fantastic way to close this discussion because I think that’s what we’re all aspiring to do: create a more effective healthcare system with outcomes in health, not just outcomes in disease treatment improving. It’s a bright light you’re shining on that future. By the way, it also gives me a great sense of confidence when I see people like you coming up in their careers that this field is going to be very robust. It will be grounded in facts, not fiction. We’ll ultimately know more than we say rather than say more than we know, and we’ll have an authenticity about this that really delivers the goods. I want to thank you for your tireless work and for all of your colleagues there at the University of Maryland program. What I say is good on you. Let’s continue to move this thing forward. CD: I agree and I’d like to thank you for all of your work over the years. It inspired me to get into this field. I agree the future is bright and I very much enjoy interacting with you and it has been my pleasure. JB: Thank you so much. Best to you. We’ll talk soon.

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Bibliography

[1] Schrauzer GN. Joel D. Wallach D.V.M.: 2011 Klaus Schwarz Medallist. Biol Trace Elem Res. 2011;143:1219-1222. [2] Andreassi MG. Metabolic syndrome, diabetes and atherosclerosis: influence of gene-environment interaction. Mutation Res. 2009;667:35-43. [3] Ceriello A. The emerging challenge in diabetes: the “metabolic memory.” Vascul Pharmacol. 2012. [Epub ahead of print] [4] Boussageon R, Supper I, Bejan-Angoulvant T, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis randomized controlled trials. PLoS Med. 2012;9(4):e1001204. [5] Delzenne NM, Neyrinck AM, Backhed F, Cani PD. Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Nat Rev Endocrinol. 2011;7(11):639-646. [6] Manheimer E, Linde K, Lao L, Bouter LM, Berman BM. Meta-analysis: acupuncture for osteoarthritis of the knee. Ann Intern Med. 2007;146(12):868-877. [7] Berman BM, Langevin HM, Witt CM, Dubner R. Acupuncture for chronic low back pain. N Engl J Med. 2010;363(5):454-461. [8] D’Adamo CR, Shardell MD, Hicks GE, et al. Serum vitamin E concentrations among highly functioning hip fracture patients are higher than in nonfracture controls. Nutr Res. 2011;31(3):205-214. [9] D’Adamo CR, Miller RR, Shardell MD, et al. Higher serum concentrations of dietary anti-oxidants are associated with lower levels of inflammatory biomarkers during the year after hip fracture. Clin Nutr. 2012. [Epub ahead of print] [10] Larsen LH, Angquist L, Vimaleswaran KS, et al. Analyses of single nucleotide polymorphisms in selected nutrient sensitive genes in weight-regain prevention: the DIOGENES study. Am J Clin Nutr. 2012;95(5):1254-1260. [11] Bisht S, Maitra A. Systemic delivery of curcumin: 21st century solutions for an ancient conundrum. Current Drug Discov Technol. 2009;6(3):192-199. [12] Link A, Balaguer F, Shen Y, Nagaska T, Lozano JJ, Boland CR, Goel A. Fecal microRNAs as novel biomarkers for colon cancer screening. Cancer Epidemiol Biomarkers Prev. 2010;19(7):1766-1774. [13] Goel A, Aggarwal BB. Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr Cancer. 2010;62(7):919-930. [14] Srivastava R. What’s the alternative? The worldwide web of integrative medicine. N Engl J Med. 2012;366(9):783-785. [15] Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;12:1-23. [16] Adams KM, Lindell KC, Kohlmeier M, Zeisel SH. Status of nutrition education in medical schools. Am J Clin Nutr. 2006;83(4):941S-944S.

Welcome to Functional Medicine Update for September 2012. Fish oils, omega-3 fatty acids. What a topic of discussion—literally thousands of articles have been published over the last 25 years since we first started hearing about the role that omega-3 fats have in cardioprotection and other immunological activities. We’re very fortunate this month to have truly one of the renowned investigators in the omega-3 fatty acid/cardiovascular lipid area. And he, from his own experience, will help us to understand better both the history and where we are now, and how this relates to cardiovascular risk factors and their modification in the reduction of the burden of cardiovascular disease. Let’s turn to our extraordinary authority for this focus on essential fatty acids.

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INTERVIEW TRANSCRIPT

Researcher of the Month William Harris, PhD Health Diagnostic Laboratory, Inc. 737 North 5th Street, Suite 103 Richmond, VA 23219 http://www.hdlabinc.com/ September 2012 Here we are once again at the section of Functional Medicine Update that you and I and all of our listeners, I think, are most excited about. It’s really the substance upon which we wrap each issue of Functional Medicine Update: our clinician or researcher of the month section. We’re so privileged to have as our clinician/researcher this month an individual who I have gotten to know over the last several years who is really in the catbird seat in the area of nutritional therapeutics, this interface between pharmaceuticals and nutritionals and what’s emerging in cardiovascular disease, lipidology, and the whole nature of risk. Bill Harris (William S. Harris). Bill is a graduate in chemistry and went on and got his PhD at the University of Minnesota in nutritional biochemistry. He has been a Fellow in clinical nutrition at the Department of Medicine at Oregon Health Sciences, where we share a kinship; that was one of my early engagements, too, in the 60s. He is a member of the American Board of Nutrition. He is presently involved in a variety of different things: the Department of Internal Medicine at the Sanford School of Medicine at the University of South Dakota, where he is a research professor, and also he is working in the analytical area at Health Diagnostics Laboratory as a senior scientist. So he brings quite a bit of background both in the…I would call it the pure science, looking at this relationship of omega-3 fatty acids, and also in the applied sciences as it relates to assessment, diagnosis, and how that relates to clinical medicine. Bill, it’s a tremendous pleasure to have you as a guest authority on Functional Medicine Update. Let’s start with the question I ask virtually everyone first and that is: How did your path lead you into being one of the experts in omega-3 fatty acids? Early Work Studying the Effects of Salmon Oil BH: Jeff, that’s a great question, and thank you for having me on the show, here. I really appreciate it. My path was certainly not planned. Hardly anybody’s is, it seems. I did my first work in omega-3 as a post-doctoral fellow in the laboratory of Dr. William Connor at Oregon, as you mentioned. Dr. Connor’s first assignment to me back in 1978 was to study the effects or to find out what the effects of salmon oil are on cholesterol levels in humans. Dr. Connor had a long tradition of studying the different kinds of dietary fats and their effects on blood cholesterol levels. Fish oils were kind of an odd duck. Fish oils were–like vegetable oils–liquid at room temperature, and we knew liquid oils (vegetable oils) lowered cholesterol. But on the other hand, fish oils are also from an animal, and animal fats had been known to raise cholesterol, although they typically are solid at room temperature because of saturated fats. Fish oils are somewhere in the middle. They were liquid animal fats, and Dr. Connor was interested in what happened to cholesterol levels. So that was my assignment, and we did a metabolic ward study feeding up to about a half a cup of salmon oil every day to a variety of paid volunteers (as you can imagine). That got us started. We really discovered the effects of omega-3 on triglyceride levels in that study. Cholesterol was not a particularly interesting outcome, but the triglycerides—and then platelet function—was improved, interestingly, as well.[1] That kind of got us beginning down the omega-3 road. Dyerberg and Bang: Observations on the Diet of Greenland Eskimos JB: I think that’s a really important chapter in history, quite honestly. Bill Connor was, believe it or not, kind of a guide to me as well. He was kind of in his start at Oregon Health Sciences when I was there in the late 60s. He, I think, really pioneered so much of what we now have taken on as some of the tenets of the lipid hypothesis. On Functional Medicine Update we had the very high privilege of interviewing Dr. Dyerberg, who—I guess arguably—would be considered one of the first people to make the observations with Greenland Eskimos that this high seal and whale fat diet that they were consuming was leading to lowered incidence of vascular disease, which was entirely in opposition with the prevalent hypothesis or belief at the time that fat caused heart disease, and this concept that you could eat 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} or more of your calories as fat and have low incidence of heart disease was totally antithetical to the prevalent hypothesis at the time.[2] So you put the Dyerberg work together with the Connor work and then lay on all the work that you’ve done and it starts to develop a whole different model that’s kind of very different than the Pritikin model of “fat is bad.” I mean, I guess we have to ask the question: Who are the players? Tell us a little bit about how your model advanced and your work has advanced since Oregon Health Sciences days. The Effects of Fish Oils on Lipoprotein Metabolism BH: It’s gone sort of fits and starts. I got interested in, of course, the effects of fish oils on lipoprotein metabolism. Connor’s lab was quite good at doing some of the lipoprotein kinetic studies and certainly metabolic feeding studies, and so we went on to do a variety of other studies, giving people less and less fish oil. Of course, a half a cup of salmon oil is a lot of fish oil—around 25 grams of EPA and DHA a day is what we were giving in those days. We eventually backed it off as fish oil concentrates, as they were called at the time, 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} omega-3 products, MaxEPA being the primary one—when they came onboard we could drop it down to 18 capsules and give 6 grams of omega-3 and we thought we were really reducing the dose. One of those studies actually showed that if you give fish oils to people who have high triglyceride levels you’ll often see a rise in the LDL cholesterol (the bad cholesterol).[3] That was in the mid-80s and that observation got a fair amount of press and put a real kibosh on the fish oil for lipid lowering (advertising that was being done by a lot of fish oil companies). Things kind of went quiet for a while as people recoiled from seeing that cholesterol levels actually went up in some people given fish oil. JB: Let me comment just as a brief side line. It’s very interesting to reflect as I’m listening to you. In 1982, I was at the Pauling Institute on sabbatical, and I was asked if I would be a consultant to RP Shearer, the company that was bringing MaxEPA, the first omega-3 fatty acid concentrated supplement, to the United States from England. And I recall doing a variety of media for RP Shearer on their triglyceride form of MaxEPA and having all sorts of very critical comments made about, you know, feeding fat to people was going to create heart disease. I mean, it was quite a controversial media tour that I did for MaxEPA back in the early 80s. And then, of course, as you said, this suggestion that maybe in some individuals you get an increase in LDL cholesterol, which was considered very, very potentially dangerous, so it got a little bit of a negative stigma. How is it that we have woven ourselves out of that—or walked ourselves out—of that concern? Have we learned more about who the genetically sensitive individuals are? Or have we learned that the LDL elevation is marginal relative to its other benefits? Publication of the DART Trial Results was Pivotal BH: Yes, that’s right. Actually what I think I can sayabout the field–what woke it up again–was the publication of the DART trial in 1989, which was really the first randomized trial in humans with heart disease that showed that increased omega-3 intakes reduced risk for total mortality and sudden death. That study, with only 2000 patients, came out of England, and was really what set the field back on fire.[4] You didn’t really need high doses of omega-3—the kind we had been giving—to achieve a cardioprotective effect. Actually about a gram a day seemed—from that study—sufficient to actually reduce a very important end point: not LDL cholesterol, but actually mortality. That set us on a new path. It has still been a bit of a rollercoaster, but that was an exciting finding. Explaining the Different Forms of Fish Oils JB: It’s interesting to me, and probably even more interesting to you as an expert in the field, that as we started to see industrial intervention to make higher degrees of concentration of these favorable omega-3s like the eicosapentaenoic and docosahexaenoic acids (EPA and DHA), that we started to see individuals go from the triglyceride delivery form into a resaponified and esterified ester form. Is there any difference that you see either in the absorption or activity of these, kind of the natural triglyceride versus the ester forms of these delivery omega-3s? BH: That’s a great question, and that’s a question of increasing interest in the last several years. Yes, it appears that the ethyl ester form—which you are correct, was created so as to make as higher a concentration as possible per capsule—is not terribly well absorbed when taken without food (taken on an empty stomach). The ethyl ester form is the form that the current pharmaceutical products are in. It’s not as well absorbed as the triglyceride form, which is the more natural form. This can be somewhat obviated by taking the ethyl ester with food, which stimulates, of course, hepatic and pancreatic secretions. It was somewhat of a surprise recently to see such a difference in ethyl ester absorption versus triglyceride. JB: And when we go back and re-explore this LDL story, which has gotten a lot more information under it over the last 20 years, what are people now saying about the potential increased LDL that occurs with fish oil supplementation? Is the opinion changing? Where does the risk/benefit lie today? What Do We Know About the Risks and Benefits of Fish Oil Supplementation Today? BH: Yes, a couple of things on that. First of all, if people are taking omega-3 EPA and DHA in the neighborhood of one to two grams a day, there isn’t an effect on LDL. And if the patients are not high triglyceride patients, there’s not an effect on LDL by and large. Typically there really is just no change in LDL when you give fish oils in doses that we know reduce risk for cardiac advance, like one gram of EPA and DHA. That does not affect either triglycerides or LDL in any meaningful way. At that level, the LDL issue is a non-event. Where the LDL issue is an event is in people taking high doses; what we call lipid-lowering doses, 3 to 4 grams of EPA and DHA a day. In those patients, LDL can go up, and does if the patient is hypertriglyceridemic, which is the whole indication for giving that dose of omega-3. Interestingly, if you’re on a statin at the same time this doesn’t happen. A statin will block that effect. And there has been now some interesting data from a group that’s selling an EPA-only product; Amarin is the name of the company and drug is Vascepa. It has been approved by the FDA just last week. It’s a pure EPA product (EPA ethyl ester), and in its trials it does not raise LDL, whereas the combination of EPA plus DHA does seem to raise LDL.[5] We’re beginning to think that the LDL-raising effect of high-dose omega-3 is related to the DHA component, not the EPA component. That’s a new development and we don’t really understand why. I think most people, again, don’t really worry about this in terms of political effects, because, again, you can get significant cardiac protection at doses that do not affect LDL. JB: Thank you. That’s really helpful news to use. As I’m listening to you I’m thinking of, again, this concept of dose response or dose effect. Aspirin comes to mind as a classic example. Aspirin can be taken in three different doses with three different physiological outcomes. You can use baby aspirin for prevention of CVD and altering platelet adhesion. You can use a higher dose aspirin for headaches. And then there is the therapeutic dose of aspirin for arthritis and autoimmune disease, and they even used to use it for type-2 diabetes as a treatment. The problem is at those high doses, obviously the risk becomes quite high to gastrointestinal complications and bleeding. It seems like we need to be always be very mindful of dose effect, because one shouldn’t assume that necessarily have the same physiology at different doses and also the same risks, so I think you brought that up very clearly with this EPA/DHA argument—that risk and effect are related to dose amount, it seems. BH: Yes, and I would hasten to add that we really don’t know, other than this effect on LDL in patients with high triglycerides, which really don’t know is a clinically adverse effect. It’s just that biochemically it changes the LDL levels. Whether that’s a bad thing or not is another question. But other than that, we really haven’t seen any adverse effects of fish oils, even up at…I think the most recent advice from the European Health Authority is that up to 5 grams of EPA and DHA a day is completely safe.[6] To continue your analogy with aspirin, we really do see an adverse effect on bleeding when you really get up to high doses of aspirin. We really haven’t seen any downside to high doses of fish oil. JB: I think that’s a really important point for the clinicians because often we’re led to believe that these numbers that relate to risk are directly related to clinical outcome. I think that risk factors and clinical outcome are correlated but they’re not one-on-one. It’s possible that one could have a marginal increase of a relative risk factor (in this case you’re talking about LDL), but yet have an overall protective effect due to other influences on physiology that net it out to actually be net-positive on outcome. I think that’s a really interesting point you’re making because sometimes I think we over-read a single biomarker or a single number and put too many eggs in that basket and not look at the composite effect of things that are pleiotropic and may have multiple influences on physiology. BH: Very good point. I think back to your aspirin point. We know that aspirin lowers risk for cardiovascular events, but it certainly does not lower LDL levels. Athero risk is not one-to-one with LDL. It’s not the beginning event. The Signaling Effects of G-Protein-Coupled Receptors JB: So there’s another part of this story that, to me, is very fascinating. This is just a few years old. Jerrold Olefsky at UC San Diego I think might be credited with making these observations first (or you can correct me if there are other people that were earlier). This concept that these omega-3 long-chain polyunsaturated fatty acids like EPA and DHA have specific receptors that are called G-protein-coupled receptors that modulate intercellular signal transduction, so the effect of these fatty acids—at least in part, mechanistically—is through their activity in influencing specific GPCRs like GPCR120, and then that has a specific signaling effect that influences the expression of cassettes of genes that regulate inflammation, insulin sensitivity, and lipid dynamics.[7] It seems like that’s a pretty remarkable part of the story—that fat can speak to our genes through these receptors (or certain types of fat). Recent Discovery of New Metabolites Further Explain Omega-3 Fatty Acid Functionality BH: Right. Exactly. And you’re right to bring up Olefsky. He led the way in this. Because I think most of us have always thought: How do omega-3 fatty acids work? Well, they work via affecting eicosanoid synthesis, or being a substrate for cyclooxygenase that competes with arachidonic acid. And that sort of was as complicated or as simple as it was until studies such as Olefsky’s showing that the omega-3s can actually activate specific receptors, and that’s a whole new concept rather than just competing with arachidonic acid for some other enzyme. So I think the world is opening up. Along the same lines, we’ve now been able to discover that there are a whole host of metabolites of EPA and DHA that are made by cytochrome P450: epoxides, some mono- and di- and trihydroides, some ketones that are normal metabolites that we’ve just never been able to measure, and now we’re discovering that a whole host of them exist, and the possibilities for how omega-3s actually are affecting health are continuing to expand as we discover these metabolites. Low-Density Lipoprotein Cholesterol: Does Fish Oil Affect Count, Size, or Oxidation? JB: Thank you. That’s beautifully expressed. I think names like resolvins, which are some of these compounds, is a really interesting name, because then it says, “Well, what are you resolving? And why did these get the name ‘resolvins’.” They got the name ‘resolvins’ because of their effect on some of the untoward physiological things that occur with inflammation and disturbed metabolism. I think it’s a really interesting story that you’re describing. Let me ask a little bit about one of the themes that we see emerging with regard to lipid factors and risk, and we get into lipid particle count, and we get into various types of atherogenic particles. Steinberg, at UC San Diego (again),has brought up the concept of oxidized low-density lipoprotein cholesterol and how that plays as risk factor. Do fish oils, from your background, have any influence on particle count, lipid particle density, and/or oxidized LDL? BH: They do have an effect on LDL size. The particle does get a little bit bigger, which is a good thing. I hasten to add that just because LDL particles are a little bit larger on fish oil than they are not, doesn’t make—all of a sudden—LDL into a good player. It’s maybe just not quite as atherogenic as it would otherwise be. I sometimes hear people say, “LDL size is now larger, therefore now it’s a healthy particle.” You know, it’s not that, it’s just not as bad as it used to be. So fish oils can make that small change in LDL particle size, but as far as oxidation, that’s been a tricky field and actually it has kind of been quiet for some years now. Fish Oils and the Oxidative Theory of Atherosclerosis BH: The whole oxidative theory of atherogenesis really caught hold in the 1990s. Of course as you are well aware, a variety of randomized trials with vitamin E or other antioxidants failed to actually prevent atherosclerosis. That threw some of the foundation of that theory into a tailspin. But nevertheless, it’s still around that oxidation is playing a role. It’s exactly how we block it that’s the question. Fish oils can chemically increase the susceptibility of LDL particles to oxidizing, at least in the laboratory and the in vitro setting, because the omega-3 fatty acids are themselves very highly polyunsaturated—4,5,6 double bonds. And the more double you have the more places there are for oxygen to attack, and so in some model systems higher omega-3 levels in lipoprotein particles make those particles more susceptible to oxidation. But that has not translated into increased cardiovascular risk or increased atherosclerosis in vivo, so there’s a little bit of a disconnect between the oxidative theory and what omega-3s do. JB: Thank you. That’s very helpful. JB: Let me shift to another part of this story that I think is very timely and topical and that’s the HDL—what used to be considered the friendly cholesterol. There seems to be a lot of controversy about HDL right now and also HDL and its relationship to omega-3 oils. Can you kind of help bring us up to speed on that? Raising HDL Levels May Not Be the Answer: What the Trials Tell Us BH: Yes, boy, nobody’s betting on HDL anymore. We’ve all decided that we don’t know what the hell it does (pardon my French). Partly because of two or three trials that have taken new approaches to raising HDL cholesterol levels in people. Theoretically, high HDL cholesterol is protective against heart disease and there’s a lot of epidemiology and other studies that support that view, which is why we call it the good cholesterol. But these new trials have tested drugs that raise HDL cholesterol by a variety of mechanisms, and they are not proving to be beneficial. In the first case there were actually increased deaths in the treated group over the placebo group, so that drug has been killed.[8] The next drug to come along to try to achieve that same kind of thing didn’t actually end up killing anybody, but it was no different from placebo in terms of outcomes.[9] And so both these studies where HDL was raised significantly (almost doubling HDL levels—huge increases in HDL) did not produce a cardiovascular benefit. So now everybody in the field is sort of throwing their hands up and saying, “Well, we really don’t know what to do.” We know HDL is a predictor of risk, but we don’t know whether changing HDL levels changes risk. That’s the problem. The role of omega-3 and HDL is…HDL really isn’t affected much by taking omega-3 fatty acids (HDL levels). Whether HDL functionality is hasn’t really been studied. JB: You know, I find this HDL controversy to be extraordinarily interesting both from the specific and general perspective, and that is that the drugs that have been used to raise HDL are cholesterol ester transport protein inhibitors (CETP inhibitors) and so one might ask: “Does that produce the same effect on vascular function as we would have in a normal kind of physiological mechanism of control of HDL without a drug that is hitting one specific protein effect (one enzyme effect) given that the HDL particle has I think over 40 different proteins?” It’s the most complex apolipoprotein particle in the whole family. Are we just looking at a specious effect of a pharmacological influence on a one-target protein out of a whole, or is it really an HDL personality problem? My intuition tells me it’s not an HDL issue. It’s a specific pharmacological impact on one component of the HDL that’s producing these difficulties. But I think that’s a hypothesis remaining to be proven, what’s going on here. BH: Jeff, I think you’re right. I think many people in the field feel like the CETP-mediated rise of HDL may not have been the right strategy and we don’t know what we’re actually affecting. Just raising HDL cholesterol levels does not necessarily raise HDL particle numbers, and that is something that needs to be sorted out. Diagnosing Omega-3 Status in a Patient JB: So Bill I’d like to close with one last area that I know you’re really an expert in, and that is: Okay, we’ve found this benefit from prophylactic administration of omega-3 fatty acids. There is large clinical outcome studies, we have some mechanistic work, we’re talking about cell signaling from an mode of action (MOA) and its effect on inflammatory prostanoids. All of this is kind of an extraordinary body of literature of thousands of references. Then the question to the clinician is: “How do I know what the status of my patient is relative to their omega-3 status?” I think there is data saying that if your omega-3 fatty acid levels in your plasma membranes get to a certain level the relative risk of vascular disease is very low, so someone might want to know: How do we know where that risk is for the individual patient? Can you tell us, from a diagnostic perspective? BH: Sure, sure. I appreciate that question. We did develop, some years ago, a test we call the Omega-3 Index, which is a blood test that is actually performed in red blood cells (not in the plasma, but in red blood cells) that measures the amount of EPA and DHA, which are the important omega-3s in this regard. And the higher the level of the EPA and DHA in the red cell the better (the higher the Omega-3 Index the better). I try to explain the Omega-3 Index as to being somewhat like a hemoglobin A1C in the control of diabetes. Hemoglobin A1C is a long-term marker of glucose control. Glucose goes up and down in plasma a lot, but the tissues see a very steady level of it. The Omega-3 Index is a similar thing. It is a stable biomarker of how much EPA and DHA are in tissues. It responds very well to taking omega-3 supplements. And as you mentioned, a high level of Omega-3 Index—up over 8{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, which is where we think the target should be—has been associated in other studies with reduced risk for sudden cardiac death, reduced risk for early aging, total mortality, and a variety of other endpoints. So, to your question of how does a doctor find out what his patient’s omega-3 index is, as of about a year ago the Omega-3 Index test has been taken on and is now being offered by Health Diagnostic Laboratory (HDL) in Richmond, Virginia. That’s a clinical lab that is really rather new, actually, but it is, I think, now the premier cardiovascular and metabolic risk assessment lab in the country. The HealthDyn HDL is the convenient name (or the abbreviation) for Health Diagnostic Lab. HDL is offering the Omega-3 Index test along with many other cardiovascular markers. It’s really the first lab that has found a way to offer this test on scale. We’re doing about 2500 tests a day now at HDL on the Omega-3 Index, and they are being submitted to third-party payers and insurance is covering the cost and that is really what has blown the door open and made the omega-3 test become much more popular. JB: I think this is a fantastic breakthrough, and it reminds me very much of…I was a clinical chemist back in the days when the fingerstick cholesterol test first got approved (the Boehringer-Engleheim Test). Prior to that, less than 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of people knew their blood cholesterol level, but after the technology became available for health fairs and shopping mall analysis suddenly almost everybody knew their blood cholesterol and the number was theirs, it wasn’t somebody else’s that their wife was reading about in a Good Housekeeping magazine and they were saying, “Well that’s not me, I don’t have a high cholesterol.” Suddenly they had their number and that actually (probably) was the thing that fueled the growth in statin use and made it the number one prescribed drug family in America probably in the history of the pharmaceutical industry, actually. So I think this test, the OmegaQuant test that you’re describing to look at the Omega-3 Index, is going to have a similar effect, I think, on allowing people to understand their own specific status, which is the motivator for complying with the interventions. So, congratulations, and that should revolutionize the field, I would think. BH: I hope it does. I hope it does. I hope we get a lot of people who will pay attention to how much omega-3 they are eating because they know they are deficient. JB: Bill, I want to thank you. Dr. Harris, as you can hear, obviously is an expert for decades in this area and has shared a lot of news to use in this last half hour. Bill, the best to you and thank you so much for bringing that high-level stuff down to a level that we can all understand and docs can use with their patients. BH: Thank you for inviting me.  

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Bibliography

[1] Harris WS, Connor WE, McMurry MP. The comparative reductions of the plasma lipids and lipoproteins by dietary polyunsaturated fats: salmon oil versus vegetable oils. Metabolism. 1983;32(2):179-184.   [2] Dyerberg J, Bang HO. A hypothesis on the development of acute myocardial infarction in Greenlanders. Scand J Clin Lab Invest Suppl. 1982;161:7-13.   [3] Dart AM, Riemersma RA, Oliver MF. Effects of Maxepa on serum lipids in hypercholesterolaemic subjects. Atherosclerosis. 1989;80(2):119-124.   [4] Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). 1989.Lancet;2(8666):757-761.   [5] Jacobson TA. A new pure ω-3 eicosapentaenoic acid ethyl ester (AMR101) for the management of hypertriglyceridemia: the MARINE trial. Expert Rev Cardiovasc Ther. 2012;10(6):687-95.   [6] http://www.efsa.europa.eu/en/efsajournal/pub/2815.htm   [7] Oh DY, Talukdar S, Bae EJ, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142(5):687-98.   [8] Bermudez, V, Cano R, Cano C, et al. Pharmacologic management of isolated low high-density lipoprotein syndrome. Am J Ther. 2008;15(4):377-88.   [9] Ghosh RK, Ghosh SM. Current status of CETP inhibitors in the treatment of hyperlipidemia: an update. Curr Clin Pharmacol. 2012;7(2):102-10.   [10] Kwak SM, Myung SK, Lee, YJ, Seo HG. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-94.   [11] Hu FB, Manson JE. Omega-3 fatty acids and secondary prevention of cardiovascular disease—is it just a fish tale? Arch Inter Med. 2012;172(9):694-696.   [12] Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006;296(15):1885-1899.   [13] Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med. 2000;28(12):1815-1826.   [14] Vita JA, Brennan ML, Gokce N, et al. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation. 2004;110(9):1134-1139.   [15] Meuwese MC, Stroes ESG, Hazen SL, et al. Serum myeloperoxidase levels are associated with the future risk of coronary artery disease in apparently healthy individuals: the EPIC-Norfolk prospective population study. J Am Coll Cardiol. 2007;50(2):159-165.   [16] Shao B, Oda MN, Oram JF, Heinecke JW. Myeloperoxidase: an oxidative pathway for generating dysfunctional HDL. Chem Res Toxicol. 2010;23(3):447-454.

Welcome to Functional Medicine Update for October 2012. We have a tremendously exciting and I think very different issue to share with you that has to do with a longstanding question, and that question is: Has our increased use of mechanized farming, and processed foods, and 21st century lifestyle—or let’s even go back a century—20th century lifestyle, had a positive or negative effect on life expectancy and on morbidity and disease patterns? And of course most of us immediately, when we are asked or are thoughtful about that question, come to the conclusion (because we’ve heard it so many times) that mean average life expectancy has gone up dramatically over the last 100-plus years and disease morbidity has gone way down, both of which are very strong supporters of the technological developments that we’ve seen over the last century and a half. One might say: “Well, that’s a trivially obvious question, the answer of which is so profound that why even ask it?” But fortunately, there is always another side of the story to create a robust discussion going, and that is the theme that we’re going to be focusing on in this month’s Functional Medicine Update with our extraordinary clinician/researcher/opinion leader of the month, Dr. Paul Clayton. As you get to know Dr. Clayton a little bit more during this interview, I think you are going to be provoked, as I was the first time I met him, in having read his incredible series of articles that appeared in the Journal of the Royal Society of Medicine titled “An Unsuitable and Degraded Diet? Public Health: Lessons From the Mid-Victorian Working Class Diet.”[1],[2],[3]I think you’re going to be very interested that sometimes what may be seen on the surface may have a deeper message and an opportunity for learning that’s below the surface, and that is the theme of this month’s Functional Medicine Update. So let’s run right to the discussion I had the privilege of having with Dr. Clayton, and then I’ll discuss some of the implications.

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INTERVIEW TRANSCRIPT

Researcher of the Month Paul Clayton, PhD c/o ALS, Ltd. 50 Aylesbury Road Aston Clinton, Aylesbury, Bucks HP22 5AH United Kingdom drpaulclayton@acceleratedlearning.com www.drpaulclayton.com Always we look forward to our clinician/researcher/opinion leader of the month. I know I say this every month, but I think I feel fairly confident once again that we have an extraordinary personality who will bring a perspective of deep importance to all of us. I’m speaking to Dr. Paul Clayton. You’re going to learn more from Paul about his background, but let me just say a few words about him. A Student of Anthropologic Nutrition It’s a very, very rich and interesting background that ties so closely together with the topics of interest we have discussed over the last three decades in Functional Medicine Update. He’s been a visiting Chair of Pharmaconutrition at University of Pecs in Hungary. He has been on the board of many different nutritionally related therapeutic companies the UK, USA, Norway, Hungary and Japan. He has been a Fellow of the Foundation for Food, Brain, and Behavior at Oxford. He has been a Scientific Director of the Albert Szent-Gyorgi Foundation of Clinical Pharmaconutrition in Budapest. He’s been involved with sports medicine/sports nutrition work at the Royal College of General Practitioners, and is a former president of the Forum on Food & Health at the Royal Society of Medicine in London. He has worked with things like novel mechanisms in weight loss including the use of food derivates to achieve up-regulation of mitochondrial uncoupling proteins and AmP-kinase; the use of natural CR-3 agonists to enhance TH1/TH2 ratios in the treatment of allergy, the classification of Saccharomyces cerevisia as an atypical and external symbiont, and the clinical use of stabilized lactoperoxidase as an anti-viral strategy. He has looked at things like the weight loss drugs and how they play roles in modifying physiology versus nutrition intervention. I mean, quite honestly…previously a visiting professor at the University of Amsterdam, principal lecturer at NutraMed International, plus graduate courses in London. I could go on and on and on…work in Norway. This is a student of the universe, of the globe, who has really been focusing his attention on this whole area of relationship to undernutrition and functional nutrition to human performance and relationship to the immune system, relationship to prevention of degenerative diseases, specifically cancer, cardiovascular, and connective tissue, and—as you will learn in a moment—a historian looking at anthropological nutrition in a very unique way that marries itself directly to many of the topics that we’ve been describing in functional medicine. So, I am so excited to have Paul as our kind of opinion leader of the month. Dr. Clayton, welcome to Functional Medicine Update and thanks for being available to us. PC: Thank you for the invitation, Jeff, and that’s probably the longest introduction I’ve ever received. Thank you for that, too. JB: Well, it’s well deserved. Let me, if I can, just quickly contextualize how we met because, you know, there is no such thing as serendipity, I’m beginning to recognize. I’m in the past-65 age group now and starting to recognize that these are guided contexts that we often have that are built around kind of receptivity to the message. So here we are, we’re both in a meeting together, we meet after a talk. It’s just one of those kind of chance happenings, and within a period of probably no more than 30 seconds, at least I recognize that I started at four degrees of separation and by the end of that conversation, five minutes later, I recognize that we’re probably two degrees of professional separation, and we may have been separated as twins at birth. I was very, very impressed with your ability to communicate very concisely and very eloquently the things that you have been working on, and this whole topic of pharmaconutrition and how that interrelates with your studies on Victorian nutrition, which was just fascinating. With that as a very lengthy introduction, tell us how you got down this path—this Victorian nutrition issue—and the things we’re going to talk about, which are fascinating. PC: Of course. I just would say that, you know, sitting in my silo, which is based mostly in Oxford and in Budapest, I knew, of course, your name, and I knew a little bit about what you were doing and what functional medicine was about. But I have to say, I hadn’t taken it really onboard until I heard you talk at the meeting in Anaheim. It was just a thrill, because the way you were talking about the issues of the day felt so familiar and so right, I felt I just had to come up and talk to you afterwards and I’m very glad that I did. I think that maybe we’ve reached an inflection point, or we are very close to reaching one, in the way in which health care is delivered. I understand now that this is due in no small measure to your own efforts and the efforts of your institute. But the problems that we’ve had in Europe in taking these ideas to the consensus—the medical heartland—has been, really, lack of data. We have the preclinical, we have epidemiology, we have biochemistry (ex vivo and in vitro data), but we don’t, as a rule, deal very effectively in the coinage that the medical profession has been taught to prioritize before all of this large scale, prospective RCTs. Those reasons are very simple—you and I know that: it’s difficult to organize the funding, and politically it is extraordinarily difficult to set these trials up, too. I have long been looking for sources of information—data that we could use from different sources—that we could use just to bolster our arguments and to force our way into the heartland of medical conventional practice. Exploring Health Data from Victorian England to Inform Current Research This came as…it was an accident in a way. I know that you don’t seem to believe in serendipity, but for me that’s how it seemed. I had an opportunity to meet a very eminent Victorian historian at a social gathering. We started talking about things like health prospects, life expectancy, lifestyles in the 19th century, and I very rapidly became aware during the course of this conversation that perceived wisdom was totally wrong. The 19th century—in Britain, at any rate—you have a population that is very physically active, eating an extraordinarily rich and diverse diet and there are quite well understood reasons for this. And as a result, they had a life expectancy that matches ours, but they are almost free of degenerative disease. The importance of this is that up until now we’ve had the Neolithic arguments, put very eloquently by people like Loren Cordain and others, but the databases, the evidence, just isn’t that good. The medical records…you have to scratch around to make your case and even then it’s not very robust. In the second half of 19th century England, the databases are very extensive—very, very detailed. Medical case notes are beautifully written up, and there are literally millions and millions and millions of data points. Nobody had really looked at this area before because of political reasons. At the beginning of the 20th century the Edwardians come in, and a pre-revolutionary fervor is in the air (this is just before the Russian Revolution). And the middle classes are beginning to become very afraid of the working classes, who were getting unionized and organized. And so the Edwardians spent a lot of time creating black propaganda, and they talk about the Victorian era as if it was an era of poverty, disease, and all things evil. And that idea has permeated into 20th and 21st century history, and into medical thinking. What we found when we went back to that period was that in fact it was a golden age, a lacuna time, if you will, when people enjoyed fantastically good health—far better than we enjoy today—and of course without the benefit of modern medicine, modern surgery, modern diagnostic techniques. That’s the case that we’ve made, and that’s the case that we have been excoriated for by our medical peers. JB: So let’s, if we can, make sure that all of us are on the same page. When we have heard statistics about mean average life expectancy, often we forget that those include all age groups, including neonatal death, infectious disease, war, accidents, so when you talk about life expectancy in the Victorian period, can you give us some sense as to how one rationalizes this, since our mean average life expectancy was much shorter in those periods, with what you are telling us now? Chronic Disease was Uncommon in the Victorian Era PC: Oh, indeed. That’s because if you look at life expectancy from birth, I would be the first to admit that it doesn’t look as good as it does now. What we have to do is to filter out the first five years after birth. This is a period of extraordinarily high risk. Once a child has reached the age of five, at that point many of the childhood spectrum of risk is now gone. If we look at life expectancy over the age of five in the Victorian period and compare that with an equivalent socioeconomic group in Britain today, yes, they match us year for year. What do they die of? Of course the Victorians were mortal, but they don’t die of heart disease and cancer. I think it’s important to make this point now. These conditions were diagnosed, and they were diagnosed without prejudice. They were diagnosed extremely carefully by the physicians who at that time are beginning to become respectable, they’re beginning to become organized, they’re beginning to move from being butchers, and blood-letters to being something that is rather more recognizable in terms of the kinds of doctors that we expect to see today. So they are taking enormous pains to diagnose causes of death. Each and every doctor at that period of time is doing two, three, four autopsies a week. And when I look through their medical records, it’s easy to see that they are better pathological anatomists than most of my colleagues are today. They keep their records in copperplate and leather-bound ledgers rather than putting it online, but they were extremely good at pathological anatomy, and when they saw cancer at the point of death, or a heart attack at the point of death, they diagnosed it very, very effectively. JB: Could I make a comment here just for our listeners, because historically, looking at timelines and medical technology development, people may not remember that Rudolf Virchow, who is credited as being kind of arguably the father of modern pathology, was living during the 19th century (the middle of the 19th century). So this is the epic golden-era of pathology, with Virchow coming up with his very, very detailed reviews of the pathogenesis of various diseases. Certainly the whole attention of the medical community in Europe was heightened as a consequence of this new concept of pathology. PC: That’s exactly correct, and it’s manifest in the Victorian medical records of the time. As I said a moment ago, these are present in their hundreds and thousands (and millions)—a period of half a century, covering a population of some, say, 30 million—the numbers of data points are just astounding. We also had access to things like the data looking at levels of physical activity, caloric throughputs, if you will. We had access to records illustrating agricultural productivity. The amount of agricultural produce that was being brought into the cities, where the laboring masses were now concentrated, from the agricultural sector, where, thanks to the agricultural revolution, productivity had increased by order of magnitude. We looked at cookbooks, we looked at the bills of fare of the foods that were sold in stalls, and shops, and hotels, hospitals and prisons. We have a very, very comprehensive and extraordinarily detailed view now of exactly how people worked, what they ate, and the impact that it had on their health expectancy and life expectancy. And it is very different from today, and it is very much better than the patterns that we see today. Healthy Food and Physical Activity Were the Norm for Victorians JB: So when you start examining the food and the activity levels, I would presume that that also brought you into examining what are the sources of the food relative to cultivars, to traditional seeds, and things of that nature prior to the Borlaug period of the Green Revolution, where hybridization became the standard of practice in agriculture? PC: Well, at that time a significant fraction of the population is still working manually in agriculture, but the people who are in the cities are no physical slouches either, because all occupations at that time—you have a broad-based pyramid: very, very small upper class, very small middle class, most everybody else is blue collar, and these are people who are working with their hands. There is no internal combustion engine. There is no modern technology. There really aren’t any very portable fuels other than coal and wood. So all the work then is done by hand, and when we look at patterns of physical activity at that time, we can see that—in contrast to today’s levels of let’s say two-and-a-half thousand calories a day, the Victorians are expending on average between four and (at the upper end of the laboring scale) six, or seven, or eight thousand calories a day. They are like Olympians. They don’t go to the gym every once or twice a week; they’re living and working in a gym. They are better muscled than we are, but that’s not the most important outcome of this. The most important outcome is because they are consuming so many calories per day, they are eating more than we do—approximately twice as much as we do. And yet, when you look at the photographs of that era—because this is also the birth of photography—you can see that the Victorian phenotype is slim to thin, because they are expending. All those calories are being used up in physical activity. We’ve been seduced. We’ve been seduced by labor-saving technology, cheap energy, and of course the internal combustion engine, and I think as a species we are very easily seduced. We hark back, I think to an evolutionary time during which it made sense in an era of food insecurity not to exert more physical activity than you needed to. I think we still do that, but of course it has become entirely counterproductive now. The Victorians don’t fall into that trap: very, very physically active, eating twice as much as we do. And when we look at the foods that they eat, then it gets even more interesting, because they’re not eating any processed foods apart from very, very basics—bread, butter, cheese, and things like that. They are eating lots and lots of fruits and vegetables, and lots of fish, because at that time oysters and salmon are foods of the poor. In fact, we looked at contracts for laborers, in which the laborers actually said in that contract: “You must not feed us salmon more than three times a week.” Hard to imagine, but that’s how it was. They are eating lots of prebiotics, because the Jerusalem artichoke is a staple at that time. Whole grains, and ten portions of fruit and vegetables a day. That’s gets very interesting because this is the level of intake that the people at the USDA Human Nutrition at Tufts talk about, and the US Cancer Society also talks about. Heirloom Varieties of Fruits and Vegetables Had Greater Nutrient Density Now, the Victorians are not eating contemporary fruits and vegetables. They’re eating heirloom varieties, and it is important to note that these are varieties that are very often more pungent. They contain more bitter or aromatic notes than many fruits and vegetables do today, because we have—through consumer demand—asked the multiple retailers for sweeter fruits and vegetables, and that demand has filtered back through to the plant growers and the plant breeders. So, for example, sugar snaps and sweet corn are a lot sweeter now than they used to be. Plants only have so much solar energy available to them, and the more they put into sugars, the less they have to put into the types of phytochemicals that we now know are anti-inflammatory, and—among other things—protect against cancer in a wide range of ways. So the Victorians are eating twice as much fruit and vegetables as we are (at least twice as much), and it turns out that the varieties of fruits and vegetables they’re eating contain about twice or three times the levels of phytonutrients that we consume today. Put that together, and they are eating levels of phytonutrients—the flavonoids, the phenolic compounds in general, the carotenoids, the xanthophyls, the methyl group donors, cyanogens, I could go on right across the spectrum—they’re consuming those types of ingredients at a level an order of magnitude higher than we eat today. And public health records show that as a result, degenerative disease in that population is reduced from the levels we see today by 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. Ninety percent; that’s a stunning figure. And that explains why, when the Victorians reached the ends of their lives, they don’t die slowly and expensively, as we do. They carry on right to the end—almost fully functional—and then die very rapidly (morbidity compression) in their 70s, 80s, 90s or beyond, generally of an overwhelming infection. That’s a much less expensive way to die, and the Victorian concept of death is very different from ours. We expect to die slowly and individually, as a rule. The Victorians expected to die very suddenly, and very often communally. You see that in the literature, for example. That’s very much the common experience. JB: I think you just said something there that I want to make a parenthetical. I’ve quoted, in years past in Functional Medicine Update, from the wonderful Oliver Wendell Holmes poem called “One-Hoss Shay,” which was written during this period of time (actually it’s the late part of the 19th century), in which the concept of the one-hoss shay is it runs fine every day (the carriage with the horse) and then one day the horse dies, and the wheels fall off, and like bubbles burst (as I recall, in the last line of the poem), it’s the end of that carriage. I think that’s a very interesting metaphor to the way people saw the end of life in the 19th century: the one-hoss shay. PC: That’s a beautiful and very precise metaphor, Jeff. I hadn’t heard of that before, but it is absolutely apropos. That is how the Victorians expected it to be. They expected to live, and to live well, and to live functionally (physically, mentally, sexually) until very, very shortly before death. I don’t know about you, but if I have those two options to choose from, then I know which one I’d go for. I want to remain alive and fully functional for as long as I can. I don’t want to put off mortality infinitely; I’m not that egocentric. I would rather die in that way than spend the last ten percent of my life in a condition of progressive medical dependency, bankrupting my nearest and dearest in my family and using up medical resources in general. I think that we have come to accept a way of living and dying that is not natural. It’s a complete artifact. Everything that we experience as a society, as aging, is not biological. It is a socioeconomic artifact, and Victorian study shows us that. It shows us—I think—that if we are eating the right kind of diet, whether you’re doing that through dietary means or by supplementation I don’t think matters. I’m a clinical pharmacologist by training and as far as I’m concerned it doesn’t really matter how you get those compounds into your system, but if you do, the only people in that population who are manifesting with, let’s say, heart disease or cancer are those who have strong genetic risk factors. Everyone else is protected. For example, if we look at the phenomenology of breast cancer at that time, the average age of onset of breast cancer (or of cancer in general, in that period) doesn’t show the usual exponential age-related curve. I suppose you can derive that all the way back to Andrew’s theory of gradually acquiring increasing genetic mutations, which finally culminates in increased risk of cancer. That’s not the Victorians’ experience. In that era, everyone is protected throughout all of their lives by a very large intake of phytonutrients. And it’s only that percentage of the population who have strong genetic risk markers coming through, and they are coming through in the blood. In that population, cancer is not age-related. I think it is interesting here to note that when you talk to the breast cancer specialists and say, “How many of your patients have BRCA1, BRCA2, BRCA3, or strong genetic risk markers?” they’ll say about ten percent. And if you talk to the cardiologists and say, “How many of your patients have got strong and clearly elevated risk markers?” they’ll say something like ten percent. Well in the Victorian period, it’s only that ten percent who present with the clinical diseases; everyone else is protected. And what has happened since then is that this protective nutritional tide has receded down the beach, exposing more and more of us to the pathologies that we have come to regard as normal, but in my view they are anything but. JB: I think that’s beautifully stated and very, very eloquent. I want to go back and pick up two points in your previous comments that I think are kind of news-to-use for our listeners, one of which is this heirloom varieties discussion you had of the traditional cultivars of fruits and vegetables that were consumed during the Victorian period and their bitterness. These bitter compounds, as you indicated (these phytochemicals) are secondary metabolites that plants produce in response to a hostile environment. They are basically defensive substances. This is the whole concept of xenohormesis that we’ve heard about recently. It would seem that as we have moved our agriculture towards “safe” conditions, with herbicides, pesticides, fertilizers, making plants really have an easy life and put cultivars out there that are very responsive to fertilizer and pesticides, that what we have done is we’ve cooled off or silenced those genes that used to be stimulated in a less protected environment to then manifest the production of these phytochemicals. So it seems like it’s a double whammy as to how we’ve moved towards a lower phytochemically dense food supply system, both changing the seeds and changing the environment. Is that in line with your observations? Making Life More Convenient Has Weakened Our Foundations PC: Jeff, I think that is beautifully and precisely observed. I think that what we have done…in an evolutionary perspective, life is a struggle, life is a dialectic. And what we have attempted to do, I think, is effectively we have interrupted the dialectic. We have wanted to make life easier and more comfortable, more consistent, more predictable for ourselves, and in so doing we have unknowingly weakened our own foundations. So I would absolutely agree one hundred percent with what you say. I think that it would be difficult to persuade people, and particularly children, to consume some of the traditional cultivars because, as I said, many of them contain a number of notes, organolectically speaking, that today’s consumers might not find very easy to assimilate. And I’ve often wondered whether there might be a compromise: whether it would be possible to take intensively reared, protected plant species (as you put them), and encourage them to increase their synthesis of phytoalexins (or as we call them, phytonutrients). There is a Dutch company that has started to look at this question, and what they have done—I think this is very interesting—is they take intensively grown species of food crops, which have been fed fertilizer and they’ve been shielded with pesticides and fungicides and whatever, and towards the end of the growing season what they do is they buy a couple of hundred locusts, they turn them into a stew and then they spray that stew onto the crops. They don’t know what the active compounds are, but there is something in that stew which the plants register as being indicative of a locust invasion. There are no plant losses, obviously, but the plants do respond by ratcheting up their production of a range of phytoalexins, including many of those which are clearly important for our sustained good health. I think that this is an example of a very beautiful kind of science where we may be able to dig ourselves partly out of this pit that we’ve made for ourselves. Why Stress is Good for Plants JB: I think that’s really a superb example, and I know the basis of a lot of the organic agriculture movement in the world is founded on some of these principles that it’s good for plants to have a little stress in their environment because it allows them to produce a full range of protective substances that has this co-evolutionary benefit in humans. So that’s that kind of xenohormetic transference factor from a plant to a human: the anti-stress compound in the plant becomes an anti-stress compound in humans, which is a very, very interesting kind of emerging thought about the role that diet plays beyond that of protein, carbohydrate, fat, vitamins, and minerals in modulating human physiology. PC: It really does demonstrate our absolute interdependence with other life species, doesn’t it? I think of it in terms of hermit crab. When the hermit crab comes across a shell that has been abandoned by some other species, it makes it its own. It becomes its own protection. When we eat plant species which have high levels of these types of phytonutrients we assume the protection that they originally generated to shield themselves from predators, from ultraviolet, from other types of stresses. And by indulging in the 20th century mass agricultural production techniques, which I accept that perhaps we needed to do to feed the increasing numbers of mouths, but I think that it has increasingly set in motion one of the pillars of the current system of bad public health. JB: Yes, I think what you’ve provided to us, Dr. Clayton, is an unbelievably important foundation upon which we build the whole edifice of therapeutic nutrition, and as you said, pharmaconutrition. What is the benefit of nutrition, culturally, to a society that is burdened by preventable chronic illness? I think it’s a tremendous framework upon which to build the bioscience and the mechanistic understanding, but you’ve got to have kind of your fundamental historical sociological background to really understand some of these more precise mechanistic understandings of roles of various phytochemicals on cell physiology. To me, this is where it all starts. Your work is just fundamentally important in understanding the bigger picture. Now, for people that want to follow up and learn more about your work, where would you direct them? PC: At the moment I’m working in a number of other areas, which I think you might find interesting, but to go back to the dietary shift and its impact on changes in public health data, there is a series of papers that I co-authored with an historian, Dr. Judith Rowbotham, which were published in the Journal of the Royal Society of Medicine three years ago. That would be a very good place to start. And could I just say, I think one of the problems that the medical profession has is—and I’m generalizing here—its profound ignorance of history. If you don’t know your history, if you don’t know where you come from, you have no idea of knowing where you are, or where you’re going to go next. The medical profession doesn’t do history, as a rule, apart from, you know, the history of great medical figures. I think that we have been in such a hurry to forget the roots of the current hegemonic medical healthcare system, that we no longer are able to see it clearly. Let me put it this way: When we first published, the howls of the program and hatred from the medical profession in Europe were pretty much universal. The medics said to us, “Look, this is just not possible. You’ve got your history wrong. We’ve just had a century of medical [largely pharmaceutical] progress, and things are getting better and better. How is it possible that the Victorians could have had better health than we have without the benefits of today’s pharmaceutical medicine?” And we went back to our books, we checked everything, and then what happened was the historians—including the top historians in Victorian England (of that period)—wrote in to the lists on our side and said, “No, this is correct. This is the first analysis of Victorian medical history that makes sense.” And at that point, the medic backed off, and I have to say that since that time, we have heard no further criticism from the medical establishment at all. They’ve preferred to ignore us, because I think that our work is profoundly critical and really undermines a great deal of the current pharmaceutically dominated model. It’s a blind alley, because what we have done for the last century, is we have invested enormous, incalculable amounts of money and a lot of ingenuity into developing rather toxic, synthetic compounds, which we use to suppress the symptoms of disease which have emerged only because we have fallen away from the nutritional standards that our great-grandparents enjoyed. And there’s the rub. JB: I think you have just basically, in a very eloquent short statement, given the elevator speech for what Functional Medicine Update has been about for the last three decades. There are a lot of details under the surface, here, below the water line, but I think this is kind of the mandate of what we’ve been really speaking to over all these many decades. I can’t tell you how much we appreciate this. We’re going to cite your specific articles for those people that want follow up on them, and we want to follow your future because I think you’re blazing a very important trail, here, and I can’t tell you how much we appreciate—on every level—the scholarship you’ve brought into this discussion and the rigor of your thinking. I think it is a very seminal perspective for us all. PC: Jeff, may I raise just two more very small points, which you may find interesting? JB: Absolutely. Please. The Economics of Shifting Away From a Chronic Disease Paradigm PC: I’m currently working with a team of med-economists, because if you want to affect healthcare policy you have to have the med-economists on your side. We have started to do back-of-the-envelope calculations based on the Victorian findings as to what kinds of healthcare savings we could make if we were to shift from this current crisis management model of medicine—this ruinously expensive and terribly ineffective model that we have now—to a genuinely preventative and dietary program based on Victorian profiles. What we have found…I mean, the figures are truly staggering. Based on this idea that approximately 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of degenerative disease is preventable in this way, let’s say we only capture half or two-thirds of that, you end up making savings that are equivalent of between ten and twelve percent of GDP. That’s how big the figures are. In other words, the types of savings to be made here would be enough to solve America’s macroeconomic problems. It would resolve your budget deficit, and ours too. What we need now is a politician with the brain and the backbone…I was going to use another more anglo-saxon term…to actually understand this concept and do something about it, because of course we’re up against some extraordinarily powerful vested interests who will do everything in their powers to prevent this type of approach. I suppose the other point I would like to make, if you’ll give me another minute, is to tell you the type of work that we’re involved in now, that—again—you might find interesting. One of the great turf wars at the moment in medicine is taking place on and around the concept of vitamin D. On the one hand you’ve got the dermatologists and the skin cancer people who have been telling us for 20 or 30 years or so, cover up—the American or the Australian model, slip, slap, slop, or just stay out of the sun. And then you have got an increasingly vocal group of people who are saying, “Well, hang on. High insufficiency of vitamin D is prevalent, particularly in the higher latitudes and is associated with a whole range of diseases, including cancer, autoimmune disease, type 2 diabetes, and depression, and heaven knows what else.” How do you resolve that? How do you square that circle? You might be interested to know that I’ve been working with a multinational team, where what we have done is to develop a food extract which we were able to get into the skin through a spray, and we’ve shown that it activates the melanocytes, and tells them to produce more melanin, tells them to distribute it to the neighboring fibroblasts, and actually creates a genuine tan. We’ve put vitamin D3 into the product as well, so this is a product that captures exactly the cosmetic and the endocrinological benefits of sunlight without any of the problems associated with exposure to ultraviolet. I just thought that might tickle you. JB: Oh, absolutely. What a wonderful application of technology. That’s your basic, humanistic technology. Wow. Well, it sounds like you’re not suffering from any lack of things to keep you intellectually and physically and emotionally interested and committed. We need to follow back up with you, Dr. Clayton. I think that this is just the first of hopefully a number of visits with you because you’re leading the pulse here. We really appreciate it. PC: Could I just say that meeting you in Anaheim was the high point of my American tour so far. JB: Well, I take that as a great compliment because I can tell you that’s how I felt about our meeting as well. The best to you and let’s keep in touch. There are going to be many thousands of practitioners that are going to be very influenced by what they hear from this discussion between us. Thank you so much. PC: It’s been a pleasure. Thank you so much, Jeff. Always we look forward to our clinician/researcher/opinion leader of the month. I know I say this every month, but I think I feel fairly confident once again that we have an extraordinary personality who will bring a perspective of deep importance to all of us. I’m speaking to Dr. Paul Clayton. You’re going to learn more from Paul about his background, but let me just say a few words about him.  

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Bibliography

[1] Clayton P, Rowbotham J. An unsuitable and degraded diet? Part one: public health lessons from the mid-Victorian working class diet. J R Soc Med. 2008;101:282-289.   [2] Clayton P, Rowbotham J. An unsuitable and degraded diet? Part two: realities of the mid-Victorian diet. J R Soc Med. 2008;101:350-357.   [3] Rowbotham J, Clayton P. An unsuitable and degraded diet? Part three: Victorian consumption patterns and their health benefits. J R Soc Med. 2008;101:454-462.   [4] Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, Wallace RB, Melzer D. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA. 2008;300(11):1303-1310.   [5] Vom Saal FS, Myers JP. Bisphenol A and risk of metabolic disorders. JAMA. 2008;300(11):1353-1355.   [6] De Coster S, van Larebeke N. Endocrine-disrupting chemicals: associated disorders and mechanisms of action. J Environ Public Health. 2012;2012:713696.   [7] Trasande L, Attina TM, Blustein J. Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents. JAMA. 2012;308(11):1113-1121.   [8] Vroegrijk I, van Diepen JA, van den Berg S, et al. META060 protects against diet-induced obesity and insulin resistance in a high-fat-diet fed mouse. Nutrition. 2012. http://dx.doi.org/10.1016/j.nut.2012.05.004   [9] Dotson CD, Zhang L, Xu H, et al. Bitter taste receptors influence glucose homeostasis. PLoS One. 2008;3(12):e3974.

Welcome to Functional Medicine Update for November 2012. As you know, we’ve been progressing over the last couple of years with a model of functional medicine that relates to manipulation of very fundamental processes that relate to signaling in the body that ultimately controls either function or dysfunction under metabolically modified conditions. It’s this interrelationship between the environment of the individual and their genes that then controls, ultimately, the signaling that relates to how these genes are expressed and how cell biology, tissue, organ, organ systems, and whole-organism response is manifest. That’s the tenet that really underlies the functional medicine model (this systems biology approach). There’s really no better example of that than our focus today on the conditions associated with type 2 diabetes.   The State of the Science: Type 2 Diabetes The central question that has arisen over the last few years is whether type 2 diabetes is, in and of itself, a disease, or whether it is really a definition of a collection of metabolic disturbances that occur as a consequence of unique interactions between certain genetic characteristics and the environment to produce an outcome that we call disturbed metabolism, or dysglycemia, or dysinsulinism that later gets defined as a singular disease: diabetes. Meaning, are there many paths to a single definition of a name (a medical taxonomic name)—diabetes? Or does diabetes stand kind of as a singular entity that is the same among all patients with that diagnosis? I think the answer to that question is fairly obvious to those of us that have been following this field for some time, and that is that the more we learn about the pathogenesis of type 2 diabetes, the more we recognize that there are multiple paths, at a physiological level, that give rise to the exigencies of blood sugar and insulin that we later call diabetes. That then takes us down the path to understand better what the individual characteristics of that person’s dysfunction and how that relates to what later is to be called, in their diagnosis, type 2 diabetes.   When we take that from the abstract level of theory down to the reality of fact in the clinic, in the exam room with that patient, and ask the question, “What does this really mean?,” it takes us to an understanding that the concept of dysinsulinism and dysglycemia is more than just that of elevated blood sugar. It’s even more than that of longstanding elevations hemoglobin A1c or glycosylated hemoglobin, which we consider to kind of be the sentinel biomarker for evaluating proper glucose control. I don’t want to suggest that there is no value clinically to the biomarker hemoglobin A1c, nor do I want to suggest that there is no value in understanding elevated fasting blood sugar as an indicator of dysinsulinism and dysglycemia. But what I really want to suggest is that as the emergent model of this condition that we call type 2 diabetes and the companion disease adjacencies that are associated with it, like cognitive dysfunction, Alzheimer’s disease, cardiometabolic disease, polycystic ovary conditions, conditions of non-alcoholic fatty liver disease, things related to sleep apnea, things related to gout—all of these conditions which are associated illnesses or diagnoses associated with type 2 diabetes are a manifestation of slight modifications of the metabolic control of complex regulatory pathways associated with bioenergetics, of which the molecule glucose plays a principal role (that’s the principal metabolic fuel to produce energy in eukaryotic organisms). And so when we start really looking at this condition that we call type 2 diabetes and its companion illnesses as more of a bioenergetic dysfunction, it really takes us into a slightly different way of evaluating the patient and possibly even how we manage the patient using variables other than solely just blood sugar or hemoglobin A1c.   This topic was very nicely discussed in a recent series of papers that appeared in The Lancetmedical magazine back in June of 2012. I did allude to these in a previous issue of Functional Medicine Update in which we talked a little bit about the concept that diabetes quality improvement is beyond glucose control itself. This was an editorial that actually appeared on page 2218 in the 2012 issue of The Lancet.[1] The authors say that quality improvement strategies in diabetes—as we look at 94 randomized controlled trials, with the findings from 48 cluster randomized trials—that it is found that there is a growing recognition that blood glucose control alone is not adequate to prevent both the microvascular and macrovascular complications of diabetes. We now recognize diabetes care is no longer glucose-centric. It is crucial to understand that other efforts that sustain a broader view—a systems biology view—must be employed if we’re going to really reduce the overall burden of the companion illnesses associated with dysinsulinism. I think it is very, very important to indicate that at present only one person in eight with diabetes has their disease controlled to the representative goals of hemoglobin A1c, LDL cholesterol, and blood pressure. What we start recognizing is that even with very tight control of blood sugar and A1c, in clinical trials the results appear disappointing for cardiovascular outcomes because we still see very significant incidence of cardiometabolic disease or cardiac complications that are associated even with tightly controlled cases of hemoglobin A1c, who have this metabolic disturbance that we call dysinsulinism.   Bioenergetic Conversion of Glucose: A Complex Metabolic System So you’ll notice there is—by this discussion—much more to the concern of metabolic disarrangement of bioenergetics associated with glucose than just diabetes itself. With that, let’s go back and explore for a moment what people are talking about as it relates to the control points for this complex metabolic system that relates to the regulation of bioenergetic conversion of glucose into things like ATP and NADPH and FADH2, these high-energy-carrying intermediates that really power up our body. We recognize that one of the control points that has gotten a lot of fashion over the past ten years are so-called nuclear orphan receptor signaling components. These would be the things like peroxisome proliferated activator receptor alpha and peroxisome proliferated activator receptor gamma, so these are PPARα and PPARγ.   The Challenges Related to Thiazolidinedione (TZD) Drugs We have seen a lot of note in the medical literature on these because these are targets for drugs to improve their function or modify the function of these nuclear orphan receptors, which signal messages from the cytosol of the cell into the nucleus of the cell to turn on specific genes that regulate insulin and glucose metabolic control points. Drugs like Actos and Aredia have been formulated and approved that have very high ligand activity specificity for PPARγ, so we call these the PPARγ agonist drugs that are there to enhance the activity of PPARγ and enhance then the regulatory effects of these transcription factors on the control of insulin response of genes. You know, the clinical trials for these medications showed very significant improvements in things like hemoglobin A1c and blood sugar in individuals who have the diagnosis of type 2 diabetes.   The challenge, however, as you probably recognize, is that these medications that are called thiazolidinediones, or TZD drugs, are pleiotropic. They don’t just influence PPARγ alone, although they have very high affinity for that ligand. It appears as if the influence that they have on PPARγ as transcription factor modulators is different than the kind of natural modulation of PPARγ that occurs through things like prostaglandin J2 and some other natural agonists that regulate PPARγ in normal cellular physiology. What we call this is slightly different PPARγ binding activities than the natural ligands, which means that they do things like what? They increase fat deposition, so we see that the PPARγ agonist drugs cause weight gain, which is generally kind of counterproductive for individuals that are trying to treat diabetes and trying to lose weight.   Secondly, we’ve seen recently that the stronger these TZD drugs are in influencing certain activities of the PPARγ, the more they seem to have cardiometabolic adverse outcomes (meaning, adverse cardiac side effects). And there is also some suggestion that they might have adverse effects on increasing risk to certain cancers as well. This kind of risk/benefit trade-off that is now being recognized with the TZDs have put them in some question, and as you know, one of the members of this family—the stronger of the two drugs—has actually been disallowed in Europe and a black box warning put on it in the United States, so now we’re starting to see the adverse potential effects of these synthetic PPARγ ligand drugs being much more well recognized and prominent.   Now, why is that? Let’s just talk about this for a second. Does it mean that PPARγ agonism is bad? Of course it doesn’t. I mean, this is a natural process in the body that helps to communicate from the outside of cells to the inside of our…what we call the book of life—our genome, the information that is important for enhancing or regulating bioenergetics through the metabolism of glucose, and so this is a very important natural part of our system of biological control. But what happens is when we start synthetically manufacturing or designing or discovering certain new-to-nature molecules that are designed and selected specifically for their very high affinity (meaning high-binding) to PPARγ? It may turn out that their binding sites to the PPARγ ligand is slightly different in its binding than that of the natural ligands, the things that normally control PPARγ function and so they could have all the effects of PPARγ natural ligands plus others because they are not binding at the same exact site. They’re not having the exact same effects. That’s what we call pleiotropic effects (multiple effects). And there are many papers that have been published now over the last few years that have demonstrated that these pleiotropic effects—these off-target effects of the synthetic PPARγ ligand agonist, the so-called TZD drugs—have been proven to be correct and different than the natural ligands, like PGJ2 (prostaglandin J2).   That raises some interesting philosophical questions, doesn’t it, about drug development, because you might have the most potent molecule you can find that will activate or inhibit a specific metabolic process in the body, but it may have off-target effects due to a slight difference from the natural way the body would regulate that function that are only seen after maybe several years of use of that molecule. In the general public you’re selecting for certain genotypes that are more susceptible to the adverse effects and it takes a while to figure that out.  Clinical trials are often limited in study size and may not be large enough to pick up those people in the cohort as a part of the whole group; their data was diluted out in the statistics of the safety trials. It is only when you get very large use of that medication in, say, millions of people that you start to see these small cluster groups over years of use starting to show these adverse effects. This is one of the problems we always have with synthetic molecules versus natural ligands–trying to better understand over time what their effects might be in specific genotypes that may have different susceptibilities or different affinities for these synthetic molecules.   As we look at the literature, we see papers being published that have titles like the following: “Insulin Resistance and Metabolic Derangements in Obese Mice Ameliorated by Novel Peroxisome Proliferated Activated Receptor Gamma Sparing Thiazolidinedione.”[2] Now, what does that mean in English? That’s a long bunch of words strung together. What it means is that people have gone back—medicinal chemists have gone back to the laboratory—and said, “Whoa, hold it just a minute. This generation of TZD drugs that we just put on the market that sold several billion dollars a year of product, now we’re finding over the long term they have some risk, so can we find molecules that are derivatives of these TZDs that don’t have some of these adverse side effects? They don’t have these off-target effects that we’re seeing with weight gain and with cardiac risk?” As that is being examined, it’s being found that yes, there are ways of tickling—I say “tickling” to use that word kind of euphemistically—the PPARγ agonists. In other words, binding at a different site on that molecule to produce slightly different effects that might reduce the risk of these adverse effects while still maintaining the positive effects of agonizing or enhancing PPARγ activity.   Here is where the medicinal chemistry–Sherlock Holmes–goes into play, where people try to explore–like a detective novel–exactly what the structure of a molecule would be, how the pharmacophore called TZD could be modified, how its scaffold could be changed in such a way to get the favorable effects without producing the adverse effects. But that then begs the question, doesn’t it, and that is: Well, what about the natural things that are controlling this all the time? Aren’t we kind of overriding these natural processes with these synthetic molecules and trying to redesign the nature as best we can? And of course that is the difference between the natural processes of substances that are produced in a system of natural biology in response to a changing environment versus taking charge with a synthetic molecule. As we’ve started to look at this in more and more depth, we start to see that there are certain characteristics of these synthetic molecules—these TZDs—that correlate with certain activities of PPARγ, so we can differentiate the kind of properties of PPARγ influence on function.[3] When you start doing that you find out that there are certain properties of these molecules that influence mitochondrial gene expression and have effects on mitochondrial bioenergetics and other effects of these molecules that have influence on other aspects away from mitochondrial function, things like influence on adipocytokines in the adipocyte cell, and things like beta cell activities in the insulin secreting cells in the endocrine pancreas.[4] So we start to look at tissue specific differential effects, recognizing that there are multiple effects that these molecules (TZDs) have, more than just a single hit and more than just one physiological functional change. I think we’re using this as a specific example of a probably more general phenomenon. If you think about medicinal chemistry, this can be seen not just for PPARγ, but you can say it about angiotensin inhibitors, or you can talk about effects of statins on HMG-CoA-reductase, but it has effects on lots of other things that influence other targets that are influencing function. These are part of the detective work that occurs (post-market surveillance) once a drug has been approved to figure out what are the other things that are being influenced in certain people, some of which may not be all that desirable?   Now, as it then takes this one to better understanding, you might say: Is there a positive outcome of this? Well, I guess the positive outcome is we’re starting to better understand who might be the best candidate for some of these drugs and who might not be a good candidate, by differentiating their unique response, but also it tells us a little bit about what we might want to be measuring in these patients as it relates to their response that goes beyond just that of glucose and hemoglobin A1c, because what we might say is, “Well, hold it. Some of these effects that we’re talking about that would be considered not so good may be seen early on in certain other changes in physiological parameters or metabolites or biomarkers, so maybe we should be looking at other things in the blood that are reflective of these things that might not, in the end, be so good for certain people, other than just look only at the things that we like that are good.” So we ought to be looking at a combination of different parameters, not just put all of our eggs in one basket, looking at blood sugar and hemoglobin A1c, which as you know are the standards of identity for managing diabetes.   Metabolic Profiling and Type 2 Diabetes That leads us into what we call metabolite profiling. How do we, then, take a broader array of substances that might reflect different aspects of how intervention influences this complex control of glucose economy and bioenergetics, other than just look at glucose and hemoglobin A1c alone? I hope I’m not losing you, here. I know this sounds fairly complex, but I’m trying to get you to understand a little bit as to how medicine is changing now to go away from a pill for an ill and looking at one endpoint as the marker for whether that pill is good or bad, to a more complex systems biology approach where we are looking at multiple parameters that help us to understand how that individual is uniquely responding to that therapy, to look at both positives and negatives, to personalize their treatment, to improve outcome and reduce risk to adverse effects. So that’s a different strategy that’s really built on a functional medicine model.   With that in mind, I’m now talking metabolite profiling in the aspect of type 2 diabetes, and there are all sorts of very interesting papers that have been published recently in this area. Let me give you one example, a paper called “Novel Transcriptome Profiling Analyses Demonstrate that Selective Peroxisome Proliferator-Activated Receptor γ (PPARγ) Modulators Display Attenuated and Selective Gene Regulatory Activity in Comparison with PPARγ Full Agonists.”[5] What this paper is really looking at is the difference in metabolite profiles in patients that have been given your kind of full PPARγ agonist drugs. This would be things like Actos and Aredia—very strong TZD modulators of PPARγ. Versus given medications that are not as strong as agonists of PPARγ, but they don’t have some of these off-target effects that I’ve described, and asking are there differences in the way they modify metabolites (the so-called transcriptome)? The answer is yes, there are differences, and when you start patterning this you develop a profile, right? Rather than looking at one number, like glucose. Or one number, like hemoglobin A1c. You have an array of different analytes that you are examining and you look at patterns of change, like shifting sands. Rather than looking at one sand grain, you’re looking at how the dunes of the sand configuration change with the changing environmental circumstances of these two different families of drugs.   Now you obviously could apply this also—this same concept—to that of lifestyle, or that of nutrition intervention, or that of exercise, or that of environmental modification, and you could examine what influence does that have on the transcriptome profiling of influence on these glucose metabolism regulatory genes and their subsequent metabolites? That’s really, I think, the direction—the trajectory—that this field is going, which is making it much more obvious through this type of research the important role that lifestyle, diet, nutrition, exercise, stress management, pollution plays in altering glucose and insulin physiology and ultimately bioenergetics, because it comes back again to looking at things not only like genes that are associated with bioenergetics in a traditional way of metabolism, but also looking at mitochondrial-specific genes that regulate bioenergetics in the energy powerhouse of the cell, and so how does this all play out in different tissues, like in the muscle, or the fat cell, or the liver cell, or the heart cell, or the beta cell of the pancreas that is secreting insulin. Would there be some energy catastrophe that’s occurring in these cells that causes their early death? This is called apoptosis, and that apoptosis, then, leads to diminishment of those cells being able to do their work, and things like, for instance, the beta cell. If you start having apoptosis of beta cells, you then have ultimately a loss of beta cell mass and beta cell function, which means loss of insulin secretary ability, which ultimately becomes, then, the patient who becomes the type 2 diabetic that requires insulin as a form of their therapy because they have lost their insulin secretary ability.   These are really very important kinds of conceptual breakthroughs and discoveries that are occurring in this whole field of diabetes prevention and management that is revolutionizing our thinking. And so when you start looking at early metabolic markers for the development of dysglycemia and type 2 diabetes and their physiological significance, it plays a very important role of going from just focusing on pathology to focusing on function, and how would you then intervene earlier when you see the trajectory of these metabolites moving towards dysfunction moving towards pathology, meaning the end stage of type 2 diabetes? So you can get involved with patient management much earlier, and you can also evaluate the effect of whatever therapy is being used earlier by looking at how these complex patterns are normalized or altered by this specific therapy that’s personalized to that patient?   That’s going to be the topic that we will share with our researcher of the month this month, Dr. Walter Gall. I think you’re going to be very fascinated about the progress that is being made in the development of the multi-parametered analyte profiling that leads us to better understand early on how that person is moving towards diabetes or some of the sequelae of events that are associated with insulin resistance well before they actually get this diagnosis of diabetes, and then how to manage them in a personalized way.   Questioning the Role of Hyperinsulinemia We’re starting to see from this the development of new strategies, other than just go with hard-hitting, high-activity PPARγ agonist drugs (these TZDs), new ways that we can actually modulate insulin signaling in different tissue types and improve functioning. Barbara Corkey, who is at the Boston University Medical School, was the recipient of the 2011 Banting Award, which is considered the premier award for diabetes researchers that is given each year. She titled her 2011 award acceptance speech “Hyperinsulinemia: Cause or Consequence?”[6]That was a question. And in this lecture, she—I think—takes a very provocative position, which is well-founded on her research and that of many other colleagues, that when we start talking about hyperinsulinemia, it’s really a consequence of metabolic catastrophe that has occurred by mitochondrial decline and poor bioenergetics, and this occurs in things like the beta cells and other cell types where you get this mitochondrial dysfunction, this bioenergetic dysfunction, that ultimately is associated with poor glucose economy and dyslipidemia and the sequelae of events that we associate with type 2 diabetes. In fact, there is a very nice paper that was published in the journal Diabetes in January 2012 that is really the transcript of her lecture that talks about the nature of this mitochondrial issue associated with the advent of the bioenergetics problems that we call dysglycemia and dysinsulinism. And that was followed up, actually, with a very, very unique and I think encompassing paper, again authored by Dr. Corkey, titled “Metabolic Master Regulators: Sharing Information Among Multiple Systems,” in which she shows you can’t just separate out this glucoregulatory pathway as being singularly isolated from the other pathways of the body, like fat metabolism, protein metabolism, endocrine control.[7] These are all interrelated through redox balance of the body. That’s reduction oxidation (we used to call this oxidative stress). I’ve been talking about redox control in Functional Medicine Update for over 20 years, so I’m kind of feeling vindicated, here, that we’ve been advancing that concept that it’s not just antioxidants, and it’s not just oxidative stress, it’s really the control of what we call the voltage of the cell. It’s like the voltage in the battery of your car. Your starter motor works best when the voltage is above 12 volts in your car. Well, you’ll still be able to turn the starter motor at eleven-and-a-half volts probably, unless it’s really a cold day, but it’s going to go “er, er, er.” It’s not going to start very quickly. If you get below that, even though you have voltage in your battery, you’re not going to start your car. This is very similar to the mitochondrial voltage, which is the electrochemical potential called the redox potential. So you might still be producing energy in your mitochondria, but if it’s below the starter motor voltage you don’t feel very good. You have muscle pain. You’re fatigued. You’re not thinking clearly. You’re not producing insulin correctly if it is in the beta cells, and that master regulator is this redox potential in the body. It’s controlled by all of these interlocking regulatory systems, one of which—or some of which—are related to PPARγ, and PPARα, and transcription factors that regulate the genes that control things like insulin and glucose economy.   Fat Cells Have Different Personalities When we take that to a clinical level, what it teaches us is that we need to look at what cell types would be most influenced and would most be important in regulating this, and kind of do a thought process about tissue-targeted regulation. So I’ve talked about the beta cells of the endocrine pancreas. That’s very important for secretion of insulin. If you don’t have proper bioenergetics in the mitochondria of your beta cells and they are dying rapidly, you’re not going to have good secretion of insulin. You’re losing beta cell mass, and you’re losing secretory ability. So that’s one cell type.   Next, of course, would be considered the adipocyte, what used to be considered this lowly cell that was just there to store extra calories in the form of fat and kind of was metabolically inactive, but we now recognize the adipocyte is very active as an endocrine organ, and its regulation is once again controlled by bioenergetic processes—redox processes—that are associated with the secretion from activation of certain genes that we call adipocytokines, a family of regulators that have names like adipsin, and adiponectin, and resistin, and TNFα, and various inflammatory proteins like IL-1. So this is a complex array of regulatory molecules produced by the adipocyte cell in response to environmental signals that are in part regulated by redox control, just as is the beta cell secretion of insulin. Similarly we could go to the liver cell and find that redox had a very important role to play in how it stored fat in its metabolic activities, like glycogenolysis or glycogenesis.   Thirdly, we could go to the myocyte (the muscle cell) and see the same thing: that it has very important regulatory effects through its mitochondria that are regulated by redox potential. And then, of course, lastly the cardiocyte, which, as you know, about three quarters of the cardiocyte by volume is occupied by mitochondria, so it has a very dependent role in its function to that of mitochondrial function.   All of these cell types, then, are interrelated with this overall concept of redox control, redox balance, and mitochondrial function. Now if you ask the question specific to that of adipocytes and say: “Well, are all adipocytes identical in terms of their metabolic regulatory function?” The answer is no. We now recognize that there are differential effects between the subcutaneous adipocytes and the omental adipocytes (the so-called central fat adipocytes) that are more around our organs, and the ones that are maybe not as cosmetically observable as the ones that sit under our skin.[8],[9] These central adipocytes are metabolically different than those of the subcutaneous adipocytes, and they have a more important regulatory role in controlling these adipocytokines that can have effects on insulin economy, on redox potential, and have this feedback relationship with circulating immune system, meaning macrophages and monocytes.[10] Macrophages and monocytes sit in the adipocyte matrix in our central fat and cross talk with them about the body’s status. So if there is a big immune response, an inflammatory response, then you have a bunch of angry macrophages and monocytes, and they speak with their angry voice to the adipocytes and say: “By the way, I’m kind of aggravated. You should be aggravated, too.” And then the adipocytes can be aggravated by up regulating the expression of these adipocytokines that get secreted, so it’s like a dog chasing its tail. It’s an amplification process. Or, if the adipocytes are activated, then they can speak to the macrophages and say: “By the way, you guys should be upset. I’m fed up with the way I’m being treated.” I think that’s an interesting metaphor: I’m fed up and I’m not going to take it anymore. This is the Rodney Dangerfield adipocyte. So then that adipocyte says to the macrophage that is circulating within the central fat mass: “I want you to take my message out to the rest of the body and say that I’m kind of upset.” And when they do that they put out a state of alarm, which then produces proinflammatory mediators like TNFα, and IL-6, and these things that we now associate with systemic inflammation.   So we recognize that there is this very complex interrelationship between fat cell types and their personality and status, and the regulation of insulin signaling and insulin secretory ability. This is a system of biology. You can’t separate one out and say: “Well, we’re only going to worry about the pancreas today and tomorrow we’ll worry about the muscle cell, and the next day we’ll worry about the heart cell, and then we’ll eventually get to the lowly adipocyte.” You have to think about all of these relative to the patient’s specific state of uniqueness with their dysglycemia and dysinsulinism. And we now recognize that there is a metabolically active form of fat called brown fat, which we’ve had great controversy about for years and years—decades. It’s been thought: “Well, it’s only found in hibernating animals, these metabolically active forms of fat. Or it’s only found in infants; it goes away in adulthood.” But now it has been found that brown fat is found in adults.[11],[12] Somewhere in the subscapular area there is a few grams of brown fat that are very important as metabolic regulators. The reason they are brown is they have a lot of cytochromes in them that are in the mitochondria of these fat cells that are thermogenically responsive, so they produce heat. They undergo what is called fetal energy cycles. They uncouple energy to produce heat to keep our temperature, as warm-blooded animals, up. And we recognize that the activity of these brown fat cells is in fact partly controlled by the neuroendocrineimmune system. Signals that are sent to it through endocrine and autocrine release of various messenger substances, like norepinephrine and epinephrine, but they are also regulated in part by communication they have with proinflammatory cytokines, and things coming from the immune system. So the neuroendocrineimmune system has something to do with brown fat thermogenesis and control of heat and the relationship, then, of body energy economy.   Type 2 Diabetes: What’s the Chicken and What’s the Egg? This is a whole new game, isn’t it, that I’m talking about? This is a whole new way of looking at obesity and its relationship to diabetes. It raises the question: Does obesity cause diabetes, or do metabolic disturbances associated with poor energy economy cause both diabetes and obesity? Meaning, maybe it is the effect and not the cause—that these are all interrelated as a consequence of metabolic disturbances. And if so, then it begs the question: What’s the chicken and what’s the egg? Where did the metabolic disturbance start? This paradox that we are talking about—can we trace it back to its origin? And when you start doing that, you find out that lo’ and behold, as the story is emerging, there appears to be some very interesting (at least path-finding) direction related to what might start this process. So you might say, well what could interrupt mitochondrial function? What could produce immune dysfunction? What could produce inflammation? Because all these things seem to be connected to this shift of the sand of signals associated with insulin signaling and glucose that at later stage, downstream somewhere, we’ll call type 2 diabetes, and if the beta cells completely kind of expire, then that patient becomes a type 2 diabetic that requires insulin. And so, how do you get there from here? You need to ask the question what could adversely affect these bioenergetics processes that are focused on mitochondria in these target cells (the cells that are beta cells, the cells that are in the adipocytes, the cardiocytes, the hepatocytes, the myocytes), what could influence, adversely, mitochondrial bioenergetics? And that then leads us into some very interesting territory that’s fairly new that is associated with things like does autoimmunity associate itself with type 2 diabetes? Are there certain kind of immune responses that could produce inflammatory response to certain cell types that lead to altered redox and mitochondrial catastrophe, meaning such that you start losing bioenergetic capability? The answer is yes. There are certain kinds of things that can influence energetics in such a way as to lose both beta cell mass and/or insulin sensitivity, like we see gluten now being associated with certain kinds of increased risk to type 2 diabetes because of the effects on these complex bioenergetics pathways. So things that activate mast cell or macrophage that then cross talk with the adipocyte cell to produce inflammatory response, not just things like gluten itself, but you might think of many different things that could activate the immune system or cause alteration in metabolic function, like, for instance, what are called persistent organic pollutants (POPs), which we’ve talked extensively about in previous issues of Functional Medicine Update. So these things that could actually poison mitochondria could be considered insulin toxic because they have an adverse effect, then, on bioenergetics, that ultimately causes the cell types that are controlling this regulatory process—this complex process—to be diminished in function. There are more and more papers now being published that indicate that certain kinds of substances like bisphenol A, or polychlorinated biphenols, or things of that nature can have adverse effects on mitochondrial function that can then have a relationship to altered energy economy in the mitochondria, altering redox, and ultimately have effects on insulin, both secretion and insulin signaling, which we then later call either metabolic syndrome and/or type 2 diabetes.[13]   I think these examples show that once you sieve this information through a functional medicine lens you start getting maybe a different approach towards clinical therapeutics other than just regulating insulin and glycosylated hemoglobin in and of themselves. You need to take a broader array of evaluation of these metabolites that are influencing or have been influenced in such a way as to alter metabolic function to later set the trajectory toward type 2 diabetes.   Now, I’ve said a tremendous number of things in a fairly short period of time in this discussion. You’re going to hear from Dr. Gall, who will do a much nicer job kind of taking this concept of metabolomic profiling down to a more clinically relevant level. But what I want to really get you to understand is that this field that we call type 2 diabetes and its relationship to endocrinology is changing just revolutionarily underneath our feet. The way that we thought about it for decades is in a state of tremendous flux. You’ve heard me speak in previous issues of Functional Medicine Update about the work that has recently demonstrated that there are agonists in a natural system for PPARγ that will have all of the positive effects on regulating insulin and glucose economy without some of the adverse effects, and we recognize that we can see how these natural agonists actually differentiate themselves from the TZD drugs. We can see how lifestyle intervention, such as exercise, modulates the natural ligands that have the positive effects on PPARγ without the adverse effects. Meaning exercise doesn’t cause weight gain, whereas TZD drugs that work on PPARγ do, so exercise has an effect on PPARγ, but it does so through a different association of the signal of exercise to the nuclear transcription factor PPARγ that regulates the genes that associate with insulin economy in a different way than a synthetic molecule TZD does.   What we take away from this is to be cautious when you start saying, “Well, I want to have a natural substance that is just like TZDs.” You probably don’t want that. What you want are effects that regulate function like the natural system does that produces this more complex pleiotropic regulatory connection without some of these off-target adverse effects. Secondly, we want to be able to recognize that there may be many environmental factors that have adverse effects upon these complex processes that ranges from everything from the food of one being the poison of another (like you wouldhave with gluten in a gluten-sensitive individual), to the exposure in a certain person to certain xenobiotic substances in their environment that poisons mitochondria in such a way as to lower their energy economy and produce insulin resistance.   To that you might say: How does our body get rid of lipophilic toxins? It does so through the activity of cytochrome P450s and phase II detoxifying enzymes. What happens if that person has a genetically modulated response, and let’s say it is a diminutive response, to a petrochemical toxin? That person becomes more sensitive, then, to the adverse effect of that toxin, which is stored, ironically, because it is fat soluble, in fat, which then alters adipocytokine signaling, which then lowers mitochondria, alters redox, which then has an effect on the inflammatory pathways that subsequently influences insulin signaling, and now that person—as contrasted to their neighbor, exposed to the same substance—may then start to move their way towards type 2 diabetes in the same exact environment of another person who has genetically got better detoxifying enzyme function. So now I’ve broadened the profile that we have to think in an endocrinological sense about detox. Or we have to think in an endocrinological sense about immune response. Or about inflammatory signaling. We can’t just go in and just modulate glucose and insulin by themselves in the absence of looking at these broader principles. So this is a very powerful reinforcing principle for the conceptual framework of functional medicine, a systems biology framework.   Does that mean that no patient ever responded to these other therapeutic molecules like TZD agonists or synthetic TZD agonists? Of course not. There can be many people that responded very well because they were in such a state that their genes responded without some of the off-target adverse effects. They’re favorable response gave them a good outcome. So I don’t want to throw the baby out with the bathwater and just say, “Oh, these molecules that we’re using as drugs are totally in absence of value.” What we’re really doing is broadening our concept to say the right tool, at the right place, for the right person by asking the right questions. That is the functional medicine model. And how does it interrelate to, then, the ability of their brown fat to do its work right? To establish proper redox? To get thermogenic response to their diet? It’s more than just calories alone. It’s more than just: You got the genes to be fat. No, it’s the whole story that interrelates the environment to that person’s genomic message, that then gives rise to their metabolic control points.[14] So what we call a disease may actually be the metabolic set point for that person’s genes in response to that environment. They don’t have a disease. They have the proper biological response of their genes to that environment in which they find themselves. We stigmatize it, and almost give it a form of discrimination. We say, “Well you have a disease. You’re flawed.” And they’re maybe not flawed. Maybe they’re working exactly as they should work in that environment. What they need to do is go out of the flawed environment for their condition and move into a different environment.   I’ve used the example of the Pima Indians concerning this for some time, saying that Pima Indians don’t have diabetic genes. What they have are warrior genes that when thrust into a high-sugar, high-fat, high-alcohol environment now suddenly are maladapted to that environment and produce a dysfunctional response to that which is their metabolic disturbance that we later call diabetes. They’re not diabetic genes; they’re genes that are actually selected for the biggest threat they’ve had for their survival throughout history, which is starvation. So they have what we call thrifty genes. The thrifty genes hold on to calories much more assiduously than other people’s genes, so you give them a bunch of empty calories and you get these responses that produce inflammation, altered redox, and ultimately rapid obesity and type 2 diabetes, but if you change the environment to say, “Hold it, you’re selected for starvation, so we need to give you a different kind of diet that’s really going to be matched to that specific biological history and your legacy.” And now suddenly they’re not fat, they’re not diabetic, they’re not suffering from inflammation, they don’t have cataracts, they don’t have diabetic gangrene, they don’t have peripheral neuropathy, and they don’t have blindness due to retinopathy, just by modifying their environment to be consistent with their own genetic history.   I think these are very, very powerful concepts that are coming out of this work and really restructuring how we think about these complex metabolic disorders. Once you open this door, then you get into a much more robust—and it also might be considered a bit more confusing—environment. For instance, now we recognize that on the surface of our intestinal lining (so-called L cells in our distal ileum) sit receptors that are picking up information from our food and actually tasting our food way down south in our intestinal tract and translating the taste—when I say taste, there are certain principals in our food that are triggering the receptors to secrete substances into our blood, and those are things like glycogen-like peptide 1 (or GLP1), and some of you know there are drugs, like Amylin’s drug Byetta, that actually are there to stimulate the secretion of GLP1 to treat type 2 diabetes. But our body does that naturally by tasting the right things in our intestinal tract, and the reason I say “tasting” is that the receptors that are tasting our food in our intestines have the same chemical conformation or make-up as the taste receptors in our tongue that are the bitter taste receptors. So we’re getting the same signals translated in a different way. We call it bitter; our intestines say, “Oh, that’s a molecule that I need to stimulate the secretion of GLP1, which goes in the blood and regulates insulin.” So diet plays a very important complex role in modulating redox potential, modulating these autocrine/endocrine and neurotrophic factors that regulate insulin and glucose control, and now we recognize—and this is a new “a-ha” that the beta cells of the endocrine pancreas actually taste nutrients to secrete insulin. Yes, they taste nutrients. Did you hear what I just said? The beta cells. So these substances that come into our bodies through our diet—things like branched chain amino acids, and various B vitamins, and other interesting molecules derived from food are picked up by receptors on the beta cells that taste these nutrients and then regulate mitochondrial redox within the beta cells for the secretion of insulin.[15]   If you think that this was all a well-understood story ten years ago, five years ago, or one year ago, I would suggest no. We are already living in a new world in which this complex interaction of genes and environment in a functional medicine matrix perspective is changing the way we will think about assessment, diagnosis, and treatment based upon the complexity and uniqueness of that individual in their environment.   Post-Prandial Metabolic Toxemia What happens if you then eat one high-fat meal? Well, probably nothing with one high-fat meal. But if you eat a high-fat meal every day of your life for weeks, months, years, and decades, what that has been associated with is altering your intestinal permeability. It’s producing what’s called post-prandial metabolic endotoxemia. So there are toxins like bacterial lipopolysaccharides that then are released into your blood. They activate your immune system, causing the production of these inflammatory mediators that then activate your fat cells, that then cause an inflammatory response and you distort your metabolism, and what’s the ultimate outcome? Diabetes. So now we say, “You mean eating a high-fat meal every day could actually associate itself with diabetes as a consequence of actually poisoning mitochondrial function through these inflammatory pathways?” Yes, that’s what it is saying and there are many, many papers now coming out on this. Dr. Patrice Cani, who is one of our colleagues in our research team work at Louvain Catholic University in Belgium has published a number of extraordinary papers with his colleague, who you heard on Functional Medicine Update years ago, Dr. Nathalie Delzenne, on the relationship of postprandial endotoxemia to type 2 diabetes.[16],[17]   It’s a now very increased understanding that you’ve got these xenobiotic substances that can poison mitochondria. You’ve got food-related functions that can poison mitochondria. And so we’re really talking about how do we reconsider metabolic disease in the context of this 21stcentury understanding of the genes and environment interaction? It’s not just a disease called type 2 diabetes. It is a complex personal relationship that we each have intimately with our environment that then signals through this complex systems biology to regulate our function through adipocytes, cardiocytes, hepatocytes, beta cells, myocytes that ultimately then regulates energy economy. An exciting chapter that you’re going to hear now from Dr. Walt Gall, how do you translate this down into asking the right questions, assessing the right information, and using metabolic profiling to better get an early understanding of what to do in that patient’s personal program. So with that in mind, let’s move to our researcher of the month, Dr. Walt Gall.

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INTERVIEW TRANSCRIPT

Researcher of the Month Walt Gall, PhD Metabolon PO Box 110407 Research Triangle Park, NC 27709 www.metabolon.com Here we are once again at what I consider to be the most interesting part of our Functional Medicine Update edition each episode, and that’s our clinician/researcher of the month component. As you know, I look forward to this and I know you do if you’ve been a long-standing FMU listener. We’re very fortunate once again. I can’t believe how privileged I am with the kind of expertise that we’ve been very fortunate to have discussions about—this whole field of emerging medical technology in 21st century—and of course we’re very lucky again with Dr. Walter Gall, who will be our researcher this month and will help us understand this very important area that we’ve been in discussion about for the better part of the last three years: diagnostic biomarkers, early warning signs, how do you understand the trajectory of a chronic disease before it becomes so acute that it requires crisis intervention? How do you then employ, let’s call it, less heroic intervention at an earlier stage to modulate disturbed metabolism and avert the necessity for very costly hospitalization and end-stage disease? You know we’ve had the privilege of talking to experts on HDL physiology. We’ve had the opportunity to speak with individuals who are in lipid particle numbers and how that interrelates with early-stage vascular disease risk. We’ve had discussions on oxidized LDL and Dan Steinberg’s work at the University of California, San Diego. We’ve done a pretty good job of laying out a landscape of areas, including Paul Ridker’s work from Harvard on high sensitivity C-reactive protein (CRP) as it relates to inflammatory assessment. So, where are we in this issue with Dr. Gall? We’re at the frontier of what I consider to be probably the most important singular area of discussion as it relates to disturbances in metabolism, and that’s related to insulin signaling, insulin activity, glucose transport, and this whole increasing understanding of the conundrum that’s associated with dysinsulinism that translates into so many varieties of chronic age-related diseases, not just type 2 diabetes and cardiometabolic disorders, but things like polycystic ovary syndrome and endocrinological effects, and translates into end-stage renal failure, neurological disorders, dementia, certain forms of epithelial cancer, hypertensive disorders leading to stroke. This is an omnibus of discussion. So how do we—as an early warning—understand whether a person is heading on towards these kinds of end-stage problems, at a point where less heroic intervention can have a measurable and significant effect on averting pathology? That is—fortunately—the expertise that Dr. Gall brings to us. Let me just give you a quick bio—kind of who is the person behind the voice and the message. Dr. Gall earned his PhD at Vanderbilt in what I would call kind of a very interesting translational science program that couples across chemistry, and biology, and physics, and mathematics, and informatics. He had an undergraduate degree in chemistry—obviously a kindred soul—in organic chemistry and biochemistry. And then later, his PhD work was in looking at cellular genetics and cellular signaling processes, postdoctoral work at the University of California at Berkeley, and a variety of very important appointments that ultimately led him on into his present position as director in the diagnostic area with the group in North Carolina called Metabolon that many of you have heard about. It is a very, very interesting metabolomics company looking at high-level pattern recognition and complex metabolic profiling in the network physiology area. The whole future of health care’s understanding of how pathways fit into networks is really the nature of understanding the organism. With that as a brief introduction of the background that Dr. Gall brings to us, Walter let me introduce you and thank you so much for your participation with Functional Medicine Update. WG: It’s a pleasure to be here, Jeff, thank you. JB: Let’s start off with the first question and that is could you tell us a little bit about the challenges that we have presently in diagnostics as it relates to dysinsulinism or dysglycemia—what some of the limitations are? The Limitations of Glycemic Diagnostics WG: Yes, I’d be happy to. Basically, what we do today in the world of identifying high-risk individuals as it relates to insulin resistance disorders such as type 2 diabetes, cardiovascular disease, chronic kidney disease, is we’re essentially working in sort of a unidimensional perspective as it relates to measuring glycemic diagnostics, whether it is fasting plasma glucose, or more recently hemoglobin A1c has moved into the diagnostic sector beyond its utility and therapeutic monitoring for diabetic patients, so now it is actually being used to detect both type 2 diabetics as well as pre-diabetics, and essentially some of the limitations that go along with that is that there is discordance between hemoglobin A1c and fasting glucose, that’s one point I would make. But there is also a low sensitivity in identifying insulin resistance. In fact, it has very little predictivity as it relates to insulin resistance. So what we’ve been doing at Metabolon is really taking an unbiased and fresh look at this unmet medical need as it relates to identifying non-glycemic novel markers of insulin sensitivity in the early stages of the disease process that precedes diabetes and cardiovascular disease, and is a very common thread, unfortunately, in our society, as it relates to chronic diseases, as well as obesity disorders such as the ones you mentioned, but also fatty liver disease, there has also been connections made with Alzheimer’s and mild cognitive impairment. It’s actually fairly pervasive as far as how insulin resistance is related to so many of these chronic diseases that ail western society and is actually moving into other parts of the world with the increased westernization of the global economy—you know, the increased urbanization, the increased ethnic risk of basically exposure to these westernized societies as far as their risk for insulin resistance and diabetes. This is basically a key factor that I believe contributes to the rising epidemic of diabetes and obesity as it continues from year to year. A New Test for Measuring Non-Glycemic Metabolites and Fasting Insulin What we have been doing is I’ve led the development of a diagnostic called Quantose™, which stands for Quantitative Measure of Glucose Metabolism, and essentially this is a simple blood test—a fasted plasma test—that can be taken from a single draw, and is measuring these novel non-glycemic metabolites plus fasting insulin. Basically an algorithm is generated to give an insulin resistance estimation of an at-risk patient so that physicians, as well as patients, can be aware that they may be asymptomatic, but they are actually in a high-risk zone, if you will, so that the physician can raise that red flag and counsel the patient accordingly with regards to lifestyle intervention or other therapeutic solutions. JB: One of the most extraordinary parts of your profile, I think, is how you derived this algorithm. Some people might say, “Well, we just chose three analytes out of a random panel,” but I think the technology you are using is quite dramatic. Could you describe it? WG: Sure. Basically Metabolon has the world’s leading metabolomics, mass spectrometry-based, discovery platform for identifying disease-based biomarkers, and we’ve leveraged that platform approach at going after developing a fasted blood test for insulin resistance. Essentially it’s an unbiased medical profiling approach that’s based on multiple mass-spectrometry platforms with regards to measuring small molecules. So this would be your cholesterols, your glucoses. But raise on an order of magnitude and that really gets into the diagnostic screening of identifying novel biomarkers, where we’re measuring several hundred small molecules at a time, in a single blood sample, to then identify which small molecule markers are actually correlating above and beyond traditional risk factors, and correlating significantly with the gold standard for measuring insulin resistance, which we use the hyperinsulinemic euglycemic clamp, which has been recognized for decades to be the gold standard and has been instrumental in a lot of nested clinical studies developing into diabetic drug development. JB: So we’ve heard many times that various biomarkers have been chosen, but then the question is validation. Could you tell us a little bit about how this connects to other traditional methods of evaluating glycemic response like the oral glucose tolerance test or the euglycemic insulin clamp? WG: Sure. When carrying out the discovery and validation studies within our CLIA- and CAP-certified laboratory in North Carolina, essentially we wanted to be rigorous in verifying it and validating these biomarkers, as well as the algorithm test maintenance and resistance. We worked with a really great consortium of researchers over in Europe that represents the European Group for the Study of Insulin Resistance, working with a seminal study in the insulin sensitivity field called Relationship of Insulin Sensitivity to Cardiovascular Disease, which represented the risk population. This is the study that had both oral glucose tolerance testing as well as the euglycemic clamp methodologies employed to essentially categorize them as normal tolerant, insulin sensitive, or insulin resistant, or one of the pre-diabetic categories: impaired fasting glucose or impaired glucose tolerant.[18] Essentially what we’ve identified from a simple, single draw, fasted blood test of these circulating metabolites, as this index of insulin sensitivity, is that it basically—from a statistical point of view—can replace the two-hour glucose value as far as identifying insulin resistant individuals. And so we believe that will be a key clinical utility message for physicians that would actually have that same question that you offered there. JB: I’ve heard you compare this—and I think it’s a very good analogy—to what happened with cholesterol and cardiovascular risk assessment 25 or 30 years ago. I think that analogy to what the Quantose™ test does in the area of type 2 diabetes and cardiometabolic disease is very insightful. Could you share that with our listeners? WG: Yes, absolutely. Traditional lipid parameters we know represents around 50 percent of the cardiovascular risk that we know of today. Essentially when looking at a disease like type 2 diabetes, we actually know just from the studies that have been done that the average time a person has actually had type 2 diabetes by the time they are diagnosed with glycemic diagnostics, they’ve had the disease for several years. You add on top of that the number of years that they have chronic insulin resistance and you can imagine some of the physiological damage that may be occurring with regards to insulin resistance and the nascent beta cell dysfunction that’s occurring as you move towards diabetes. We believe that this test is going to be a game-changer as it relates to identifying asymptomatic, high-risk subjects that may have certain risk features such as family history of diabetes, or maybe they are overweight and may be at risk for hypertension. These are the type of patients the physicians may be concerned about, and now they have a tool to basically quantify their level of risk—whether they are normal, intermediate, or severely insulin resistant. One of the other key features of the test that I believe is of critical importance as far as clinical utility is that we’ve done studies as it relates to therapeutic monitoring. We’ve looked at insulin sensitizing interventions such as pioglitazone, or bariatric surgery, as well as exercise–all three insulin sensitizing interventions. And we’ve shown that our index of insulin sensitivity tracks that with a very high correlation. You mentioned the question about validation earlier. We essentially have validated this in large IR-related outcome studies, with regards to the Botnia prospective study, which is a very well-known family history diabetes population that has been followed and exquisitely phenotyped.[19] That validation has been mirrored with the Act Now study, which is a diabetes prevention study done here in the US, where we actually looked at the correlation of rigorous measures of insulin sensitivity such as the Matsuda index, which was championed by one of our collaborators, Ralph DeFronzo in San Antonio.[20] And essentially, with the additional validation and multiple population studies, and then showing on top of that that it tracks the change in insulin sensitivity with placebo groups as well as groups that are being intervened with to improve their insulin sensitivity and the fact that it tracks that really underscores the utility of tracking improvement or lack thereof when counseling a patient. JB: So now let’s go from its clinical utility to what you learned after examining several hundred metabolites in these populations. What popped out to be really an unexpected “a-ha” for you as it pertained to these risk factor markers? Alpha Hydroxybutyrate is a Top-Ranking Marker for Insulin Resistance WG: Great question. Essentially what was fantastic about taking an unbiased approach was that identified, statistically, these metabolites that came up as the highest correlates to insulin sensitivity. The top-ranking marker is a marker called alpha hydroxybutyrate. This is not a ketone body. Beta hydroxybutyrate is a common metabolite that is perturbed with diabetes as far as ketoacidosis. This is a different metabolite in a different pathway, with regards to energy metabolism. This is a metabolic pathway that is right juxtaposed next to the tricarboxylic acid cycle (TCA cycle), which occurs in the mitochondria with regards to energy respiration. Conventionally speaking, we actually believe that insulin resistance may originate in the mitochondria, and so the fact that this metabolite is a reduced form of a precursor substrate that is a very common substrate to amino acid metabolism and glutathione synthesis as it relates to oxidative stress response. What was really interesting was another marker that was number two in line is a novel lipid signaling molecule—what’s called a lysophospholipid—that is in the phospholipase A2 pathway in the liver, as well as lecithin-cholesterol acyltransferase in the circulation, and what’s interesting about that molecule is it is actually decreased with insulin resistance, and as well as further decreased with type 2 diabetics. We believe, just from the literature done by others, that this class of lipid represents a very interesting molecule to continue to watch and monitor with patients because of its implicated action with pancreatic beta cells as far as insulin secretion, as well as its action in the enteroendocrine system with the gut and the incretin access. So we believe that looking at these nonglycemic metabolites and characterizing a person’s level of insulin resistance and their potential improvement with therapy is a critical step forward in identifying the high risk individuals and then tracking their success with improving that. JB: I think all of our listeners who have been following Functional Medicine Update for some time, their ears probably immediately perked up when you talked about mitochondrial oxidative stress, and redox potential, and bioenergetics associated with insulin resistance and beta cell mass and beta cell function. That’s a topic we’ve been talking around, and glutathione biochemistry and NAD-NADH ratios and so forth for the better part probably of ten years. It sounds like these clinical markers are really starting to pop out of these multivariate analyses as kind of maybe defining the hypothesis as having clinical utility, it sounds like. WG: Yes, absolutely. We see that these markers do represent an energy imbalance. In fact, alpha hydroxybutyrate is generated when you do have this redox imbalance, where you have increased NADH reducing equivalence that’s a result of high lipid oxidation events, which is characteristic of insulin resistance. So the fact that we see this metabolite as one of the key markers really validates that hypothesis that there is an energy metabolism abnormality. I would go on to further say that we’ve seen this metabolite have effect on insulin sensitive tissues. We’re looking at the effect of these metabolites on insulin release as well as mitochondrial respiration that’s important for insulin release as well as glucose uptake. We’re very interested in looking at the mechanistic questions in a rigorous way to further increase our insights into these novel biomarkers. JB: I know you were recently at the American Association for Clinical Chemistry meeting, a big international clinical chemistry meeting, and presented your new profile. What kind of response did you get both positive and negative? Anything new always has some critics and some skeptics. What types of things did you see at this large national meeting? WG: Yes, we had a couple of scientists that are a part of our team. One collaborator at UNC presented a poster as it relates to both diabetics as well as non-diabetics, essentially looking at the utility of measuring their insulin resistance. One of the cautions was you’d have to be careful of measuring patients that are actually on insulin, so that is one limitation. We’d be really targeting this test toward non-insulin-dependent diabetics, as well as non-diabetics (that would include the high-risk, pre-diabetic group). But overall there was a lot of positive enthusiasm for having a simple blood test for measuring insulin resistance. It was very well received, and we look forward to showcasing this in subsequent meetings. JB: I know that you’ve done a tremendous job of linking the development of your test and the clinical validation with real strong opinion leaders that have a long history as being leaders in the field diabetes pathophysiology and etiology. You’ve mentioned a few of those individuals. Tell us a little bit about you’ve gone about networking with these individuals in collaboration for the development of the test. WG: Sure. When essentially calling on some of the key investigators that have done these large outcome studies, such as the RISK study, employing the euglycemic clamp, Ele Ferrannini, the former president of the European Association for Study of Diabetes has been a fantastic colleague through this clinical research effort, and I just want to acknowledge him and his team, as well as his colleagues within the European Group for the Study of Insulin Resistance, at working with us as far as clinical counsel and basically the development of this test, looking at the utility and the hard questions that you’d like to address in developing a diagnostic. Ralph DeFronzo, who championed the clamp back in the late 70s, as well as other investigators at Joslin Diabetes Center, such as Ron Kahn, Elizabeth Patti, have been instrumental in looking at these metabolic pathways, not just in adults, but in diabetes animal model systems, so we can actually look at the origin of these metabolites, as well as looking at adolescent obesity development, and looking at the perturbations of these metabolites in that setting, which is an enormous public health medical need as far as being able to identify not just adults that are high risk, but really the pediatric segment. JB: I can tell you the first time I heard you speak I had every neuron alive and well and totally focused on what you were saying. I think you’re hitting right in to a huge unmet need that may open up the opportunity for absolute patient stratification and recognition early on of the people that we really want to spend time on counseling and getting into appropriate programs, and then to track the success of those programs—those therapeutic programs—be it either lifestyle management, nutraceutical, medical foods, and/or pharmaceuticals so that we really are tailoring and personalizing those programs to maximize outcomes. I want to really compliment you, Dr. Gall, on the way that you’ve approached this with your colleagues at Metabolon, and also with the way that you’ve described it. I think it makes this very user-friendly to the clinician, and I think also ties back to these long-standing questions of mechanism, bioenergetics, mitochondrial function, and specificity of insulin-mediated responses in different tissues. Thank you for the extraordinary work and sharing this with us. WG: Thank you, Jeff.  

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Bibliography

[1] Funnell MM, Piatt GA. Diabetes quality improvement: beyond glucose control. Lancet. 2012;379(9833):2218-2219.   [2] Chen Z, Vigueira PA, Chambers KT, et al. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor γ-sparing thiazolidinedione. J Biol Chem. 2012;287(28):23537-23548. [3] Fukui Y, Masui S, Osada K, Umesono K, Motojima K. A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice. Diabetes. 2000;49(5):759-767. [4] Bolten CW, Blanner PM, McDonald WG, et al. Insulin sensitizing pharmacology of thiazolidinediones correlates with mitochondrial gene expression rather than activation of PPAR gamma. Gene Regul Syst Biol. 2007;1:73-82. [5] Tan Y, Muise ES, Dai H, et al. Novel transcriptome profiling analyses demonstrate that selective peroxisome proliferator-activated receptor γ (PPARγ) modulators display attenuated and selective gene regulatory activity in comparison with PPARγ full agonists. Mol Pharmacol. 2012;82(1):68-79. [6] Corkey BE. Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes 2012;61(1):4-13. [7] Corkey BE, Shirihai O. Metabolic master regulators: sharing information among multiple systems. Trends Endocrinol Metab. 2012; 23(12):594-601. [8] Hamdy O, Porramatikul S, Al-Ozairi E. Metabolic obesity: the paradox between visceral and subcutaneous fat. Curr Diabetes Rev. 2006; 2(4):367-373. [9] Gil A, Olza J, Gil-Campos M, Gomez-Llorente C, Aguilera CM. Is adipose tissue metabolically different at different sites? Int J Pediatr Obes. 2011;6 Suppl 1:13-20. [10] Altintas MM, Azad A, Nayer B, et al. Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice. J Lipid Res. 2011;52(3):480-488. [11] Cinti S. Between brown and white: novel aspects of adipocyte differentiation. Ann Med. 2011;43(2):104-115. [12] Boss O, Farmer SR. Recruitment of brown adipose tissue as a therapy for obesity-associated diseases. Front Endocrinol (Lausanne). 2012;3:14. [13] Ruzzin J, Lee DH, Carpenter DO, Jacobs DR Jr. Reconsidering metabolic diseases: the impacts of persistent organic pollutants. Atherosclerosis. 2012;224(1):1-3. [14] Lodhi IJ, Yin L, Jensen-Urstad AP, et al. Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARγ activation to decrease diet-induced obesity. Cell Metab. 2012;16(2):189-201. [15] Henquin JC. Do pancreatic β cells “taste” nutrients to secrete insulin? Sci Signal. 2012;5(239):pe36. [16] Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57(6):1470-1481. [17] Harte AL, Varma MC, Tripathi G, et al. High fat intake leads to acute postprandial exposure to circulating endotoxin in type 2 diabetic subjects. Diabetes Care. 2012;35(2):375-382. [18] Gall WE, Beebe K, Lawton KA, et al. alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS One. 2010;5(5):e10883. [19] Lyssenko V, Almgren P, Anevski D, et al. Genetic prediction for future type 2 diabetes. PLoS Med. 2005;2(12):e345. [20] DeFronzo RA, Tripathy D, Schwenke DC, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364(12):1104-1115.

Welcome to our year-ending edition of Functional Medicine Update, the December 2012 issue. Always at the end of a year we try to highlight someone who really exemplifies where medicine is going, and the new technologies, and the new concepts that are going to advance healthcare delivery, and we’re very, very fortunate to be able to finish up 2012 with just such an individual as our key opinion leader, clinician, researcher of the month. Dr. Dale Eric Bredesen is Professor and founding President/CEO of the Buck Institute for Research on Aging, which is in Novato, California. Probably you are mostly familiar with this as a world-renowned institute that is really focusing on biological mechanisms of aging and how that interrelates with age-related diseases.

INTERVIEW TRANSCRIPT

Dale Bredesen, MD The Buck Institute for Research on Aging 8001 Redwood Boulevard Novato, CA 94945 www.buckinstitute.org December 2012 Dr. Bredesen is a neurologist by background and training, and also an internist, but he has—I think—a much broader imprint in terms of what his accreditations imply. He got his Bachelor’s degree—again kind of showing his Renaissance person background—in both biology and literature from the California Institute of Technology. He went on to get his MD at Duke University, and did his residency in neurology and became Chief Resident at the University of California, San Francisco. He went on from that to work in the laboratory of Dr. Stanley Prusiner, a Nobel Prize winner that you probably are all aware of because we’ve had the chance to speak about his work over the last 20 years, on the discovery of prions and how that relates to neurodegenerative diseases. He then became, obviously, an NIH postdoctoral fellow with Dr. Prusiner, and from there on, then, has a rich background at UCLA, at the Burnham Institute, at the UCSD neuroscience department, and now most recently at the Buck Institute, where he has led the charge in looking at neuroscience as it relates to neurodegenerative disease, specifically Alzheimer’s disease is one of the major focuses. When I first met Dale—to now go from the kind of academic to the real person—I was immediately struck by the breadth of his understanding, his interest, his compassion, and his willingness and receptivity of thinking out of the box. These are the kind of paradigm-shifting individuals that really create great advances in health care by their intelligence, wisdom, and background, but also their willingness to step out of the straight lines of their discipline and think cross-disciplinarily and maybe even be a little bit of kind of a fugitive in their own discipline. It’s with unbelievable privilege that we have Dr. Bredesen as our Clinician of the Month, here for the month of December, and also, just as a person, Dale, I want to thank you for your advocacy, the work and your breadth of impact that you are having. Let’s start with the first question, and it’s kind of a common question that I use to get into the topic: What led you into neurosciences? Obviously as a person with a background in biology and literature, you had a wide breadth of things you could have explored. Why neurosciences? DB: Thanks, Jeff. First of all, let me thank you for your kind introduction, and also I comment on my own interest in what you’re doing, which I think represents the future of medicine. So, thanks very much again for all the great work you do and for the invitation for today. With respect to the question about neurosciences with a background in medicine, it was actually the other way around. I was a freshman at Cal Tech, and I read a book called The Machinery of the Brain, by Dean Wooldridge, of TRW fame, and I was so intrigued by his comparison of human brain function to the computer (this was in 1971).[1] I thought that the workings of the human mind were so incredibly interesting and had such far-reaching implications for whether we’re ill or not, what we do, how we act, how we grow up—all of these important issues. I really fell in love with neuroscience. And then, at the time, Seymour Benzer (at Cal Tech) was doing some very exciting work. He was one of the fathers of molecular and behavioral genetics. Instead of just asking was the eye of a Drosophila white or red, asking whether the Drosophila could learn, whether the fruit fly could learn, and whether it had an appropriate 24-hour cycle, and these remarkable fundamental processes, which he was able to narrow down to single genes. In fact, his group was the first to find a gene called “Dunce” that was for memory.[2] I thought this was fascinating. So I took his course, and also, at the time, was fortunate enough to work in the lab of Nobel Laureate, Roger Sperry, who had done the split-brain work.[3] So it was a very exciting time, but as I got close to the end of my college career I thought, “Gee, I really want to understand how diseases happen to the nervous system. What actually happens to make things fall apart? What happens to make things go awry? Whether it is an affective disorder, or whether it is a neurodegenerative disorder.” So that’s how I got interested in medicine. JB: Well, I think it’s very interesting because undoubtedly you have run into in your career, as I have, with many people who have had a common maybe “a-ha,” wanting to take on these very big questions, and then you ask: “What’s the difference between those that have been aspirants and those that have been successful in really pioneering, and staying to the task, and over decades of contribution really carving out new disciplines?” Often that comes back to not only the intelligence, and inquiry, and hard work, and commitment of the individual, but also the mentors and the people that have affected their careers and kept them on their task. You mentioned Professor Sperry as a Nobel Prize winner that had an impact. Have there been others along your lines that you would say this becomes part of your guidepost as you have developed your career? Work with Dr. Stanley Prusiner DB: Yes. When I came here to UCSF to work as a resident first and then fellow, I ended up working in the laboratory of Stan Prusiner. Stan is a truly remarkable scientist. Stan made what I believe is one of the most important biological discoveries of the 20th century, which is to discover what he dubbed “prions.”[4] Of course, up until that time the thought was that any sort of heritable trait had to be passed on through nucleic acid, be it DNA or, of course in cases of some viruses and viroids, RNA. But he showed that in fact information could be transferred via protein, and initially with PrP it appears to be protein conformational changes to show that there is a protein only, and yet multiplying agent, which he named prion. That was a fascinating finding and it has turned out to be relevant for far more than just the scrapie and what were thought to be other prion diseases. It now looks as if it will have relevance for diseases like Alzheimer’s disease, Parkinson’s disease, and possibly even some things like diabetes. JB: You know, I know that for many of us we’ve heard the story about Jakob-Creuzfeldt disease, and we’ve heard about the infection with prions by feeding one animal part to another animal (through sheep to cows), but I think we probably have a fairly unclear understanding as to the significance and the implications of this whole prion concept. Could you take us through a little bit more detail about this? Because I think this concept of shape versus function, which Linus Pauling talked about 60 or 70 years ago, really pertains so beautifully to this whole disease model. Explaining the Concept of Prion Disease DB: Yes, that’s a good point. Of course, in the distant past the idea was one protein, one correct shape. You might have misfolding or unfolding, but in general the idea was you had one protein, you had one shape, you had one function. And of course it’s become clear over the last couple of decades, now, that you can have one protein, multiple conformations, and interestingly, multiple normal functions, which makes things much, much more complicated. What Stan found was that in the case of what he named prion protein (PrP), there is a form—PrPC—which is the cellular isoform of prion protein that has a normal function. The function at this point is unknown, but it is clearly a normal part of all of our brains and actually cells outside the brain as well. On the other hand, there is a different folding—and I should add that the PrPC has a certain percentage (about a quarter of it or so) that is folded in a classical alpha helix (something that was originally described by Linus Pauling for proteins). And so about a quarter of it has this alpha helix, whereas when it converts what’s called PrPSC, or the scrapie form (this is from the disease scrapie that affects sheep, and mule deer, and many other animals—similar to mad cow disease), when this protein folds in a different conformation, it loses, basically, its alpha helix and it features a much higher degree of beta pleated sheet, another classical protein conformation, and it changes its function, and importantly, it is able to seed a process that amplifies, that is to say it is able to beget more of itself through interactions with PrPC. It’s not yet clear how this occurs, but in any case, it ends up with the protein refolding in a way that produces a protein that amplifies over time, and ultimately gives rise to a brain disease (a prion disease). Now interestingly, this is a process that can be infectious because of the fact that PrPSC is so stable. However, what we now believe is that this is actually the tip of the iceberg for a much more general process: if you think about what we were all taught in medical school, we were taught about homeostatic feedback, and if you have a single-goal outcome and don’t require amplification of a biological process, then homeostatic feedback is what occurs. As a simple example, we all want our serum pH to be 7.4, we never want it to be 10.4 or 2.4, so if you happen to drink a soda or something and it gets a little acidotic, of course you have respiratory and metabolic compensation, which drives it back to 7.4. However, if you think about it, there are other processes that require amplification and have multi-goal outcomes in which the system functions as a molecular switch. A simple example is blood clotting. If you’ve got a cave person who accidentally cuts off his finger, if he doesn’t clot rapidly he’s going to die, and so, of course, you have a system of serine proteases that in fact amplify their own activity, ultimately producing a thrombus that is then degraded proteolytically over time. These systems feature anti-homeostatic feedback, and by definition then, they are essentially what we would call prionic loops. We find these to be very common, creating molecular switches, and believe that these are actually at the heart of what, in the pathological case, becomes prion disease. JB: Well that is unbelievably fascinating, both for the specific and the general concepts of pathology. I’d like to—before we move on a little bit more on that because I think that’s a really fascinating concept—I’d like to just take a weigh station for a second and just do a historical review. I had the chance many years ago when I was at the Pauling Institute to meet Carleton Gajdusek, who had won a Nobel Prize for his discovery of “slow-reacting viruses” and their relationship to kuru.[5] I think there was a very significant interesting interplay between Gajdusek and Dr. Prusiner as it relates to this controversy. Could you kind of bring us up to speed, because I think that’s kind of a specific example of a more general theme about controversy in medicine and paradigm-shifting thoughts? DB: Yes, this is a very good point. Of course, Dr. Gajdusek brought these diseases to the attention of the world. Some of the original work on slow infections was written in 1954 by Sigurdsson, actually, who talked about his idea of chronic and very slow infections, assumed to be viral in origin (and in most cases, these did indeed turn out to be chronic viral illnesses).[6] And then later, Gajdusek identified these in kuru and studied them extensively, showing that what had been thought of as degenerative illnesses—kuru and Creutzfeldt-Jakob disease—could actually be transmitted as infectious processes, but at that time the nature of the agents themselves was not clear, and it was thought that most likely these were viral in origin. Stan then really brought beautiful basic chemistry and chemical approaches as well as genetics and biochemical approaches, to bear on this problem, and was able to show that these agents have no DNA or RNA, surprisingly. It was actually very reminiscent of the original work on DNA by Oswald Avery, showing that DNA was, in fact, the heritable agent. When Avery’s work was initially published, the idea was “Well, you know, are you missing some small amount of protein in there?” because people weren’t ready to believe that DNA was in fact the heritable agent. Stan essentially had the opposite problem of showing that you could have a heritable feature with protein only, but he did a beautiful job genetically and biochemically of showing exactly that. JB: So, as this model now has gone from kind of “theory” to accepted, which is a major shifting paradigm within physiology and pathophysiology, then it starts raising questions about the structure of all sorts of macromolecules, and their different conformation, and their relationship to disease (this structure/function concept that we were describing earlier), and it takes us back to the whole family of amyloid-related disorders. How does this interrelate clinically with our looking at different conditions associated with amyloid accumulation? The Theory of Prion-Nativity and Alzheimer’s Disease as a Prionic Loop Process DB: Yes, that’s a great question. The original suggestion we now call “the special theory of prion-nativity,” in which you have a conformational change in prion protein or other proteins, potentially things like alpha-synuclein that can also accumulate. However, what we now believe is that there is a much more general theory of prion-nativity, in which any x plus y, producing 2x, leads to amplification, and as I mentioned earlier, as long as this functions normally in things like blood clotting, then this is a physiological process. However, to do that you have to balance—of course, you have to degrade—the amplified product over time, which you do, of course, with things like a thrombus. When this gets out of hand you have things like disseminated intravascular coagulation (DIC), and our view of Alzheimer’s disease as a prionic loop process is that it is essentially that same sort of process over a longer period of time in the nervous system. If you think about it, you will realize that prionic type amplification could, theoretically, occur not only with protein folding (which is the basis for the conversion of PrP-C to PrP-Sc), but also with imbalances in protease cleavage (which occurs in the conversion of APP to the A-beta peptides in Alzheimer’s disease), kinase activity, transcriptional activity, and other processes, as well. And the bottom line is that these are not just single molecules altering conformation, but these are biochemical loops. We now call these prionic loops. And things that dampen these down we call anti-prions, which can inhibit the loops. So you have exquisite modulation of these pathways that are physiologically relevant, but in the case in which there is amplification out of the physiological range—essentially like a snowball rolling downhill—you get to the point ultimately that these become pathological. And what we have found in the laboratory is that we can add small amounts of these seeding molecules, and through these prionic loops, amplify the original product and produce disease-related molecules. And in the case of Alzheimer’s disease, we see this both at the level of the A-beta interaction with APP itself, and at the level of tau and phospho-tau, and there are likely to be others as well. But interestingly for these, the A-beta loop is a little bit like having a benign tumor—it’s essentially the upstream part of the problem. And you can actually live for many years, as Pittsburgh compound B (PiB) scans are now showing us, with this A-beta prionic loop acting. On the other hand, the downstream loop, which would be analogous to the metastatic tumor, occurs when you have tau abnormalities and hyperphosphorylation of tau; this is more associated with symptomatic disease, so it’s typically a later event in this chronic process. JB: You just said something that to me is really a potential “a-ha.” I go back and think about MS and neuritic plaques. The hallmark, traditionally, for the assessment of the severity of MS would be to look at the density of neuritic plaques. And then people started saying, “But hold it. If we really match up symptoms against neuritic plaques, they don’t really correspond very closely. We can see plaques without severe symptoms in some patients, and in other patients we can see not-so-severe plaques and very severe symptoms.” So we can’t say necessarily the pathology that we call MS comes from the plaque. It is more kind of a second association. Is that at all related to what you were just describing? Is that a clinical example of this kind of sequence of events related to alteration of function and form? DB: Yes. What’s important here is that the pathological entity is essentially the end result of physiological processes that are normally in balance. Our view of Alzheimer’s disease is quite different than the current dogma. It suggests that in fact you have a normal process of plasticity that is ongoing. What’s really interesting is that the molecules already known to be involved in Alzheimer’s disease, such as the amyloid precursor protein, and A-beta peptides, and tau, and presenilin 1—are all molecules that are involved in the normal process of plasticity, so literally they are involved in the physical events that lead to plasticity. They are involved in neurite extension, in synaptic maintenance, in synaptic efficacy and synaptic turnover, in caspase activation, neurite retraction, and ultimately programmed cell death. These are all processes that are involved in normal plasticity in the making and maintaining of the one quadrillion synapses that you have in your brain. And of course if you look at Alzheimer’s disease, it actually works backward, starting from the most plastic synapses to the lesser plastic synapses, so that—no big surprise—you lose your memory early on, before you lose more basic and less plastic abilities. So the critical piece here is the synaptic efficacy and the loss ultimately of synapses. You begin with a chemical abnormality at the synapse, but you progress to a physical loss of the synapse, then you progress to neurite retraction, then of course you ultimately progress to neuronal loss. These are all essentially taking a physiologically balanced process and, unfortunately, imbalancing it toward one direction. So imagine that you have your car and normally you balance the forward and the reverse, to get where you want to go. Now imagine that every time you step on the pedal it will only go forward a few feet but it goes in reverse extremely well, so you are most of the time going in reverse. That’s what’s happening in the Alzheimer’s brain. You have minimized the ability to go forward and you have maximized the ability to go in reverse. So it is a brain that is very good at forgetting, but very poor at learning new material. And the important part is that we can measure the molecules that are involved in the forward process—which supports memory formation and retention—and in the reverse process—which supports forgetting—and then identify both pharmacological and non-pharmacological processes that alter this critical ratio, favoring memory formation and retention and improving Alzheimer’s disease. This is analogous to identifying agents that improve the HDL:LDL ratio—we are altering a ratio, favoring a desired physiological process and inhibiting a pathological process. Synaptic Processes Are Affected by Diet, Exercise, Stress, and Sleep I should add, the big surprise to me and the big excitement to me occurred when I realized that the mechanisms that we’re looking at—this critical balance—is affected by exactly what my wife has been telling me for over 20 years. My wife is a family practice physician, and she has always said, “Well, whatever it is you guys ultimately find, it’s going to have some important relationship to DESS (Diet, Exercise, Stress, and Sleep).” And the surprise is that these very fundamental molecular mechanisms that balance the laying down and picking up of synapses, and the laying down and the reorganization of these synapses, are indeed affected heavily by exactly those processes of diet, exercise, stress, and sleep (as well as other things, of course). Things like where you stand with your homocysteine—this has a beautiful molecular mechanism, which is actually through its impact on protein phosphatase 2A and how PP2A is post-translationally modified. When your homocysteine rises, you in fact inhibit your protein phosphatase 2A, which leads to, interestingly, more phosphorylated tau, so you are unable to dephosphorylate your tau, and you are essentially throwing that neurite growth into reverse. With this higher phosphorylated tau, this pops the tau off the microtubules, and essentially now throws it into reverse, allows the microtubules to destabilize and drive back, and similar things occur with the mechanism of actin depolymerization. So if you look at this from 30,000 feet, what you see is that this is fundamentally related to the process of plasticity, of making and reorganizing synapses, and it has an important relationship to your exercise state. Exercise drives up brain-derived neurotropic factor (BDNF) and actually puts you on the positive side with respect to laying down synapses. In contrast, as you know, if you eat simple carbohydrates, then in fact you drive up your insulin level. Insulin must be degraded, of course, by insulin-degrading enzyme, which interestingly also is one of the enzymes responsible for degrading A-beta. So if you drive up your insulin chronically, then in fact your A-beta accumulates because your IDE is breaking down your insulin. Multiple processes like this feed in beautifully to the molecular mechanisms involved with plasticity. JB: The last five minutes was a gem of unmeasured consequences. I mean, just amazing density of insight that you just shared with us. One could tease apart almost every word in those sentences and have a deep learning opportunity, so I want to go back and just pick up a few thoughts because I think the way it just flows so beautifully off your logic trail may still leave a lot of us who are still in the learning curve a little bit trying to catch up. Let me, if I can, go back to this concept of the forward and reverse. We might call that a balance point. Every activator in physiology has a deactivator. Every accelerator has a break. This, in traditional Chinese medicine, might be called the yin and yang—the balance points that create regulatory networks that orchestrate functional changes against environmental perturbations. What I just heard you say is that it’s not necessarily that these proteins that we’ve often associated with the pathology of Alzheimer’s, like amyloid precursor protein, or presenilin, or phosphorylated tau, or A-beta are in and of themselves pathological molecules. They don’t get labeled as bad. They have a function, but when that function is out of balance then you can get this accelerator/reverse gear type of imbalance, and now what you start doing is creating over time an alteration of function, in which the system loses its plasticity and we eventually start losing those functions that are associated with that plasticity. Am I all summarizing accurately, on a simplistic level, what you were sharing with us? DB: Yes, absolutely. There are a couple of key points here. First of all, epidemiologically, there are many things that have been associated with Alzheimer’s disease, and any theory that seeks to explain Alzheimer’s must take into account all of these remarkably disparate risk factors for Alzheimer’s. So if you are a woman who had an early oophorectomy, at the age of 40 or earlier, you are at a two-fold risk for Alzheimer’s disease, for example. If you had little education, if you hit your head, if your vitamin D levels are low, if your homocysteine is high, if you ate a lot of carbohydrate, if you have a large waistline—all of these things—as you well know, men with low testosterone levels, you can go on and on and on. There are remarkably disparate biochemical associations with this problem, so whatever we come away with here must explain the relationship. The second thing is that there are a number of paradoxes that are unexplained by the current theories. As a simple example, there is some beautiful work out of Cattaneo’s lab in Italy, in which he produced what’s called the AD11 mouse. This is a mouse that simply has a germ line insertion of an antibody fragment against nerve growth factor (against NGF), and over time it develops both plaques and tangles, and classic theories of Alzheimer’s do not explain that.[7] And there are many other currently unexplained apparent paradoxes. What we’re arguing is that Alzheimer’s disease is no different than other chronic illnesses, such as cancer, osteoporosis, and atherosclerosis. These all have to do with chronic imbalances that are because of the physiological set up—that these unfortunately feature amplification. As a simple example, if you look at cancer, cancer can result from a rare somatic mutational event because of the amplification. Once you have the imbalance between oncogene activity and tumor suppressor gene activity (both of which are normal, of course), you have an imbalance between your proliferation and survival of cells versus your programmed cell death (your turnover of cells), either because you’ve smoked cigarettes, or because you’ve been out in the sun too much, or you’ve been exposed to chemical carcinogens, whatever—anything that puts that out of balance leads to cells that select themselves in a Darwinian fashion because they now have an advantage in terms of proliferation rate and/or survival rate, so that you can end up with a clinical disease that we call cancer. In the case of Alzheimer’s disease, this is a molecular cancer, because the amplification process occurs not at the cellular level, as in a neoplasia, but at the molecular species level. This is a prionic loop disease. And instead of focusing on cellular proliferation, the focus is on plasticity, i.e., the making and breaking of synapses, the growth and retraction of neurites, and the modulation of synaptic transmission, etc. So Alzheimer’s disease is in many ways analogous to cancer, but what’s interesting is that instead of the amplifying process being at the cellular level, where you produce more cells, the amplifying process is now at the molecular species level, where you’re producing more of a molecular species, be it prion protein, or be it A-beta, or be it phosphorylated tau, or be it alpha synuclein. In all of these cases, what we’re suggesting is that there are biochemical feedback loops related to plasticity. As you will recall, we talked earlier about the idea of a thrombus: this is the structural result of the amplification process—in that case mediated by serine proteases—that results in a transient structural change that inhibits blood flow. So, in the case of AD, we’re talking about the same thing, with the molecules involved in a transient change in structure, which is at the synapse level now, that has effects on information flow instead of blood flow, but it’s the same idea with the same sort of amplification process. And it also tells you why it is that these different epidemiological processes all feed into this process that is involved with synapse maintenance. The Role of Dependence Receptors in Alzheimer’s Disease About 20 years ago, actually, we discovered a new kind of receptor that we called dependence receptors, and these receptors essentially sample the milieu, which includes the hormonal state of the cell, the neurotransmitter interactions, trophic factor interactions, extracellular matrix, and so forth and so on.[8] And ultimately they integrate over that biochemical space to determine whether the cell is going to survive and is going to put out processes, maintain processes, or is going to pull back and ultimately commit suicide. This is what’s occurring in Alzheimer’s disease. The amyloid precursor protein, APP, actually turns out to be one of these dependence receptors, so ultimately it senses the trophic/anti-trophic balance. One of the interesting corollaries, here, is that the A-beta peptides themselves actually have a physiological function as anti-trophins. They interfere with, for example, insulin signaling through the insulin receptor. They interfere with neural transmission through the cholinergic system, and affect glutamatergic transmission as well as other systems. They interfere with trophic signaling through NGF and BDNF, for example. So the literally have a physiological function as anti-trophins and anti-transmitters. JB: So, as we hear you, it just strikes me so strongly, Dale, that this model that we birthed a little over 20 years ago—the functional medicine model—which has this functional medicine matrix in which you sieve antecedents, signs, and symptoms through this matrix to try to understand clinical imbalances, that that model really aligns itself so, closely, it would appear, with this emerging understanding of the etiology of Alzheimer’s disease. This construct of balance, the construct of effectors and inhibitors, the construct of environmental interrelationships with gene expression factors that create new proteins that then have differing regulatory functions on cell outcome. It seems like these models are very consistent with one another. I’m just fascinated as to the precision by which you’re developing this understanding at the Alzheimer’s disease-level and how it—I think—relates with this kind of broad brush functional medicine matrix model that we’ve been working on for 20 years. Approved Alzheimer’s Drugs Have Minimal Therapeutic Effects DB: Absolutely. I think that these chronic illnesses are network abnormalities and relate extremely well to the functional medicine model. This, to me, has very important implications. One of the implications is in the treatment of Alzheimer’s disease—and as you know, this has been a real problem with literally billions of dollars spent so far developing therapeutics that have virtually all failed. The currently approved drugs for Alzheimer’s disease, such as donepezil and memantine, have absolutely minimal effects on the disease. If you look at the last several years, it has been uniform failure, one drug after another, from Dimebon to Rember to Alzhemed to Semagacestat to Flurizan. You just go on and on and on, and there have been no successes. It may well be that the important point here is not what you choose to treat, but what you fail to include in your therapeutics. For example, just as it doesn’t make sense to tell someone with atherosclerotic cardiovascular disease to stop their cheeseburgers, but leave the fries and the cupcakes—this makes no biological sense—it makes no biological sense to hand a single mechanistic drug to someone with Alzheimer’s and then leave their homocysteine at 18, and their vitamin D at 17, and their cholesterol at 250, and so forth and so on. Here is another analogy: we know of over 30 molecular mechanisms underlying Alzheimer’s disease pathogenesis, many of which are interconnected, so imagine a house’s roof with over 30 holes, many of which are interconnected; now one drug company says, we’ve got a great drug that covers this hole over here very well; and another company says, we’ve got a drug that covers that hole over there very well; and everyone is arguing about which hole should be covered, but after every trial, the floor is still wet. Now, on the positive side, these “failed” drugs may ultimately turn out to be part of the optimal cocktail, but to know that, you need to get the rest of the holes covered. This requires understanding the critical thresholds for the various processes, because so many of these parameters play on to the ultimate thresholds. Just as people like Caldwell Esselstyn have shown, and Colin Campbell, and yourself and others, you have to get to a certain threshold before you are actually picking up plaques instead of laying down plaques in your vessels. The same, of course, occurs with cancer: as long as you’re driving a cell toward proliferation and metastatic survival, you’re not going to be successful in treating cancer. We believe now that the same occurs at the synaptic level with Alzheimer’s disease. And the important point here is we don’t know yet where that threshold is. Will we have to change seventeen parameters? Two parameters? If you go back to what happened with HIV, which is likely to be a much simpler disease, in that case, you had three drugs that barely worked by themselves. Fortunately, they did work enough to have a statistically significant effect, and David Ho was able to put them together and create triple therapy, which works very well for HIV. Now, let’s imagine for the moment that Alzheimer’s is a more complicated illness, and let’s imagine that it is going to take 15, or 20, or 25 different parameters that one has to normalize to hit that threshold where you are now forming and maintaining synapses instead of losing them. This is going to be difficult, and therefore what we want to do is create therapeutics that hit as many of those network abnormalities that feed into this ultimate decision as possible. In fact, we have our first clinical trial now coming up in just a couple of months, which will be the first trial to have a comprehensive approach, where it includes all of those different mediators that have an impact on this synaptic maintenance threshold, so things like exercise, and diet, and drugs, and a whole array of specific supplements and herbs that feed into this specific balance of synaptogenesis and synaptic maintenance. JB: You know, you just continue to enrich the story as we listen. I’m just thinking, as you’re speaking, about this book that I recently read that was recommended to me by Dr. David Jones, the president of the Institute for Functional Medicine, titled The Music of Life by Denis Noble, who is a cardiovascular researcher/physician at Oxford.[9] He’s a professor emeritus, now, of medicine. He advances a very strong case, using his experience of over 40 years in the field of cardiac research, that the only solution to these chronic illnesses will be through the introduction and application of integrated systems physiology and integrated systems medicine—that you cannot treat these complex diseases one point at a time. I think this is obviously a very strong story that you are leading us to recognize as applicable to Alzheimer’s as well—that there has to be a new system of medicine in order to get to these diseases whose etiology are associated with complex disturbances of network physiology. I think I’m reading your conclusion correctly. Is that okay? Am I on the right track? DB: That’s absolutely right, and what we’ve been talking about is that these chronic illnesses have revealed the fundamental flaw in our current medical practice. Our current practice tells people when you feel bad, when you feel sick, you come to your doctor; you are now at the symptomatic phase. Now that works well if you have pneumonia. If you’ve got bacterial pneumonia, we’re probably going to cure you. However, as you well know, the problem with chronic illnesses, which are the ones that are killing most of us at this time in our civilization, is that by the time that you get the symptoms, the pathological process is typically approximately 80 percent over. Probably the best data for that come from Parkinson’s disease, where by the time you get the first symptoms of Parkinson’s disease, you’ve lost approximately 80 percent of the dopaminergic input to your striatum.[10] Perhaps not surprisingly, when the process is so far along, we haven’t been able to do very well at the symptomatic stage with reversing it. That brings up two issues. One, as you said, is to attack this not with a monotherapy, and I think that chronic illnesses will ultimately be the death of monotherapies. We will ultimately realize that you need to attack these at multiple points in the pathological network. But secondly, of course, it brings back the fact that all of us should be practicing prevention from day one, and we should be looking for the earliest indicators. Don’t wait until you have symptomatic Alzheimer’s disease. We should all know what our CRP is. We should all know what our homocysteine level is. We should all know what our insulin level is. You can go on and on, and that includes genetic markers as well, so we know where we stand in this process. Of course, the Achilles’ heel of these chronic illnesses is that you can see them coming in a way that you can’t for the acute illnesses, so that you have a long-term warning system, if you choose to look at it, to warn you far ahead, and potentially avoid these illnesses. So I couldn’t agree more that this will require a change in medicine, to focus on pathological networks and much more on prevention and on integrative ways to approach these diseases. JB: Let me…first of all, I don’t want to at all diminish, by a subsequent question, the significance of what you just said. I mean, that in itself is iconic. It’s almost like a haiku that ought to stand alone and be imprinted in every one of our nervous systems. With that said, I just would like to follow up on this question of genetic susceptibility. We’ve heard a lot about apoE4, double alleles, people call them the dementia genes or the death genes. What is the status of this as a guidepost for relative risk? DB: This is a very good point. As you know, a number of people have looked at how much is nature, how much is nurture? Jack Rowe is among them, for example, with the MacArthur study, and interestingly, multiple groups have all come to a pretty similar conclusion: that in the big picture somewhere around 50 percent of what’s going to happen is based on your choices, your lifestyle, etc., and somewhere around 50 percent is the result of your genetics.[11] Now, obviously, in some cases, genetics trumps experience: for example, if you have an increased number of CAG repeats in your Huntingtin gene, then genetics is critical. But across the board, as an average for all of us, we’re talking about something like half and half. So, in fact, you can have a huge impact on your risk of chronic illness, but yes, you’re absolutely right, genetics plays an important role. As people used to say, if you want to live a long time, then choose your parents carefully, and of course there is some truth to that. With respect to apoE, it fits very well into the model we talked about earlier: when we first looked at this plasticity balance, we realized that you can measure this balance biochemically by looking at an interesting phenomenon: the way the amyloid precursor protein is cleaved.[12] It can be cleaved in two completely different ways, reflecting the fact that it functions as a molecular switch. If it is cleaved by proteases at three sites—at the beta site, the gamma site, and the caspase site—then it produces four peptides: sAPP-beta, A-beta (which of course is the one that has had so much work done on it), Jcasp, and then C31 (this this the carboxy terminal 31 amino acid peptide). Those four peptides all are physiological mediators of neurite retraction, synaptic reorganization, and ultimately programmed cell death. That is the one side of the switch, and on the other side, if you cleave it at the alpha site, you get two peptides: sAPP-alpha and alpha-CTF, that, interestingly, both inhibit programmed cell death and support synaptic maintenance and neurite extension. So literally these are diametrically opposed, and these have different impacts, and therefore of course the first question that came up was: What about the risk factors for Alzheimer’s? So we were very interested to see what happens when you have apoE4 in that equation versus apoE3, and it is absolutely striking: ApoE4 pushes that balance toward the four neurite retractive peptides, whereas apoE3 does not do that. As you well know, that’s not to say that if one has apoE4, he or she will necessarily get Alzheimer’s disease, but it is a risk factor, of course, just like a high LDL and a poor HDL-to-LDL ratio would be a risk factor for atherosclerotic cardiovascular disease. So it is a risk factor, but it also suggests to you, “Okay. There are things that you can do ahead of time.” There was a very interesting presentation a few months ago showing that the impact of regular exercise on Alzheimer’s risk is on the same order of magnitude as the effect of one apoE4 allele. So, in fact, there are things we can do to counter the impact of genetics, and I think it’s actually important. It’s certainly a good thing for people to know. I realize that a common question is, “Why would I want to know my apoE4 status since there’s nothing I can do about it?” Well, in fact, there is a lot you can do about it, and it has to do with your lifestyle. It has to do with your exercise status, your dietary status, your homocysteine level, and on and on and on. There’s a whole series of things that in fact you can do about your risk for dementia. Of course, the drug candidates that we’ve identified through our screens have impacts on that same balance, on that same 4-to-2 ratio of the peptides to essentially drive you toward the making and maintaining of synapses. So, you are absolutely right, genetics plays a key role. In fact, interestingly, the genetics of neurodegeneration appear to be fundamentally related to the genetics of aging and longevity. I think that this is also telling us something interesting about what was originally called antagonistic pleiotropy, this idea that you can evolve genetically characteristics that in the short term increase fitness and thus give you a competitive advantage, but in the long run can be a disadvantage with respect to longevity. JB: Well, you know, I gave an introduction to this discussion saying that this was the appropriate way to highlight and to celebrate the year end of 2012 in Functional Medicine Update, but I really under spoke. I think this was an epic chapter in the evolution of Functional Medicine Update, but more importantly in our understanding of how dysfunction arises from imbalance. That’s a fundamental construct, I think, of the Institute for Functional Medicine and its paradigm. I just can’t thank you enough, Dr. Bredesen. I think the work you’re doing, the implications of it are significant for Alzheimer’s and have broad spreading effects across the range of the other members of the family of chronic, age-related, degenerative diseases. This has been an epic discussion, and one that we feel like we’ve just taken a little vision into the future with you. We don’t have all the answers, but we have a new model. This model that you’re carving out is a model that gives us an opportunity–if we are willing to accept the challenge as a scientific medical community–to address these issues with a new lens, with a new frame of reference, from which we sieve observables through this new frame of reference to hopefully come out with more successful ways of both preventing and managing these complex diseases that are associated with 21st century living. I would say thank you—a deep thank you for what you’re doing, you and your team, at the Buck Institute. I hope we’ll be able to keep closely connected with progress that you’re making because to me it is at the frontier of where medicine should be going. Therapeutics for Neurodegenerative Diseases Possible this Decade DB: Thanks very much. I think that this upcoming decade is going to be tremendously exciting because I think we will have the first real therapeutics for these neurodegenerative diseases, and really be able to prevent them and treat them in a very significant way. I’m honored that I got to talk with you about this because you’ve done so much—and so far ahead of most others—to put models into place that I think the rest of us have been able to utilize in developing new therapeutics for chronic illnesses, so thank you. JB: Thank you, and we’re going to keep very closely in touch as it relates to this extraordinary clinical trial that you’ve just queued up and will be starting. That, to me, sounds like it’s something that every FMU listener, supporter, and every other member of our medical community will be interested in finding out about. The best of luck in the trial and we’ll be checking in soon. Thank you so much.

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Bibliography

[1] Wooldridge, Dean E. The Machinery of the Brain. New York, NY: McGraw-Hill, 1971.   [2] Dudai Y, Jan YN, Byers D, Quinn WG, Benzer S. dunce, a mutant of Drosophila deficient in learning. Proc Natl Acad Sci U.S.A. 1976:73(5):1684-1688.   [3] Sperry RW. Cerebral organization and behavior: the split brain behaves in many respects like two separate brains, providing new research and possibilities. Science. 1976: 133(3466):1749-1757.   [4] Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. 1982;216(4542):136-144.   [5] Gajdusek C, Gibbs CJ, Alpers M. Slow-acting virus implicated in kuru. JAMA.1967;199(7):34.   [6] Poser CM. Notes on the history of the prion diseases. Part II. Clin Neurol Neurosurg. 2002;104(2):77-86.   [7] Houeland G, Romani A, Marchetti C, Amato G, Capsoni S, Cattaneo A, Marie H. Transgenic mice with chronic NGF deprivation and Alzheimer’s disease-like pathway display hippocampal region-specific impairments in short- and long-term plasticities. J Neurosci. 2010; 30(39):13089-13094.   [8] Mehlen P, Bredesen DE. Dependence receptors: from basic research to drug development. Sci Signal. 2011;4(157):mr2.   [9] Noble, Denis. The Music of Life: Biology Beyond Genes. New York, NY: Oxford University Press, USA, 2008.   [10] Rommelfanger KS, Edwards GL, Freeman KG, Liles LC, Miller GW, Weinshenker D. Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice. Proc Natl Acad Sci USA. 2007;104(34):13804-13809.   [11] Seeman TE, Charpentier PA, Berman LF, et al. Predicting changes in physical performance in a high-functioning elderly cohort: MacArthur studies of successful aging. J Gerontol. 1994;49(3):M97-108.   [12] Bredesen DE, John V, Galvan V. Importance of the caspase cleavage site in amyloid-β protein precursor. J Alzheimers Dis. 2010;22(1):57-63.   [13] Bredesen DE. Key note lecture: toward a mechanistic taxonomy for cell death programs. Stroke. 2007;38(2 Suppl):652-660.

I promised you that you were going to be in for a high energy experience. I bet your mitochondria were enlightened and activated through that journey that we just took with Dr. Tarnopolsky. It was really an amazing discussion and tour de force as it pertains to so many areas that we touched upon in our discussion with him. I’d like to follow up with a few closing, news-to-use comments. You might need or desire a little bit more follow up on some of the specifics we talked about in the interview. I want to focus on agents that cause mitochondrial dysfunction, and those agents that Dr. Tarnopolsky alluded to that might improve mitochondrial function. I’m going to go back, in this discussion, to my meeting at Emory Medical School (the Center of Molecular Medicine), focusing and specializing on mitochondropathies in children, which occurred in the late 1980s. I’ll discuss the evolving understanding (both my understanding and, more importantly, that of the field) since that period of time and how that interrelates with Dr. Tarnopolsky’s comments. First of all, what can we say about mitochondria? We can talk about the fact that really it establishes the redox potential of the cell (the reduction/oxidation potential). It raises the potential energy of the cell through these high energy cofactors, these reducing factors (ATP, NADPH, FADH2), the carriers of energy in the cell. As the mitochondria—the energy powerhouse of the cell—is under stress, that stress can come from various factors, including chemical stress and immunological stress, as well as sedentary stress. As we learned very beautifully from Dr. Tarnopolsky’s concepts, the best therapy of all is activity and movement and conditioning.  All create cellular stress, which then alters the redox potential of the cell and its ability to do work, in terms of redox signaling. What happens is potential energy that could have put into good work gets put into promiscuous work. We call that oxidative stress, and it causes injury through oxygen, nitrogen, and sulfur radicals, on other biomolecules that cause cross-linking of proteins, or mutations of DNA, or oxidation of unsaturated linkages and fatty acids and so forth. We recognize there are a variety of agents that can cause this kind of cellular stress to modify mitochondrial function, and we hit upon a number of those, including things like the nucleoside reverse transcriptase drugs that alter mitochondrial activity, uncouple the cofactors involved in the electron transport chain, and set in motion what we see clinically as buffalo hump, or as lipodystrophy and metabolic storage disease. When the body can’t use the energy of food, it stores it for a rainy day that might never come. There is an argument that one could also apply to obesity—that maybe some factors related to obesity–like the AZT connection to lipodystrophy in the HIV patient–may also interrelate to the problem of toxicity in the average individual from other sources that alters their metabolic efficiency at the mitochondrial level, their ability to process calories efficiently, and store that, then, as energy storage and triglycerides in contractile tissues we call the adipocyte, for rainy days that never come, meaning obesity could come from toxicity. There is going to be a lot more we’ll be discussing on this topic over the months to come because this is a very big area of research that is occurring presently. Oxidative processes can injure biomolecules like omega-3 fatty acids, and in so doing produce secondary byproducts like hydroxyl nonenal, and these go on to further serve as agents that interrupt mitochondrial function and cause uncoupling. This is like the dog chasing its tail: it gets worse as it cycles into greater inefficiency in terms of energy processing by the electron transport chain. So agents that cause exposure to these toxic byproducts of fatty acids may interrupt mitochondrial function. These would be things like rancid food products, or oxidative stress on the high omega-3 intake. The redox environment established by the mitochondria also regulates adipcyte differentiation, and therefore has an influence on insulin sensitivity, and on adipocyte signaling through adipokines like adiponectin. Therefore, if you alter the redox environment of the mitochondria, the cell becomes less efficient, its intercellular signal transduction changes, and it starts altering its friendly personality to that of a personality under stress by altering insulin sensitivity, changing the economy of energy production from that of energy of activity to energy of storage. Now you get what’s called the “thrify” genotype—basically the phenotype of the cell is transitioned into storage rather than into energy processing, which I think is very interesting. When you think of patients who have high BMIs, you might think, “Wow, they’ve got all this energy they have stored; they must be very energetic.” Each pound of fat is about 4000 calories of stored energy. You might say, “Wow, they’ve got more than enough energy to do all sorts of things.” Yet these patients often present themselves as having low energy, fatigue, and hypotonia, because there is a switch metabolism: energy is going into storage rather than into utilization, and that can occur as a consequence of these defects in mitochondrial oxidative phosphorylation. There are many drugs (not just the AZT-like drugs) that can be engaged in mitochondrial interruption and can create toxicity of various tissues, both in acute stages and in chronic stages. The chemical environment plays a role. It’s interesting to note that the redox status of the mitochondria, as we mentioned, is regulated through things like transcription factors such as the nuclear receptor factor 2, which activates mitochondrial function and is engaged in an interrelationship between the antioxidant response element and the xenobiotic response element. The xenobiotic response element is the portion of our book of life in our genome that controls the production of the detoxifying enzymes, and thus is connected, through similar gene promoter regions, to the antioxidant response element that regulates the production of the superoxide dismutase catalase superoxide or glutathione peroxidase/glutathione reductase, the antioxidant enzyme system. There is an interconnection between regulation of antioxidation and detoxification that are associated through mitochondrial function. There are a variety of environmental chemicals that can engage in altered mitochondrial function. The one that really came to light dramatically back in the 1980s was MPTP, which is a byproduct from the metabolism of an herbicide, paraquat. When marijuana was found to be contaminated with paraquat and people smoked it, they were exposed to this chemical MPTP that caused a unique form of Parkinsonism.[17],[18] Neurological Toxicity and Mitochondrial Poisoning We recognize that neurological toxicity due to mitochondrial poisoning can be very dramatic in the acute case, but what about in the chronic state? Is there a connection between low grade chemical exposures that are not properly detoxified and altered mitochondrial function that is seen as—I guess you would call it—a degeneration of neurological function over time? There is a very interesting paper that was published in Science magazine back in 2004 titled “Biomedicine: Parkinson’s Divergent Causes Convergent Mechanisms” that talks about this whole connection.[19] This came out of the Emory School of Medicine, where a lot of this mitochondrial work was first pioneered. In Neuroscientist back in 2002 there was a wonderful paper titled “Environment, Mitochondria, and Parkinson’s Disease” that really started looking at the first level at this connection between excitotoxic death in neuronal cells as a consequence of complex I and complex II deficiencies in mitochondrial bioenergetics, and how the environment could contribute to altered toxicity and poisoning of mitochondria.[20] So there is this mitochondrial paradigm for degenerative diseases and aging. An author by the name of Dr. Wallace wrote a very nice paper in the Novartis Foundation Symposium in 2001 looking at a mitochondrial paradigm for degenerative diseases and aging and how that relates to all sorts of different animal species, not just humans but going all the way into mice.[21] When you expose animals to agents that interrupt or poison mitochondria, you get accelerated neurological and immunological problems. That ties together things like dystonia that we saw with Dr. Tarnopolsky’s discussion. Endotoxins are capable of inducing mitochondria interruption as well. Bacterial endotoxins have been shown to alter the mitochondrial respiratory change and capacity in hepatocytes. A leaky gut—a problem related to dysbiosis—may also contribute to alteration in mitochondrial bioenergetics and how that ultimately controls and regulates function. What are the therapies? We talked a lot about the interesting nutrient pharmacology, because there are really no drugs available today that specifically target, effectively, these metabolic functions. In fact, the orthomolecular substances are probably the best tools we have available today for modulating the role of these protective systems within mitochondria and keeping electrons on the wire, so to speak, and the insulation of the wire intact, if you think of the electron transport chain as being kind of a wire between the generator, like the turbine in a hydroelectric dam, and ultimately transmitting that energy and electrons to the site of need as reducing power for metabolism. How does that work? From Dr. Tarnopolsky you heard a very nice discussion of how these various substances participate in regulation of metabolic function at multiple sites along the mitochondrial bioenergetic area. In fact, it was very interesting that in Pediatrics in 2010, a review paper was published titled “Therapies for Inborn Errors of Metabolism: What has the Orphan Drug Act Delivered?” looking at, from the FDA perspective, how various substances have been found to have roles in modulating mitochondrial disorders.[22] On that list are things like resveratrol at very high dose; things like lipoic acid; things like N-acetylcysteine; coenzyme Q10; creatine; the various orthomoleculars that Dr. Tarnolpolsky was sharing with us. The doses that are often required in these families of nutrients, however, are generally far greater than that employed in traditional wellness medicine or prevention. In cases of inborn errors of metabolism associated with mitochondropathies, the doses may be a hundred or more times the nutrition dose to push through these metabolic blocks. There is a very nice review paper published in Nature Biotechnology in 2010 looking at screening for agents that are able to modulate mitochondrial respiration and mitochondrial function.[23] It was found that out of the more than 3500 small molecules that were screened, the most active compounds were often found to be “natural substances” that provided potential neuroprotection.  I think when you start talking about doses,  these are generally much higher doses than one normally employs for prevention-focused applications (or a general wellness focus). These treatments are expensive. These are not inexpensive substances (these nutrient pharmacological substances), and so these are not something for everybody. These are targeted nutritional cocktails (mitochondrial cocktails, to use Dr. Tarnopolsky’s language) that are designed to specifically try to overcome these metabolic blocks or these conditional interruptions in mitochondrial function. Some Thoughts on N-Acetylcarnitine Omega-3 fatty acids, by the way, also play a role here. I want to emphasize that membrane integrity and fluidity of membranes works along—in mitochondrial function—with the other conditionally essential nutrients that are used pharmacologically. Again, the DHA/EPA formulations are high dose. The other conditionally essential nutrient that we didn’t talk about in our discussion which I think has some good literature is N-acetylcarnitine. N-acetylcarnitine has been shown to be helpful in preserving mitochondrial function in the elderly. There is a very nice paper on this in Advanced Drug Development Reviews in 2009, in which, (again, using animal models first–the aged rat heart and then later going to other animals) it was found that supplementation at fairly high levels of N-acetylcarnitine was helpful in preserving mitochondrial bioenergetics, both neurologically and cardiovascularly.[24] The places where you most frequently see mitochondrial deficiency (or energy deficit symptoms) are in the cells of tissues that are most rich in mitochondria. That includes cells of the heart, so you see cardiovascular effects; cells of the muscles, where you see muscular deficiency problems; and cells of the respiratory system, where you see pulmonary and respiratory symptoms. And lastly—really at the head of the list—should be neurologically.  Neurons are associated with mitochondrial dimension, so you have a very crowded environment within the interplasmic reticulum of mitochondria in the neuron. There is a tremendous amount of neuronal mitochondrial function that is going on, and there is a lot of oxygen being processed. Remember, we can live without food for weeks (generally), without water for days, and without oxygen for a matter of minutes because oxygen is what powers the neuronal function and keeps mitochondrial function active. It is a very important nutrient, and it’s probably the primary nutrient for powering up neuronal function. If we put all of this together and we say, “What are the symptoms people present with when they start having some degree of mitochondrial aging?” it’s the things that Dr. Tarnopolsky was sharing with us. This includes symptoms like forgetfulness, cognitive decline, memory loss, depression, altered respiratory function, poor V02 max (maximal oxygen uptake and utilization under work), muscle-related dysfunction, strength changes, musculoskeletal pain, fibromyalgia (which we have talked about previously) that relates to central metabolic disorders as well as relationships to the neuroendocrine immune system function. We start seeing a whole array of things, not just in the exercising athlete or in the ALS patient, but across the range of aging and age-related chronic diseases that are related to these issues of mitochondrial dysfunction. I think probably the most important (probably) clinical takeaway from Dr. Tarnopolsky was this urgency—this mandate, this stand-up-and-be-counted advocacy—as it related to activity and exercise, both strength conditioning exercise and aerobic conditioning exercise. He talked about mitochondrial hypertrophy, increasing mitochondrial activity, increased oxygen processing into bioenergetic molecules. He spoke to the fact that when you do that along with strength conditioning you build size of mitochondria, function of mitochondria, and you build healthy muscle mass. Muscle mass is a bioactive tissue. It is very important for processing glucose and for stimulating insulin-regulated pathways, so as one starts to engage in altered mitochondrial activity, you start seeing, as he said, a decline in mitochondrial function within a matter of few days to weeks after putting a person into a sedentary situation. When that person’s insulin sensitivity goes down, their glucoregulation goes down, their bioenergetics go down, their oxidant stress goes up, and their damage to biomolecules (including DNA and proteins and lipids) all start to increase, and so they move more into an oxidative stress and inflammatory state of function. The exercise component, both strength conditioning and aerobic conditioning is almost like a prescription pad for improving mitochondrial function and defending against biological aging across those mitochondrial-rich tissues that includes the skeletal muscles, the respiratory system, the neurological system, and the cardiovascular system. Beyond that, we have these augmented nutrients—nutrient pharmacology—for those individuals who have a deep hole that needs to be filled in. There is obviously still a lot of work to be done, because Dr. Tarnopolsky shared with us the unusual example of a cocktail mix of very high ORAC antioxidant potential substances that in the test tube were extraordinarily useful in quenching free radicals, but when put into human trials were found to actually serve as pro-oxidants (increasing the oxidative stress). I think this is a lesson to us all as we close this issue, because there are many substances that are being sold and marketed as having very high ORAC activities as if they are the best and the be-all for antioxidants, and what we are learning is that the in vitro activities of antioxidants is not nearly as important as what happens in the body. We need human clinical trials on these substances. We need to know how they affect function at the human level, not just in the test tube, and I think there is a lot of over-selling right now of various antioxidants as being the best in class based upon the wrong kind of data. What is really needed is human intervention data to show biomarkers are improved and mitochondrial function is enhanced. I hope this is helpful in following up on some of the extraordinary contributions that Dr. Tarnopolsky shared with us, and I think we’ve opened the door to the next step forward in our understanding of mitochondrial bioenergetics and its relationship to health and disease. Welcome to Functional Medicine Update for January 2011. Yes, it’s the first issue of the new year, and what a start for the year we have. You want to start off the year with good energy, and fortunately we are going to do so. This month our topic is mitochondrial bioenergetics and its relationship to things like oxidative phosphorylation, which then translates into neurological function; musculoskeletal function; immune function, and metabolic function in various ways. Our extraordinary clinician/researcher of the month, Dr. Mark Tarnopolsky will discuss the extraordinary work he has been doing over the years at McMaster University in the neurology, psychiatric, and pediatric areas. We’re going to let him tell his story first, and then we’ll come back after you’ve had this kaleidoscopic exposure and follow up on a few of the details.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Mark Tarnopolsky, MD, PhD McMaster University 1280 Main Street West Hamilton, ON L8S 4L8 CANADA Once again we are at that place that I look forward to and I know you do as well, and that’s our discussion with a researcher or clinician of the month who is doing something quite remarkable. This month we are very fortunate to have someone who is both a clinician and a researcher. He is unbelievably productive across a very wide landscape of medical disciplines. Dr. Mark A. Tarnopolsky is an MD/PhD at the McMaster Children’s Hospital in Canada. He is a professor of pediatrics, and he is also the Chair in Neuromuscular Disorders and the Director of the Neuromuscular and Neurometabolic Unit. He has a tremendous publication record behind him (more than 200 publications) and is a world leader in mitochondropathies and the relationship of mitochondrial function to neuromuscular and neuroendocrine function. I want to give a short thanks to one of our long-standing Functional Medicine Update supporters, Dr. Sheila Dean, for recommending to me some time ago that we follow up on this work of Dr. Tarnopolsky. Sheila, thanks so much for opening up this extraordinary world and thank you, Dr. Tarnoposky, for being available today. MT:    You’re welcome. The Endosymbiotic Hypothesis of the Origins of Mitochondrial DNA JB:      Let me start with the first question. Years ago I had the privilege of meeting Dr. Lynn Margulis—this was, I think, back in the late 70s—who, at that time, was talking about the endosymbiotic origin of mitochondria and how the mitochondrial DNA is circular and looks more bacterial in origin, and therefore this may be an evolutionary example of an infection that ended up being beneficial to the host eukaryotic cell, and this is why we get maternal transmission of mitochondria. What do you think of this whole origin of mitochondrial function and how does that relate to where we are today in understanding mitochondria and disease? MT:    It’s an interesting hypothesis. Obviously we can’t go back and prove it. The hypothesis is that about 1.5 billion years ago, when the oxygen content of the environment was going up, we took on this endosymbiotic relationship where what was thought to be probably a purple photosynthetic-type of bacteria invaded what at the time was called a protoeukaryotic cell, which then went on to form eukaryotes. We have eukaryotic cells throughout our body. What they think is that as the oxygen content went up, these mitochondria, which were bacteria, allowed us to detoxify the oxygen in our environment so that we weren’t producing as many free radicals. But probably more importantly, it allowed us to extract more energy from our food. Some of the first energy pathways that we had were the anaerobic pathways, such as the breakdown of sugar through glycolysis, which is rather energy inefficient. In the mitochondria we can use fats, proteins, and carbohydrates, in the presence of oxygen, to extract much more ATP, or units of energy per gram of protein, carbohydrate, and fat. What is interesting is that throughout evolution, the some 1500 proteins that make up a mitochondria are now encoded for by our nucleus. So through this evolutionary process, the blueprints, if you will, to make this little engine for our cells were transferred to the nucleus. Essentially how this works is the food is broken down and what are called reducing equivalents come into complex I and II. They flux through a chain of linked proteins called complex, I, II, III, and IV, which really pump what is called a proton from the matrix of the mitochondria to the intermembrane space, and much like water would flow down a waterfall and be trapped by a turbine, they come back through complex V to make energy. The core link between complex I, III, and IV, and some components of complex V still retain their genetic code in this little vestigial piece of DNA called the mitochondrial DNA. That’s the part that you referred to that is passed on from mums to all of their children. Certainly as a clinician, when we see a history of a kid coming in with seizures and strokes, and it appears to be maternally inherited and there is a strong maternal inheritance pattern, that’s very helpful for us to rule in disease. But given that most of the genes are now encoded for by the nucleus, we’re now finding many more diseases that have classic Mendelian inheritance patterns, such as autosomal recessive, autosomal dominant, and even some X-linked recessive diseases. It is an interesting hypothesis. We’re left with this vestige, if you will, which is this circular piece of DNA. One point about that circular piece of DNA is that it doesn’t have histones, which we have in the nuclear DNA, and it is very tightly packed, so essentially everything in the mitochondrial DNA (with a few exceptions) codes for a protein or a ribosomal RNA or a transfer RNA. So, it’s more susceptible if it takes, for example, an ionizing radiation hit, or some other mutagenic hit. It’s more likely that you’re going to get a coding region, and therefore you are more likely to get pathology from mutations in the mitochondrial DNA, and that’s probably why they are still overrepresented as causes of primary mitochondrial diseases. JB:      That was a fantastic, concise explanation. My compliments. I notice in one of your more recent publications—I think this was in October 2010 in Biochem Biophys Research Communications—that you describe some work that you’ve been involved in for some time: mitochondrial encephalopathy with lactic acidosis syndrome, or MELAS syndrome, cardiomyopathy and rhabdomyolysis and how that may interconnect with autism and with mitochondrial DNA deletions.[1] Are we moving in the direction to understand the interconnectedness and how that translates to problems that we call, for lack of a better word, autism? At Least 300 Point Mutations Are Found in Mitochondrial DNA MT:    It is an interesting point. We had kind of an explosion onto the scene of this area of mitochondrial medicine back in the late 1980s, where people found point mutations responsible for Leber’s optic neuropathy, which is a painless blindness usually affecting males in their late teens; the MELAS syndrome which you talked about, which is an acronym for Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes; and another disease called Kearns-Sayers syndrome. From that time, we have now evolved, if you will, to the point where we have at least 300 point mutations that we found in the mitochondrial DNA and an expanding repertoire of mutations in the nuclear DNA responsible for clinical phenotypes. The first ones that we described were more neurologic disease: strokes, and seizures, and epilepsy and children with neurodegenerative disease called Leigh’s disease or Alpers syndrome. And these really dramatic—for lack of a better term—and strongly suggest that those mitochondrial diseases with high lactic acids and very abnormal muscle biopsies were pretty easy to pick up, and the relationship between the gene and the phenotype was very strong. What you are talking about is the complexities of the new emerging area. What about more subtle mutations, and more common diseases such as developmental delay, autism, and various other neurological and non-neurologic disease? What role could mitochondrial DNA mutations have in the pathogenesis or in altering the expression of some of these diseases? And what nuclear genes encoding for mitochondrial proteins have we found and might we find in the future that are responsible for—or at least modify the expression of—more common diseases? It’s really complicated and I’ll use autism because you brought that up as an example. Of all the kids with autism, there are probably going to turn out to be a hundred different genes that are responsible, because autism is a clinical or a phenotypic description (to make the diagnosis). That phenotype can come from a large number of genotypes. So if we start with kids with autism, we’re probably going to find, as time goes on, that at most ten percent of all of those kids with that label have mitochondrial disorders. But if we look at kids with primary mitochondrial disorders as a starting point, a fairly high proportion will have autistic features or pervasive developmental features. So it depends if you start from the chicken or the egg—either from the disease perspective or from the autism perspective as to the relationship. But I think it’s important to know about these and to look for them, because it helps you with family planning, with counseling, and something we’ve been involved in, which is, how are you going to treat these primary mitochondrial diseases, or even secondary mitochondrial diseases, which could be involved in aging, diabetes, obesity, which we’ll get to eventually. Can Mitochondrial Dysfunction Be an Acquired Condition? JB:      Thank you. That is really a beautiful job of laying a groundwork for these—I guess you would call them—inherited, constituative mitochondropathies. There is another question which has arisen in greater controversy recently, and that is probably spawned a little bit by experiences like Greg LeMond. You probably recall the elite Tour de France bike racer who retired from competitive racing because he had lost what he said is his competitive edge because of a mitochondrial deficiency, and said he was still functional, but not at the elite level of his performance in bike racing. And so people said, “Oh, here’s an example of an acquired problem.” Because there was no family history of mitochondrial disease in his family, this was thought to be an acquired problem, not a constitutive problem. Is there such thing as acquired mitochondrial dysfunction through injuries that somatic mitochondria might experience over living? MT:    That’s a complicated question. Specific to your example, I was at the American College of Sports Medicine meeting a long, long time ago. There was a huge symposium on this specific story (the Greg LeMond story). They presented absolutely no evidence whatsoever that there was primary or secondary mitochondrial dysfunction, and I guess they didn’t expect to have a metabolic genetics person at an American College of Sports Medicine meeting to challenge their hypothesis. But there was absolutely zero evidence for this. Essentially we get older, we do get mitochondrial dysfunction, which is aging. We’re not all 23 and at the peak of our V02 max, and there is always going to be some young buck that is going to beat you. But to try and claim that it was a mitochondrial disease or dysfunction that caused him to no longer be winning the Tour de France is illogical. He was shot in the gut—I think by one of his relatives—and retained pellets in his belly, so I’m sure that’s going to inhibit his performance much more than any supposed mitochondrial myopathy. They also talked about him doing two-hour ski races. That’s not what you see with real mitochondrial disease. There’s no question that aging is associated with some mitochondrial dysfunction.[2] When we look at brain and muscles from older adults over the age of 65, we do see some point mutations. There are some deletions which start to occur, and that probably is due to a number of factors. Just through the normal process of living and eating we generate free radicals, which are in close proximity to the mitochondrial DNA, so it’s not surprising that with some drugs that we might take throughout our lifetime, and with ionizing radiation and other hits, that we would get some damage to our mitochondrial DNA, which may not be repaired in the normal repair process. So we sort of stochastically, if you will, accumulate these problems throughout our lifespan in a very segmental region of the muscle, but eventually it becomes quantitative, because if we have these tiny little changes occurring scattered throughout a muscle fiber, ultimately that muscle fiber will slowly shrink, or the heart will slowly be less functional, or the brain will be less functional over time. Certainly our work and the work of many others does support that there is a role for mitochondrial dysfunction, and likely an interactive role with oxidative stress, which contributes to the aging process of humans. Aging, we know, is multifactorial. But I think these are two important components of aging which are going to lead to a decrease in V02 max, and that’s why people are not top sport athletes when they are 65 in endurance sports, and V02 generally declines, which is your maximal aerobic capacity. From your mid-20s until you are 50 or 60, you’re probably going lose 30 to 40 percent of your V02 max from aging-associated mitochondrial dysfunction. JB:      This is an interesting paradox. I recall I interviewed Bruce Ames, whose name I’m sure you are familiar with, a number of years ago. He was saying that oxygen we breathe gets converted into activated forms of oxygen, superoxide hydroxyl, singlet oxygen, and so forth, so our body has to work very hard to protect itself against this main of oxygen, knowing that we have this boon of the added advantage of oxidative phosphorylation—this energy that you talked about (energy efficiency). Can you describe for us how the mitochondria protects itself from this oxygen that goes into these high oxidant forms? Controversy Over Free Radicals MT:     We know that the electron transport chain does produce free radicals. I think where the controversy lies is the question of are those deleterious or are they adaptive? There is no doubt that in certain neurologic diseases free radicals can be at such a high concentration that they can damage fat, protein, or DNA, and can contribute to the pathology. However, there is accumulating evidence that in normal physiology—for example, if you get up and go for a run—that when we flux through the electron transport chain, the slight burst, if you will, of free radicals that are produced function as signaling molecules for our own physiologic adaptation. For example, if you go for a run, you get a pulse of free radicals. That activates a series of signaling molecules, which then activate genes, which then function to attenuate the production of free radicals in the future. 2 That’s standard physiological adaptation, or sometimes people use the term “hormesis.” What happens in such a process is we increase what are called our endogenous antioxidants, and there is a host of them in the cell—things like manganese superoxide dismutase, copper zinc superoxide dismutase, glutathione, glutathione peroxidase system, which can serve to quench these free radicals and make them less toxic, or into nontoxic products. What we find is in older adults, who often show elevated basal levels of oxidative stress, when they finish exercise training, even though you would predict that you’re going to flux more free radicals through and you may have higher markers of oxidative stress, in fact after exercise training they are lower, due to the fact that our bodies are homeostatic and they adapt by increasing antioxidant enzymes.[3] A whole area of controversy has emerged where people are very concerned that during normal physiologic adaptation, if you are to quench those free radicals by taking excessive amounts of antioxidants, you could actually attenuate the body’s own endogenous production of antioxidants, or this term called hormesis. JB:      Boy, in what you just said is buried a huge amount of extraordinary, interesting information. We interviewed Dr. Edward Calabrese, who has arguably been called the father of hormesis; maybe you are familiar with his work. He talked about these nonlinear dose-response relationships where you get close to the origins of certain substances and their effects seem paradoxical relative to what you think of in a normal pharmacological model of increasing concentration, increasing dose. In my discussion with him, he talked a little bit about things like antibiotics at low dose, or chemicals in our environment (xenobiotics) and how they can have a xenohormetic effect, or even metals, like palladium, platinum, nickel, cadmium, mercury. It seems like all of those things that I just mentioned have some relationship to altered mitochondrial function. Is there potential for this environment xenohormetic effect on mitochondrial function? MT:    It’s certainly possible. That’s definitely not my main area of research. I think what we do find and where there is good precedence is that pulses of stress, which allow enough time for the body to respond, generally are favorable in that they cause the hormetic response and they cause the body to withstand future stressors. That’s gone back for many, many years, where people did a thing called preconditioning of the heart, where in animals if you transiently decrease the blood supply to the heart and then you cause, essentially, a myocardial infarction, there is much less damage if the heart was preconditioned.[4] That’s a very similar process. I think what would happen is if one were exposed to drugs which are known to increase oxidative stress (we use a whole bunch of these toxins, like rotenone and such, in our lab) chronically and you don’t allow the system to have a period of time to adapt, they become deleterious. Whereas sometimes, for example, with rotenone, which poisons complex I of the mitochondria, if you give little pulses, after a period of time you almost can’t kill the cells by giving extremely high doses of rotenone to try and poison the cells, which otherwise would be massively deleterious had you not preconditioned the mitochondria. And the same, I think, holds true of exercise. Even though, yes, there is damage that occurs and we do produce free radicals, when it comes in pulses and the body is allowed to adapt to that pulse and create its own endogenous detoxification system to up regulate, I think it generally ends up being a favorable thing. It gets back to things like, “No pain, no gain” when one does exercise. If you don’t cause a little bit of damage, you don’t get the adaptive response downstream. This even connects with Selye’s theory of stress.If you have chronic pulses of stress which stays elevated in a sustained fashion, eventually the organism can’t compensate, and you get failure of the system, and it’s deleterious. The same analogies I think hold true for neurodegenerative diseases, and perhaps even for aging and some of the adaptive responses that occur. HIV Drugs Can Be Related to Mitochondrial Injury JB:      Let’s go away from the hormetic question for a second to the pharmacologic question. I’ve been told that there are some antibiotics that are mitochondrially toxic, which may suggest the bacterial origin of the mitochondria (sensitive to certain antibiotics). And I also think I have read that certain of the HIV drugs produce a lipodystrophy that’s related to mitochondrial injury. Is this correct that there are these potential relationships in some classes of drugs?[5] MT:    I think the evidence is strongest for the HIV drugs, especially AZT, which is the quintessential HIV drug which really sort of changed management. Marinos Dalakas at the NIH was first to describe the ragged red fibers, which we usually use as a hallmark for primary mitochondrial disease, as starting to appear in muscle biopsies of HIV patients treated with the AZT.[6] That’s not surprising because the polymerase which replicates the mitochondrial DNA is called polymerase gamma, and it has very similar structural properties to the DNA replication mechanism in the viruses. NRTIs (nucleotide reverse transcriptase inhibitors), which were developed for AIDS, also inhibit polymerase gamma. So as a consequence, if polymerase gamma can’t go through and replicate the mitochondrial DNA, you therefore would stop the ability for the mitochondria to repair themselves and to replicate, and eventually you would accumulate mitochondrial damage, which eventually causes these dysfunctional mitochondria building up and causing this histological hallmark of mitochondrial disease called the ragged red fiber. JB:      That’s a very interesting point you made. Is it possible, through conditioning, to actually increase the number, or is it just the function of mitochondria? I‘m talking about aerobic conditioning and strength conditioning. Do you increase number by replicating mitochondria or do you just increase function of mitochondria within trained cells (myocytes)? Exercise Training and Endurance and Mitochodrial Biogenesis MT:    Turning to exercise training, we’ve done some studies with just two months of endurance training in young people. People talk about mitochondrial biogenesis as though these mitochondria are floating around as individual little parameciums or amoebas inside our muscle, and we replicate them and make more of them. We didn’t find that that is the case. When we used electron microscopy, what we saw was that the size of the mitochondrial fragments were enlarging. In some cases they were doubling in size. Three dimensional tomography of muscle shows that in fact we don’t have these small, little paramecium-like structures of mitochondria scattered throughout, but rather the mitochondria forms this reticulum, which intertwines its way through the various contractile proteins of muscle and forms almost a board-like (for lack of a better term) interconnected reticulum. So mitochondrial biogenesis is to some extent a misnomer, I think. What we really see is that the mitochondria does enlarge, and we do get a biogenesis in that we get copies of mitochondrial DNA that replicate so those increase in number, but the mitochondria just enlarge; they hypertrophy, or get larger with endurance exercise training.[7] JB:      I want to go back and pick up on something else you said earlier related to signaling processes (intercellular signal transduction) and how signals from the outside reach the mitochondria and the genome. I remember that you published at least one paper looking at kinase signaling through various kinds of signaling molecules like Nuclear regulatory factor 2, and ECG-associated protein or Keap1, and how that interrelates with mitochondrial function.[8] Can you tell us a little bit about what we are learning about intercellular signal transduction and the signaling process of mitochondrial function? MT:    Sure. The Nrf2-Keap1 story more relates to—and that whole pathway is involved in—sensing oxidative stress and up regulating class II antioxidants. But specific to the mitochondrial biogenesis, there are a host of signaling pathways which can activate mitochondrial biogenesis. Most of these converge on a protein which was first described by Bruce Spiegelman called PGC1alpha. For example, there is calcium signaling pathways and we know with exercise calcium goes up, which can then signal through some of the CAM kinases (or the calcium-dependent kinases) to increase PGC1alpha’s localization in the nucleus. PGC1alpha then is a cofactor (or co-regulator is probably a better term) of some of the transcription factors which increase the nuclear encoded subunits, which then end up going to the mitochondria through mitochondrial targeting sequence. Now what is interesting is that PGC1alpha is a very ubiquitous co-regulator. When activated through a signaling process such as increased calcium transduced through CAM kinases, migrating into the nucleus it activates a host, in a coordinate fashion, of proteins which then are destined to go to the mitochondria and coordinately increase the electron transport chain components so that the total capacity of the mitochondria goes up as the mitochondria swells and starts to get larger and be more functional. There is a host of other signals, however. For example, the cell can sense low energy charge, and one of the main pathways there is something called AMP kinase. ATP breaks down and forms AMP, the increase in AMP concentration activates AMP kinase, which in turn can phosphorylate the PGC1alpha, and that in turn can translocate to the nucleus and function as a co-regulator. And there is a host of other signaling pathways, including P38 MAP kinase, which can also activate PGC1alpha. So there is a lot of redundancy in the system, but generally all of those processes I’m talking about are things that occur in the context of physical exercise or some cellular stress, which—again—gets back to hormesis: if there is a stress, you need some disabling pathway that is going to counteract that stress in the future, and this represents a really nice integrated pathway, converging on PGC1alpha. Correlation between Mitochondrial Function and Obesity and Type 2 Diabetes JB:      Now, of course, you’ve opened up the big door, at least for me. For the clinicians who are worried about this rising tide of insulin resistance, and pre-type 2 diabetes, and metabolic distortion, when we start talking about PCG1alpha and coactivators that takes us almost to crosstalk with the PPAR gamma system. It also takes us into mTOR and how that relates to insulin sensitivity and bioenergetics (Spiegelman’s work crossing over into diabetes). It seems like there is a correlation here. Can you tell us a little bit about how these fit together? MT:    Oh, there’s no question. It sounds like I’m really pushing exercise, but the safest and easiest way to have a favorable effect on all of these pathways, and probably the most effective preventative strategy for obesity and type 2 diabetes, is physical exercise. And we know that the only way to safely and consistently increase PGC1alpha content and translocation to the nucleus is physical activity. People hand wave about different medications which might do this, but usually the medications have significant side effects, which is a real issue. Even things like the PPAR gamma agonist which people have worked on, or the PPAR alpha agonist which people can use clinically, are not without side effects. But unfortunately people don’t want to hear that message. They want a pill to increase PGC1alpha’s abundance, not the safe, effective way, which is through various types of physical activity. We know this epidemiologically, but we know at the biochemical level why it is so effective. And what is very interesting, too, is that there is also data that if you over express PGC1alpha (this is genetically, in an animal model—work by Carlos Moraes which was published in Cell Metabolism about a year ago) with a muscle-specific promoter, so it only expresses in muscle, it actually ameliorates much of the diabetic phenotype in the animals.[9] What that says is that there are signals that come from muscle which have a systemic effect, probably through a variety of hormone-like substances like myokines. It has a favorable effect on the rest of the body and reduces insulin resistance. JB:      Let me, if I can, just trace back to one other thing we talked about earlier, and that was the work you’ve done on Nrf2 and Keap1. It is interesting to me that those both correlate, I believe, with co-localization of the ARE and the XRE in the genome, the antioxidant response element and the xenobiotic response element. It would seem, as you mentioned, the redox signaling controlled through those nuclear regulatory factors tie together antioxidant response and also xenobiotic response to toxins. Does that have a teleological explanation or rationalization? MT:    Hmmm. It’s an interesting question. I hadn’t really thought too much about that specifically from a teleological perspective, but I suspect that probably from an evolutionary perspective those two probably go hand in hand, and certainly when there is some deleterious stressor on the cell, upregulating both of those processes may be beneficial. But, again, I haven’t really thought intelligently about that specific component of things. JB:      I know when we up regulate cytochrome P450s, because they are monooxygenases we increase oxidant stress, so maybe it makes sense in a teleological fashion that the antioxidant opportunities come up to prevent hepatic injury or something of that nature. They are kind of coupled. MT:     That certainly is as good an explanation as I’ve ever heard or thought of. That does make a lot of certainly phylogenetic and teleological sense. Clinical Assessment of Mitochondrial Disorders JB:      Let’s move now to what a clinician might be interested in. We’ve done a very good job, I think, of setting some background, but now let’s talk about assessment of mitochondrial disorders. There are several levels that one might consider how we assess: histology, molecular genetics, functional effects, biochemical analysis. Maybe you could start on histology and molecular genetics. How do we understand whether a person has these mitochondrial underpinnings of some of their clinical presentations? MT:    Sure. I think it is first very important to separate primary from secondary mitochondrial disease. The primary mitochondrial disorders are, by convention, considered to be the disorders that primarily or secondarily affect the electron transport chain assembly or function. These are felt, at this point, to affect about 1 in 5000 individuals. I think as time goes on we are going to find many more diseases that we didn’t think were mitochondrial are going to fall under that umbrella, and that incidence of 1 in 5000 is probably going to increase. People think that primary mitochondrial diseases are rare, but 1 in 5000 is really not rare, because probably every listener will know about Lou Gehrig’s disease or ALS, which has a prevalence of about 1 in 50,000. So these are ten-fold more common, and likely that number is going to keep going up. The primary mitochondrial disorders usually present with some neurological dysfunction: stroke, seizures, developmental delay, developmental regression. It tends to be seen mostly in the neurology clinic. However, there are a host of other issues which can be seen, for example, hepatic failure in children, ataxia, visual loss (which, again, is the retina which is an extension of the central nervous system, but usually ends up going to ophthalmology). So the clinical picture, I think, can point one in the direction of these things like Leber’s, and MELAS, and MERFF, and all of these other acronomic-type of mitochondrial diseases. To approach someone, the first thing that we do is assess a history that is suspicious for mitochondrial disease, for example, under periods of stress like exercise or fasting the person’s symptoms were to come out, one would be thinking in that direction. We would next do blood work. In the blood, probably the main chemical that we are looking at is lactic acid, which is reflective of an increased flux through anaerobic glycolysis, which is the cell’s response to an aerobic energy crisis, and that is to try and flux through the anaerobic systems. In adults, the elevated lactate is seen in about 65 percent of our patients. So an elevated lactate can be used for ruling in–but it doesn’t always rule out–disease. In children, most kids tend to have an elevated lactate in the presence of mitochondrial disease, so it has a bit more sensitivity. We also find that due to alterations and increased flux through protein metabolism we get an increase in alanine, so measuring amino acids and finding elevated alanine is helpful. Many of the patients also have some damage to skeletal muscle and creatine kinase is variably elevated as a marker of muscle membrane damage. But, again, on its own, elevated CK can be reflective of any other muscle process. In the urine there are metabolites of the leucine pathway called 3-methylglutaconic acid, which can be elevated, and that’s picked up on urine metabolic screens or urine organic acid screening. Then, if we are suspicious of mitochondrial disease, the next thing we do is a muscle biopsy. Histologically what we find in adults is the accumulation of abnormal mitochondria in the subsarcolemmal region, called a ragged red fiber, which is, again, attempts by the cell to compensate for the mitochondrial dysfunction. They undergo massive mitochondrial biogenesis and we get this proliferation, or expansion, of the mitochondrial reticulum in the subsarcolemmal region, which comes up as the ragged red fiber with a stain called Gomori trichrome. One can also get reductions in various enzyme activities. The one that we use most commonly is called cytochrome C oxidase, or complex IV. So finding Cox negative fibers, as we call them, is reflective of mitochondrial dysfunction and often seen in mitochondrial disease. An important note for the pediatricians out there: Often the classic hallmarks of ragged red fibers and Cox negative fibers aren’t seen early on. It takes a bit of time; it takes some aging, if you will, with the muscle for those to occur. And it is on the electron microscope that we see the earliest manifestations of mitochondrial dysfunction, where the nice three-dimensional and two-dimensional architecture of the crystae become abnormal, the mitochondria become pleiomorphic, so we have large and small mitochondria that have very bizarre shapes. And often they will start to accumulate abnormal densities within the mitochondrial membrane. One of the hallmarks is called the paracrystalline inclusion, which reflects oxidative damage to mitochondrial creatine kinase which then crystallizes in the mitochondria. That can be seen in various toxin exposures, which can damage the mitochondria, including the exposure to the anti-HIV drugs like the NRTIs, but is a hallmark of many of our patients with mitochondrial disease. Once we have that, the next step is to start thinking from a genetic perspective. If there is a strong maternal history we would be thinking about something in the mitochondrial DNA. If there is a very specific clinical phenotype, like Leber’s hereditary optic neuropathy, if you check just three mutations (the 11778, the 14484, and the 3460), you’ll get 95 percent of your patients and you’ve got your diagnosis and you don’t need to go any further. With a MELAS clinical phenotype, there are about 20 mutations, but you are going to get most people by just checking the 3243 and 3271 specific transition and transversion mutations. You can be really targeted about it, but if you have a nonspecific clinical feature, one may wish to sequence the entire mitochondrial genome, which is now very readily doable with garden-variety capillary sequencing. Next-Gen sequencing can do that very rapidly and to a high degree of coverage. And then, of course, there is a host of other diseases: the mitochondrial deletion syndromes, when you have multiple deletions; things like polymerase gamma nuclear gene mutations and Twinkle should be looked for; if there is a single deletion in an older person with failure of eye movements, that’s pathognomonic for something called chronic progressive external ophthalmoplegia; and, again, the list goes on and on, but we don’t have time to go through an entire diagnostic workup. JB:      Thank you. That was brilliant. If we have a person who has, I would say, a functional mitochondrial problem–let’s say the kind that we are talking about with aging–can you correlate the whole body (musculoskeletal function, strength, and respiratory function like FEV1 and cardiovascular fitness) at all with these decrements in mitochondrial function? Is there a clinical correlation? Secondary Mitochondrial Dysfunction MT:    None of the things that you mention really correlate well. Weakness is seen in mitochondrial disease, but there are thousands of causes of weakness, so it’s not really a good measure. And we do also have, for example, patients who have Leber’s optic neuropathy or even severe MELAS syndrome who have totally normal muscle strength. The one thing that we do see in most of these disorders, especially if they affect skeletal muscle, however, is a decrease in maximal aerobic capacity. And that gets back to the whole thing with Greg LeMond. Greg LeMond and Lance Armstrong and all of these guys have high V02 max, which is the maximal amount of oxygen that they can consume in their body per minute. And really, if you think about it, at complex IV that’s where all of the oxygen we breathe ultimately ends up, so any deficit in the electron transport chain right to complex IV or even complex V would cause it to back up. You’re going to get a decrease in the ability of that oxygen to be reduced to water at complex IV, and hence your V02 is going to go down. One of the reasonable screening tests, which has a sensitivity of about 70 percent, is a low V02 max, or a low maximal oxygen consumption. People who are familiar with that type of testing know that often the respiratory exchange ratio goes up very rapidly during exercise, which is indicative of an early anaerobic metabolism shift, and those are probably the more sensitive tests. The difficulty, of course, is—as with everything—there are multiple causes of a low V02. If your heart isn’t pumping, if your lungs aren’t exchanging oxygen, and for other various different reasons your V02 is going to be down. But if you see a low V02 and you don’t have a cardiovascular explanation for it, it is reasonable to put mitochondrial dysfunction on the list of things that one must consider. I’ll just say one more thing about that, and that is we’ve also published a paper recently where we took perfectly healthy 20 to 25 year old university students, we put their leg in an immobilization brace for two weeks, and in two weeks we lost 30 percent of their mitochondrial protein content and 30 percent of their mitochondrial enzyme activity.[10] What that points to is that if people are sedentary—in bed, inactive, not moving—we can get very rapid secondary mitochondrial dysfunction. I think that’s probably the plague of most societies now—at least developed societies—is that people don’t move, they get secondary mitochondrial dysfunction, and as a consequence they tend to get overweight, and they eventually become insulin resistant, and the whole thing forms a vicious cycle which spirals downward. JB:      Thank you. That was brilliantly said. That’s really good news-to-use for the clinicians as they talk to their patients. Are there any correlations of what you have described as uncoupling of complex IV with biochemical markers (biomarkers) for oxidative stress like AOHDG or isoprostanes or lipid peroxides? Do they have a correlation, serologically? MT:    Yes, in a number of diseases, and in our patients with mitochondrial disease, we sometimes see—but not always—increased markers of oxidative stress, and there is a host of them that are available. Again, I don’t believe anyone is doing this clinically, but certainly in the laboratory things like protein carbonyls, malondialdehyde, and the ones you mentioned—the 8-isoprostanes and 8-hydroxy-2-deoxyguanosines—are biomarkers that oxidative stress has occurred, and that will cover the lipid, the protein, and the DNA damage, as we talked about. And we can use those as markers of efficacy and intervention. And what we do see in our patients with some of the therapies–and one in particular is coenzyme Q10, alpha lipoic acid, creatine, and vitamin E—is those markers of oxidative stress went down when people were on those mitochondrial cocktails. We’ve seen that those markers of oxidative stress also go down in older adults. Where they are basally elevated, they come back down towards normal following exercise training. So either exogenous targeted antioxidant cocktails which we use for therapy or exercise training will reduce those biomarkers, but I don’t think clinically, at this point, that that’s going to really help you to differentiate patient from non-patient. JB:      You’ve really taken us to the next really important step and I bet everybody who is listening is just on the edges of their seats because everybody always wants to know, what do we do about these things? I recall in the late 80s I visited Emory Medical School. I went to their Center of Molecular Medicine where they deal with mitochondropathies, and I found that they were using at least some empirical mixtures of things like sodium succinate, and creatine, and CoQ10, and lipoic acid. You recently published a very nice paper I saw on CoQ10.[11] Could you tell us what the status is of these things in nutrient pharmacology for these mitochondria-related dysfunctions? Experimenting With Mitochondrial Cocktails MT:    Let’s go back to the mitochondria. What happens when it doesn’t work? First of all there is an increase in flux through alternative energy pathways. We know that you crank through glycolysis, but you also increase the breakdown of phosphocreatine. And the latter point is why we started to use creatine as a therapy. Way back in 1997 we published our first paper to try and give an alternative energy source, because we knew that brain and muscle in patients with mitochondrial disease were low, so that was the reason for the inclusion of creatine.[12] Next, as we pointed out before, if there is damage to components of the electron transport chain, especially at complex I and III, and we get the excess generation of free radicals, it would make sense to quench them if they are present in excess. We chose CoQ10 because it is an integral part—essentially it receives electrons from complex I and complex III, and shuttles them to complex III—of the mitochondrial respiratory chain, and can function as an antioxidant. Alpha-lipoic acid is another potent antioxidant which interestingly has been also used in type 2 diabetes, and it may be that the secondary mitochondrial dysfunction in type 2 diabetes is what was responding to the alpha-lipoic acid trials, which were used to treat diabetic neuropathy. Alpha-lipoic acid also localizes in the mitochondria, which was the reason why we used that. The other reason why we throw in the antioxidants in combination is that every antioxidant can become a pro-oxidant. When they gain an electron and become reduced, they can give up that electron. There is good biochemical and biological precedence for combination antioxidants to function as what we call redox couples, and I’m sure when you talked to Bruce Ames he was talking about that as well. So that’s why we usually include several antioxidants and not just one. Consequently, over the years, we put forth the concept of a mitochondrial cocktail to target some of the final common pathways of neurological and muscle dysfunction, including the oxidative stress, the alternative energy pathways, and also to try and bypass energy deficits. So if you have a deficit, for example, at complex I, succinate, which you mentioned, or CoQ10 in theory, could provide reducing equivalents distal to the site of the block. Our concept was if we’re going to have any inroad on treating mitochondrial dysfunction—because there are so many pathological consequences—we need to target more than one pathway. Hence, we were in favor–back in 2001 in Annals of Neurology we published the hypothesis–that we should be having cocktails, hitting not just redundant pathways in one area, but targeting multiple pathways.[13]And we came up with the combination of creatine, CoQ10, lipoic acid, and vitamin E, which we used in a randomized, double-blind, crossover trial in 2007, published in Muscle and Nerve, and showed reductions in lactic acid, and we showed reductions in two markers of oxidative stress in patients with primary mitochondrial disease.[14] Would these work in people who have secondary disease? We don’t know at this point, but I think that evidence was even stronger than the second paper you mentioned, where we just used CoQ10 and really didn’t show the same consistent effects that we saw when we used the combination back in 2007. I think if we are going to have any in-roads, we have to take a cancer/chemotherapeutic approach, and that is to use combination drugs and not just single therapies to target the multiple pathogenic mechanisms in mitochondrial dysfunction. JB:      Thank you. That was very helpful. One of the conditionally essential nutrients that you didn’t mention (or nutrient pharmacological substances) was N-acetylcysteine, which I know has a pro-glutathione biosynthetic effect. That’s something that obviously doesn’t hit on your target. Why? MT:    That’s a very reasonable thing and I think there would be precedence and good biologic logic, as you pointed out, to use NAC (N-acetylcysteine), or Mucomyst is a brand name here in Canada, as a therapeutic strategy. Part of the reason why we didn’t is that it is—I don’t know if you have ever given it before, clinically—a little more challenging to give and some people don’t like the taste, so we tended to stay away from it. But definitely I think that that would be another combination, and one could think, probably, of 40 or 50 other things. The real difficulty comes with how are we going to eventually test these different combinations when they are readily available, in most states and provinces in Canada, over the counter? Big Pharma (indeed most groups) really don’t have that much vested interest in testing the number of potential combinations that one could come up with. Now, there may be some in vitro ways that we could do a form of high-throughput screening, and making a special cell called a cybrid out of our patient cells versus control cells, which we have done in two instances and published.[15] This one way that you can target, specifically for a mitochondrial disorder, what should go in your cocktail. I think certainly NAC would be something worthy of consideration in the future. JB:      My last question on that list of potential nutrient pharmacological agents has to do with this emerging understanding of phytochemicals. The list expands daily, it appears—resveratrol being in the news, curcumin, EGCG, ellagic acid, ferulic acid, and the list goes on. What is your thought about those as mitochondrial, conditionally essential substances? MT:    Again, I think that these are all reasonable things to consider and try. There are a plethora of studies out there using resveratrol as a mitochondrial enhancer, if you will, for lack of a better term. Resveratrol is limited, however, in terms of its absorption. You’re probably familiar with the whole story of the company…the name escapes me right now… JB:      Sirtris Pharma MT:    Sirtris, yes. They were bought out by… JB:      GSK. MT:    GSK, yes. So anyhow, they were very cognizant of the fact that the resveratrol was not well absorbed and came up with small molecules that activate the same sirtuin pathway. So I think the absorption issues are something that one needs to consider, because what you see in vitro doesn’t always translate. The second point I would make (and we’re in the process of publishing it, so I can’t give out all the details): we took the approach that you were talking about—we added curcumin and whole host of other antioxidants into a slurry, which in vitro was unbelievably potent as an antioxidant. We have a thing called the oxygen radical absorbance capacity (ORAC) assay where we essentially measure the ability of the media that we have to quench free radicals. We almost couldn’t even generate free radicals when we added this slurry of different compounds into the media. However—because they were all available over-the-counter and they’d been mixed together and sold as supplements—we gave them to healthy individuals. And to our surprise—and I had my grad student go back because I didn’t believe the data—it was actually a pro-oxidant in vivo. So I think we need to be very careful and we need to do animal studies and human studies to test the combinations, like we did with CoQ10, lipoic acid, creatine, and vitamin E, to prove that in the human it is functioning as an antioxidant, and show that biomarkers are moving in a favorable direction.  Things may look good on paper, they may look good in cells, but they really need to transition to animals and eventually to humans before we should be convinced and we should be starting to consider giving these to our patients with disease. Mitochondrial Function and Sarcopenia JB:      Thank you. You’ve been very, very kind in giving this amount of time. I want to close with probably the big 400 or 500 lbs. gorilla in the corner, which is the aging of our population in North America and the increasing risk to mobility-related issues, including sarcopenia, which is really this extraordinary loss of flesh, loss of muscle with age and with disease. Can you tell us a little bit about how the mitochondrial story connects to sarcopenia and maybe where you see medicine going to help take this new understanding and apply it clinically? MT:    I could talk for an hour on that alone. As I mentioned, there is no question that there is increased oxidative stress markers in older muscle and there is mitochondrial dysfunction. There are some pretty strong experimental lines of evidence suggesting that that can contribute to sarcopenia. Trying to enhance mitochondrial function is very likely beneficial. Taking that, then, to the epidemiological side of things, we know that there are numerous studies. Take, for example, the Stanford study published in 2008 on runners, where they compared a group of runners who were 51 years of age or older to either their spouses or sedentary friends, and they followed them for 21 years.[16] The mortality rate in the non-runners was 34{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} over that 21 years, and 15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in the runners. So we do know that exercise is a countermeasure for mortality. I think that endurance exercise certainly has a plethora of benefits, not just in the muscle and with function, but also in terms of decreasing all-cause cardiovascular deaths, and in that study all-cause neurological deaths and all-cause cancer deaths as well. So right there I think, “Good evidence.” And many studies show that endurance activity is beneficial and possibly it is related to the increase in mitochondrial biogenesis in muscle, which has the systemic effects. We also know that exercise helps the hearts and the lungs. Now, the problem is if you just do endurance exercise, it doesn’t target sarcopenia as well. In older adults there is a slight increase in muscle mass and a minimal increase in strength when you do endurance exercise, but the most effective countermeasure for the weakness of aging is weight training. Folks even in their 90s will respond to weight training in increased strength and muscle mass. So at the end of the day, my strong feeling is that for older adults we need to have a combination of both weight training and endurance exercise to truly combat the aging associated decline in function and in weakness that we see, and I think the two are related. Now, whether we can prolong life or not is open for question, but I think we certainly can compress aging and keep people functional and healthy for a much longer period of time, and keep them out of old age homes and not swamp the American and Canadian healthcare systems with people who need wheelchair assistance and have difficulty just getting up from the toilet. JB:      Dr. Tarnopolsky, this has been one of those—in my nearly 29 years of doing this—great moments of experience. We’ve gone over everything from the microscope to the telescope in this discussion. We’ve covered subjects that cross boundaries. We’ve had courageous discussions when probably most people who like to keep conversations in disciplinary-constrained boundaries would say, “How could you be so expansive in your thinking? You’ve cut across medical disciplines from basic science through clinical works and translational science.” But this is the way I think the big problems that we are confronted with today are going to be solved—by this kind of expansive thinking and sometimes taking a little bit of risk to move out of the disciplinary comfort zone. I think you’ve done it with grace and extraordinary wisdom. I think every listener has valued from your expansive discussion. Thank you very, very much. MT:    Thank you.

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Bibliography

[1] Connolly BS, Feigenbaum AS, Robinson BH, Dipchand AI, Simon DK, Tarnopolsky MA. MELAS syndrome, cardiomyopathy, rhabdomyolysis, and autism associated with the A3260G mitochondrial DNA mutation. Biochem Biophys Res Commun. 2010;402(2):443-447. [2] Safdar A, Hamadeh MJ, Kaczor JJ, Raha S, Debeer J, Tarnopolsky MA. Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults. PLoS One. 2010;5({56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}):e10778. [3] Tarnopolsky MA. Mitochondrial DNA shifting in older adults following resistance exercise training. Appl Physiol Nutr Metab. 2009;34(3):348-354. [4] Koning MM, Gho BC, van Klaarwater E, Duncker DJ, Verdouw PD. Endocardial and epicardial infarct size after preconditioning by a particle coronary artery occlusion without intervening reperfusion. Importance of the degree and duration of flow reduction. Cardiovasc Res. 1995;30(6):1017-1027. [5] Caron M, Vigouroux C, Bastard JP, Capeau J. Adipocyte dysfunction in response to antiretroviral therapy: clinical, tissue and in-vitro studies. Curr Opin HIV AIDS. 2007;2(4):268-273. [6] Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med. 1990;322(16):1098-1105. [7] Tarnopolsky MA, Rennie CD, Robertshaw HA, Fedak-Tarnopolsky SN, Devries MC, Hamadeh MJ. Influence of endurance exercise training and sex in intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity. Am J Physiol Regul Integr Comp Physiol. 2007;292(3):R1271-R1278. [8] Safdar A, deBeer J, Tarnopolsky MA. Dysfunctional Nrf2-Keap1 redox signaling in skeletal muscle of the sedentary old. Free Radic Biol Med. 2010;49(10):1487-1493. [9] Wenz T, Diaz F, Spiegelman BM, Moraes CT. Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab. 2008;8(3):249-256. [10] Rakobowchuk M, Crozier J, Glover EI, Yasuda N, Phillips SM, Tarnopolsky MA, Macdonald MJ. Short-term unilateral leg immobilization alters peripheral but not central arterial structure and function in healthy young humans. Eur J Appl Physiol. 2010 Sep 18. [Epub ahead of print] [11] Glover EI, Martin J, Maher A, Thornhill RE, Moran GR, Tarnopolsky MA. A randomized trial of coenzyme Q10 in mitochondrial disorders. Muscle Nerve. 2010;42(5):739-748. [12] Odland LM, MacDougall JD, Tarnopolsky MA, Elorriaga A, Borgmann A. Effect of oral creatine supplementation on muscle [PCr] and short-term maximum power output. Med Sci Sports Exerc. 1997;29(2):216-219. [13] Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol. 2001;49(5):561-574. [14] Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve. 2007;35(2):235-242. [15] Pelletier R, Hamel F, Beaulieu D, Patry L, Haineault C, et al. Absence of a differentiation defect inmuscle satellite cells from DM2 patients. Neurobiol Dis. 2009;36(1):181-190. [16] Chakravarty EF, Hubert HB, Lingala VB, Fries JF. Reduced disability and mortality among aging runners: a 21-year longitudinal study. Arch Intern Med. 2008;168(15):1638-1646. [17] Smith J. Spraying of herbicides on Mexican marijuana backfires on US. Science. 1978;199(4331):861-864. [18] Richardson JR, Quan Y, Sherer TB, Greenamyre JT, Miller GW. Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci. 2005;88(1):193-201. [19] Greenamyre JT, Hastings TG. Biomedicine. Parkinson’s—divergent causes, convergent mechanisms. Science. 2004;304(5674:1120-1122 [20] Sherer TB, Betarbet R, Greenamyre JT. Environment, mitochondria, and Parkinson’s disease. Neuroscientist. 2002;8(3):192-197. [21] Wallace DC. A mitochondrial paradigm for degenerative diseases and ageing. Novartis Found Symp. 2001;235:247-263. [22] Talele SS, Xu K, Pariser AR, Braun MM, Farag-El-Massah S, et al. Therapies for inborn errors of metabolism: what has the orphan drug act delivered? Pediatrics. 2010;126(1):101-106. [23] Gohil VM, Sheth SA, Nilsson R, Wojtovich AP, lee JH, et al. Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nat Biotechnol. 2010;28(3):249-255. [24] Rosca MG, Lemieux H, Hoppel CL. Mitochondria in the elderly: is acetylcarnitine a rejuvenator? Adv Drug Deliv Rev. 2009;61(14):1332-1342.

Welcome to Functional Medicine Update for February 2011. The Methuselah dilemma. Ponce De Leon. Life forever. Pro-longevity. Anti-aging. These are all interesting terms, aren’t they? They conjure up all sorts of things youthful. This concept of longevity and no senescence has been part of literature, art, music, and poetry for hundreds of years (probably thousands of years). It has also been part of the human dilemma: Why do we get older, and as we get older why do we age, and why do we ultimately die? Even with all that work, and all that thought, and all that wonderful writing, literature, and creative contribution, the answer is still, “We don’t know.” But there are very remarkable steps being made at the cellular/biological, molecular/genetic, and biochemical levels that are starting to unravel this very complex story. The answers may not all be in, but what we are starting to witness is that many age-related decrements are associated with the loss of function: loss of function, as the patency of our book, of life has been water-spotted, defaced, or damaged over the course of living so that we’re no longer able to translate messages effectively from our genesto the function of our cells. The lack of appropriate translation ultimately can give rise to dysfunctions that are seen in distorted metabolism, and pathology, and things that we associate with apoptotic cell death and senescence of cells. Loss of function biomarkers as well as biochemical markers can be measured in the individual: loss of strength, flexibility, endurance, hearing threshold, vibratory sensation, cognitive function, number recall. All of those kinds of things are whole-organism manifestations of the cellular loss of function. Is Progress Being Made in the Field of Aging Research? What do we do about this? Where is the field going? Is there any hope? Are we making progress? These are remarkable questions that tie back to the substance of function. There has never been a monozygotic gene that has been identified to be associated with death, per se, nor is aging necessarily a prescription to disease; there is clearly a very strong association between aging and disease, but we can’t say that aging in and of itself is a disease process. In our own experience, we may know people whose birthdays may number 90, and whose function may be that of an average 60 year old. And then we know the converse: people whose birthdays are 50, who are performing biologically like average 90 year olds. There is a correlation between age, and disease, and health, but it’s not a direct connection. What is the variable that gives rise to our outcome as an individual–our functional capacity–as our birthdays come and go? It’s that question that we are going to be discussing with a person who, for me, represents the new era of cellular biology, molecular genetics, and molecular medicine. His name has almost become—at a young age—a buzzword. We’re going to spend the better part of 45 minutes of this issue talking with this leader, this vision tender, this paradigm shifter, about his contributions to science and his thoughts on gerontology, geriatrics, and loss of function with age and how it relates to disease. From that, I will try to weave some threads of takeaway value that might be guides for our future. That’s a big promise to fulfill, but I think it will be done very adequately by this month’s clinician of the month. Let’s turn to our interview.

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INTERVIEW TRANSCRIPT

David Sinclair, PhD Department of Pathology Harvard Medical School, Room 931 77 Avenue Louis Pasteur Boston, MA 02115 http://www.hms.harvard.edu/agingresearch/ Here we are in 2011—another chapter in the history of Functional Medicine Update. For those of you who have been longstanding listeners and participants, you know this is my favorite point in every issue issue. This month we are absolutely, I think, going to be stimulated with the story of our expert, Dr. David Sinclair. For many of you who have kept up with this field, the name is probably very familiar. Dr. Sinclair is an Associate Professor in the Department of Pathology at Harvard Medical School. I want to compliment him because he is recently tenured, which is no easy task at Harvard Med—and tenured at a very young age, which is another major accomplishment. David received his Bachelor of Science in Australia. He is originally from Australia. He received a PhD in biochemistry and molecular genetics from the University of New South Wales, a wonderful school. I have been on that campus and done a number of lectures over the years; it is a great institution. He moved from there to do his post-doctoral work at MIT, and then later he joined Harvard Med to work in this whole area of molecular gerontology in the Department of Pathology. Dr. Sinclair is known for being the father of the resveratrol revolution. But there is so much more to this story than resveratrol; there is so much more that Dr. Sinclair has brought to this field that has opened up the domain of healthy and successful aging, age-related diseases and modification thereof, and this whole biological senescence process that we are going to be discussing with him. Dr. Sinclair—David—thanks so much for being available for us today on Functional Medicine Update. DS: You’re welcome, Jeff. Thanks for having me on. JB: Let me start down the path here. I’ve made some mental notes of the people I’ve had the privilege of speaking to over the last 29 years of doing this, and one of the personalities that came to light immediately that bears a little bit on your work is Roy Walford, a medical doctor who started in 1954 at UCLA in the Department of Pathology at the medical school. Many of us know him as the biospherian in Biosphere 2 from 1991 to 1993. He was very actively involved in kind of putting proof to Clive McCay’s work at Cornell on calorie restriction. I know your work has borne on trying to discover some of the molecular mechanisms that relate to this. Can you give us some historic context as to how you took this early stuff from Clive McCay and Roy Walford and others and wove it into this extraordinary tapestry that you’ve developed in molecular gerontology? Dr. Lenny Guarente and Yeast Research: Important Discoveries DS: Sure, I’ll give it a shot. The names you mentioned, among many others, laid the groundwork for the research we still do in my lab. Of course I’m standing on their shoulders, and Roy contributed a great deal to our early understanding of how important this dietary calorie restriction is to understanding not just the aging process itself, but how we might actually slow it down. It’s still regarded as the most robust way to slow down aging in mammals. The way I got involved in this actually goes back to when I was a teenager. I went into college, and I was dismayed at the thought that our generation may be the last one to live a normal human lifespan, and in the future this new wave of what we were calling genetic engineering would give rise to knowledge about aging and being able to slow it down. I was a little bit younger and more selfish in those days, but it really disturbed me that perhaps I was born just one generation too early to see this happen. So I was driven by the thought that maybe I could not just contribute to my children’s and their children’s health, but also, perhaps if I was really fast, have an impact on people like myself who are currently alive and were born in the 20th century. I finished my PhD and looked for someone who was doing the cutting edge research in the biology of aging, and I was very lucky to have met—in Australia—a fellow who is now still one of my closest friends, Lenny Guarente, who at the time was just starting up work to understand why yeast cells grow old and what we might do about it—what we might learn from these simple yeast cells. To me, that seemed like the best way to go about studying aging, because after decades of work on humans and even mice, I thought very little progress had been made at the molecular level, and it’s not because these people like Roy Walford weren’t smart, it’s just that the system is extremely complicated. In yeast, we thought we could grab hold of it. And that’s what we did from 1995 to 1999/2000. Lenny’s lab (I was part of the team) made some extraordinary discoveries; at the time even we didn’t realize how important they were. We were having a lot of fun just figuring out why yeast grow old. Lenny and I published a paper in the journal Cell that identified a cause of aging in yeast cells (it turns out it’s got to do with their genomic instability).[1] The Discovery of Sirtuin Genes The next big discovery came from another student in the lab who tried to slow down this genetic instability in yeast, and showed that a gene called Sir2 was able to do that, and he extended the life of those yeast cells. So if you fast-forward to the present day, these sirtuin genes—as they are called—that we co-discovered back about 11 or 12 years ago, are now known to be found in all life forms, and that includes bacteria and plants. What we think is going on, and there is a lot of evidence now, is that they are major players in getting the health benefits of this diet calorie restriction. What we have been able to do is to not just genetically manipulate mice, but even feed them moleculesl (including resveratrol) and give the physiology of calorie restriction without the mice having to actually diet. We’ve published this, and we’ve made inroads into clinical trials trying to give the benefits of dieting and even exercise to mice and to humans with a pill. That’s where we’re at, and that’s where I came from. JB: That’s a really beautiful, succinct summary of a lot of hard work, and a lot of insight, and a lot of midnight oil. Genomic instability reminds me of another person who is actually one of your fellow Australians that we’ve had a chance to talk with a couple of times, and that’s Michael Fenech at CSIRO down in Adelaide. Mike was talking about histone compatibility, histone integrity, the nucleosome and how it is constructed, and what happens when you have imperfections in the protective coat of our book of life material (our genome). The sirtuin discovery that you and Lenny Guarente made really relates also, it seems, to this histone integrity, in part due to the fact that the sirtuins are NAD-dependent histone deacetylases. Can you tell us a little bit about that whole connection between sirtuins and their function, and genetic stability/instability? Sirtuin Genes and Genetic Instability DS: Sure. It is a fascinating area. The discovery in yeast told us that these enzymes control the chromatin, which is the building block of the chromosomes—essentially the way DNA is wrapped up around protein. It does that specifically by clipping acetyl groups off the histone tails. It is a very elegant reaction, and requires NAD, which is a cofactor in metabolism. We now know that the levels of NAD and the amount of sirtuin activity in a body—we know in mice and it looks like it is true for us as well—varies during the day; it even varies with our circadian rhythms and can get out of whack when you are jet-lagged. So this is very central. But getting back to chromatin, what we have since discovered is that this is also true for mammals. We looked at mice and we had a paper in 2008 in Cell that showed that SIRT1 does two things: it controls the way genes are turned on and off (which is a major function of chromatin), but also we found that this protein (SIRT1, which is the mammalian version of sirtuin yeast) is involved and required for efficient DNA repair (when the chromosome is broken; when DNA is broken).[2] So we’ve got two functions: its control of genes (whether they are turned on and off), and we’ve got it also repairing DNA. What we found was that if you damage a cell, with too much damage SIRT1 becomes distracted, going off to repair all the damage and the genes that it normally would control and maintain in a youthful pattern of expression ends up getting disrupted. And we were able to slow down the changes with aging by giving a mouse more of this enzyme. Essentially we call this the “RCM hypothesis.” It stands for “Relocalization of Chromatin Modifiers.” It is a way to explain why the way our genes are switched on and off when we are young ends up getting dysregulated as we get older and no one really understands why. We’re saying it’s actually because DNA damage accelerates that process by distracting proteins that would otherwise control our genes. So that’s where we are. We are hopefully going to be able to reverse aspects of aging one day because that’s the implication: if only we can send SIRT1 back to where it should be instead of being distracted, we could make organs function like they used to when we were young. Connecting Aging Research to the Xenohormesis Concept JB: That takes me back again to a very extraordinary part of your work. Over the last 10-plus years you have put together more than 110 publications in top-tier journals. You haven’t been sitting around waiting for things to do, that’s for sure. One of the many—I call them seminal—publications, from my reading, is a publication on xenohormesis.[3] It reminded me of an interview that we did some time ago with Ed Calabrese, who has been kind of a father and maybe a voice in the wilderness, to some extent, concerning this concept of hormesis (some small agent having unexpected large effects on a system). I think your development of this concept of xenohormesis is a seminal platform concept in biology. I think the article that you had in Cell was just one of those really “aha” articles that should be mandatory reading for every medical student and every bioscientist. Could you tell us a little bit about what xenohormesis is, and where this concept came from and your support for it? I think it is a fascinating concept. DS: Sure, thanks. I should, at the outset, also give due credit to my co-author, Konrad Howitz. He and I have worked on this theory for a number of years, and he was actually the first person who had the initial insight: why would it be that a molecule like resveratrol can hit so many different proteins and targets in a cell, seemingly for the benefit of the organism? Another example of that would be aspirin. Why is aspirin so beneficial in, as people have found, many different targets? Aspirin seems to modulate pathways just in the right way that is healthy. What Konrad and I have been developing is the idea that this is no accident—that it really is our body’s way of getting a sense of the environment and hunkering down in advance of food shortage, for example. The concept, at its core, is that early life forms evolved to sense other life forms when they were stressed so you could get a heads-up about deterioration in your environment. What we proposed was that when plants are stressed (as an example—it probably works between very different organisms, not just plants, but fungi and others), they make high levels of secondary metabolites (resveratrol, aspirin, many others). And what we think is going on is that we have evolved to sense those chemicals because we are consuming plants, we’re consuming other organisms over time, and we can get a sense of how our food supply is actually doing in the environment. You could imagine a scenario where one organism can sense whether its food supply is stressed and another organism cannot, and the one that can sense it through what we call xenohormesis is able to prepare in advance for the loss of its food supply, or some other stress that is coming that it cannot sense itself but other species can sense, and that it gets ready for the stress, and the other organism is oblivious. The oblivious organism ends up dying out, and you are left with organisms on the planet that can sense other species when they are stressed. JB: I think there is a beautiful poetic social metaphor there. I know you have spoken to it or related to it in some of your writings—that this almost speaks to the concept that has been often, in genetics and evolution classes, considered a non sequitur, and that is co-evolution, where we are actually getting cooperation among organisms by one organism doing a lot of work for another and getting a benefit in return. It’s a very interesting concept. I guess in some senses, we could even look at tryptophan and its conversion to niacin in the body as being somewhat like that as well, because niacin is a conditionally essential nutrient—our body makes it to some extent, but it’s nice when plants do more of it for us. It seems like a very interesting concept that talks about network biology. DS: Yes, a lot of people have come up to Konrad and me and said that this has explained a lot of things that have been just brushed aside as a coincidence. It’s a very hard thing to prove. We did try in the lab—a little bit—to prove this and never ended up publishing something. We were trying to feed aphids arabidopsis plants that had been stressed out by light. Although we made some progress and had some early data, we never finished it (or I should say that the student gave up because it was an extremely difficult project). Right now, what we rely on is a whole body of associations that support this idea, but we don’t have the proof yet, and I’m hoping that either my lab one day or someone else will come up with that clear evidence. Contrasting between the Pharmaceutical and Xenohormetic Models JB: Let me, if I can, play off that for just a second. I know that this kind of xenohormetic model (“xeno” meaning foreign, and “hormetic” meaning small things having bigger effects than expected) is a slightly (maybe even significantly) different model than the pharmaceutical model from which many of our medicines are derived, which is a one disease, one biomarker, one molecular target model. It is kind of a linear model. It has led to the development of a very robust Physician’s Desk Reference (PDR), with a lot of new-to-nature molecules that do specific things, but it raises a question as to whether there is a molecule that actually does just one thing, or whether we have pleiotropic effects that then give off target influences that give rise to all sorts of other things that we previously didn’t understand because we don’t know what we don’t study. Can you comment a little bit on the pharmaceutical model as it contrasts to the xenohormetic model? DS: Yes, sure. The xenohormetic model predicts that a single plant molecule could hit maybe a dozen or more different proteins and modulate them in just the right way to provide health. As I mentioned, we see that in botanicals that are used as medicines all the time, and even medicines that are natural, such as metformin for diabetes. The alternative view, which is predominant in the pharmaceutical industry, is that you should make a drug that hits just one target, because if it hits more than one, there is much greater chance for what are called off-target effects and toxicities. Which is true, but that’s only because we end up—in the pharmaceutical industry—making synthetic molecules that we have not evolved, ever, to experience. They are really two different worlds and I don’t think it is correct for one to say negative things about the other even though they do, because they are two different worlds: one is synthetic and never experienced, and the other is natural, where organisms have been bathed in these types of molecules for a billion years. What it actually predicts, though, is that the pharmaceutical industry could identify medicines, particularly from plants that have been stressed. I’m unaware of anybody who is taking that strategy—that if you wanted to look in the natural world for a new medicines, you should isolate molecules particularly from those plants that have been stressed. The other thing that is interesting is that the agricultural industry, except for perhaps the organic side of things, tries to make plants as happy as possible (they tend to grow faster). But as Ed Calabrese would say, if you give a little bit of stress to plants they can actually do better. What we believe with xenohormesis is that you would have a healthier food supply if you did stress plants just before picking them. And actually if you look at the best red wines in terms of flavor and even health (levels of resveratrol as well), these wines come from grapes that are under stress, either from fungal attack or dehydration. But we don’t typically apply those types of approaches to our other foods. JB: You know, one of the colleagues of yours at NIH that has referenced your work extensively and is following this same theme is Mark Mattson—I’m sure you know him—in the neurohormesis area and his work on neurodegenerative diseases and phytochemical modulation of neurological function. Does his approach seem consistent with what you have observed from your work? DS: Sure. They go hand-in-hand—the idea that a little bit of self-stress is good for you—is really not just the basis for his work and mine, but the whole field of calorie restriction now has realized that the reason that this diet works (in the brain, in the body, for metabolism) is because it is invoking a perceived stress on the body. And what’s happening is it is not just changing metabolism and slowing it down, which was the early theory, but it is invoking a stress response in the animal. By that I mean it is turning on particular pathways that we are now characterizing, like the sirtuin genes that I mentioned earlier. That actually now means that it is feasible for Mark and myself to find particular genes that can mimic the benefits of these stresses without actually having to experience them. I think that’s a real breakthrough in concept as well as practical approach. Sirtuins and Prion-Related Diseases JB: Of the many papers, two that really struck my fancy was a paper looking at prion-related diseases and the influence that sirtuins might have (or sirtuin activation and/or calorie restriction).[4][5] If I think of damaged chromatin, then I also can think of damaged protein. Prions are mis-folded proteins. Can you tell us a little bit about that? That seems like a fascinating part of the story as well. DS: A number of labs now have realized that the sirtuin genes don’t just control histones and the way genes are turned on and off, but they actually control other defense pathways, like antioxidant defenses and also, as you mentioned, protein mis-folding defenses. That’s an area of extreme interest because what we know about prion diseases and also about the aging process itself is that mis-folded proteins are a key cause. We’re also looking intensively at Alzheimer’s disease and finding that the sirtuin genes—at least 2 out of the 7 we have—are highly neuroprotective, enabling the body to get rid of mis-folded and aggregated proteins, like A-beta. So this is an area that is extremely important, and actually it goes back to the days of the yeast cells, where researchers found that the original gene, Sir2, doesn’t just control genomic stability, which is what we worked on, but also that this Sir2 protein is able to detect damaged proteins (oxidized proteins), and prevent the offspring from getting those proteins, so that the offspring are rejuvenated. There is still a lot to figure out. We don’t know how Sir2 does that in yeast, and we certainly don’t understand much more about mammals as well. But I think the important point, Jeff, here is that these sirtuins do a lot of things, and that’s what you would expect of a gene that underlies the benefits of caloric restriction and can actually slow down aging. JB: I’m thinking back, also, to my kind of very naïve understanding of the etiology of Werner’s syndrome (or Werner’s disease), which is a precocious aging where children with this genetic issue end up often going through what appears to be the whole senescent process by their teenage years. As I recall, one gene that has been located that relates to this has to do with helicase, which has to do with the tertiary structure folding of proteins. Is there any connection at all between this precocious aging and helicase and the sirtuins, or is that a stretch of the story? Sirtuins and Telomerase Activity DS: It’s not a stretch at all. In fact, I read a paper—at least the abstract of a paper—a few days ago that showed that resveratrol, and ostensibly SIRT1 that it’s targeting, is able to upregulate the activity of the Werner’s protein, as well as telomerase.[6] I think many of your listeners will know telomerase is the enzyme that extends telomeres. And the reason that’s important not just Werner’s syndrome but also in normal aging is there is increasing evidence that telomeres are important for diseases. And actually some of the early work we did in my lab was to show that the Werner’s syndrome helicase is necessary for the maintenance of telomeres in yeast cells, and it looks like that is also true for patients and the problem that leads to their symptoms is rapid telomere erosion and hence rapid aging. But there are a lot of other problems, of course. They have defects in general DNA repair. But also, it is known that the SIRT1 protein (the enzyme) can regulate the Werner’s helicase directly. So there are very clear links between what I work on and premature aging diseases (progerias, like Werner’s syndrome). Sirtuins and Epigenetics JB: That’s fascinating. I want to go back to this chromatin story with SIRT1 for a second. We talked about SIRT1 being an NAD-dependent histone deacetylase and it has to do with the acetylation/deactylation of histone protein, which then raises an interesting question to me, because that would be—I guess we would call it—an epigenetic type of regional specificity. And when we get into epigenetics, then we translate the portion of our book of life—our human genome—that is readable or unreadable based upon whether it is methylated or acetylated. That takes us into things like Randy Jirtle’s work with folate and B12 and what they found in the Agouti mouse, or what Moshe Szyf is looking at at McGill as it relates to kind of psychosocial impacts on the epigenome, or Mike Skinner at Washington State who has been looking to the role of low level biocides on the epigenome. Clearly there appears to be a convergence or an interface between what you have done with SIRT1 and phytonutrient modulation of SIRT1, and some of these other people that are working in epigenetics. Can you tell us a little about this domain? It sounds like it is really advancing quite rapidly. DS: Yes, it is. The paper that I was talking about that impinges on our work clearly says that the SIRT1 enzyme controls how we age not just based on what genes we inherited, but how those genes are expressed during aging, and that this can be accelerated by DNA damage by distracting this protein. In general, the field of epigenetics—as you mentioned—is exploding, particularly in aging, where we have realized that there is a lot more than just the genetics involved in predicting how we age. Some of the most interesting work, I think, is done by researchers who are studying the effect of maternal environment, and that even before you are born you may have a gene expression pattern set up in your cells that then predisposes you to particular diseases late in life. That’s been done very effectively in rodent studies where rodents that are stressed, or, for example, fasted extensively during development, that these offspring go on to develop diabetes and obesity more often.[7],[8] That area is really exciting. It’s a little scary because of how much of an impact your mother’s behavior can have on you potentially, but it also—as you mentioned, Jeff—is important because as we head off into the genomics era, we have to realize that there is more to know than just reading your genome at the DNA level. Research on Resveratrol and High Fat Diets JB: One of your many important papers was the paper in Nature that talked about the role of high fat diets on inducing distorted metabolic signaling and the relationship that it has to insulin resistance and inflammatory effects and how resveratrol could have a positive impact in ameliorating that.[9] It sounds like one of the stresses that we are talking about other than calorie restriction would be– I guess you would call it–the malnutrition of overconsumptive undernutrition: too much of too little, or just overwhelming. Is this stressor of the American diet one of the precipitators for altered sirtuin regulation based on what you’ve found to date? DS: You’ve hit the nail on the head. When we first proposed that a high fat diet could be at one end of the same spectrum as caloric restriction there were a lot of doubters. Now it is actually taken for granted that that’s true, but about six years ago when we first started working on this and proposing it most people thought of caloric restriction (calorie restriction) as something rather special. How we viewed it was at one end you’ve got the high fat diet and at the other end you’ve caloric restriction and in between you’ve got a standard diet. What we proposed was that you could feed mice resveratrol if they are on a high fat diet and push them towards calorie restriction and end up having a fat mouse that looks more like a lean mouse. And then if you took a lean mouse and fed that one resveratrol we could push them towards caloric restriction. When we proposed that, like with most crazy scientific theories most people said, “This is never going to work.” The postdoc, Joe Baur, who started the project, was convinced that his career was going down the drain. But what happened was it was borne out. The mice on the high fat diet ended up having the physiology of a lean mouse, even though they were still obese; their organs seemed to be oblivious to the fact that the mice were fat. And then when we fed resveratrol to the lean mice, they had the health, and the gene expression pattern, and the physiology of more like a calorie-restricted mouse.[10] That now is just taken for granted. It’s funny to think back only five years ago how strange that sounded to most people and how risky the project was. But you are also right: the high fat diet is a stress. One area that I’m thinking more about (or actually trying to understand) is why a high fat diet that most of us consume in the Western world accelerates the aging process. This is not a common view. In fact, a high fat diet has been thought of rather with derision by the aging community, but more and more I think people are coming to the realization—I certainly am—that a high fat diet actually is important to understand the aging process, and that it’s an accelerator of that process. And if you wanted to know why I think that happens, my best guess right now (and we are testing this in the lab) is that the high fat diet turns down our body’s natural genetic defenses against aging, like the sirtuin genes and others, and that if we eat a big hamburger, what we are really doing is turning off these defense pathways, and in the long run that accelerates aging. Comments on the Hypoxia-Exercise Connection JB: That’s fascinating. One of the other things that has been discussed—and probably controversially—as a stress or maybe even as an activator (so they’ve got a lot of difference of opinion), is this whole exercise connection and how that also relates to hypoxia. I think you have done studiesin which you published the role of hypoxia on some of these signaling pathways.[11] Some people might say, “Exercise is good as a positive stress.” And other people might say, “Exercise produces hypoxia, which is overly stressing and now we induce oxidative injury and genomic instability and so forth.” What’s your thought on the hypoxia-exercise connection? DS: That’s been one of the hottest areas recently. Not only are the sirtuins involved apparently in the benefits of dieting, but also of exercise. Some of the evidence is that when you exercise a rodent or even a human, the amount of some of these sirtuin genes goes up dramatically, as does their activating molecule, NAD, and the effects of exercise can be recapitulated. We’ve done some of these in my lab by turning up these pathways, so you can mimic the benefits of exercise just with a genetic manipulation and get the boost in mitochondrial activity, and even down regulation of antioxidants. Really the challenge is to figure out what the right dose of exercise is beneficial. You mentioned that maybe you could overdo it. I think that’s true. I think there is probably a balance where you can do the right amount of exercise without creating too much damage, and then that is a lasting effect that keeps these defense pathways up for the next few days, maybe even a week, and you get the benefits of the exercise without counteracting that with the damage that you can cause. JB: I remember years ago talking to Dr. Edward Schneider, who I know you are familiar with. I think now he is the director of the Andrews Center of Gerontology at USC, but at the time I talked to him he was at the National Institutes of Aging as the director; he took over for Bob Butler. He made the comment at that point (probably two decades ago) that what had been learned about aging was moderation—that if you really looked at things, we have this curvilinear kind of response curve that is more parabolic: too little of something is not good, too much of something is not good, and at the zone of optimal function you’ve got the right amount of whatever it would be. Does that hold true, from what you’ve seen, as it relates to these modulators of sirtuins—resveratrol or whatever we are talking about, that there is some kind of a parabolic curve of dose response or effective response? Dose Response is Still Undetermined DS: Yes and no. Let’s take SIRT1, for example, the one that we know the best, the sirtuin gene. It gets up regulated about 5-fold when you fast an animal overnight. So the “yes” to the question is that it is true that if you don’t give enough of this gene—if you only up regulate it 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} or so, or you give resveratrol at a relatively low dose—you don’t activate these pathways enough to get any meaningful of significant health benefits. The “no” part of it is that we haven’t yet found an upper limit where SIRT1 is bad for you. With resveratrol, of course, you can make an animal sick by giving too much, but I haven’t seen compelling data saying that too much resveratrol can be extremely harmful. The one exception to that was a clinical trial that was halted in multiple myeloma patients, where there was suspicion that there might be kidney failure.[12] But in normal individuals, and I’m aware of at least 200 that have been given gram quantities of resveratrol, there wasn’t anything that was obviously bad. I’m not sure about the upper limit, but there is definitely a low limit where you need some sort of either fasting or some other type of stress or genetic manipulation that will get the levels up to where you can have benefits. That’s where we are. What we have done is we’ve made mice with different levels of SIRT1, and we are asking “What is the optimal level?” The question might actually be the wrong one because you may need to cycle the levels throughout the day, which is what happens naturally. What we’re doing is fairly crude, just blasting the animal throughout its life with high levels of this gene. We’ll have to see whether that works or it doesn’t. JB: I’m sure you’ve been asked a million times—in fact, I had a discussion with Rick Weindruch at the University of Wisconsin, who is a calorie restriction researcher about this question—about the level that would produce a meaningful effect on enhanced sirtuin-1 function in a mammal. He’s working with monkeys, but he’s also interested in humans as well. I guess there is a big controversy about that. We’ve seen a lot of people move in to exploit this by putting 50 or 100 milligrams of resveratrol in something and then citing your work. Do you have a sense as to whether we know where we start getting a gain of function response to resveratrol? DS: Yes. I certainly avoid making any judgments about products. There are a number of companies that get fairly angry with me if I say anything. But as a scientist I can tell you that the mouse experiments that we’ve done predict that if you scale up allometrically, the amounts that we see an effect with would be roughly 250 milligrams per day in a human, but that doesn’t take into account things like the fact that we’re a human not a mouse and there might be physiological differences in bioavailability. But if you just did the crude scaling up, it’s about 250 milligrams. Addressing Controversy about Resveratrol Research JB: Every new theory, every new advance, every new discovery has its naysayers. We’ve seen this happen almost reproducibly with any paradigm-shifting concept. There was the Amgen work and the Pfizer work that was published recently, suggesting that the influence of resveratrol or sirtuin was really an artifact of the methodology of the fluorophore that was used in the assay.[13][14] I know you have gone back and re-looked at that. Can you comment on that really quickly?, DS: There has been a lot of work just in the past year since those papers came out, and all of it, without exception, has been supportive of our view and our published work, which is that the resveratrol and also the synthetic molecules that have been made since directly bind to the enzyme and this fluorophore artifact is not the case. There is a lot of evidence, of course, and I would have to spend another hour with you, but actually some of the best evidence is that you can just take that fluorophore out of the assay and the experiment still works. So that’s the best argument. It was actually a pretty simple experiment. That fluorophore is a bulky hydrophobic chemical, and there are bulky hydrophobic amino acids so we just replaced that fluorophore with tryptophan and the thing still worked. It’s got nothing to do with a fluorescent artifact per se. There is a lot of evidence now. In fact, just in the last two weeks I could point to three—maybe four—papers where the effects of resveratrol have been negated by removing SIRT1. And so the effect of resveratrol clearly requires SIRT1 in many physiological effects.[15][17] In my lab we’re working on muscle metabolism and resveratrol clearly requires SIRT1 to change muscle metabolism. So I think that this last year has been helpful and it will continue to be controversial, but I think the weight of the evidence is swinging back in our favor.[16] Mammalian Target of Rapamycin (mTOR) is an Emerging Area of Research JB: I want to close with one last question. It appears one of the things that your extraordinary work has done is to provide a framework for the landscape of research in the area of molecular gerontology, which has been kind of in search of a Holy Grail for many years. I remember years ago talking to Caleb Finch, who was one of the early researchers in this area (I think back into the 70s, actually). He was always talking about how there will be ultimately a discovery that will help guide the research so that we will round up all these different theories—the Denham-Harman free radical theory, and antioxidants, and all these various things like the hormonal theory and so forth. It appears as if your work and that of your colleagues has started to provide a framework for this kind of structured approach towards understanding aging at the genomic and cellular level. With that in mind, one of the things that seems to be emerging out of this field from this type of work is this whole question of intercellular signal transduction through kinase signaling pathways and how that ties through central switching areas like mTOR. I find mTOR to be interesting when you think of the whole discovery of rapamycin as a fungi metabolite and how this “antibiotic” has now been found to have a very important role to play in this energy economy switching gene expression pattern and its connection with adenosine monophosphate kinase and nutrient sensing. Can you tell us a little bit about what your thoughts are as it relates to the trajectory of this field and the whole mTOR area? Is it part of this landscape that you are interested in? DS: It absolutely is. There are really four horsemen of the aging field now: sirtuins, which we’ve talked about and which I work on predominantly; there is mTOR and rapamycin—rapamycin turns down TOR signaling; there is AMP kinase—you mentioned that; and then there is insulin signaling. These four systems, when I go to a meeting on aging there are some very strong personalities and typically someone will stand up and say, “My pathway is the one that is most important. Mine’s the one that underlies aging and calorie restriction.” And someone else will say the same about their pathway. It’s becoming clear, at least to myself and a few others, that it’s a crazy thing to argue whose pathway is more important because this is a network of environment-sensing genes that talk to each other, and if you tweak one, without exception the other three will change. The sirtuins lie right within this network and they control mTOR, and insulin controls it, and AMP kinase is both upstream and downstream of SIRT1. So the challenge for the field, besides calming down and realizing we’re all holding the same elephant, is that we would like to figure out what’s the best way to tweak these pathways that is beneficial without causing side effects, and that’s really the challenge that my lab is working on right now. JB: Could you give us just kind of a quick view to the future? You’re probably the best prognosticator of what might be over the horizon that I know. Can you give us a sense as to what you think might be the light of the dawn here? DS: Well, I could flip a coin. The reason I say that is there are clinical trials in progress right now. They are being run by GlaxoSmithKline, which (full disclosure) I consult for. I’m aware of how well these trials are progressing, and so far I remain just as optimistic, if not more than ever, about their progress through the clinic and into the market, but there is still a phase two, and of course anything can happen and probably bad things will happen; that’s the nature of drug discovery. The best case scenario is that those drugs end up reaching the market for a disease. It may be an eyedrop, it may be…who knows, a pill, a suppository? I don’t know what it will turn out to be, but that could be the first—and I think is most likely to be the first—application of this research (practical application). But longer term, I think that we’ve turned a corner. I think that we now know how to manipulate health and aging. We know how to—at least in theory—control these major processes. Some drugs are already on the market, such as metformin. But longer term, I think that companies have realized that the study of these pathways and their integration and how they might control aging is important and that more people will work on them. The thing that a lot of people who don’t think about this everyday forget or don’t realize is that this is not about making a medicine to slow down aging. In fact, any company that tries to do that will probably go out of business. It’s about making medicines that treat diseases of aging and even diseases in young people by turning on these defense pathways that we know at least in animals can extend lifespan and slow down aging. So the future, I think, is that best case scenario, within the next few years, the GlaxoSmithKline molecules will hit the market. I thing with drug discovery is we never know how that’s going to turn out, but I think that the original goal of mine when I was in college may be achieved in my lifetime, which is that we may see the fruits of understanding how aging is controlled in our bodies. Recommended Reading about Dr. Sinclair’s Research JB: That’s a very exciting and very optimistic perspective. For someone who would love to be able to read all of your 110+ publications but doesn’t have the time, would you be comfortable with listeners getting a sense of your work via The Youth Pill, the David Stipp book?[18] I think it is a very fascinating kaleidoscopic overview of this whole concept that science is at the brink of this understanding aging revolution. Are you comfortable with that as being a good first start for many of our readers? DS: I highly recommend David’s book. I’ve known David for years and he has really done in-depth research and knows all the players and is a great writer. Yes, absolutely, that’s probably the best way to start. For a little more detail, if you’d like it, I wrote a Scientific American article a few years back with Lenny Guarente, my mentor, that talks about longevity genes and how they work. So, that’s in Scientific American.[19] JB: I know you had a very nice paper—a response—in Science magazine in the summer of 2010 that re-looked at the sirtuin concept and gave us an update on what’s happening.[20] We’ll follow your publications very carefully because they are the pulse of really what is happening in this field. I can’t thank you enough for spending this amount of time with us. This is more than fascinating. What we are hearing in a very measured way from you, and I know you are doing a very good job to meter your words, is really the birthing of a shifting paradigm that will really change the way of medical thought and medical therapy as it relates to this age-related disease process. David, thanks so much for being with us and thanks for your tireless work. It is extraordinary. DS: Thanks. It’s conversations like this that keep me going. Thanks a lot, Jeff, for having me on  

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Bibliography

[1] Sinclair DA, Guarente L. Extrachromosomal rDNA circles—a cause of aging in yeast. Cell. 1997;91(7):1033-1042. [2] Oberdoerffer P, Michan S, McVay M, et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell. 2008;135(5):797-798. [3]Howitz KT, Sinclair DA. Xenohormesis: sensing the chemical cues of other species. Cell. 2008;133(3):387-391. [4] Kim D, Nguyen MD, Dobbin MM, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J. 2007;26(13):3169-3179. [5] Chen D, Steele AD, Hutter G, et al. The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration. Exp Gerontol. 2008;43(12):1086-1093. [6] Uchiumi F, Watanabe T, Hasegawa S, Hoshi T, Higami Y, Tanuma S. The effect of resveratrol on the Werner syndrome RecQ helicase gene and telomerase activity. Curr Aging Sci. 2011;4(1):1-7. [7] Fish EW, Shahrokh D, Bagot R, Caldji C, Bredy T, Szyf M, Meaney MJ. Epigenetic programming of stress response through variations in maternal care. Ann N Y Acad Sci. 2004;1036:167-180. [8] Meaney MJ, Szyf M, Seckl JR. Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health. Trends Mol Med. 2007;13(7):269-277. [9] Milne JC, Lambert PD, Schenk S, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450(7170):712-716. [10] Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337-342. [11] Yang H, Yang T, Baur JA, et al. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell. 2007;130(6):1095-1107. [12] Whalen, Jeanne and Peter Loftus. “Glaxo’s ‘Red Wine’ Drug Trial Halted Over Safety Concerns.” The Wall Street Journal. 5 May 2010. Web. 10 February 2011. <http://online.wsj.com/article/SB10001424052748703866704575224110336797160.html> [13] Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des. 2009;74(6):619-624. [14] Pacholec M, Bleasdale JE, Chrunyk B, et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem. 2010;285(11):8340-8351. [15] Torres G, Dileo JN, Hallas BH, Horowitz JM, Leheste JR. Silent information regulator 1 mediates hippocampal plasticity through presenilin1. Neuroscience. 2011;179:32-40. [16] Dittenhafer-Reed KE, Feldman JL, Denu JM. Catalysis and mechanistic insights into sirtuin activation. Chembiochem. 2011;12(2):281-289. [17] Lee SJ, Kim MM. Resveratrol with antioxidant activity inhibits matrix metalloproteinase via modulation of SIRT1 in human fibrosarcoma cells. Life Sci. 2011; 88(11-12):465-472. [18] Stipp, David. The Youth Pill. Penguin Books. New York, 2010. [19] Sinclair DA, Guarente L. Unlocking the secrets of longevity genes. Sci Am. 2006;294(3):48-51, 54-57. [20] Baur J, Chen D, Chini EN, et al. Dietary restriction: standing up for sirtuins. Science. 2010;329(5995):1012-1013. [21] Bland J, Madden P, Herbert EJ. Effect of alpha-tocopherol on the rate of photohemolysis of human erythrocytes. Physiol Chem Phys. 1975;7(1):69-85. [22] Scheschonka A, Murphy ME, Sies H. Temporal relationships between the loss of vitamin E, protein sulfhydryls and lipid peroxidation in microsomes challenged with different prooxidants. Chem Biol Interact. 1990;74(3):233-252. [23] McCay CM, Pope F, Lunsford W. Experimental prolongation of the life span. Bull N Y Acad Med. 1956;32(2):91-101. [24] Anderson RM, Weindruch R. Metabolic reprogramming, caloric restriction, and aging. Trends Endocrinol Metab. 2010;21(3):134-141. [25] Son TG, Camandola S, Arumugam TV, et al. Plumbagin, a novel Nrf2/ARE activator, protects against cerebral ischemia. J Neurochem. 2010;112(5):1316-1326. [26] Mattson MP, Son TG, Camandola S. Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals. Dose Response. 2007;5(3):174-186. [27] Son TG, Camandola S, Mattson MP. Hormetic dietary phytochemicals. Neuromolecular Med. 2008;10(4):236-246. [28] Calabrese EJ, Mattson MP, Calabrese V. Dose response biology: the case for resveratrol. Hum Exp Toxicol. 2010;29(12):1034-1037. [29] Calabrese V, Cornelius C, Stella AM, Calabrese EJ. Cellular stress responses, mitostress and carnitine insufficiencies as critical determinants in aging and neurodegenerative disorders: role of hormesis and vitagenes. Neurochem Res. 2010;35(12):1880-1915. [30] Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell. 2010;40(2):310-322.

Welcome to Functional Medicine Update for March 2011. Why “Functional Medicine”? The definition of functional medicine, as it now is used within the Institute for Functional Medicine, is built around the ‘omics’ revolution that includes nutrigenomics, genomics, proteomics, metabolomics, lipomics—all these various new things that we’re learning about cellular biology, cellular physiology, and intercellular signaling. As we got into discussing this concept in greater and greater detail and seeing how it spread out to have so many implications in medicine, it became more and more clear that alteration in the functional status of cells precedes the onset of pathology: functional changes in signaling, functional changes in gene expression, functional changes in the way proteins are manufactured, how they are post-translationally modified, how they interact with substrates, how those are activated by co-factors, and how ultimately the expression of all these is influenced in their cellular organization to give rise to this dance of life that is called the phenotype of the cell. Looking at how the collection of cells to make tissues, tissues to make organs, organs to make organ systems, and organ systems to make the whole body then starts to demonstrate how individual changes at a cellular level could ultimately influence function of the whole organism. The Whole is Greater Than the Sum of Its Parts I think it’s important to recall that the whole is greater than the sum of its parts. I don’t want to sound reductionistic to the point of saying that if we understand each cell in the body that we would understand the organism as a whole; there is something greater than the sum of the individual piece parts. I think if we were to look at the emerging understanding of the origin of disease, we would recognize that the genes interact with the environment to give rise to the changing architecture of function, which ultimately gives rise (over some period of time, generally) to what we call a diagnosed disease. Understanding this dynamic systems biology process is very different than just driving for the diagnosis, which is the sine qua non for medicine (from the diagnosis comes the ‘treatment’). The functional medicine model that has emerged over the last 20 years looks at antecedents as encoded within genetic pluripotentiality. This means the genetic background of the person, their family history, their individual genetic history, the things that wash over them as it relates to their lifestyle, the ecology that they’re living in, their home (ecos—the home), their diet, exercise patterns, workplace, and relationships—all of these things are antecedents which then are worked upon by various triggers. Triggers are things that come up in the environment. It could be a motor accident, a problem with your employer, a change in the world economy, being laid off from your job, a serious infection. These things trigger the production, at the cellular level, of mediators. Mediators reflect the status of the function of the organism. Mediators could be things like proinflammatory molecules, such as cytokines or chemokines that regulate the function of cells at a distance. It’s a cross-talk situation. Now the body is under alarm. It is responding to an apparent offender or an onslaught; it perceives it needs to mobilize its defenses. Sometimes the body recognizes that the best defense is a good offense. It goes on an active seek-and-destroy-type mission to find the origin of these invaders and to try and do them in. Sometimes, however, what the body is doing in are its own host cells–the kind of auto-suicide types of situations that occur with apoptosis, oxidative stress, and activation of caspase genes that then cause the cell to be extinguished. This leads to senescence: loss of biological reserve, increased frailty, loss of metabolic degrees of freedom, and sarcopenia (muscle loss in the aged). All of these things are ultimate manifestations from years of living with this alarm process that the body has been shifted into. From that will ultimately occur a pathology–maybe a a dementia of Alzheimer’s, or it might be a motor dysfunction like Parkinson’s disease, or it might be a metabolic disturbance that we call type 2 diabetes, or it might be a cellular proliferative disorder that we call a cancer, or perhaps an atheroma (a benign tumor on the interior of the arterial wall that restricts blood flow). All of these are outward manifestations of this inward alteration of function from the gene-environment interaction. That is how we differentiate the functional medicine model from the histopathology model. They both have a place, obviously. It’s not that one necessarily replaces the other. There is a place for each. Certainly in the emergency room–in the hospital environment where there is a need for immediate intervention–the histopathology model may be very primary in managing that patient quickly and rescuing them. In the chronically ill patient, however, it may require a different model and that’s what we’ve been talking about in Functional Medicine Update over these many years. We interviewed Dr. Halsted Holman last year, from the University of California at San Francisco, who is a professor emeritus of medicine. He talked about a patient-centered model that we need to implement for the chronic disease patient, the ambulatory patient, the one who never really completely gets rid of their disorder but rather it has to be managed. There is an element of the patient managing their own situation and teaching them how to do that and giving them the right tools. This is the place where functional medicine has its biggest role to play and its biggest opportunity to provide value to improve patient outcome and to reduce unnecessary expensive medical services. Why “functional medicine”? I hope this summary I have give distinguishes the point of differentiation from a traditional pathology-based model. Functional medicine can be applied to the dominant patterns of dysfunction today in our society–these chronic disease areas that now constitute over 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of our healthcare expenditures. This month in Functional Medicine Update I’m very pleased to interview a person who has taken this concept I’m describing and woven it into a very effective management program. Interestingly enough, this individual, Dr. Steven Gundry, has come through the histopathology model of medicine very, very skillfully as the head of adepartment of a medical school. In the department of cardiothoracic surgery, he has refined his skills and developed his expertise in the interventional model of medicine. It has only been in the latter part of his career (now) that he has transitioned to what we might call the functional part of medicine: the management of the chronically ill patient. He’s going to tell us his story and give us news to use in a way that I think makes very, very powerful sense. With that in mind, let’s move to our Clinician of the Month, Dr. Steven Gundry.

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INTERVIEW TRANSCRIPT

Steven Gundry, MD The International Heart and Lung Institute The Center for Restorative Medicine 555 Tachevah Drive, 3W-103 Palm Springs, CA 92262 www.drgundry.com This is the time we always look forward to; it’s our future, pace-leading clinician or researcher of the month. I’m very fortunate this month to introduce to you a person I think fills both of those bills. He is a master clinician, and he also has a research mind that is obviously very unique and very effective in assembling data in a complex area. I’m talking about Dr. Steven Gundry. Dr. Gundry is an MD. He has a very interesting background. He was a cum laude graduate at Yale, where he was a special honors student in a very interesting degree: human biology and social evolution. After graduation he went on to the medical college at Georgia and completed a general surgery and thoracic and cardiac surgery program. He was at the University of Michigan as an academic, both looking at the research side of surgery and the clinical side. He ended up at Loma Linda University in southern California. Loma Linda is a very interesting medical school and medical institution that focuses on the interface between lifestyle, environment, and high-technology medicine. Dr. Gundry was department chairman there, and he did remarkable things in developing new surgical techniques. I’m going to let him tell you his own story of how he made the transition from being one of the leaders in the technology of interventional medicine, and coupling that with lifestyle medicine and nutritional intervention. It’s a robust journey that Dr. Gundry has been on. He’s written a book that I would call mandatory reading for all of us, Dr. Gundry’s Diet Evolution, which is available on Amazon and elsewhere and in bookstores.[1] It has become mandatory reading among all of the members of our research staff and our clinical group here. I think it is a news-to-use, “aha”-type of book because it talks about the evolutionary approach—kind of a molecular anthropological/genetic anthropological approach towards understanding what type of diet, what type of foods, what type of nutrition might be best for beating back the chronic disease epidemic that we’re starting to see right now. With that in mind, Steven, it is wonderful to have you here at the Functional Medicine Update audio studio. SG: Thanks for having me, Jeff. Great to be here. JB: I’ve given, I know, a very cursory snapshot of your background. Maybe you can fill in the gaps with your personal experience, which I think will help to set the context for what you are going to tell us. One Patient Led to a Change in Perspective SG: Sure. I’m a researcher (primarily a bench and a clinical researcher). Most of my research interests were in the lab, in preserving heart tissue from ischemia or from resurrecting dead hearts. Believe it or not, we developed a technique where you could take a heart out of a baboon that had been dead for 30 minutes—literally lifeless—and resuscitate it, and give it a bunch of cute little chemicals through its blood supply, and put it into another baboon and it would start right up as if nothing had happened. I’ve got a nice little Lazarus poster in my office from my colleagues. I’m interested in taking things that would seem to be irretrievably damaged and figuring out how to stop that damage from happening or reversing it. That wasn’t so much the case in my own life. I was pretty much a big fat guy most of my life, particularly when I was at Loma Linda. I ate a standard Seventh Day Adventist low-fat vegetarian diet, and yet my weight had spiraled out of control. I weighed about 228 lbs at my top and I’m only 5’9” or 10”. My cholesterol profile was terrible. I had pre-diabetes, I had hypertension, I had arthritis, and I tried every diet in the world and was very successful at them for a couple of months. You name the diet, I was good at it. All that changed about ten years ago. A guy came into my office. I call him “Big Ed” in the book. He’s from Miami. Big Ed had inoperable coronary artery disease. Every one of his blood vessels was clogged up; so clogged up that you couldn’t put stents in, and you couldn’t do bypasses because there wasn’t any place to land the blood vessels. Ed had been going around the country looking for a surgeon who was crazy enough to operate him. I fit that bill. I’m famous for operating on people nobody else wants to touch. I looked at Big Ed, and I looked at the angiogram (the movie of his heart), and I said, “You know, everybody who has seen you is right. I’d love to help you, but I just don’t see how I’m going to do you any good.” Big Ed lets out a sigh and he says, “Well, that’s what everybody else says, but, look, here’s what I’ve done. It’s been six months since that angiogram was made, and I’ve gone on a diet, and I’ve lost 45 lbs.” Now, Big Ed was still a big guy; he weighed 265 when I saw him. He says, “I went to a health food store. I bought all these supplements.” He brings in, actually, a big huge shopping bag of supplements. He says, “I’ve been taking these supplements every day. Maybe I did something with my weight loss and these supplements.” So I’m kind of scratching my professor beard and patting my big belly, and I said, “Good for you for losing weight, but that’s not going to change anything in your blood vessels. And I know what you did with all those supplements; you made expensive urine.” And I really truly believed that at that time. I said, “At the most you’ve just wasted all your money.” He said, “Well, I’ve come all this way. What do you say we get another angiogram? What would it hurt?” So I said, “Okay.” We got another angiogram and then the next day I did a five-vessel bypass, because in six months’ time he had cleaned out fifty percent of the blockages in his coronary arteries. He still had blockages, but now there were places to actually land blood vessels. If I had known then what I know now, the last thing I would have done is operate on him, but I didn’t know. After I operated I said, “Big Ed, give me that bag of supplements.” I started looking through these supplements and a lot of them that he was taking I was using down in the laboratory in the form of intravenous solutions to protect hearts for heart transplant or to resuscitate hearts that had been dead. I was giving them through the veins of the heart; it never occurred to me to swallow them. The other thing was I started talking to him about how he’d constructed his diet (because I loved diets). As he is describing it, light bulbs were flashing off in my head because, as you mentioned, I had a very fascinating major at Yale. For four years I investigated, basically, how we evolved from a great ape into a human based on social pressures and environmental pressures; basically, how our genes interacted with our environment and the foods we ate, and how that could turn a great ape into a human. I had a thesis that I got an honors for, and of course my mother had my thesis, so I called her and said, “Still got it?” And she said, “Oh yeah, absolutely.” She sent it up to me and I’m looking through my thesis and I said, “Son of a gun, this is what I should have been doing for the last 20 years.” Self-Experimentation Leads to Healthy Results, a New Practice, Better Patient Outcomes, and a Book I put myself on this diet, which is pretty well described in Dr. Gundry’s Diet Evolution, and I started taking a ton of supplements. Not just willy-nilly—I actually started reading about them, which really, for me, would be the last thing I thought I’d be doing. I started sending my blood work up to Berkeley Heart Lab in northern California (it wasn’t called that then). Lo’ and behold, within a couple of months, my good cholesterol of 32 (which was terrible, my HDL) went up to 80 mg/dl, and my total cholesterol went from about 266 to 166 mg/dl, and my LDL went from 166 down to about 70 mg/dl. I said, “Son of a gun. I was told that this is impossible.” Then several of my staff members started doing it, and the same thing happened on their blood. So whoever I operated on at Loma Linda I would kind of enroll them into this program—teach them what they should eat and start giving them supplements—and the same thing started happening to them. Not only did their lipid profile get better, but a lot of these folks would call in a week or so and say, “What supplement are you giving me that is making me dizzy?” I’d kind of look at my nurse (I didn’t know much about supplements at this time) and I’d go, “There’s nothing in this that would make you dizzy. Get back into the clinic and let’s see what’s going on.” Of course their blood pressure was like 80 over 50, and they were on two or three blood pressure medications, and I said, “Well, son of a gun. I guess we better stop your blood pressure medicines.” “Are you sure that’s okay?” “Well, look. It doesn’t look like you need them anymore.” And then another patient would call and say, “Gee whiz, I think my blood sugars are getting really low. What are you giving me that’s making my blood sugar low?” “Get back in here.” And sure enough, we have to start backing off on their insulin, or backing off on their metformin, or their glyburide. This kept happening, so much so that after about a year of doing this at Loma Linda I looked at myself in the mirror one day and basically told myself I was in the wrong business. So I made a leap of faith. I moved to Palm Springs to set up an institute, which I called the Center for Restorative Medicine, where I basically teach people how to restore their health. If they have heart disease, we basically teach them how to get rid of it. If they have diabetes or hypertension, we teach them how to get rid of it. And through the years it has expanded. I have a real interest in Parkinson’s and Alzheimer’s, which I actually think is the same disease (just a variation), and in autoimmune diseases, and more recently I’ve gotten into stage IV cancer patients. I’ve been actually surprised—maybe I shouldn’t have been—with the effect everybody can have on seemingly dire problems. So that’s basically what I do, and being a researcher I decided that I was going to continue this as a research project, so everyone who comes in my office gets labs drawn that we send to a national lab every three months. We have an incredible database that we use to track what is happening to people. One of the first things that appeared (very, very consistently) was I noted that the more people’s triglycerides went down on their blood work, the healthier they got in almost anything I cared to look at. I said, “Isn’t that odd?” That actually took me back further into my book (my thesis) and I said, “Son of a gun, I could have predicted this based on millions of years of evolution.” And that’s how most of my thought processes have evolved. JB: It’s an unbelievably interesting story. There are so many levels of this to me when I hear your story. I’ve heard it now three times and each time there’s another nuance that I catch. People who are real seekers are exploring all sorts of domains that are not necessarily within the midline of what they were trained to do. You find that as a characteristic in all innovative people—that somehow they were willing or inclined to go way outside the boundaries of what they were told they should be focusing their energy on. And that’s how discoveries are made: by putting all that stuff together in a new perspective, which you’ve done so beautifully. Obviously the proof of the pudding is the outcome with your patients. So this transition you made from academic medicine into private practice—that’s a huge cultural change in its own right: the whole concept of billing, and office management, and procedures that used to be maybe handled by somebody at the institution now get handled by you, and how you make known your services, and all those things. Those are kind of the nuts and bolts part of it, but then the big issue is, of course, the transformation that’s occurring both in you and your patients through this new advocacy. Tell us about this 565-patient retrospective. I guess it is really more of an ongoing clinical observational trial or study. It’s really very interesting. Data From An Observational Study of Cardiac Patients Using Nutritional Therapy SG: We started with a few of these patients, and then we started really enrolling them. One of our most recent studies has been to look at 500 patients that we’ve tracked now for almost six years. At the five-year mark (last year) we gave a paper at the American Heart Association. These were patients who had known coronary artery disease. They either had an MI, or they had a positive angiogram with lesions, or they had stents, or coronary artery bypass, or they had positive stress tests and didn’t want a cardiac or surgical intervention like a stent or a bypass but wanted to try nutritional therapy. We enrolled these people in my dietary program. The dietary program is actually fairly simple. We have fun little rules (they’re rhymes). The first principle is, “If it’s white, you keep it out of sight.” We basically take away everybody’s ground up grain products. The corollary to that is, “If it’s beige, behave.” Most beige foods are ground up grain products masquerading in some form. The third rule is, “If it’s green, you’ll become lean.” We actually made our patients—and still do—consume a bag (or the equivalent) of dark green lettuce a day (however they want to get it into their system). If they want to cook a bag of spinach down into creamed spinach that’s fine with me. If they want to eat a spinach salad that’s fine with me. But dark greens: Romaine lettuce (Iceberg lettuce is banned), arugula, some of the really dark greens like kale, and Swiss chard, things like that. Those are the fundamental principles. We ask them to use only olive oil or canola oil for their salad dressings (to not buy any commercial salad dressings if at all possible). We ask them to eat—hopefully—grass-fed animals (that’s pretty impractical, but it’s getting easier and easier every year—eat animals that ate what they were supposed to eat): omega-3 eggs, grass-fed beef, lamb—the last lamb that is grass-fed now comes from New Zealand (almost all lamb is grain-fed), wild fish (get your good old Northwestern salmon that is out doing what it is supposed to do). These are our main principles. We then started them on some supplement programs that we would actually tailor based on the results of the Berkeley Heart Lab tests, which told us whether they had insulin resistance or what sort of other genetic profiles they had. Obviously we would have a completely different dietary program for someone who carries an ApoE 3,4 or 4,4 gene (the so-called Alzheimer’s genes). We might have a totally different statin recommendation based on whether or not they carry a mutation of a gene called KIF6. I think actually any practitioner who deals in heart disease should get a KIF6 on their patients. It really can guide who should have statins and who shouldn’t. Fifty percent of us probably have no business taking a statin drug because it will be totally ineffective, even though your LDL cholesterol comes down. We enrolled these people in the trial. Every three months they had to have a complete set of Berkeley Heart Labs. We would check compliance by actually looking at how people’s triglycerides were going. If I was going to get one blood test, that’s the blood test I’d get on someone to predict their problems with heart disease. The lower the triglycerides the better. Most people will soon learn that the ratio of HDL to triglycerides is the best predictor of avoidance of heart disease or getting heart disease. That ratio should be at least 1:1, and the higher the ratio of HDL to triglycerides the better off you are. And yet most people walking around this country with normal levels of triglycerides and normal levels of HDL actually have a terrible HDL-to-triglyceride ratio. I think that’s a huge cause of why we see so much heart disease in healthy living people. At the end of five years, these people would be predicted, on the basis of very large (10,000 people) studies, to have somewhere in the range of 25 to 50 percent recurrence rates of heart disease (in other words, a new event—a new heart attack, a new bypass, a new stent, a new stroke, a new death). That’s the standard of most tests, even on statins. Even on statins, the best statin trials still show an around 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} recurrence rate in 2 ½ years of a new event. So clearly this is not acceptable. In our patients, in five years, 2 out of the 500 patients had a new stent put in, which is 0.4{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. One other patient had a carotid artery endarterectomy, which I did (because he didn’t listen to me), and one patient had a stroke who was in atrial fibrillation and refused to take Coumadin. So our overall cardiac event rate in five years in 500 patients was 4 out of 500 or 0.8{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, so virtually nothing. This is 500 people with known coronary artery disease following a very simple diet and supplement program. This is not an irreversible process. This is not something that is going to happen to you. This is something that can be stopped. And the really exciting thing is we now have angiograms of people who have volunteered that show that the process is reversible, and it is reversible very, very quickly. I had the pleasure of showing you one of our more recent patients, who, in basically nine months, did a remarkable job of cleaning out his coronary arteries. The proof is in the pudding. JB: I hope everybody is taking a deep cerebral breath to oxygenate those frontal lobes as they are hearing you speak. Let me, if I can, for those of you who don’t have the privilege of seeing Dr. Gundry because you are listening to him, just mention—he would not say this himself—he’s an extraordinarily fit, lean and mean as they say (in the best sense of the term), highly capable, good looking, fit, and raring-to-go professional. He showed us pictures of what he looked like a mere 10 to 15 years ago. I’m sure he was intellectually lean and mean back then, but I think his physical frame and his physiology demonstrates a remarkable transformation in the 10-plus years. We can talk a lot conjecturally and theoretically. There is lots of stuff we can theorize on, but where the tire meets the road is the real outcome. When we talk about 500 patients and a 0.8{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} secondary event in high-risk individuals, even if it’s not double-blind, randomized, placebo-controlled and structured in biostatistical perfect language at Harvard Med, this can’t be just dismissed as cocktail talk. There’s something really serious here that we need to pay attention to. Just think of the cost savings, not to mention the potential human lives saved. It’s just amazing. Let’s trace back briefly to a couple of things you said that I think are real ahas. I believe these would be considered “new” information for a lot of people. The first is the use of particle count versus normal lipid panels and your belief that routine use of these can make forecasting or trajectory assessments possible. And secondly, this triglyceride thing that falls off your lips very easily because you’re very familiar with it, but for the average person who may be “Framingham-ized,” triglycerides doesn’t even end up on the Framingham Risk Factor trials. To say this is really a major determinant is an aha. Maybe you could speak a little bit more in-depth about those two. The Use of Particle Count Versus Normal Lipid Panels SG: Sure. Let’s talk about particle size first. I really don’t look at people’s total cholesterol counts. I really don’t look at their LDL counts. In fact, it may amuse your listeners to realize that there are major international lipid meetings that occur on a yearly basis. At these international lipid meetings, we vote once a year as to whether we should eliminate LDL from our nomenclature in talking about people’s risk factors. Most lipidologists will absolutely tell you that LDL has really no meaning because there are seven particles of LDL (that are at least known now). They are generously described as either big and fluffy or hard and dense. I actually use for my patients the idea that LDL carries fat around your body. These are mainly moving vans that carry fat. And if you have big moving vans—big professional moving companies—these are actually good for you. They carry fat around safely. They deposit it safely and so much the better. On the other hand, these little hard particles are what I call little pickup trucks. These are guys who put three rooms of furniture on the back with bungee cords and have mattresses flying off down the freeway. In fact I think the analogy is actually really good because these little guys are the ones that get activated, get oxidized, they’re the ones that burrow into the endothelium that cause the foam cells, that bring the macrophages, and start this whole process. So the big guys are doing their job; it’s the little guys that we have to worry about. The nice thing is that in general, triglycerides are a very, very good indication of what kind of particle size you are going to make. Triglycerides are the first form of fat that we manufacture from sugars and starches, A long time ago in our evolution, the only time we ever saw sugars and starches was when fruit ripened on a tree, and that happened to be once a year in the summer, and we needed to store fat for the winter. If we’re making lots of triglycerides, we actually kind of overwhelm this moving van system and we tend to make quite a few of these little pickup trucks. On the other hand, if we’re not making very many triglycerides, we don’t overwhelm any of these systems and we actually don’t make very many of these little guys. That’s simplistic, but it’s amazing how accurate this is. The corollary to that is that HDL, the so-called good cholesterol, is actually five different particles. There are little ones and big ones, and you might guess that the big one is good for you and you’re right. The big one, called HDL-2B, is nicknamed “Pacman” because it literally goes around and gobbles up fat off of blood vessels where ever it can find it. It is produced by the liver and it goes out as kind of an empty sac. As it goes around it literally fills up. You can actually watch these particles fill up with lipids. It’s really kind of exciting to watch. If it is winter time you need to go pick up fat, so you make a lot of HDL in the winter when you need it. But if you are trying to store fat for the winter, the last thing you want to do is make HDL, because if you are trying to store fat for the winter you wouldn’t want to pick it up. That’s how I could go from 32 HDL to an 80 HDL by changing my triglycerides. The really fun thing I get to watch is that people can actually control, by their sugar and starch intake, what their lipid panel can look like. I don’t really care if a patient has a very high LDL if 70 {56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of his or her LDL is these big fat moving vans. That is the vast majority of us—about 75{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of us carry a normal gene called the ApoE 3,3 gene. All bets are off when you carry an ApoE 3,4 or 4,4 gene (the so-called Alzheimer’s gene), and unfortunately those individuals: 1) need to know they have that gene, and 2) need to know because there is something they can do about it. They are somebody who we would manipulate much differently than the average human being. JB: I think that’s another very extraordinary part of your program. As I’ve heard you describe it, I can imagine the extraordinary reaction your patients have when you are talking about personalization. Often we have these generic thoughts of, “Okay, you’ve got elevated lipids, we see a high cholesterol and LDL, so you need this statin, and if that one doesn’t work for you we’ll try another one.” It’s not personalized to that person’s own specific genotype, and it also doesn’t serially measure how what they’re taking is influencing their overall dynamics. Maybe you can describe how you tie your Yale experience into this personalization. I think it’s a very important part of what you are doing. Genes: As Any Gambler Knows, It’s Not the Hand You’re Dealt, It’s How You Play the Cards SG: Our genes are, in the scheme of things, not very important. You and I have almost the identical genes. We have a few different ones. You have blue eyes and I have brown eyes, but in general most of our genes are exactly the same. What is different in each individual is the information that we give those genes via the food we eat, the nutrients we ingest, and the environment that we live in. It’s now becoming clear that epigenomics–the information that these materials, these particles, these compounds have on turning genes off or turning genes on–makes all the difference in the world. I like to say genes are just like little mini computer programs—they’re either off or they’re on. It’s the switch that throws things off or on that makes all the difference. The gene just tells things what to manufacture. It’s telling the gene to get activated or not to activate that makes all the difference. That’s the incredible power that people don’t realize they have. There are bad genes. They actually aren’t bad genes; they actually served an incredibly useful purpose, and most people don’t seem to realize that. Bad genes got weeded out a long time ago. The genes we have had a very useful purpose. It may not seem very useful to the individual who has them, but I can guarantee you that they had a very good role, and that’s one of the exciting things about looking at the interaction of genes and the environment. A person who carries thalassemia minor—it’s a wonderful gene to have if you live in the Mediterranean or live where malaria is because malaria can’t reproduce in these little cells because they are abnormal. On the other hand, if you have a double copy of that gene and you have thalasseniaminor, that’s a big problem, but that’s weeded out usually. It’s the same with sickle cell trait. Sickle cell trait is a great thing to have if you’re in Africa where there is malaria. If you have full-blown sickle cell it’s a terrible thing to have. And it is the same with these genes in cardiac disease. The neat thing about genes is, as any gambler knows, it’s not the hand you’re dealt, it’s how you play your hand. The wonderful thing about genetic testing is that as long as you know the hand you’re holding, and know what you can do about that hand, it actually—to me—is incredibly empowering. I think it’s a far better thing to have a patient know that they carry the Alzheimer’s gene than not know. Just yesterday I met a new patient who was from Los Angeles. She is in her early 70s and we did her testing. She’s a very thin woman, and she is ApoE 3,4. I start going through the diet that she should eat, which is primarily a green-based diet (almost a vegan diet without the grain products). She said, “Isn’t that funny? Since I was a little girl the only thing I like to eat is greens. I don’t like animal products. I don’t like grains. All I eat is greens. My favorite food is a big pot of collard greens or mustard greens and my husband thinks I’m crazy.” And the interesting thing is (this was her first test that I had), she had the most perfect lipid panel for someone who has ApoE 3,4 gene, and she had designed her diet herself. Whether her genes told her “this is the food you ought to eat so I won’t kill you” I don’t know, but it was so great to hear, “Doctor, this is the diet I designed for myself,” and lo and behold, she couldn’t have done better in designing this diet for that gene. JB: That’s fascinating. One of the things you talk about in your book is an extension of this model. It’s more than a model really, it’s a fundamental paradigm that you’ve developed related to this interface between our outside environment and the antennae (the way I envision it) of the body—the immune system—that’s picking up information all the time. We have an increasing tide of nonspecific autoimmune disease in our culture: thyroiditis, SLE-like, rheumatoid arthritis-like, multiple sclerosis-like symptomatologies. You have a very remarkable and, I think, clear distinction and explanation for this that relates to this gene-environment connection. Could you talk through that with us? The Immune System Doesn’t Make Mistakes SG: Sure. I like genes. It turns out that we—in our intestines—have about 5 lbs of bugs. There are probably about 500 different species of bacteria, protozoa, and viruses that live in our intestines. There is 1000 times more genetic material in that 5 lbs than in the entire 150 lbs in our body. It’s actually staggering to think about. We have about a trillion genes in each of our bodies, and yet there are a thousand trillion genes in that 5 lbs of crap. Most people have really forgotten their basic biology course. Our alimentary tract, starting at our mouth and ending in our anus, is actually the outside of us. All the contents that flow through are the outside world. We now realize that those bacteria have been with us through evolution for as long as we’ve been evolving. We inherit our colonic bacteria from our mother. As we pass through the birth canal, her fecal material actually inoculates us. So for each one of us, our colonic bacteria are maternal (our father gives none of our colonic bacteria). It’s fascinating that babies who are born by caesarian section take a full six months to establish a normal colonic bacteria because they never get inoculated. The “old friends” theory says if we’ve got that much stuff in there they are obviously doing important things, and we really ought to find out what they are doing. We now know that for most animals, the bacteria in our colon, in one way or another, contribute to most of the food we actually absorb. Herbivores have to have bacteria to break food down into absorbable fats. A gorilla gets 58{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} percent of his diet from the fat the bacteria ferment, so a gorilla—believe it or not—eats a high fat diet. The fascinating thing is that we get about 500 calories of fat from bacterial fermentation in our colon. We now know that that fat, which is primarily butyric acid, carries a lot of information. The old friends theory says that these bacteria are doing another job: they are the outside world. They have so much more genetic material and if they are going to have a free ride inside of us they ought to contribute something. And the contribution we now think they do is to tell our immune system what’s going on in the outside world as an early warning system. They do this in a number of ways. The first is butyric acid, a fascinating compound that lets our immune system—our gut—know how happy the bacteria are. If they are busy making a lot of fat, they’re actually very happy. It’s no surprise to anyone looking at the gut—and I was a general surgeon before I was a heart surgeon—that the vast majority of our lymphatic system lines our alimentary canal, from our mouth all the way through our intestines. We’ve always thought of these guys as the first line of defense. Well, we’re beginning to think that it’s actually more than that. These bacteria may be the first messengers of information from the outside world. The second thing that is fascinating is that our intestinal wall is one of the most impervious barriers there is. The tight junctions are incredible. Literally—as with our skin—we don’t want the outside world inside. And we’re realizing that it is the bacterial happiness that contributes to the integrity of that wall. The compounds that the bacteria make actually make that wall good or bad. Why is that important? Well, if a bunch of rogue bacteria were to come in, or if you take a bunch of antibiotics and kill off all your good guys, and you feed those bacteria things that you shouldn’t eat, all of a sudden you have a peaceful neighborhood that is being invaded by a gang war. The walls of our intestines get little breaks in them. A large molecule like gluten could easily get through a break. Like with any splinter, when our body sees a molecule that’s not supposed to be there it makes antibodies in an attempt to signal to killer cells to kill it, and that’s a wonderful thing. But these molecules bear very striking resemblances to other protein structures in our body. When you look at the ladies who develop Hashimoto’s thyroiditis, they, to the person, are generally skinny, grain-eating women. There is a fascinating correlation between gluten and Hashimoto’s thyroiditis. Multiple sclerosis has incredible predilection for wheat-eating countries. Hard-wheat areas have much higher incidence of multiple sclerosis than soft-wheat eating areas. And you don’t even need that. All you need is a mixture of a problem in your intestinal flora—maybe a viral illness, maybe food poisoning—to just for a few brief moments break that intestinal barrier and let these compounds in, and then the whole cascade starts. I don’t think the immune system makes mistakes. This whole idea that all of sudden we’ve got this epidemic of our immune system making mistakes just doesn’t make any sense to me. The immune system has been around a lot longer than the last 100 years. We never saw these problems before the advent of antibiotics, and that’s because in general our gut flora was there and did what it was supposed to do and was being fed proper things. It turns out that gut flora in humans actually loves two-leafed plants. They actually like cruciferous vegetables the best. On the other hand, they actually hate one-leafed plants (grains). By eating grain products, you will totally change the gut flora in any human being. It’s how happy your gut flora are that actually determines how happy you are. The prevailing theory now is that the gut bacteria actually tell your brain what they want you to do. For people who find that so hard to believe, we have more neurons (more nerve tissue) in our gut than we have in our entire brain. Truly this is the second brain, and in fact it may actually be more important than this thinking thing up above. Each of these neurons is capable of thinking, and each of these neurons gets information from its surrounding environment, which just happens to be the one thousand trillion bits of genes that are pumping out material to tell us what’s going on. JB: This is really, really fascinating. I interviewed–it must have been nearly 15 years ago–Michael Gershon, the author of The Second Brain, about this topic that you are describing.[2] I also had the privilege about a year ago to interview Dr. Nathalie Delzenne and Patrice Cani at Louvain University in Belgium, who were the first to discover this connection between gut bacteria and obesity.[3][4] That was another aha. I think what you’ve layered on, here, is a systems biology interaction of how all this ecology contributes to gene expression and modulation of function. , I want to go back and pick up one last topic before we finish this more than stimulating discussion, and that relates to the personalized supplement program. I know you probably have a whole array of different things that you use for different patients, but are there some that that you find that are extraordinarily helpful to fill in some of the gaps that should be in everybody’s thought process as they are evaluating patients? Recommendations and Rationale for Certain Supplements SG: Yes, I personally like the idea of using the anthocyanins, the procyanins, and the polyphenols as a large packet of individual supplementation. Ancient hunter/gatherers used to interact with about 250 different plant species on a rotating basis (on a yearly basis). And the animals that they ate also interacted with those 250 different plant species. I don’t care if you’re the best organic food eater in the world, I would dare say that none of us interacts with 250 different plant species today, nor do I think those 250 different plant species were grown in six feet of loam soil with all the ecology of the root system that we now know exists between the bacterial interplay with plants. Having said that, I think even the best possible human diet right now can’t possibly duplicate what we used to encounter. I used to be one of the biggest anti-supplement persons there was, but now I think a person who doesn’t supplement is not going to achieve the ultimate health that they could. Certainly the berry extracts are important. I am a big fan of tree bark extracts of all kinds, particularly in my cancer patients (pycnogenol, just to name one, Pau D’Argo, cat’s claw). The other thing that I think is very important to look at is mitochondrial health. I’m a big fan of L-carnosine as another generator of mitochondrial health. As you know, there are a number of “longevity experts” who have gone so far as to put themselves on metformin (glucophage). I haven’t made that step yet. I can understand the logic. I would much rather use something like L-carnosine to break the glycolytic pathway down a little bit. I think the next area of my interest is getting the mitochondria to function as well as it can. JB: I know you have spoken also very eloquently about magnesium, which is a soil-depleted nutrient. Maybe you can just say a word about that as well. SG: I think every practitioner ought to ensure that their patients take supplemental magnesium. Magnesium is so important for so many things. It is one of the major membrane stabilizers of all cells, and certainly of nerve cells and of cardiac muscle cells. I study (obviously) patients with heart disease, and if someone is coming in for a coronary artery bypass, we have to give them two grams of magnesium sulfate intravenously every six hours for 48 hours to replete their magnesium stores. Potassium is kept in serum at all costs. You will completely, totally, utterly get rid of your potassium from every cell to keep your serum level normal. For instance, if you have a patient who has a low potassium, you can say that that patient absolutely is probably 400 milliequivalents deleted just off the bat. Same way with magnesium. Most people walk around with a “normal” magnesium level, but they are so depleted of magnesium that it is startling how much we have to give them. Magnesium stabilizes the brain. Magnesium may be one of the best sleep aids there is. Magnesium is an incredible antidepressant. It’s amazing how many people who are depressed, if I can get them swallowing 500 milligrams or 1000 milligrams of magnesium (you build their tolerance to it), that helps with depression. People who walk around with restless legs, get your magnesium levels up. One interesting sideline of my diet: magnesium is actually stored with glycogen in muscles, and one of the effects of an initial sort of low carb diet is obviously to deplete liver and muscle glycogen stores. When we first started doing this patients would call in and say, “I’ve got muscle cramps. What’s the deal with that?” I didn’t know it at the time, but I said, “Well, take magnesium and that will solve it,” and of course it did. Then I started investigating why they would they get muscle cramps. It turns out it is because the magnesium is pulled out with glycogen, and so your muscles are depleted of magnesium and they go into spasm. JB: That’s a nice segue to maybe the last part of this discussion. Again, I really recommend listeners obviously should follow up with Dr. Gundry’s Diet Evolution book. I think it will give a lot more of the details. One of the things you describe in that book is the power of a ketogenic diet and how that could be considered kind of a therapeutic diet. Can you tell us a little bit about your experience and why you feel that’s a desirable therapeutic approach? Discussion of a Ketogenic Diet SG: We’re certainly designed, as an animal, to go through prolonged periods of starvation. Those of us who are walking now are the result of our ancestors being able to tolerate long periods of starvation. Starvation in and of itself, and a calorie restricted diet, puts animals (or ourselves) into a period of ketosis. The really interesting thing about us, as an animal, is that we have absolutely no need for carbohydrate as a fuel source. Just ask an Eskimo. Eskimos don’t eat fruit and they don’t eat plants; they eat blubber (they eat fat and protein). We, of course, have the ability to convert fat into ketone bodies, and actually free fatty acids are incredibly good fuel. These fats live on phosphate backbone. When fats are broken down, the phosphate it is a phenomenal fuel for ATP. We’re designed to be able to not only survive on a ketogenic diet, but actually to run quite well on a ketogenic diet. The heart prefers fatty acids as a fuel far more than glucose. This is well known. The interest in ketogenic diets as a therapeutic diet probably first started in the treatment of epilepsy. A very, very high fat diet (particularly a high fat diet with medium chain triglycerides, which generate ketones) was very therapeutic for seizure disorders. The brain clearly loves glucose. In fact, the brain is the major consumer of glucose in our body, but the brain will run on fat. It doesn’t particularly like it, that’s why you get a headache when you go on an Atkin’s diet for a couple days as your brain switches over to burning ketones. Your brain says, “No, no no. I want sugar. Give it to me now.” That’s why we get a headache. We are now beginning to realize that Alzheimer’s, and Parkinson’s, and a lot of the neurodegenerative diseases, are the brain cells actually starving from insulin being unable to deliver sugar into cells. We’ve not really appreciated how important insulin is as a hormone in delivering sugar into brain. For many years we thought it really wasn’t necessary, that the brain didn’t need insulin to use sugar. In fact, we now know it does. Brain cells develop insulin resistance just as the rest of our body does. There is now an increasing theory of type 3 diabetes, where literally we have insulin resistant brain cells. One theory is, “Okay, let’s give those brain cells insulin,” and interestingly enough you can spray insulin into the noses of Alzheimer’s patients and for a couple of hours they’ll get smarter. It’s not a long term practicality. The alternative is that brain cells don’t need insulin to use fat. And so you can actually use a ketogenic diet to feed brain cells. Where I first started using a ketogenic diet is in patients with Parkinson’s and Alzheimer’s. One of my best examples is my father. My father, five years ago, was on three Parkinson’s medications. He could walk maybe across the living room and that was about it. I took my mother aside—my father was 80 at that time—and I said, “Look, you’re going to have to intervene here and I want you to try my diet on him.” My father now walks five miles a day. He’s on no Parkinson’s meds. He looks, unfortunately, like me a great deal. He lost about 45 lbs. We were in a winery the other day and the fellow serving us said, “So are you two brothers?” It pissed me off. This is a classic example. We totally changed what we’re feeding his brain. We took away his starches. We took away his fruits. We took away his grain products. He eats quite a high fat diet. He gets cheeses. He takes coconut oil. But it totally changed the fuel that his brain was capable of using. That experience led me into using a ketogenic diet for cancer patients. I think cancer cells are fascinating because they have an Achilles’ heel. Cancer cells have to have glucose because they can’t do glycolysis properly; they can’t do oxidative glycolysis. They have to use huge amounts of glucose. I tell my patients, “Guess how we found your cancer cells? We took some sugar. We attached radioactive isotopes to it. We injected it into you. And we put you under a scanner. And guess what? The hotspots, where the sugar is being eaten most quickly, is where the cancer cells are and that’s how we found them, because they’re eating the sugar.” This is such a simple concept: If that’s what they eat, starve the little devils. You and I do not need sugar. Our cells will run perfectly fine on fat and will run perfectly fine on protein. We don’t need sugar. The really interesting thing is that if cancer cells try to use fat as a fuel, they actually explode; they produce hydrogen peroxide. They kill themselves. I use a very extreme form of my diet, in which basically people don’t get any fruit. They get no seeded vegetables. Seeded vegetables are fruits: cucumbers, squash, tomatoes, zucchini, peppers, eggplant. These are all fruits. And I take away all their grain products because ground up grain products are just sugars. We give them quite a bit of coconut oil (extra virgin coconut oil). It turns out there are polyphenols in extra virgin coconut oil, and that’s actually probably where the benefit is; it’s about one-tenth of what’s in olive oil. I think there are a whole host of reasons why a ketogenic diet is useful. The last reason is that during starvation, our system (our body) is designed to go around and look for cells that aren’t pulling their weight. There is only so much food to go around, and we have an incredible system to create apoptosis in cells that aren’t doing their thing because they’re dead weight and they ought to be disposed of. There is periodic fasting in every great religion. This is not hocus pocus. Every religion has some form of fasting built in. You look at people who practice calorie restriction, or you look at animals. We’ve now done it in Rhesus monkeys. The University of Wisconsin published, in 2009, a 20-year study.[5] You can have two littermate monkeys and one 40-year-old looks like a grizzly old arthritic animal and the other one looks like a teenager bouncing around in the cage next to him. This is ketogenesis. These guys are on a slightly ketogenic diet. I’m a big believer in it. I see patients whose cancer “miraculously” goes away, I see Parkinson’s people like my father pick up their cot and start walking. This is not placebo effect. This is real. JB: That’s about the most extraordinary advocacy that we could probably have to end this discussion. Obviously all of you who are listening I think want to look at Dr. Gundry’s Diet Evolution book and fill in some of the gaps here. Steve, I really want to thank you. This has just been extraordinarily uplifting. Also, clinically, news to use, for the people who are looking for where the tire meets the road and how you speak to your patient in the exam room. You are a master of the metaphor, which is always the best teaching tool. I just want to compliment you. You’re very courageous. It’s a very complicated thing to make a career change as you have and to do it with grace and provide value to your patients. All we can say is be very, very successful. We really appreciate your leadership. SG: Thanks for having me here. You’ve been a real beacon for all these years and keep up the good work. JB: Thank you so much. I hope you enjoyed Dr. Gundry’s comments as much as I did. There was some really interesting and important information captured by Dr. Gundry. Again, I think his book is really worth looking at because it brings this whole concept he described to life: modifying the environment of the individual to quell some of the genes that are expressing alarm and inflammation. I want to say a few things in close about that because this theme that Dr. Gundry has been speaking about so eloquently is not just a side bar of minor importance. We’re seeing more and more–in peer-reviewed top-tier journals–discussion of this concept of genes and environment and how to modulate the function of an individual who is in a state of distress (distress meaning proinflammatory, or pro-oxidative, or in an apoptotic model where they are losing cell mass prematurely and losing biological reserve, increasing their biological aging). This concept is really at the forefront of molecular and cellular biology, physiology, and even at the etiology of tertiary diseases. For the first time we are starting to see emergence of a mechanistic understanding of the origin of so many of these age-related diseases. They derive from this concept of gene-environment interaction, as Dr. Gundry was speaking to us about.  

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Bibliography

[1] Gundry, Steven R. Dr. Gundry’s Diet Evolution: Turn Off the Genes That Are Killing You and Your Waistline. New York. Crown, 2008. [2] Gershon, Michael. The Second Brain: A Groundbreaking New Understanding of Nervous Disorders of the Stomach and Intestine. New York. Harper Paperbacks, 1999. [3] Muccioli GG, Naslain D, Backhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani P. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010;6:392. [4] Cani PD, Delzenne NM. Involvement of the gut microbiota in the development of low grade inflammation associated with obesity: focus on this neglected partner. Acta Gastroenterol Belg. 2010;73(2):267-269. [5] Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009;325(5937):201-204. [6] Ahmed F. Health: edible advice. Nature. 2010;468(7327):S10-12. [7] Neyrinck AM, Cani PD, Dewulf EM, De Backer F, Bindels LB, Delzenne NM. Critical role of Kupffer cells in the management of diet-induced diabetes and obesity. Biochem Biophys Res Commun. 2009;385(3):351-356

Welcome to Functional Medicine Update for April 2011. It has been quite a busy start for the 2011 year. Things are going on with healthcare financing, and with new biological discoveries and changes in the pharma industry. A global rising tide of chronic age-related diseases continues. These western diseases are not just isolated to the shores of western countries, but rather can be exported as a consequence of the lifestyle and environment. In the east, the rising tide of diabetes has become almost a hockey-stick increase in prevalence. Global Chronic Disease Trends are Changing In 1984 or 1985, when I had a chance to first visit Hong Kong as an invited lecturer at Hong Kong University Medical School, I gave my presentation on type 2 diabetes. After my lecture the dean came up to me and said, “Dr. Bland that was a very interesting lecture. We really appreciated how well you prepared and how well you presented that, but really we don’t have type 2 diabetes here in China, so it’s not of a very high clinical relevance.” It’s ironic or interesting, I think—maybe it’s even a sign of the times—that in 2006, when I was invited back to speak (this was a new dean at the same medical school; probably many of the faculty were new), the topic that they asked me to speak on was type 2 diabetes. In the intervening period of 20-plus years, a condition that was not seen with any clinical importance suddenly was of major importance, and their interest was, “Could you tell us a little bit about the origin of type 2 diabetes? How environment interacts with genes to induce and produce a phenotypic expression of insulin resistance and hyperglycemia and all the secondary untoward consequences of that?” I think this illustrates a changing tide and a changing complex environment globally. We are starting seeing the age of first infirmity actually going down to a younger age.  We saw the landmark paper that appeared in the New England Journal of Medicine some five years ago that described how children born today will have, on average, a mean life expectancy less than that of their parents (the first time in the history of our country—the United States—where that’s occurred).[1] These are all very dramatic, big picture changes/transitions/observations that illustrate the fact that we’ve got an issue that requires a new approach—an approach that is different than treating the symptom when it develops. Rather we need to be digging deep into understanding the origin of these complex, age-related chronic diseases and treating their cause and not just their effect. We need to understand the metabolic disturbance that later goes on to become a diagnosable disease with an ICD-9 code. The metabolic disturbance is a consequence of some relationship the environment has to genetic expression that is unique to that individual’s response to their environment. This month in Functional Medicine Update we’re privileged to have an expert in lifestyle medicine, Dr. Garry Egger from Southern Cross University in Sydney, Australia. Dr. Egger and his colleagues have authored what I think may be the first textbook in the area of lifestyle medicine that has recently been revised into a new edition, which I believe starts to codify, specifically, the components of a lifestyle-based medical intervention program.[2] We’ll talk about the standard of identity and standard of care as it relates to lifestyle medicine. Lifestyle is a Patient’s Environment What I often tell people when they say, “This sounds interesting but I really don’t do lifestyle medicine or nutrition in my practice,” is, “Lifestyle is shared among every patient. In fact, there is not a single patient who doesn’t have a lifestyle. They don’t have an environment that is not without impact upon their genes and how they express their function.” If a person is practicing scientific medicine, which we all say that we are here in the 21st century, then they would want to control as many variables in producing reproducible outcome in their patients as possible, and one of the wild cards that can influence the outcome of any therapy is that of lifestyle and environment. If you don’t control that wild card—that variable called lifestyle—then you are at some kind of risk, I believe, relative to the reproducibility of outcome and relative to the therapy that is chosen. That therapy could be pharmacology, it could be structure/function type, it could be structural, it could be acupuncture, it could be nutritional—all of these various interventions are modified, in part, in outcome into the phenotype as a consequence of the lifestyle of that individual patient and how it interrelates with their genetic uniqueness. Some people call this concept genetic susceptibility. I think that term is a little bit misleading because it suggests that all of the factors that are in our genes somehow make us susceptible to some disease. If you really think about it, we’re not susceptible; we’re unique in our response. Some of those things that we think are susceptibilities really may have been evolutionarily advantageous at an earlier period in our cultural history, under a specific set of environmental circumstances. However, when they are expressed in a disadvantageous way, we label them as a disease. The term “disease,” in and of itself, somewhat has bias in it, has some bigotry in it, has some discrimination in it. Because once you say a person has a disease–be it diabetes, or cancer, or heart disease, or arthritis, or whatever name you would like to put on their condition–they then become that disease. They become Mrs. Jones, the diabetic, or Mr. Smith, the coronary heart disease patient. As a consequence they then fulfill those criteria of that specific set of diseases. Even though we recognize each patient is unique to their own condition, we tend to lump them into a descriptive term, calling them a disease. That would suggest, in the mind of that person, that they are flawed, they are less capable, they have some kind of inherent weakness. It was the luck of the draw. Rather than that kind of a model, we might say that actually their genes are unique to their own specific situation, and they are actually selected for value in an environment that goes way back to the early legacy of that person’s genealogy. So what we consider a disease today is really, I believe, a story that can be reframed. And that story is that individuals—all of us, every one of us—has our own unique response to our environment, and the environment for one to maximize their function may be vastly different than the environment for another. The body is responding, as it should, to that specific environmental set of conditions based upon its own unique genetic background. We could say, “Hyperlipidemia is not just the genes for heart disease, it’s the genes that relate to an exposure of a certain environment that then induces—in that person’s genetic expression—the biosynthesis of cholesterol, or triglycerides, or lipoproteins.” Similarly, arthritis or systemic lupus erythematosus or rheumatoid arthritis is not just a consequence of flawed genes, it’s a consequence of a specific immunological response to the environment, internal and external, that gives rise to that particular set of autoantibodies that we then associate with that particular disease.  Cancer is a response to a proliferative cell type of signaling that occurs from that set of gene responding to that environmental message. You can’t change the genes, but you can change the environment to match an individual’s own unique set of characteristics. That takes away the burden of saying, “I’m flawed, I’m injured, I’m imperfect, I have a disease,” to saying, “Actually I need to find the environment to modulate my function so that I’m not displaying an alarm reaction, which we see in the physiology as a pre- or post-pathology process.” I think this is a very different concept and context of looking at dysfunction and how it interrelates with what we later call disease than saying a person is flawed, imperfect, and they have something wrong with them that makes them have heart disease or makes them have arthritis. Why do I believe this is even a worthwhile conversation to bring up? Because it has a much more optimistic plasticity associated with it. It is much more able to be modified by engaging the right kind of activity, rather than this deterministic model that says, “Well, you’re diseased. You have this problem. It’s probably because you have bad genes: your father had heart disease, your uncle had heart disease, and you should just expect to get it too.” I think we’re into a different kind of frame shift as it pertains to how we describe, and how we model, and ultimately how this translates into therapeutics, and prevention, personalized medicine, and functional improvement in the individual in 21st century medicine. That is the context from which is born this view of lifestyle medicine. We’re fortunate in living today, where the tools are available to start pulling together the root origin of cellular disturbances and how those metabolic disturbances translate into alarm responses that later become tissue pathologies that we call disease. Lifestyle and environment interface with genetic expression patterns and signal transduction so that they ultimately regulate what we see as our function over time–over the decades of living–and ultimately smooth our function and change our body shape and how we actually respond to the world, whether it is responding physiologically in an alarm state, which could be inflammation, it could be dyslipidemia, it could be hyperglycemia, it could be glycation, it could be oxidative stress. All these things are alarm responses of our genes to a specific environmental set of circumstances. Lifestyle medicine is recontextualizing itself to be married to the concepts of personalized medicine. As I mentioned, we’re very fortunate to have as our guest today, one of the experts in this area, one of the coauthors of a textbook on lifestyle medicine. He is an individual who I think brings a tremendous perspective related to the emergent application of the gene-environment connection in the clinic and ultimately into patient management. With that, let’s move to our Clinician/Researcher of the month, Dr. Garry Egger

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INTERVIEW TRANSCRIPT

Garry Egger, MPH, PhD Director, Centre for Health Promotion and Research, Sydney, Australia Professor, Lifestyle Medicine and Applied Health Promotion, Southern Cross University, Lismore, NSW Australia 14 Arthur Street Fairlight, NSW 2094 Australia What does the future look like? What are the landscape and topography areas that are shaping health care? And how can we really be more successful in managing this burden of chronic disease that has been a rising tide in the developed world for the last decade or so? Our Clinician/Researcher of the Month today has a very remarkable background and productivity record. His name is Garry Egger. Garry is currently a Professor of Lifestyle Medicine and Applied Health Promotion at Southern Cross University. It is an esteemed university I’m familiar with in Australia. He has spent most of his life as a consultant in epidemiology and health promotion throughout Asia and the South Pacific and Australia. Years ago–I was actually familiar with this—he innovated a concept called “GutBusters,” which was the world’s first men’s weight loss program. He is an advisor to the World Health Organization on chronic disease. He was instrumental in establishing the Australian Lifestyle Medical Association (similar to the American College of Lifestyle Medicine that I’m a member of here in the United States), and he is currently investigating the relationship between obesity, climate change, environment, and economic growth. He is the author of more than 30 books, including six texts, and more than 150 peer-reviewed articles. For me, this is a very interesting closing-of-a-circle. About six months ago I was searching for a good text on lifestyle medicine for some of teaching, and I happened onto this book called Lifestyle Medicine. The authors are none other than Andrew Bynes, Stephan Rossner, and our own Garry Egger. Closing this loop and now having the chance to talk with Dr. Egger, I recognize that there are so many areas where we share a similar theme and these fit nicely into the concepts we’ve discussed in Functional Medicine Update over the last couple of decades. One of Dr. Egger’s recent papers, co-authored with Dr. John Dixon from Stanford, really got my attention because it is titled “Should Obesity Be the Main Game? Or Do We Need an Environmental Makeover to Combat the Inflammatory and Chronic Disease Epidemics?”[3] It is a very provocative title, and a very interesting article that appeared in Obesity Reviews. Dr. Egger, welcome to Functional Medicine Update and thanks for being available today all the way down in Australia. How did you go down the path of being an expert in lifestyle medicine? What took you in this direction?” The Relationship Between Economic Growth and Chronic Disease GE: Thanks, Jeffrey, for that introduction. It’s a big introduction—I can’t wait to hear what I’ve got to say now after that introduction. I’ve been working in this area for 40 years. I come from a bio-behavioral background and an epidemiological background. I’ve always been interested in what is the cause of the causes, in Geoffrey Rose’s terms. When I look at the epidemiology of a particular problem, I like to go back and span out, if you like, and look at the big picture. Let’s talk about obesity and type 2 diabetes, for example, as the big chronic diseases of the era. You could say that the immediate and proximal causes are an individual’s behavior, particularly what they eat, how active they are, whether they get good sleep, whether they are highly stressed—all of these sorts of things. But these are really just the immediate causes. They are causes of those causes. And then there are causes of those causes of those causes. If you track these causes back, it becomes very interesting because it leads not just to the individual behavior and an individual response, but it’s the environment that drives that response. And when you take it back, the big driver of all of this is the modern environment in which we live, which is really economic growth. There is no doubt that growth and development in all countries has tremendous advantages up to a point, but beyond the point you have to get negative returns when you’ve got exponential growth in anything. None of the early economists would ever admit that this can go on forever, and now we’re starting to see the consequences of that, particularly in obesity, which is probably a warning sign that there are other things going on in the community that are not healthful. I don’t think obesity in itself, after many years of working in that area, is necessarily all that important. I think in some cases it is, but I think in many cases it’s a warning sign; it’s a canary in a coal mine, if you like, that there are other things going on in society that we need to look at. That’s basically where the whole lifestyle medicine approach comes in. JB: You said some things just in that introduction that I think are extraordinarily interesting and provocative. In the states, as I’m sure it is in Australia, we’re often told in the medical world that the cause of all these chronic diseases is obesity, and therefore just applying the first law of thermodynamics of calories in versus calories expended is really the solution to the problem: reduce the calories in and increase the calories expended and we’re going to solve the problem. But when I look at China, which has a rapidly rising prevalence of type 2 diabetes and heart disease, I find that the BMIs of the Chinese are actually not that large. They are not above 30. They are starting to have problems with BMIs that are in the mid-20s, that we would consider (in the states) to be still in the acceptable range. It suggests that there is something about the environmental relationship with those genotypes that spreads itself out to increase the risk of chronic disease related to these lifestyle changes that may make these individuals more of a canary in a coal mine (to use your analogy) than in the Western world with our sand pile genotypes. I think this obesity concept of “Is it the cause or the effect ?” (the question you are raising) is very, very important, because I think we’ve always assumed it’s the cause, but I think what I’m interpreting is that maybe you are suggesting it is the effect. Am I on the right track? Growth Beyond Maturity is Either Obesity or Cancer GE: Yes, you are. With the Chinese it is a slightly different suggestion because as you’re aware, Asians genetically are more prone to metabolic diseases at a lower proportion of, particularly, abdominal fat. We don’t know the reasons, but it’s probably an evolutionary thing that they are more prone to that. What we are seeing in China is virtually a microcosm of what’s happening in the rest of the world, but it’s happening so fast in China because of development. My belief is that it’s not so much the obesity that is leading to the diseases, it’s the things that lead to the obesity, which is the change in diet, and the change in activity, and other aspects of the industrial environment. We see in China, as we see in all other developing countries, a point at which you get a crossover between the infectious diseases and the chronic diseases, which is called the epidemiological transition. This occurs through natural development in developing countries. India is about to go through it as well. At that point, because the infectious diseases start to go down dramatically as a result of development and as a result of hygiene, in particular, and changes in lifestyle (not just the availability of antibiotics and medications and so on), you’re also getting a rise in chronic diseases as a result of lifestyle, and the chronic diseases start to take over from the infectious diseases. It seems like that is the sweet spot in development. Beyond that point we start to get diminishing returns on investment, as the economists would call it. And any good economist knows that when you invest money in any project, that project starts to yield enormous returns to start off with, but as you continue that investment you start to get diminishing returns on your investment. That’s exactly what’s happening with development throughout the world. This is very difficult for medical scientists to get their heads around because it involves an understanding of macroeconomics. This growth train that we’ve been on started after the Second World War. It was instigated, initially, 100 to 150 years ago, by the early economists. I It was really trains that put us on track for this modern growth phenomenon. One of your well-known physicists over there made the point that growth beyond maturity is either obesity or cancer. I think that sums it up quite brilliantly because I think we’ve got to that point where we’ve got growth beyond maturity. The Turkish prime minister made an inadvertent slip about democracy once when he said, “Democracy is a tram that you ride until you get to your destination, but then you get off.” I think if we paraphrase that and say that economic growth is a tram you ride until your destination and then you get off, it really sums up the modern medical conundrum: we’ve gotten to that destination, and we really have to change it if we want to continue to improve our health and well being. JB: I think that’s a very provocative comment—very interesting. Were you a friend to John Cameron, the physicist? Because I know he did a lot of work in cancer and that area. GE: No, no. I was referring to John Maynard Keynes. He was the great economist that started the revival after the Great Depression in the 1930s. The physicist that I referred to was Al Bartlett, who is from Colorado, who just made that statement. It came out in the Colorado daily press, I think it was. It has been quoted ever since that growth beyond maturity is either obesity or cancer.[4] I think it is a great statement. JB: Yes, it is. It’s uncontrolled growth, isn’t it? It’s unregulated growth. GE: Exactly. Uncensored growth, basically. One of the interesting things that we’ve been doing here—Boyd Swinburne, my co-author on a new book we’ve got out, and myself—has been looking at not just obesity in developing countries and developed countries, but looking at the differences between those developed countries. We’ve actually found (if you look at this just from a desktop epidemiology perspective) that what happens when a country that is quite poor starts to become richer is you start to get a healthy increase in obesity and you get a decrease in infectious diseases, but you start to get a rise in chronic diseases. Beyond a certain point you get a split and obesity starts to flatten out in most countries, but in some countries (countries we’ve called the hard capitalist countries, and that includes Australia, the United States, the United Kingdom, New Zealand, and Canada, in particular), obesity continues to increase and it is greater than other countries that we call soft capitalist countries, such as Sweden, Norway, Germany, France, and even Japan. We’re trying to now tease out what it is within those different types or different forms of governance, if you like, in countries that would lead to obesity as a signal that chronic diseases are getting worse in those countries. JB: That’s very interesting. In the article that you authored with John Dixon (the one I mentioned earlier, “Should Obesity Be the Main Game?”), you have a proposed model (this is one of the figures in the paper) on the effects of lifestyle on metabolic outcome. And I think that model is a testable model. It has to do with lifestyle influencing various metabolic functional statuses, such as oxidative stress, inflammatory response, and insulin resistance. It’s like a dog chasing its tail; once it starts it becomes self-replicating. Could you describe that model you have developed? Explaining “Meta-Inflammation” GE: Yes. Inflammation—or meta-inflammation, rather than just inflammation—is a relatively newly discovered phenomenon. It’s a low-grade systemic form of inflammation that seems to run throughout the body, particularly through the epithelial tissue, but even through other tissue and through glial tissue, which is even more interesting for reasons which I’ll point out in a moment. Our theory is testable and I’ll talk about some testing that we’ve done on it. Human beings have evolved in an environment in which they have had hundreds of thousands of years of consistency. The human body—the immune system—develops a sort of friendship with that consistency, such that there is no adverse reaction. In other words, if we are eating fruits and vegetables as we have been doing for the last hundred thousand years, the immune system perceives this is something that is quite natural. It’s like a bacterial virus that we’ve evolved over hundreds of thousands of years. And we have several of these. Of course, we call them our “little friends”; they are very friendly bacteria and microorganisms that we’ve grown with, and in fact we’ve come to depend on them. The sudden change that occurred around the time of the industrial revolution—let’s say mid-19th century—has meant that our lifestyle has changed dramatically so that we’re eating processed foods that haven’t evolved with us over those hundreds of thousands of years. We’ve become much, much less active as a result of technology. The stress levels have changed dramatically. Our sleep levels have changed because we’ve got lights and electronics and so on. As a result, the body has reacted—the immune system has reacted—in this low grade, systemic, meta-inflammation response. It has been called meta-inflammation because it is inflammation of the metabolic system. The theory is that the immune system is reacting to our lifestyle. Not to microorganisms as it has done over the past and with which we are very familiar (we’ve known this for 2000 years). The response is to inflammation. Now we are saying that it is reacting—it’s responding—to our lifestyle. Nobody wants to give up the modern lifestyle, of course, because this is the spectral progression and we’ve gotten enormous advantage out of the modern industrial way of life, but there are obviously disadvantages and the immune system just hasn’t had time to adjust to these. A Pilot Trial on Immune System Reaction to Diet We put this to the test in a study that has just been published in the British Journal of Nutrition, where we actually got people here to eat—and this is a random crossover trial—a lean form of meat, which was kangaroo.[5] Aboriginal people, here, of course, have been eating kangaroo for perhaps hundreds of thousands of years, and hence you would expect the body to have adjusted to that and to not respond in any immune way to the type of meat that is kangaroo meat. We’re not saying that all humans have evolved with kangaroo, but they’ve evolved with that type of low saturated fat, high mono unsaturated fat meat. We compared that with a meal of what’s called Wagyu beef. I’m sure in the US you are familiar with that, as we are here. It has only been around for about 30 years. It came out of Japan. It is a high-grade form of beef. It is a very fatty, saturated fat form of beef, and humans haven’t evolved with a high level of saturated fat. What we found is that after eating the kangaroo, there is no reaction by the immune system. It just carries on as if this is a normal type of thing that happens to human beings. After the Wagyu beef, on the other hand, we get this huge rise in what are called inflammatory markers—things like CRP, interleukin-6, and TNFalpha. These are measures of the immune reaction, which is the early stages of inflammation, which we then know leads on to (or possibly even comes from) oxidative stress, which then leads on in a course or chain to insulin resistance and other forms of chronic disease. It supports the hypothesis. There’s a lot more work to be done, obviously. This whole area of meta-inflammation I find is both useful in itself and it’s useful as a metaphor for what else is going on in the environment. If we talk about inflammation of the environment, you can see that chronic disruption (chronic change, as it is often called, but I think it is probably preferable to talk about chronic disruption) is a bit similar to insulin resistance in the body, in the climate. It’s virtually carbon resistance in the atmosphere, which leads to a lack of sequestration of this carbon, which leads to the potential problems through carbon buildup. That’s a big step to take and it’s a huge step for most medical researchers to take because it is stepping right outside of their comfort zone. I think all of us are pretty uncomfortable in doing it, but we think that it’s got to be done because we think that health is such an important issue it has to be considered in the broader environment. JB: I very much like the model you’ve proposed in your review. I think you have a table in there that discusses proinflammatory and anti-inflammatory loads that would contribute to meta-inflammation, including things like nutrition, obesity, inactivity, smoking, and exposure to oxidant stress in the atmosphere and so forth. I think we’re subjected to a total load of all these environmental factors that are picked up by receptor mechanisms at our cellular level and transmitted into genes and into an alarm reaction that we call meta-inflammation. Metabolic distortion is a very, very interesting new model of the etiology of chronic disease. GE: Yes, and I’m fascinated to talk to you about this because you’re obviously dealing very intensively with the end stages—the cellular processes—that are involved in this. That’s certainly not my expertise, but I think the combination of what you’re doing there and what we’re proposing (and I say proposing because it really is in a hypothesis stage) is the starting process of all this, the change in the environment that is brought about by things like the agrarian revolution and the industrial revolution. It’s a great combination to have, because you can follow the slowest route right from the environment through to the cellular level. I think that’s the issue that’s got to be presented to medical scientists to convince them to look at the bigger picture, rather than to just deal with the disease at its end point. Lifestyle and Gastric Bypass Surgery JB: I know John Dixon, your co-author on this paper, is an expert in the bariatric surgery area. We’ve come to recognize that when you take people that are morbidly obese and you put them through Roux-en-Y gastric resection surgery, their metabolic distortion (like their diabetes and their cardiac arrhythmias and their dyslipidemias) correct without major weight loss. How does this all fit? GE: It fits beautifully, actually, and it was a bit of a revelation, I think, to John, who has been dealing with—at that end—looking at the reasons for why this happens. When I presented this idea to him we discussed it, and together with Boyd Swinburne we had long and arduous conversations about this, I can assure you. There is no sort of set pattern in what we are doing because we think we are stepping outside the mold, if you like. In many instances—John being much more of a clinician than I am—he feels a little bit more uncomfortable doing that than I do. What you say is perfectly true. We don’t know why the gastric banding in the Roux-en-Y surgery and so on works. We know that there is some connection there with hormonal influences. We do know that what it does is change the causes of the obesity so that people don’t get hungry and they don’t eat the types of foods that they were eating before. Now the big question is: If you didn’t have the surgery but you just were able to change the lifestyles that lead to the obesity, would that have the same effect? It’s really difficult to test that. It would seem that is the case. The work that has been done on that suggests that it is the case: that it’s not so much the obesity, it’s the lifestyle that leads to the obesity which is causing the metabolic problems. You change the lifestyle and you change the metabolic problems. JB: Tell us a little bit about this book that you have just recently co-authored with Boyd Swinburne, Planet Obesity.[6] It sounds like it takes this theme to the next level. GE: Yes, and we’re hoping to get this published in the United States shortly, because obviously that’s the big market that would create a bigger interest in this environmental approach, I think. The book is basically about the influence—the distal causes—of obesity as being economic growth, and looking—as we have talked about—at meta-inflammation, and meta-inflammation as an underlying factor associated with obesity. But the fact that you can change meta-inflammation by changing lifestyle and by changing environment without actually changing obesity—that obesity itself is probably a warning sign to the rest of the world that we’re going down the wrong path. We’ve gone too far along that path, and now we have to start reconsidering what the alternative is. There’s no economist in the world—there’s nobody in the world, surely—who would say that anything can continue to increase exponentially as economic growth has done over the last 100 years. Even with the early economists, none of them suggested that was sustainable over the long-term, and nobody would be foolish enough to suggest that. But economists aren’t thinking about (at this stage) what the alternative is because we’re still in a gray phase, which is rewarding, in many respects, for most people. Our standard of living has improved up until this point. It is starting to decrease in the western countries, but nobody wants to talk about that. They all want to talk about the continued need to grow. It’s not until we get the economists on board, and we are starting to do that. There are some very good and free-thinking and outward-thinking economists who are starting to say, “Well, maybe we’ve got to rethink this whole growth system.” We’ve got medical scientists now who are starting to think, “Well, maybe we’ve got to bring in the economists, we’ve got to look at the economic side of things as well, in terms of health.” And it is once we start to get those two groups of people together that we’ll start to see a major change in thinking. Hopefully it can happen before anything dramatic occurs in growth, such as what occurred in the 2008 financial crisis. If you just look at that for a moment, it didn’t actually go long enough for us to be able to tell accurately whether there was a change in obesity during that period. Does an Economic Recession Increase or Decrease Obesity Rates? Some analysts actually suggest that if we have difficulties in the economy, if we do get another recession like that, we’ll get increases in obesity. I’m of the opposite ilk. I think it’s exactly the opposite, as we’ve seen in Cuba, for example. When the Russians left Cuba in 1989 and left them without fuel, the Cubans had to adjust, and during the period from 1989 to 2004 there was some very good epidemiological work done, and they actually decreased their obesity level by about 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. Their heart disease rates went down by about 18{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. Everything went down. Diabetes went down. Everything went down except cancer, and that’s probably because there wasn’t enough time for that to decrease. Another example is Nauru, which is a little island in the Equator where I’ve worked with the World Health Organization. They have the highest rate of type 2 diabetes in the world and also the highest rate of obesity (about 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the population are obese). But that is based on the fact that they are a very wealthy little pacific island country with a genetic predisposition to get obese very quickly. Once you add those two things—a genetic predisposition plus the wealth that they got from superphosphates that they used to send down to Australia, particularly to put on farms—then the obesity rate increased dramatically and their diabetes rate (they had 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} diabetes in the country). They ran out of superphosphate. There’s only a certain amount of superphosphate; it’s a finite resource, as is petroleum. Once they ran out, they went broke. And when they went broke, their health improved (it didn’t decrease, it improved). Their diabetes rate has dropped; we think it’s about 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} now, doing those measurements with WHO. The obesity rate is dropping dramatically. All of the individual efforts, if you like, to get people to eat less and to move more—to change obesity at the individual level—have been superseded by this national environmental accounts that dropped obesity and the chronic diseases back dramatically as a result of changing the big picture, if you like. JB: It’s really interesting for you to be talking about this because it brings back a memory that I had kind of put in dormancy in my own life. In 1973 I was a professor at the university and I was teaching a course on environmental science, and I had Dennis and Donella Meadows come speak to us, the authors of Limits to Growth.[7] They did some of the early computer modeling about growth models. As you probably recall, they were not received with a lot of enthusiasm by much of the world economic community and they were considered to be kind of antithetical to good thinking. GE: Exactly. JB: I think if you go back and review their book and their work closely you’ll find it mirrors very nicely. This is 38 years ago, but it is very comparable to what you are talking about today—the results or the outcome of not having looked at some of the things they said seriously. GE: And it has been revised, of course, that book. There is a new edition that came out in 2004.[8] Interestingly one of our scientists out here at the CSIRO actually has checked the predictions from the 1974 edition and found that we are very much on track for the business-as-usual scenario they predicted. The business-as-usual scenario is quite a dangerous one, because if you continue with business as usual, they predicted that between 2010 and 2020 there will be major disruptions to the way we live because of big oil and a whole range of other factors. Overview of Lifestyle Medicine Textboook JB: That’s very, very fascinating. Let’s just touch upon this book that really got me connected to you through the literature, and that’s Lifestyle Medicine. You tell me there’s a new edition that just came out in December of 2010. I’ve got to pick that up because I’m still working with the first edition. I find the chapters to be very interesting. Not only did you introduce lifestyle medicine and its epidemiology and relationship to chronic disease, but you went on to talk about prescription for health with physical activity, about nutrition, about fitness, fatness, and body composition (the difference between visceral adipose tissue—so-called being VAT versus being fat), how stress plays a role, depression as an outcome, understanding addictions, sleep. It’s a very, very nice overview of the complex nature of how people’s experiences in their environment interact with their genetic pluripotential to give rise to an outcome that we call epidemiology. What kind of feedback have you gotten on the book? GE: We got great feedback from the US, surprisingly. The new version is actually 2011; it’s only just come out. There’s an American version. We’ve had to change a few of our expressions, as your listeners will understand from listening to me. There are probably things that I’ve said that are very Australian and they don’t quite understand, so we’ve changed some of the expressions. The feedback so far has been extremely good. We’ve got very good relationships with the American Lifestyle Medicine Association. We have run two Australian Lifestyle Medicine Association conferences out here in the last two years. We’ve got one hopefully in November again in Sydney this year, if there is anybody interested in coming down. Don’t forget to pay your carbon offsets if you do, of course (if you fly down). We’ve added extra chapters now, and we’ve done one on the meta-inflammation which explains that it is the underlying basis of just about all chronic diseases, if not all chronic diseases (in my view anyway). And we’ve added another chapter on chronic pain because we think chronic pain, like other lifestyle causes of disease, is actually a disease in itself and can be considered in terms of lifestyle. I mentioned before the glial hypothesis. We know that glia has a connection to the neural system, and we know that glia is also associated with chronic pain. We’re beginning to put together a picture of lifestyle and lifestyle influences on glia in chronic pain. We’re about to do some research—we’ve just applied for money to do some research—looking at changes in lifestyle to see if this affects chronic pain and inflammatory markers as much (or more than) just the linear approach to chronic pain, which is “You’ve got pain therefore take a medication.” What we are talking about here in lifestyle medicine is really systems theory approach. It is getting away from the linear notion of, “Yes, you’ve got a disease. Here’s the treatment.” You’ve got to go back and look at the systems and what leads to what, and then what leads on to disease. So you go back and look at the cause of the causes, as I pointed out before. JB: Yes, as I said in our introduction, this marries itself beautifully with the whole construct of functional medicine, as we defined it over 20 years ago. The Institute for Functional Medicine is now certifying doctors in this whole area. It sounds like there is a very nice tie-together in systems biology and medicine between the functional medicine activity and the lifestyle medicine activity. Teaching Lifestyle Medicine in Australia Let me just ask one final question, and I thank you for all the time you have given us on this discussion, by the way. What’s your experience in Australia, and maybe in your other contacts with the American Lifestyle Medicine College, in changing doctors’ thoughts about integrating this within their practices and seeing the value of it as it relates to beating back the rising tide of chronic disease? Are we getting stickiness, in your perspective? GE: I have to be honest with you, Jeffrey, that is the big gap at the moment. In a lot of the work that I am doing here I actually teach GPs in this area. We run lifestyle medicine courses around the country. And, in fact, we do not only lifestyle medicine courses in a classroom (I run a course out of Southern Cross University), but we take doctors on adventures where we teach them lifestyle medicine on the run, so to speak. We have a saying, and I hope I can use it on your program, that teaching lifestyle medicine in the classroom is a bit like teaching sex in a nunnery. So we take them out to take them pedaling. We have a trip organized to the Swedish archipelago where Stephan Rossner is our connection in mid-July this year. We go bush walking out in the central Australian desert. We actually sit around the campfire and do a course in lifestyle medicine at night. We find the doctors that get the experiential experience like that actually are able to put it into practice with their patients. Doctors have come into a classroom (and there is a lot of them who do), and for many of them there is a period of awareness where they get it. Where they actually get it and they realize that because 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of their patients are there because of chronic diseases, they have to change their whole paradigm in dealing with these patients. It’s a difficult process, though, because that involves understanding motivation. This is something that medical practitioners haven’t had wide experience in: to understand and apply motivation to the patient, so that the patient becomes the self-manager. Self-management is one of the other chapters in our new book. You have to be able to understand how to get the patient involved in their own self-management. You cannot treat chronic disease with a drug. Surely you can add a drug as an adjunct, but you cannot treat it solely with a drug. It has to be self-management of the patient over the long term, working with the doctor in combination. So it’s got to be a partnership arrangement, not only with the doctor but with other allied health professionals as well. Readiness to Change: Doctors and Patients JB: I think you’ve really set a beautiful and important theme there that has been kind of a theme through our last 29 years of doing this, and that is this readiness to change: where is the patient in their readiness to change? And where is the doctor in their readiness to change model? GE: Exactly, yes. JB: And then Albert Bandura, from Stanford, and his self-efficacy model, which is really part of what you’re talking about. And then lastly Halsted Holman, who is also at Stanford Medical School (a Professor Emeritus there) who has talked about the need for a new model for chronic disease management because nearly 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of expenditures go for treatment of chronic disease and yet we are still teaching, almost exclusively, an acute disease model to medical students. GE: Exactly. JB: It sounds like you’ve got all these things wrapped beautifully into your work. I want to really compliment you. This is an advocacy that the time has come for. I think you’re doing a great job in getting this information out. I love your article, and I think this textbook is something that should be in everybody’s hands. Thank you for your tireless efforts. GE: Thank you very much for listening. It’s a fascinating area, but I must admit we’re on the cusp, here. There’s not a lot of understanding so it’s great to have somebody like yourself and your program to allow us to expand on this much more. Thanks very much. JB: Thank you. Keep up the great work and we’ll be in touch.

Anniversaries: FMU Marks 30 Years While IFM Celebrates 20 Here we are at the May 2011 edition of Functional Medicine Update. This is the 30thanniversary of this audio/digital information product. Over 30 years I’ve interviewed luminaries and thought leaders that have created the context of change, the evolution of what I used to say was 21st century medicine. What an epic moment it is to have Dr. Mark Hyman as our guest for the 30th anniversary edition of Functional Medicine Update, which happens to be coincident with the 20th anniversary of the foundation of the Institute for Functional Medicine, for which Mark is now chairman. Synchronicity, how the world turns, the evolution of ideas, and people, and culture, and organizational structure—how does this all work itself out in magic ways? Mark, what a pleasure and privilege to have you for the 30th anniversary of Functional Medicine Update as our clinician/opinion leader of the month, of the year, and of the decade. Thanks for being with us.

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THE INTERVIEW Clinician/Researcher of the Month Mark Hyman, MD Chairman, IFM Board of Directors Founder, The UltraWellness Center 45 Walker Street Lenox, MA  01240 www.functionalmedicine.org www.drhyman.com www.ultrawellnesscenter.com   MH:     Thanks for having me, Jeff.   JB:      I think your history within the movement of functional medicine really is a very great and significant. So many docs have made transitions in their professional lives over this last 20 or 30 years. Of course you’ve been extraordinarily successful as a clinician, as a thought leader, as a writer, as an author, and as a mover of change at so many levels. You’ve really become the paragon of what the movement is all about.   Give us a little history. Where did you start? You were a Chinese studies major at Cornell. Maybe you even want to go back before then to tell us how your lineage prepared you for this extraordinary transition.   The Path to Leadership MH:     I don’t really think I was interested at all in medicine when I was a kid. I wanted to be a writer. I studied philosophy and religions. Actually, when I went to Cornell I studied Buddhism. I realized that it was a way of looking at the world in a systems model, and there was a way of understanding how the mind worked, and it was based on direct observation. It led me to sort of look at the process of the healing of the mind from a Buddhist perspective. That gave me really a sense of the possibility of a kind of medicine that I might want to practice someday. In the healing tradition in Buddhism, you have to be a monk before you can be a doctor. It was all intertwined. Spirituality, and religion, and discussion of the connections between things wer really integral to my thinking and my shaping as a young man. So I sort of naturally fell into looking at the healing systems of the world. In fact, I did a course in Cornell in healing systems of the world. I was able to study all of the planetary healing systems, and at the same time I was living with a PhD student in nutrition at Cornell who was studying the gut and bacteria and fiber. He introduced me to Roger Williams, and I actually read Nutrition Against Disease in college and began to study with Colin Campbell at Cornell.[1] These early influences had a huge impact on me.   I did end up studying Chinese and Chinese religions and Buddhism, but when I graduated I realized that I didn’t really want to go to a fascist dictatorship and study Chinese medicine because I didn’t want to spend my 20s in an environment of fascism, so I chickened out and went to medical school. I figured I would try it out and if I didn’t like it I would do something else. And I liked it. I really sort of dove into it and got a sense of the mystery of biology and magic of it. But through the course of the training–I started out from an integrative and a nutrition perspective (I was a yoga teacher before I was a doctor–I sort of got brainwashed. I remember it almost like getting into a cult.   JB:      Let’s talk about that brainwashing because I think that’s a seminal, interesting characteristic of people who ultimately decide to break from the norm and take the road less traveled in the functional/integrative medical space versus those that feel comfortable just standing within the body politic of traditional medicine. I want to go back a step farther because I want to explore what it is that makes some people receptive to this transformation—I would say even courageous against forces of change.   What was the culture like in your home? I’ve met your sister; she’s a very, very free-thinking, highly competent person. There must have been something in your home as you grew up that maybe sponsored or fostered thinking from the norm.   MH:     My family was very unusual. My father quit high school when he was 13 and he lived on his own and then joined the Navy at 17. When he joined the Navy he lied about his age and went down to Antarctica with Admiral Byrd. He came back and put himself through high school, and then through NYU under the GI Bill, and Columbia School of Journalism. He studied Chinese and was about to go to China for the revolution there. Then the Bamboo Curtain came down and he couldn’t go, but he and my mother went to Europe and lived in post-War Europe for 11 years, where I was born. So they had a very unusual life. He was traveling all over and my mother was a teacher (principal of the American School of Barcelona). I grew up in a very unusual family. We were focused on intellectual development, and reading, and the mind, and exploration, and even being an iconoclast (very disruptive and unusual). I think it was sort of bred into me to not be like everyone else and to think differently, and it was sort of just part of my culture growing up. I was encouraged to do anything, and to be anything, and to go everywhere. My mother really fostered that, and I think that was a huge factor in my development.   JB:      So now we take that, which is really a very strong epigenetic imprinting on what was probably already genetic propensity, and now we go to medical school, which is very codified, very structured, and very linear. How did your nervous system respond to that kind of educational model?   MH:     I loved it because I came from an analytic model where I was taught to think and question and inquire and analyze. Most of my colleagues in medical school were simply taught to memorize and were from science backgrounds, not from a liberal arts/philosophy background. When they were inundated with reams of information they couldn’t discern what was important and what was not. They couldn’t see the pattern that connected things. They couldn’t see the story within the detail. And that was easy for me, so actually medical school was very easy for me. I graduated near the top of my class. I always had fun and enjoyed myself. I did yoga in the back of the classrooms. I was kind of a little bit of an outlier, but I had an extraordinary time in medical school and found it intellectually stimulating. I was always questioning why, why, why? And there was never an answer. I was perplexed at that, but I kind of went along with it. I said, “Look, I’m just going to try it on. I’m not going to fight it. I’m just going to swallow it and then I can reorganize it later.” I had that instinct.   Then I went to a very unusual family practice residency in Santa Rosa, where I was the token white male; everybody was either gay, or had skin of a different color, or some other kind of unusual characteristic like they were the teamsters union bargaining guy or something. That was an interesting environment as well, but I really learned how to be a family doctor. In a sense, family doctors are route systems, and that was part of that training as well. So I learned to be a systems thinker in family medicine and went to Idaho and practiced in a small town there and worked with lumberjacks. I got a real second residency there.   Family Practice: The Magic is in the Bigger Picture JB:      Before we go there let me just stop you because I think you’re again hitting on a very interesting part. What I’m trying to develop through your experiences is, is there a commonality that differentiates the psychographics of docs who decide to make this break from what has been the tradition of the guild into this new emergent 21st century functionally based medicine and who then are very successful at it versus those that just stay the course? I’m trying to explore the psychographic analysis. During your residency and this fellowship in Santa Rosa when you were starting to look at how this arrangement fit your own need and fully expressed your capabilities, was there ever a moment when you said “I think family practice is too general? I need to really focus. I need to become a specialist in a certain area.” There is a motivation to really be the best of something in one discipline, or did you always have this sense of the magic is in the bigger picture?   MH:     I never wanted to be a specialist. It just never crossed my mind because I couldn’t understand how you could separate out everything. We are one organism, one body, one soul, one being. That was something I just knew intuitively, and I didn’t understand how you could separate those things out. I knew there was a need for experts, but from my own personal sense of how I wanted to practice it was completely in synergy with who I was and what I felt and how I thought about the world.   JB:      Let’s take the next step. Moving into the reality of dealing with patient management in that kind of a family setting, and the diverse number of things that happen in the daily life of a family doc, did you find it was too prescriptive? Did you find that it wasn’t exactly what you thought it was going to be (was the magic of dealing with the individual being stolen by the repetitive patterns of the system)? Or did you feel like, “This is the nurturing ground that I really have always thought it to be?”   MH:     I loved it. I was actually talking about this the other day. When I was in medical school I was in Budapest at this meeting of International Physicians for the Prevention of Nuclear War. There was a woman standing next to me who was a pediatrician, and I said, “Don’t you just get tired of seeing runny noses and ear infections and sore throats?” She said, “The ear infection may be the same, but the person is different.” And that’s the magic. For me it was always about the relationship and never so much about the diagnosis. The tools that I got in conventional medicine were great tools. I was able to really do a lot of good as a family doctor in a small town dealing with acute issues, delivering babies, running the ER, dealing with trauma, doing small procedures, and just dealing with various problems. One guy had tendonitis of his elbow and was miserable and I gave him a little shot and he said, “I’m going to be dancing down the street praising your name.” There was a lot of joy and connection in that, and I had no problem with it.   But I did realize that there was a sort of limit to the success of the interventions that I was doing. It particularly became evident to me once I started working more full time in the ER. I realized that everybody who came in usually got there because of something that happened in their life that could have been different. Other than it being a car accident or some trauma that they had no control over, there was something that lead them to that moment, whether it was an asthma attack, or a heart attack, or a stroke, or stomach pains. Whatever it was, if you looked back in the continuum of the illness there was some moment in time where they could have taken a different course. Not to blame them so much, but to just understand that these conditions didn’t just show up just sort of static like this.   That led me to reawaken my desire to go back to my roots, which was to really go back into integrative medicine–I didn’t know about functional medicine at the time—and to look at alternative approaches and mind-body approaches, so I began to sort of branch out. Once I made that decision, that’s when I got the job offer at Canyon Ranch without any application. I just literally ran into someone in the store buying Andy Weil’s book on spontaneous healing and they said, “Why don’t you come over for a tour.” I said, “Okay.” And I talked to the director of health and healing as we were having the tour, and then a few days later she called me and said, “Hey, I want you to meet Mel and Jerry.” And I thought, “Who are those guys? They sound like cartoon characters (Tom and Jerry).” They are the owners. I said, “Why do they want to talk to me?” She said, “Well, we’re thinking of expanding our medical department.” I met them, and it was going to be a ten minute meeting that was a two hour meeting and I got a job offer the next day. And that was sort of the beginning of a living laboratory for exploring functional medicine.   JB:      That’s great. I want to take a little sidebar with you. You mentioned this period in which you were in Budapest. The name Helen Caldicott comes up, who I think you probably knew very well. Now  I am going forward to 2010. You and I were in a cab, and we were with a very fashionable, stylish, intelligent, forthright family doc (a woman) whose last name happens to be Caldicott. I’m slow on the uptake. I’m riding in the cab with the two of you, and I’m thinking to myself, “Wow, this woman reminds me a lot of the Helen Caldicott I knew 20 years (plus) ago.” Tell us a little about that experience, because it’s interesting how cycles work within cycles, wheels work within wheels. I think it’s an experience that shows how we set ourselves down and things come back to revisit us.   MH:     Yes, there is no—I think—coincidence. Someone said to me once, “Coincidence is God’s way of staying anonymous.” In college I was very much an advocate against nuclear war and nuclear power plants, and did a lot of activism around that. When I got to medical school I joined the Physicians for Social Responsibility and I heard Linus Pauling speak. It really moved me and I became much more active in that. I went to Budapest to this conference where we heard Helen Caldicott speak, and Bernard Lown, and Evgeny Chazoff, who was Breshnev’s doctor. That was the year that organization won the Nobel Peace Prize.   Penny Caldicott is Helen’s daughter and she joined a group of medical students who were from about 20 countries to go to the Soviet Union at the time to do a citizens’ diplomacy mission to try to break down some of the barriers between the nations. We figured if we could just connect people to people that there would be a shift in the movement. We spent weeks traveling around the Soviet Union and bonded and got very close. I lost touch with Penny for many, many years, and she showed up at this conference in New York a few weeks ago and said, “Mark!” And I said, “Wow!” And it turns out she has been doing functional medicine in Australia for a long time and has a clinic of a dozen practitioners and is one of the pioneers of functional medicine in Australia, which was just such a funny sort of circle of history that tied us together that was really amazing.   JB:      It really was. For me to have known her mother and not to have even known about Penny at all, and then to be sitting in the cab and looking at her and saying, “Boy, she reminds me of Helen Caldicott.” It was just one of those really magic moments. We lay stuff down and then we come pick it up. Those things you lay down can either be very positive and reinforcing, or you can lay down stuff and come back later and you wish you wouldn’t have re-picked it up, right? How do you set the tracks of continuity that lead you into joy, bliss, and fulfillment? That’s kind of the path that we’re all trying to be on. How do we make those choices along this road of life that has many off-ramps and on-ramps and try to keep some sense of principle around where we’re heading? Your life has a very strong principle-centered component to it. You can see these divergent things clustering around a pattern, right? I think that’s a characteristic that defines some of the unique aspects of the practitioners in functional medicine, because they’ve had to do something a little different probably to get there.   Now let’s go back to Canyon Ranch and pick up the story. You passed the Mel Zuckerman test and you’re now hired. Obviously they probably never had any idea who they really hired and who Mark Hyman really was. They probably knew he was a very bright, capable, affable medical doctor but they probably didn’t understand the innovation that you might bring to the facility, so tell us what happened.   MH:     Nor did I, really!   JB:      Well, you met Kathie Swift, I would presume, and other people at Canyon Ranch. Tell us how it goes from there.   Amid Exciting Life Changes, A Sudden Illness Occurs MH:     What happened was an interesting collusion of events. I got the job in April, and in September I got really sick. I went from riding my bike 100 miles a day (you know, the Boston to New York AIDS ride), and from being extraordinarily fit and healthy to barely being able to function. Here I had this new job, I had just gone through a divorce, I had two little kids that I was taking care of, and all of a sudden I found my body breaking down. I knew I was under stress, but I knew there was something else going on. I went to doctor after doctor after doctor. I went to the neurologist in New York City, I went to the rheumatologist at Harvard, I went to a gastroenterologist for symptoms. I had autoimmunity bodies. I had low white count. I had elevated liver function. I had high CPK. I had digestive problems. I had diarrhea for years. I had severe muscle aches, brain fog, and insomnia. I really couldn’t function. I literally would just survive each day, and it was a real struggle. I was trying to sort this out. I thought it would go away, but after a few months it didn’t go away and it just got worse and worse and worse.   Functional Medicine “Just Makes Sense” Around that time, Kathie Swift, who was the nutrition director at Canyon Ranch at the time, dragged me to one of your lectures. I heard you speak (it was the improving gene expression and aging seminar you did). I listened to you sort of in rapture and realized that what you were saying just made sense. I asked a friend, “How do you think about functional medicine?” She said, “Well, it’s just medicine that makes sense. Functional medicine is medicine that makes sense.” And it’s true. It’s like what TH Huxley said when he heard the theory of evolution from Darwin. He said: “How stupid not to have thought of that.” That’s sort of the same epiphany I had: “This just makes sense.” I said to myself: “Either this guy’s crazy (meaning you), or you’re a genius and this all is true. I owe it to myself and to my patients to figure this out and to ask the question.”   I began to explore and experiment with it on myself and see changes, but it was a tough road because I didn’t really have a map. Functional medicine—even in those days—was still in formulation. I thought it was an established field, but it was just really in formulation. This was just a few years after the establishment of the Institute for Functional Medicine. We hadn’t even had the AFMCP course yet. It was really early on.   I had all of these patients who were extraordinarily wealthy. Doing $5000 worth of tests, for them, was like buying a Coke or a Starbucks for most of us. And they were interested in being explorers with me. I said, “Look, I don’t really know what’s going on here. I don’t know this model very well. It seems like it might have some merit, and certainly you’re not getting better doing what you are doing with conventional care. Let’s try it on together and see what happens.” So I started to try it on them. I tried it on myself. I began this sort iterative process of experimenting with myself, experimenting with my patients, gathering data, and then people started getting better. I was like, “Oh. This works.” I remember being surprised. I would actually be doing follow-ups with people and six weeks later they’d say, “I’m better. This is better.” And I’m like, “What? You’re better? You did that—you changed your diet—and you’re better? You took these supplements and you’re better?”   At first I didn’t really believe it. It just was too extraordinary (the changes that happened). One woman who was sick since she was five years old with chronic sinus infections, she had inflammatory bowel disease, and IBS, and chronic fatigue. She was a banker, but had to go on disability. She was 36 years old and had endometriosis and infertility. She couldn’t eat anything, and she had swollen fingers. She called me after a couple of months. I had put her on fish oil and an elimination diet—just basic stuff that I had learned. She said, “I’m feeling so great, but there is one thing with my fingers. There are all these bony things on my fingers.” And I said, “Well maybe you have just had edema in your fingers your whole life and you haven’t actually seen your fingers.” All of her symptoms went away, and then six months later she got pregnant and had a baby. It just was extraordinary to see that. I realized, “Holy mackerel. There’s something here.”   I purchased every single CD—well they didn’t have CDs back then, they were just tapes—every tape done by you. FMU wasn’t called that at the time. By Sidney Baker, by Leo Galland, whoever. I would beg them to let me sit at their feet, and I would go down to Sid’s office and I sit with him, and Leo’s office and sit with him. I would find all the other experts and I would call them up and I would talk for hours on the phone with labs, and with different people who were experts in the field, and I was like a sponge. Thank God for rewind because I could rewind Jeff until I learned how to speak Bland-ish. I really had trouble, but finally understood what mitochondria were, and Th1 and Th2, and oxidative phosphorylation, and all these things I really had sort of forgotten about. It was like learning Chinese: you work hard, you work hard, you work hard, you study, and then all of a sudden it all connects up: “This is the story of how God made us. This is the story of the mystery of biology. This is the story of how everything connects.”     Then I began to really apply this and became—over 10 years of doing this and having literally millions of data points from clinical history, from examination, and from laboratory data over time, prospectively, with my patients—I began to see this was real. And I began to see that it was like a prism. If you looked at a person’s biology through this prism, you would see the same thing manifested all the way around. So I would do different labs from different companies, but they would be reflecting different aspects of what’s going on. I would see patterns. For example, in heavy metal patients you would see oxidative stress, you would see mitochondrial dysfunction, you’d see depletion of glutathione, you’d see certain SNPs–clusters of phenomena that I knew nobody else was seeing and noticing.   I began to observe things in the clinic that were just bizarre. I treated someone for IBS with Flagyl because she had elevated clostridia overgrowth, and her depression went away. I was like, “What happened there?” I began to really see the matrix of human biology, and I realized that if my calling was to be a healer, that this is the future. This is the future, and it was incumbent upon me to learn as much as I could about it, and really to be an advocate and an activist for this new medicine. Once I realized this was true and real and it was reproducible over, and over, over again—and, yes, it wasn’t done in large clinical trials, and yes it was just my practice—but it was also other doctors who trained at Canyon Ranch and it was also other people who were getting these results.   The patients were coming, and the practice grew, and we hired eight doctors. The financial people came and said, “We don’t know what you’re doing, but just keep doing it.” People would get better. I realized that it was incumbent upon me to do something. And then I realized that if conventional medicine isn’t providing these solutions, and there’s a model of care that actually can relieve suffering and we’re not doing it, it’s criminal and it made me angry. It made me really angry. That’s what has really been driving me. It sounds corny, but it is the passion for the relief of suffering of others. It’s like if you see a solution here and a problem here and they don’t connect, it makes me nuts, which is why I have a hard time saying no, because I feel so passionate that we just have to connect the dots and let people see how extraordinary this model is to provide a solution for chronic disease. It doesn’t fix everybody all the time for everything. And, yes, there are complex patients that we’re still trying to understand this model for and how it applies, but it’s not because the model isn’t right, it’s because we haven’t figured it out yet. I just feel every day I wake up so passionate and work so hard because I see what’s going on out there and it just kills me, because I know how sick I was, and I know how good I feel now, and I know that I never would have gotten there, and I know this is true for many people in the field. It’s a shame that most of the doctors who are in this either because they were sick or someone in their family was sick and that’s what motivated them to look for something different.   JB:      Yes, I think you hit upon very, very important point. By the way, thank you for sharing. That’s an incredible rich and deep story. We all live by stories, really. We think we live by all these facts, but the facts are there to rationalize our feelings, right? What you gave us were some very powerful feelings about the reason for living—how we travel on this journey. For some of our listeners/viewers, let me go back and pick up where they are on their journey. People might come up to a point that would be comparable to where you were when you went to Canyon Ranch: they’ve had an experience, maybe they’ve seen what they were told was going to work in their training didn’t, they’re a little disillusioned but they are still in the flow. They’re making a living out of what they are trained to do. They want to make a change but it’s really an awkward kind of contemplation: “Well, I’ve got responsibilities, I’ve got a family, I’ve got a mortgage, I’ve got this, I’ve got staff, whatever it might be, and I also have medicolegal responsibilities and I also have a licensure.” All these things weigh on the shoulders. And then they are confronted some night when it’s quiet, when they are with themselves, with asking “What am I going to be? Where am I going?” I don’t care if they’re 25 or 65 or 75. They may have that moment where they say, “What am I going to be?”   What went into that kind of process of thinking for you and what have you observed in your colleagues in which that kind of moment of truth comes up, saying “This is really a truth that I see, but to move that direction is so complicated that I really need to stay the course.”?   MH:     For me, I don’t know if it’s applicable to what I went through because my personality is extremely risk taking. I basically trust in the uncertainty of life to take me where I need to go, and have a really strong belief that if I show up, tell the truth and be straightforward, and then be welcome to whatever the outcomes are, things will work out. From my own sort of development, this is sort of what I carry through every day. I was willing to let go of things in order to try something different. And as soon as I did that—as soon as I released from the fear of: “Well, I’m a single parent. I have two kids. How am I going to make a living? What am I going to do? How am I going to be able to do the ER (it’s a guaranteed source of income)? How am I going to do something different?” As soon as I set the intention for what I wanted to do, then the right solution showed up. That’s when I got this job offer without applying at Canyon Ranch. I was like, “Oh wow, how did this happen?”   IFM and Other Leaders Must Come Up With Solutions For Practitioner Transitions There’s a bit of magic in that, but I think if we can engage a little bit with that magic in life, things happen. At the same time I also would say it’s incumbent upon the Institute for Functional Medicine and other groups that are leaders in the field to really come up with solution sets for practitioners that help them transition. It’s really a transitional system that allows them to find a way within their practices to create models that work that are insurance based, that are financially viable, that provide good care, but that—like I always say—change the way we do medicine and the medicine we do. So the delivery models and the content models have to change. And it’s a process, and it can be done incrementally, and people can start very subtly. When I started, I just started with the gut. I just started with doing one thing: “I’m going to work on learning the gut and fixing peoples’ digestive tracts, and doing elimination diets.” And then I would add on later: “Oh look, now I understand hormones.” You don’t have to do everything at once; you can just take one step at a time. I think we do need—as a community—to come up with real solutions for our practitioners that allow them to do this in a way that isn’t that disruptive, that they can scale, and that it’s not everyone having to recreate the wheel every time and reinvent a model that is effective. I think we need to focus also—we’ve talked about this, Jeff—on policy and reimbursement, because doctors get paid to do things and they do those things, and if they get paid to do different things they’ll do different things. We need to create changes in corporate health that are driving some of the decisions around health and insurance. We need to look at how we change our medical education, which we are working on at the Institute. So we need multiple platforms at the same time to be able to build the infrastructure that trains up a new generation of practitioners and provides them with real business and clinical models that work in real life and in real communities.   JB:      That’s a wonderful segue into institutionalizing and providing a support program for people who have elected, at that moment of truth, to make the decision of change. So you go to the Institute for Functional Medicine 20th anniversary—May 2011—a very big anniversary with its second decade. Tell us a little bit of your evolution with IFM. I remember the first lecture in which you gave some 10 or 12 cardinal rules for change (kind of transition rules like you would do with a twelve step program). Tell us how this evolution has occurred both for you within IFM and IFM as you have seen it over the 15 years that you’ve been affiliated.   IFM’s Evolution MH:     Well, like I said, when I first joined I didn’t realize IFM was in early development. I sort of realized that we had an extraordinary opportunity and have watched the organization grow from an idea to a leader in the field of education, in functional medicine but also in the integrative medicine field. I think what has happened is the Institute for Functional Medicine has really become sort of the graduate program for integrative medicine. Most people who go through the study of integrative medicine end up in functional medicine if they continue to explore and teach. I know many of the practitioners of integrative medicine are leaders in integrative medicine and actually go to functional medicine doctors themselves, which says something about what is missing from the integrative medicine piece. I think we, at the Institute, have created and worked very hard, with the leadership of David Jones and with Laurie Hofmann, to actually create a curriculum that is a solid foundation—a certification program—along with relationships with many, many institutions. We have almost one-quarter to one-third of all medical schools actually coming to training programs through the Institute and looking at bringing these concepts and programs back into their institutions. We’re actually in over 40 countries in terms of education. I think that the Institute has really grown up and is ready to scale our educational model. With more resources and more funding, in our strategic plan (we’re got a 5-year plan), we’re going to—through education, through research and collaboration—build a foundation for a new educational infrastructure that is going to seep into conventional care and also post-graduate care.   JB:      You’ve made a really interesting statement that for some people, if they are not familiar with this field, might be somewhat obscure as to how they interpret it. Let’s go back and revisit. Integrative medicine, functional medicine. They are parts of a whole—we’re all in this hologram of life—but they’re slightly different components of the hologram. Could you differentiate, from your experience, how integrative vs. functional medicine are slightly different?   Integrative Medicine is about the Tools, Functional Medicine is about the Map MH:     Sure. I wrote an article a number of years ago, an editorial called “The Map: Integrating Integrative Medicine.”[2] Because integrative medicine is about the tools. Functional medicine is about the map. It’s about navigating. It’s about thinking. So functional medicine isn’t a specific tool, or a modality, or a treatment, or a test, or a supplement. It’s a way of analyzing information: sorting it, organizing it, processing it in a way that tells a story about how people got sick and how they can get better. It helps to choose which therapies to do, which may be alternative therapies or what we call integrative therapies such as acupuncture, or biofeedback, or herbs, or nutrients. It’s a fundamentally different way of thinking. If someone comes to an integrative medicine case conference, take someone with depression—you’d have the homeopath recommending a certain remedy, you’d have the acupuncturist saying they had spleen qi deficiency and they need certain acupuncture points, the psychologist might say they had early-life trauma and this made them depressed, the nutritionist might say they have a folic acid deficiency, the internist might say they have a serotonin reuptake inhibitor deficiency, and so on. The question is, what do you choose? How do you figure out what’s going on? The unfortunate part of integrative medicine is it is saying we’re going to integrate alternative therapies with conventional medicine. That’s what “integrative” means for most people. I think some people conceptualize it a little differently and understand it’s about the whole person, and on the mind-body level, on the relationship level, I think they’ve got it nailed. But where it falls down is you have this smorgasbord of choices about modalities for diagnosis, the problem is the diagnosis is irrelevant. The question is, what’s the cause? It’s sort of the medicine of “why” (functional medicine) instead of the medicine of “what.” It is not what the diagnosis is and what the treatment should be, it’s what’s the underlying cause, why is this person out of balance, how is this system dysregulated? zThe disease becomes increasingly irrelevant in terms of understanding what to do.   I was speaking with Joel Evans, who is faculty, the other day. He said, “I don’t really care what people have. If they get their diet right, they exercise, they learn how to deal with stress, they sleep, and they drink enough water, most problems go away.” I think that is sort of one of the premises of function medicine: it’s about understanding the different elements that go into creating our system (our biological system), how to work with those, how to understand where they become out of bounds (how they get imbalanced), understanding those things that Sid Baker talks about (what do you need to get rid of to get healthy, and what do you need to get healthy, what are the things you’re missing that your body needs to thrive, and what  are those elements that are disrupting these basic systems in your body?). And then from there you can kind of say, “Okay, let’s prioritize and figure out how to unwind this knot, or how to peel the onion of chronic disease.” As opposed to saying, “we’re going to try a bunch of these different modalities on a diagnosis that’s a western diagnosis that is an ICD-9 code that is sort of irrelevant in terms of our understanding of systems biology. As we begin to understand, there is not “depression” there are “depressions”; there is no “diabetes” there is “diabetes’”; there is no “cancer” there are “cancers.”   I remember being at an NIH think tank on systems thinking and biology. There were NIH researchers and National Cancer Institute staff looking at prostate cancer, and gene profiles and prostate cancer, and I said, “You know what? We look at these genetic profiles in prostate cancer samples and you get 10 guys with prostate cancer and they are all diagnosed with prostate cancer, but they aren’t the same, they are all different. They may have different patterns, they may have different responses, different treatments, they have different etiologies. We call it prostate cancer but it is kind of meaningless as we begin to understand things.” I think we’re in an extraordinary period where with functional medicine we have an overarching architecture—a framework, a way of thinking, a navigational system, a GPS model for thinking through the problem of disease in chronic disease. Integrative medicine represents an incredible wealth of tools and resources to use, but they are the tools, not the map. Functional medicine is the map.   JB:      Mark, in this conversation, which has really been just fantastic, to look at the topography of change, of how people’s lives weave themselves into these interesting moments of transformation and personal evolution. I think everybody that is listening or watching this probably has a moment where they can identify part of the story with their own lives, where there has been a watershed event, or there has been a branch in the road, or there has been an opportunity to do something dramatically different than that which they have done in the past, standing courageously on the edge saying, “Okay, am I ready to take that jump, that leap?”   With all of that in mind, and the way that you’ve described functional medicine, it seems—like you said earlier in this conversation—that it is self-evident that this is the right thing to do. But somehow, it must not be perceived by the body politic in general to be the right thing to do or there would be a groundswell/tsunami/cultural change overnight and we would see this kind of thing being incorporated as a way of thinking. There must be some barriers still, even though—as you’ve described it—it seems so self-evident. It’s like gravitation; we do stick to the earth. What’s retarding the acceptance of this model (whatever we want to call it—functional medicine or whatever)?   MH:     Well, it’s a lot of obvious things. We’re talking about a major paradigm shift in our scientific conceptualization of disease, as big as what happened with Louis Pasteur, with the theory of evolution, or with Columbus and the earth being flat. These are huge scientific shifts that didn’t catch on very quickly. When you say diseases don’t exist, that challenges the entire infrastructure of a two-trillion dollar industry. That’s not going to change overnight. The financial incentives around how doctors get paid and what gets paid for also are driving practice. There are a number of obstacles that have to do with the very fundamental scientific conceptualization of disease changing, which is, I think, one of the biggest obstacles. How do we reorganize medicine so that it’s not structured by specialty and siloed? How do we reorganize it by systems and thinking? How do we do that? It’s a daunting problem.   I think we are also dealing with “structural violence,” as Paul Farmer calls it, where the very social, economic, and cultural conditions are actually depriving many of us of health as a human right. Those are things that are sort of embedded in our culture, where you can’t drive down Main Street USA and find anything edible, or only food-like substances are available—things like what Michael Pollan says are “made in a plant, not grown in a plant.” It’s very difficult to overcome a lot of the inherent obstacles to getting healthy in America. Functional medicine is, I think, the standard bearer for a new way of thinking, but it’s the best kept secret around.” I think that’s just by the natural process of this major paradigm shift. As Thomas Kuhn said, “It’s not easy to shift normal science.” We’re at one of those moments (those transition moments). It will happen, but it’s going to take a little while.   I think the second reason is just economic. That’s really where I’m looking to find the leverage. Where are the economic levers where doing the right thing is also doing the most profitable thing? If we can pull those levers and get some key players to change in the healthcare industry, whether it’s the insurers, whether it’s some reimbursement policy based through things like the VA, which have align incentives, then we’re going to see the self-evidence of this model being shown and then I think the changes will happen, but it’s going to take a little bit more groundwork in establishing those demonstration projects showing the money. As they say in Jerry Maquire: “Show me the money!”   JB:      I think that you have said something inherent in your very eloquent response to a complicated question, and that is you’ve illustrated that our present system is a procedures-focused system, in which the more interventional the procedure, the more social value has been perceived for its worth. So the more bizarre intervention, really (when we look at it in a purist state), the more you get into really doing something very heroically interventional, the more value you will get in terms of its perceived economic outcome versus those things that we’re talking about that are not so procedures-focused as process-focused, in which the person in the life process is modulating their genes and response to the environment to produce a favorable outcome. That seems to have a low-value aspect associated with it in society. You’re talking about a fairly profound transformation in how we establish value (principles of value). Do you have any thoughts on how the Institute for Functional Medicine and its doctors can help foster this?   Practicing Lifestyle Medicine Must Be Made Economically Viable MH:      Absolutely. I’ve thought a lot about this. One of the things that needs to change is reimbursement. If doctors get paid to do lifestyle medicine, then they will. If we all of a sudden made it as economically viable to do group programs of intensive lifestyle behavior change, which are the only things that have really been proven to work great (sustainable behavior change) and we actually reimburse that, then there would be Institutes of Lifestyle Medicine showing up in every major institute of health care in this country. Instead of cardiac institutes there would be lifestyle institutes and there would be these programs going on that would be paid for and reimbursed. You know, if you got paid as much to do that as you got paid to do an angioplasty, things would change. I think that kind of creative restructuring of reimbursement to deliver on outcomes is key.   When I was working in Washington with Dean Ornish and Michael Roizen, we created a bill introduced in the Senate called “Take Back Your Health.” It had a double-payback provision and was still not passed. The double payback was that with intensive group lifestyle support of integrative teams of health professionals that were reimbursed at a reasonable rate of $100 an hour, that if patients actually didn’t get better and ended up with an event, the doctor would have to pay back the amount they got. The second provision was they only got paid if there was a reduction in the biomarkers and an improvement in outcomes. So, (1) you only got paid if you succeeded, and (2) if you failed you had to give the money back. Even with the double payback, which was a no-risk proposition, it still couldn’t pass. And the reason we put those in there is we believe so strongly that this model works better. Imagine if I said to you, if you were a cardiologist, “Well, if your angioplasty fails, you have to give back the money you got paid doing that angioplasty.” That’s essentially what we did, and I think that’s the power of lifestyle medicine.   We’re still working on it; it’s still in process. I think those kinds of shifts are going to happen. And if we can provide economic models for primary care physicians within their practices to do a different delivery model that includes groups, which I think is a very sort of disruptive of delivery model, but can be reimbursed under current reimbursement rules, and is actually even something that groups like the American Academy of Family Practice are promoting—if we can provide models for that that are plug-ins for primary care doctors to deliver this content, and we package the content, and the Institute helps with other organizations to collaborate, to actually deliver these models and plug them into existing infrastructures, I think we can create change.   JB:      I think what you are really describing very eloquently is a landscape, to go back to your Thomas Kuhn reference, that is a paradigm shift (Kuhn having coined that term, “paradigm shift”). And this transformational shift that is occurring is something that has many levels of synchronicity. It’s not just like a doctor changing, it’s an economic model changing, it’s a social structure changing, it’s a personal responsibility changing. It’s going from a victim space to a participant space. There are all sorts of interesting contextual changes, to use the concept of self-efficacy. It’s building the person back into their own model as being the central person in their life. I think all of these are really dramatic, dramatic changes, and I think it’s very interesting that they seem to be converging and intersecting at a time and place in the 2011/12 year, that it becomes coincident with the 20th anniversary of the Institute for Functional Medicine, with the 30th anniversary of doing Functional Medicine Update, back through its Preventive Medicine Update and through its Metabolic Update years, starting with a small study group in the early 70s that was the kind of germ seed of some of these things that have emerged out of the last 30 years. It seems—without making up a story that doesn’t exist—that there is a really dramatic moment in history to do something impactful, to change the course in a more positive way.   MH:     Absolutely. I think things want to be changed, and I think it’s an opportunity waiting for a leader to come through and deliver a model that actually makes sense, and a medicine that makes sense.   JB:      When you look at this transition, how do you draw from some of the historical legacy? When you look back at the early days at the Linus Pauling and the Roger Williams era and the forefathers and mothers of this movement, what do you pull back to go forward?   MH:     For me it is sort like the raw clay that can be used to shape the sculpture of what the future of medicine is going to be. Elements built over the last decades into an extraordinary picture of human physiology, biochemistry, genetics, and functioning that were sort of hinted at in the early days have coalesced into an extraordinarily robust clinical model that’s an application of systems biology, which is functional medicine. And the Institute for Functional Medicine has really encapsulated that in its curriculum and training programs, and that’s why everybody is seeking out the Institute to help build this into their medical schools and into their institutions (and corporations and insurers). I think that’s really where this has got to go. We can take what we’ve done now and say this is the full expression of those early ideas into a model that’s going to be a robust clinical model to change health care.   We Have to Not Only Change the Way We Do Medicine, But Also the Medicine We Do Something we really haven’t talked about that goes along with this is the idea we have to not only change the way we do medicine, we have to also have to change the medicine we do. We have to change both the delivery model of care and the content of care. These early ideas of functional medicine were really the refining, and the polishing, and the developing of the content model: What is the DNA of the future of medicine? What’s that going to play into in the clinical practice setting in the healthcare industry? How does that actually intersect with that? I think that’s where we are coming from. I think we’ve matured enough in terms of the content development, and out of the evolution of all these masters, and all these thinkers and leaders like you, we’ve been able to come up with a model that actually works clinically, but now we need the delivery system for that. We need to lay the railroad tracks so this model can be rolled out across the healthcare nation.   Deciphering the Human Genome Was Just the Start JB:      Let’s take that as a very powerful little moment of getting oxygen in the brain and thinking about where the next neuronal firing is going to take us. When I’ve spoken over the years to practicing clinicians–often very skillful docs–often they would say there was very little translation of basic science into clinical practice. In everyday life, they are not really leveraging science; they are leveraging clinical acumen. This is probably where this interesting dynamic of you as an MD and me as a PhD meets in the middle to create an opportunity for synergism. I look back and I say, “And yet, what happened in 195 with the publication of one small paper in Nature magazine that had fewer than 700 words in it, I recall, which was written by two young heretics in Cambridge that didn’t even have any scientific proof of principle, but had an idea that was cut out of the back cardboard from their starched shirts and the hangers upon which those shirts hung, in which they wove that pattern into the double-stranded helix to create a sense of what is encoded with what we called our genetic heritage going back to Gregor Mendel and even back to the Greeks, and then opening up the construct that there was something locked into that heritage in molecules—in molecular structure and function—that could, when uncoded, could create, then, the diversity of plants and animals that we see on this planet and help us to understand the origin of health and disease?”[3] That shifting paradigm, which seems so far away, probably, from medicine when it was first published, and even the scientists of its age didn’t accept this because it wasn’t that good of science. It was built more on a theoretic model, it was built more on conjecture, on kind of molecular modeling. Yet it seems to follow some rule of reasonableness—in other words, a lot of work that had been done in electron microscopy with Rosalind Frankin and so forth that kind of seemed to kind of support it, but how it was going to translate didn’t seem obvious. Then over the years we get to the human genome project. Basic science. The big huge science. It’s like building the linear accelerators to look at particle physics. And big science produces big ideas. So here is President Clinton on the lawn of the Rose Garden with the two major competitors, both announcing simultaneously that they’ve deciphered the human genome, and that we’re going to suddenly now understand everything that’s going to be needed to be known about health and disease. So it’s a basic science major discovery. It’s going to be a frame shifter for health and disease. And yet now, some 11 or 12 years later we’re finding that it was only the start—that discovery—of really how our genes are modulated in their expression by our environment, and that the action is not just the hard wiring of the genes, but it’s what is going to be expressed out of that message in our book of life in ways that are going to be seen in our phenotype, our health and disease patterns. And now suddenly we learn that this renegade group of scientists that have been keeping alive a concept that goes way back to John Paul Baptiste called epigeneitics, that was the debate between Darwin and Baptiste as it related to adaptation versus mutation/natural selection, in which any student in an American university—actually in any reputable university anywhere in the world—that would have talked about that animals and plants adapt to their environment would have been excoriated because it was considered to absolutely be a ridiculous principle; we were all on board with natural selection, this slow moving process to weed out mutants that were selected from those that were not. And suddenly now we come back in the year 2011 to recognize, no, there is a fine tuning knob on how our genetic information is expressed by these tags, these marks, that are put on our genome called epigenetic marks that regulate what portion of our book of life can be read. And those epigenetic marks are put on there by life experience: life experience from what we eat, what we think, what we do, what we’re exposed to. So that there is an adaptation, and it is transgenerationally transmitted; it can be sent on to the next generation. This construct, which comes from basic science, is morphing and changing all of the presumptions of medicine, and yet we’re still practicing a medicine that was really the artifact of 1950s thinking.   MH:     That’s true.   JB:      How does that get woven, do you think, into the functional medicine model—into its advocacy and ultimately into its teaching and training programs?   MH:     That’s actually a perfect question because I recently wrote an article called “The Failure of the Promise of the Human Genome Project.”[4] In it I said that really the future is not in the genomics, but it’s in the exposome, which is the sum total of the environmental influences affecting gene expression, which accounts for 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of all disease. It’s in the epigenome, as you just said, which is how genes are tagged and modulated by environmental experiences and then control gene expression. It’s in the nutrigenome, which is the way in which food regulates our gene expression. As you have said so often, food is information, and it’s how that information translates into molecules that affect health and disease. And it’s the microbiome, as we are learning in the 20th anniversary Symposium. It has enormous effect on our health. We have ten times more bacteria in our gut than our human cells. We have 100 times more DNA from microbes than we have from our own DNA. How does that influence our health? These are the concepts that are really embedded in functional medicine that have been talked about in functional medicine by you for almost decades now that are beginning to see sort of the light of understanding. To me, that’s the intersection where we need to be shifting from focusing on sort of gene-based therapies or pharmacogenomics, which is a very narrow view of the human genome project and personalized medicine to really thinking about how personalized medicine incorporates this whole notion of nutrigenomics, and microbiomics, and epigenetics, and the exposome, and even something that I call sociomics, which is the power of social networks to influence our gene expression patterns, to influence our health and disease patterns. We’re understanding that social networks are important as molecular networks in determining health and disease. So, as we begin to piece all these parts of the puzzle together, we’re creating an extraordinary story that has direct clinical application, and the functional medicine matrix is the lens through which we can actually interpret all this data and come up with real solutions for real patients in the clinic every day, which is what I do every day. I’m a practicing doctor. I go back on Monday from the Symposium and I’ve four days straight of patients every day. I do this as really my life source of energy. It’s what gets me excited every day because I see that there is a way to take all this esoteric information and turn it into, at the end of the day (which is what got me started) the path of relieving suffering of others.   JB:      We’re really talking here about translational research (translational information). It only is good when it does something good, right? It only has value when it enriches to produce benefit. When I think of the 30 years, now, of Functional Medicine Update, going back through Preventive Medicine Update and Metabolic Update, I’m reminded that for 30 years every month I’ve had the privilege of interviewing someone who is a luminary, has a certain view in this lens that you’re talking about—the multiple facets of knowledge—that is creating a change (a cultural change, a belief change, an attitudinal change, and a procedural change in the way we think about health and disease. I think of people like Moshe Szyf that we recently interviewed from McGill University, who is in the laboratories of Hans Selye. It actually brought Jay Johnson, who has shared the audio studio with me for all 30 years (been the audio tech all these years), it brought us both to tears, literally, this interview, in which Szyf was showing from his animal studies that by putting animals in a socially distressful situation they could induce epigenetic marks going on their genes that lock those genes in the expression of alarm and of fear, so the molecules that were produced in their bodies on a perpetual basis were fear-based molecules, meaning behaviorally these animals started to be aggressive, and they became fearful, and that was transmissible to the next generation. He asked us, in this interview, “What do you think the implications are of a world at unrest, in which you have poverty as such a major dominant theme, that you have war, that you have violence against children, that you have violence against women and people of different races?” What’s the implication of that as it pertains to the lineage of the human species, which doesn’t have a large litter size, it’s not that strong for body weight, it can’t run that fast, it only has its view of the universe as its protection to all the other elements of environmental change? And if you start modulating that by setting marks of fear, alarm, and hostility, what are the implications for the survival of the species? Those are profound questions that come out of basic science but have huge social implications, because we don’t have enough docs at hospitals and rescue places to handle all those problems. Just Gulf War veterans—and he brought up the coming back from Iraq and from Afghanistan and the number of people that will be injured that are going to require care. And not just physically injured but emotionally—epigenetically—injured, by situations that the human being should never be in. What do we do to manage those huge cultural gaps between the sense that we’ve got the answer somewhere in the emergency room and the hospital centers of America and the real origins of these problems, which are these functionally based frame-shifters that are creating the origins of these disturbances?   MH:     Powerful question. I’ve thought a lot about it and I wonder if we can create epigenetic marks that can be passed on, can we undo them? Can we retag those epigenetic sites that allow us to undo the stress that has been placed on them by our toxic environment and our stressful world? I don’t know the answer to that, but it seems to me there may be some “undoing” possibly in there. I know we can create more tolerance in the immune system. We can shift things that are seemingly intractable in human biology; I’ve seen it happen. I’ve seen kids with autism wake up. I’ve seen things that shouldn’t happen happen. I ask myself, “How resilient are we as a species? How resilient are we as individuals? And what can we learn from understanding biology at the level that we do to actually change the inputs to change the outputs? I think we can.   Where the PhD Meets the MD JB:      Yes, I really share your optimism. One of the things that I’ve learned, and again this is where the PhD meets the MD, is that the way we often learn metabolism in school are these wall charts, right? The metabolic pathways that we had to commit to memory and recite on exams to move ahead. It gave us a sense that it was this linear relationship, like glucose got converted on into energy through the Krebs cycle ultimately and down into ATP, and so we got the sense of A goes to B goes to C to D in kind of a linear system. As we have emerged an understanding of animal biology (and actually plant biology as well), we recognize that those linear systems don’t actually exist. We’re not linear biology. We’re not linear systems at all. We’re very complex networks. It’s like trying to examine a spider’s web one tendril at a time. You might say, “Oh I understand a spider’s web. It’s this line that connects one part of the web to another.” That’s one web (part of the web); that’s a pathway. But that is really embedded within the structure of the web—of the network—that creates the strength and integrity of that spider’s web. A similar thing holds true for human physiology. We have this redundancy, so that the resiliency is built into what I call degrees of freedom. We have built all these physiological degrees of freedom through these redundant pathways. It’s like the rainforest versus the cornfields in Iowa. If you have monoculture, if you have one blight or one insect or one problem with a nutrient it can wipe out the whole state’s corn population. How do you stabilize that? You put a lot of external energy in the way of fertilizer, in the way of pesticides and herbicides and biocides, to keep that unstable system—that very linear pathway system—stable. If you go to the Brazilian rainforest, however, it’s very complex; it’s a network system. If one specie of plant or animal is jeopardized it’s not good, but you’ve got so much other redundancy built into the system that it stabilizes itself. So the question is, what is human physiology? In the natural state it is the rainforest; it’s not the cornfield in Iowa. But as we move our physiology more to a compromised state it becomes more cornfield-like. How do we maintain these metabolic degrees of freedom, which is resiliency, which is organ reserve, which is decreased biological aging. All of those things that then track and map against chronic disease?   MH:     Are you asking me that question?   JB:      Yes.   MH:     I think it’s actually quite a simple answer. How do you create a thriving ecosystem? Sid has taught us simply to think about it as, how do we remove those things that impair thriving? How do we provide those things that are necessary for thriving—everything from food and nutrients, light/air/water, to love, meaning, purpose, connection, community? All those are necessary for necessary ingredients. I think the human organism is resilient and can reset and we’ve seen this happen, even at advanced ages in people with extraordinary inputs that change physiology in a dramatic way to reverse aging. I think it’s possible. The epigenetic marks are an interesting piece for me. As you were talking I was recalling a group of my patients that are children of holocaust survivors. And there is a hypervigilance that exists in all these patients. It’s almost imprinted in them. I don’t know if it’s an epigenetic imprinting, or an emotional imprinting, or what exactly happened, but it’s a phenomena and I don’t know if anybody else has observed this. Is it possible to undo that level of stress that happened as an early influence in an epigenetic way? I don’t know. It seems to me that the only thing we can do is apply the model of functional medicine. To me, what’s so extraordinary about this model of functional medicine is that it doesn’t matter what the condition is. If you simply create healthy ecosystems as best you can and try to understand what that ecosystem is, and remove the impediments for thriving, and provide the ingredients for thriving, that most of the time there will be a resetting. Sometimes there won’t and there are other factors that we haven’t thought of, but for most of the time and most of the patients I see this happen.   JB:      I think there is good—again the PhD interfacing with the MD—support for what you are saying in science. Years ago, and you’re familiar with this, Pottenger (this is back during World War II and shortly thereafter, and Weston Price even before him, observed some very interesting changes in actually people and then later Pottenger did studies in his cats (the so-called Pottenger cat studies) and even in plants, showing that if you fed cats a suboptimal diet (in fact, he produced—as far as I know—the first hyper-allergic cat by putting them on a cooked meat and a cooked milk diet for generations, and by the third generation of cats he had these cats whose eyes were watering constantly, they were allergic, their fur was all mottled), and they couldn’t reproduce. He was unable to produce a fourth generation. Then he took those cats and renourished them, and it took four generations to bring them back to the F0 generation.[5]   Now, let me follow that up with a more controlled study (that was more an observational study). A very highly acclaimed nutrition researcher now deceased, Lucille Hurley, had done some similar studies but under controlled conditions in primates.[6] She retarded one nutrient in the diet of the mother (the pregnant mother) in primates, and that was zinc. It was not to the level that the mother, during pregnancy, was mortally ill; just a marginal deprivation of zinc so that she went through her pregnancy with zinc deficiency. Those offspring that were born had immunological deficiencies. They became immune incompetent, so to speak. And it took—again—three generations of zinc repletion of those animals to inbreed them back to the F0 generation of immune competence. So that means you can both see degeneration, but the other side of the story—the one that you’re talking about—is you can see regeneration. But it requires hard work. It requires change. And that’s the functional medicine model, right? It is designing the program for the person to deliver what they need to reset some of these pathways.   MH:     That’s right. Amazing.   JB:      So, we’re kind of at the end of our extraordinary time together. This is epic. I use the term “epic” because I think it really is deserved to be used on the 30th anniversary for Functional Medicine Update, the 20th anniversary for IFM. Anything at this period that really stands tall for you that you would want to acknowledge at this major landmark transition?   Looking Ahead to the Next 20 Years of Functional Medicine MH:     Yes, I think when I started in this field there was a sense of sort of being a lone island in the field of health care. Now what is see is happening is that the influence of functional medicine is embedding itself throughout our healthcare system and throughout our culture in ways that are actually not even sort of recognized as from the functional medicine lineage, but it is just kind of embedding itself within our understanding. From Dr. Oz, who has got his show, who actually calls upon functional medicine as one of his major influences, to large insurance companies that are looking at this model, to people in Washington beginning to look at how we can do this, to even major hospitals and institutions trying to figure out how to bring this in. I think it speaks to an extraordinarily big shift in thinking that has happened. It’s happened sort of subtly, but it’s actually fairly quickly—over the last couple there has been a shift. I think we all feel it, and now we have to show up and help create that transition for the next 10 to 20 years of functional medicine.   JB:      That’s how I feel. I think, having 20 years ahead of you in timeline, I’m feeling that very same thing here at this moment. What I’ve recognized that this thing we call life, no matter what the procedures, the policies, the standards of practice, the guidelines, what we’ve learned, how we’ve been licensed, what we’ve codified, it’s still a people-related function. It’s a social function. Everything we do is interconnected to exchanges of people, no matter if it is social networking on Twitter or Facebook, or if it’s a face-to-face meeting like we’re having here, there is an exchange of human energy. There is something uniquely intangible, off balance sheet, which really drives—on balance sheet—everything. All the measurable come out of the interactions of human in a social discourse, and we’re in a great period of extraordinary exploration for what the human spirit will be like as a group consciousness over the decades and the centuries to come. My feeling is of extraordinary privilege. I watch the dedication, and I watch the people like yourself that are coming up to take the standards, and hold the banner, and keep the flame lit, and to move it to the next level. It’s beyond anything I would have imagined when I was 25 years of age and just starting as an assistant professor and hoping I could make a living for my family and my kids could go to college eventually and so forth. To watch this whole field emerge to really be a collaborative group of courageous spirit that can overcome the expected and do the unexpected—do the magic—to transform society, and fight back against the covenants of “We can’t do that”; and “That will never change”; and “Institutions are too big”; and “That’s beyond our abilities.” I think we’re really seeing—and I believe (hopefully) I’ll be around here long enough to actually witness this shift—the wall coming down, the thing that happens in the mid of night and we wake in the morning and see the news and everybody says, “Oh yeah, I understood that all along. It was just the standard of care. There’s nothing new about that.” I don’t care who invents it. I don’t care who takes ownership of it. I don’t care what you call it. But I think we are close to whatever that vibratory frequency is that leads to that change. And this experience I’m having at the 20th anniversary of the Institute for Functional Medicine and the 30th of Functional Medicine Update reminds me that it is a life worth doing, it’s a road worth traveling. You’re hanging out with the right people; the people that are asking the right questions.   Thank you for being a major part of this change.   MH:     Thank you. It’s extraordinary. Just as we have seen this last year, social networks can topple despots in the most crazy places like Egypt and Libya. I think, as a community, we can together change health care.

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Bibiolograpy [1] Williams, Roger J. Nutrition Against Disease. Pitman: New York, 1970.   [2] Hyman MA. The map: integrating integrative medicine. Altern Ther Health Med. 2009;15(1):20-21.   [3] Watson JD, Crick FH. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. J.D. Watson and F.H.C. Crick. Published in Nature, number 4356 April 25, 1953. Nature. 1974;248(5451):765.   [4] http://drhyman.com/the-failure-of-decoding-the-human-genome-and-the-future-of-medicine-3361/   [5] Pottenger, Francis Marion, Jr., MD. Pottenger’s Cats: A Study in Nutrition. Price Pottenger Nutrition: Lemon Grove, CA, 1995.   [6] Keen CL, Hurley LS. Effects of zinc deficiency on prenatal and postnatal development. Neurotoxicology. 1987;8(3):379-387.

Welcome to Functional Medicine Update. What a time this is. We just finished the 20thanniversary meeting of the Institute for Functional Medicine at its annual Symposium in Bellevue, Washington. As I reflect back on my history with the Institute for Functional Medicine, and the concept of functional medicine that we’ve been defining over these decades, I’m reminded that a very interesting understanding has evolved of how function in the human body results from the interactions between the physiology of a person and his or her environment. It’s this gene-environment interaction that leads to specific personalized responses that we call health outcomes.   We cannot modify the structures of our genes directly, but we can modify the environment that we expose our genes to. The story that has been evolving over the last decades is that of the epigenetic modulation of our genetic message. It’s been very interesting to follow the evolution of this concept of epigenetics, or modulation “above” the genome of its ability to express its function, in Functional Medicine Update.  Epigentics encompasses the methylation, acetylation, ubiquinitation, and phosphorylation patterns of the genome and the histone code of the genome (the “book of life”) that regulates how the genes are expressed, and how environmental factors and experiences in life, starting even pre-conceptually and moving through early fetal development and into infancy and even (now we’re recognizing) adulthood can modulate the epigenetic patterns or the marks on the genome that regulate its function.   This story related to function has really changed its complexion over the last 20 to 30 years, and chronicling this story in Functional Medicine Update has been a privilege and an extraordinary “ah-ha” experience for me. It’s been like being at the side of a great author who is writing a tremendous novel, and being able to read each page as it comes off her or his pen. It’s very interesting to watch the evolution of knowledge.   In this issue of Functional Medicine Update, we’re going to be talking about a component of this story. During the early days when the tenets of functional medicine were being discussed, we talked about the difference between a differential diagnostic model (the traditional pathophysiologically based model) and the functional medicine model. We talked about how the diagnosis, in functional medicine, is less important than knowing the etiology of the condition.   Review of the Functional Medicine Model Antecedents, triggers, mediators, and signs and symptoms are now the sine qua non in functional medicine. Antecedents encompass the genetic background, the family history, and the environmental factors that relate to a particular individual. Triggering events are stimulations in the environment that actually modulate the expression of the antecedent factors. Mediators are the modulators (the messenger molecules) that modulate function at the tissue specific/cellular specific level that ultimately give rise to the outcome that we call function. Outcome is measured in a patient with disturbed metabolism or disturbed function as things such as signs and symptoms of increasing duration, frequency, and intensity. That is the functional medicine model, as contrasted to the differential diagnostic/driving to the disease nomenclature model.   Mediators, these signaling molecules, are like smoke that tells us something about the fire. Often the mediators, in medicine, get relegated to the term “biomarkers.” Biomarkers could be primary or secondary. They could relate specifically to a disease entity (primary), or they could be secondary biomarkers that kind of–using Plato’s Myth of the Cave analogy–give us shadows of understanding as to what the origin of the dysfunction might be. Established biomarkers—clinically validated biomarkers—are things like serum cholesterol  or blood pressure. With biomarkers such as these, we use an anatomical, physiological, or biochemical tool to evaluate what’s going on at the cellular level, which reflects how the genes and the environment are interacting in that individual. It’s working backwards towards an understanding of the origin of function or dysfunction.   Inflammation and Disturbances in Metabolism Associated with Aging I interviewed Dr. Garry Egger from Australia recently, who talked to us about disturbed metabolism and altered function in the world that we live in today (21st century society)–this alarm reaction that the body goes into, this inflammatory response. It could be inflammation of the nervous system associated with Alzheimer’s or Parkinson’s, or it could be inflammation of the vascular endothelium related to heart disease, or it could be inflammation of the beta cells of the endocrine pancreas related to diabetes, or it could be inflammation of the angry fat cells—the adipocytes—that release their adipocytokines that are inflammatory molecules that relate to a variety of things, including non-alcoholic fatty liver disease or non-alcoholic steatohepatitis (NASH). What we’ve said is that inflammation appears to be a marker of disturbances in metabolism that are associated with the dysfunctions of our age.   Dr. Egger talked about how we would examine inflammation at a whole-organism level, and how environmental factors play a role in that inflammatory process. The example is a recent paper he and his colleagues, David Sullivan and David Colquhoun, published in the British Journal of Nutrition in 2010 paper titled “Differences in Post-Prandial Inflammatory Responses to a ‘Modern’ versus Traditional Meat Diet.”[1]   In this preliminary study,  Australian individuals who ate Wagyu beef (a feedlot-fed, high fat, marbled, very tender, gourmet beef), and elevated levels of various types of inflammatory mediators (so-called mediators that are biomarkers of disturbed metabolism or altered function) were measured as a consequence of eating that type of diet. If, however, the individuals ate the same amount of wild meat (kangaroo) that was very low in saturated fats and much higher in animal protein on a percent calorie basis than the Wagyu beef, there were not elevations of things like tumor necrosis factor alpha (TNFalpha), and C-reactive protein, and interleukin-6, which are all proinflammatory mediators.   This is a classic example of how an environmental change—a diet of wild game instead of Wagyu beef—produced a very different physiological response across a wide range of different genotypes. This suggests that there might be some people with polygenomic characteristics more highly sensitive to that change, so they might get a very rapid increase in inflammatory markers. Maybe other people, based on their genetic predispositions and sensitivities, would have a lower response. But overall, the findings of this study indicate that when you give different types of meat to a random population in Australia with different genotypes, you get a shift in physiology towards a proinflammatory state.   I think you can line up proinflammation as a characteristic of mediators that are associated with triggers that are associated ultimately with the onset of a variety of chronic age-related diseases: dementia, heart disease, diabetes, maybe certain forms of cancer, certain arthritis relationships to things like osteoporosis, fatty liver disorders, inflammatory bowel disease. All of these can tie into a disturbance of metabolism associated with an environmental perturbant. This  has been a general theme I’ve been developing in Functional Medicine Update, and has really been a hallmark of the conceptual framework of functional medicine that differentiates it from that of a histopathology-focused, disease-diagnostic model.   Nitric Oxide: An Important Physiological Mediator Molecule This month I was very fortunate to interview a leader in this field of cell signaling. In this case the cell signaling substance is nitric oxide. Nitric oxide was the Molecule of the Year. It won the Nobel Prize in medicine and physiology for three extraordinary investigators who independently discovered nitric oxide as being an important physiological mediator molecule. Nitric oxide, or NO, is nitrogen and oxygen (not nitrous oxide, which is laughing gas). NO was found by Ferid Murad and his colleagues, and by Farragut in a different lab, and was ultimately recognized to be a very important modulator of physiological function related to signaling through the guanosine monophosphate signaling pathway (or cyclic GMP pathway), that has to do ultimately with phosphodiesterase, endothelial function, and vascular tone.   Sildenafil: A Drug Designed for Hypertension Becomes a Lifestyle Drug and Nitric Oxide Gains Commercial Interest Later, this got translated into an interesting commercial application through a drug that was being explored as an anti-hypertensive drug that had effects on nitric oxide, cyclic GMP, and phosphodiasterase. It was a drug called sildenafil. In the studies that it was being employed in to evaluate its effect as an antihypertensive, sildenafil had an off-target effect in males: it increased erections. I can imagine the marketing staff at Pfizer said, “Now hold on. We’ve got two applications for this drug. One is the indication to treat hypertension, and there are many medications in that class. And then here’s another interesting…not disease application, but certainly what we might call a lifestyle drug application for treating a condition that we can promote to become a really major new syndrome: erectile dysfunction syndrome (ED). We’re going to promote this as being a pandemic problem, and here’s a solution to it.”   Sildenafil ultimately became a billion-dollar, blockbuster addition to a category now called lifestyle drugs. That medication is basically managing this defect in nitric oxide production by the vascular endothelium. That really took the nitric oxide story to a new level of interest commercially, and built a huge business around it.   But leaving behind the erectile dysfunction component, there is this whole other story about endothelial tissues that line the whole surface of our body and how they relate to environmental agents and ultimately trigger the release of mediator substances that regulate the tone and function of those tissues. It’s that story that we’re going to hear much more about in this extraordinary interview with Dr. Nathan Bryan, who is the author of a well-written and highly information-rich book (a very readable book) titled The Nitric Oxide Solution: How to Boost the Body’s Miracle Molecule to Prevent and Reverse Chronic Disease.[2] 

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INTERVIEW TRANSCRIPT

Researcher of the Month Nathan Bryan, PhD The University of Texas Health Science Center at Houston 7000 Fannin, Suite 1200 Houston, TX 77030 Once again we’re at the high point of the edition, which is our Clinician/Researcher of the Month. Nitric oxide was the molecule of the year about 15 years ago. I’ve talked about the nitric oxide story and its interrelationship to physiology in Functional Medicine Update before. The three forms of nitric oxide synthase are the endothelial, the neuronal, and the inducible immune. I’ve had the pleasure and privilege of talking with two Nobel Prize winners in medicine and physiology who were in the group of three that discovered this nitric oxide physiology connection: Dr. Ferid Murad (right after he won the Lasker Award for his work) and also Dr. Louis Ignarro from UCLA, one of the co-recipients of the Nobel Prize. Today, there is even more clarity and understanding of the nitric oxide physiology story. I’m excited to talk with a person who is working with Dr. Murad in this field of nitric oxide physiology, Dr. Nathan Bryan. Let me tell you a little bit about Dr. Bryan in case you are unfamiliar with his name. He is the author of a book on this topic: The Nitric Oxide Solution: How to Boost the Body’s Miracle Molecule in Preventing and Curing Chronic Disease. It is a very descriptive overview of the extraordinary research work that Dr. Bryan and his colleagues have been doing at the University of Texas (UT) Health Sciences Center in Houston. Beyond that, he has been extraordinarily involved in the fundamental research in this area as faculty working in the school of biomedical sciences at the UT Houston Medical School. Dr. Bryan is an active member of the Nitric Oxide Society. He has been published extensively in Free Radical Medicine and Biology, and he is working with the American Heart Association as a member of the AHA. Dr. Bryan was recognized as the university’s most accomplished young investigator in 2007 (not a small achievement whatsoever). He has published over 30 peer-reviewed papers in top-flight journals, and he has been cited over 1200 times for the pioneering work that he is doing in this area, which ties together with nutrigenomics and the gene-environment connection that we have focused on so heavily in Functional Medicine Update. Dr. Bryan, with great thanks we welcome you to Functional Medicine Update. Maybe you can help us get into your fascinating story by giving us a little bit of background about what led you to this work on this extraordinary molecule? NB: Thanks, Dr. Bland, for the great introduction. It’s certainly a privilege and honor to join you today. We’re certainly excited about where the field is moving. We think we’ve made some seminal discoveries that really are changing the paradigm of how we look at nitric oxide regulation and production within the human body. I’ve been in this business for over 10 years now. I started out training under Martin Feelisch, a pharmacologist who was involved in the early work on nitric oxide, looking at the mechanism of action of nitrovasodilators. After that I was at Boston University School of Medicine and worked under Joe Loscalzo in the Department of Medicine at the Whitaker Cardiovascular Institute. And then I was recruited by Ferid Murad at the Institute of Molecular Medicine in Houston to join their drug discovery program in trying to figure out how to develop and create novel, safe, and effective nitric oxide-based therapeutics. Thirty years after the discovery of nitric oxide (or what was then endothelium-derived relaxing factor), and 12 to 13 years after the Nobel Prize, there has really been no hallmark discoveries in terms of novel therapeutics aimed at restoring nitric oxide physiology or homeostasis. That’s where we’ve come in and—I think—made some important discoveries. Being trained as a physiologist, I was always taught that the body has an enormous redundancy, so there is more than one pathway to generate such a fundamental molecule. Today, really the only pathway discovered or described in the literature is through the 5-electron oxidation of l-arginine, so this l-arginine-nitric oxide pathway. It’s inside probably one of the most complex and complicated reactions that takes place in the human body. Why would nature divide such a complicated and complex pathway to create such—what we think—is one of the most important and fundamental molecules in physiology? Nitrite Has Been Found to Be Bioactive and Cardioprotective Serendipity really factored into where we are today. We were looking at how people have used the oxidative end products nitrite and nitrate for 20-plus years as kind of proxies or biomarkers for local nitric oxide production. What we found back in the early 2000s was that these molecules, particularly the nitrite anion, have some biological activity. We published a paper in Nature Chemical Biology showing that nitrite can actually modulate post-translational modification of proteins through these nitrosylation events that can induce gene expression and elicit cell signaling events.[3] So it wasn’t this innocuous, inert biomarker of nitric oxide; in fact, it was actually bioactive itself, particularly under conditions where the NOS (or nitric oxide synthase) production of nitric oxide becomes dysfunctional. We, and others, have done a lot of studies since looking specifically at the physiological activity of nitrite, and what we’re finding is that it is extremely cardioprotective. If we subject, in experimental models, heart attack or stroke and have this anion on board, we see enormous protection from injury in the brain from stroke, and enormous protection in the heart from a heart attack. We study finding ways that we can restore nitric oxide homeostasis independent of this nitric oxide synthase production of nitric oxide. JB: I have had the chance to read your really fascinating 2005 paper in Nature Chemical Biology that talks about nitrate as a signaling molecule and a regulator of gene expression. I think this is a very interesting new chapter you are describing. I know many people have historically looked at urinary nitrate as a surrogate marker for nitric oxide. Given what you said, is there some ratio between urinary nitrite versus nitrate that is more specific in terms of assessing nitric oxide physiology, or is it looking at the total of the sum of nitrite plus nitrate in the urine that kind of gives you a surrogate evaluation? Measuring Specific Nitric Oxide Biochemistry is Proving Complicated NB: If it were only that simple. In assessing biological samples from patients in the clinic, sampling a single compartment at a single time point really gives you very little information. What we’ve always tried to do is take plasma samples, urine samples, or any tissue or biological sample we could from patients at the same time and over time, because really the renal excretion of these two anions depends a lot on renal function, so people with renal insufficiency or renal failure are going to have different excretion profiles from otherwise healthy people. What’s happening in the urine is completely different from what’s happening in the plasma, and we know from experimental animal models that what’s happening in the plasma isn’t always a direct reflection of what’s happening locally in a specific tissue of interest (in the heart, for example). In terms of fingerprinting specific nitric oxide biochemistry in a specific tissue bed, it’s really difficult to get a handle by measuring either urine or plasma samples, but we’re developing techniques and technologies that give us a better handle on what’s going on. Typically nitrate is the oxidative end product, and there is some reabsorption that happens in the proximal gut which then mixes with the nitrate in your diet and what’s produced endogenously through the oxidation of nitric oxide, and then there is some tubular reabsorption in the kidneys of this anion and then what’s left over spills out into the urine. Broadly speaking, you can get a feel for total body nitric oxide availability by measuring certain biological compartments over a period of time. JB: I know you’ve done some work on looking at salivary nitrite as a surrogate secondary biomarker. Does this appear to have some broad brush potential in evaluating aspects of nitric oxide status? NB: It does. We’re actually very excited about this. One of the things we’ve been trying to do as we move this field forward is to bring more awareness about nitric oxide. We, in the biomedical science arena, are really excited about it and we’ve known about it for 20-plus years, but if you go out on the streets and ask the lay people, “What is nitric oxide?” I’m guessing probably 75 to 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of people don’t know what it is or they confuse it with nitrous oxide, the anesthetic they get when they go to the dentist. We realize that there is a huge educational hurdle to overcome. You can’t go to your physician and ask for a lab to determine your nitric oxide level like you can for vitamin D, or get a reading for your cholesterol, or for magnesium, or any other blood labs that are standard measurements. Knowing that, we’ve been doing correlation studies for a number of years and trying to get a sense of a way that we can noninvasively determine a person’s nitric oxide status. As we mentioned, there is an entero-salivary circulation (a recirculation) of nitrate/nitrite and that then creates what we call a human nitrogen cycle. For instance, about 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the nitrate that is produced within your body and also what you take in through eating certain foods (for instance green leafy vegetables) is absorbed in the proximal gut, and then that’s concentrated in your salivary glands, so there is an entero-salivary circulation. Colormetric Evaluation of Salivary Nitrite May Be A Powerful Screening Tool Each time you salivate you get a burst of nitrate in your mouth. And then the cyclic anaerobic bacteria that reside on your teeth and in the crypts of your tongue then have a functional nitrate reductase. This nitrate reductase produces salivary nitrite levels that are anywhere from 100 to 1000 times higher than the concentration that is found in your plasma. Each time you swallow you get a burst of nitric oxide because the PKA of nitrite is about 3.2, so in the acid environment of the stomach each time you swallow, provided you have sufficient entero-salivary circulation, you get a burst of nitric oxide in the stomach. This pathway has been shown to enhance gastric mucosal blood flow, increase absorption of nutrients, and prevent overgrowth of food borne toxins or bacteria, including H. pylori. So it’s really an essential pathway for modulating nitric oxide homeostasis. What we realized then was that we could capture this through a colorimetric noninvasive diagnostic. We developed really the first and only nitric oxide diagnostic through the UT Health Science Center, Houston. JB: I’ve seen this and I think it is really fascinating. It’s basically a dipstick that does colorimetric evaluation of saliva nitrate, which to me is a very, very powerful kind of screening tool. Have you had some occasion to clinically evaluate how this matches nitric oxide status? NB: We have, and we took really an extreme population. We took people that have been on chronic dialysis, so people with kidney failure, because really these people suffer from usually a 10 to 20 times higher incidence of cardiovascular disease. These people die of cardiovascular-related events, not anything to do with their kidney failure (although one could argue there’s a direct connection). We recently just completed a study where we sampled the blood from these dialysis patients going into the dialysis unit and coming out of the dialysis unit. We sampled their blood and saliva after 4 to 5 hours of dialysis. What we saw and found was the salivary levels of their nitrite and nitrate were actually much more predictive of the scavenging effects of this chronic dialysis procedure in scavenging nitric oxide than what was reflected in the blood (or I should say just as predictive). We’re finding that if you increase endogenous nitric oxide production either through therapeutics such as organic nitrates, or if you increase endogenous nitric oxide production by eating certain foods or adopting a diet that may be rich in nitric oxide activity, then you can enhance this nitric oxide production through this entero-salivary circulation. And if you become nitric oxide deficient or depleted, then we can see a reduction in the entero-salivary circulation or the recirculation of nitrites. Obviously this is new technology and we’ll do more validation studies as time goes on, but as we stand right now we have a pretty good correlation between total body nitric oxide production or availability in what we are able to pick up through our salivary test. JB: That’s an exciting next step in kind of making this more real to the clinician, having the availability of a surrogate marker. Let’s now talk about nitric oxide at the physiologic level. When we first learned about this we learned about the three isoforms of nitric oxide synthase or NOS, which were the neuronal, endothelial, and immune-inducible, and we had this concept that two of the forms were constitutive and one of the forms was inducible. I think since then much has traveled to better understand the form of these enzymes that are involved with nitric oxide production and how they relate to physiology. Could you give us an update on that as it relates to what’s now known? NB: Right. That was obviously a misnomer, as we know now and as you pointed out, because there are constitutive forms of the inducible isoform (you can actually induce or up-regulate the constitutive eNOS and nNOS), so now they are commonly referred to as isoforms NOS 1, 2, and 3. The constitutive NOS is still recognized as a calcium-dependent, tightly-regulated production of nitric oxide where with the inducible (the inflammatory) component you get this chronic, nauseous overexposure/overproduction of nitric oxide. What we have most recently realized is that you can specifically modulate the constitutive (or what we think are the beneficial) isoforms of nitric oxide, specifically through the modulation of citrulline in the body, so via the urea cycle in our body. L-arginine is classified as a semi-essential amino acid, meaning that your body produces it but not in a net effect that it is sufficient to sustain all metabolic activity, so you need L-arginine from the diet. But what we are realizing is this urea cycle production of L-arginine, specifically from L-citrulline, is this particular pathway preferentially shuttles L-arginine into this constitutive nitric oxide pathway. The L-Arginine Paradox As you are probably aware, there is an L-arginine paradox, and the paradox lies in the fact that the Michaelis constant (Km) and the saturation kinetics for the NOS enzyme is about 5 micromolar, but intracellular concentrations of L-arginine are typically 100 to 200 micromolars. Even under basal steady state conditions, the NOS enzyme is theoretically saturated, so the paradox lies in the fact that if you give L-arginine, in some cases you can then produce more nitric oxide. There are a number of hypotheses out there on how to do that, though. Lou Ignarro suggests—and I think it is probably the prevailing paradigm—that you may be out-competing the endogenous inhibitor, asymmetric dimethylarginine. But we are finding is that you can actually preferentially shuttle L-arginine into the nitric oxide pathway by giving the body citrulline. You are basically providing the body with the substrate it needs to locally and specifically turn that citrulline into L-arginine that can then make nitric oxide. There are at least eight metabolic pathways to utilize L-arginine, and it is estimated only about 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} goes to the nitric oxide pathway, but we can make this much more efficient through using L-citrulline instead of L-arginine. JB: This is fascinating, I think, on multiple levels. For those that are not biochemists that are listening—a preponderance of our supporters are clinicians who may not be completely up on their enzyme kinetics and enzyme activity—let me just say a couple of quick words about what we just heard from Dr. Bryan. This concept that there is this difference between the Km value of the enzyme and the in situ concentration of its substrate, suggesting that at the concentration in situ that you are completely saturating the enzyme, so giving more wouldn’t necessarily have any more beneficial effect because you are already totally loading it. But yet clinically you see effects, even against the paradox of this enzyme kinetic saturation. It is not only very interesting relative to arginine and its relationship to nitric oxide, but I think there is a general concept that may be very interesting as it relates to the role of a number of putative precursors to various substances that are regulators of intercellular signaling and have some nutritional relationship. For years we’ve had this discussion about mass action effects, and actually it comes out of Linus Pauling’s article in 1967 in Science magazine titled “Orthomolecular Psychiatry,” where he talks about Km and talks about concentrations and pushing, by Le Chatelier principle, equilibrium more to the right.[4] Some of these pathways are more than just linear pathways, as Dr. Bryan is pointing out. There can be circuitous routes in order to facultative respond to metabolic pressure by increasing substrate concentrations that are not just this linear A-goes-to-B type of model. I think this is a very important chapter, in general, to our understanding as to how substances may work at higher concentrations than would be normal. We say, “But the enzyme, for its single pathway, is already saturated. There may be multiple routes to conversion.” That’s number one. Number two, which I would like to ask you to follow up on is when nitric oxide is produced through maybe this interrelationship of the citrulline-arginine conversion pathways and these eight different metabolic pathways, is it then serving as an autocrine, a paracrine, or an endocrine messenger, or is it all of them? NB: We have evidence to believe it is all. Great point on the follow-up for the enzyme connection. I think you’re spot on in terms of it is not just a single pathway, it’s much more complicated than that. When nitric oxide is produced, it’s a gas so it is produced by endothelial cells, and its first function is that it diffuses into the underlying smooth muscle, so it acts on a neighboring cell in a paracrine fashion. Once nitric oxide is produced it only stays around for about a second, and much less under certain conditions. The question has always been: Is there an endocrine function of nitric oxide? It is so short-lived, how can it survive transport in a sea of oxyhemoglobin, which is its known scavenger, to elicit distal functions? We’ve played with that question for a number of years, and in 2007 we actually demonstrated this—quite convincingly, I think—through a paper we published in the Proceedings of the National Academy of Science with Dave Lefer’s group, who was then at Emory.[5] We over-expressed the nitric oxide synthase enzyme, specifically in the heart. If you subject these animals to left anterior descending artery ligation and subject them to a heart attack, they are very protective. They heart sees very little injury. They recover quite nicely, and they do very well. What we also did in these mice, even though nitric oxide is over-expressed and over-produced, specifically in the heart when we measured their liver and blood levels of nitric oxide, they were elevated as well. And then if we subjected these animals to hepatic ischemia reperfusion injury, we found that there was enormous protection from injury for IR injury. Obviously there was an endocrine function because the nitric oxide that was only over-expressed in the heart then spills out into the circulatory system. It is transported into distal tissues and elicits a level of protection from insult. We recognize it is one of two (if not both) carrier molecules. One was nitrite, which was elevated, which we know is tissue protective, especially under ischemia reperfusion conditions, and also nitrosothiol, so these low molecular weight nitrosothiols that can then be transported through the blood and elicit these trans-nitrosations that may affect protein structure and function. JB: This is why these conversations are so exciting, because you never know how they might morph and where they might take us. First of all, I just want to compliment you on that PNAS paper, “Dietary Nitrate Supplementation: Protecting Against Myocardial Ischemic Reperfusion Injury.” I think it’s a brilliant bit of work—a really well-written, very articulate paper. I think the companion paper, is also from your group, in the Journal of Biological Chemistry in 2008, “Tissue Processing and Nitrate in Hypoxia.”[6] It seems to frame a whole different model, or let’s say the next step in our understanding of this nitric oxide/nitrate/nitrite connection. Now let me, if I can, ask you the following clinical questions. A lot of our listeners might be saying, “Oh boy, I’ve been administering arginine to patients to try to enhance their nitric oxide production, but given what I’ve just heard you say, is it possible that I could be enhancing aspects of nitric oxide that might be deleterious to as patient that has inflammation onboard because I’ve now maybe done something or upset an important equilibrium in a harmful way?” What’s our thought about that question? Clinicians Should Consider Adverse Events Related to L-Arginine Therapy NB: I think that’s a very good point. I’ve seen anecdotal evidence in the clinic of people having adverse events. In fact, there was a JAMA paper published in 2006 where they tried to give post-infarct patients L-arginine therapy after a heart attack to see if they could improve patient outcome from the heart attack. They had to stop the trial because the L-arginine was actually killing more people than the placebo.[7] I think without understanding the context of that little black box from arginine to nitric oxide, that naiveté is what leads to these adverse events, I think. As I mentioned, it’s a 5-electron oxidation requiring six different co-factors and substrates, and if one or several of those substrates aren’t at the right place at the right time, you can actually get superoxide produced instead of nitric oxide, thereby exacerbating any condition. There are two things there: 1) not understanding the full context (if you give L-arginine with some antioxidants to keep this reduced co-factor pool reduced and available to be used by the nitric oxide synthase enzyme, then it becomes much more effective); 2) the underlying inflammatory condition (if you just seed this enzyme L-arginine, the inducible isoform utilizes L-arginine too, so you may be fueling that inducible isoform by feeding L-arginine and really not feeding the constitutive form which is what you really want to be doing. So there is enormous complexity in the regulation, and specifically modulating the constitutive (or beneficial) isoforms of nitric oxide. How you segmented this is trying to understand: How do we restore nitric oxide homeostasis in a patient population? I think part of it is through this L-arginine oxidation pathway, but I think at least half of it (if not more) comes from a dietary influence. We’ve done a number of studies looking at nitrogen oxides that are found naturally in foods (particularly green leafy vegetables) that can then undergo this reductive pathway from nitrate to nitrite to nitric oxide. This seems to account for—in our hands and many others—about 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the bioactive pool of nitric oxide. This was exciting for us because then we had a dietary intervention to overcome so-called endothelial dysfunction, or an insufficiency of endogenous nitric oxide production. Seeing Nitrites in a Different Context JB: Which translates clinically into hypertension and poor vascular endothelial responsiveness. I think the article that you were the principal author of that appeared in the American Journal of Clinical Nutrition in 2009 titled “Food Sources of Nitrates and Nitrites: The Physiological Context for Potential Health Benefits,” is really a landmark paper because in many peoples’ minds nitrites are only associated with methemoglobinemia, and they’re a problem, and they should be removed from the diet, but this puts a whole different context and spin on it.[8] Have you had people raising their eyebrows at all when you talk about the beneficial effects of nitrates and nitrites in the diet? NB: We have. We get a broad spectrum of response, sometimes a visceral reaction from people who grew up in the 60s and 70s who were taught that these were human carcinogens, they were unwanted contaminants in our food and water supply. But you know that was long before it was ever discovered that these anions were actually produced within our bodies, so they’re not contaminant foreign food additives; they’re actually naturally occurring molecules that are produced within our bodies. The notion that they’re toxic…you know, nothing is without toxicity. Obviously there is a context for health benefits and for toxicity and it has to do with concentrations or total exposure. We’ve gotten mostly positive response because I think this completely changes the paradigm of how we think about nitrogen oxides in our food supply, how we think about modulation of endogenous nitric oxide production, and really then begin to put together a program or a strategy to treat people who may be nitric oxide insufficient. I think it’s a combination of fueling that endogenous pathway and creating a reservoir of dietary interventions of a bioactive pool of nitric oxide. Summary of Nitric Oxide Points JB: Let me just summarize as a weigh station, here, as we move on to the next series of questions. We’ve learned a tremendous number of things already from you. We’ve learned that dietary nitrate and nitrite has an impact upon nitric oxide function and also works directly through some of this regulatory processing to regulate gene expression. Secondly we found that nitrite and nitric oxide both are cardioprotective as well as vascular endothelial active and help in smooth muscle relaxation (vasodilation). We’ve heard from you that if you use the appropriate kind of nutrient mixture which includes things like citrulline, and nitrite, and various antioxidants, that you can modulate various pathways that are associated with nitric oxide production, not just the single-A-going-to-B nitric oxide synthase pathway. You’ve also told us now that the role of nitric oxide is far greater than we thought originally as it relates to its signaling effects. It’s more than just its first name: vascular endothelial relaxing factor. Now we’re talking about its role in modulating things like bioactive sulfhydryls, and oxyhemoglobin, and many other molecules by nitrosation, which then can have a pleiotropic series of effects, and then that raises, obviously, a question. I think the highest concentration of active thiols intracellularly is in glutathione, which has that cysteine residue (the central amino acid in glutathione) sitting there. What do we know about the interconnection with redox in glutathione and nitric oxide? It seems like that’s an emerging part of the story. NB: It is and I think probably one of the main vascular carriers of nitric oxide activity is through low molecular weight thiols such as free cysteine or glutathione. In fact, it’s glutathione or nitrosyl glutathione that acts as the intermediate between these transnitrosation reactions that act to post-translationally modify protein thiols. We always think about it in terms of phosphorylation, so you’d have kinases and phosphorylations that add and remove phosphate groups to proteins that then affect structure and function. We have this same paradigm now with nitric oxide. There are nitric oxide congeners such as either hydroxyl or ML+ that can then directly nitrosate files, either chemically (and there are some enzymatic pathways that have been discovered where you can then modify a critical cysteine residue within a protein and then do a denitrosation).hat was kind of the first new paradigm, particularly put forth by Jonathan Stanley (then at Duke) on a novel signaling aspect of nitric oxide. Then the question was: If this is a signaling event then doesn’t there have to be an on/off reaction, particularly an enzymatic denitrosation? There have been a number of enzyme systems now to hide the dehydrogenase system that can denitrosate protein nitrosylthiols through the intermediary of glutathione. As you alluded to, this free file pool, particularly within glutathione, is very, very important and probably critical in modulating nitric oxide modulation of protein thiols. JB: Now let’s take that to a clinical perspective for many of our listeners who are bearing with you and I having a wonderful exotic discussion about biochemistry and are waiting patiently for when this has a clinical application. Let’s talk about the patient who is insulin resistant and hyperinsulinemic. A person who has elevated uric acid and/or elevated homocysteine and elevated hsCRP, so they’ve got an inflammatory biomarker, they’ve got some indication of alteration in homocysteine/folate processing, and they’ve got this xanthine/oxidase thing that is seen as an elevated uric acid. And, if they even do more extensive laboratory testing (let’s say that they measure asymmetric dimethlyarginine (ADMA) —this would be more of an esoteric analyte but it can be done so they have an ADMA level that is elevated), how would that all fit together with the model that you are emerging around nitric oxide, or what kind of clinical thoughts might derive out of that kind of a patient? NB: I think it presents the perfect scenario of global nitric oxide insufficiency because everything you talk about there, from a clinical standpoint, talks about dysregulated nitric oxide production. Starting with the first part—the insulin resistance—part of the insulin signaling pathways is this production of insulin by the beta cells, and then activation of certain cell signaling pathways that eventually lead to GLUT-4 translocation and glucose uptake in the cell. Intermediate, in that pathway, is nitric oxide. What we’re finding is that particularly in pre-diabetics or even diabetics, they’re nitric oxide insufficient or they become dysregulated and that’s the reason for the cardiovascular complications or higher incidence of cardiovascular disease in diabetics and why it’s a risk factor. If you have a roadblock at that production of nitric oxide then you can’t have part of this GLUT-4 translocation pathway as nitric oxide-dependent. What we think is that nitric oxide produced through the insulin signaling pathway leads to a nitrosation event of GLUT-4, which then signals it to translocate to the membrane, take up glucose, and then you get normal glucose metabolism and uptake. But when you have dysregulated nitric oxide production that event doesn’t occur. Although you’re getting sufficient insulin production, you’re not completing the pathway. We think if you can restore normal nitric oxide signaling or homeostasis then you can eliminate that roadblock and complete the insulin signaling pathway. The inflammatory biomarkers of the CRP—obviously I think a lot of people (biochemists and physiologists) consider nitric oxide an anti-inflammatory molecule because it can actually squash the inflammatory response. And then the uric acid—the xanthine oxidase–is one of the prime mediators, or it’s an active nitrite reductase, so you can actually out compete that uric acid production pathway by having sufficient nitrite around to where we can have another source of nitric oxide. Actually we have seen, anecdotally, people that we’ve given our nitric oxide intervention to that have less flare-ups of gout and actually see symptomatic relief. Clinical Connections to Nitric Oxide JB: Thank you. I hope you clinicians now feel a sense of satisfaction—like taking a deep sigh, here—that now you’ve endured our biochemistry to recognize that that patient with the marginally elevated uric acid, and maybe homocysteine elevations, high sensitivity CRP, and some insulin resistance with central adiposity, and if you measured ADMA in their blood, you might find it elevated: there you go. They might have marginally elevated blood pressure too, and they might have increased carotid intimal medial thickness (or CMIT tests are not looking so good). Think nitric oxide, and think the citrulline/arginine/antioxidant/nitrite connection. In fact, Dr. Bryant authored a very interesting paper that really talks to this titled “Dietary Nitrite: Preventing Hypercholesterolemic Microvascular Inflammation in Reversing Endothelial Dysfunction.”[9] This was in the American Journal of Physiological Heart Circulatory Physiology in 2009. There’s lots of stuff to support what we’re alluding to here. Let me ask the next question that follows on the heels of this. Because you’ve talked about dietary nitrates and nitrites playing a role in the systemic production of nitric oxide and the role that nitrite itself has, that also begs a companion question and that is: Are there known phytochemicals that could modulate this pathway not through direct nitrite contribution, but through effects through kinase pathways or other regulatory mechanisms to influence the enzymes that are then are involved with nitric oxide production? I know the answer to that question because you authored a paper on this looking at traditional Chinese medicines and the relationship to nitric oxide bioavailability. What about phytochemicals and the role of nitric oxide production? Nitric Oxide and Traditional Chinese Medicine NB: Yes, I think they’re absolutely essential. I can’t take full credit for that. I had a post doc contact me several years ago who was trained in traditional medicines; he was an MD from China. He was working here in the US as an interventional cardiologist and he was interested in some of the work we were doing and he said, “I wonder if there is a connection between the traditional medicines we use in China to treat cardiovascular-related diseases and nitric oxide production?” We actually just did a very simple experiment and got really profound results. He went to a local acupuncture shop and I told him to purchase only herbs or botanicals that were used specifically for cardiovascular indications. We put them through our nitric acid assay. We looked at how they activated soluble guanylate cyclase, how they activated endothelial nitric oxide production, as well as their ability to turn these anions, nitrate and nitrite, into nitric oxide. What we were thinking was kind of a rescue pathway to restore nitric oxide, because most of these herbs contain very, very high concentrations of nitrate, and in some cases nitrite. To kind of preface the importance of that, and really the importance of the phytochemicals and this whole pathway, is the fact that we’ve done a number of studies—particularly the JBC study in 2009.[10] Mammalian systems are grossly inefficient at converting these anions back into nitric oxide. There is a three-leg order of magnitude of inefficiency from nitrate to nitrite to nitric oxide. One could argue that from the physiological concentrations that we have in our blood and our tissue, can you get any appreciable amount of bioactive nitric oxide from the steady state concentrations that are normally there? One can argue that, but people who have endothelial dysfunction and risk factors for cardiovascular disease, clinically they have less nitrite and nitrates in their blood and their tissue. So then, when they need that pathway even more than healthy people, we’re so inefficient that we can’t do it. My point is that we’ve recognized traditional medicines are herbs and phytochemicals that do this reaction for us. When you ingest these in traditional medicines, they provide this reductive pathway to then take the inorganic nitrate to nitrite and the nitrite, particularly, to nitric oxide. This then becomes an oxygen-independent reaction that’s very, very efficient. You can actually pick up this activity in the blood after you’ve taken these medicines. Whatever it is, it’s surviving first-pass metabolism. When we got really excited about that, we were interested in trying to isolate and identify that active component that was responsible for this. We did a number of extractions and counter current chromatography to try to identify the active components to where we could then synthesize and call it a drug, which was the business we were in at the time. Not surprising to naturopaths and people who use functional medicine, when we fractionated the parent compound, the activity fell apart. So it was really the synergistic effects of the parent compound in its unrefined form that had the activity and it wasn’t any one particular component. In terms of drug discovery we really hit a roadblock and we couldn’t move forward. We scent screened probably over 200 traditional medicines and botanicals and found really a handful of hits that are very, very effective at this reductive recycling to nitric oxide. We realized that if we could harness that activity and its parent compound form, then we would probably have something better than a drug—something that didn’t inhibit a single pathway but acted synergistically that restored nitric oxide production. You could harness that activity, and hopefully without all the adverse side effects that many drugs have. JB: I want to really compliment you. This paper that you authored with your post doc in Free Radical Biology and Medicine in 2009 is titled “Nitric Oxide: Bioavailability of Traditional Chinese Medicines Used for Cardiovascular Indications” and is a really interesting and provocative step forward in our understanding of how agents within traditional medicines influence these regulatory pathways.[11] I think in the article you write about frankincense and red peony root and ginseng as part of the several hundred things that you studied having effect. I know you’ve seen things with horse chestnut extract as well. I think this is a very powerful contribution to our understanding of this whole field. It is more than just the amino acid, arginine, or the amino acid, citrulline. There is a whole variety of different things in our environment that influence this regulatory pathway. NB: Right. Yes, we’re excited about it. We think it now creates a new strategy to intervene naturally and restore normal nitric oxide production. Nitrate and Nitrite Measurements in Breast Milk, Bovine and Soy Milks JB: Let me close with one last part of this story. This is certainly not the end of this story; we could spend hours talking with you. I know we’ve just touched the surface of the envelope, here, of the things that you are working on and the things that you’ve discovered. One thing that I think our listeners would find very interesting is this whole concept of infants. They are born with a sterile gut and obviously their conversion from microbes may be different from that of adults that have gut resident colonization, and they’ve got biofilms, and a microbiome that is working as a secondary conversion factor for them. You’ve authored this recent paper in Breastfeeding Medicine talking about “Nitrate and Nitrite Content in Human Formula, Bovine and Soy Milks: An Implication for Vascular Health in Infants.”[12] Maybe you could tell us a little bit more about this. It’s a very interesting chapter in the story. NB: Yes, this is interesting. I’m curious by nature. Three years ago my wife gave birth to our now three-year old. Kind of nonchalantly, the nurses and the physician, when we left the hospital, said, “You’ll want to breast feed [and this was our second son], but if you don’t then give the baby this formula.” I got to thinking about what’s in this formula that is not in the breast milk and vice versa. After a little bit of a struggle, I convinced my wife to go to my lab and I expressed some of her breast milk (at the time, colostrum) and then did a biochemical comparison to what was in the formula. What we found was astounding: there was about 25 to 30 times more nitrite and nitrate in that early colostrum—in that breast milk—than what was in that commercially available formula they gave us when we left the hospital. I wanted to know if it was just an anomaly (that she, being my wife, probably had high nitric oxide activity in her breast milk). We got an IRB approved. We tested over 70 mothers that were admitted to Memorial Herman Labor and Delivery, and we sampled breast milk throughout postpartum time periods, from day 2 all the way up to 4 to 5 weeks postpartum. What we found was the ratio of these anions changed with the transition of milk. As you are probably aware, the early milk is the colostrum. People think it is high in immunoglobulins. It is really the essential nutrients for these first days of life. After day 4 to 5 to two weeks, you get what you call transition milk, and then from two weeks on it is what’s classified as mature milk. Physiologically, what we think is happening is when the infant is born, they have a sterile gut; there is no bacteria that are colonized in their gut. We as humans don’t have a functional nitrate reductase; we rely on the bacteria in our mouth and in our gut to perform this. As the gut becomes colonized over the period of the first several days, nature has provided a way—we think—as a source of nitric oxide. It’s the nitrite in the milk that when the baby takes the colostrum it’s reduced to nitric oxide in the stomach and the gut, but then as the bacteria begin to colonize, there is really a perfect overlap in the time of colonization to the timing of the change in these anions taking place. Once the bacteria are colonized, then they have the machinery in place to reduce the nitrate in the milk to nitrite, which then becomes nitric oxide. Clinical Importance of the Breast Milk Study This becomes really exciting and important clinically in, particularly, a condition called necrotizing enterocolitis (NEC). Premature babies that are subjected to hypoxia and are in the NICU are fed formulas developed for this and I think it’s still about a 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} mortality rate. Babies that are breast fed don’t develop NEC. We have some very preliminary data showing (and we have nanomodels of this): if we replete the missing nitrite in the breast milk and just fortify it in the formula, we can completely prevent the development of necrotizing enterocolitis. In fact, we’re about to take this into the clinic. From a neonatal standpoint, this nitric oxide story stays with us from the time of birth until we pass on, so it is something that we can’t ignore at any point in life. JB: First of all, the last sentence in your abstract of that paper I think is very powerful for those of us that think in kind of web-like physiology. I’m quoting: “These data support the hypothesis that the high concentrations of breast milk nitrite and nitrate are evidence for a physiological requirement to support gastrointestinal and immune homeostasis in the neonate.” That has a spreading effect of impact other than just the neonate about the whole relationship between gut, immune, and regulatory control mechanisms. I want to applaud that sentence. I think it’s a great one. NB: Thank you. JB: I also found it very interesting, when you look at your data, and you contrast the nitrate/nitrite levels in colostrum, and transition, and mature breast milk. Let’s take mature just as an example. The formulas were extraordinarily low, in general, in these constituents compared to mature breast milk, but some of the soy milks were in the same range as breast milk, which I found interesting. NB: Right. We’ve started a study on soy-based products versus their non-soy counterparts (soy milk, regular milk, soy-based proteins versus meat-based proteins). It’s a common theme. The nitrate/nitrite content, or what we think is this nitric oxide activity, is much higher in these soy products and I think may be the reason for a lot of the health benefits of soy versus non-soy products or food-based products. JB: Lastly, Dr. Bryan, for anyone who wants to follow up there is an excellent review article that you have co-authored with Dr. Murad on this whole concept of nitric oxide signaling pathways and targets—a Frontiers in Biosciences article that I think is a very, very good review paper on eNOS, iNOS, nNOS, nitrovasal dilation, the cyclic GMP relationship, how that relates to the Viagra story and sildenafil, which then has to do with vascular perfusion and endothelial function.[13] I just think your contribution to this field and tying it to nutrition and phytochemistry is truly groundbreaking. I would recommend, again, for our listeners, if you want to follow up and get a more simplified explanation of this whole discussion, look at Dr. Bryan’s book The Nitric Oxide Solution, which I think you’ll find really is news to use. Nathan, thanks so much for spending this time with us. I know we’ve taken you away from the laboratory and your work, but we greatly appreciate it. I know our listeners will value from the clinical news to use that comes out of this. NB: Thank you very much for the invite. I’ve enjoyed the conversation. JB: Thank you. The best to you and keep up the great work. I hope that your appreciation of what Nathan Bryan had to say is as great as mine. That was a very eloquent and informative discussion about this complex topic of nitric oxide physiology, and nitric oxide chemistry, and nitric oxide’s role as an intercellular and extracellular mediator, an autocrine- and endocrine-like mediator molecule. Really, really fascinating news to use.  

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[1] Arya F, Egger S, Colquhoun D, Sullivan D, Pal S, Egger G. Differences in postprandial inflammatory responses to a ‘modern’ v. traditional meat meal: a preliminary study. Br J Nutr. 2010;104(5):724-728.   [2] Bryan Nathan, Janet Zand and Bill Gottlieb. The Nitric Oxide (NO) Solution. Neogenis Labs: Webberville, Michigan, 2010.   [3] Bryan NS, Fernandez BO, Bauer SM, et al. Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues. Nat Chem Biol. 2005;1(5):290-297.   [4] Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(825):265-271.   [5] Bryan NS, Calvert JW, Elrod JW, Gundewar S, Ji SY, Lefer DJ. Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. Proc Natl Acad Sci USA. 2007;104(48):19144-19149.   [6] Feelisch M, Fernandez BO, Bryan NS, et al. Tissue processing of nitrite in hypoxia: an intricate interplay of nitric oxide-generating and –scavenging systems. J Biol Chem. 2008;283(49):33927-33934.   [7] Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006;295(1):58-64.   [8] Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic context for potential health benefits. Am J Clin Nutr. 2009;90:1-10.   [9] Stokes KY, Dugas TR, Tang Y, Garg H, Guidry E, Bryan NS. Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction. Am J Physiol Heart Circ Physiol. 2009;296(5):H1281-H1288.   [10] Sanghani PC, Davis WI, Fears SL, et al. Kinetic and cellular characterization of novel inhibitors of S-nitrosoglutathione reductase. J Biol Chem. 2009;284(36):24354-24362.   [11] Tang Y, Garg H, Geng YJ, Bryan NS. Nitric oxide bioactivity of traditional Chinese medicines used for cardiovascular indications. Free Radic Biol Med. 2009;47(6):835-840.   [12] Hord NG, Ghannam JS, Garb HK, Berens PD, Bryan NS. Nitrate and nitrite content of human, formula, bovine, and soy milks: implications for dietary nitrite and nitrate recommendations. Breastfeed Med. 2010 Oct 19. [Epub ahead of print] [13] Bryan NS, Bian K, Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci. 2009;14:1-18.   [14] Ni, Maoshing. The Yellow Emperor’s Classic of Medicine. Shambhala: Boston, 1995.

Welcome to Functional Medicine Update for July 2011. In this issue we’re going to talk about some extraordinary new work in phytochemistry—plant-derived chemistry—and how this relates to cellular function. The complex nature of secondary metabolites in plants, this rich array of compounds that is unique to plants that has to do with things like chlorophylls, xanthophylls, carotenoids, flavonoids, isoflavones, glucosinolates, and polyphenols. There are literally thousands of compounds that are manufactured by the biosynthetic machinery of the genes of specific plants that then are being found to have unique effects on human physiology when consumed as part of the diet. Secondary Metabolites in Plants I find this to be a very remarkable chapter in the evolution of our understanding of nutrition and health. We’ve known from epidemiological work that plants, when consumed in the diet on a regular basis, are associated with lowered incidence of a variety of diseases. We’ve said that plant-based diets are healthy. And as we’ve more commercialized diets and processed plant foods to produce white starch and sugar and extracted fat (so-called compartmentalized foods), we have lost a lot of the value of what’s found in “natural foods” that then are health-promoting. What is it in plants that has this influence on health in a beneficial way that upon their removal somehow lowers the health benefit of that food product? There has been wide-ranging discussion, speculation, and sometimes even controversy around what these secondary metabolites in plants do, and what role they have to play in human physiology. One of the simplest explanations that we’ve kind of last 20 years is that many of these compounds in plants are antioxidants, which means that they help to soak up adverse effects of activated forms of oxygen, such as singlet oxygen, superoxide anion radical, hydrogen peroxide, hydroxyl radical. In this role they serve as cellular protectants. Phytochemicals Are More Than Antioxidants Most of us came to say, “Well, that sounds reasonable. Good, I’ll accept the facts that these phytochemicals are antioxidants. But as more work has been ongoing, particularly over the last decade since the human genome project was completed, we’ve started to recognize from more intimate cellular studies that these phytochemicals have a much more specific role than this general kind of catch-all phrase called antioxidation. They have very specific functional characteristics based on the structure of the secondary metabolite of the plant, meaning the individual phytochemical or phytonutrient, and how they regulate specific cellular function at the genomic level. So they have the ability to speak to genes indirectly, through regulatory mechanisms that ultimately control both genetic and epigenetic expression into what we call the phenotype of the cell, or its functional state. And it is this emerging story that I think is so fascinating because it puts a whole different level of interest and importance clinically as it pertains to the complex nature of phytochemicals and their effect on human health. It also ties nicely back to the longstanding epidemiological associations between higher plant food diets that are minimally processed being associated with lower incidence of chronic disease. It gives us a mechanistic hypothesis as to how these substances—this rich array of secondary metabolites in plants—in a diverse diet that is plant-based, can have very dramatic health benefits, and how the absence of these compounds in the diet by over processing or eating foods that are devoid of these phytochemicals may have lost some of the beneficial attributes of the diet through the loss of the normalization of genetic expression or cell signaling. We’re going to have the privilege this month of talking with an expert in this field, a person who has been studying—at the cell biology and immunological level—the role that these phytochemicals play in various cellular functions. We’ll specifically focus on one of them as a representation of the field in general, and deeper drill into this specific phytochemical. This phytochemical is really even more interesting because it is a secondary metabolite in the gut of a primary phytochemical produced by plants. A Review of the Biochemical Processes Related to Phytochemicals Let me go back and trace that again because this shows you this story is even more complex than we might have initially thought it. The plant, under conditions of its own physiology and the environment in which it is grown, induces its genes to produce these metabolites called specific phytochemicals. Those are then consumed by humans (in those edible portions of the plant). The human then chews them, and subjects them to stomach acid, and they go down the intestinal tract. Those secondary metabolites get converted, by the process of digestive exposure, into a new class of secondary metabolites that really I guess we would call tertiary metabolites that have names like indole-3-carbinol, and diindolylmethane, and phenyl isothiocyanate, and sulforaphane. These are byproducts of digestive juice influence on glucosinolates made by the plants in response to their environments. Now we have an even more complex story of the rate of conversion of those glucosinolates into substances that then have the ability to be absorbed into the body and influence human cellular function. We find this story being reproduced with many other phytochemicals. For example, a family of phytochemicals called lignans is found in many plant foods. The soybean is known to have high lignan content. When ingested, it gets broken down from lignands into lignans, and those then get converted by gut bacteria by their own metabolism into a set of additional new phytochemically-derived metabolites with names like equol, or enterodiol, or enterolactone. These compounds have the ability to be absorbed and influence cellular function. They might seem to be removed from the plant because they are produced by the digestion of the plant material by gut bacteria (certain families) to produce these new chemicals which then influence human health. The story sounds very ecological: we’re connected to our soil and plants through this very interesting chemical cellular matrix that has to do in part with the production of these secondary metabolites in plants called phytochemicals, and they’re further influenced by digestive process and gut microbial fermentation by specific types of symbiotic bacteria into compounds that then influence human health in beneficial ways. I love this story because it ties us into this web of life in a very different way than just thinking about a pill for a problem, or a molecule for a diagnosis. We’re really talking about a symphonic orchestration of interrelationships among the soil, the plant, the environment, the human, and ultimately to even its gut microbiome and how that influences the production of these secondary products that can have a favorable effect on human health and physiology. You’re going to learn much more about this from an expert, Dr. Edwin Lephart from Brigham Young University, who will tell us a lot about the evolving story around equol. Phytoestrogens: Molecules in Soy that Influence Estrogen Signaling We started talking about equol in Functional Medicine Update some years ago when we interviewed Dr. Ken Setchell from the Cincinnati Children’s Hospital, and before that Dr. Herman Adlercreutz from Helsinki University Medical School in Finland, who was actually the person that was credited with coining the term “phytoestrogen.” Dr. Adlercreutz was the first person to actually find these molecules in soy that influenced estrogen signaling (things like genistein and daidzein—the isoflavones). He developed the conceptual framework of how these molecules—these phytochemicals—found in soy foods influence human health, which has been a part of the emerging story of how these thousands of different substances produced by a variety of different plants influence cellular physiology beyond antioxidant effects. If you were to examine a contemporary textbook of nutrition that is used in university courses, in medical school training courses, or anywhere in the United States (actually anywhere in the world), and ask how much of that textbook is devoted to understanding the role of phytochemicals in cellular physiology, you would find a very small number of pages that have any real discreet explanation about the role that phytochemicals play in human health and cellular physiology. That’s because this topic that I’m describing is rather new. It has been only ten years or so in which we’ve started to really understand how these complex mechanisms of action of compounds in plant foods influence health. Textbooks are generally at least ten years behind in reporting the cutting edge of contemporary new knowledge. The textbooks being studied today and the classes that are turning out nutritionists use information that is truly is outdated in terms of understanding the role that phytochemicals play in human physiology. So there are still people going out into the world with degrees in nutrition who consider themselves experts, but unless they are reading the primary literature and listening to the right colleagues, they don’t understand the story. In this issue you’re going to be exposed to news to use at a clinical level that many people have yet to really understand. You’ll have to become an ambassador for bringing this information to your colleagues, and if they—when you talk about it—have a funny look in their eye, like “I’ve never heard about this,” don’t be surprised because this is a fairly new area of evolution in the field of nutrition and health. Retinoids: A Family of Phytochemicals with Unique Effects on Cellular Physiology With that in mind, let’s talk a little bit about the family of substances called the retinoids. The retinoid family is a classic example of how specific families of phytochemicals have unusual and unique effects on cellular physiology beyond their “antioxidant effect,” meaning the ability to just soak up oxygen radicals and prevent free radical pathology. You probably know the retinoid family to be associated with vitamin A, but also recognize that vitamin A retinol can be converted in the body into things like retinaldehyde and retinoic acid, which are interesting derivatives of retinol vitamin A. You also probably know that vitamin A can be derived from beta carotene through conversion in the body by an enzyme that cleaves the beta carotene molecule into two retinol molecules by breaking the bond right in the middle (the double bond) and oxidizing that into what ultimately becomes vitamin A. So the conversion of beta carotene into all-trans retinol requires an enzyme. That enzyme is activated by thyroid hormone and it is dependent upon the trace element copper. Through cellular physiology, retinol inter-converts members of this retinoid family into a variety of additional forms, including cis and trans isomers, because there are many double bonds in these molecules. Remember, they started off as pigments—as things that we could see, like the color red in carotenoid-containing food, and then they get converted by the cleavage reaction into retinol. Retinol loses its color, but it still maintains this unsaturated conjugated double-bond matrix that we found in carotenoids. Vitamin A becomes a part of the color characteristics of the carotenoids, and so these all-trans double-bonds that are conjugated are part of the vitamin A family and they can be isomerized by different kinds of processes that occur within the body into mixtures of cis and trans so we have all-trans retinoids. Those are the ones that are derived directly from all-trans beta carotene. And then you have cis /trans mixtures of different double-bond configurations that are members of the family, all of which have different physiological effects and different effects on cell membrane signaling. I hope I haven’t made that too confusing. I’m trying to give you a sense that beta carotene in the body gets converted into a variety of members of the retinoid family through these enzyme conversion processes. Once converted into retinoids, what role do these phytochemicals that are derived from plants (the carotenoids) have on cellular function? You probably know you can get retinol and vitamin A directly from animal food. The animals have already done the conversion of the carotenes into retinoids for us, so they are present in the food as vitamin A itself. Or, you can get them from plant foods as precursors (as beta carotene that gets converted into retinoids by cellular physiology). So animal foods can directly deliver vitamin A, and particularly because it is a fat soluble vitamin it is found in the fatty components of various animal products, such as whole-fat dairy and so forth, but the precursors are found in your orange-red vegetables (the carotenoid-containing plant products). Retinoids and Xerophthalmia Once you get to retinoids, now the question is: What happens in cellular physiology? Are these antioxidants? What do they do? We’ve been told that beta carotene is an antioxidant. We’ve been told that vitamin A is a substance that helps to strengthen or support the immune system. We know that in children that are vitamin A deficient they get a deficiency disease called xerophthalmia. Xerophthalmia is a condition that leads to the most common form of juvenile blindness in the world, which is the result of a vitamin A deficiency that can be treated by giving children, usually, one big dose of vitamin A that lasts for some time in the child that may not be getting adequate levels of either carotene in their diet or getting adequate vitamin A directly through animal foods. There are projects being done by philanthropic groups to try to improve vitamin A nutriture in the developing world—a not-for-profit organization called Vitamin Angels is very actively involved in providing supplemental sources, free of charge, for the nutrients necessary to prevent blindness in children. It has had a very, very nice track record over the last five years of saving the sight of literally tens of thousands of children. So we know that vitamin A deficiency has something to do with the function of the rods and cones in our eyes (with visual function). But way before you get into a situation of frank vitamin A deficiency leading to a condition such as xerophthalmia, there may be a functional insufficiency of retinoids, and that’s where the story gets more complex. All-trans Retinoic Acid: Like Vitamin D, an Important Regulator of Gene Expression So what role do retinoids play in cellular physiology that manufacture or manifest control of cellular function? I’m going to specifically talk about all-trans retinoic acid. All-trans retinoic acid, which is a product of retinol vitamin A conversion through cellular physiology, , is a very, very important regulator of gene expression like vitamin D is, which we’ve heard so much about over the last several years. Vitamin D is converted into a hormonal form called 1,25-dihydroxyvitamin D3, which then binds to what are called the nuclear orphan receptors (specific vitamin D receptors that sit on the nuclear envelope). That triggers a signal from the cytoplasm of the cell into the nucleus of the cell. Of course we know what’s inside the nucleus of the cell; the book of life (our human genome). This signal activates various transcription factors through this nuclear orphan receptor agonism that ultimately turns on specific genes. There is some controversy still about the specific number of genes that are under control of the 1,25-dihydroxyvitamin D3, but let’s say in the range of 50 or more genes are turned on. So vitamin D is much more than just a vitamin that promotes calcium metabolism. We now recognize that it has effects on insulin sensitivity, cell reparation, immune function, cell cycling, and oncogenesis. We’ve learned that it is much more dramatic even in its influence. Even vascular endothelial function is, in part, related to vitamin D function, as well as immune vigilance. These are all consequences of the pleiotropic effect of vitamin D and these nuclear orphan receptor influences on specific gene activation in different cell and tissue types. I hope I made sense of all of that. Let me kind of simplify it: When a person is suboptimal with regard to vitamin D nutriture, what happens—well before they get rickets—is incorrect signaling through transcription factors that regulate gene expression, so the cellular function gets disturbed or distorted. And it can get distorted into states of suboptimal performance that are related to chronic illness that occur—in a differential way, in different tissue types—depending upon what specific genes are not activated in those cell types as a consequence of the hormonal form of vitamin D being deficient or insufficient. With that as a model, now let’s talk about retinoids. With retinoids we have a similar story. The difference here is that retinol (vitamin A) is not converted into a hormonal form, but rather it is converted into secondary members of the retinoid family, like all-trans retinoic acid. All-trans retinoic acid, then, also binds to nuclear orphan receptors (different ones). In fact, it can even co-hybridize with things like the vitamin D hormonal form (1,25-hydroxy D3) to activate regulation of transcription factors that turn on different genes. So, retinoic acid is a gene response modifier. It influences gene expression, or how our book of life is read, and it does so in different ways in different tissues. Therefore, it differs in its function from vitamin D, but it has an analogous influence on regulating pleiotropic effects across wide ranges of different tissue types in outcomes. Insufficiency of vitamin A can influence (adversely) cellular function in the absence of xerophthalmia, just as vitamin D can do in the absence of rickets). So there is a difference between deficiency and insufficiency as it relates to optimal cellular function. Clinical Implications of Retinoic Acid Insufficiency With that in mind, let’s go into a little bit more detail about what the clinical implications of this could be. What has been discovered over the last decade is that retinoids influence these retinoid receptors in the control of energy balance, and have influences, then, on obesity and diabetes. That might be new news to you. Maybe you’ve never thought about vitamin A or carotenoids having influence on obesity and diabetes, but the influence of the all-trans retinoic acid at the receptor sites and activation of the various cell signaling mechanisms is dependent upon nutritional status. If you don’t have the precursor (i.e., retinol or beta carotene), you don’t have the molecules available to be converted into these signals that are going to regulate gene expression. So insufficiency, based on the genotype of the individual (meaning biochemical individuality), may have a variety of subtle effects on cellular physiology that map against obesity and type 2 diabetes. Could There Be a Connection Between Vitamin A and Obesity and Type 2 Diabetes? Now let’s just take this a step farther, because this might be kind of mind-blowing information for you. You probably never thought about vitamin A and obesity and diabetes unless you are following this literature. Obesity and type 2 diabetes are closely related metabolic disorders which have increasing incidence worldwide, and there is no clear-cut pharmacological treatment available for these metabolic disturbances because they’re generally not just a consequence of one thing going wrong. It’s really a shift in the web of metabolism, and it distorts many, many different processes related to a variety of families of genes that are all modified in their expression. So it is not like a one-disease/one-drug/one-outcome type of a problem. That is why it is so challenging to manage a diabetic patient, because there is no one single therapeutic target that one can focus on to correct these distortions or disturbances in metabolism. New directions, however, as we’ve been talking about in Functional Medicine Update for some time, for the management of these disorders, are now starting to emerge from a more complex understanding of these alterations in cellular signaling that occur as a consequence of the interrelationship between the environment of the person and their genetic uniqueness. This is why diet and lifestyle play such important roles in conditions like obesity and type 2 diabetes, because the environment is what sends the signal to the cells which contain the unique genomic book of life of that person, to give rise to their cellular expression called their outcome. Diabetes doesn’t necessarily derive from obesity, but rather obesity and diabetes arise together as manifestations of altered metabolism occurring as a consequence of this relationship between the unique genome of that person with their environment. If their environment sends an alarm signal to their genes through their regulation of gene expression, a disturbed metabolism is then seen as the trajectory towards type 2 diabetes and obesity. What is it that increases adiposity, alters so-called energy expenditure), and changes insulin signaling when the environment is sending a message to the genes of alarm? That’s been a central question for investigators around the world over the last few years. One thing that is emerging is that all-trans retinoic acid is known to inhibit the adipocyte (the fat cell) differentiation by the signal it has to its genes that are expressed. So retinoic acid (all-trans retinoic acid), to say it again, is known to inhibit adipocyte differentiation from a pre-adipocyte into a mature fat-storing adipocyte. As a consequence, it also influences cellular signaling of the adipocyte through things like adiponectin and leptin, molecules that regulate things like appetite, energy expenditure, immune function, and insulin sensitivity, meaning it has an influence on the web of control of energy economy and inflammatory response. Now this is a very, very interesting part of the story. You might say, does that mean, then, that vitamin A is an anti-inflammatory? No, what it means is that beta carotene/vitamin A/retinoic acid then participates in the regulation of cellular function in such a way as to diminish the response of the genes to the environment to produce an inflammatory response. It is not that vitamin A all-trans retinoic acid is an anti-inflammatory. All-trans retinoic acid, at the proper place at the proper time, helps to regulate gene expression in such a way as to buttress against an adverse response that we call inflammation. This is a very important new development in our understanding of the role that retinoids play in cellular physiology. What happens if a person is marginally insufficient with vitamin A then? Couldn’t they start to develop a distorted metabolism in response to a triggering event? Could retinoids have an effect on the progression of autoimmune diseases? That seems like a logical hypothesis that you would take away from this discussion. Of course the answer is yes. Recent papers, such as that published in Molecular Immunology in 2009, have talked about how retinoids differentially regulate the progression of autoimmune diabetes in clinical models in animals.[1] I want to emphasize these are animal studies trying to demonstrate a proof of concept. When an animal is put on a marginal insufficiency of retinoids a more rapid progression of this model to autoimmune diabetes is observed. When an animal is supplemented with all-trans retinoic acid, a return of proper cellular physiology and a resistance in autoimmunity is observed. These results are found even in animals that are treated with substances that kill the beta cells, like streptozotocin, which is known to be a toxin to beta cells in the islets and cause diabetes. Retinoic acid insufficiency greatly accelerates diabetes in these cases. Data like these indicate that maybe there is something about the role that retinoids have in regulating energy economy, regulating insulin signaling, and regulating inflammatory response to a stimulus as a consequence. This could be similar to vitamin D and the role it plays in orphan nuclear receptor activation of transcription factors that regulate specific gene expression and ultimately control proper response to environmental triggers. Evaluating Vitamin A Status Clinically What does that mean clinically? It means that we should be very mindful about adequate evaluation of vitamin A status: making sure carotenoids are being consumed in the diet, making sure the person is not hypothyroid (that would lead to under conversion of carotenoids into retinoids), making sure that person has adequate copper in their diet because copper is necessary for the conversion. How do you help to support proper thyroid hormone conversion of T4 to T3? It is T3 that activates the conversion of carotenoids into retinoids, so you make sure that the deiodinase enzyme, which requires selenium, is being properly promoted by proper selenium nutriture. Regulating cellular signaling through the retinoids shares aspects in common with the regulation of cell signaling through the cholecalciferol (vitamin D) family. As we move into this discussion with our researcher of the month talking about equol, I hope you’ll keep in mind this discussion that relates to the retinoic family, and phytochemicals in general and how they have this remarkable influence on regulating function well beyond prevention of deficiency diseases. That is the story that we will be talking about, reapplying it now to the discussion of equol.  

INTERVIEW TRANSCRIPT

Researcher of the Month Edwin Lephart, PhD Brigham Young University We just seem to be so privileged with having individuals share their thoughts and their hard work in pioneering the new concepts in medicine. We’re privileged once again: Dr. Edwin Lephart is going to be our Researcher of the Month this month. Let me tell you a little about Dr. Lephart. I think you’ll find his background to be both fascinating and perfectly consistent with the topic of our discussion. He received his PhD in physiology from the University of Texas Southwestern Medical Center, a world-renowned research institute in Dallas, TX. He comes from a very good background, with two of his committee members being National Academy of Science members. He did postdoctoral training at the Department of Psychiatry and then took a position at Brigham Young University, where he is currently Professor of Physiology and Neuroscience in the Department of Physiology and Developmental Biology. He has authored over 85 publications across a wide range of topics, many of which we’re going to touch upon in this discussion. He has over 8 book chapters or scientific reviews coving wide topics, including reproductive biology neuroscience. The topic of our discussion will be the area of phytoestrogens. I want to introduce this concept of phytoestrogens. If you are long term Functional Medicine Update subscriber, you’ll remember that we’ve previously spoken to two notable luminaries in this field. The first is Dr. Herman Adlercreutz, who was from the University of Helsinki Pathology Department and Medical School there and has been credited as the father of the term “phytoestrogens.” We had a very wonderful and robust discussion over 15 years ago with Dr. Adlercreutz, in which he said that of all the things he had done in his some 600 publications over the years, the one thing that he regretted was calling these soy-derived and plant-derived materials “plant-derived estrogens,” because he said this term causes a misunderstanding in a lot of peoples’ minds, causing them to think of these things exactly as they think of 17 beta-estradiol. Their mechanisms of action are actually different. They have weak agonist activities as estrogenic substances, but unfortunately the transliteration of the term “phytoestrogens” in the minds of many led them to think of them as estrogen itself. We’re going to talk more with Dr. Lephart about that, but I want to just set the tone that that’s kind of a legacy that goes back of 25 years in the literature. The other individual that we have had the fortune of speaking to in this area within about the last 10 or 12 years was Dr. Kenneth Setchell at the Cincinnati Children’s Hospital. Dr. Setchell, who was a post doc for Dr. Adlercreutz many, many years ago, was credited in really discovering this lignan family of bioactives in plants and how they interrelate with things like soy effects of physiology. He has obviously been very, very active in the field that Dr. Lephart himself has been involved in that we’ll be speaking more about, which is the secondary metabolite of these lignan materials derived from bacterial fermentation in the gut, which is called equol. There’s an intellectual lineage that traveled through Functional Medicine Update, through Dr. Adlercreutz into Dr. Setchell , and now we’re very fortunate to have Dr. Lephart. With that kind of lengthy introduction, Dr. Lephart, thanks so much for joining us on Functional Medicine Update. We’re going to be very pleased to hear your story, so thank you for being with us. EL: Thanks for having me on. This is a real privilege. JB: Let’s start down the road here quickly. I think for a person with your background, as I have described it, it might not appear obvious to the listener why you would ultimately have gotten into the soy phytochemical research. It maybe sounds like kind of an interesting twist or turn as it relates to your background. What led you into this whole field? Studying Phytoestrogens and Brain Chemistry EL: My background really is a story of biochemistry. We had an associate of mine out to give a seminar, and he was telling me about how he was studying phytoestrogens. I had no idea what phytoestrogens were and he was telling me how fascinating these molecules were. He really peaked my interest. After he left I looked up some names (that you just described) in the field and made contact with Ken Setchell and Herman Adlercreutz. We’ve published together in the past on these different topics, and they are fascinating molecules, having these polyphenolic structures that have similarities to natural stories, but as you described, are much different and have, in many ways, a broader range of biological activity. That’s been over 15 years ago that I got this indirect introduction to phytoestrogens, and then a little bit on my own because my area is more involved in brain research. At that time, no one was looking at these particular molecules in depth in brain research, so it turned out to be a very fascinating area to study, and it has been very profitable as far as a research avenue over these past years. The Origins of Equol JB: The soybean is a very interesting plant that manufactures many secondary metabolites that are bioactive, and one of those that ultimately is seen in human physiology that has been the focus of your research is equol. Could you tell us a little about the origin of equol? Where does come from and how is it produced? EL: Equol was first seen in fractions of biological samples from pregnant mare urine in 1932. It has a rich history but it really didn’t gain any really high profile prominence in research until Ken Setchell, in the early 1980s, identified this molecule in human biological fluids, when humans consumed soy products like soybeans (as you just described). This particular molecule is a metabolite of daidzein, which along with genistein is found in the aglycone form soy or soybeans. Ken did a lot of work looking at production of equol in humans, which is much, much lower than animals, and then he came up with an equol hypothesis that soy-based diets could be enhanced if you could increase the efficiency of converting daidzein into equol. That could have health benefits. That was around 1996 (around there). And then if you look at the number of publications on equol, it has gone up dramatically since that time because equol is such a powerful antioxidant. We found that it can bind specifically 5-alpha-dihydrotestosterone (DHT), which is the most potent androgen in the body. And it is also expressed in two different isomers, R and S, and both of these isomers are biologically active, which is unique because it has a chiral carbon, and it is unique because genistein and daidzein aren’t expressed in these particular biochemical properties. JB: That’s fascinating. Does both the right and left handed form of equol have the same biological effects or do they have slightly different effects? EL: For binding specifically 5-alpha-DHT, R and S equally have a high affinity (for specifically 5-alpha-DHT). For example, we’ve studied more than 30 different steroid types of molecules, and it doesn’t bind 5-beta-DHT, it only binds 5-alpha-DHT. And both R and S equally have high affinity for binding 5-alpha-DHT. JB: That would be very, very interesting when you starting thinking that equol is really a secondary—almost a tertiary—metabolite, isn’t it? Because first the plant makes it as a precursor, and then, as you said, in the gut, various microbes ferment that which is daidzein into this metabolite which is equol, and do so into…I guess two enantimers (the R and S form), which then are absorbed and have their effects on different receptors. That would suggest that maybe with its influence on DHT—obviously, in your work, you’ve published a number of papers that it might have favorable effects on prostate health. In fact, there is a nice paper that you are a principal author on with Dr. Lund in Reproductive Biology and Endocrinology in 2011 on equol and its potential for improved prostate health.[2] Tell us a little bit about that connection between 5-alpha-DHT and equol. Equol and Androgen Hormone Action EL: Equol having these really unique biochemical properties (being a powerful antioxidant), but this unique property to bind 5-alpha-DHT is really important with aging, especially in men for prostate health. This is because it is thought that even though the principal circulating androgen, testosterone, decreases with age (say around 40 or 50), and it starts to decline, if you look at the enzymatic make up in the prostate, the 5-alpha-reductase enzymes actually increase their expression. So even though the substrate is going down, the enzyme expression is increasing, and so you’re making more 5-alpha-DHT.This is the molecule that is causing proliferation, especially of the epithelial cells in the prostate, and causing the condition benign prostatic hyperplasia. So if we could bind that, we could decrease androgen hormone action at the androgen receptor. But what is really fascinating about equol is the S form has a relatively high affinity for estrogen receptor beta, and beta, in the prostate, along with breast tissue for women for breast cancer, if you bind beta then it indirectly will decrease the expression of androgen receptors. So in two different ways we’re decreasing androgen hormone action. We are, in a modest way, binding 5-alpha-DHT, and then we are decreasing the expression of androgen receptor by activating estrogen receptor beta in the human prostate. There is a great review looking at the difference between ER-alpha (the really traditional receptor) and then ER-beta that was discovered in about 1996 by Jan-Åke Gustafsson at the Karolinska Institute, who happens to be at the University of Texas in Houston right now.[3] By binding beta, both for the prostate and for breast tissue, that seems to be a positive influence for prostate health. That’s the main mechanism of what’s going on. JB: You’ve raised some interesting kind of halo effect questions from that very insightful discussion. First of all, when you talk about epithelial tissue in the prostate having a favorable impact in males with the equol exposure then it also raises a question: What about epithelial tissues in the scalp? What about follicular loss? What about male pattern baldness, knowing that there is a 5-alpha-DHT connection there? Is there any interconnection between baldness and prostate problems, or between equol and all of this? Equol: Hair and Skin Health Implications EL: There certainly is because this particular receptor (estrogen receptor beta) is richly expressed in the base of the hair bulb and around the hair shaft. The expression of the 5-alpha reductase enzyme is not only in the prostate, it’s in the hair follicle, it’s in skin and fibroblasts. There is application not only to prostate health but to female and male pattern baldness. Also to skin health, as far as cosmetics and wound healing because androgens decrease wound healing, whereas estrogen-like molecules enhance it. So there are different target tissues or applications that have really great potential for utilization of equol. JB: I note that you’ve been a principal author on another very interesting paper about the effects of equol in human skin as it relates to modulation of function of the extracellular matrix.[4] That sounds like it ties together very closely with this dermatological potential impact, and maybe even ties together with things like wrinkling, which we know is a consequence in part of oxidative damage to connective proteins that cause cross linking. Any connection there that is of value from this research? EL: Yes, we’ve done a great deal of research examining equol and the enhancement of skin health, both in vitro data and also gene array data. We’ve looked at 40 different genes, and in general equol will enhance collagen elastin, which is a really important dermal protein for skin health. And at the same time, it will decrease the matrix metalloproteases, and there are many different molecules. These matrix metalloproteases have the ability to break down collagen elastin. What we found in the gene array studies and also in the in vitro studies is that equol at very low concentrations (in vitro at 10 nanomolar) will enhance collagen expression and elastin expression, but also at the same time decrease this enzyme that breaks down collagen elastin (the MMPs). If we look at the antioxidant arm for equol, it’s a great stimulator for many different anti-aging and antioxidant genes. This particular aspect of our research has been translated, and equol is actually used in the cosmetic product currently and it has really positive effects for skin health. Males and Soy Consumption JB: When we examine this pleiotropic effect of equol it takes us back to one of the questions I know has been on a lot of peoples’ minds that don’t understand the complexity of this field. They’ll say: “Hold it. If these compounds are phytoestrogens, won’t they—in males—block testosterone and cause feminization?” There are even some reports, I think, in the literature suggesting that males taking soy-based products have significant decreases in testosterone. What have been your observations as it relates to the male effects of equol? EL: Yes. The question is not only for equol, but it has also been for soy, and I think a couple of really good reviews have come out, especially for male physiology, whether it is for soy or for equol. We don’t see, either in animal studies or in the small clinical studies, any change in the steroid hormone pattern in males in the low effective doses that we have calculated for either prostate health, or for cosmetics, or for male pattern baldness, etc.[5] The properties, because of the modest way that it binds 5-alpha-DHT, and also the estrogen receptor, we have not seen any negative influences on steroid hormone patterns or other hormonal patterns in males. JB: Let’s go back, once again, to ask: where does equol come from, and if it is, in fact, the result of microbial modulation or a conversion of daidzein ultimately into equol, is there a variation from person to person based upon their gut microbiome or the speciation of gut bacteria? High Variability in Equol Production EL: That’s an excellent question because a lot of research has gone into that area. The answer is that there is a lot of variation. It would appear that cultures that consume fermented soy products produce more equol, meaning that fermentation process has drawn the conversion process closer to equol (say the Asian cultures compared to western cultures). But even if you look within those particular environments, those study populations, there is quite a bit of variability in the ability or the levels of producing equol that might range from 20 nanograms to 50 nanograms per mL, up to a couple of hundred to maybe 500 nanograms per mL. So there is a lot of variation in humans compared to animals. Animals seem to have the ability to produce equol at incredibly high levels. If we just took the rodent or the rat as the experimental model, equol levels can represent 70 to 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the circulating isoflavonoid molecules, ranging from about 1500 to almost 2500 nanograms per mL. Humans produce low levels of equol, and the variation is quite high. JB: Is there any data available that correlates the serum level of equol epidemiologically with relative reduction of risk to certain kinds of conditions? Do we have any sense of what the desired physiologic range would be? The Equol Producer Concept EL: Yes, the concept of equol producer was generated, I believe, by Ken Setchell and his associates.[6] Also, investigators out of Japan came up with this concept that if there could be a threshold level and it’s an arbitrary level of around 20 nanograms per mL, they looked at prostate health studies and also breast cancer and osteoporosis.[7] If you stratify the data in those individuals that have the ability to produce equol at 20 nanograms per mL or higher have a lower incidence of prostate health issues (breast cancer, osteoporosis, etc.). This is still an evolving area, but right now it looks very promising, and that’s really where the equol hypothesis came from. If you could enhance the efficiency of converting daidzein to equol, and so far that hasn’t proved to be a very easy thing to do (meaning can you change a person’s diet or would they consume probiotics, etc.?). It really points to the fact that if you could have sustained relatively high equol levels, there could be health benefits associated with that. JB: That’s very, very interesting. People might have jumped to the conclusion of, “Wow, I’ll just give more good bugs by probiotic supplementation and that will improve the conversion of things like daidzein into equol and get them to the proper blood levels.” But what you’re saying is that—at least to date—oral supplementation with favorable symbiotic organisms hasn’t resulted in a demonstrable increase in equol production. I think that’s what I’m taking away from your comments. EL: Yes, that’s correct. There’s a lot of research done in that area, and so far in the literature I don’t think there has been a really good application to increase the efficiency of converting daidzein to equol by probiotics or even consuming combinations of foods, short of fermenting your food. And for Western cultures, that’s a very difficult thing to accept. JB: That might suggest that if people were consuming fermented soy, which I know in Asian cultures is one of their ways of actually consuming the product, that you would get some equol that is a byproduct of the fermentation process that you would not get if you ate the soy without fermentation. Is that the appropriate take away? EL: I think that’s correct. The fermentation process breaks down the molecule and converts it so there are fewer steps that the intestinal bacteria have to make in order to get to the equol molecule. JB: That then raises the question: “Well, it sounds like we ought to be giving equol as a supplement for those individuals that are low equol producers, who are below the 20 nanograms per mL threshold.” What’s the regulatory status of equol? Is it a dietary ingredient that is considered, under DSHEA, unacceptable, or is it an NDI, or what is its regulatory status? The Regulatory Status of Equol: Recent Discovery Complicates Things EL: That’s a great question. The status is…I can give you a really simple answer and that is I don’t know because in 2009 equol was actually discovered in white cabbage and that’s the first report where equol was discovered in a food product, and until that point it was thought that all equol had to be converted by intestinal bacteria. But in 2009 researchers were studying antioxidants, and they happened to select equol as one of the biomarkers in white cabbage. It’s a very good antioxidant and it’s very stable over 9 months of storage. So I can’t say one way or another what the regulatory status is because now equol has been discovered in a food product and that has usually been a hallmark for the regulatory perspective, so I’m not sure how it would be evaluated to date. JB: That’s very interesting. Let’s go back to the clinical effects, which I know for many of our listeners is really very, very important information. We’ve talked about prostate health. We’ve talked, indirectly, about breast health. You alluded a little bit to the osteoporosis effect (anti-osteoporotic effect) as a consequence undoubtedly of the favorable effect on ER-beta. And you’ve also talked about the effects in the skin in relationship to wound healing and wrinkling and so forth. In your background we know that you have a deep kind of both training and research experience in the neurology/neuroscience area. Tell us a little bit about what you have learned with regard to equol and neuroscience. Equol and Neuroscience EL: Yes, we just had a recent paper come out on soy diets and supplementing with equol in relationship to depression in animal models. We examined the rat model that uses the Porsolt forced swim test as an indicator (an index) of depression.[8] We found that when we supplemented animals that have naturally gone through ovarian failure (in rats, that takes place about 300 days of age), and then if we supplement equol on animals that are consuming a soy-free diet, we could actually enhance serotonin levels and improve the performance in this Porsolt forced swim test that is an indicator of depression in this animal model. And so, again, the concept isequol is binding estrogen receptor beta and it’s very important in different brain sites for depression, but due to its polyphenolic biochemistry and ability to bind estrogen receptor beta, it also improves (possibly) the transport and the synthesis of serotonin, which is a very important neurotransmitter associated with depression. And so, at least in this animal model for this particular hormonal status of natural ovarian failure, it seems to be a very promising application for brain health. JB: You know, it’s very interesting because epidemiologically there is association in the literature between soy in postmenopausal or peri-menopausal women and the reduction of dysphoria and the depression associated with estrogen loss with ovarian loss of function.[9] It seems like what you’ve observed in the animals at least tracks with what has been observed epidemiologically with females. EL: Yes, and not only in that area, but when we were talking about prostate health, an Asian study supplemented men with high PSA levels with soy, and when they looked at their 5-alpha-DHT levels (and this was with high supplementation), their 5-alpha-DHT level actually decreased by about…I’d say 10 to 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} with a corresponding positive decrease in PSA levels and improvement in BPH symptoms.[10] I believe these different tissue sites and applications throughout the body due to the antioxidant properties–binding specifically 5-alpha-DHT and then having two isomers that are biologically active—is really unique. JB: In the paper in Neuroscience in 2011 looking at neuromodulation by equol, you also have another interesting observation that relates to its antiobesity effects. Could you tell us a little bit about how that connection is made through equol? I think it is fascinating. EL: Yes, that connection, again, is made through the impact of estrogen homorne action. If you were to take a rat model and take away all the estrogen, the animal gets obese. If you give back estrogen, then you can control that obesity. When women experience menopause, one of the common challenges is that they gain weight, along with increased challenges in skin health and wrinkle formation, etc., because of the loss of estrogen. But if you look at the receptor subtypes (alpha and beta), alpha seems to be the important estrogen receptor in fat as far as the major modulator or control factor. However, when they knocked out estrogen receptor alpha in animal models, and then they gave estrogen to induced obese animals, they also lost weight. So the concept was, even though estrogen receptor alpha is the major receptor for controlling fat deposition, the ERbeta component is also very important, and it is not only for the fat tissue site, but it is also for the hypothalamic influence of having molecules that would regulate metabolic hormones like thyroid. In other studies we’ve seen that thyroid slightly increases, associated with a decrease in body weight and also, with the hypothalmic connection, there seems to be an increase in activity, meaning the animals move more (there is more local motor activity). As we’ve talked about before, there are multiple actions to equol in binding ER-beta, having influences at the hypothalamic level, and at metabolic hormone levels, too. JB: The more we talk, Dr. Lephart, the more we see this pleitropic effect of equol being quite amazing. I think you’ve touched on something, there, that I know our listeners want me to ask about, and that is if we’re talking hypothalamic effects (central effects in the nervous system), then would that influence the hypothalmic-pituitary-adrenal thyroid axis. In other words, would it have an effect on stress response in animals as kind of a modulator of stress? Is there any evidence that it has a regulatory effect on stress modulation EL: We haven’t examined equol specifically in the pituitary-adrenal-stress axis, so I can’t say for sure. What I could maybe speculate on is because of the influence on serotonin in the pilot studies that have been conducted people have reported that they seem to handle stress better, and not necessarily through the hypothalamic-pituitary-adrenal stress axis, but I think because of the overriding influence of increasing serotonin and activating estrogen receptor beta in various parts of the brain actually would be a stress modulator. JB: Very, very interesting. The other interesting thing you kind of touched on is that often you hear people talk about the fact that soy is anti-thyroidal;(it’s a thyroid antagonist). But you’ve just suggested at least one of the byproducts of soy metabolism, equol, might actually be a thyroid modulator in a positive way. It seems very interesting and almost paradoxical to some of the reputation that soy has. Soy Allergies EL: That’s correct. You have to think about the soy allergies that are probably connected with the carbohydrate portion of soy, the protein portion, and then the lipid portion. When we talk about equol we’re just talking about one isoflavonoid molecule compared to the total global soy concept of having hundreds, if not thousands, of molecules and all their interactions. And so far, when we’ve examined equol, the enhancement is either equal to or better than what we’ve seen with soy supplementation. JB: Oh, very interesting. Thank you so much for your gracious sharing of this very, very important information. As you undoubtedly know, soy has been through an interesting consumer perception cycle, not uncommon in the nutrition area where things wax and wane and the pendulum swings back and forth. We went into a period of probably about 30 years when soy was almost considered anti-American because it was in things that Asian cultures ate (it was kind of xenophobic a little bit when I first started in the field of nutrition in the late 60s/early 70s). Then it went into favor and we saw soy become considered a very important part of the diet to regulate all sorts of functions and in fact even an NLEA (National Food Labeling and Education Act) claim was allowed for soy. And now the pendulum has started to swing back and people are now villifying soy, saying that it has all these dangerous and untoward effects of stimulating cancer, and causing pancreatic enlargement, and the list goes on and on. From your perspective as a research leader, do you have any sense as to how we put this in balance (when patients come in and want to know the soy story)? EL: I think the media does a great job, but in science they fall short. I know they try very, very hard to do a good job, but part of the issue is—and it is also in the scientific literature—when researchers mix and match animal data with human data.I In some cases they go together, and in some cases they don’t go together. For example, the levels that are used in some of the animal studies are incredibly high. It’s difficult for someone in the general public to sort all this out. I believe that if someone is knowlegable, and I’ll use individuals that are pure vegetarians (they are really sharp about health in general, and nutrition, and biochemical properties of different foods, and antioxidants, etc.), it takes a level of investment on the part of the media that is telling the story or the individial that is in the public to try to sort this out, and unfortunately I think it gets mixed up. If you look at the animal studies and the potential negative aspects you could look at the administration and especially the levels that they are using. My kind of evolution in this particular field is, “We’re going to use the animal model as a starting point—as a screening tool—and then as we transition to the human study, whether it is negative or positive data, does it translate to humans?” If it does, the story is much easier to tell. But in many cases, the negative data has been reported in animals studies, whether it is for thyroid or for other topics, and if you translate that into the human model, that transition doesn’t hold. It makes it much more difficult on the general public to sometimes make sense out of this. JB: I’m sure you’ve probably had this kind of conversation offline as well. People will say, “Okay, well given all of this—this is really high-falutin’ science—what do you do? Do you consume soy yourself?” Is it something that you or your family eat, if someone asks you? Because that’s a where-the-tire-meets-the-road kind of question. I think we each have our own opinions as to how we translate the science into our own daily activities. What kind of recommendations do you have about soy as a part of the standard diet? EL: From all the literature, and especially from the recent reviews, in general, unless someone has a soy allergy, or they have just an unusual medical history for cancer or for some other really novel aspect of their health, in general I believe that soy is safe and that all of the studies we’ve done using a very low effective dose of equol in our animal studies and also in our pilot human clinical studies, I believe that in general for a very broad population covering human health that it is safe. JB: I think you’ve touched upon so many interesting areas. We use the word “pleiotropic” which means “multiple effects.” You’ve covered, in this short discussion with me, prostate, and breast, and skin, and obesity, and its effect on brain and neuroscience as it relates to depression, and osteoporosis. These are a fascinating array of web-like effects that are connected with the cellular signaling associated with equol, and how it influences gene expression, and things that you have been researching and publishing papers on for some time. It is certainly a fascinating story. If you think that we eat a food that has a precursor in it that then is further consumed by bugs in our gut into a secondary metabolite from those bugs, and it is then absorbed and has this really remarkable effect of normalizing functions across this wide range of tissue types. There is something about an ecological model of nutrition, about a web-like physiology, about our kind of deep interconnection through cell signaling with our plant world that is quite fascinating. It is really an amazing chapter in our evolving understanding of where health and disease comes from and how it relates to our diet. EL: I agree with you. And because it’s so abundant it is really almost impossible for those individuals that may have concerns because exposed to these molecules all the time. It might be at low levels, but they are in corn and wheat, and in many, many plant products and so it is very difficult to try to exclude these molecules (if not impossible) in your dietary consumption. With that perspective, we are always being exposed to these molecules, and in the right dose or right levels, and with correct knowledge, they could have health benefits, but I think it is going to take a little time to tell the story where people can grasp on to the difficult, multi-faceted action for molecules like equol. JB: Personally, I’m pretty persuaded I’d like to be on the threshold of my serum levels of 20 nanograms per mL. Your work looks pretty convincing to me. I want to thank you so much. This has been a very, very fascinating discussion and one that I think opens up all sorts of further chapters of review as we move down the road. Keep up the great work and thank you for sharing this with us. EL: Thank you for having me on.

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Bibliography

[1] Stosic-Grujicic S, Cvjeticanin T, Stojanovic I. Retinoids differentially regulate the progression of autoimmune diabetes in three preclinical models in mice. Mol Immunol. 2009;47(1):79-86.   [2] Lund TD, Blake C, Bu L, Hamaker AN, Lephart ED. Equol an isoflavonoid: potential for improved prostate health, in vitro and in vivo evidence. Reprod Biol Endocrinol. 2011;9:4. [3] Nomura M, Akama KT, Alves SE, Korach KS, Gustafsson JA, Pfaff DW, Ogawa S. Differential distribution of estrogen receptor (ER)-alpha and ER-beta in the midbrain raphe nuclei and periaqueductal gray in male mouse: predominant role of ER-beta in midbrain serotonergic systems. Neuroscience. 2005;130(2):445-456.   [4] Gopaul R, Knaggs HE, Lephart ED. Restructuring of the ECM in human skin by equol: a plant and soy-derived isoflavonoid. Gene expression and protein evidence. 2011. Unpublished.   [5] Hamilton-Reeves JM, Vazquez G, Duval SJ, Phipps WR, Kurzer MS, Messina MJ. Clinical studies show no effects of soy proteins or isoflavones on reproductive hormones in men: results of a meta-analysis. Fertil Steril. 2010;94(3):997-1007. [6] Setchell KD, Cole SJ. Method of defining equol-producer status and its frequency among vegetarians. J Nutr. 2006;136(8):2188-2193.   [7] Morton MS, Arisaka O, Miyake N, Morgan LD, Evans BA. Phytoestrogen concentrations in serum from Japanese men and women over forty years of age. J Nutr. 2002;132(10):3168-3171.   [8] Blake C, Fabick KM, Setchell K, Lund TD, Lephart ED. Neuromodulation by soy diets or equol: anti-depressive & anti-obesity-like influences, age- & hormone-dependent effects. BMC Neurosci. 2011;12:28. [9] Nagata C, Shimizu H, Takami R, Hayashi M, Takeda N, Yasuda K. Serum concentrations of estradiol and dehydrepiandrosterone sulfate and soy product intake in relation to psychologic well-being in peri- and postmenopausal Japanese women. Metabolism. 2000:49(12):1561-1564.   [10] Ide H, Tokiwa S, Sakamaki K, Nishio K, Isotani S, et al. Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate. 2010;70(10):1127-1133

Welcome to Functional Medicine Update for August 2011. I believe we have a very, very interesting and insightful issue for you this month, one that takes me back to—believe it or not—the 60s. This goes back to the completion of my doctoral work and when I was starting my career as a professor in 1970. The Fluid Mosaic Model of Membrane Structure In the late 60s, I attended a very interesting conference, which at the time was kind of groundbreaking. The conference was on the development of a new conceptual framework for the understanding of one of the most dynamic and important organelles in cellular physiology: the cellular membrane. In eukaryotic biology (meaning the biology of animals), the membranes of cells were known to be composed of lipids. The new model that was developed and discussed in the late 1960s by a professor at the University of California at San Diego—a very esteemed professor, Dr. Singer—and his postdoctoral research fellow, Dr. Garth Nicolson, was called the fluid mosaic model of the membrane. That discovery and its acceptance have revolutionized our understanding of cellular biology in eukaryotic cells. It certainly has translated into revolutionizing our understanding of many diseases that are membrane-related or transport-related disorders. And it has ultimately led to the development of what could arguably be considered the most well-supported nutritional supplement in the world right now: fish oil supplements that are rich in omega-3 fatty acids. Connecting the Membrane Model to the Role Nutrients Play in Human Health You might wonder how I am making this expansive connection between the membrane model and a nutritional supplement, because it may sound to you like a leap of abstraction. But I think you will learn over the course of this issue that this dynamic field of membrane physiology is really at the cornerstone of understanding how nutrients play roles in human health and disease. Membranes of cells are in fact the boundary between the outside and inside. Dr. Sidney Baker often refers to: “Having the right things in and having the wrong things out of cells.” Barrier function and defining how substances are pulled into cells (through nutrients and effector molecules that influence positively the expression of genes and cells that ultimately regulate their function), and expels toxins and metabolites from cells (and debris) are related to membrane function and bioenergetics that power membrane pumping actions. This is at the fundamental nexus of understanding how nutrients work, how they get to the right place, how they influence intermediary metabolism and ultimately things as complex as cell replication, cell repair, and bioenergetics. The bilayer lipid membrane of the eukaryotic cell has a relationship to other membranes within the cell and within other organelles that reside within the cell, such as the mitochondrial membrane. The mitochondrial membrane is its own barrier of defense that allows the mitochondrion to swim around or be attached within the intercellular milieu in such a way that they are the metabolic furnace of the cell. It produces the bioenergetic energy necessary to power functions, including membrane transport and all the other cellular assembly functions that relate to cell renewal and cell repair. The mitochondrial membrane is slightly different in its construction from the cellular membrane (the outer envelope of the cell). Its own unique composition and construction gives rise to its own characteristics of transport of substances that are necessary for serving as fuel or feedstock for bioenergetics, like fatty acids that are transported by acylcarnitine types of transport mechanisms, or glucose, or amino acids that are utilized within the mitochondrion as a source of a fuel for powering up energetics. And the membrane of the mitochondria is very important, in terms of its composition, for establishing the function of this transport process. So this emerging concept that was really initiated in the late 1960s has grown up now to be an extraordinary fundamental component of understanding health and disease: the integrity of membranes and barrier functions and how the structure and function ultimately translate into regulating complex processes. For the sake of history, let’s quickly build a model that relates to the question I raised: How does omega-3 fatty acid supplementation relate to function through cellular membranes? In the 1970s, a very important paper was published. I think it is arguably considered to be one of the most important cited papers. It was published in an issue of the very well-respected Science magazine in 1972. This paper was authored by SJ Singer and GI Nicolson, both of whom I have already mentioned, who were then at the University of California, San Diego. The title of the paper was: “The Fluid-Mosaic Model of the Structure of Cell Membranes.”[1]In this paper a model was advanced that is now considered–I think globally–to be THE actual representation of the cellular membrane. The fluid mosaic model is kind of a plum pudding model. Explaining the History and Connection What do I mean by that? It is a bilayer of lipids with the hydrophilic heads of various types of phospholipids sticking out towards the water environment or sticking inside the cell towards the water environment, with the inside of the membrane being the oily portion where the hydrophobic tails of the long chains of fatty acids are connected to these polar head groups to make up phospholipids and also make up triglycerides. These particular unsaturated tails, or—excuse me—long fatty acid tails could be composed of either saturated fatty acids, monounsaturated fatty acids, or polyunsaturated fatty acids. The polyunsaturated fatty acids can be from a variety of different families, including omega-3 and omega-6 fatty acids. So you have differing personalities of phospholipids and triglycerides that comprise the membrane and give rise to different levels of oiliness within the membranes. Embedded within this lipid bilayer (this two-layered sandwich) are the plum pudding components, which are proteins. These specific proteins can be of three different types. They can be proteins that are principally attached to the outer surface of the membrane, which have to do with certain things like receptor function. Or they can be transverse proteins that span the whole domain of the bilayer and have an outside and an inside personality within the cell, like cyclic GMP-related proteins, the G protein family with five different loops that span the lipid bilayer; they can attach to substances outside the cell and they can communicate influences inside the cell due to their changes in confirmation across the membrane. And finally you have proteins that are attached to the inner surface of the lipid bilayer inside the cell that regulate other functions. This complex plum pudding model of proteins embedded within membranes having specific functions as it relates to translation of information from outside the cell to inside the cell, and their ability to produce that effect, is dependent upon the composition of the sandwich structure, meaning the lipid bilayer. And that is in part connected to what type of fatty acids are in the tails of these phospholipids and triglycerides, and the composition of the phospholipids and triglycerides within the membrane. It all gives rise to what we call the fluid-mosaic model, meaning that this is kind of an oily composition. It is not static like a brick wall, but rather it is actually able to aggregate and disaggregate. It is more like a hummingbird’s wings in terms of its function: things are moving around in the membrane. We sometimes call these fatty acids lipid rafts, meaning you’ve got this lipid matrix—this fatty matrix—of triglycerides and phospholipids, and sitting on it and floating around are these protein and cholesterol islands that then are involved with the changing structure and function of the membrane with time, under different conditions. It’s a very, very dynamic process, and I want to emphasize that its dynamic nature is in part related to the degree of unsaturation that is found in these lipid tails within the membrane. As you have higher degrees of saturated fatty acids, the lipid tails have a higher melting point: they’re more rigid/more stiff, and they are less fluid. You have a high polyunsaturated fatty acid component of the lipid membranes, and now it is a lower melting point, more fluid, and more dynamic. As we’ve learned over the last 30 or 40 years, the composition of the diet changes the incorporation of various components within the membrane structure. You change, actually, the dynamic processes by which membranes interact with their outside and inside environments, and can affect translation of information from the outside to the inside. This was all really beautifully outlined in the extraordinary paper published in Science magazine back in 1972 by Singer and Nicolson.1 This became known as the Singer-Nicolson model of membranes. In this seminal, paper, some of the thermodynamics of how membrane function occurs through these dynamic processes are described They look at the formation of these membranous materials as it relates to their biosynthesis, their insertion within the membrane, the construction of membranes, and how that also relates to things like mitochondrial membrane function and regulation of bioenergetics, which is related to the transport of nutrients inside the furnace of the cell, the mitochondria, and the expulsion of waste products. All of this was born from these discoveries in the late 1960s/early 1970s and became more well understood in the 1970s.This paper in 1972 in Science magazine was the most cited paper in all of science literature for a couple of years after its publication, and stands as one of those seminal contributions to our understanding. There are many different families of phospholipids: phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine. These are triglycerides that have a phosphate at the polar head group, and then attached to them are different types of fatty acids at the 2 and 3 positions. They have different degrees of other groups attached to phosphates: a choline to make a phosphatidylcholine, or a serine to make a phosphatidylserine, or an ethanolamine to make a phosphatidylethanolamine. Each of those families of phospholipids has different personalities and characteristics when incorporated within the membrane. These are tightly regulated in terms of synthesis, but they are dependent also on substrate availability. In other words, if you don’t have a supply of these materials needed to build these membranous components, then you can’t build them. That would result in a situation of deficiency or insufficiency. When we start really looking at how all of this fits together, there is a nutritional dependency/relationship that relates to the availability of these different types triglyceride or fatty acid building blocks. If your diet is heavily preponderant in saturated fatty acids, then the membrane construction will incorporate more of these saturated fatty acids as a consequence of their availability. If you have more omega-3 fatty acids, then you’ll incorporate more regulated balance between omega-3, -6, and saturated fatty acids. So again, there is this dependency on dietary quality that relates to the regulation of membrane construction. Fatty Acids and Membrane Structure: Studies Demonstrate the Connection This relationship was documented in a human trial that was published in the Lancet medical magazine back in the early 1980s. In this study, researchers looked at men from Edinburgh, Scotland and men from Stockholm, Sweden, who were the same age, and they examined dietary intake and found that the Swedish men consumed more fish and when looking at their membranous components they found much higher levels of omega-3 fatty acids in their membrane phospholipid composition than the Edinburgh, Scotland men, who ate more meat (lamb, in this case).[2] They then also looked at things like membrane action, red cell stickiness, and tendency of cells to clot, and they found that in the Stockholm men, unsaturated fatty acids, when incorporated within cell membranes, had much less of a tendency to clot, or stick, or form aggregates than those in the Edinburgh, Scotland men. Based on these findings, I think there is some connection between relative risk to certain chronic-related diseases, like stroke or heart attack, and the composition of membranes and diet. Cardiolipin: An Interesting Member of the Phospholipid Family One of the interesting families of these phospholipids has the name “cardiolipin.” Cardiolipin is a very interesting member of the phospholipid family. It is basically a polymer of phosphate groups that relate to phospholipids, so it is a longer chain component of a normal phospholipid. Cardiolipins are specifically synthesized with cardiolipin synthase, , and that is, in part, controlled by a variety of different regulating functions within the cell, one of which is, interestingly enough, thyroid hormone. It turns out that hypothyroidism has a negative impact on cardiolipin biosynthesis, and that then alters the construction of this very interesting and important family of phospholipid-like materials. Cardiolipins are found particularly in the cell membranes of liver, and within liver cells they are found principally within the mitochondrial membrane, so they play a very important role in function of liver cell bioenergetics. They are found, also, to be incorporated at high level at various types of nervous system tissue, and—obviously by the name “cardiolipin”—in cardiac membrane cell tissue, principally in the mitochondria, so they have a very important role to play in terms of mitochondrial membrane structure and function. Because of their highly anionic charge relationships, cardiolipins bind protons, and they also bind a large number of proteins themselves to form a different kind of aggregate structure in this fluid mosaic model of the membrane. They are very important as a constituent of cellular membranes, particularly mitochondrial membranes, in regulating the function and the transport of ions in and out of the mitochondria, which is all part of the flux of energy. That’s how the electron transport chain works: through proton efflux and transport. Cardiolipin plays a very important role in maintaining bioenergetics through mitochondrial integrity, and it is principally found in high energy tissues like nervous tissue, heart tissue, muscle tissue, and liver tissue. It also—as a consequence of its composition, in which it has fatty acid side chains and phosphatidyl head groups—is dependent, in its synthesis, on nutritional status; you can alter the composition of cardiolipin. There was a very nice review paper published in the Journal of Lipid Research in 2008 on cardiolipin biosynthesis and its assembly into mitochondrial membranes, again showing the important role that it has in the structure and function of mitochondria.[3] We recognize that cardiolipin has to be biosynthesized, obviously, and it also has to be transported and delivered to the place of need, like the construction of the mitochondrial membranes or the repair of mitochondrial membranes. There are transport proteins that appear to do that. One that has been talked about is a protein called ATP8B1, which is a cardiolipin importer. There are undoubtedly a number of different transport proteins within cells of specific cell type and specific tissues that are involved with transport and the regulation of cardiolipin’s delivery into specific cellular membranes, particularly mitochondrial membranes. However, as I mentioned, situations like hypothyroidism, can lead to poor cardiolipin biosynthesis and altered transport. Things that we start seeing with hypothyroidism include: impairment in bioenergetics, mitochondrial uncoupling, oxidative stress, cardiopathies, cognitive impairment, and poor muscle tone. Those are the very tissues I just talked about that are important for mitochondrial bioenergetics and cardiolipin integrity relative to mitochondrial membrane function that map against those conditions that are associated with hypothyroidism. I think this is not coincidental; there are some very distinct relationships. I don’t want to put all the eggs in this one basket, but certainly some very interesting relationships between the conditions of energy dysfunction in various diseases and mitochondrial membrane compositional dysfunctions. As another part of the story, these cardiolipin molecules–when they are oxidized, or injured, or damaged–can induce an immune response in which anti-cardiolipin antibodies are produced. In fact, there are anti-cardiolipin antibodies found in the sera of patients with chronic fatigue syndrome, suggesting that the integrity of mitochondrial membranes and the patency of cardiolipin is an important part of maintaining proper immune function and also lowering the relative risk to what we call autoimmunity that may be associated with energy-deficit types of problems, like chronic fatigue syndrome and fibromyalgia. There was a nice paper published in the Journal of Clinical Laboratory Analysis in 2009 about anti-cardiolipin antibodies found in patients diagnosed with chronic fatigue syndrome and fibromyalgia, indicating that there is a possible relationship between the expression of these anti-cardiolipin and the presence of chemically modified cardiolipin and how that interrelates with poor bioenergetics and mitochondrial interruption (or mitochondrialopathies).[4] I think that there is a very interesting story emerging as it relates to the mitochondrial membrane integrity and the unique personalities of its composition as contrasted to the cellular membrane. How to maintain integrity of that important barrier defense and that transport characteristic of the mitochondrial membrane against agents that induce things like oxidative stress, or free radical injury, or immunological adverse response against certain constituents of the membrane is also very important. How can you manage this? What can we do? That will be the topic of this month’s clinician/researcher of the month interview. We are so fortunate to have with us, Dr. Garth Nicolson (of the Singer-Nicolson duo), who is going to tell us what has happened over the past 40 years in the evolution of the fluid mosaic model. There have been specific opportunities for new clinical therapeutics on fatty acid replacement therapy and specific targeted approaches towards cardiolipin integrity within mitochondrial membranes. Thiscuts across things like energy deficit disorders and the whole nature of oxidative stress for bioenergetics. Mitochondrial Injury and Dietary Intervention When studying injury to mitochondria, you must ask this question: How does this relate to overall lifestyle principles and dietary intervention? In days gone by we might have said, “Well, they just need more antioxidants. They need more vitamin E, or vitamin C, or carotenoids, or flavonoids, or polyphenols, or green tea (EGCG), or co-enzyme Q10.” All of those are important adjunctive supportive agents, but there is more to it than that alone. We have to ask not just how do we trap the oxidant radicals, but why did they exist in the first place? What is the cause of increasing oxidative chemistry that causes membranous damage and ultimately loses the integrity of bioenergetics and causes this kind of free radical storm? What is emerging as a part of that answer is that alterations in things such as insulin signaling, and the things that keep coming back time and time again as it relates to the adverse effects of a high fat diet and the postprandial state seems to really drive some of these injuries. The Case for a Fatty Acid Tolerance Test What do I mean by the “postprandial state”? This means after eating. To measure blood glucose, we do what is called the oral glucose tolerance test, which means we fast a person, take a fasting blood sample, then we administer a Glucola drink (75 grams), and we then measure their blood sugar postprandially after the oral glucose load and we evaluate how much they can mobilize response based upon their organ reserve, and their endocrine pancreas, and their insulin regulatory process. How much they can control the postprandial load of glucose? With regard to fats, however, how do we measure fats? We generally bring people (fasted) in for a blood sample. We look at triglycerides, we look at cholesterol, we look at LDL, VLDL, HDL, and we make kind of an assessment as to whether they are hyperlipidemic. Why don’t we do the same thing with fats that we do with glucose, and that is, why don’t we challenge that person with a fatty acid tolerance test? We know we can pick up many people in glucose dysregulation who show normal fasting glucose but become abnormal in a glucose tolerance test because they are having dysinsulinism that is a precursor to more dysfunctional states like diabetes. Why don’t we use a fatty acid challenge test? There are people that are starting to do that. They are using certain graded does of a standard lipid mixture to orally challenge a person. As in the case of an oral glucose tolerance test, a person has a fasting blood lipid level done, they are then given an oral dose of a liquid mixture of fats, they then have their blood drawn at times thereafter, and the relative regulation of their lipemia after a challenge is then a measurement of lipid tolerance.. When you start looking at the postprandial relationships to fatty acid management, what you find is that there are peaks that occur after eating a high fat meal that really induce the significant potential for injury to cell function, and punch holes in membranes, and lead to mitochondrial alteration and oxidative stress. In fact, there are papers that have been published on this recently. Let me give you a couple of examples. In the Journal of Clinical Science in 2010,, a very interesting paper was published about a human intervention trial looking at postprandial oxidative stress by differing dietary fat consumption (in humans). In this study, people were put on different fat composition diets for 12 weeks: a high saturated fatty diet, a high monounsaturated (oleic acid or olive oil) diet, and two low fat/high complex carbohydrate diets, one supplemented with long chain omega-3 fatty acids, and the other with sunflower oil (high in oleic acid).[5] Among 75 participants randomized across these diets, they found that the diet that was high in monounsaturated fatty acids had the least adverse effect on oxidative stress, meaning the glutathione-to-glutathione disulfide ratio was normalized, the protein carbonyls were reduced, the inflammatory markers like hsCRP were reduced. It appeared as if monounsaturated fatty acids, as found in the Mediterranean diet, for instance, had a much more favorable effect on postprandial lipemia and oxidative injury and mitochondrial dysfunction than did the other three programs. They also point out that the Mediterranean diet probably has some desirable effects because of the diverse nutrients and biofactors in these foods that help to provide higher levels of NADPH, which is necessary for maintenance of proper bioenergetics. This is very similar to another recent paper that was published in the Journal of Hepatology in 2010 page 727. This was a controlled study in animals, a specific type of rats that are bred to basically have a defect in their cholecystokinin signaling system, so they tend to overeat and become obese and diabetic.[6] These rats basically have a problem with appetite regulation, not unlike—probably—some of us in the human species. What they found in these animals that tended to overeat was that as they got more obese and their fatty acid levels increased, they got hepatic steatosis, meaning infiltration of fat into the liver, and nonalcoholic fatty liver disease, which affects about 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of all US adults presently, and 75 to 100{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of obese and morbidly obese people. It is not an uncommon situation in the population of humans today. In fact, it is estimated that 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of lean and 38{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of obese children have fatty livers, and that this is a significant contributor to liver failure and ultimately the need for liver transplant, as well as having a very close correlation with the morbidity of insulin resistance and type 2 diabetes. In this animal model, it was found that as the animal got more derangement in their postprandial fatty acid management, they got more and more oxidative stress. It is a two-hit model. The first hit is to interrupt the relative ability of the membranes to form proper integrity, and the second hit is in oxidative leakage and ultimately cellular derangement. They again call for the need for dietary intake that would regulate postprandial hyperlipemia (or lipemia postprandially), and reduce then the load of these untoward lipids on cellular chemistry. I think these are some very important things to keep in mind as we move into this discussion with Dr. Nicolson. We must consider not only lipid replacement therapy, but dietary intervention using a modified Mediterranean intervention that is high in oleic acid and rich in the phytochemicals that modulate oxidative chemistry and mitochondrial function. This may play roles in conditions not just related to metabolic syndrome, but also things like chronic fatigue syndrome and fibromyalgia.. About fifteen years ago, published work suggesting conditions such as these could be connected to mitochondrial dysfunction were heavily criticized. I recall presenting this at a chronic fatigue syndrome conference in San Francisco over 15 years ago and having some of the leaders in the field criticize this hypothesis as having no merit, even though I presented clinical and biochemical information suggesting that it was a relationship to the condition. It now seems much more respected that mitochondrial oxidative injury, oxidative stress, and toxicity (as it relates to energetics) are companions of the etiology of chronic fatigue and fibromyalgia. I think what you are going to hear from Dr. Nicolson will relate very nicely to the emerging literature. The beautiful take away from this discussion is that once you understand the membrane connections and the connection of diet to the manufacture and biosynthesis of these important structural and functional lipids that are found in membranes, it now gives rise to the opportunity for selective intervention, nutritional therapy, and a targeted, personalized medicine approach—a functional medicine approach—to these conditions. Let’s now move into the extraordinary discussion with our clinician/researcher of the month, Dr. Garth Nicolson

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INTERVIEW TRANSCRIPT

Researcher of the Month Garth Nicolson, PhD The Institute for Molecular Medicine This is the section we all look forward to. This is the theme, this is the energy center, of Functional Medicine Update—our Clinician and/or Researcher of the Month section. My history with Dr. Garth Nicolson actually goes back to 1970. In 1970, I was just finishing up my PhD in biochemistry and was at the University of Oregon. My thesis advisor said, “You know, we ought to go over to Corvallis [our kind of competitive institution on the other side of the state] and go to this seminar—this 3-day symposium, actually—on cellular membranes.” The concept as to the structure/function of membranes was just emerging. This concept of the fluid mosaic model, lipid bilayers, and embedded proteins (sometimes called the plum pudding model of the lipid bilayer) that we were exposed to at that 3-day meeting was the so-called Singer-Nicolson model of the lipid bilayer. It was a very, very revolutionary change in thinking about an organelle that had not just structure, but function)—the cellular membrane. Of course, the Nicolson of the Singer-Nicolson duo was none other than our guest this month, , Dr. Garth Nicolson. It turns out Dr. Nicolson and I overlapped at the University of California, Los Angeles. We were both chemistry majors. He graduated in 1965 and went on and got his PhD in biochemistry and cellular biology at the University of California at San Diego. He was involved with the Nobel Prize-nominated work that ultimately resulted in scientists understanding much more about the nature of this boundary layer, this compartmentalization that we call the membrane, and how it plays a functional role in cellular physiology. We’re extraordinarily fortunate to have Dr. Nicolson tell us more about how this field has evolved over 40+ years. He’s presently the President, Chief Science Officer, and Research Professor of Molecular Pathology at the Institute of Molecular Medicine in Laguna Beach, California. As most of you know, I had the fortune of spending a couple of years on sabbatical with Linus Pauling, who used the term “molecular medicine” in his landmark paper in 1949 in Science magazine, when he wrote about (with Charles Itano) the concept of sickle cell anemia.”[7] With great privilege, Garth, nice to have you on Functional Medicine Update and welcome. GN: It’s a pleasure to be with you. JB: I know it sounds like it may be ancient history, but I’d like to take us back and start with the emergence of the work that you are engaged in and the development of your thoughts about the composition and the activity of the membrane. Could you take us back and work us up from there? GN: When I first started my work on membranes I was actually interested in mitochondrial membranes. I did some work on mitochondrial membranes before I switched (with Singer) to the cell membrane. This ended up the fluid mosaic membrane model of cellular membranes, but it also held for all of the intracellular membranes in the cell as well. My interest in the mitochondrial membrane centered more around the function of the membrane in the production of energy inside the cells, and of course the mitochondria are the little batteries inside our cells that produce the energy. I’ve recently come back to that because of my interest in fatiguing illnesses and the role that mitochondria play in fatiguing illnesses. This really, again, is integrated into membranes because the whole apparatus of energy production takes place in a membrane matrix inside the mitochondria, and so we were very interested in some of the problems that occur in cells, particularly when they become diseased. Mitochondrial Function, Chronic Illness, and Aging During chronic illnesses we know that the mitochondrial function goes down, and we were very interested in how to restore mitochondrial function. The role that the actual membrane and the membrane lipids play in this whole process turned out to be incredibly interesting. The upshot of it all is that we were able to replace the damaged lipid membrane. I should say that lipids get damaged like other structures of our cells (the proteins and the DNA) by excess oxidative events (oxidative stress is what we generally call it), which is really the production of excess oxidative molecules that tend to damage molecules in our cells. Lipids turn out to be very sensitive to this whole process, and it turns out the inner mitochondrial membrane, which is the functional part of the membrane in terms of energy production, is exquisitely sensitive to these oxidative events that occur inside cells. When the lipids get damaged, the inner mitochondrial membrane becomes leaky, and because it becomes leaky the potential across the membrane can’t be maintained and this is absolutely integral to the production of energy (that membrane dynamic and also the chemical potential across the membrane must be maintained for energy production). It turns out that when the lipids are damaged this can’t be maintained and energy production goes down. We’ve tried to think about how to fix this when it occurs, and it occurs naturally during aging. For example, it occurs during all types of disease processes: infection, chronic illnesses, cancer. All kinds of different situations cause destruction of the inner mitochondrial membrane lipid. It turns out we have a natural process for repairing lipids in our cells anyway, and by making use of that natural process and providing undamaged lipids for this natural process, we’re able to actually see the complete circumvention of destruction of energy production and a sudden reemergence of mitochondria that, with their repaired membranes, are capable now of producing the energy at the levels that they normally should. We see this on an organismic level or holistic level as the resurgence of energy and vitality and the reduction of fatigue. In a nutshell, that is what we’ve been working on the last few years. JB: For the sake of many clinicians who may still be brushing up on some of their cellular physiology and biochemistry, let’s go back and just make sure we have some of the terms all in line. You talk about the fluid mosaic model of the membrane. Could you take us through a descriptive review so we’re all looking at the same picture with those words? What does that mean? GN: What it means is there is a lipid bilayer of phospholipids, and in that lipid bilayer are intercalated proteins and glycoproteins of the cell. This occurs not only in the cellular membrane but other membranes of the cell, including what we’re going to talk about eventually (the mitochondrial membrane). These intercalated proteins and lipids are not static. They are in movement because it’s a very dynamic structure. The lipids, in fact, form the matrix of that membrane, and that was the whole idea behind the fluid mosaic membrane model. That membrane actually is a two-sided membrane. The inner part of a membrane (in any particular membrane) is different from the outer part in terms of its composition, and in terms of the lipids, for example, and in terms of the proteins as well. To maintain that polarity, we have to have some kind of a structural arrangement, and to maintain the dynamics we have to have a structural arrangement. The best way that explained this was that it was a dynamic process where the lipids were in constant movement and so were the proteins, and they did maintain a polarity across this membrane. The dynamics of the membrane turned out to be very important for many processes of cellular function. Also–again–the fluidity was important, and also the polarity across the membrane and the fluidity were tied up with this chemical potential across the membrane (the electrical potential, essentially, across the membrane). So it all kind of fits together in an integrated sort of structure of membranes. JB: Let’s review. You talked about phospholipids. I think most of us remember that phospholipids are somehow like a glycerol backbone, where the three position has some kind of a phosphate-related group on it, and the first position and second position are occupied by fatty acids. Could you tell us a little bit about the classes of phospholipids and their composition? GN: In terms of membrane phospholipids, we generally categorize both by their fatty acid chain and also by the constituent groups that are attached to the heads of the phospholipids (the hydrophilic parts). These are amphipathic molecules; they have a hydrophobic part or a more lipid part, which are the fatty acid acyl chains, and they have a hydrophilic part, which exists essentially in the water milieu of the cell. These constituents can vary. For example, they can contain attached serine, glycerol, and so on and so forth molecules. That turns out to change not only the dynamics of the membrane, but it is also important for the structure of the membrane and its function as well. So these molecules are really very asymmetric molecules. They’re very different in terms of each side of their structures, and also their functions are really quite different in terms of what they provide to the membrane and what they provide to the cell. JB: And those fatty acids that are connected to the phospholipids, I presume they can be members of a number of different classes, such as the fully saturated, or they could be omega-3, -6, or -9 unsaturated. How does the composition of these fatty acid chains get established? GN: Of course there are enzymatic mechanisms to produce these. What’s important is the overall mix of these different molecules in a structure like the membrane of the cell. Whether they have double bonds or single bonds, and then whether they are saturated or unsaturated turns out to be very important for the structure and validity of the membrane. And when this changes—for example, by oxidation—this can result in a slight change in the structure, which eventually causes these lipid moieties not to fit exactly the way they should, and not to be quite as fluid as perhaps they should be. And this causes discontinuity of the membranes and eventually this might cause a discontinuity that results in leakage across the membrane. When that sort of leakage occurs, that can destroy the chemical electrical potential across the membrane. So that is something that we have to be well aware of because the membranes are constantly being turned over, repaired, and replenished all the time. So when this damage occurs that could affect the overall structure and the potential across the membrane, we have to exchange out those damaged lipids for lipids that are undamaged so that we can return back to the physiologic state that is imperative for various processes that occur in the membrane. JB: I want our listeners to understand that you’re an individual who has not only been in this field since its beginning, but has been one of the emergent contributors to our understanding of membrane structure and function. Dr. Nicolson is approaching 600 publications across this vast array of research experiences in the field. I hope you’re all listening carefully because you’re getting news-to-use from the right person here. As it relates, then, Garth, to this composition, presuming then that you could have more fluidity by more highly unsaturated fatty acids, and less fluidity (more rigidity) with more saturated fatty acids, in a normal individual how much of these fatty acids would be, say, the more highly unsaturated, like the omega-3s? GN: Well, of course, there is the balance between them. The balance is really what is important. When this balance goes out of sync, more or less, what happens usually is that the lipids get oxidized. And when the lipids get oxidized they get converted to a different chemical form. The different chemical form, then, really perturbs the membrane, more or less, when enough of the lipids get oxidized. This is, for example, what happens during aging. This is what happens during a variety of chronic disease processes. This is something that we have to be aware of because it is very important for our physiology. JB: Let’s take that and ask the simple question. I know it is implied in what you’ve said, but let’s make it clear for everyone listening. Does the status of nutrition have any role to play in the composition of those membranes or are they controlled by other factors that are nutritionally independent? Nutrition and Membrane Composition GN: Oh, absolutely nutrition is really important in this. We have to provide our body with the correct constituents in order to replace the damage that occurs on a daily basis, and it is damage that is accelerated during disease processes. If we don’t have the correct precursors, for example, for our lipids and for the other structures of our cells, then we can’t keep up with the damage that occurs, and eventually it throws our cells out of sync. And so with the membranes, we have to repair this damage because if we don’t the membranes can become less fluid, they can become more leaky, other things could happen, there is less functionality of the membrane, and so we can see that with this type of damage, our cells can no longer function as they should. JB: With that in mind, one might ask the question: What’s best? Should we give the precursors to these membrane constituents like the fatty acids, or should we give structured lipids that contain all the requisite requirements to make these phospholipids, which means more of a complete phospholipid molecule in order to stimulate proper membrane construction. What’s the research tell us? Stimulating Membrane Construction: What is the Best Method? GN: The research tells us that it depends on the speed in which you want this to occur, because they are natural processes in our cells which can interconvert all these things anyway. But it turns out when it is diseased it doesn’t always have the capacity to do this in a timely manner. In other words, the damage may outstrip the ability to repair this whole process from occurring. As we get out of sync in our bodies, and our cells get out of sync, we then can accumulate damaged molecules in our cells which are not being replaced rapidly enough. So it is a whole dynamic process. If you’re very healthy you can get by with less. But if you are ill—if you are sick and if you have damage inside your system and damage inside your cells—then you may not be able to keep up with that. In that case, it actually helps to have a more complete set of molecules that are very capable of repairing—without a lot of chemical changes occurring inside the cells—the damaged structures within the cells. If you’re really very, very healthy you can get by with less than if you are in a process where you’re not so healthy and a lot of damage has accumulated inside your cells. JB: That then leads clinically to something everyone that is listening is familiar with, I think, and that is we have seen a very, very interesting rise in fatty acid therapy becoming kind of a standard of care or an accepted therapy (almost like a pharmaceutical therapy). GlaxoSmithKline acquired the company that manufactures what they now call Lovaza, which is a medical delivery form for omega-3 fatty acids. Its condition of use is for hypertriglyceridemia. This seems to have a much broader implication in terms of health and disease. GN: I think it does because we’re actually providing the direct precursors for membranes rather than one of the constituents of the precursors, so it is one step further in the whole process (the whole metabolic process) of generating membrane structures. We feel that this is an important dance because people that are ill don’t always have the capacity that they should to perform all the enzymatic features necessary to make a fully functional membrane. JB: So now let’s go to—I’m running forward really quickly from 1970 to 2003, but I want to take us up to one of the many of your very extraordinary publications—the Journal of Chronic Fatigue Syndrome in 2003. It is an article talking about a clinical intervention in severe fatigue patients that are older aged and who have altered mitochondrial function and lower bioenergetic potential, who then responded very favorably to a structured lipophospholipid dietary supplement.[8] Could you tell us about this study? It is very interesting. Studying a Natural Approach for Solving Problems of Loss of Energy Production GN: We’ve been working on this for a few years now. Again, it is a very natural approach for solving the problem of loss of energy production, which occurs inside the cells of people that are having any chronic illness, and also with aging and with other processes that can go on that can damage membranes. This is a very common occurrence these days in people, essentially because of all the environmental insults they are exposed to, as well as aging and other natural processes that occur. What we’ve tried to provide is a very balanced dietary supplement called NTFactor™, which provides the glycophospholipids in a format that essentially compositionally matches the membranes of the cell fairly closely. This provides a very rapid way to repair the damage that occurs, and to keep above and beyond the damage that will continue to occur to these cells during normal day-to-day living, and help repair the process inside the mitochondria, the little energy production centers of our cells, and return them to a more physiologic state where they are capable of producing enough high-energy molecules to perform all the functions necessary in the cell. And what this dietary supplement does is it really utilizes the natural transport features that are present inside our bodies to distribute these precursor molecules to all the cells of the body, and then replace the damaged molecules that are there in a more efficient way and therefore return the cells to a more normal physiologic state more rapidly, and to maintain them in that situation. With the mitochondria it is very important that we maintain the chemical potential across the membrane and that’s what these help to do very quickly (quickly, meaning now that we’ve had our new formulation this could occur within a week). So we can see very dramatic increases in energy production and decreases in fatigue now within a week of administering our newer lipid supplement. How Do You Measure Mitochondrial Function? JB: A lot of individuals probably would be interested to know about the design of this study. How do you measure mitochondrial function in human subjects? What is the readout? I think that would be an interesting thing to share with our listeners in terms of this clinical study. I found the way that you actually assessed the before and after effects on mitochondrial function very fascinating. GN: One of the ways to do this is to measure the ability of mitochondria to produce high-energy-reducing molecules in the cell. We can take cells, for example, from the blood of patients and show that their blood cells have the capacity to do this to various degrees. People that are aged, or people that are sick, or people that have chronic illnesses of various types lose the ability to produce these high-energy reductive molecules. By putting in a fluorescent dye of a potential redox potential so that it will access electrons (but only if they are high-energy energy electrons produced by the inner mitochondrial membrane), we can actually show that the mitochondria will fluoresce if we feed this dye to the cells, if they can produce the high-energy molecules. If they can’t, they’ll fluoresce to a lesser degree, or not at all if they have completely lost function. So we can actually get a quantitative measurement of mitochondria this way. There are other ways to do this as well, such as measuring high energy molecules like ATP and so on. But all these measurements are really focused on the ability of mitochondria to produce the high energy molecules or to reduce the high energy molecules that are needed for various enzymatic features inside ourselves. So that’s the one way that we’ve done it. By using a cell sorter we can separate out the white blood cells and measure on a cell-by-cell basis the ability of the mitochondria to produce these high energy molecules or reduce them by the dye we put in, and we can see that when the dye fluoresces. So we can get a quantitative measurement of return of mitochondrial function this way. JB: So that takes us now to 2006 and another really interesting paper. You have been authoring a series of papers in the Journal of Chronic Fatigue Syndrome. This paper is about an intervention trial using the NTFactor supplement for restoring mitochondrial function in fatiguing illnesses. This is with Dr. Ellithorpe as your co-author/clinician. I find this paper is really beautifully written. I think it has a very sensible introduction to this complex topic of mitochondrial bioenergetics, and redox potential, and membrane boundaries, and leakiness of electron, and all those kinds of things that relate to oxidative stress and free radical pathology. But for the clinician, the outcome in this study I think once again showed very, very significant effects on clinical outcome in the patients correlated with the improved mitochondrial function.[9] How did you measure the clinical outcome in these patients with fatiguing illnesses? GN: What we used was a validated instrument for studying fatigue. It was actually developed for cancer patients who suffer fatigue. By the way, these products are also very useful in cancer—particularly during cancer therapy—to reduce fatigue, which is the number one complaint of the patients during cancer therapy. Basically it is a questionnaire-type of instrument and it has been validated in thousands and thousands of patients for being a valid instrument for looking at fatigue. Fatigue is a multi-dimensional phenomenon and it has very different sorts of aspects to it, which I won’t go into in detail about. This instrument covers the various aspects of fatigue so we can get a pretty good and accurate measure of fatigue. This is not really our development. Barbara Piper and her colleagues, over many, many years, had developed this to study fatigue in cancer patients. We simply utilized her very useful instrument to look at chronic fatigue in chronic fatigue syndrome patients and other patients that suffer from tremendous fatigue. We would give these patients the lipid supplements and not only look at their mitochondrial function, but also look at fatigue at the same time. Where we found the mitochondrial function was restored, the fatigue level went down, and was reduced anywhere from 35 to 45{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in different studies. So this turned out to be a very useful instrument. JB: We move from that to 2010. This is a paper that appeared in the Journal of the American Nutraceutical Association looking at this upgraded NTFactor intervention with a glycophospholipid antioxidant vitamin formulation that then seemed to compress or reduce the time to efficacy quite significantly.[10] What was the nature of improvement that you had learned about to actually hasten or to make more quick the outcome? GN: The biggest improvement, in my own mind, was the fact that we put in more immediate precursors of some of the most important molecules in the membrane. So that’s the first thing that we did. For example, in mitochondria there are molecules like cardiolipins, which are exclusively sensitive to oxidation. When they are oxidized, they really modify the function of the mitochondria very dramatically. Cardiolipin has important constituents, such as phosphatidylglycerol. By supplying the precursors to cardiolipins we are able to speed up the entire process, which before depended in part on interconversion of some of the cardiolipins into the cardiolipin precursors. As I mentioned earlier in the conversation, if you apply the more immediate precursors to membrane functional molecules then you seem to get a faster process because it doesn’t require the enzymatic interconversion in between, so these things can functionally work sooner than if we apply less intermediate or less immediate precursors. By doing that and by also adjusting some other aspects of the mixture, we tended to speed up the entire process. That’s the good news, and we’re tinkering with this all the time. My colleague, Bob Settineri, who has really been doing a lot of tinkering with the lipid composition has really come up with some really outstanding formulations, which I think will push this even further. JB: As you talk about oxidation of membrane lipids it reminds me of the reactions that occur due to oxidation that produce aldehydes like malondialdehyde, and how those can have effects on intracellular proteins by tanning the proteins, forming shift spaces and cross linking. Do you ever have occasion to measure some of these of these oxidation products, like the aldehydes that are produced? I think you can measure these, even things like the thiobarbituric acid reactive intermediates. Do you see a correlation between the reduction of these reactive aldehydes and the preservation of membrane integrity? GN: It is interesting that you bring that up because it is one of the next things that we are actually going to get involved in. The lipids that we’re providing also have an antioxidant effect as well, and, of course we do put in antioxidant with them. This is an important aspect, I think, of the whole process: preventing and eventually reversing the oxidative events that occur inside a cell. These are not only to lipids, but they are also to other structures in the cell as well (to proteins, and to DNA eventually). I think in this entire process, we’re going to look at it in much more detail. We haven’t yet, but we plan to do that. Mitochondrial Function, Functional Foods, and Cancer Therapy JB: That leads me, then, to 2011, and what I call (in my vocabulary) a “seminal” paper that you’ve just put into the literature that is available by open access in the Functional Foods in Health and Disease journal. This is a wonderful review titled, “Lipid Replacement Therapy: A Functional Food Approach with New Formulations for Reducing Cellular Oxidative Damage, Cancer-Associated Fatigue, and Adverse Affects of Cancer Therapy.”[11] Again coming back to what you talked about earlier: that many of the cancer therapies themselves cause mitochondrial perturbation and induce oxidative injury and the cancer process even in the absence of therapeutics increases oxidative reactions due to the anaerobic metabolism that is often occurring within cells that shifts mitochondrial function into an oxidant pro-production situation. Could you highlight this extraordinary review? GN: Thanks for plugging the paper because it is a fairly new journal. We have been kind of interested in the functional food aspects of this because that’s really what we are talking about in terms of a lot of the dietary supplements. If we can provide them as a functional food then more and more people would have access to this technology. I think that’s the way of the future. So we have been looking at the wide variety of different ways that these lipid supplements, and antioxidants, and so on can be provided in the future, to not only patients but to people to generally improve their lives and generally help to protect against the environmental insults that they are seeing on an increasing basis these days. This is just kind of a review of what lipid replacement therapy has done, and it concentrates on cancer because it is an interest of mine and it has been for some time—how to reduce some of the morbidity of cancer. Of course, a lot of this, as I mentioned, is due to the direct effects of not only the cancer, but also the drugs that are taken to treat the cancer. We’ve tried to figure out ways to reduce not only the effects of the cancer on morbidity, but also the effects of cancer therapy on morbidity. This could be radiotherapy, chemotherapy, or whatever. We know that these processes result in a lot of oxidative stress in our systems. The difference –and the reason why we are not interfering with the actual therapy against the cancer itself—is that that therapy actually takes place in a fairly short window. There is a very short window of opportunity to kill a cancer cell. The time we are talking about is a much longer time period, and that is the effect on the normal cells and tissues that occurs due to the cancer therapy—the residual problems that are associated from the cancer therapy. And this is what we want to improve, to improve the quality of life of cancer patients, and to also help them overcome the morbidity associated with therapy. JB: I find this very, very interesting. Probably like you, we’ve been around in this field long enough now to see cycles within cycles, and wheels developing, and lineage of thought from an initial kind of a-ha discovery ultimately into a broader kind of formalism. It was more than 15 years ago in Functional Medicine Update that we had the opportunity to interview Dr. Martin Pall, who presented to us what, at the time, was a very provocative concept: that fibromyalgia syndrome and chronic fatigue syndrome were associated with oxidative stress, and peroxynitrite formation, and activation of the immune system that induced nitric oxide-mediated free radical pathology and a cascade of events, including oxidative chemistry as well as nitrogen chemistry. He is a biochemist at Washington State University and had been studying himself. He, himself, had had chronic fatigue. It just came out of the blue for him after a flu that he had at a science meeting in Spain. So he made this the topic of his work for the last 20+ years. At the time a lot of people said, “Well that sounds like a very audacious concept that doesn’t seem to really ring true. That’s not the dominant theme of the origin or the pathophysiology of chronic fatigue or fibromyalgia. It sounds like just a wild speculation.” But he continued on with this work. He published a number of papers in this area. That seems to converge very nicely with your emerging concept as well. Are you familiar at all with Dr. Pall’s work? GN: Oh, yes. In fact we cite his seminal references in our papers. In his case he is concentrating on nitrogen oxidation/nitric oxide oxidation, but it is all part of a general scheme that occurs inside our cells, and that general scheme occurs when the cells are damaged. Our part of it is, how do we repair this damage? How do we return the cells back to a more normal state so they can be fully functional? JB: So then that leads to another therapeutic question. There are those people that are detractors of this whole lipid replacement concept that say, “Just a minute. I don’t understand how this can work. You’re administering therapeutically a few thousand milligrams of lipid to the person per day, yet their body is composed of 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} or more of fat (of their whole body weight), so if they are a 70 kilogram person they have from 14 to 25 kilograms of lipid and that’s like 14,000 grams and you’re only giving them just a couple of thousand milligrams, so that’s like a breath of wind in a storm. How could that have any therapeutic effect?” What would be your answer to that? GN: For one thing, we’re not talking about the total lipid stores of a body, which are considerable. We’re really talking about some very important functional membranes of the body, which is a minute percentage of that total store. Then there is even a more minute percentage of that, which are actually the functional lipids, which are the target of oxidative events inside the cells. So we are really talking about something that is really very, very small compared to the total amount of lipid in a body. But those are the functional lipids that really determine—in terms of energy production—whether it will occur or not. We’re really going after the functional molecules. JB: Again, to kind of trace back to our history of Functional Medicine Update, this sounds very similar to an interview that we had with Dr. Edward Calabrese, who is kind of the father (at least, arguably) of hormesis, this concept that small things can have bigger effects than expected if they hit regulatory regions within cell physiology. He has talked a lot about the nonlinear effects of a dose response curve when you get down near the origin at high dilution, that sometimes substances have different signaling effects. It seems like we’re almost talking about a hormetic effect:  

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Bibliography

[1] Singer SJ, Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science. 1972;175(23):720-731.   [2] Logan RL, Riemersma RA, Thomson M, et al. Risk factors for ischaemic heart-disease in normal men aged 40. Edinburgh-Stockholm Study. Lancet. 1978;1(8071):949-954.   [3] Schlame M. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes. J Lipid Res. 2008;49(8):1607-1620.   [4] Hokama Y, Empey Campora C, Hara C, Kuribayashi T, Le Huynh D, Yabusaki K. Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome. J Clin Lab Anal. 2009;23(4):210-212.   [5] Perez-Martinez P, Garcia-Quintana JM, Yubero-Serrano EM, et al. Postprandial oxidative stress is modified by dietary fat: evidence from a human intervention study. J Clin Sci (Lond). 2010;119(6):251-261.   [6] Rector RS, Thyfault JP, Uptergrove GM, et al. Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J Hepatol. 2010;52(5):727-736.   [7] Pauling L, Itano HA, et al. Sickle cell anemia, a molecular disease. Science. 1949;110(2865):543-548.   [8] Agadjanyan M, Vasilevko V, Ghochikyan A, Berns P, Kesslak P, Settineri RA, Nicolson GL. Nutritional supplement (NT Factor™) restores mitochondrial function and reduces moderately severe fatigue in aged subjects. J Chronic Fatigue Syndr. 2003;11(3):23-36.   [9] Nicolson GL, Ellithorpe R. Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses. J Chronic Fatigue Syndrome. 2006;13(1):57-68.   [10] Nicolson GL, Ellithorpe RR, Ayson-Mitchell C, Jacques B, Settineri R. Lipid replacement therapy with a glycophospholipid-antioxidant-vitamin formulation significantly reduces fatigue within one week. JANA. 2010;13(1):10-14.   [11] Nicolson GL, Settineri R. Lipid replacement therapy: a functional food approach with new formulations for reducing cellular oxidative damage, cancer-associated fatigue and the adverse effects of cancer therapy. Functional Foods in Health and Disease. 2011;4:135-160.

Welcome to Functional Medicine Update for September 2011. Functional gastroenterology. Oh boy, there’s a long, polysyllabic term. What is this all about? What does it mean? How does it differ from traditional views of gastroenterology? What role does it have to play in the management of a variety of chronic, age-related diseases or dysfunctions? How does it complement traditional gastrointestinal pathology and pharmacology? What might be the future of the field of gastroenterology as it relates to the emergent view of functional disturbances? That’s a lot of questions and that’s what we’re going to be discussing in this issue. Functional Gastroenterology: A Clear Example of Applied Systems Biology From my experience in this field, I would say the topic of functional gastroenterology incorporates more of a unique understanding of systems biology at an applied level than any other single area that one might choose. Cardiology, or neurology, or obstetrics/gynecology, or any other subspecialty in medicine does cut across organ systems and all have a systems biology underpinning, but I think the gastrointestinal system is uniquely framed and a good starting point in our journey into systems biology as it relates to functional medicine. The Gastrointestinal System Has Many Roles We know that the gastrointestinal system has a very strong mechanical role as a digestive organ: it breaks big stuff into small stuff. We also know that the gastrointestinal system is the seat of the associative immune system. Fifty percent of the immune system is clustered around the GI tract. In his book titled The Second Brain, Michael Gershon told us the gastrointestinal system represents the second brain due to the enteric nervous system and its production of various neurotransmitters and neuromodulators and how it may interact with the neurotransmitters from the brain.[1] This conceptual framework–that the GI system has multiple roles to place across multiple organ systems–is a model for a systems biology approach to thinking. It may present, in the patient in the exam room, as a GI problem, but it connects to all these other aspects of function in the organism. That will be the theme that we’ll be discussing over the course of our interview with our two thought leaders—key opinion leaders—who have (cumulatively) more than 60 years experience in this field. With that in mind, let’s move into the heart of the matter—actually, it’s the gastrointestinal digestion of the matter—with our clinicians/ researchers of the month.

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INTERVIEW TRANSCRIPT Clinicians/Researchers of the Month Gerard Mullin, MD Kathie Swift, MS, RD, LDN September 2011 This portion of Functional Medicine Update is the cornerstone of each issue, and that’s our interview with our clinician and/or researcher of the month. I’m going to interview two luminaries this month and have kind of a round-robin discussion with them. They are experts in gastrointestinal physiology and the functional medicine approach, and also the interrelationship of that to diet, nutrition, and this whole intercommunication of the gut to nutrition. Who am I speaking about? I’m speaking about two luminaries that have been in this field for 30-plus years each: Dr. Gerry Mullin, who, as many of you know if you have been following the functional medicine field for some time, is considered one of the cornerstone gastroenterologists. He is an associate professor of medicine and Director of Integrated GI Nutrition Services and Capsule Endoscopy at Johns Hopkins Medical School. Gerry and I go back, actually, to probably the early 80s. I think he might have been a medical student at the time we first met. He finished his medical training at New Jersey Medical College. He went on Mount Sinai for his residency and Johns Hopkins for his fellowship. Kathie Swift is our other expert. Kathie is a registered dietitian. I would say Kathie’s is probably the principal premier background in dietetics and functional medicine anywhere in the world. Kathie has been a leader in developing functional medicine applied to nutrition at the clinical level. Kathie was head of nutrition services at Canyon Ranch. She has also worked with Dr. Mark Hyman for many years in clinical practice. And Kathie is also the person who has been in charge of the very, very interesting program that I think most of you are familiar with called Food as Medicine, sponsored by the Center for Mind-Body Medicine. She is just a national leader in dietetics and nutrition as it applies to integrative functional medicine. These two are, I think, extraordinary prospectors of the yet-to-be-fully understood and found. They are constantly learning and helping guide us in new ideas. Both Gerry and Kathie, welcome to Functional Medicine Update. GM & KS: Thank you. Thanks for inviting us. JB: Gerry, let’s start with you. We’re going to be speaking today about functional nutrition and functional medicine. I think it might be helpful for the listeners if we could start with a review of some of the conditions that a gastroenterologist deals with on a routine basis. This is more than just a piece of plumbing in the body. Could you start with gastroesophageal reflux disease (GERD) and then work down and tell us a little bit about the types of pathologies that a gastroenterologist is concerned about? Gastroesophageal Reflux Disease (GERD) is the Most Common GI Disorder GM: Yes, thank you. GERD is the most common GI disorder that we know of, at least in this country. It has been estimated that at any point in time, half the population develop some symptoms of GERD over the course of a year. That’s pretty impactful in terms of the number of people who experience these problems. Gastroesophageal reflux disease, as the name implies, is a reflux of gastric contents up into the esophagus. That can be a combination of acid and also bio- and pancreatic enzymes, all of which can degrade the esophageal mucosa and create symptoms and also complications. When we think about how to approach people with GERD, we think of ways to help coat and protect the lining of the esophagus, and also promote the motility of the stomach and the esophagus to keep the forward flow of enzymes and acid (keep that away from the esophagus). Those are some of the things that we think about when we approach these people. There are certainly natural ways to do that with herbs which promote motility of the stomach, such as ginger, licorice root, and slippery elm. GERD and Barrett’s Esophagus JB: I learned recently that GERD has a connection—when it is chronic and long term, and depending upon the severity and the genetic uniqueness of the person—to a condition called Barrett’s esophagus. Barrett’s esophagus, I found out from some work ongoing at Fred Hutchinson Cancer Research Center in Seattle, is a condition that is associated with the greatest genomic instability in cells that are affected within that tissue type of any known condition. It has huge adverse impact upon the integrity and the patency of our book of life (our genes), which is why it probably has such a high incidence to risk to cancer, and ultimately, then, metastatic cancer that can be very, very life-threatening. It’s interesting. It must be something about that caustic environment that leads to this very significant risk to genomic stability. Do you have any thoughts about that? GM: I think it’s a combination of something in the genes, because not everybody develops Barrett’s, and not everybody with Barrett’s goes on to cancer, so there is something there that is the interaction of the environment (that we are discussing here) in combination with the genes. It could also be that some individuals have greater cytoprotection. Maybe those who don’t develop cancer are the ones that have greater antioxidant capacities, or maybe their diets are healthier, so there are a lot of different things that haven’t been looked at yet that may have impact on the outcome of that particular condition. How it develops, interestingly enough, is there is a noxious stimuli through the irritation of the lining by degradative enzymes, which causes an inflammatory response underneath the epithelium. Perhaps that chronic proinflammatory response plays a role in turning on those genes. JB: I’ve also heard that GERDis called a “functional gastrointestinal problem” because it doesn’t seem to have a specific pathognomic indicator. From a gastroenterological perspective, is that a true statement? That it is more functional than it is tied to a single histopathological origin? GM: Well, according to classic definitions GERD is a separate entity, but it is also connected to (and very common with) functional gastrointestinal disorders that can include gastroparesis, irritable bowel, and those types of syndromes. Those all seem to connect with poor motility, and any part of the upper GI tract will put you at greater risk for gastroesophageal reflux disease. JB: So Kathie I’d like to shift over to you. Given what Dr. Mullin just said about the prevalence of GERD, clearly in your experience as a clinical nutritionist/dietitian you’ve seen many patients who have come in with that as one of the presenting symptoms or part of their symptom profile. What, in your experience, has been the nutritional connection to this kind of a problem? Nutritional Approaches to Treating GERD KS: Well, Jeff, I found that that is highly individualized, and as Dr. Mullin mentioned, often connected to many other things that are going on in the gut. Traditionally we may have a GERD-type diet that eliminates spicy foods, tomatoes, citrus, and certainly we’re finding that for a certain individual it varies and this is why creating nutritional plans that really are individualized is important. There are some common gastric irritants. I find that alcohol can certainly be the most incriminating factor. Coffee—you know, we have a lot of people who love their morning brew. Sometimes you can experiment with peppermint. I find that other food antagonists could be dairy products or gluten, and this is really a holistic approach to the nutritional protocol. Atopic Gastritis JB: Let’s move downstream a little bit to the stomach and talk about a condition that is often brought up, atopic gastritis (ARB), which is associated with poor acid secretion from the parietal cells and then that has a downstream effect on absorption. Could you, Dr. Mullin, tell us a little bit about your experience with the prevalence of hypochlorhydria and its association with atopic gastritis? GM: We do see it on occasion, in particular in those who are elderly, because the older you are unfortunately the capacity to make stomach acid is weaker, and also there are individuals who are afflicted with an autoimmune condition, such as pernicious anemia, where antibodies are attacking the parietal cells and thus rendering an individual less able to make stomach acid. What happens over a period of time is that there will be malabsorption, or an impairment, in the absorption of minerals (iron), which leads to anemia, and also over a period of time the individual may have poor bone development or osteoporosis. So these are concerns that happen long term, and also something I see very commonly is that if you don’t have the acid present you need to kill bacteria in the stomach, individuals develop a condition called small intestinal bacterial overgrowth, and that itself runs a whole gamut of symptoms and problems, which now we are finding many different connections to. JB: Kathie, I know that many people that come in with the GERD condition are on various types of acid-suppressing medications. It could be antacids, or proton pump inhibitors, or something that is blocking the parietal cell production of acid. Have you found that that has any correlation, then, with inability (or let’s call it altered digestive capabilities) in some of these things that Dr. Mullin is talking about? KS: Absolutely. Part of the process as a nutritionist is for me to help uncover some of the dietary triggers that might be aggravating the problem, and also providing the nutritional support with respect to the nutrients that are compromised—protein, for example. They may not be able to break down and absorb the protein as they should when there is a compromised acid problem. Dr. Mullin mentioned small intestinal bacterial overgrowth, and another approach we may employ is limiting foods that may be contributing to the bacterial overgrowth and some of the short-chain carbohydrates that the bugs can be feeding on and such. H. pylori and Peptic Ulcer JB: Let’s move from there down a little bit farther south into the duodenum and talk a little bit about peptic ulcer. Of course, Barry Marshall was iconic (maybe iconoclast that later became iconic) in his recognition of H. pylori. It always seems interesting to me, however, that there are places within the world where H. pylori infection is high but peptic ulcer disease is low. There must be something beyond that of H. pylori infection itself. Gerry, could you tell us a little bit about the emerging view of the peptic ulcer-related conditions in physiology? GM: It’s interesting because up until the discovery of H. pylori we didn’t really know much about how peptic ulcers developed except for, of course, the noxious stimuli of alcohol, and aspirin, and non-steroidal medications, etc. With the treatments now available, we’ve seen a decline in some of the peptic ulcers, but unfortunately we still see people who develop complications once they get peptic ulcers. As you know, non-steroidals are very commonly used in this day and age for treatment of pain as front lines of therapy, and that is creating a large market spill for people who need to be medicated for peptic ulcers. The H. pylori itself is readily treatable. It is interesting that half the world’s population has H. pylori, but only a fraction of them develop problems. So there is something really unique within the host—perhaps even genetic—that we haven’t discovered, as to why some develop complications of H. pylori and others don’t, or perhaps other environmental factors that are triggers or cofactors in disease development. JB: Kathie, as we take what Dr. Mullin just shared with us and move it over to the nutrition side, let’s look at non-steroidal anti-inflammatory drugs (NSAIDs). You undoubtedly have many patients who come in for nutritional counsel that are taking routine doses of NSAIDs for various types of osteoarthritis or other pain-related issues (chronic pain). What does one do if you’ve got this problem of gastric erosion and you’re trying to form a diet and you’re trying to manage the chronic pain-related issues? KS: First off, what we can share is the ability of the body to heal and repair, that the GI tract is resilient, and that food is the ideal medicine and to embark on an anti-inflammatory nutritional protocol that really is plant-centered, that is removing some of the incitants that are fueling the inflammatory cascade. These can be varied depending on the dietary assessment and learning what the person has been eating. It may be that they are fueling the inflammatory process with the wrong types of fats. It may be that they are not eating enough of the antioxidant-rich vegetables and fruits; this is a very, very common deficiency. So by exploring an anti-inflammatory path through the vehicle of food, it really can inspire someone to get on track. Irritable Bowel Syndrome JB: Let’s move from there, on our journey heading south, down into the small intestine now and start looking at what I know, as you have already mentioned, Dr. Mullin, is one of the most prevalent functional GI disorders: irritable bowel syndrome (IBS). I think IBS is a term that encompasses many different things: constipation, diarrheal disorders, alternating constipation/diarrhea, gut pain. What’s the status of our understanding of IBS these days? GM: It’s very complex. The gut in and of itself is complex, but IBS is just really complex as an entity. It appears that it is a syndrome that develops as an interaction between alterations in our emotional motor system or mind/body processes, but also there seems to be an infectious component. For some people who have been traveling or developing a post-infectious syndrome from food poisoning, that’s about 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the IBS patients who develop in that manner, while many others have what I described before as small intestinal bacterial overgrowth as one of the lead causes of their symptoms. Once they are treated for their small intestinal bacterial overgrowth and go into remission of that, their IBS symptomatology improves. I have to say that within the last five years, the two major advances are the discovery of a post-infectious IBS that happens after some type of acquired infection (bacterial in nature, most commonly) or the harboring or misplacement of that bacteria in the small bowel. JB: From your experience, Gerry, what role, therapeutically, do antibiotics have to play and what role do probiotic and prebiotic supplements have to play with IBS? GM: Great question. For the treatment of the small intestinal bacterial overgrowth, the gold standard presently is antibiotics, most commonly rifaximin. Here at Johns Hopkins I finished a study that we’re in the process of writing up for publication, where we compared some herbs (mainly oregano oil and berberin extract) for the treatment of individual small bowel overgrowth, and we found remission rates comparable to rifaximin. Everybody has different proprietary herbs on the market, and it’s something they consider in the treatment of small bowel overgrowth. Probiotics in and of themselves have been shown in meta-analysis to be helpful for irritable bowel syndrome.[2] Again, as you readdress the microflora and as you balance it out, it appears that you can help people with irritable bowel syndrome. JB: So, Kathie, let’s move to you for a minute for a nutrition perspective. Again, this is one of those big animals in the corner, this IBS issue. I’m sure you see many patients that come in with this as a complaining symptom. Tell us a little bit about how you approach this nutritionally. Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols (FODMAPs) KS: Again, it is looking at all the possible influencing factors. I have found that an emerging dietary approach that has been very, very helpful is limiting the short-chain carbohydrates, referred to as the FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols [sugar alcohol]), so foods that are high in fructose: lactose, fructans (wheat is certainly a major source of fructans in the American diet), and, again, sugar alcohols that are commonly found in sugar-free gums and mints. This is an emerging protocol that I’ve been using and by limiting some of these types of foods, some of the symptoms–pain, and gas, and bloat–can certainly be improved. Uncovering unique food triggers and also exploring a limited FODMAPs approach is important. JB: That’s very good news to use. And by the way, I should mention your collaborative book, which has recent been published: The Inside Tract, the Good Gut Guide to Great Digestive Health, which you—Gerry—and Kathie have authored, and which is available now from Amazon.[3] It is really a great publication that takes a lot of these concepts we’re talking about and puts it into user-friendly language. I want to refer our listeners to this wonderful resource to follow-up and amplify some of the things we’re discussing here. The Inside Tract is a great addition to the literature, so thank you both. Crohn’s Disease and Ulcerative Colitis Let me ask Gerry now, as we move south even a little bit farther into the large intestine and ultimately to the colon: What about these conditions that seem to be increasing in prevalence (at least in the news they are)—Crohn’s disease, which has some small and large bowel implications, and inflammatory bowel disease? Can you differentiate between those two for us and how they are seen in traditional gastroenterological circles in terms of their pathophysiology? GM: Crohn’s is a disease that can affect any part of the gut, from mouth to anus, and ulcerative colitis is a disease that is limited to the colon. That particular disease tends to be very continuous along the colon, whereas Crohn’s disease tends to be patchy (in different places). The immunopathologies of the two diseases have differences and similarities. The treatments of those (as least from the immune-biological point of view) have been targeted towards specific cytokines and different signaling pathways that they share in common (at least in pathophysiology). How one would approach an individual who has those syndromes from a natural medicine point of view would mainly include diet and lifestyle, which are chronic triggers for these diseases. Also looking to make sure they have enough anti-inflammatory nutrients, whether through foods (food-based approaches we’ll talk about) or even from a nutraceutical point of view. There are many different inhibitors of a signal transduction pathway called NFkappaB that are available naturally, like vitamin D, and curcumin, and green tea extract. These can suppress the inflammation and some of these have been studied in clinical trials to be quite beneficial for inflammatory bowel disease. Fish oils have been found to be quite effective for both diseases, and also for ulcerative colitis because those patients appear to be deficient in the short-chain fatty acid, butyrate. Individuals who receive butyrate by enema can go on to remission when they fail other medical therapies, so there is a big link between nutrition and inflammatory bowel disease. JB: I want to follow on with a question that seems to have been emerging in the literature related to the use of TNFalpha blocking agents like Remicade or Enbrel for the treatment of these types of acute inflammatory conditions of the digestive tract. At one time I thought that it was felt that Crohn’s disease was not a TNFalpha-mediated process, yet now there is literature suggesting that you can use these TNFalpha blocking agents for its treatment as well. Is the standard of care now, in an acute case, using these blocking agents, and if so, what kind of relative risk does a patient experience over time on these medications? Debate About Use of TNFalpha Blocking Agents GM: A very good question. The use of these blocking agents for TNFalpha has been around for awhile. When to use them seemed to be the question. More recently, I guess, many academic individuals and certainly others used this approach for top-down therapy. So they used the heavy biological first in the approach to therapy rather than the “step-up” therapy in terms of stepping up with lifestyle, and diet, and some lighter medications and supplements, and working up to the heavier biologicals when needed. There is debate in our community as to which to use first. Some can argue that in the case of more aggressive disease the biological makes more sense because if their diseases aren’t controlled then you need to step up to the highest therapy, whereas for others who have very mild symptoms and are very functional, you may not want to go in that direction right away. We have our own little controversy within our field as to when to use these biological agents. JB: And what’s the relative risk if a patient was to be placed on those over the long term? Are there things that have emerged from your experience that are kind of the risk/benefit part of our decision making? GM: Yes, I rarely use those medications in my own practice, but what I have seen and what I know of is that patients can develop all kinds of infections. These can range from bacterial infections to the most concerning, which would be tuberculosis, because you are really surveilling and shutting down the immune system. Others have concerns about lymphoma or malignancies. There have been many studies. Some studies show there is a marginal increase in lymphomas and other studies show there is no increase, but we’re aware that there may be something out there with malignancies because you are certainly suppressing immune surveillance with this biological-type of approach.[4],[5] JB: Kathie, let’s shift to you and pass the ball over to your court. What kind of diet and nutrition counseling do you discuss with patients that have the ulcerative colitis/inflammatory bowel/Crohn’s kind of presentation? KS: Jeff, this is where a therapeutic, comprehensive elimination diet can be extremely powerful. I usually start with finding out from the individual what they suspect most. What I have also found from years of working with patients with inflammatory bowel conditions is that common aggravating foods are dairy, gluten-containing grains, and FODMAPs, so I typically will limit the FODMAPs, remove dairy and gluten, and I’ll support the healing with a medical food that is also providing some targeted nutraceuticals, like glutamine. I just had a patient recently and, not too long ago, her C-reactive protein and other markers were extremely elevated. Interestingly, within one month of dedicated adherence to this type of elimination diet, her gastroenterologist was really kind of shocked at the results. It’s quite encouraging that once we uncover the food triggers and support the healing process with nutraceuticals, it can be very, very dramatic. JB: Gerry, let’s bounce the ball back to you. You authored a book that was recently released titled Integrative Gastroenterology, which is a very powerful review of many of the things that you have been touching upon in answering my questions.[6] Undoubtedly, your colleagues in—I’m going to call it—the traditional pathophysiological-based gastroenterology may have looked at this with some jaundiced eye, or may have looked at it with inquiry. How has your work been reviewed by your colleagues and do you think there is some traction that is happening within the field of gastroenterology to look at GI issues from a more functional perspective? GM: Well, you know Jeff, I meet many individuals in my own field and in the community who are looking for other options in terms of getting people better. But despite their best efforts, there are still challenges in overcoming that onus. The book was just released so I really haven’t had much feedback within my own particular field or within the academic community, but many have given me positive feedback about how helpful this book is in their own practices. So I think there could be a paradigm shift in terms of how we can approach these illnesses and how we can change them from a functional perspective and in how we approach people as a whole (a more holistic point of view). JB: Kathy, let’s shift over to you. I think just as physicians often have some pushback on things that are outside their circle of learning, so do patients who often have some preconceptual view about the role that diet plays. How do you get patients to actually respond to these things you are talking about, like an elimination diet, when that may be very different than the way they have viewed their diet in the past? KS: The first thing I attempt to do is help them understand how this can be helpful, what benefits will they see, what benefits will they gain by perhaps giving up foods that they may have a special relationship with—foods that may be providing them emotional comfort, or special memories, foods that are linked to social events, really foods that you may revere. I always try to keep in mind that when we are asking a patient to give something up, they need to understand what they are going to gain. If we take away a particular food, for some people we may be taking away some of the meaning of their life. I think to expand their understanding, to share success stories, can be very motivating. To share research that expands their understanding of how this nutritional prescription can help them is important. I also have to mention that I work often with patients who come to me and are already very motivated. They may have tried other things. They may have had other dietary trials and tribulations, but they are really ready for another lens. They need to know what the process is, what it includes. A common question I get is, “What can I eat?” Having menus and shopping lists—some of these tools—is very, very useful for them. They also need to know what this is going to take. They want to know, “What’s the timeline here—the beginning, the process—of perhaps food reintroduction, and challenge, and eventually the transition to an integrated eating plan?” I think another really, really important aspect is that I try to help them understand the other ingredients in this recipe for healing, so to speak: the mind-body practices that are going to help them relax their enteric nervous system, whether it is something like yoga, or soft belly breathing, or a guided imagery tape/DVD that has been designed for individuals suffering with GI symptoms. I think all of those things are important in troubleshooting some of the challenges an individual may have (time being often the number one thing that I hear). Environmental challenges: eating out, travel, support from friends and family. I encourage their expression of anxiety and fears—for them to be able to voice concerns like, “I’m not sure if this will work either” or “What happens if I eat something that I know is bad for me?” As a clinician, I try to troubleshoot and provide assurance that it’s a journey, and one dietary indiscretion doesn’t thus break or blow a healing process, and use all of these things as teachable moments and opportunities for nutritional skill-building and empowerment. I also have found that groups can be really very, very helpful, which is one of the reasons I started a digestive health and healing program at Kripalo, a center for yoga. The group experience has been especially helpful because then they form a community, together, of individuals for ongoing support. JB: I can tell you, your book—the book that you and Dr. Mullin have authored and has recently been released, The Inside Tract, really does a beautiful job of describing what you are talking about. It is really about a relationship to food and how that gets translated through our gut. I’d like to now kind of pass the ball back to Dr. Mullin for a second. Gerry, it seems that if you say “gastroenterology,” many people will think of—if they think about it at all—a model of a digestive conduit, a piece of plumbing, something that connects the mouth to the southern hemisphere of the body, breaking big stuff down to small stuff and excreting stuff we don’t want. So it’s a very mechanical-type of view. In your books (both Integrative Gastroenterology and The Inside Tract), that you describe a different kind of understanding that is now emerging around the GI tract, which has to do with the enteric nervous system that Kathie was speaking to, the second brain that Michael Gershon talked about; that there is all this plexus of nervous system activity and neurotransmitters that are signaling from the gut to the brain, and the brain to the gut. This is kind of a network view of the immune system (50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the immune system being clustered around the gut). Could you tell us a little bit about how that concept is emerging in gastroenterology and how it relates to patient management? Obesity and Gut Microbiota GM: Very good point. I mean, it really is the inner tube of life. It is not just junk in/junk out and it’s a piece of plumbing. We’re finding out that there are so many different roles of the digestive tract in overall health and well being, and particularly the gut microbiota, which are continually being developed and explored and discovered. At one point it was 500 organisms, and now I’m hearing up to a thousand organisms that we harbor within our gut. These organisms have a role in terms of our overall metabolic function, but also they affect different areas of the body. For example, they control our appetite. Researchers are looking at ways of manipulating the gut’s microbiota to deal with obesity, as an example. If your microbiota are not well developed, you may be at more risk for heart disease. We’re finding that the gut, in health, really has an impact on other areas of our body, and even our brain—with depression, and anxiety, and mood disorders—may be secondary to different enteric passages in our gut microbiota. The gut microbiota is just one piece of the puzzle, but it is a large piece of the puzzle. When we have a healthy gut flora and a healthy gut, chances are we’ll have much better health than if we don’t. JB: I think that’s a really great insight. You know, I’ve had the privilege of sharing the podium with a psychiatrist who is also an immunologist by the name of Michael Maes, from Belgium. His studies (he has published a number of papers) have tied together aspects of GI function to chronic fatigue syndrome, fibromyalgia, and dysphoria and mood disorders.[7],[8] It seems like there is a very interesting interconnection that’s being made among different medical specialties now and the GI system. Certainly your books really start to get us to think in a very different way about gastrointestinal function than maybe in the past, where it was more of an isolated, siloed view of this as a piece of plumbing. Kathie, let me shift to you. I know that you have been a pioneer. It goes back so many years that you and I have known one another—all the physicians you have trained, what you’ve done in terms of education of nutritionists and dietitians, your leadership role in getting the concept of functional nutrition to really be seen as a major theme in the advancing field of clinical nutrition. What kinds of things are you seeing, from your lens, as it relates to the evolution of the field and the role that GI function plays in this whole diet/health connection? KS: It is absolutely as we discussed—the inner tube that connects all systems of the body—and an area that I am particularly fascinated with is that of the whole mind-body/gut-brain conditions, such as depression and anxiety. This isn’t all in peoples’ heads. I think in my work at the College of Mind-Body Medicine (Saybrook University) that for these doctoral students and MDs this was a real “ah-ha” for them—that actually food can make a difference in conditions like depression and such. I think that we will continue to see forward movement in that area, and nutrition becoming absolutely foundational for all those working in the field of mental health. JB: There are so many interesting subtopics of topics in this field, but for the sake of time let me ask one last question. Gerry, we’ll start with you (it’s the same question for both of you). As you look forward in your crystal ball, where do you see medicine going as it relates to these concepts that we’ve been describing and the increasing burden of various chronic diseases? How do you see this playing out, say, over the next 10 years? GM: If I had a crystal ball, I guess I would say that I see medicine becoming a little more personalized (first of all, more personal). Hopefully, at some point, we’ll spend more time with our patients and be able to really deliver more effective doctor/patient relationships, which have been shown in many studies to have better outcomes (just as a result of those relationships). I think we’ll have more of a personalized approach to medicine. Some of that can come from genomics, such as nutrigenomics, so we can characterize an individual’s response to food and food-based nutrients and supplements. Secondly, I think we’re going to find that the more we study the gut, and particularly the gut microbiota, we’re going to find how impactful that is to the rest of the body, and I think we’ll go back to the old adage that “a lot of things start in the gut.” I think we’ll find more and more of that over the years. And I think largely it’s about gut microbiota, and that’s going to really bring that to our attention. I think at the end we’re going to be treating people a little bit more with foods and food-based therapies and probably with probiotics as well. And even those probiotics may be individualized for different people, so that can be personalized as well. JB: A very interesting kind of perspective. Kathie, how about you? This is your shot at looking in your crystal ball. Moving Medicine into the Kitchen KS: Quite simply, I see medicine moving into the kitchen. I see this on all fronts: in our home, which can be our healing center, with the patient in the driver seat; I see hospitals developing sustainable food systems; more demonstration kitchens in schools and in all arenas; I perhaps even see the return of something that is a long-lost art, and that is home economics (and hopefully gym class along with that too). We need partnerships and networks—more partnerships with, I hope, gastroenterologists, and dietitians, nutritionists, and more social groups forming that really can make an impact. I think that it is, on all fronts, moving into a food as medicine approach. JB: I want to thank you both. I think this has been one of those very, very remarkable moments in Functional Medicine Update’s 30-year history—to have two luminaries bring two very complementary perspectives together on a topic, and it shows, really, the advancing evolution of this whole concept: functional medicine, functional nutrition, functional physiology and how different backgrounds can complement and enhance, in a synergistic way, the approaches towards the management of very complex chronic health problems. Again, I want to compliment you both on your authorship of The Inside Tract, this good guide for great digestive health. I think it is a tremendous contribution to the literature, and thank you for your leadership in the field all these three decades. It’s pretty remarkable. Thank you for both your friendship and for all your contributions. KS: Thank you so much, Jeff. It’s been a pleasure. GM: Yes, thank you very much, Jeff.

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Bibliography

[1] Gershon, Michael. The Second Brain: A Groundbreaking New Understanding of Nervous Disorders of the Stomach and Intestine. New York, NY: Harper Paperbacks, 1999.   [2] McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol. 2010;16(18):202-2022.   [3] Mullin, Gerard E. and Kathie Madonna Swift. The Inside Tract: Your Good Gut Guide to Great Digestive Health. New York, NY: Rodale Inc., 2011.   [4] Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KF, Yocum DE. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum. 2005;34(6):819-836.   [5] Callen JP. Complications and adverse reactions in the use of newer biologic agents. Semin Cutan Med Surg. 2007;26(1):6-14.   [6] Mullin, Gerard. Integrative Gastroenterology. New York, NY: Oxford University Press, USA, 2011.   [7] Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008;29(1):117-124.   [8] Maes M, Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008;29(6):902-910.   [9] Gutierrez-Aguilar R, Woods SC. Nutrition and L and K-enteroendocrine cells. Curr Opin Endocrinol Diabetes Obes. 2011;18(1):35-41.   [10] Neary MT, Batterham RL. Gut hormones: implications for the treatment of obesity. Pharmacol Ther. 2009;124(1):44-56.   [11] Tharakan G, Tan T, Bloom S. Emerging therapies in the treatment of ‘diabesity’: beyond GLP-1. Trends Pharmacol Sci. 2011;32(1):8-15.   [12] Faith JJ, McNulty NP, Rey FE, Gordon JI. Predicting a human gut microbiota’s response to diet in gnotobiotic mice. Science. 2011;333(6038):101-104.

We’re here today in a very special environment to talk about lifestyle medicine, which has kind of now moved up onto the marquee. Actually there are now even textbooks on lifestyle medicine. Lifestyle Medicine is the name of a text authored by Garry Egger and Stephan Rossner.[1] I’ve met them; they are medical school professors at Southern Cross University in Sydney, Australia. This book outlines kind of the manifesto for how lifestyle medicine could be integrated within the scope of traditional medicine, both in primary care and in specialty medicine.

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INTERVIEW TRANSCRIPT

  Mark McIntosh, MD October 2011 Clinician Roundtable Introductions I’m very fortunate, as I sit here today, to talk with leading experts from a variety of different backgrounds about their impressions of what lifestyle medicine really means. How does lifestyle medicine interrelate with things like functional medicine, or integrative medicine, or good medicine in such a way as to deliver improved patient outcomes? Around the table, we have the president of the Institute for Functional Medicine, Dr. David Jones. We have the person who has been a sports medicine expert and worked with athletes for the better part of 40 years and has a family practice clinic that is focused on preventive and functional-related medicine, and that’s Dr. Graham Reedy. We also have Dr. Jay Lombard, a psychiatrist/neurologist from New York, who has a rich background in integrating all sorts of things, from very traditional acute care (psychiatric care) into aspects of wellness-focused medicine. We have Dr. Jim Weiss, who is a leading expert and a clinical success story in integrating lifestyle medicine into his diverse general family medicine practice, which he shares with a partner. We have Dr. Ken Browning and his wife, Sandy, who have very successfully integrated First Line Therapy (lifestyle medicine) into their practice in Riverside, California. Dr. Kristi Hughes from Minnesota, who has been a leading proponent, advocate, formulator, and developer of lifestyle medicine programs. We’ve just had join us Dr. Mark McIntosh. This is quite an esteemed panel of individuals representing all sorts of different backgrounds. If we can, let’s have ground rules of using sound bytes because we are on a limited time. We love the content, but we want to cut down the speeches as much as possible. David, maybe I could start with you, in that we go back 30 years in our experiences in this field. What does lifestyle medicine mean to you in your mind? What Does ‘Lifestyle Medicine’ Mean? Differentiating Lifestyle Medicine From Public Health Guidelines DJ: Well, when you talk about lifestyle medicine, you put medicine on the back end of what, in the past, has been thought of as public health. When you look at the national guidelines—whether for asthma, or atherosclerotic heart disease, or metabolic syndrome—all of them start with the admonition that you start with lifestyle intervention, and yet those interventions are not taught to any of us that graduate from medical schools. It reminds me of the article in JAMA where Dr. Halsted Holman actually apologized to the graduates of Stanford Medical School.[2] He’s an emeritus professor at Stanford Medical School, and he basically apologized that they had prepared their students for 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of what they would see, which is acute medical disease, and that they should be preparing them for chronic illnesses. With chronic illness is the issue of lifestyle medicine, and that’s beyond the public health issue of diet and the four food groups, etc., etc. Lifestyle medicine is about finding a personalized way of applying the science of nutrition, the science of exercise and movement, the science of sleep and restorative activities, the importance of relationships, and resiliency and stress. The science behind those is incredibly deep and robust, and how you apply that to the individual patient is what makes that a medical–not a public health–issue. That’s my response to the importance of lifestyle medicine. It’s the next level of intervening with outcomes that are usually thought of the domain of the public health officer. It’s the domain of the primary care physician, and specialists in certain areas. And it’s recognized. I mean, it’s in every national guideline, and yet it’s not taught. It’s one of those things that everyone knows is true, but there hasn’t been education. We could get into “Where’s the money?”, but that isn’t where we’re going tonight. The money should be there because every time they do a face-to-face test between lifestyle interventions versus drugs/families of drugs, lifestyle is much more powerful. It’s an absolute black mark on medicine that they deny the importance of that in the first step of intervention for the problems that we see 70 to 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the time in our offices. JB: That’s a great segue. Thank you, wonderful introduction. Let’s switch to Dr. Reedy. Graham, I know you come very heavily from a sports and activity focus as it relates also to the construction of lifestyle medicine. Can you tell us a little bit about how you might weigh in on this topic? How Physicians Communicate GR: I think that we’re trained, as professionals, to tell everybody what a professional we are and to convince them that we are. There is a concept I think that I have especially learned more recently: that we, as physicians, have medi-speak. We have a lot of medical sounds. It has been said that in our medical training, there are some 13,000 or 14,000 new words that we learn. Those new words that we learn we tend to try on people, and consequently we do not listen very well. There is a form of medicine that we talk about. It has been said we have a tell-ask-tell sort of thing: Tell me your problem, ask me one question which has one answer, and then tell them again what I think the answer is. We have not been ask-tell-ask, which means: How can I help you? How can I be a part of this? Not: You are scheduled for what you are scheduled for, but how can I help you today? What is your immediate problem as you sit here in the waiting room, which may have changed from how it was when you came driving here? So the ask-tell-ask is help us not have medi-speak. The second part that comes to great mind for me is the communication. I deeply believe in a study done in some 27 different countries that talked about how communication best occurs. I like a phrase that says, “Everybody communicates, few connect.” I really like the fact that then the next part is: How do we not only connect, but how we collaborate as partners in this particular dilemma as a third person? To make the goal a third part of what we are dealing with together as a team? And then we covenant. That means we covenant together to work on this journey to make it worthy of our time (yours’ and mine). Not just mine, not just yours’: ours’. And that covenant is a critical piece. And then finally the part that comes to me, I think, that is so important is in the study around these countries it said that it has been found, in over thousands of people, that communication happens only 8{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} by words, 17{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} by tone inflections, and 75{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} by body language. And we’re busy becoming a word system. And we’re violating the very essence of that. I’d like to hear your thoughts on this around the table because all of you, as far as I know, have heard that sentence. I feel like the biggest thing about integrating lifestyle is to shut up and listen. Be quiet, and not convince somebody how smart I am, but to talk about what excitement I get in a “get to” world, not a “got to” world. JB: Beautiful, thank you. Dr. Lombard—Jay—from the subspecialty area that you represent (the neurology/psychiatric area), often dealing with very critically emotionally ill patients? Physicians Have Become Disassociated From Patient Contact JL: The brain-based perspective. By the way, I would want you to be my doctor, because something that I try to stress to residents in training is the key component of communication and listening with an unbiased and completely open way of hearing from the patient’s perspective: what actually they are suffering from as opposed to us trying to contextualize it in our categorical (as opposed to dimensional) models of disease. I think we are really at a very critical stage in medicine right now. For those of us that have been in academia recently, I think that we can all talk about with dismay what we see (or at least what I see personally) as almost an autistic-like healthcare delivery system in which a physician almost completely disassociates from patient contact. Histories and reviews of systems are given by ancillary health practitioners, not by physicians themselves. Forms are filled out with questionnaires, and lab tests are looked at, and MRI scans and radiological procedures are done without any real involvement or interaction between the patient the physician. Our esteemed moderator here, Jeff Bland, had said something many years ago that really struck me—I think it was in my first year of residency—which was that “We’ve taken the sacredness out of medicine.” And that sacredness of healing is about the relationship itself between physician and patient and we can’t neglect that. I think where we are as a society—not just in health care but I think in all aspects of our current society—is that we think of problems as being one-dimensional in terms of how to fix them. This is obviously a recipe for disaster. Lifestyle medicine, I think, offers us the ability to change a paradigm, to look more at a patient-centric way of intervening. The last thing I want to say, since I am a neurologist and the brain is one of my favorite organs (not the only one, but…), is that if you think about change and how difficult it is for people to change behavior, behavior change occurs really only occurs in two ways: to avoid pain or to move towards pleasure. If we hold out that basic principle about how our brain operates and use it to improve compliance or ways of engaging our patients in more healthy lifestyles, I think that principle can go a long way in understanding how to improve the delivery of such a complex network of health care. JB: Thanks, beautiful. That was some real news to use—some very pithy gems. Jim—Dr. Weiss—you know, you made an interesting transition in your career from many years in subspecialty (a very successful practice—into this more general area. Tell us a little bit about that transition. JW: Yes, I’m a board-certified pulmonologist and I’m board-certified in internal medicine as well, and for the first 16 years of my practice I did a lot of ICU medicine, or as I call it “end-of-life” medicine. About 8 years ago I made the transition because I wanted to prevent people needing what I was doing. It has been a long journey. I have certainly learned a lot over the last 8 years. When I made the transition the natural thing was to do primary internal medicine, and I found myself counseling people. I knew lifestyle changes were the backbone, but I didn’t know what it meant or what to do, and so I found myself writing in the plan “diet and exercise,” and I began to question myself and think, “What does that really mean?” I started investigating, which I guess has led me to this table today. Prevention of Chronic Diseases For me, lifestyle medicine is really about two things. It’s about not only prevention, but I’m really struck by the data about how well you can treat these chronic diseases, and I think that has to be of paramount importance to all practitioners, whether they are MDs or DOs or NPs or whatever. And the other thing for me is it is about healthy gene expression and the use of multi-modalities. Frankly, my interest is nutrition, but I certainly understand the concept of exercise and—I know there are MDs here in this room, but I’ll say the word out loud, which I typically don’t use—meditation, as well. It’s really multi-modality for healthy gene expression. JB: I think you are in the right group to use the word “meditation.” These are kindred spirits. JW: No, no—here I understand, but in other groups I hesitate to say that. JB: So Ken, you and Sandy have done just a masterful job of converting your clinic into a place I would call an oasis of lifestyle medicine. Tell us about that transition and what drove you or encouraged you to make that transition? From Treating Conditions to Helping People KB: Like Jim, I was very traditional, board-certified, in my case, in family practice. I did a high-powered residency with the Air Force at Fort Warden, Georgia, so I came out being able to do all these amazing critical medical things. I did OB for a number of years. I went through a transition of private practice to groups and finally came back to private practice. And I woke up one morning and it dawned on me (and I look around this room and there is a lot of maturity in this room, and so I think it is a product of age, experience, journey): I’m not making a difference in anybody’s life. I’ve seen enough colds, and I’ve seen enough flus, enough UTIs, but what was I really doing with my passion? About this same time, we moved from a group back into a 1902 heritage house, which is very welcoming and patients love it. As Jeff says, it is an oasis in the medical world. I had patients asking me, “You know, Doc, I take horse chestnut,” or “I take glucosamine for my knees so I can play golf,” or “I take this, I take that.” “How does that mix with my medication?” And I had to be honest with them: I had no clue. But I heard this so often that I realized I needed to find out. So it was just a stroke of luck that I called somebody who put me in touch somebody who put me in touch with somebody. We spent months courting, as I like to call it, because this was new language. This was a whole new world for me. I went through a couple of lifestyle educators. I was banking on them to hold me by the hand and lead me on my way, and one day at my doorstep was Chris Katke, who is the lifestyle educator extraordinaire in the world. We’d sit around in the mornings and I like to say that I’d have a cup of coffee and he wouldn’t because he’s the purist, and we would solve all the problems in the world. You know what I’m talking about: How do we do this and how do we do that? I often say that I was so stupid I didn’t know what I didn’t know, and that I shouldn’t be able do what we started to do, and all we started to do was do lifestyle medicine. We started doing FLT before it was FLT, and it’s been a great journey. JB: Sandy, how about you? You have shared this journey. You have been a local spokesperson, working through the patients. Has it been a transition, as Ken described it, for you? SB: Certainly. The transitioning was tricky, but I think what really kind of powered it was realizing that we were helping our patients—his patients—by giving them really simple usable tools, and then them having the results they were looking for. You were talking about avoiding pain and working towards pleasure. Well, a lot of people were motivated by the conditions that brought them in and were actually being vocal about wanting something other than another prescription, and were given some things that they could pretty easily implement, starting day one. And that kind of just fed on itself. JB: Did you find from your experience that word of mouth became kind of a transition force to change your practice? As people had success they went and talked to other people and suddenly you started getting the Dr. Browning reputation of where to go? KB: At first it was like pulling teeth because this was 8 years ago and the public was not as aware as it is today that there are alternatives out there to just giving a slew of prescriptions. I was also very shy when I first started. My confidence level was not high. Nowadays I’m accused being “House-ian” (Greg House, from TV). Because I will tell people and I’ll just get in their face. I mean, I will read their personality and such, but I will get into their face and say, “This is what you need to do. I will write you a prescription or 10 prescriptions if that’s what you want, but in this office we don’t do that. We’re going to teach you how to eat. We’re going to teach you how to eat a modified Mediterranean diet, and how to do it 5 times a day, and you’re going to get control back of your life. How does that sound?” When I always ask my new patients, “How did you find me?” “So and so sent me” or “I heard about you.” And that makes the journey with them much easier because I’m not having to start from square one. JB: So Kristi this is a great segue to you because a lot of what we’re talking about was pioneered by you and Lyra Heller in the form of FirstLine Therapy (FLT). Tell us about your journey on this whole revelation process. Empowerment: Helping Patients Take Control of Their Health KH: Well, it has definitely been a process, there’s no question, and a journey (a heck of a journey). As someone already commented, we were doing lifestyle medicine before it was called lifestyle medicine and I think that’s a really interesting review, when you look back over this last decade. If I were going to summarize lifestyle medicine in one most important term, I would use the word “empowerment.” Empowerment for the patient. It is a joy to be able to hand that locus of control back over to the patient with knowledge. It is an honor to be in a relationship with a patient. I would state that’s probably the second most important thing that’s taking place in lifestyle medicine: everything is about relationship. It’s relationship to self. It’s relationship to your provider, your coach, your doctor. It’s about your relationship to food, your relationship to want to move your body or not move your body. And so I would say empowering the patient, really encouraging them to come full circle. In a non-demeaning way, to me it is so comparable to managing the transition of bringing a little person from age 2 until age 5 or 6 because you have to teach skill sets. You have to teach ways in which that person will come to that discovery on their own, and they don’t realize that you guided them to realize, “I want to eat more legumes in my diet, I need more color in my diet, I need to get up and move my body because it’s the right thing for me.” So to really bring yourself to the other side of the table and get out of the advice giving and to the empowerment position. I think that’s probably the greatest privilege of doing lifestyle medicine. I had the absolute joy of getting to come to medicine through a naturopathic medical background training, and then I found functional medicine immediately right outside of my naturopathic training. To me, this is the only language I know. In a sense I grew up inside of this mindset and for me it’s a bigger challenge to step outside and try to look at the challenges because I think lifestyle medicine is common sense. It’s so much common sense. It’s what the patient is asking for, and intuitively, on so many levels, you just need to give them permission to go there. JB: Mark, thanks so much for being here all the way from Florida. Mark is at the University of Florida. He is one of our co-investigators and just was one of the lead authors on a big multi-center trial we were involved in. Wonderful papers.[3],[4],[5],[6] Thanks, Mark, and thank you for being here. We’re just talking about what each individual thinks, in their mind, lifestyle medicine means to them. MM: Pleasure to be here. JB: Nice to have you here, thank you. Emergency medicine seems like almost 180 degrees away from lifestyle medicine, but yet you’ve done some extraordinary things in segueing these concepts into your practice and into your mindset. Seeing the Result of Poor Lifestyle Choices in the Emergency Room MM: Well, I’m still on the journey. Really, spending many nights in the emergency department, you realize that we’re done a tremendous job with acute care medicine, but I realized that probably 75 to 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the patients that I would see at night were there because of poor lifestyle choices. I felt like I was at the bottom of the cliff picking up the pieces. If I was just able to build a fix at the top of that cliff, then we could perhaps have true impact and prevent a lot of the things that I was specifically seeing. The Impact of Corporate Wellness Programs I really began to delve into the concept: How do we deal with chronic disease? With Dr. Jones as well as yourself I had the opportunity to be introduced to the concept of lifestyle medicine. The way I would really define it is it is really whole-person medicine or patient-centered medicine. The type of medicine I was so used to doing was really physician-centered medicine, and I definitely want to reiterate the point that we are empowering. At that point, I wanted to ask the question: “How can I have an impact within a university setting—the training of physicians who are residents, and also specifically the staff and physician population?” I moved into corporate wellness. I’m still doing emergency medicine—I can’t leave that love—but I realize that corporate wellness is where we spend 40 hours a week. This is where our employees are and our patients (quite often they become our patients). I realize that we can intervene in their lives: how they think, how they work, how they eat, how they move or exercise. It really comes down to the fact that lifestyle medicine. The physiology is really complex, but really the underlying causes of so much of the chronic disease has so many interacting nodes, and it’s really looking at how our environment—our work environment, the air we breathe, the food we eat—really washes over our genes and determines whether we have health or whether we do not, and I think lifestyle medicine is really the tool which we can use to change behavior, and really even at the genetic level really have a phenotypic response in a very healthy way. Just the privilege of participating in the multi-center trial just showed me this is really possible, and it is through behavior, and through walking into that room with real intention and interacting with those patients, and determining who they are as a whole person. JB: Wow, I tell you, this round-robin just once around the table is enough food to feed you intellectually and emotionally for quite awhile. A lot of power words were discussed: relationships, empowerment, intention, collaborate, connection, covenant. How we might work on developing this high-level communication. Being good listeners—active listening is another powerful concept. Jay’s concept of how people make decisions on the basis of either avoiding pain or moving to pleasure and how do you navigate through that matrix to use the nervous system as guidance for compliance and adherence. Then this whole concept of really recognizing that late stage disease starts off with altered function, so using the lens to focus on the right things, because if we just wait for pathophysiology we may have missed all sorts of precedents that could have been guides for us earlier. So with that, David, let me turn to you as one of the longstanding founders and developers of the functional medicine concept. How would you see a differentiation, if at all, between what we call lifestyle medicine and functional medicine? Where do they connect or overlap? Differentiating Lifestyle Medicine from Functional Medicine DJ: Well, I think the participants at this table would probably say the same thing, but if you go to the American College of Lifestyle Medicine–if you talk to Colin Campbell, for instance,–lifestyle medicine has a certain degree of one-size-fits-all: that there are certain common foods that we should be eating (that we should do a modified Mediterranean diet is a very common thought), one-size-fits-all in terms of so much exercise each day. My experience was that I got into this early on because it is pretty obvious that lifestyle—the day-to-day, minute-to-minute choices of my patients—was impacting them in such a way that they ended up with a diagnosis that, by standard of care, I needed to put them on drugs, and I’m sitting at my desk at the end of the day wondering, “Can I keep doing this?” I was seeing the side effects from drugs and wondering if I shouldn’t be calling them and saying, “The best thing for your health would be to stay away from me.” That literally happened. That’s when I went searching and that’s when we started working together. That was almost 40 years ago. Functional Medicine Offers Powerful Tools The personalization of lifestyle medicine is the next step, and knowing what the difference is. The core diet—you say the Mediterranean diet, but what if the person has, say, metabolic problems versus toxicity problems versus endocrine problems versus…and the list goes on. How do you create an architecture that can take these concepts of lifestyle and physiology and marry them to the patient in such a way that it has a very specific and focused application? And that’s why some of the people in lifestyle medicine say, “Well, this functional medicine stuff is just too complex.” Well, I’m sorry. If you do lifestyle medicine, you’ll get 60 to 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of people better, because the marketing to keep them imprisoned in very bad habits is very effective. If you can get them out of those habits of eating the wrong way, and sitting on the couch and watching football games, and being more interested in their rotisserie group versus taking care of themselves, you’ll get 60 to 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of those people better. But it is that other group that, as physicians, it’s a very focused issue of how do you apply these powerful tools so I know from the specific kind of genetic testing, from questionnaires, from getting to know the patient, that they need something tweaked in their relationships, in their stress, in their diet? That’s the specific functional application that is very personalized and takes it to another level. I deal with almost all my patients rather than 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} because they come in and they are already on some kind of diet that they have read is good for them, and they’re already exercising, and they’re already doing the basic issues of looking at their lifestyle, but how do you focus that so it affects them, and it is different than the same dog-and-pony show you do with everybody else? One of the big issues in lifestyle medicine is this: How is this different than public health? It is different from public health if you have an architecture of thinking methodology for making it specific to their needs. If you don’t, you are doing lifestyle public health measures. In my mind, lifestyle medicine and functional medicine are the same thing, but in the minds of people that I talk to that are experts in the area of lifestyle medicine, we do something different because I spend time doing things that they think are too specific and too complex. I make it too hard. Well, complex problems require complex thinking. I mean, you just can’t do one-size-fits-all. I think, in terms of the actuality of lifestyle medicine versus functional medicine, our particular approach takes it to that next level. Yes, all of those measures that we’re talking about in terms of standard lifestyle medicine teachings, those are part of the formula and the relationship that one emerges in my clinic when you bring that specificity to that patient, and then you let them choose because you understand the different doorways they can walk through. That’s looking at their specific functional issues. So that’s the way I see it and I see it when I talk to practitioners that have a different kind of approach. What we are teaching is complex, but the human organism is complex. JB: Good, thank you. “Complex” is a good place to segue to Dr. Reedy, who has 50 patients waiting in his waiting room that he’s going to see over the course of the day. It is having been in that environment I can feel the sense of complexity that must work through his nervous system. Graham, from your experience, what are the barriers that you’ve encountered in introducing these concepts successfully in a general practice? “When All Else Fails, Ask the Patient” GR: I have the advantage that the only patients in the office exercise, exercise, exercise. So that culls herd. In the northwest that means that if the milk’s not milking, then I’m sorry, love, you’re gone; the cow’s not there anymore. So we’ve culled the herd in terms of people that want to be well, people that already want to be there. Then from that particular group we have built on asking a set of questions. There is a great quote they said to us in medical school by wise people: “When all else fails, ask the patient.” So I will oftentimes say, “You came in and we had you scheduled for this, and this, and this. What would you say, of the things you are most concerned about, is the biggest concern?” It is to teach my staff, because the staff is a key person—in the front, they do the check in and they’ve got the computer and such. I oftentimes start the staff by saying, “This is a lifestyle practice. Listen to the words not said. Listen to the phrases that they feel. Listen to what it is you think they want to say but are afraid to say. And what you’ll do is they may not tell you, but you’ll open a door where they may tell me, and that way we’re doing it together.” And then I have a staff person with me, as well as computerized records, in the room the entire time. So if I say, “These are the things it seems to me that you are saying to me and what you want most. Is that correct?” And I love one statement I heard not long ago that said: The average physician time with a patient in front of them before the doctor interrupts is 17 seconds. Given that, it has been shown by studies that if you merely listen for two minutes, then 75{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of what the visit is about will be told to you, and about 25 to 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the solution will come from them, not me. And in that regard, it’s as though if I then feel that they are making headway, I validate them and when they walk out, they feel they’ve been heard, but more than that they feel valued as a person. If that does happen, then they feel that, “You’re stressed as much as me,” and so there is a reason to put them there. We put the patient at eye level, never on an exam table. The computer’s here, I’m here, they’re here. Never, ever, anything in between. I’m touching all the time. My patients say, “I’ve never seen anybody touch so much.” Not inappropriately, but what I’m trying to do is to find a way to get the connection. You can’t and to make them open the door to lifestyle change unless you find the connection. And then finally I’ll say: “Of all the things you said to me, I want you to go home, and these are three things I heard. I’m not really sure that’s what your three things look like. So what I would like you to do is go home, I would like you to write them out and then bring them back. And then in some situations I may do what he does and I may sit them on my chair facing myself and say, “So, I have this problem. What are your top three solutions?” And by giving a paradigm shift, I give them the responsibility. I make people as smart as me. I tell them, “You’re just as smart as me. I just learned 13,000 words you haven’t heard of before. And the thing is that doesn’t make me smart, that just makes me stuck. I’m narrow. I’m very, very narrow.” So, involvement is a technique I use. JB: Yes, I really notice that in your practice. The people that are there, no matter the age, be it high school athletes or weekend warriors or aspirants in middle age, they all have a common bond of being on this journey with you, and feeling as a participant, but with a good guide. It’s not like a journey that you are wandering off with a scout and they have no cartography, so there is a guidance principle that goes on there that is very solid, right? It ties itself to something that is both sacred and substantial. I think that’s an interesting way of thinking about lifestyle medicine. And by the way, that concept of the 17 seconds to make a snap decision, that comes from the book, How Doctors Think, which was written by the Harvard Medical School professor.[7] It talks about the linear, Cartesian, Baconesque way that we train people to think: we train out of them reductive reasoning and we train into them rote reasoning and memorization. I think that that kind of breaks the pattern, which is—as has been said by all of you—more of a web than a single bullet. It’s more of an interconnected web than a single explanation. Jay, you’ve been in the medical school teaching environment, you’ve been in the clinical trauma unit, you’ve been in private practice, you’ve been an educator, you’ve an author, you’ve been a scholar, you’ve been on a spiritual journey. How does all of this interesting mosaic and texture weave itself into the relationship that you have with your patient? I would imagine it’s very different than a traditional neurologist or psychiatrist. JL: I think it’s hard to follow Graham because I think what Graham says is really quite a powerful role model for physicians to follow. I think that everybody here shares this concept about the importance of relationship and healing. I know when I am very effective as a healer it is because I’m completely present in that interaction that is occurring, even if it is only two minutes. It requires us to sort of step out of ourselves and into the perception of who that person is that is coming to see us who is ill. Again, I love the analogy that you gave about sort of changing roles and having the patient themselves be the problem solver. I think it’s a brilliant technique to engage patients in. Illness is More Than Just a Physical Disorder One of the things I think that we all have to understand, and this is again maybe a brain-centric approach, but we have to understand that illness in many ways reflects not just a physical disorder, but really an existential or spiritual disorder as well, and that all illness can be seen as a reflection of both a physical disorder and also an emotional or mental disorder. Unless we address that in our toolbox, if you will, to understand the driving forces that create illness based upon a person’s perception of themselves—their relationship with themselves, the relationship that they have with their spouse, their children, with their community? Those are key elements of a healing process that we’ve neglected to really discuss in current western paradigms of medicine. Those sometimes are the most important elements. Sometimes it’s just really a matter of a patient being heard for the first time. I can’t tell you how many times someone will break down and start crying just because it is the first time they were actually ever listened to. It’s not rocket science. There is a famous quote from, I think, Cecil’s Textbook of Medicine: “The secret to care for patients is to care for patients.” It’s not that complicated. But we forget the basics. Kristi, I’m sort of the opposite of you. I grew up outside of functional medicine or whatever words you want to put on it. I think that if we look at some of the obstacles that I see from a sociological perspective in terms of adoption of some of the common sense things that we’re talking about here, some of them are really economical. We have to really understand that there are cost barriers that are very real. We’ve created sort of a medicine which is really accessible only to people who can afford it. For this to be a transformational type of medicine for society, we have to find ways of making it more economically scaled to all comers, not just people who are able to pay out of pocket for it. That’s something I think that we should be cognizant of. JB: Some really good pearls there, and I think that’s a good segue to Dr. Weiss. Jim, as you’ve made this transition from pulmonology over into a more health promotion/wellness-based practice, how did you handle the economics? How do you deal with the reimbursement to services? Is it something that you are still modeling? Is there an approach that you’ve seen that makes sense? Support Staff is Very Important to Success JW: I’m blessed to have the second best lifestyle educator. Insurance reimburses for my time, and also reimburses for my lifestyle educator’s time, assuming that you follow the proper prescriptions. I want to tag onto something David said: It’s absolutely true that it has to be personalized. I haven’t been doing this for 40 years, I’ve been doing it less than 8. My lifestyle educator has a different personality, so there are certain patients who connect with me and I work with them. I try and give them the time they need. I have a practice style that’s really designed for that, which is a benefit. And I listen to those patents. There are other patients who connect better with Stephanie. Initially—I’m catching up to her now—but initially, she frankly had a better understanding of the supplements, etc. We are talking about a paradigm shift in medicine. For a classically trained physician who has no clue it takes time to learn. In my office, we try and keep it as low cost to the patients as possible. The one stumbling block is the cost of the medical food or the supplements, but I have had very little pushback against that. My experience—I’m in southern California—is this is what the population there wants. They don’t have to be super wealthy to be willing to reach into their pocket to pay for the medical food or to pay for the fish oil, etc. They know that they are going to be healthier, which is absolutely spiritual and existential, and potentially have their healthspan approximate their lifespan. That’s very important. That’s what people want. It’s a question of priority. There are some people who won’t reach into their pocket for it, and it makes it harder to help them. But I have not had a problem getting people to pay for it. Granted, I’m in an affluent area of the country. I don’t know what it would be like in other places. JB: Ken, let’s ask you the same question. I know in Riverside County you probably have a very mixed socioeconomic population of patients (from my experience in Riverside). You probably have a wide array of differing abilities to have discretionary income available. How does that influence how you deliver the program? Balancing a Practice with Managed Care and Lifestyle Medicine Patients KB: Riverside is a very blue collar area (Riverside, San Bernadino, that whole area). I’m still trying to figure this out. My practice is still heavily laden with managed care. We all know the joke or the one-liner that you have five minutes to spend with the patient. Every patient that I see, even if it is mom-brings-in-Joey-with-an-earache, I throw something out there about wellness. I throw something out there about lifestyle medicine, about how we’re different. They walk into the office and one of the first things they see is our natural pharmacy. That spurs questions. I search for ways to open dialogue with patients, whatever that may be. Typically, I will throw out these tidbits on the five- or seven-minute visit (whatever it make be), and then finally a hook is set, and that seven-minute visit becomes 20 minutes or a half hour, right? Then you’re behind. But it gets my passion going because I just so much love that aspect of medicine because finally we can give people tools to prevent or even get their lives back so that they can have a great life. They can have a healthy life. They can have an abundant life. What we do with our HMO patients (probably 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} are HMO), I work with them when I can and I send them up to see my lifestyle educator for their co-pay. Business-wise, that’s not real sound, but if it is about getting people well, then that’s what you do, with the hope that they will go out and tell their friends and tell their family and more people will come and more people will come. My experience with the PPOs and Medicare is if you bill it correctly (or hopefully what you believe is correctly—in the spirit of correctness), they pay okay. They pay okay. For the physicians out there that are wondering, “Can I make a living doing this?” Yes, you can. Yes, you can. But you have to get creative. You have to pay more attention to what’s going on with your people. Graham, I love what you said. I’ve heard it before but I haven’t heard it for a long time. I appreciate what you said. Just shutt up and listen. We’re all kind of designed—especially the male part of us—as what? We’re fixers. “Tell me what’s wrong and I’ll fix it.” For some things—emergency room medicine—that would be perfect. For critical medicine that would be perfect. But in the folks that just come into our office, they may not even know what’s wrong with them until they can get it out, voice it, so thank you for that. JB: Ken, you know, we’ve had the privilege (many of us) to see some of the videos of your patients. There are several that have just struck me deeply. They are kind of like mental images etched on the inside of my neurons that, when I get tired and wonder what I am doing, I remind myself of these experiences. I’m reminded of the one of the high school teacher that you had that was transformed. I think at the end he looked at the camera and he said, “I thank Dr. Browning and Chris, my lifestyle educator, for saving my life.” How do you value these? How do you put a return on the investment on those kinds of comments? They are very, very powerful. I really appreciate your patients sharing those things. They are the most powerful learning tools, when we see these personal transformations occur. DJ: It is so different than sitting at your desk looking at the list and reviewing the number of side effects from the medicines that you give them. The difference in my life from sitting at the desk and saying, “I’ve either got to quit this profession or I’ve got to go out and find different answers because I can’t live with this.” And now what happens when you engage and something emerges from that context of healing that is bigger than you instead of being smaller than you. KB: In our office we call it, “We do the happy dance.” JB: That’s a good visual metaphor. So Kristi, a lot of these principles we’re talking about are the tradition of natural medicine and naturopathic medicine, so maybe that’s why it is so deeply in your DNA. I’m sure you get questions because you’re educating all sorts of different disciplines about “How can you be so presumptuous to tell people that are believing in pharmacology as solutions to these issues that lifestyle medicine would be a successful different approach?” How do you manage through that? Remove the Obstacles to Healing KH: At first, do no harm. I think it’s really the oath that we’ve taken. And what is so powerful in lifestyle medicine, which you experience within the first couple of months of truly doing it and living it, and you see it in patient care and patient results as often the most powerful is helping the patient identify or flag their obstacles in their healing path. What is it that is holding them back from healing? Just that identification alone. Is it your job? Is it where you live? Is it your home? Oh, you’ve got lead in your well water; you didn’t know. So, the first step for me in lifestyle medicine is to identify those triggering events. You know, if we’re going to talk about a functional medicine model, it is triggers and triggering events in your ATM (antecedents, tiggers, mediators) model: What is triggering the disease or has triggered the episode? With lifestyle medicine, number one: remove the trigger, remove the obstacle. And then number two, you go to the foundations of health. You really open up the storyline and say. “Well, what else is holding them back from their healing as it relates to their food choices, their movement, their sleep, their resilience, their relationships, and their social network?” You live it in practice, you see it transform your family’s lives, your patients’ lives. You see this, and as Dr. McIntosh spoke to, you’ve seen it in a large group experience as well. And you become a believer in that sense. So through great confidence, through clinical experience. I think one of the most important aspects of the journey for the clinician who is learning lifestyle medicine is to learn discernment in knowing which program or direction to place the patient. If I were going to take a patient who presented with minimal intra-abdominal visceral fat, who was really holding weight in other areas of the body, or below the waistline, who struggled with weight loss for 20 or 30 years, who didn’t have elevated triglyceride levels, and who wasn’t suffering with blood pressure concerns, and they walked in the door and they needed lifestyle transformation, I would have to give them a program that would be more targeted and more designed to deal with the underlying causes of their disease. If we’re going to come back to the roadmap, for me the map is a functional medicine map that lifestyle medicine lives and exists within: remove the obstacles, identify your antecedents, triggers, and mediators. Remove the obstacles to healing. Next, go to the foundations of health. Deal with the lifestyle medicine concerns. Again, transform the diet. Help move them through behavior modification, and then just step back and watch it happen. I like to just give it two weeks. Two weeks, four weeks, in eight weeks miracles will happen. And at that point I want to know what’s left. And when I can see which symptoms are left or what are the areas or concerns that aren’t clearing or moving in the right direction, then I’m going to take a more advanced therapeutic intervention route and apply the systems biology approach to functional medicine. For me, it is so remarkable. It is such a remarkable experience to have the patient come in, sit down, across the desk from you or next to you, and just sob for joy, which is a very different experience from them sobbing from the pain, and thanking you profusely. Our practice is 95{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} referral at this point, and I’m either the patient’s first choice, or they’ve been through ten other providers.I chose to go back to the Midwest because there weren’t other providers doing this, so I end up with the patients from the functional medicine and the integrative practitioners who don’t know where to go next. And I go right back to the basics: What are the triggers? Remove the obstacles. Transform the foundations to health and wellness. And then let’s dive into the other areas of pathology. Then we’ll look at our assimilation and our GI concerns, or we’ll deal with detox, or we’ll move into the endocrine system. But there is just so much power in just giving the body the chance to heal. JB: The beautiful statement you’ve made reminded me of conversations that we’ve all had or listened to with Mark Hyman, who when he was working at Canyon Ranch always would introduce himself as a “resort doc”: the doctor of last resort. Because he was the guy at Canyon Ranch that was providing a different kind of medical service than traditional pharmacology. Mark, you made a comment which I want to follow back up with because I think it’s a very, very interesting comment: that you learned a lot by participating in this multi-center clinical trial. Your site was one of the three sites on a metabolic syndrome intervention trial. I’d love to know, as you’ve had a chance to kind of get away from it a little bit and look back, what did you learn? Other than the data, what was the most impactful for you in the learning experience? The Macro Level: We Have a Sick Care System, Not a Healthcare System MM: Probably the major thing that I’ve learned is that we truly do have a sick-care system and not a healthcare system. By doing the project, most of the participants, most of the people that we enrolled in the study, actually were employees on the floor staff. Actually by implementing the therapeutic lifestyle changes and using the nutraceuticals, we truly had major successes on the campus, and you can see, for those people, their lives transformed. That was extremely powerful to our administration that, you know, we needed to do something different. I’m taking it more to the macro level because what happens now is I have a sick system, not exactly a sick patient. I’m using every opportunity that I can to use the functional medicine model and essentially address the whole system. From the experience in the clinical trial, now we have moved into developing a whole corporate wellness program. We did not have corporate wellness at our organization. Right know it is hard to do corporate wellness on a personalized level, but a lot of the principles we are using—how to eat well, think well, breathe well, move well—all of those aspects are really coming from this model. So we started corporate wellness, and secondly, within the past year, we developed a physician-directed weight management program. Some of those patients will potentially entertain bariatric surgery, but bariatric surgery is just a tool, and if you don’t learn lifestyle changes, you will not have the success. Obviously our hope is that many of those patients will not have to entertain bariatric surgery. We have also started a palliative care program in the past year. Palliative care: these are the patients who are suffering chronic disease, whether they are being cured or not cured. Once again, the model of whole-person medicine can be applied. So, out of the study we developed a corporate wellness program, physician-directed weight management program, and palliative care within the past two years. It is looking at the macro more than the micro. We’re making some steps and that’s how I think we are going to change medicine. In the future we’ll see the successes from that standpoint and the administration will see it and it will shift down, hopefully, to our physicians and our residents as well. It is a different approach than one patient at a time, but we can see it is taking place. JB: Very inspiring. Thank you. That’s a wonderful collateral benefit from being engaged in a clinical trial. Fantastic. I wish all trials would end up with that kind of revelation in the participants.

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Bibliography

[1] Egger, Garry, Andrew Binns and Stephan Rossner. Lifestyle Medicine. North Ryde: McGraw Hill Book Company Australia, 2007.   [2] Holman H. Chronic disease—the need for a new clinical education. JAMA. 2004;292(9):1057-1059.   [3] Jones JL, Comperatore M, Barona J, et al. A Mediterranean-style, low-glycemic-load diet decreases atherogenic lipoproteins and reduces lipoprotein (a) and oxidized low-density lipoprotein in women with metabolic syndrome. Metabolism. 2011. [Epub ahead of print] [4] Jones JL, Fernandez ML, McIntosh MS, et al. A Mediterranean-style low-glycemic-load diet improves variables of metabolic syndrome in women, and addition of a phytochemical-rich medical food enhances benefits on lipoprotein metabolism. J Clin Lipidol. 2011;5(3):188-196.   [5] Ackermann D, Jones J, Barona J, et al. Waist circumference is positively correlated with markers of inflammation and negatively with adiponectin in women with metabolic syndrome. Nutr Res. 2011;31(3):197-204.   [6] Fernandez ML, Jones JJ, Ackerman D, et al. Low HDL cholesterol is associated with increased atherogenic lipoproteins and insulin resistance in women classified with metabolic syndrome. Nutr Res Pract. 2010;4(6):492-498.   [7] Groopman, Jerome. How Doctors Think. New York: Mariner Books, 2008.

Welcome to Functional Medicine Update for November 2011. This is the continuation of a theme that we initiated in the October issue that I’m very excited about, which is this roundtable forum that we orchestrated on lifestyle medicine. What is lifestyle medicine? How is it applied in the clinic? What is its point of differentiation from traditional preventive medicine? And does it have value in reducing the burden of chronic disease and turning back early stages of pathologies associated with various chronic illnesses? Those were the questions that were raised during the forum. Before we get into the completion of the discussion among the expert physicians that were present for this forum that we had in Gig Harbor, WA a month or so ago, I’d like to set the context as to why I think this is an appropriate theme for this period of time in the evolution of the functional medicine model. I think what I’m going to say is well-known for most of you, but it never hurts to have a refresher and reinforce basic principles that underlie the work that we engage in everyday in healthcare delivery. Health Care and the Global Economy: The Impact of Five Non-communicable Diseases How do we improve the state of the world and the people that reside in it? This particular 2011 year, the world economic forum met specifically to look at healthcare-related issues pertaining to the global economy.[1] The results of this were truly, I think, remarkable for those of us who have been living through the global economic disaster of the last few years. We have been experiencing, both in the United States and in the global economic community, these wide swings—almost whipsaw-like swings—in the economy. Through the so-called trickle-down model, that ultimately influences the daily lives of people and their ability to maintain status, both in the developed and developing world. The question of how this all interrelates with health care and the prevalence of certain diseases is not an esoteric or tangential topic. It’s really at the cornerstone of understanding how the world community is going to meet the challenges that lie ahead, in that an unhealthy population that is burdened with chronic disease cannot mobilize the kinds of necessary focus on building an economic model of success that may be required under a time of great global financial turmoil. With that in mind, what’s the global economic impact of the five leading non-communicable diseases? I’m not even going to go into the HIV or influenza, or other communicable types of diseases like tuberculosis and malaria. I’m just going to talk about the non-communicable diseases—the leading chronic, age-related, degenerative diseases: cardiovascular disease, chronic respiratory disease, cancer, diabetes, and mental health issues (including Alzheimer’s disease). The result of this forum, in terms of looking at that from a global perspective, was—I think—overwhelming. The suggestion was that these particular diseases—these five diseases—could mean for the global impact on economy, about $47 trillion dollars over the next 20 years. Forty-seven trillion dollars. Which means that this deficit that we have gotten the United States into of a couple of trillion dollars would pale in comparison to the depth of the whole burden that chronic disease will make on the global economy over the next 20 years. Mental Health Issues Are Now Included in the List of Top Non-communicable Diseases The global economic burden of non-communicable diseases report analyzes the overall costs of these non-communicable diseases to the global economy. What it suggests is that it represents about 4 percent of the annual global GDP that is going to have to be dedicated to maintenance of therapeutics related to the rising tide of these diseases. Historically mental health was left off the list of the top non-communicable diseases, but as a consequence of the rising tide of Alzheimer’s in the aging population, when you add that to the list it accounts for more than 16 trillion dollars (or 1/3) of the 47 trillion dollars anticipated. If we were to look at where we see the greatest growth of concerns and the lack of good therapeutics in this area of chronic illness, it appears it is in the chronic mental health area, particularly Alzheimer’s- and dementia-related. Poverty as a Risk Factor to Disease More than 60 percent of deaths worldwide are due to the non-communicable diseases. Low and middle income families are disproportionately affected, as we’ve talked about in previous issues of Functional Medicine Update. You’ll recall we—about 10 years ago—cited the studies looking at poverty as one of the most significant risk factors to disease.[2] We said that poverty, from this study, was more than just annual income; it was related to feeling impoverished, which was low attribution, lack of acceptance, of value, lack of love and appreciation, lack of meaning in life. This broader definition of poverty (or being impoverished) correlated very strongly with early-stage disease and death, even in the absence of traditional risk factors (the so-called Framingham risk factors). So there are many different components that relate to the rising burden of disease, including isolation, lack of attribution, and “poverty.” In 2010, 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the non-communicable disease deaths occurred in the countries where they have premature working age (actually taking people out of the work force and reducing their ability to contribute to the overall economic growth, or even economic stability, of their countries). The global population beyond the age of 60, as you know, is expected to double between now and 2050. This development coupled with increasing urbanization means a sharp increase in the non-communicable disease rates, and the study concludes that the cumulative bases of cardiovascular disease, chronic respiratory disease, cancer, and diabetes in low- and middle-income countries are estimated to surpass 7 trillion dollars in the years 2011 to 2025. We’re seeing a very, very significant change in what we might consider lifestyle-related diseases (lifestyle and environment). This interaction between genes, and environment, and lifestyle that gives rise to a change in the function of the organism that we, at later stage, diagnose as a disease. Is there an economic argument, then, for a functional medicine intervention earlier with, we might say “pre-clinical” signs of disease? Meaning, a trajectory towards disease: functional decrements in performance of the individual as measured by changes in biomarkers, or psychometric performance, or physical performance that indicates a premature acceleration of loss of function associated with biological age? These are very important questions that are now really at the cornerstone of trying to address how we’re going to fight back against this 47 trillion dollar expected cost to chronic disease globally over the next 20 years. Analyzing the Economics of Disease Prevention That takes us to a very nice editorial that appeared recently in the Journal of the American Medical Association titled “A Closer Look at the Economic Argument for Disease Prevention.”[3] This marries itself very nicely to the functional medicine, patient-centered assessment, personalized medicine approach. This article goes on to say that disease prevention has always been the preferred option for promoting health and reducing disease rates. This health argument is the reason why people have suggested that we should be investing in prevention. Others, however, have criticized this, saying that there are really no great long-term outcome studies showing that one would be able to save a measurable amount of money in healthcare expenses by engaging in prevention, and so it lacks a proof-of-concept that preventive services will actually result in these savings as a consequence of improved health benefits over time. So these outcome studies are really kind of pivotal in people making a decision about the best way to spend dollars is on the early stage of intervention with preclinical disease and prognosis rather than diagnosis as watchwords for intervention. So the question as to whether prevention saves money has been incorrectly framed, according to Dr. Woolf in his editorial. He says: “Health care, like other goods, is not purchased to save money. The dollar can be stretched further and more goods can be acquired by optimizing economic value. The proper question for preventive intervention is: ‘How much health the investment purchases.’” This is measured generally in terms of cost effectiveness or cost utility, which in health care, as you know, is quality of life years, so we might ask: What is the quality of life adjusted life years that you would get by a prevention strategy for a particular disease versus waiting until it is diagnosed and you do an intervention? So we could say “cardiovascular disease prevention,” meaning functional medicine improvement of cardiovascular function versus waiting until you have cardiac pathology and intervening with a hospital-based or interventional therapy. How did the quality of adjusted life years relate between these two approaches? Those types of data are now starting to become available. Services that are ordinarily considered to have reasonable cost-effectiveness in the interventional model are between 50 thousand to 75 thousand dollars per quality adjusted life year. But payers from the insurance world will routinely cover treatments that cost more than 100 thousand dollars per quality adjusted life year. So that is kind of the benchmark that you could use to then compare functional preventive or functional early interventional studies against. If you could have data that would allow you to understand the cost of a functional medicine intervention and its relationship to quality of adjusted life years and compare that to the benchmark of a pathophysiologically-based intervention model, which is between 50 and 100 thousand dollars per quality of life adjusted years, you could then form some kind of an understanding of cost-effectiveness or benefit. Specific Questions to Consider When Doing Economic Analysis That’s a very interesting way of approaching it, and as Dr. Woolf points out, in order to do that we might start looking at several kinds of specific things that would pertain to this. First of all, what type of services are we talking about in terms of measuring early intervention versus late intervention? Are we talking about a public health intervention, which has to do with things like seatbelts, mammography, low cholesterol diets, or are we dealing with personalized interventional trials that relate to the individual needs of a patient-centered approach? Number two, what evidence are we going to use for determining our quality of life adjusted life year outcomes? The evidence-based clinical services needs to have objective markers for tracking benefit because the outcome that we are going to use is not going to be the endpoint called death. We’re going to use something that has more functional decrements. Will we use biomarkers like cholesterol-to-HDL ratios, or will we use carotid intima medial thickness levels, or will we use cardiac performance on a treadmill test? Will we use some type of imagery of wall motion studies? All sorts of different variables might be considered important for determining how we are going to objectively measure the quality of adjusted life years for our intervention by maybe surrogate markers that are tracked against longer term outcome variables that have to do with things like life expectancy. And then next is, what is a core set of services that will be delivered? Is there some kind of a reasonable, replicable protocol that we can implement, both in terms of screening—in other words, a set portfolio of evaluative tools that are tied to the outcome treatment that we are going to employ in these preventive, functional medicine-focused services? I think when you start adding all this together, it starts to form a system or a schema, so to speak, that would allow us to both have a replicable way of intervening in a more functional medicine, early stage, preclinical milieu, and then have ways of evaluating outcome and look at cost-effectiveness from quality of adjusted life year comparisons with more pathology-based interventions. The way that this field is evolving, if we’re going to actually demonstrate at a large regulatory level, legislative level, reimbursement level, these types of data need to be accumulated so that we can actually sit down and measure apples against apples in terms of cost benefit and outcome-related studies, and what is the economic value for this functional medicine/personalized lifestyle medicine approach? A Recent Article Authored By Dr. Bland This has to do a little bit then with finding the right therapy and how that gets personalized appropriately. Recently an article that I authored titled “Finding the Right Therapy: A Look at Personalized Medicine” appeared in the Integrative Medicine: A Clinician’s Journal.[4] I talked about how this whole theme had evolved since the turn of the last century, with the concept of biochemical individuality through Archibald Garrod’s discussion of genetic metabolism diseases. I moved into Roger Williams and Linus Pauling with biochemical individuality, genetotrophic disease, and orthomolecular medicine, and has now moved into the postgenomic era with regard to the deciphering of the code of the human genome, and then into gene expression understanding and how we recognize the genome, in and of itself, is not the ultimate determinate of our phenotype, but rather it is the interaction of the genetic code (meaning our genome; our book of life; 23 chapters encoded in our 23 pairs of chromosomes)—how those stories in our book of life called our genes are ultimately expressed as a consequence of the interaction with our environment. Those personal environmental exposures then give rise to different expression patterns that ultimately become our phenotype: how we look, act, feel , and how our health process evolves over the course of living. With that in mind, we then see the emergence of a concept that really is a revisited concept from the 1800’s. It’s the concept of adaptation, because it is not just the determinism of the genes as they are hard-wired from our parental legacy (the sperm and the egg when they met), but it is also the influence that our environment has had on setting marks on those genetic codes that then allow different expression patterns to pursue, and this is the process that is called epigenetics, as we’ve talked about at length in previous issues of Functional Medicine Update. You’ll recall the magnificent discussions we’ve had on two occasions, actually, with Dr. Randy Jirtle at Duke. He is kind of the father of nutritional epigenetics, and the discussion we had with Dr. Michael Skinner at Washington State University on Functional Medicine Update that talked about exposure in the environment to various substances that are toxins that induce epigenetic marks on the germ cells and alter, then, the function of subsequent generations. He talked about transgenerational inheritance of those epigenetic marks into the third generation. So we’re starting to see a re-validation of what Jean Baptiste was talking about in the 1800s as it relates to adaptation, which now is being seen, at the molecular/genetic level, as epigenetics—these methylated, stop function, or silencing of gene functions, or the phosphorylation or acetylation or the ubiquitination of genes that are all post-translational effects that occur epigenetically to put these marks on the genome that allow only certain messages to be expressed and others to be silenced. What Role Does Nutrition Play in Epigenetics? So we are actually witnessing the bridge between the environment and the genome through epigenetics. That takes us, then, to the question of: What role does nutrition play in this epigenetic understanding? In the past we might have felt that nutrition was a third- or fourth-level variable that had very little to do with how our health proceeded as we grew older, and was relegated in medicine to kind of a spot way at the back of the class. Recently, however, as Randy Jirtle’s discoveries have now been validated and many, many other investigators are starting to look at the role that nutrients have in epigenetic influences on gene expression, it is starting to be seen that this epigenetic concept may represent a bridge between nutrition and the phenotype of health or disease. We now recognize that nutrients can reverse or change epigenetic phenomena, such as DNA methylation and histone modifications within the genome, thereby modifying the expression of critical genes associated with physiologic and pathologic processes, and includes such things as embryonic development, aging, and even carcinogenesis. In fact, there are individuals who have questioned whether epigenesis is in part related to the increasing frequency of such conditions as autistic spectrum disorder in our society. Could it be that altered methylation patterns caused by changes in fetal stress that are seen in utero—and that stress could be chemical stress, or a variety of different kinds of inputs—that would then alter the way the imprinting of the genome occurred during fetal development, and changed, then, ultimately, the expression patterns of the genome into the phenotype that we call autistic spectrum disorder (ASD)? This has been a very robust area of inquiry and research over the last several years.   Chronic Diseases Can Be Epigenetic in Origin We now recognize that we might be able to say that many of our chronic, age-related, degenerative diseases are in part epigenetic in origin. As was recently talked about, these might be considered long latency nutritional disorders, as contrasted to short latency nutritional disorders like scurvy, beriberi, pellagra, xerophthalmia, and rickets where you can omit or prohibit the intake of a certain vitamin for a short period of time, like vitamin C, and in a matter weeks to months, you can induce scurvy in a human. But what happens if the alteration of a nutrient intake has a much longer timeline in its effect on epigenetic modulation, ultimately of gene expression, and then the sequence of events that lead into pathology, so that it is not just weeks or months, but it is years or decades in which that starts to be seen. How does a person know the origin of that disease (say, cardiac disease), when the origin occurred as a consequence of the cumulative influence of epigenetic changes on the genome over years of living? It might have started, actually, in utero, and then been continually re-stimulated through the environment that that individual was living, to ultimately encourage, then, the outcome that we call this chronic disease, which may be thought to have no nutritional relationship, but really if we knew its etiology from the initiation through its progression, we would see it’s a functional outcome of an early stage epigenetic change.   Phytochemicals and the French Paradox These are the questions that are being asked as it relates to the importance of nutrition and its relationship to epigenetics. It appears that nutrients and bioactive food components, which includes things like phytochemicals—this rich array of thousands of different secondary metabolites of plants that are unique in their ability to modulate cellular communication—influence epigenetic phenomena, either directly or indirectly, by influencing enzymes that catalyze DNA methylation or histone modifications, or by altering the availability of substrates necessary for these enzymatic reactions. The one that we’ve probably heard the most about recently is the so-called sirtuin gene family that regulates aspects of histone acetylation/deacetylation, and therefore the folding and unfolding of the genome to be accessible to reader enzymes.   You probably know that this marries itself very closely to what we call the French Paradox, where it has been said that people in France eating a traditional high fat, but natural, French diet and drinking red wine have a very low incidence of cardiovascular disease. When they consume a more highly processed diet that is less natural and contains less phytochemicals, their incidence of cardiovascular disease goes up. So the suggestion is that fat in and of itself is not the causative agent, but rather it is the kind of diet that brings information that alters the expression of genes that in the absence of those nutrients then results in pathology. So French Paradox, red wine, resveratrol gave birth to the increasing ordering at restaurants of red wine. It was wonderful for the red wine business because everyone said, “Oh, yeah, I’m drinking red wine for the health value now—for these phytochemicals.”   Resveratrol Modulates Genome Structure and Function in an Epigenetic Way The resveratrol story is a very fascinating story as a concept that lies within this epigenetic theme that is emerging (nutritional epigenetics) because resveratrol is just one of many phytochemicals that has been identified to modulate various aspects of genome structure and function in an epigenetic way. Resveratrol has been shown to influence the regulation of function of the SIRT1 gene in mammalian eukaryotic mammalian cells, and as a consequence it leads to alteration in histone deacetylase, one of the enzymes that is responsible for taking off acetyl groups from the histone proteins, which then allows these proteins to open up and to say “Read Here” (transduce or to basically translate the message of that gene into messenger RNA ultimately into protein). So this particular phytochemical—resveratrol—is one of a family (a literally large family) of specific plant-derived materials which influence genetic structure and function in such a way as to alter the phenotype (meaning alter the communication in that cell that produces its function.   This is a very dramatic shift in our thinking, isn’t it, about diet? To think that somehow there are information molecules within our food that can influence specific regions in a very kind of tailored, lasered way. The regions of expressions of genes by epigenetic modulation of their structure/function. “Epigenetic” means “above” the actual code itself. We’re not altering the ATGC kind of pairing in the DNA code; they remain constant. What we are changing is the way that that code can be read: either by silencing the genome by allowing certain messages not to be read (or prohibiting them from being read), or activating certain other genomic messages to be read by acetylation, for instance, which is known to open the genome to being read.   Will Epigenetics Research Lead to Treatments? These are very, very interesting changes in how we view the interrelationship between diet and ultimately function and health of the individual. So could there be the emergence of treatments focused on either prevention or dietary management of specific epigenetically modified functions that give rise to what we see later stage as long latency disease, like cardiovascular disease, or Type 2 diabetes, or cancer, or arthritis?  The emerging understanding of this field seems to suggest the answer is yes, that is where the data is taking us. In fact, there is a very interesting review paper that was published on this whole topic in Advances in Nutrition in 2010 that talks about this bridge between nutrition and health as connected to nutrient modulations of epigenetics and how these phytochemicals in food can modulate intercellular signal transduction, meaning alter the way the environment speaks to genes to regulate gene expression.[5] Small Inducible Inhibitory RNAs This particular epigenetic revolution that is occurring goes beyond just things like methylation and acetylation of the genome. It moves itself also into another topic that we discussed previously (two years ago) in Functional Medicine Update, that for many was probably very esoteric and seemed to have little clinical application, and that was an interview I did with a primary investigator at the Scripps Institute on the small inducible inhibitory RNAs (siRNAs). You’ll recall—if you go back with me for a moment—that he indicated that what is being seen in cells is that there are literally thousands of differing RNA molecules that are produced specifically by a cell, many of which have unique inhibitory functions on the expression of genes. It is like they are blocking RNA fragments from the ability to read specific messages. So this is another part of the epigenetic regulatory pathways—that cells are producing these kinds of jamming messages that prevent specific regions of the genome from being read.   Clearly we’re still witnessing the emergence of understanding of how inhibitory RNAs actually play roles in physiology. But there are big research projects going on at many institutions now to find out how to harness specific siRNAs to block the production of certain oncogenic proteins associated with cancer. So this is being seen as a potential new route towards cancer treatment by modulating cellular function at the siRNA level. The interesting theme of this is that these small inducible inhibitor RNAs are also produced by plants in their regulatory machinery (it’s not just seen in human cells), and these small inducible RNAs have just recently—in 2011—been found to be consumed in the diet of plant foods, and have been found (at least in the case of rice) to actually be seen in the blood after consumption, meaning that these micro RNAs actually can survive digestion and end up being transferred across the GI barrier into the blood, and therefore may have influence (and I want to emphasize “may”) on modulating, through epigenetic mechanism that occurs through the diet, the expression of certain genes in the host organism that has consumed that food.   Now this is a pretty dramatic observation, isn’t it? Because what it is saying is we’re getting information from food that could potentially modulate gene expression through an inhibitory mechanism that is specific to regions of the genome that would alter health or disease patterns. The title of the article is quite esoteric: “Exogenous Plant miRNA-168 Specifically Targets Mammalian LDL Receptor AP1.”[6] There is evidence from this study of cross-kingdom regulation by these micro RNAs. This appeared in the journal Cell Research in 2011. It’s pretty amazing, really.   Previous studies from this group had demonstrated that stable micro RNAs (miRNAs) in mammalian serum and plasma are actively secreted from tissues in cells and can serve as a novel class of biomarkers for diseases, and they act as signaling molecules in intercellular communication at an epigenetic level. In this particular paper, however, they went on to report what I think is an absolutely fascinating finding: that exogenous plant miRNAs are present in the serum and tissues (and I want to emphasize “tissues”) of various animals that have orally consumed these plants, and that those exogenous small inhibitory RNAs are primarily acquired orally through food intake. The specific example that was chosen in this study was this small inducible micro RNA 168A. It is abundant in rice, and is one of the most highly enriched exogenous plant micro RNAs in the sera, as found in Chinese subjects consuming rice. Does this have any role to play in gene expression? When they did the in vitro functional studies (and in vivo), they demonstrated these micro RNA 168A could bind to human/mouse low density lipoprotein receptor adaptor protein (or so-called LDL RAP1), inhibiting then the expression in the liver and consequently decreasing LDL removal from the mouse plasma. These findings, they suggest, demonstrate that exogenous plant micro inhibitory RNAs in food can regulate the expression of target genes in mammals.   Let me let that set in just for a second. You want to talk about a shifting paradigm? This is one. This has us really looking at diet and food and its relationship with information and gene expression and how that translates out into non-communicable chronic disease in a very, very remarkable way. In fact, it even suggests that epigenetic changes are not just hard-wired; they can come and go based upon the type of dietary intake a person has and the presence and exposure to these micro inhibitory RNAs in their food.   So what can we say about this extraordinary discovery? Investigators at the Max Planck Institute of Developmental Biology in Germany really have discovered what might be the first comprehensive inventory of how spontaneous epigenetic changes can be brought about through food, and that these changes could be considered reversible as diets change, which means that epigenetic changes may not always last; they may come and go as it relates to the changing diets of the individual.[7]   Now if you tie this together with my previous discussion concerning phytochemicals that influence genomic structure, like resveratrol and the SIRT1 genes, you’re starting to see that this regulatory series of pathways that ultimately regulate how genes are expressed and become our phenotype is much more related to environmental factors than we previously have acknowledged. Therefore, the concept of a personalized lifestyle medicine intervention program that is functionally based is starting to have a molecular/genetic and a cell/biological explanation that is absolutely profoundly intelligent when we start asking the questions, how, why, when, and what do we do? We are really starting to develop a new medicine that translates ultimately into studies that would allow us to look at cost-effectiveness of personalized intervention (early stage), based on certain new emerging biomarkers, and then tracking that against quality of adjusted life years so that we start to see, for those who are planning health economies and health expenditures and are really trying to deal with the broad-brush questions of 47 trillion dollars to be spent for the next 20 years on non-communicable chronic diseases, how this could move the needle, how this could improve outcome.   I was very impressed when I looked at a recent paper that appeared in the journal Cell, which reports a very nice study of the influence of 30 days of supplementation of resveratrol on metabolic parameters and body fat in obese humans.[8] This is a very interesting study in which resveratrol—the same compound I was talking about, a constituent of grapes and grape skins—which is known from previous studies to affect energy metabolism and mitochondrial function, and has been suggested to serve as a calorie restriction mimetic. These are themes we have talked about earlier and we interviewed, as you recall, Dr. Christoph Westphal, the CEO of Sirtris Pharma years ago, before they were acquired by GlaxoSmithKline, who had really been exploiting the discoveries of David Sinclair at Harvard related to resveratrol in the SIRT1 gene.   Results of a Human Trial on Resveratrol In this particular study, researchers treated 11 healthy obese men with a placebo and 150 milligrams per day of a special form of bioavailable resveratrol in a randomized, double-blind, crossover study for 30 days. What they found after the 30 days with this group of 11 individuals who were randomized was that resveratrol was found to significantly reduce sleeping and resting metabolic rate, and in muscle resveratrol was found to activate adenosine monophosphate kinase (or AMPK), which is kind of the energy thermostat of the cell. You’ll recall we’ve talked about it previously as having a direct effect on mitochondrial oxidative energy production. It was found to increase SIRT1 expression and increase citrate synthase activity without change in mitochondrial content, and improve muscle mitochondrial respiration on a fatty acid-derived substrate. It was also seen that resveratrol was found to modulate or influence intramyocellular lipid levels, and it decreased intrahepatic lipid content (meaning lowered fat infiltration into the liver), and it lowered circulating glucose, triglycerides, and liver enzymes like ALP, and it also reduced inflammatory markers like hs-CRP.   So this was a very interesting study in humans. Again I want to suggest that this was an early stage-type trial (we’re only talking about 11 healthy obese men randomized between resveratrol and placebo, with the resveratrol being 150 milligrams per day of this unique formulation of resveratrol that was made more bioavailable). By the way, 150 milligrams a day would be equivalent to something like 70 glasses of wine, so we are talking about an amount that is more pharmacologic and less nutritional because you’re not going to pick up 150 milligrams in a food and beverage delivery system under normal conditions. In that nutritional pharmacological intervention with resveratrol in these modestly obese, presumably healthy individuals, it appeared to have very salutary and beneficial effects on modulating expression that ultimately was seen as lowered triglyceride, lowered inflammatory markers, lowered glucose, and improved liver function. I think that these are very, very exciting kind of clinical takeaways from the discussion we’re having concerning nutritional epigenomics and genetics—whether they really play a role or is it more of an esoteric academic topic as it pertains to the burden of disease and the rising tide of chronic non-communicable diseases in the world.   How does that relate, then, to this discussion among the experts that you are going to hear in the remainder of this issue of Functional Medicine Update? It really relates directly to the question of the efficacy of a functional medicine approach towards personalized lifestyle intervention. Does it really deliver the goods? Is it more than just a feel good experience? Does it have an outcome that really can reduce the progression to more serious pathology? Will it be cost effective? Will it increase the quality of adjusted life years of the individuals? All of these are very, very important questions that appear to me, from the way that the literature is emerging and how things are being developed, to have a revolutionary conceptual affirmation for this model.   A Published Study by Dr. Bland’s Research Team on a Phytochemical Formulation In fact, recently the group that I am very privileged to work with at the Functional Medicine Clinical Research Center just published a paper in Nutrition Research, volume 31, page 347 in 2011, reporting on the role of the complex phytochemical formulation that contained hops iso alpha acids, berberine, vitamin D3, and vitamin K, having a very profound and favorable effect on bone biomarker profiles in postmenopausal women who have metabolic syndrome.[9] This particular study demonstrated that by giving a certain concentrated mixture of bioactive phytonutrients that are known to influence certain gene expression patterns, you actually can enhance the osteogenic potential within certain cells that would help to prevent bone loss and help to maintain proper bone integrity. So we’re talking here about giving more than just calcium and vitamin D to mineralize bone, we’re really talking about the active process of bone formation and bone resorption—that balance between osteogenesis and osteolosis—and how that triggering event of that equilibrium is in part controlled by the environmental exposure to certain phytochemicals that can modulate the gene expression patterns. This is sometimes called hormesis, as we’ve talked about in previous issues of Functional Medicine Update: small amounts of the right things hitting certain regulatory nodes on the gene expression patterns can have a larger effect clinically than we would have predicted. Hormesis.   These concepts of berberine, and vitamin D, and vitamin K, and rho iso alpha acids from hops having unique gene personalities to enhance the orchestration of the phenotype of cells that are associated with bone integrity and maintenance is, I think, another of the myriad of examples that are coming out in the literature recently as it pertains to improvement of function with the appropriate information from food. So it is food, exercise, stress management, the reduction of exposures to environmental xenobiotics or chemicals or heavy toxic elements—all of these things then play extraordinary roles in sending signals to cells that ultimately create expression patterns that become the phenotype.

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INTERVIEW TRANSCRIPT

JB: I’ve got two last questions I want to ask each of you, and they can be probably fairly short answers. The first one, which comes up frequently in conversations I have with individuals who may be considering integrating a portion of lifestyle medicine into their practice, is: What are my peers going to think of me? This is a guild—medicine is a guild—it’s really passed down from the Medici family in Italy. It has had generations of refinement, but it’s still a very strong guild of internecine communications. What happens when you start breaking the guild, and how does that have an impact on you, and your life, and your vision, and your identity? Maybe it could be none, but my experience is that it is generally something. David, I’ll start with you. DJ: I wonder about that question because lifestyle changes in my clinic included doing home births with a midwife. Ashland is a small town of 18,000, but we’re right next to the large referral center, so you have no idea how people think about you. I go merrily along my way delivering babies at home and going about doing lifestyle medicine, and eventually we got into what we call functional medicine. So managed care comes along, and all the doctors are scared because they can sit with a patient and make decisions about that patient that is a life-and-death decision, but when it comes to confronting an insurance company that holds your money purse, somehow they just…I’ve never seen such change. It was a bipolar experience for me watching how doctors dealt with managed care. They actually came to me to be their president, to help them with the insurance companies, because somewhere in there they realized, “They’re going to ask us to do something about prevention, and we don’t know anything about prevention, and David, we’d like you to come.” It surprised me because I thought I was considered more radical than that. To have that kind of respect in the community when you think of yourself as, “That Dr. Jones over there in Ashland, he’s pretty weird.” So I had exactly the opposite experience: making decisions about my patients, the way that I referred patients, and what the patients said about me. Now I had other doctors in the community that came out of medical school and they felt such a sense of betrayal that they created a certain disharmony between the establishment and themselves. For whatever reason, I had such great respect for the skills (that I could refer my patients to people with skills in areas), but I also knew what not to take from their advice. And over time there was a respect that was developed, and I was their president for 10 years until I came and was asked to be the president of IFM. So I didn’t have a bad experience being the granola doctor in Ashland. Establishing Respectful Relationships Among Colleagues JB: I think you said something very, very important, and I’ve observed this not only with you, but other very successful people that swing over this and have feet in multiple areas of activity. You really create a relationship with your community of respect. You never passed a sense of disrespect for people that did things differently. In fact, you honored their skills in areas where you needed them, and didn’t look through their liabilities and limitations as the major barrier. I think that’s a really important lesson because, as you said, there are some people who get into this field and they have the conversion experience, and then everything that they did before was wrong, and all of the people in that field are wrong, and suddenly we end up with a polarity and now it’s a fight. JB: So Graham, how about you? You’ve made this transition from Oakland Raiders team doctor all the way up through the years of dealing with a myriad of different medical referral specialists. How has it been for you? GR: Well, a couple of things. I’m a nut about leadership reading and I love the stuff that Einstein said, you know, “What the solutions are you had that brought you to the solution today are not necessarily applicable to the problem you’ll have tomorrow.” The issue is that we’ve got to continue to have a dynamic of change and not be caught up in finding out what the next thing current therapy says we should do, but we should also not ignore that. We should live in it and past it. So it is easy to do one thing, I think, in medicine, but we fail to embrace the system that parented us. It parented us, and if we disrespect it, then you run a risk of now feeling as though others really can’t associate with you because they’re frightened about this. So I end up doing this: I gather consultants around me. Covey says: “Every breakthrough must first start with a break away.” That’s a vital part of everything we do: every breakthrough has got to start with a break away. But it doesn’t mean a break with things out there that you have been trained in. It means break with their control over you. The big thing is: Who is the person we need to fix most? It’s me in the mirror. That’s who. I’ve got to fix me first. The next thing, I think, is I have a phrase for patients: The difference between good and excellent care could be the miles on your car. I really don’t care much about it. I’m sorry about that—that gas is high—I know that, but the point is: I’m going to find you the very best consultant, is what I’m going to do. I have my nurse practitioner and 27 consultants that she will, in the next four months, come to see. They’ll be here. They’ll be around. They will become an integrated partner and they know that. I sent 380 patients to our orthopedic group in Seattle because I had so many. We did 600 MRIs and CTs because by the time because by the time they get to us they are already pretty damaged. In that regard, those people already know how I think. They’ll come back and say, “That’s great because he knows how to fix this food for you, because if you don’t do the food you won’t get better.” What you are doing is you go home and you gained all this weight and now you’ve got this knee and you want me to fix the knee. I can’t go, “Darn it, I can’t fix that knee unless I can cut and fix it, but it will not make you well.” Those are the people we gather around us, and they become both purveyors of the truth (in my mind) and our truth. It’s a shared truth. It’s not one that comes from me; it’s one that is given out easily. I’ll say: “You get to go see one of the best guys I know or one of the best gals that I know. You get to do this.” I’ll pick up the phone in front of them and call and say, “Scott, this is who I’ve got. This kid’s been at this, he’s come in today, he’s got four-and-a-half weeks on his ankle today. The physical therapist said the doctor said he could play three weeks ago, but he’s having a hard time walking.” This is the fun part: somebody said, “Who referred you?” And he said, “All the coaches in the area.” I said, “Well, the problem is you have a little fracture. We did the digital x-ray.” So I said, “You can play tomorrow and this is what the brace is for and this is why. But you’ll not be good, so you have to play as a wide receiver— a wide receiver, not a defensive back. You have to stay on the left side, so you play at this end. You do not run out in the middle. If you don’t do this, you can play. But you can act like everything’s fine. You’re just fine. Just stay on the left side. Tell the coach. Go tackle all you want, but if a guy goes on your left, you’re dead.” We do that in basketball, we do that in volleyball, and the point is you become a participant in their life, you become a participant in their sport, and they, all of a sudden know, “You know what I’m talking about!” If you’re playing tennis, don’t rush the net. I’m getting too carried away, but anyway it’s about living in their life with them. JB: Jay, how about you? You’ve transcended many different boundaries. Anything that you would offer as kind of your observations? More Controlled Clinical Studies on Lifestyle Medicine Needed to Increase Acceptance JL: I think a few points come to mind. One is that I would like to see more of the kind of research that we heard about earlier today and see controlled, double-blind studies. It is very difficult to sort of contextualize functional medicine and lifestyle medicine in terms of a clinical study, but we really have to do it, because in order to effect change and allow ourselves to adopt these important principles we’re going to have to show the research that it does matter (even though we know that it does matter). I think that there is obviously a hurdle that—again, Graham, I think very eloquently talked about—which is that in order for us to effect change in medicine we have to effect change in ourselves and see where our own roadblocks are in terms of how we operate and how the things that we accept as being true are not necessarily so, and that’s a difficult thing for people who are smart like we are: to accept the saying that “We know what we know, and we know what we don’t know, but we don’t know what we don’t know.” A lot of the alternative medicine is in the area of “we don’t know what we don’t know,” and that’s something that we’re all uncomfortable with, but in order to help overcome intractable problems we have to embrace the unknown. So it is really two-fold. One is discovery of evidence-based practice and showing that it does improve outcomes. And two, it is willing to accept that there is just a lot we don’t know about health and disease, and having an openness to things that take us out of our comfort zone are important to listen to and to have an open mind to. JB: Thank you. Jim, as you made this transition, is there anything that you have observed with your colleagues? JW: Yes, I’ve gotten beaten up a couple of times, but I would say not from anybody who I respect, and from people who I do respect, never for a good reason and when I have called them on it or talked to them about it I usually get an apology because they did it for the wrong reason or lack of understanding or something. It was very important to me going into this that I not be thought of as a kook, so I’m very careful about making sure what I do is evidence-based. That’s what we’ve been taught. When I sit down and have the thoughtful discussion with my colleagues who are not necessarily on the same page, I can usually prove to them that what they are doing is not the best medicine on the basis of evidence. I would say I haven’t yet had the experience where I was beaten up for the right reasons. In Orange County they have this Lipid Alliance. They have a yearly conference. One year, a year or two ago, I went to the conference (it’s a one day conference) and there was a lifestyle medicine lecture that was terrible, frankly. So I have been talking with one of the two organizers of the conference. Hopefully I’ll be able to give the lifestyle medicine conference to a roomful of mostly cardiologists and primary care physicians, to tell them what the truth is and what they need to know based on the evidence, which is what they are there to hear. JB: You have a pretty good referral practice with Hoag, right? With Hoag Hospital, which is really one of the big medical centers in the area? JW: Yes, that’s essentially the only hospital I use for my patients. JB: And have you had reasonable acceptance when you go and you do your visits there with the staff and the people that know you are doing a little bit of this kind of medicine? JW: Honestly, I really transitioned my practice and I do very little in-patient work now. There is this wonderful thing called intensivists and hospitalists and they get woken up at night and I don’t get woken up any more. So I haven’t had that experience because I really don’t do that much anymore. JB: Great. Ken, any thoughts about your transition with your peers (if you want to call them peers)? Members of the community? KB: Colleagues…Looking back, the primary care physicians in town kind of look over the paper, because they are kind of interested in what we are doing because they hear things from patients. The high school teacher that you talked about earlier—his brother is a well-known family practice doc in town. I tried to reach out to my fellow primary care physicians and say, “I don’t need more clinical patients but I’d love to take care of those metabolic syndrome or type 2 diabetic patients that you don’t necessarily want to. I finally realized that they didn’t do it because they were fearful that they would lose their patients. As I mentioned earlier, our office is a beautiful 1902 heritage house with a big wraparound porch, and when people walk around there they are going to go, “Why do I need to go anyplace else?” The staff treats them well. So I got over that. Recently I was invited to a hospital…kind of a staff meeting…well, it wasn’t a staff meeting, but sponsored by the hospital. There were interventional cardiologists, some vascular surgeons, and a handful of family docs. It was about peripheral artery disease and doing PAD screens. So they all went and said their piece, and one of the cardiologists says, “Let’s ask Browning what he does because he does things a little bit differently.” Fortunately I had been preparing to go speak up in Grants Pass, Oregon, so I had all my stats ready to go. In fifteen minutes, I was doing it, and I felt really good about it, and I told them why we were different, and shouldn’t we be treating the whole person? My server came up to me when she was giving me another glass of wine and she goes, “Great talk.” I thought, “That was very cool.” My other encounter was with another cardiologist at the hospital. The hospital does ask us to speak often to employee group meetings or luncheons—things like that. We have picked up a lot of the ER nurses. We’ve picked up a lot of the cath lab nurses and management nurses. They come to us and they get better, and so we’ve tried to worm our way into the hospital to do things—similar, I think, to what you’re doing. But this cardiologist got up and spoke after we had spoken and he says, “You know, I could sit here and tell you—as a cardiologist—you need to quit smoking, and you need to eat better, but if you really want to get well, go see Dr. Browning.” And that was unsolicited and it was like, “Wow. Thank you very much.” DJ: They do recognize it (in the community). They do recognize when you do the respectable work in the community, as long you aren’t bad-mouthing them and saying, “Why aren’t they doing it?” KB: Taking care of people. JB: Kristi, how about you, as a naturopathic physician? That’s Mayo territory up there. What’s been the general sense that you see? Patients Will Carry the Message about Successful Treatment KH: I am just starting my 14th year in private practice. The first 5 to 6 years, the focus was on the patient, not as much the healthcare community, because most of the healthcare providers had never heard of a naturopathic physician where I live. I was the sixth in our entire state; this was back in 1997. I let the patients do the talking for me. After that first five years/half decade passed, all of a sudden the results that the patients were getting—under the care of other physicians for 10, 20, 30, 40 years—was really what opened the door for me. In my own personal community, I allowed for the patient results and the patients to really carry the message for me. I continued to focus on the patient—their goals, their needs—and do patient education and a lot of community education. As you pointed out, a lot of my first pass patients, when I look back to my first few years, they were nurses, they were not physicians, but they were other healthcare providers in the system, who worked in the system and knew the system was broken (as they would say) and coming in looking for other options. So I would say the community (breaking through) hasn’t been nearly as challenging as speaking on this topic to medical doctors, to osteopathic practitioners, to multidisciplinary practitioners, and having my own naturopathic provider say: “What are you doing teaching naturopathic medicine to the other guys?” That has probably been one of the most interesting journeys I have gone through because as many of you know, functional medicine has some very strong naturopathic principles within it, and naturopaths do lifestyle medicine. That’s what you spend your four years of medical school focusing on: all lifestyle medicine. My skin has had to get a little bit thicker. I’ve had to toughen up, more against my own team I would say, because they want to know: What am I doing out there teaching them all of the secrets? And I just look back and say: “Why would you not want to empower every physician to just go back and transform ONE patient? Just one patient’s life with a little something you had to say?” I’m taking the high road on this one. I truly believe in some of the key foundational principles. “Docere” means “teacher.” You teach the patient, you teach the doctors, you teach the community, and from there you are going to pay it forward. JB: Thank you. Really, that’s a model. So Mark, clearly in your academic environment, maybe the swirling guild is a little bit tighter. I don’t know. Have you experienced any kind of interesting conversations with your colleagues about this whole model? Practice Teams Can Have More Impact on Patient Success MM: I think one of the major things is the concept of teamwork has now become so clear. Meaning that we as physicians essentially dictate to our patients, but now the conversation that we have had is that really if you are going to have an impact on patients, it really takes a whole team. You mentioned your life educator and your nutritionist. They are the ones who are—in their day in and day out—really doing the motivational interviewing, and helping patients change behaviors, and really empowering them as well. Likewise, patients themselves. There are some group settings that we utilize. Other patients are tremendous assets to each other. They quite often learn a lot more from other patients than they will learn from me as a physician. I’ve heard that likewise amongst our physicians as well. And the families—they can have a very positive role. If there is a mother who is trying to change behaviors and eat correctly, she needs the support of her husband as well as her children (if she doesn’t have that support). So I’m just a small piece. We, as physicians and clinicians, are just a small piece of the whole pie that we’re developing. Likewise, the researchers are in the background who give us the real tools to help change behaviors and to have an impact. Teamwork. I really think that’s key. JB: That’s a really nice message. I want to ask one quick question. This is going to be a sound byte. I’d like you to each think about this. I’m going to give you a magic wand and I’m going to give you one wish to be realized—granted—for the successful implementation of improved patient outcome in your practices with chronic ill patients. What would it be? This would be your sound bite wish. David? DJ: I don’t understand the question. JB: Let me give it to you again. If you could be granted one wish to make your patient population more successful than they are today in outcome, what would it be? DJ: I still don’t really think I understand the question. JB: You can frame the question any way you want. You can answer it any way you’d like to frame it. DJ: What I have found is the most important thing, when I see transformational change in my patients, is that I have the faith to create a context where I don’t have the answer—where I walk into a room and I just simply let the answer emerge. Because I come with a lot of information. I come with a lot of knowledge. I have a certain architecture I use for sorting that. But to actually go into a room and create context where something happens—that emerges—between us just talking and listening, where I am not the answer man, where I let that one go, and have the faith that something will emerge that will change my life while it is changing their life. That’s the hardest thing for me, because my training is that the buck stops here, that I have to somehow play 62 card pickup until I pick up the right card, and I’m a good doctor if I figure out which card it is. It’s not like that. The big things, where the walls fall down and something magical happens, is where I’m just there. I just happen to be a witness to what’s happening. And to have the faith that that will happen and not get into that thing where it’s my reputation, I don’t want to be embarrassed—all those things—that I just simply say, “Together we’re going to find an answer. I may have some of that. I know that you’re probably the one that is going to come up with an answer. And we’re just going to have a dialogue here until we figure this out.” And then something happens. When I get in the way—like when a patient comes back a couple of times— I will sometimes say, “I just can’t figure this out, so I’m going to step out of the room, and I’m going to ask Dr. Brown to come in the room, and then you explain to Dr. Brown what Dr. Jones doesn’t know.” Then I’ll come back into the room and say, “Dr. Jones sent me in here.” And every time, the patient—within two minutes—tells me what the answer is. Creating that context where something like that can happen has become probably one of the greatest joys because it’s like I don’t have to carry that heavy responsibility—that mantle that I was given (when I finished medical school they put a mantle on me—a green sash—and I was the answer man). I don’t have to do that if I have enough faith that if I let it happen it will happen. JB: So let me make an observation. First of all, you did answer my question, because what I take away from your response is that if you had this wish granted, what you would do is you would wish that the context of healing was established in every interrelationship you had in that privileged moment of the exam treatment room. DJ: That’s what I’ve always loved about you. I can say something and then you can translate it. Establishing a Context for Healing JB: And vice versa. And you also said something else that I want to really emphasize for the group and for this discussion. That is the abilities that you have, and your colleagues who are at this table who are all masters in their areas, to establish context is deeply studied and developed; it didn’t just happen magically. This isn’t like some kind of a divine process where you spiritually came down from the mount and you suddenly had the wisdom to create the context. All the things that you have done throughout your career and in your personal life create, then, the environment for establishing the potential context for many different people to have that experience. So I think this concept of deep training—we don’t know exactly where it takes us, and the architecture of learning, and the constant pursuit of wisdom, and all of those things that go into “I don’t know the answer” that keeps driving you, creates a context that is an expanding the opportunity for healing. That’s really was Osler was talking about in his writings about really great medicine. DJ: People around the table have talked about the sacred nature of what we do. For me that sacred nature is where something emerges between the two of us and it’s sacred, but I didn’t do it. JB: But you prepared the soil. DJ: I may have prepared the soil, but mainly I get the hell out of the way. JB: So Graham, you’ve got your magic wand. Is there anything that you would say? Anything you would like to have to complete the circle? GR: I was saying some of it before, when we started the evening. I’m 74 and I’ve got so much more energy than anybody I know at 74. I’m just kind of getting started in a whole lot of this. I have a lot of phrases I use with patients a lot. For instance, I say: “My job is to teach you not to need me, so I’m busy helping you do this. I’m doing techniques and studies (lab studies). I do a blood count so in one minute I know whether you have a virus or a bacteria. And I’m not going to give you an antibiotic, but in case don’t this is what you do. You take the CBC. If it’s 3000, you don’t have that. If it’s 10 or 15 thousand, you do. You’ll know, in the future, that we’ll start with vitamin C, 3000mg three times a day for three days, and then if indeed you are still sick and really coughing, then I will help you with this antibiotic. You don’t need to come back if you don’t want the antibiotic, but if you do think you need the antibiotic we’ll check your blood.” We empower them. To teach them not to need me. That’s one thing. The second thing is I need to be present to the moment when they call. I give all of my patients my cell number. Every one. All my coaches. Everyone has my cell number. I maybe, once a month, have violators. In a total week I might get 7 to 8 phone calls. Total. That’s a gift. Partly because they feel free to call and they don’t want to interrupt me because they know there are other people I’m with. I tell the staff, “Be present to the sacred invasion of their lives.” I love the phrase “invasion” and I love the word “sacred.” It is a sacred and it is a hallowed moment. I want to honor that, and then I want to help them discover the multiplicity of their diverse gifts, because they have many gifts and I want to broaden their life spiritually, to move their life from being full to being fulfilled. “What would help you be fulfilled?” JL: I’ll be very succinct and paraphrase a French philosopher: To grant the potential for consciousness to jump over its own shadow. JB: That’s really powerful. DJ: Say it again. JL: To grant the potential for consciousness to jump over its own shadow. JW: I don’t know if I can follow that. For me, the question is “What? What do I do? Doc, what do I do?” I always say, “More important that the ‘what’ is the ‘why.’” For me it comes down to education. It’s very important to educate people about why they should do what we have been talking about. Because once they understand that, then the “what” is easy for them to be compliant with. If I had my magic wand, it would be to know what that hook is for each patient before I walk into that encounter. JB: Thank you. Ken? KB: “Hook” is the word I use, too, but the magic wand—for me—is to take all of the data, the communication, and be able to process it concisely (or even have it make sense) and give it back to the patient in a way that they get it. Does that make sense? Clean, Colorful, Affordable Food KH: If I had a magic wand…I live in the middle of an agricultural hub in the middle of Minnesota, so I would say since my principle is food first, I would want clean, colorful, affordable food because that would reach everybody and I think that would do my patient populations the greatest good. JB: Mark, you can round us out. Run us through the stretch. MM: It’s hard to follow all of these wonderful comments, but I think, if I had a magic wand, I would restate the ability to listen. It’s not only to the patient, but also to the community. When you are working, sometimes, in the environment that I am (in the emergency room, for example), you have your hand on the pulse of the patient, but you also have your hand on the pulse of the community and what’s going on in that community, and also in the corporate environment as well. All of those are interacting together to impact the health of our patients, so I need to be able to listen to all of those inputs and to synthesize those in a way that can actually help the patients. That’s the wand that I would like to have. JB: Thank you. We obviously way exceeded the hour that I said we were going to have, but I should have known that with this group of deep thinkers and experienced souls. This has been a privilege. David, Graham, Jay, Jim, the two Brownings, Kristi, Mark—thanks. This has really been one of those magic moments. We often don’t get this chance. This is like the great circle that, probably, chautauquas were built around (the Indian tradition of great sharing). This will be shared with many other people and I hope it will be as inspirational for them as it has been for me. Thank you very much

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Bibliography

[1] The World Health Forum and the Harvard School of Public Health. “The Global Economic Burden of Non-communicable Diseases.” September 2011. http://www3.weforum.org/docs/WEF_Harvard_HE_GlobalEconomicBurdenNonCommunicableDiseases_2011.pdf   (November 15, 2011) [2] Lantz PM, House JS, Lepkowski JM, Williams DR, Mero RP, Chen j. Socioeconomic factors, health behaviors, and mortality: results from a nationally representative prospective study of US adults. JAMA. 1998;279(21):1703-1708.   [3] Woolf SH. A closer look at the economic argument for disease prevention. JAMA. 2009:301(5):536-538.   [4] Bland J. Finding the right therapy: a look at personalized medicine. IMCJ. 2011;10(1):41-43.   [5] Choi SC, Friso S. Epigenetics: a new bridge between nutrition and health. Adv Nutr. 2010;1:8-16.   [6] Zhang L, Hou D, Chen X, et al. Exogenous plant MIR168a specifically targets mammalian LDLRAP!: evidence of cross-kingdom regulation by microRNA. Cell Res. 2011:1-20.   [7] Becker C, Hagmann J, Muller J, et al. Spontaneous epigenetic variation in the Arabidopsis thaliana methylome. Nature. 2011. [Epub ahead of print] [8] Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell. 2011;14:612-622.   [9] Lamb JJ, Holick MF, Lerman RH, et al. nutritional supplementation of hop rho iso-alpha acids, berberine, vitamin D3, and vitamin K1 produces a favorable bone biomarker profile supporting healthy bone metabolism in postmenopausal women with metabolic syndrome. Nutr Res. 2011;31:347-355.   [10] Christensen, Clayton M. The Innovator’s Dilemma. New York, NY: McGraw-Hill, 1997.   [11] Christensen, Clayton M. The Innovator’s Prescription. New York, NY: McGraw-Hill, 2008.

Welcome to Functional Medicine Update for December 2011. Let me start this issue with a little bit of a provocation. We all have learned certain aphorisms that indicate or symbolize things that are beyond words. Let’s use the little aphorism “An apple a day keeps the doctor away.” What does that really mean? Or another little sound byte that appeared in marketing for Wonder Bread, a white enriched bread, and that is “Helps Build Strong Bodies.” What do those sound bytes mean and how do they relate to the future of functional medicine, nutritional medicine, and nutritional therapeutics in the age of a rising tide of chronic disease? That question really attaches to what we see happening in our environment today, and how patients will be managed in the office, and ultimately how that translates into the evolving future healthcare system. So that’s the theme of this month’s Functional Medicine Update, and we’re very, very fortunate to have as our senior consultant/representative/opinion leader today a person whose background, as you will see, is very different than anyone that we have ever had on Functional Medicine Update over its 30-year past history. I believe it could not have come at a more timely moment to have this expertise shared with us on Functional Medicine Update. I don’t want to spill the beans yet and tell you exactly who you’re going to be listening to, but I do want to say if you keep your ears “peeled” (using my apple analogy), that you’re going to be very, I think, interested in the message and the story that will evolve over this month’s Functional Medicine Update. Scientific Interest in Biological Response Modifiers has been on the Rise Let me say a couple of things in preparation for where we are going to go. We’ve talked a lot about the bioactive ingredients in foods and natural products as being a focus of discussion and study at higher levels of scientific inquiry than in the previous, say, 50 or 60 years. If you follow the research citations that are being published in the world’s literature, you will see an exponential increase in the number of studies, both basic science and clinical science studies, that are being published around the role of various of food-derived or natural-product-derived materials in modulating physiology in humans. Therefore, we would call these substances biological response modifiers. An example of this would be essential omega-3 fatty acids, the long-chain polyunsaturated fatty acids such as eicosapentaenoic acid or docasahexaenoic acid (EPA and DHA). EPA and DHA: What History Tells Us About Study and Acceptance We could go all the way back to the early 1980s, during which the first studies were being published around the potential role of essential fatty acids in human physiology. I recall a paper in the New England Journal of Medicine by Elias Corey and his colleagues at Harvard.[1]  They had done some of the first work published in a high-level, peer-reviewed medical journal on the role of EPA fish oil supplementation influencing leukotrienes and influencing monocyte activity (meaning immune system activity) in humans, and inflammatory response. That was some five to six years after people had started to recognize that the observations made by Dyerberg and Bang in Greenland with Hugh Sinclair, an Oxford Medical School professor and nutrition expert, on Greenland Eskimos who were consuming high levels of fat in their diet as oils rich in EPA from marine animals, particularly seals, and that these very high fat diets were associated, in these individuals, with the low incidence of cardiovascular disease and a very significant reduction in thrombotic events, meaning thinning of the blood.[2] When they studied the relationship between these high fat diets and the health outcomes in these individuals, they found that it was a consequence of the consumption of these high levels of omega-3 long-chain polyunsaturated fatty acids. So that goes all the way back into the 60s and 70s, these observational studies with the Greenland Eskimos. You probably recognize that at first this was considered kind of artifactual because the dominant thought of the body politic at that time was that fat was bad, and so how could there be good fats when we recognized that too much fat was the cause of heart disease? We got into this paradoxical situation. I recall, actually, in the early 1980s, being a consultant for the RP Shearer Company. It was the first company to actually commercially sell fish oils in the United States under the name MaxEPA, and I was involved with the media tour We had done some research on fish oils at the university (I was overseeing a research group at the time as a professor).  It was considered quite heretical to thought that oils or fats would be good. I recall getting very critical questions asked of me, and a lot of I-can’t-believe-it type of response that these could be beneficial. From the early 1980s fast-forwarding to today, literally thousands of papers have been published on the nature of the bioactive ingredients in these marine oils that have these dramatically interesting effects as biological response modifiers. We would call them pleiotropic effects, meaning effects across multiple actions or functions of the body. It has taken that 25 or 30 years to evolve a general state of understanding as to the positive benefit of omega-3 fatty acids in the diet.   If we really start looking at a lineage of ideas and how we’ve evolved our understanding over 30 to 40 years, it’s to start to recognize that there are molecules present in foods that are produced by the biosynthetic processes of plants and animals that then induce alteration in function of humans consuming them, and they can have both prophylactic and therapeutic effects, depending upon dose, and form, and delivery system. Those bioactives found in food, which we would call natural products, then have a range of potential benefit in a culture that is burdened with chronic disease that might be incorporated within therapeutic goods that we would call nutritional supplements, functional foods, medical foods, or other types of goods that could then help to reduce the burden of disease and impart positive benefit on reducing metabolic disturbances that we associate with things like diabetes, heart disease, arthritis, and cancer. That is been the summary of how this field has evolved: this increasing weight of scientific evidence that supports the value of these substances.   Through that, we have obviously seen some very interesting changes in the regulatory framework and the oversight of these discoveries as they get translated into commercial products and ultimately available to consumers. We call those dietary supplements in the United States. They have been regulated by the Food and Drug Administration, as you know, and also advertising claims by the Federal Trade Commission of the United States.   1994: The Dietary Supplement Health and Education Act Passes Creating a New Regulatory Framework for Nutritional Supplements That ultimately resulted, as you know, in this most remarkable transition in American law, which occurred in 1994 (October), which was the passage of the Dietary Supplement Health and Education Act (DSHEA) that was passed by both houses of Congress and set up this new regulatory framework for nutritional supplements in the United States. Substances that had been in free trade or sold as nutrition supplements were called “Old Dietary Ingredients” (ODIs) that were grandfathered in as safe and did not require, at the time, extensive testing of toxicology or safety because they were assumed to be safe. That gave birth to the emergence of the new nutritional supplement industry guideline and regulatory framework surrounding not disease claims, but rather structure/function claims, where you could promote a specific product that was useful for the promotion and support of particular types of structure and implied function in the organism. This would be things like: “Product X is known to support proper immune function, or proper bone function, or proper brain function, or nervous system function.”   Many Discoveries Have Taken Place Since 1994 and the FDA is Reviewing DSHEA Now with that as a context, what has occurred over these many years since 1994 is a change in the understanding of the role that these substances have within biological systems. We have also seen a change in the number of substances that are now known to be biological response modifiers. This discovery work has proceeded at a very, very rapid rate—as I said, exponentially—so the number of citations around new ingredients that are found as biosynthesized substances within plants and animals has increased dramatically. Also, the clinical proof of safety and effectiveness for many of these ingredients has increased in human studies as well. We’ve seen a changing of the architecture of the environment as it relates to these products that are derived out of foods, and spices, and other natural products, including things like traditional Chinese medicinals, or Indian Ayurvedic therapeutics, or Brazilian rainforest medicines, or traditional Native American medicines, like Echinacea, that have bioactive ingredients within the constituents of these complex mixtures, and how that then ultimately fits within this regulatory framework as described through the 1994 DSHEA.   We have seen many new dietary ingredients emerge on the marketplace that are now in commerce as part of the therapeutic goods available to the consumer. The FDA has just recently—in 2011—said, “You know, we need to go back and take a look—a hard relook—at how we’re actually regulating the provisions of the DSHEA, particularly this New Dietary Ingredient convention, and ask ‘Are we making sure that we’re doing the proper oversight at the FDA level to provide proper protection for the consumer as it relates to the safety of these products?’”  That changing regulatory environment is part of what ultimately shapes the products that are available, the things that can be said about them, who controls their manufacture, marketing, and distribution, and how that ultimately could influence patient management with a complex array of bioactive ingredients that are derived out of natural products.   Lovaza is a Fish Oil Product that has become a Blockbuster Drug With that said, let me go back to the fish oil story. Once again, I think it is instructive in helping us to understand how that translates or maps against the overall changing of the architecture of this regulatory framework and the available products. So what’s happened, over the last couple of years, is a certain product called Omacor, which was a fish oil supplement, went through clinical trial work and regulatory oversight as an investigational new drug for the management of triglycerides in patients that have elevated triglycerides, into an FDA-approved formulation of fish oils, which was then purchased by one of the world’s largest pharmaceutical companies, GlaxoSmithKline, and rebranded as Lovaza, which is a therapeutic fish oil specifically designed (or let’s call it “labeled”) to treat a medical condition called high blood triglycerides, or hypertriglyceridemia. This product then became a number-one-selling fish oil product. Generating over a billion dollars of revenue, it would be considered, in the context of the pharmaceutical world, to be a blockbuster drug. It is said that a blockbuster category in the pharmaceutical world is a product that sells a billion dollars or more annually. This fish oil product became the first, really, nutritional supplement to become a blockbuster drug in the pharmaceutical world as Lovaza. As such, this product also, on formulary, was able to command insurance reimbursement as a tier 2 or tier 3 drug, and therefore it had a fairly high co-pay, but it was still considered “insurance reimbursed” for a medical condition called hypertriglyceridemia.   I think that this is a very, very important historical perspective that we need to be mindful of as it relates to the changing environment today within health care and how it affects functional medicine, which uses lifestyle medicine as one of its key therapeutic intervention tools. As you probably recognize, the translation of the fish oil story, or the omega-3 fatty acid story, from the 70s into Lovaza is a very interesting path of evolving science, evolving understanding, evolving consumer recognition, and then evolving commercialization ultimately into a proprietary product that has regulatory oversight as a pharmaceutical-like product.   Will We See More Lovaza-like Transformations in the Future? With that in mind, one might ask the question: Does that then set the tone for what we are going to see happen in terms of nutritional therapeutics, or these bioactive ingredients from food and natural products that will occur in the years to come? Will we see more of the Lovaza-like transformations in which something that emerges out of kind of a consumer product application in the nutritional supplement field ultimately becomes codified as a drug for specific clinical indication, and regulated by a different framework of the Food, Drug, and Cosmetic Act, no longer as a nutritional supplement, but more as a pharmaceutical intervention tool? And if so, what are the other ingredients or materials that might make this transformation, and how does it color the future of the availability of products and claims that can be made for these products within the field of nutritional intervention/nutritional prophylaxis and therapeutics? I find this a very important discussion if we start asking the questions such as how does medicine incorporate nutrition, and how does it get reimbursed, and how does it get incorporated into formularies, and where are the points of distribution for these products? This becomes part of a medical systems question as we are moving to recognize that our present is not really effective in beating back the rising tide of chronic illness. We need a different solution to the problem and we’ve been speaking to this extensively for years in Functional Medicine Update, with the interviews we’ve had with clinicians and researchers talking about different ways of approaching this. Halsted Holman, from Stanford,particularly did an eloquent job of sharing with us his views about the need for a new clinical education, and more patient involvement, and patient-centered medicine, and how that can be incorporated within a distributive medical system that is less involved with hospital care and more involved with self care.   I think all of these are points on a curve that are painting a picture of where medicine will go to try to more effectively and cost-efficiently deal with the rising tide of chronic disease. We recognize that 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} or more of these conditions that we see as burdening the global community with the rising tide of disease are lifestyle-related illnesses. That’s not revelation; that’s become an absolutely understood fact: that these lifestyle-related illnesses constite the major burdens on our healthcare delivery systems globally. Therefore, lifestyle solutions are needed for lifestyle-related medical problems, and we recognize that as part of lifestyle, nutrition plays an important role. It is not the be all and end all, but it is certainly a major component of what we consider lifestyle modifiers of physiological function that translates into disturbed metabolism and ultimately into disease. Functional impairments in physiology that occur from altered lifestyle translate later into discrete disease diagnoses.   What’s the length of time for the trajectory to go from a functional disturbance ultimately to a disease? We could argue about that based upon the genetic uniqueness of the person and the degree of the strength of the signal of the disturbed metabolism, but I think that we would all agree that ultimately these conditions move forward in the trajectory towards increasing severity and increasing pathology, in which eventually a very clear diagnosis of a disease will result. The functional decrements of changes or disturbances are the early stage signs of the shifting of the sands that ultimately will give rise to the need for expensive hospitalization and medical intervention. The variables for the modification of that trajectory are therefore lifestyle-related. They are not drug-related, they are lifestyle-related. The question is: What role do bioactive ingredients within our foods play in determining the trajectory towards a chronic disease that becomes an acute disease, and how do you modify those signals by modifying those bioactive ingredients in the food or in the therapeutic intervention in such a way as to change the course of altered function and renormalize homeostasis of health.   Now we come to the regulatory framework in which these concepts are embedded. How does it get codified into standard of practice? How does it get codified into the regulation of prophylactic or therapeutic goods? How does it get trained and taught and ultimately implemented? What is the degree to which patients understand this and can actually make use of these concepts and have availability of the appropriate personalized agents that are necessary for restoration of proper function in states of disturbed metabolism that are individual to that patient’s own unique state of health and genotype?   Those are very philosophically high-brow questions, but they really translate daily into how a healthcare practitioner speaks to their patients in that intimate moment within the exam room. The fish oil example is really a very important case history of a more general sense or discussion as to where we are going to go and what’s going to be happening over the years to come. With that in mind, let’s take a little window or a snapshot of the therapeutic category called medical foods.   The Medical Food Concept We’re going to talk about medical foods with our key expert today. I think the medical food concept was born out of the recognition of genetic metabolism diseases of infancy and the need for specific formulations for children born with unique requirements. Of course, the one that comes to mind immediately is fetal ketonuria, in which if you fed the infant the diet that is rich in the amino acid phenylalanine in the protein, that would then induce, as a consequence of the genetic imperfection and the metabolism of phenylalanine, phenylalanine toxicity, which then would translate into retardation and early death. But if you feed these infants a defined food that has a protein constitution that is limited in phenylalanine, now you have avoided this metabolic block in their genetic programming, and as a consequence they do not have the build up of the toxic metabolites and they can lead a fairly normal developmental pattern in life. So that defines a medical food for this genetic metabolism disorder of infancy . It’s a protein-like formula that is devoid of phenylalanine as one of the essential amino acids. In fact, it would have tyrosine in its place as the downstream metabolite of phenylalanine by an enzyme called phenylalanine hydroxylase, which by the way, is the enzyme that is genetically altered in children that have PKU syndrome; they can’t convert phenylalanine to tyrosine as effectively as a consequence of the altered genetic programming for the synthesis of the enzyme, phenylalanine hydroxylase.   This condition gave birth to the concept of foods for special dietary purposes (or therapeutic foods), and ultimately, then, a definition for medical food, which is a food formulated to be consumed or administered enterally (that means by mouth) under the supervision of a physician and which is intended for the specific dietary management of a disease or condition. I want to emphasize: It is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements based on recognized scientific principles are established by evaluating the patient medically.   So that’s the definition of a medical food as contrasted to a dietary supplement, a nutritional therapeutic, or a functional food, or a food with National Food Labeling and Education Act health claims associated with it. This is to be prescribed by a licensed healthcare practitioner, and administered under the oversight and care for specific nutritional needs as exemplified by this disease condition or health state.   I think now the question is: Once you have this category, how does it get differentiated in terms of its proof of concept from that of a traditional food or a dietary supplement? We’re going to be talking about this at greater length, but one of the things that we recognize is that it requires some degree of clinical testing to demonstrate its proof of concept, that it is, in fact, a therapeutic food for that specific medical condition that will produce measurable outcome for that condition that is positive and it meets the specific nutritional needs of that medical condition or diagnosis. This is an interesting category that has remained, I think, over the last 20 years, a category not really well understood either by the medical field nor the healthcare consumer. Food is considered to be kind of like energy. It is considered to be something you eat for hedonic pleasure. It has something to do with satiety. It’s not something that you would think is a medical component of your daily environment. But what has happened—again using fish oils as the example—is over the last several decades we started to recognize that there are these bioactive ingredients that are found in foods that have therapeutic benefit in specific demonstrated need for the remediation or the support of people in specific disease states. These bioactive ingredients, like the use of omega-3 EPA for the treatment of hypertriglyceridemia can, in fact, be used therapeutically, and therefore they have more of a “medical” application.   More Rigorous Standards for Medical Foods In order for medical foods to have a medical application and be proven safe and effective, however, they have to be subjected to a higher standard of identity for clinical proof of concept, so they have to go through a more rigorous safety evaluation. These are things that are done through what we call Generally-Regarded-As-Safe-types of evaluations (or GRAS evaluations). They have to be put through certain kinds of clinical studies on that formulation that demonstrate clinical outcome in people with that disease state that are positive, that are better than they would have gotten from a normal ad lib diet, so it has a higher evidentiary standard, somewhere in between food and drug, for their support.   I think this is a very, very important chapter in our evolving understanding of the regulatory framework, of the technology that relates to lifestyle medicine principles such as diet and nutrition, and how these ultimately influence an outcome—the trajectory, in this case—of health and/or disease. So where are we going to go in this discussion? I think where we are going to go is to try to get you to understand why “an apple a day keeps the doctor away” has some interesting historical evidence as it relates to the complex ingredients within an apple: things like pectin, things like polyphenols, things like various vitamins that participate in functional support of an individual.   If you say, “Well, what’s the difference between an apple a day and prevention versus an apple or twenty for therapeutics?” That’s the difference between a good diet and a medical food. I’m using this as kind of an analogy, so one might consider concentrating specific principles out of that apple into a formulation that would be considered to contain GRAS (generally regarded as safe) ingredients for the specific nutritional needs of individuals in a specific disease state, and then you have to put that to a clinical test, so it might become a bushel of apples a day (again, I’m using that in kind of as an exaggerated example) for therapeutic remediation of a specific disease state. Or you might consider this other example that I used, which is “builds strong bodies.” That claim was for Wonder Bread, which we would now laugh at, wouldn’t we, to think that white bread enriched with a few vitamins helps build strong bodies? Taking that from the ridiculous to the more serious, you might say: How do you build a strong, effective physiology—a functional physiology—in an individual that has a specific disease state as a consequence of something like insulin resistance that appears ultimately as metabolic syndrome, or type 2 diabetes, or a condition of autoimmune disease, or of gluten enteropathy, in which maybe a gluten-free diet is required therapeutically to manage their specific genetic personal need to support proper physiology?   All of these are defining, really, the framing of nutrition and medicine. It is that controversy, that confusion, that regulatory ambiguity, and that degree of rising discovery—exponential understanding of the bioactives in food—that is creating the landscape of today and how that will ultimately see itself in the recommendations of health practitioners to their patients for specific therapeutic agents, not just nutritional supplements, but agents that actually modify the trajectory in that individual patient’s situation toward proper physiological function and away from disturbed metabolism.   With the interview that is coming up next, we’re going to take a very, very good snapshot of the regulatory framework of these goods: where they are going, how they are viewed by the Food and Drug Administration and Federal Trade Commission, and how that ultimately may shape, in 2012 and beyond, the therapeutic pharmacopeia that is available for intervention in patient management. With that, let’s move to our key opinion leader of the month.

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THE INTERVIEW

Expert of the Month

Susan Brienza, PhD, Esq

Ryley, Carlock, & Applewhite

JB:          You all know how much I look forward—and hopefully you as well—to this portion of our monthly Functional Medicine Update, which we have called the “Clinician” or “Researcher” of the month focus. You’re going to be very privileged because this is the first time in 30 years that we’ve ever had a professional in this specific area of expertise on Functional Medicine Update. Our expert this month is Ms. Susan Brienza, who is an attorney.   Let me say something about why Functional Medicine Update would have an attorney, and specifically Ms. Brienza, as our expert. You can probably recognize that we live within this complex social milieu where things are interconnected and very, sometimes, what I would call like a multi-headed-hydra—almost like a network that is sitting behind the scenes but becomes a web that regulates activities, behaviors, and beliefs. Certainly that is the case in the very complex area of health, health products, and medicine. The regulations that underpin much of the activity that relates to licensure, and standard of care, and therapeutic goods is regulated by the Food and Drug Administration, as we all know, and it is interfaced in the United States with regulatory agencies of comparable responsibilities elsewhere in the world. There is a global interface of these standards of behavior in policies and procedures.   This area of natural medicine, functional medicine, integrative medicine, and therapeutic goods that come from natural products has been one of those very complex and sometimes hard to pinpoint regulatory functions of the government. As we know, we have the Office of Food and Drugs, but this blurring of the lines between foods and drugs has been obviously apparent as the science has emerged to recognize that drugs and foods actually travel through the same pathways of physiology and influence the same biology. We don’t have pathways for drugs in the body and pathways for natural products and orthomoleculars in the body; they all share the same type of biology, just with different mechanisms of action often.   The blurring of the lines between what would be considered food and what would be considered a drug has really occurred as a consequence of change in our biological understanding of physiology and biological response modifiers. It is because of that context that I thought it would be very helpful to have an expert in this field, which Ms. Brienza represents, to help guide us through where we are in 2011, moving into 2012. I can’t think of anyone that is better prepared to share some of these concepts with us.   Let me just give you a quick thumbnail of the interesting personality you’re going be hearing from. Susan has a background in literature, actually. She was a university professor in the area of 20th century American and British literature, a PhD-level activity at the University of Pennsylvania.  I’m convinced, knowing her now (I didn’t know her at the time she was a professor), that she was a highly valued instructor because of her eloquence, and her academic rigor, and just her personal style. I bet she was a loved professor.   And then she had an opportunity to do jury duty. Many of us have had that opportunity, but in her case I think it influenced her in a much different way, probably, than most of us who do jury duty. She ended up in an interesting trial. She really was taken to this and found it extraordinarily interesting. It hit both an intellectual and professional chord for her, so much that she ultimately made the decision that she would give up her university professorship and go back to law school after the age of 40. She successfully completed law school at Stanford, and then went into the kind of law that we’re going to be discussing today that is engaged in the oversight and regulation of therapeutic goods, particularly now focusing on natural products and the medical foods/functional foods, and nutritional supplement categories.   So it is a very interesting history, and a very interesting series of background experiences that Ms. Brienza brings to how she would contextualize some of the things that are going on in our field today. Having had the privilege of working with her in a recent workshop on medical foods that we produced at the World Health Forum at Harvard Medical School earlier this year, I was very, very struck by her insight, her expertise, and really broad range of understanding of this field.   So with that as a context, you’re in store for hearing from an individual who I think has a unique perspective on this whole area, which influences, as you know, everything we do. It ultimately attaches itself to guidelines, regulations, and the law, and translates into activities at the patient bedside. Susan, it really is wonderful to have you as our guest authority here on Functional Medicine Update.   SB:          Thank you, Dr. Bland, for that introduction.   JB:          I think the place we might want to start is how did you take this interesting history that I just kind of superficially summarized and translate it into a focus on the whole area of dietary supplements, natural products, and ultimately the legal implications of those?   Litigation Work Led to a Focus on FDA Law SB:          In my legal practice I worked as a litigator (trial law) for five years, and some of the cases there involved a failure to warn the consumer. That was one link. Also, the jury duty that you mentioned. One of the trials that I was a juror for was a product liability case, and it had to do with the defendant not using the state-of-the-art science in a particular glass container, so that segued into my interest in science. And then five years into my legal career I got a position at Patton Boggs in FDA law, and at that time there were several lawsuits pending, as you probably remember (this was 1997)—lawsuits against dietary supplement marketers making diet pills with ephedra in them. There is a very checkered history of ephedra, both scientifically and in terms of the FDA, and as we all know, eventually in 2004 ephedra-containing supplements were banned. So my first legal project was actually a merger of litigation and FDA law with those ephedra cases.   JB:          That’s a great way to cut your teeth in this field. That was certainly a very intense period of time.  And now you are at Ryley, Carlock, and Applewhite, so I presume that you’ve taken your Patton Boggs experience and now moved it over, maybe, into a really interesting time and place in the history of this whole regulatory framework, which is what the Dietary Supplement and Health Education Act (DSHEA) will look like in its interpretation in the 21stcentury. Maybe you could tell us a little bit about it.   The Potential Impact of the New Dietary Ingredient (NDI) Draft Guidance   SB:          Yes, I continue my practice in FDA law and also advertising law. Of course, the FTC has joint jurisdiction with the FDA in regulation of both dietary supplements and medical foods. You are absolutely correct that this is an interesting juncture—a very challenging time—some would say a crisis point in the supplement industry, and of course I’m referring to the NDI draft guidance, for which comments from the industry are due tomorrow. This NDI guidance really could impact 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the supplement industry and that statistic came from the Nutrition Business Journal. So it’s really quite an important development. In my mind, and in the minds of other attorneys, and trade associations, and commenters in the field, this new NDI guidance provides new definitions of what a new dietary ingredient is, what even grandfathered-in dietary ingredients are, and essentially seeks to rewrite not just Section 4 and Section 8 of the Dietary Health and Supplement Education Act (DSHEA), but even Section 3, which is the very definition of a dietary supplement.   JB:          For our listeners who may not be quite as understanding of the history here, let me just help us define some terms. Within the DSHEA, the 1994-95 act that set up the regulatory framework for dietary supplements, there were categories called “Old Dietary Ingredients” (or “ODIs”) and “New Dietary Ingredients” (or “NDIs”). Maybe you can just differentiate those two for our listeners so we understand how they—in the law—were set up.   Explanation of the Current FDA Guidelines SB:          Sure. Old dietary ingredients are also called “grandfathered in” ingredients, meaning that any dietary ingredients in dietary supplements that were on the market before October 15th of 1994, which was the date of passage or enactment of DSHEA (the statute), were called “grandfathered in” and they were presumed to be safe. This is in a very famous Senate report that led up to the passage of DSHEA. All supplements are presumed to be safe unless they are new, and there’s a certain logic to that: “New” meaning that they were on the market only after October 15th of 1994. For a new dietary ingredient, the FDA requires—and this is under Section 8 of DSHEA—a notification (and we want to keep in mind not preapproval, not pre-market approval as you would have for a drug). It was meant to be a simple notification, 75 days before market, where the manufacturer or the distributor (and this could be the manufacturer of the supplement or the supplier of the ingredient) would send to the FDA a packet of safety materials that would show that the new supplement containing the New Dietary Ingredient (NDI) would be reasonably expected to be safe. I want to point out that that safety standard, as you know, is a lower standard than Generally Recognized As Safe (GRAS). It is also a lower standard than the Food Additives Petition that requires a reasonable certainty of safety among experts. So it was an important victory of the industry in passing DSHEA: 1) supplements were presumed to be safe, and 2) dietary ingredients were exempted from the GRAS requirement and the food additive requirement and that new dietary ingredients were held simply to this lower standard of reasonable expectation of safety (again, pursuant to Section 8 of DSHEA). But all of that is about to change if this new NDI draft guidance should become the final guidance.   JB:          Before we get into some of the subtleties of the difference among food additive categories, GRAS, drugs, and dietary supplements, could you tell us what the proposed guidelines, if they were enacted, would mean for anything that would be considered an NDI? What would change under those new proposed regulations?   Explanation of Proposed Changes SB:          Certainly. Several important changes. Number one is the NDI guidance is requiring much more documentation to prove that an old dietary ingredient is in fact grandfathered in—much more documentation of records of, for example, invoices and certificates of analysis pre-1994, which of course are records that most people do not have. The director of dietary supplement programs specifically has said in numerous seminars and webinars that the trade association lists of grandfathered ingredients will not be credited at all, and therefore much more documentation will be needed. That’s number one.   Next, the FDA, with this draft guidance, is saying that any new formulation, even of older ingredients, if it is some newer combination of even standard vitamins and minerals—let’s say a children’s multivitamin—that will be considered an NDI requiring a notification.   Another very basic change is if an older dietary ingredient will be processed using a slightly different manufacturing process, or extracted using a different solvent (that sort of thing), that will be considered an NDI, and then this notification requirement will kick in. And for the notification the FDA is now requiring a much higher level of science in terms of detailed toxicology tests, carcinogenic tests—just way beyond more traditional animal studies. That’s why I indicated that the tests and studies now required are more like for a food additive petition or a GRAS petition. Just as one example, instead of something like an LD50 test, the FDA is requiring that your new dietary ingredient be safe at twenty thousand times the normal serving size. So it is a very, very high level of restriction, which some people are convinced have been the requirements, kind of behind the scenes, in the FDA’s evaluation of NDI notifications during the intervening 17 years, we just haven’t known about it. As you probably know, the percentage rate for the pass/fail rate is about 50-50 at best, meaning that most NDI notifications are not successful the first time around. Sometimes they are accepted on the second try.   JB:          Yes, I think that’s a very good overview for our listeners. I think that one of the takeaways that people are thinking about as they are listening to this (the way you are describing it) is in complex formulations, such as traditional Chinese medicinals, or Ayurvedic formulations, where there may be multiple ingredients from different plant sources that are all put together, the imposition of this kind of a new interpretation of an NDI and the regulation as it relates to proof of safety under the terms of this proposed rule-making sounds like it would make these types of products extraordinarily difficult to pass muster under this higher level of scrutiny, and would certainly be a tremendous financial burden to the industry to go through each one of these formulations with the kind of rigor that we’re talking about in terms of new toxicological methodologies, further proving the proof of safety. It sounds like this would be very cumbersome, very expensive, and probably would end up—under the terms of these guidelines—in many products being unavailable.   Costs to Meet New Standards Could Be Exceptionally High for Supplement Manufacturers SB:          That is exactly correct and I like your example of the Chinese herbal formulas. One of my clients has a traditional Chinese herbal formula for a supplement with over 20 different ingredients, and all of these ingredients, of course, have been used in China for centuries. But under the new NDI guidance, if that particular collection of the 20-plus herbs was not on the market in precisely the same formulation pre-1994, it suddenly becomes an NDI requiring a notification. And you are right about the cost of all of these tests and studies that are now required under the guidance also. There has been one computation by an economic expert retained by Jonathan Emord, who of course is the famous (almost infamous, to the FDA) litigator and regulatory attorney. It was Jonathan Emord, just as a footnote, who has won six or seven famous federal cases against the agency, including the famous case in which the court required the FDA to permit qualified health claims, such as “Some studies show that walnuts may reduce the risk of heart disease.” Jonathan Emord, in representing the Alliance for Natural Health, actually retained an economic expert, I believe from Emory University, and she reviewed the draft guidance very carefully and estimated that it would be up to over a million dollars for every single NDI notification, and under the new guidance some companies would have close to 100 NDIs (so-called NDIs).[3]

JB:          Yes, I think we’re starting to recognize that this is a major potential change in the implication to the industry that supports natural products for both prevention and therapy. I guess we’re going to have to stay closely tuned to watch how this plays out. Certainly this won’t be a knee-jerk decision. There will be—I would hope—adequate time for spar and parry on this and that rationality will prevail. But I think it is important for our listeners to recognize that this is a very important changing landscape that is not occurring only in the United States. This is interfacing global regulatory change in the review of safety-related questions or issues pertaining to dietary supplements. It occurs in Europe. It occurs in Australasia. It seems to be a very interesting change of the tide.   SB:          Yes, you’re correct, both in safety and efficacy. I believe the latest development in Europe is that the EU organization is getting tougher on permitting various health claims.   JB:          Obviously we could spend—and you do spend—hundreds of hours on this topic, but let’s shift over to a category that is also regulated by the FDA, that really relates very closely to probably many of our listeners who are practitioners that are treating patients with various illnesses and are using lifestyle medicine/nutritional medicine as maybe a component of their practice. This category is called medical foods, which is not directly under the DSHEA; it’s a separate category. It has a different history, coming out of the F.D. & C. regulations, and it had, also, its own changing domain in the 2011 year. Maybe you can tell us a little about where medical foods came from and how does it differentiate itself from dietary supplements?   More Detailed Explanation of the Medical Foods Category SB:          That’s a huge question, but I’ll start by saying that in some ways “medical foods” (the name itself) is a type of misnomer and is very confusing to many people, even to MDs. One way to think about a medical food is that in terms of nutrition science and in terms of regulatory law it is almost precisely in the middle between a dietary supplement and a prescription drug, and I can talk more about that in a few minutes. The “medical” in medical food has to do with the medical purpose of the product, and the “food” has to do with the fact that these are all food-based ingredients. So most of the ingredients in a medical food would be the same ingredients that you would find in a dietary supplement—vitamins, minerals, amino acids, botanicals—but they are in a different formulation and very often in greater amounts. The most critical difference, though, between a medical food and a dietary supplement is that a medical food is used for the dietary management of a particular disease or abnormal condition. That’s its intended use. So, in that sense, not only may you make a claim having to do with a disease (in this case, though, dietary management, not treatment, of that disease), but you actually must make that sort of claim (“For the dietary management of X abnormal condition”) or the product would not be considered a medical food. Of course, as you and your listeners know very well, for a dietary supplement you may not make a disease claim or a drug claim of any sort, but simply a structure/function claim. So those are the key differences. JB:          So it would sound, from the way that you have described a medical food, that it has kind of a higher authority associated with it as it relates to intended use, in this case a therapeutic use for a specific medical condition. I guess the question our listeners would have is whether maybe all dietary supplements should be labeling themselves as medical foods and get around these NDI new proposed guidelines, but there are some things that I guess we need to know about as to why there is a differentiation in labeling between a medical food. Maybe you can help us to understand the difference between a dietary supplement and medical food as it relates to proof of safety and efficacy.   SB:          Sure, and it is not a simple matter of merely changing the label, changing the statement of identity from dietary supplement over to medical food and then you are suddenly permitted to make dietary management of disease claims. First of all, the medical food is not exempted from the GRAS requirements as are dietary ingredients for a supplement, so all of the ingredients in your formulation for a medical food must have either GRAS status or must be an approved food additive. But you are also right, Dr. Bland, in your suggestion that clinical trials are in essence required for medial foods, whereas they are not for dietary supplements under current law.   JB:          I think that’s a very, very important point of differentiation. It’s interesting—you and I had some discussions when we were back in Boston at the World Health Forum talking about the medical food category, in which we both were commenting about, in dietary supplements/nutritional supplements, because there is no direct claim that is allowed for therapeutic intervention, then the question of safety and efficacy becomes a very interesting question because you could prove safety, but if you can’t make a therapeutic claim then you assume it has no efficacy because you can’t say anything about it. When you look at risk/benefit, risk is a safety parameter and benefit is a therapeutic value kind of benefit, and if you assume that it has no ability to have a therapeutic benefit then the risk/benefit equation becomes entirely focused on risk with no benefit. And now you have to have something that is as safe as water to have value. These are very interesting regulatory sticky wickets, I think, as it relates to how you actually would use a natural product in a medical application, and this proof of safety and efficacy as a medical food appears to me to be much more in line with where most doctors might be applying a nutritional therapeutic versus a nutritional supplement. I’m kind of generalizing here, but maybe you want to comment from your perspective on that.   SB:          Okay, in the case of both medical foods and dietary supplements, showing both safety and efficacy is the responsibility of the manufacturer or marketer. I’m switching now to efficacy. A dietary supplement claim is in the form of a structure/function claim, something like “Green tea extract helps support the immune system.” That is an efficacy claim even though it is not a therapeutic claim, and under both the FDA and the FTC (for advertising), that claim must be supported by—and here’s the standard from the FTC—“competent and reliable scientific evidence.” But the key difference between the two types of products (medical foods and supplements) is that for supplements, traditionally (and this is still permitted under current law) the manufacturer or marketer may use for scientific support what some people call “borrowed science,” simply the existing scientific literature, even existing scientific studies done by someone else or some other company, as to each of your individual ingredients. And there is no requirement—again under current law, but this could change in the coming years—to have a clinical trial on the precise formula in your current dietary supplement products.   Dr. Bland, you are exactly right, there is no DSHEA, there is no set regulatory schema, with detailed regulations for medical foods, so there are a lot of legal judgment calls that need to be made. But from the existing documents, which include a guidance document and a few others, and from some warning letters to medical foods companies who have had some violations, it is fairly clear that the formula itself must be the subject of clinical trials to show that your particular medical food really does have therapeutic value for the endpoints of the disease for which you are claiming dietary management.   How Does a Therapeutic Claim Differ from a Structure/Function Claim? JB:          I know we’re now into the deep morass of medicolegal technology, and languaging, and interpretation, but if we start looking at what is considered a therapeutic claim, as I recall it was a very broad definition of intent to treat, manage, or even prevent a disease, so you get into does prevention claims also lop over into what are considered therapeutic claims, or is it just in the treatment of a disease in and of itself?   SB:          That is a great question. I think what you are referring to in your series of words there is one of the legal definitions of a drug. So here what we need to do is distinguish between a medical food and a drug. Even though in a 2007 short guidance document the FDA does say (and in the one regulation the FDA does provide) that a medical food has therapeutic value, it can be only in the form of dietary management of the particular disease. Now let me give a specific example here because I think it will be clearer. I’m thinking of osteoporosis or osteopenia, which certainly meets the threshold issue for a medical food, and that is: “Is this a disease that is characterized by a distinctive nutritional requirement?” The answer of course is yes. Someone with osteoporosis is missing the particular nutrients in their body that are absolutely essential for bone growth, not just maintaining bone, but growing the bone. So that medical food must have good evidence that it is therapeutic for the dietary management of the disease, not that it cures it, not that it prevents it. And in fact, there are at least three warning letters sent to medical foods marketers in which the FDA objects to improper claims for the product that either state or imply that the product will actually prevent a disease. So the only types of products that can make a disease prevention claim are drugs, or interestingly enough there is a certain type of prevention claim that may be made for foods and for dietary supplements, but it is only under the rubric of the preapproved health claim (the authorized health claim). I can give an example here, too. Of course a classic health claim would be: “Calcium may reduce the risk of osteoporosis.” That’s a claim that can be on your milk carton or on a calcium supplement. But ironically enough (or maybe logically enough), a medical food for the dietary management of osteoporosis may not claim “prevents” osteoporosis or even prevents osteopenia.   You might remember there was a famous case about five years ago where about 26 marketers of cherry juice (cherry products, but primarily cherry juice) received warnings from the FDA saying: “You may not make a health claim about ‘Cherry juice may reduce your risk of cancer’ because that is not an authorized health claim that has been preapproved by the FDA.” Same thing in the POM Wonderful case, where the POM Wonderful company was making claims about how pomegranate juice or pomegranate supplements may reduce the risk of prostate cancer or breast cancer. The FDA, and actually the FTC in this case, prosecuted that particular violation and said there is no authorized health claim. There may have been some pretty good science, but not significant scientific agreement, so there is no health claim on which you can base this prevention of cancer claim.   JB:          Well, I can see that you have job security for the next several decades.   SB:          The more complex the better for me!   JB:          Let me, if I can, kind of distill down to maybe a couple of sound bytes. I always worry when I try to do this that I have inappropriately distilled, but let me try this on you. Given that our listeners are practitioners in the main and they are asking, “Okay, this is obviously very confusing and I’m probably not going to go back to law school so it’s going to get figured out by people like Ms. Brienza, who have a lot more knowledge than I, but what does this mean for me in my practice?” It would seem, from the way that I’m listening to this interpretation, and the changing playing fields of the NDIs and so forth, that for a practitioner who is managing a specific disease state, that if their products are labeled correctly (that means assuming that the manufacturers of those products have fulfilled the intention of the law), that a medical food product, which requires clinical studies on that condition with that product looking at what would be considered acceptable endpoints, would be a product that would have a history of therapeutic application to that condition and also a history of safety given that it had to have GRAS ingredients, which is a higher standard of identity for proof of safety, and therefore a medical food product would be a category, if properly labeled, that would more align itself to a physician’s needs for those specific conditions. Does that seem like a reasonable interpretation?   SB:          Yes. What you said is generally true, that a medical food can certainly be part of a healthcare practitioner’s resources (it doesn’t have to be an MD)—although let me drop another footnote here, and that is another requirement for a medical food, which places it closer to the drug category, is that it is intended for patients under ongoing physician care and a medical food must be administered under a physician’s supervision. And that all makes sense given that it is for the dietary management of a particular disease characterized by a nutrient or metabolic imbalance.   Let me now not be a total legal wet blanket, as I sometimes call myself, and give your listeners some good news if they are licensed healthcare practitioners, and that is that the FDA is on record as stating categorically that the FDA does not regulate the practice of medicine. I’m sure many of your listeners have heard that. What that means essentially is that it is absolutely legal/acceptable/permitted for any healthcare practitioner to recommend, or in the case of a medical food actually prescribe, a product for “off-label” use. So that is absolutely permitted. That’s the particular physician’s or healthcare practitioner’s freedom and discretion under the practice of medicine. Now, conversely a marketer of a product may not promote it for off-label use. Take an example of a drug that has been in the news in the past couple of years. If a drug has been approved for, let’s say, uterine cancer, a marketer—a company—may not promote that particular product for breast cancer because it has not been approved for that. That would be an off-label use. But that prohibition does not apply to recommendations or prescriptions by a physician.   Functional Foods is a Category that is yet to be Defined JB:          Thank you. I think that’s very, very helpful. One of the other questions that might come up in the minds of our listeners is the differentiation between a medical food and a functional food, because we hear those terms being used now and actually some products labeled at “functional foods.” Could you give us a quick differentiation between those two categories?   SB:          Those are very different. As hazy as the medical food definition might sound, functional foods has a much broader and even hazier description. First of all it is important to note the term “functional food”—and you, Dr. Bland, may even have coined that term, I’m not sure, but  certainly “functional medicine”—but there is no such regulatory FDA category as “Functional Foods.” It is a term that the FDA is looking into because the agency certainly recognizes that functional foods of various sorts have been on the marketplace for at least 10 years, more like 15 years, really. So they are looking into whether there should be a category that would be exactly midway in between a conventional food and a dietary supplement. That’s where the agency would probably place it. Who knows what the requirements would be, but most probably they would be permitted to make some structure/function or health-type claims. The problem, I think, with the term “functional food,” which in many ways I very much like, and which, by the way, is a regulatory category in other countries such as, for example, Japan, but a functional food can mean anything from fresh blueberries, which obviously have wonderful functions and benefits for our nutritional system and for our brains, so that could be called a functional food (or tart cherries), to some sort of conventional food that has been infused with a botanical or vitamin enriched. I think you remember—I can say this since we worked together on the workshop in Boston at the World Health Forum and we seem to be in the same age group—the old commercial for Wonder Bread: “Helps Build Strong Bodies 12 Ways.” Well, that in a way is a functional food, but the FDA would call is a conventional food that is simply vitamin and mineral enriched. So you see the problem. It defies categorization.   JB:          Yes, I think that what you’re again helping me to understand and probably our listeners as well is that within this regulatory environment, which clearly has some boundary fuzziness, that it appears as if medical foods as they are presently defined does mandate a certain requirement for proof of efficacy and even safety through the GRAS ingredient provisions that might give a little bit more clearer, I guess you would call it, regulatory oversight for a doc who is managing a patient and wants to know how a product relates to safety and efficacy to the condition of interest. I think I can see now how medical foods have risen to kind of a higher standard of identity than these other areas that I think are a little descriptively ambiguous.   SB:          That is absolutely accurate, what you just said, and I do think more and more traditional MDs, not only NDs, are becoming more familiar with the category of medical foods. I was very surprised a couple of weeks ago when I saw my own primary care physician and was asking her if I could try a medical food instead of a drug and she said, “Oh yes, I’m very familiar with that product. Oh yes, their sales reps have been to visit me and are very knowledgeable about it and I’ve written many prescriptions for that product.” So I was happy to see that it is becoming more widely known.   JB:          Thank you, by the way for the time you are spending with us. This is very, very valuable and very information dense.   SB:          My pleasure.   JB:          I’d like to close with just kind of a broad brush question. In your professional activities, which span quite a wide range of different areas of application to what we have been talking about, at Ryley, Carlock, and Applewhite, I’m sure that either your clients or firms at times have asked for your professional opinion as a soothsayer, as a forecaster, as a clairvoyant: What might the landscape look like on the horizon? We all are caught with the difficulty of not knowing what the future might hold. Do you have a sense as to how this is likely to work out, the new NDI proposed rule-making, and whether this will go back to business as usual, or whether there is going to be some degree of change, and whether medical foods as a category will continue to survive as a unique category? What’s your professional assessment as to the landscape?   Probiotics Could Come to be Defined as a New Category if Changes are Implemented SB:          Some bad news about NDIs and supplements and some good news about medical foods. The bad news is another big problem with the NDI guidance which I didn’t mention earlier, and that is, as you might remember, Section 3 of DSHEA defines what a dietary supplement is, and of course it can be a vitamin, mineral, and actually a botanical, or any dietary ingredient that supplements the diet. That, of course, is where the huge and beneficial category of probiotics currently sits, and I don’t need to tell you and your listeners all of the huge benefits of probiotics. It’s a very important category of supplements. Under the NDI draft guidance, however, which of course was just issued in July, the FDA expresses grave doubts about: 1) the safety of probiotics, and also 2) whether it is a dietary ingredient at all, and states that because probiotics consist of living microorganisms, there is a chance that they should be reclassified as “Probiotics,” in other words as if they were the same as a vaccine. Of course probiotics require pre-market approval by the FDA. So that would be a huge change and that could essentially wipe out or decimate at least the probiotic supplement industry. So that is the horror story news. The good news is that I believe that medical foods, as a category, will grow and will be especially important for our baby boomer generation. I think that you and other researchers are showing more and more that up to 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of all diseases—certainly all chronic diseases—are fundamentally nutrition-based problems, or metabolic-based problems in the body. This is precisely what can be addressed via dietary management with a medical food. I think it is a wonderful window of opportunity for, say, the next five years even for companies to do good R & D and develop mew medical foods, which will be accepted, I believe, by the medical community.   JB:          I can’t tell you how much we appreciate this time spent with us. This is really, really important news to use. It sounds like we’re going through an epic period of what I think is an interesting conundrum, because we’re faced with the changes of a regulatory environment that probably could have unprecedented impact upon product suppliers/marketers at the same time that the basic understanding of the biology of natural products and how they influence physiological function is increasing exponentially. So we’re getting more and more understanding of the important role that bioactive ingredients within foods have on regulating health and disease at the same time that we’re seeing a very, very significant trend to regulate these categories with greater degrees of specificity and more requirements to manage it as if these products are drug-like in terms of proof of safety and maybe even efficacy. So it seems like that’s the inevitable pincer movement, right? We’ve got two forces that are moving that are going to change outcome as it relates to how we’ve seen the environment over the past, say, 17 years. That would be my takeaway from listening to you.   SB:          Yes, I think that’s correct. What we might see is a shrinking of the supplement market or supplements becoming more drug-like in terms of both safety and efficacy testing, and real growth in the medical foods market. Medical foods, by the way, were defined in 1988, so before DSHEA.   JB:          I want to thank you and we’re going to keep our ears to the tracks and follow your work at Ryley, Carlock, and Applewhite very closely. What a magnificent resource you represent in your experience and knowledge. Thank you so much.   SB:          Well, thank you. You were asking me terrific questions, so it brought out the best I hope.   JB:          Thank you so much.   Closing It’s my hope that through this extraordinary journey we took with Ms. Brienza that you recognize that we are at a threshold period in our evolving understanding of how to manage chronic illness and what role nutrients and nutrition will play, and how they’ll be regulated, and branded, and ultimately reimbursed for their application. This is an epic period. I mean, there is just no two ways about it. Over the next year or two, we’re going to see very remarkable change in the way that this whole category and this whole field is managed, reimbursed, described, regulated, integrated within the standards of care. I would suggest that the healthcare practitioner, in the use of medical foods and therapeutic goods that are properly labeled will have a catbird seat in implementing this new medicine and fighting back against the rising tide of chronic disease. Stay tuned. More to come on Functional Medicine Update.  

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  Bibliography [1] Lee TH, Hoover RL, Williams JD, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med. 1985;312(19):1217-1224.   [2] Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr. 1980;33(12):2657-2661.   [3] The Alliance for Natural Health. “Comments of The Alliance for Natural Health – USA.” June 3, 2011. http://www.emord.com/FDA-2011-N-0410{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20-{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Comments{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20of{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Alliance{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20for{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Natural{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20Health-USA{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}20(Aug{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}202,{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}202011).pdf

Welcome to Functional Medicine Update for January 2010. I always love starting a new year. To me, a new year is so refreshing and exciting. We’re not exactly sure what the year will bring, but we know how much can change. You can see how dramatically and rapidly the field of functional medicine is changing already: epigenetics, hormesis, gene expression, intercellular signal transduction and the connection between the outside environment and inside cellular function. All of these things can affect function of cells, organs, tissues, organ systems, and whole-body signs and symptoms. In terms of chronic, age-related, progressive disease, new research may lead to new mechanisms of both prevention and treatment. I think the term “functional medicine” will come to be seen as fairly prescient. A lot of the dysfunctions that we later call pathology start early on as dysfunctions in functional physiology (in the network of interconnectedness within the cellular milieu). Organelles are influenced and molecular signals affect gene expression and epigenetics. It is a very rich and robust time of a changing paradigm in health care. Ultimately the objective is not just to intellectually titillate us, but to really deliver more effective and safer interventions and therapies for individuals with progressive age-related diseases. It is to achieve what we have been talking about for many years, which is the concept that James Fries brought us to recognize in 1980. That is to compress morbidity, rectangularize the survival curve, and allow people to live to the limits of their biological age determinant and have a natural death (to pass on to the next level without significant years of infirmity). That is the objective, that is what a healthcare system is all about, and that is the reason functional medicine came into being: to put health into the equation of the disease-care system. Let me start 2010 by talking about another major change that is occurring within health care: the nature of pharmacotherapy. Pharmacology, over the last hundred years, has been what we call “a-pill-for-an-ill”-type concept. A single molecule (generally) is used to treat a single endpoint to produce a single disease treatment. With this model, we have statins for cholesterol, or we have SSRIs for depression, or we’ve got H2 blockers for hyperacidity and gastric reflux, or we’ve got ACE inhibitors for blood pressure, etc. This model has been fairly successful in building a very profitable and robust pharmaceutical industry, and has led to many, many tools within the Physician’s Desk Reference that are very valuable in managing crisis (managing acute illness by blocking, inhibiting, or having some antagonistic effect upon one metabolic step within this complex tree that we call intermediary metabolism). If we think of a selective serotonin reuptake inhibitor (and, similarly, HMG co-A-reductase inhibitors), it has a specific effect on an enzyme that regulates serotonin dynamics. If we assume that the effect of statins is to block that enzyme (that rate limiting step in cholesterol biosynthesis), we’re led to believe that we can block that enzyme and inhibit the production of cholesterol from the mevalonate pathway, and thereby reduce the risk and incidence of coronary heart disease. These are all “single-hit”-type of mentalities: find a very high potency and a low-IC50 (meaning the dosage required to inhibit something being very low), and that becomes a molecule of choice that is taken from phase 1 through phase 3 of the FDA investigation and approval process, and ultimately results in an approved medication for a clinical condition. This model, as I said, has been successful. It was born out of the development of a pharmacology around antibiotics early in the 20th century. Antibiotics-fungal metabolites like penicillin-are really remarkable discoveries that birthed an industry that was buoyed with enthusiasm and confidence around this pill-for-an-ill/single-hit-type of approach. Antibiotics are specifically focused on blocking a series of specific metabolic steps that are unique to bacteria, primarily those necessary for construction of their cell walls. By blocking the production of the cell wall, the bacteria are able to be a viable bacterium and this is called an antibiotic. What is unique about this chemotherapy is that humans don’t have the type of cell walls in their eukaryotic cells, and we generally call these cell membranes. For example, humans don’t have the polymer of n-acetylglucosamine and n-acetylmuramic acid, which is part of the constituency of bacterial cell walls. As a consequence, the selectivity of the antibiotic is very high for the diseases associated with certain bacterial infections, without having an effect upon the physiology of the host cell (the eukaryotic mammalian cell). It’s a wonderful pharmacological concept/paradigm that sounds so specific and so marvelous that we built a whole edifice around this that is presently our medical school education. Some Agents are Extraordinarily Useful in the Short-Term, but Long-Term Use is a Concern To a great extent, this paradigm has worked. By blocking or inhibiting certain steps in this complex web of metabolism, we are able to take charge of metabolism in a very specific way. There is no ambiguity in the emergency room when you give these drugs. They allow for the lockdown or the control of specific processes that may be deranged. The difficulty is encountered when we try extending this model to chronic illnesses, where you are blocking a specific function very efficiently over many, many years of pharmacology with a patient. The particular effect that was seen as benefit in the acute stage may have an adverse effect in the long term because in other cells you are blocking some of the fundamental positive effects that are necessary to regulate proper function. As an example of this, let’s discuss the use of things like TNF-alpha blocking agents (monoclonal antibodies) that have been developed in the generation of these new, disease-modifying anti-rheumatic agents (or DMARD drugs) that are used in rheumatology. These are extraordinarily useful in the short-term for blocking the acute pain of inflammation in arthritis. But over the long-term, the black box warning on these drugs suggests things like “Be cautious of opportunistic infections,” or maybe “Be cautious of increasing risk to lymphoma.” The reason for that is, over the long-term, by blocking TNF-alpha, which is in excess and enhancing the inflammatory response and causing joint injury and musculoskeletal injury, the drug is also is blocking some of the favorable effects that TNF-alpha has in immune defense. So the price to be paid over the long term could be increased risk to opportunistic infection or lowered surveillance of transformed cells and malignancy. These are the kinds of things that occur when you extend an acute rescue remedy (a pill-for-an-ill drug) into a chronic disease management approach. It may be that worrisome adverse drug reactions can start appearing. The classic example people often use is Vioxx. Vioxx was a wonderful, successful, high-affinity, selective COX-2-inhibiting drug that was useful for management of acute inflammatory pain. Then people began to extend use over long periods of time for chronic pain. Now this very efficient drug-highly potent-was blocking COX-2 not only where it should (in the inflamed areas of the body), but it was also blocking it in the vascular endothelium and preventing proper prostacyclin formation, which is necessary to prevent platelets from adhering and forming thrombi. Now you start to get increased thromboses and risk to stroke and heart attack in genetically susceptible individuals. These are the kinds of conditions that occur when you have very strong molecules that are very effective in the acute management of a condition that are extended into a longer term management program. What’s the alternative to that? I think that’s an interesting question. What’s the good news? The good news is there is an emerging paradigm of pharmacology called network pharmacology, which may be the next major paradigm in drug discovery and development. I think this next paradigm is reflective of what probably has gone on naturally in our environment, relative to how natural substances in our food and things that we consume have been influencing our physiology through time in memoriam. What is Network Pharmacology? What is network pharmacology? Rather than trying to develop one single molecule that has a very high affinity for a substrate, where ligand-substrate interaction then blocks the function of a particular metabolic activity through inhibition, network pharmacology is defined as a molecule that has pleiotropic effects that modulates multiple steps along the metabolic pathway associated with disturbed metabolism and diseases of that outcome, and does so in a more mild way. Rather than blocking one thing in a very tough way-a very rigid, high-affinity way-a network pharmacological approach would have the ability to influence many things that cluster together to regulate the function that is associated with that pathology, but in a more mild way each step along the road. It still allows what is called “housekeeping” function in cells or tissues or organs that you want to be maintained. By maintaining housekeeping function, you maintain the good functions of those processes. By blocking (through this network pharmacology) the high points of activated function, you attenuate that, modulate those effects, and do it in a safer way because you’re allowing the housekeeping function to be resident and still active where it is needed. I hope you understand what I just said. This is a very interesting contradiction or contrast to the way we have traditionally thought about pharmacology, which is single agent to single outcome, and finding the highest potency drug with the highest affinity for inhibiting that substrate. What we are doing in this particular model is looking for things that may have a little less activity for a substrate, but much more regulatory effect over a series of steps in that network that are distorted and associated with that specific pathology. We are still modulating the function, but not inhibiting a specific step in that function to where we start getting adverse drug reactions occurring elsewhere. It’s a very interesting concept, and has been eloquently described in a recent review article that appeared in Nature Chemical Biologyunder the title “Network Pharmacology: The Next Paradigm in Drug Discovery.”1 In this article the authors write about this dominant paradigm I’ve talked about in drug discovery: the concept of designing maximally selective ligands to act as individual drug targets to inhibit those steps in metabolism. Many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology (which is a theme that underlies that of functional medicine) are starting to reveal that there is a robustness in this network structure of metabolism strongly suggesting that exquisitely selective compounds (very strong drugs for single activities), compared with multi-target, more mild drugs, may exhibit not-so-good effects or undesired long-term clinical safety issues over years of use in a patient. This new appreciation of the role of poly-pharmacology and network pharmacology has significant implications for tackling the major issues of chronic disease management, including both safety and efficacy. We have talked about improved safety, but also efficacy may be improved by allowing attenuation of multiple steps within a group of a distorted family of metabolic steps that then regulate, overall, signs and symptoms at the whole-organism level more effectively than single-agent pharmacology. The Significance of the Kinase Pathways This is a very interesting new approach that I think is being developed. I find it very interesting because it is very similar to the way that nutrients and phytochemicals have recently been discovered to influence cell signaling and gene expression through the kinase signaling pathways. They do so by multiple hits in families of inter-related kinases, rather than just very hard hits of a single step in metabolism. That makes pretty good sense, doesn’t it, when you think of it from a teleological argument? Why would the things we eat in our foods have robust effects on multiple pathways in a milder way than single hits? Think of what would happen if we had agents in our foods that had the same pharmacology as our drugs. Every time we ate, our physiology would whipsaw all over the map and we’d be kind of a mess. Rather, we have evolved a relationship with the bioactive ingredients in our diet so that these molecules modulate function across network pharmacology to enhance or influence function in cell signaling and ultimately gene expression and epigenetics (and the phenotype of cells, tissue, organs, and organ systems over time) in a very mild way-a way that modulates their function versus therapeutically blocks function. Vitamin D as an Example of Pleiotropic Influence In 2008, Alternative Therapies published a guest editorial that I wrote titled “The Future of Nutritional Pharmacology.”2 I tried to address how we are seeing an emergence of a new understanding of nutrients, even in things like vitamin D. The vitamin D receptor signals through multiple different pathways to regulate function across a wide range of cellular physiological outcomes (not just a single hit). We often think of vitamin D as the “bone vitamin,” but now we recognize it is really a pro-hormone and it has intercellular signaling effects. It interacts with the vitamin D receptor in a very significant number of pleiotropic ways to influence function across so many different organs and that is why we now see so many signs and symptoms related to vitamin D insufficiency. Vitamin D may be a useful substance for modulating so many different disease-related entities. I think it is a different model. We are now starting to recognize this model probably has more historic implications relative to the way our physiology has been modulated over time than the pharmacology that has been developed over the last 150 years. This construct (that there are substances within our food and in our environment that can influence multiple signaling pathways and influence what we call network pharmacology) then suggests that these kinases-these some 500 different enzymes that are expressed in cells that transduce messages from outside the cell to inside the various organelles in the cell to alter cellular function-must be also modulated in a network way through natural substances, including nutrients that we find in our food (macronutrients, micronutrients, vitamins, and phytochemicals). That’s what is starting to emerge to be much more well&ndash;understood. Published articles have appeared just within the last few years on the role that various nutrients have in influencing these kinase signaling pathways through a network effect (not just a single kinase, but through families of inter-related kinases that regulate cellular function). New therapeutic agents are being developed to modulate these kinase pathways in kind of a network-sympathetic, peaceful way, turning promiscuous, heavy-hitting, kinase-inhibiting drugs that have been used in cancer therapy, for instance, into new types of therapeutic agents that are safer and that have modulating effects across networks of kinases that then regulate distortion of the net of physiology (the system of physiology). In fact, this has actually been discussed very beautifully in a recent review paper about turning the promiscuous kinase-inhibitor drugs into safer drugs by influencing positively their ability to modulate, in a more mild way, individual kinases, but across multiple kinases as polypharmacology. This article appeared in Trends in Biotechnology, and this whole construct of modulation of kinases to produce safer chronic disease management therapeutics was discussed.3 I think we are starting to see an extraordinarily interesting pharmacology develop out of these new discoveries. I was very intrigued when I saw an article in Nature Biotechnology titled “New Therapies from Old Medicines,” which is about botanical drugs-how they actually work and their potential future in developing new therapies for management of chronic disease.4 In this article, the authors write about the fact that there are multiple molecules within a botanical (it’s not a single molecule), and each individual molecule in the mixture that is extracted from those botanicals may be a weak agent relative to its ligand binding. These botanicals would normally not pass muster with a pharmacologist who might say, “Well that’s really too weak and has too high an IC50 to really be an effective drug.” But when you put them together in a family of interrelated molecules and see how they work in cellular systems, you find that they may be modulating a network of interrelated functions. Each one of the effects could be fairly minimal (or let’s say lower activity), but taken as a family of interrelated activities, they modulate the distorted web to produce improved function. In phytomedicines and phytopharmacology, this is often referred to as an adaptogenic effect. This means we are helping the cell find the right adaption to its environment and modulate function rather than just produce inhibition of a specific function. This adaptogenic quality occurs when you have therapeutic agents that have more mild activities for ligand binding and can serve, really, as almost agonist/antagonist. They have effects of both loss-of-function and gain-in-function capabilities as it relates to their activity at the active site of various target molecules. These safer drugs might actually start emerging from the pharmacology of phytomedicines and from that of nutrients that have been found in our foods, particularly colored, complex, phytonutrient-rich foods. Resveratrol is Another Molecule with Pleiotropic Influence That concept can even be taken into the recent discussion around resveratrol, which has gotten a lot of press recently. Resveratrol is a stilbene-like molecule. It has a phenolic structure. It has a capability to modulate the SIRT1 genes (the histone deacetylases) that are involved with epigenetic alteration of genomic message expression. These SIRT genes have to do with regulation of insulin and inflammation and what has often been called longevity-related functions. Resveratrol is a molecule found in foods about which we would say, “Well it has a specific action.” But with further discoveries, it has now been found to have pleiotropic effects on multiple pathways that are interrelated to distortions of physiology that we often associate with chronic disease, like hyperlipidemia, insulin-related hyperinsulinemia/insulin resistance and diabetes. There are things within foods-molecules or families of molecules-that influence cellular physiology in a different way than that of a high activity/single molecule inhibiting a single step in a physiological network to produce a single outcome (so that’s that “pill for the ill”-type mentality). These more mild molecules are regulatory molecules that have effects over longer periods of time. That construct may be very desirable and is starting to gain traction. It is staring to gain a placeholder in the mindset of pharmacology, therapeutics, and ultimately the development of a science-based new medicine Let’s talk about one of the most significant concerns people have about altered physiology over the course of their life, and that’s cognitive function, or Alzheimer’s disease, or dementia. There has been a search (a very extensive search since the decade of the brain) to try to understand neuropathologies and try to get a better mechanistic understanding of neurodegenerative diseases. Certainly tremendous strides have been made, as have been chronicled in an understanding some of the molecular pathologies associated with neurocognitive disorders, like Alzheimer’s disease, and Parkinson’s disease. What we are starting to recognize is that the principal mechanism by which these conditions occur over years of living is through interaction of genes with environment to induce altered cellular signaling, which then creates an environment in that region of the body (say the hippocampal region of the brain in Alzheimer’s disease) that induces things like neurofibrillary tangles, tau protein release, the amyloid bodies that we associate with amyloid protein deposition, and ultimately apoptosis of that neuron that leads to cell death and lowered neuronal function and neuronal reserve. Mechanisms are starting to be understood. We know about the relationship to inflammation. And we know about the relationship to oxidative stress. And, as has been discussed extensively in FMU in the past, we know about precipitating triggers that might induce some of this, things like alpha gliadin in people who are gluten sensitive. We just spent, in the summer of 2009, two issues of Functional Medicine Update going over, extensively, the role that these specific molecules in grain-related products can have–deleterious effects as neurotoxins in some individuals through activation of the immune system, and production of antibodies against various neuronal tissues, and triggering some of these processes as it relates to oxidative injury, apoptosis, and neurofibrillary tangle production. Studies on the Mediterranean Diet and Cognitive Impairment It is starting to be recognized that some of the triggers for neurocognitive degenerative diseases occur through environmental/gene interaction. As a consequence of that, studies have been published looking at dietary relationships to both Alzheimer’s disease and Parkinson’s disease. It is really quite fascinating to see these data accumulate. A paper that I think reflects this emerging understanding appeared in Annals of Neurologyand titled “Mediterranean Diet and Risk for Alzheimer’s Disease.”5 The investigators did a case-controlled evaluation over time looking at the appearance of Alzheimer’s disease in individuals who self-subscribed to consuming a Mediterranean-type diet versus those who were on kind of an ad-lib diet (more of what we might call a traditional Westernized, more highly processed, higher sugar/higher saturated fat diet). They did incidence-of-Alzheimer’s-types of evaluation over years (actually they followed these individuals for ten years), and they found a highly statistically significant difference between the rate of appearance of Alzheimer’s dementia in those that consumed the ad lib diet versus self-subscribed to the Mediterranean diet. Again, these are association studies, they are not intervention trials-I want to be very cautious that we don’t overstate the point-but the associations are quite strong between the compliance and adherence to a Mediterranean diet and the relative reduction in incidence over time (over a ten-year period of time) of Alzheimer’s disease. You might ask the question: Does this follow also for mild cognitive impairment? I’m talking about memory loss, in which a person doesn’t have Alzheimer’s, but they say, “As I’m getting older I seem to be losing my short-term memory and I just can’t pull things back as well as I used to be able to.” There is another similar study that was published that addresses this. It was also published in the Archives of Neurology -in 2009-in which the investigators looked at the relationship between those who consumed a Mediterranean diet and mild cognitive impairment.6 This is kind of your functional stages (pre-Alzheimer’s); we’re not talking about going all the way to pathology. They used standard psychometric questionnaires to evaluate cognitive function in these patients. The setting for this study was New York City, and people self-selected to be on a Mediterranean diet versus those who were on the standard American diet. What they again showed is that the higher the compliance to the Mediterranean diet, the slower the rate of cognitive impairment. What I would like to point out, is that no matter whether the person had an apo A2, 3, or 4 genotype, and no matter if they were older or younger, male or female, or Caucasian or African American or of Oriental descent, or whether they had a high education or a low education-when you take all of those variables out and just look at adherence to the Mediterranean diet versus non-Mediterranean diet, what you find is those who adhered by self-compliance to a Mediterranean diet had a much lower rate of appearance of mild cognitive impairment and also had a much lower appearance, later, of Alzheimer’s disease as shown in subsequent other studies. I think these are very interesting concepts that suggest that something is in those diets that may regulate neuronal function through intercellular signal transduction by communicating the dietary principles somehow through the neuroendocrineimmune system to the host through cellular signaling, and ultimately into physiology that is associated with cognitive impairment and later Alzheimer’s disease. One of the possible mechanisms-and I don’t want to say it’s the only mechanism, but certainly one of the possible mechanisms-has to do with the role that insulin plays in cognitive impairment, and how diet may influence insulin signaling, and how that might influence a range of diseases that are associated with cognition and neurological function. We are going to hear more in this issue from one of the world’s most well-informed investigators in this area, Dr. Suzanne Craft. This topic was reviewed very nicely in the Journal of Alzheimer’s Disease in 2009. The title of this paper is “The Alzheimer’s Disease/Diabetes Angle: Inevitable Fate of Aging or Metabolic Imbalances Limiting Successful Aging.”7 You are going to hear much more of the evidence through the pioneering work of Dr. Craft, but this paper indicates that as individuals consume different diets, it influences their cellular signaling in the neurological regions of their body to then either enhance or decrease things like inflammation, or oxidative stress, or alarm reactions that are associated with accumulation of injury to the neurological system. Studies of Hibernating Animals Provide Insight on Kinases and Phosphatases Interestingly, hibernators such as ground squirrels and hamsters demonstrate comparable annual recurrent periods of obesity with concomitant insulin resistance and key features in Alzheimer’s disease, such as tau protein phosphorylation. These pathologies, however, are reversed by a time dependent metabolic shift between carbohydrate and fat-based metabolism. This is all regulated by this delicate balance and dance of kinases and phosphatases that regulate intercellular signal transduction. As they come out of hibernation and start eating their traditional diets, this tends to clean out some of the debris that was accumulated in the nervous system during this period of hibernation in which they had temporal insulin resistance. Massive fat depots serve as the main source of metabolic fuel throughout the winter in these hibernating animals, and phosphorylation of tau protein during this hibernation process seems to be reversible. What we are starting to witness is a sense that maybe the system can move both ways We have been told that damage to our nervous system (particularly our central nervous system) is kind of irreversible. I recall the old story given to every college-age student that if you binge too much on your Friday and Saturday nights you are losing brain cells and you’re never going to get them back again. (It didn’t seem to be a deterrent, but it was a message.) Now we are starting to recognize that even alcohol-induced encephalopathies have some reversibility by getting off alcohol and utilizing nutritional support and regeneration. I think we need to be cautious about what we call “irreversible.” Some of these processes may have slow reversibility, but there are still inherent within systems this reverse capability (different cell signaling and cell regenerative possibilities). This connection of Alzheimer’s disease to diet may have something to do with insulin signaling, and insulin sensitivity, and the interrelationship that insulin signaling has to kinase regulatory pathways. These pathways go through things like SYK and Bruton’s tyrosine kinase (BTK), and ultimately through phosphatidylinositol 3 kinase (or PI3 kinase) and down in to glycogen synthase kinase 3, which regulates ultimately things like Glut 4 receptor translocation to the cell membrane and glucose transport. All of this also has to do with gene expression patterns and regulating the promoter regions of genes associated with inflammation (there’s an inflammation connection to the insulin signaling story). And that then has a role to play in neurological function and proper neurological stability. We are going to learn much more about this, as I said, from the expert, Dr. Craft. I wanted to set the context for her extraordinary work. We also recognize that there are a variety of phytochemicals that are being discovered that can reduce insulin resistance and improve insulin sensitivity through modulating specific kinases in these regulatory networks. In my own work, I have published studies now showing how a variety of phytochemicals from things like garlic, and various fractions of hops, and berberine, and cinnamon participate in modulation of regulatory networks that are associated with insulin resistance. Dr. Deanna Minich and I published an article that appeared in Nutrition Reviews that was called “Beyond Macronutrients” that speaks to this whole discovery and extraordinary increasing understanding of how phytochemicals play this role in intercellular signal transduction.8 Berberine is an interesting compound because it has been found and published (both in our work and others’) to have a very interesting influence on insulin resistance through modulation of specific kinase signaling pathways that control insulin receptor expression. One such paper was published in 2009 in the journal Metabolism Clinical and Experimental.9 Epigenetic effects can modulate insulin signaling and neuronal effects and ultimately regulate things that could induce adverse effects in production of neurological injury and neurofibrillary tangles. So things like methylation patterns can have an effect on the neurobiology of disease. This was discussed in an article in the Journal of Neurosciences about how insulin can influence things like methylation patterns of tau protein and protein phosphatases that are associated with things like homocysteine and Alzheimer’s disease.10 A complex mechanism has been established for us to understand the relationship between dietary signals and nutrients, and how that may translate into neurological function, interconnection with insulin signaling, and ultimately the appearance of cognitive function or dysfunction over years of living. This is a very new view of the potential of pharmacology-a very new view of, in fact, how these whole systems of biology fit together to create what we see at the whole organism as function. It also clearly opens up a mechanistic understanding of back to the future: how what we have learned in the past around traditional diets and complex diets with color and flavor can influence, in their natural ways, health in a positive way. We have made kind of the gross observation that minimally processed, organically grown fruits and vegetables seem to have a positive benefit on health, when we look epidemiologically. But we haven’t understood a mechanism of how that really occurs, so people have dismissed it as kind of artifact. But this mechanism of network pharmacology, and kinase signaling, and regulatory networks, and systems biology is emerging now to be the paradigm upon which will rest the understanding of how these things interrelate. There is no better person I can think of to help us understand this emerging connection, particularly as it relates to insulin and neurological function and how that interrelates with dietary signals than Dr. Suzanne Craft, who is our esteemed clinician/researcher of the month for January 2010.

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INTERVIEW TRANSCRIPT

Researcher of the Month Suzanne Craft, PhD Professor Department of Psychiatry and Behavioral Sciences University of Washington Seattle, WA 98195 Associate Director Geriatric Research, Education, and Clinical Center (S-182) VA Puget Sound Health Care System 1660 South Columbian Way Seattle, WA 98108 I’ve already given you a tip off to the fact that we are going be having a conversation with Dr. Suzanne Craft this month, but I haven’t really said much about Dr. Craft yet (I was holding that for this introduction). She received her PhD in neuropsychology at the University of Texas at Austin, and later fellowships at Boston University and Harvard Medical School specializing in behavioral neurosciences. Currently she is a Professor of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine (which we are very proud of, being here in the State of Washington), and an Associate Director of Geriatric Research, Education, and Clinical Center at the VA Hospital Puget Sound. Dr. Craft’s research team has investigated the relationship between insulin resistance and the development of cognitive impairment and dementia in older adults, which is probably one of the most important singular issues that people are concerned about. I have a mother who is in her mid-80s. When I visit with her and her friends at their retirement facility, I recognize that this seems to be the number one concern that individuals in that age group have. My mom always is very sad when one of her colleagues starts losing her cognitive function and she starts seeing them slip away. I think this topic that we are going to be discussing is a real-world topic; it’s not just a research lab intellectual enterprise. Dr. Craft has done just an extraordinary job in pioneering this field, and you’ll hear about her extraordinary work and diligence. Dr. Craft, welcome to Functional Medicine Update. It’s just a treat to have a fellow Washingtonian and a person in this field with such an esteemed background be our clinician/researcher of the month. Let me start off with my first question. I have had the privilege of reading a number of your manuscripts. I think I’ve read at least all of your papers that have been published since 1996. I would like to mention a paper you authored in 1991 in Diabetes.11 You have made this interesting connection of insulin and blood sugar and how that relates to cognitive function for a lot of years. How did you get started down this path? SC: First of all, thank you, Jeff-thanks for the invitation to be here; it’s a pleasure. I think my interest in neuroendocrinology grew out of the appreciation that changes in cognitive function with aging were closely related to glucose metabolism, I think in a couple of ways. One, of course, is the very well-established finding that patients with Alzheimer’s disease have hypometabolism in the brain. They have reduced cerebral glucose metabolism. This can be observed, actually, years before the diagnosis is made. So there is something very fundamental about the changes in glucose metabolism that occur centrally, both with respect to aging and pathological aging, such as Alzheimer’s disease. I think-as many of your audience are likely aware-the brain is unable to synthesize or store glucose, so all of the glucose that it receives for its many functions, it receives from the periphery. The question I began to wonder about was the degree to which disorders that are associated with disrupted peripheral glucose metabolism may potentially impact the CNS, in that the brain may not be able to get adequate supplies of glucose in patients who have such disorders. I think that led me to the study of conditions like diabetes and insulin resistance and how those conditions might affect brain function and cognition. JB: Recently I know that you were the recipient of what really is a very prestigious NIH award-the MERIT Award-for excellence in your aging research. I actually also caught you in the HBO documentary “The Alzheimer’s Project,” where you were a principal in describing your work. It seems like there is an interesting paradox. I think you had a paper in 1996 in the Neurobiology of Aging that was about what happened when you gave insulin to Alzheimer’s patients and it improved their memory.12 One could say,, “Now hold it. Isn’t elevated insulin associated with hyperinsulinemia, which is like type 2 diabetes and how does this work?” It seems paradoxical that increased insulin improved memory and we might think that that would be not so good for a hyperinsulinemic type 2 diabetic. Insulin Has Both Positive and Negative Effect SC: I think the story with insulin, as I describe it, is very much what I consider a “Goldilocks” story. Insulin, one of the most evolutionarily conserved of all peptides, is absolutely essential for a number of functions, and was early on best known for its critical role in promoting glucose uptake, peripherally. Removing insulin, either through a condition such as type 1 diabetes or in genetic models of insulin receptor knock-out transgenic rodent models, is lethal. So I think insulin has many beneficial roles to play. What I think is essential is the appreciation that optimal levels of insulin, in a healthy physiology, have many beneficial effects when insulin is secreted and cleared very quickly in a normal healthy individual (and I think this is the key to its positive effects). When, however, insulin is increased chronically or is increased to too great of a level, then I think negative effects begin to occur, like the ones that you mentioned, of course-the insulin resistance, where tissues become resistance to the effects of insulin (insulin can no longer carry out its normal functions in tissues), or proinflammatory effects of chronic elevations of insulin. A number of negative effects occur when insulin is too high and around for too long a time. In the studies that we conduct, we’re modeling, really, acute insulin challenges, and giving insulin acutely at a level that, again, mimics sort of its optimal effects usually has a beneficial effect on memory. JB: That is a beautiful segue into a couple of your other papers and earlier publications in which you reported insulin increasing cerebral spinal fluid (A beta 42) levels in normal older adults, and then also report-I think maybe it was even the same year in another journal-as to how those individuals who carry certain apolipoprotein E genotypes may be at higher risk to this insulin-amyloid plaque relationship. Can you tell us a little bit about that? That’s an interesting part of the evolution of the story.13,14 The Relationship Between Insulin and Beta-Amyloid SC: I think a very-as you say-interesting part of this story is the relationship between insulin and beta-amyloid, which of course is the peptide that collects in the brains of patients with Alzheimer’s disease and becomes the senile plaques, which are a histopathologic feature-in fact, a defining feature-of Alzheimer’s disease. I think it was about six or seven years ago that people began to understand that insulin and beta-amyloid have something of a reciprocal relationship, and insulin can regulate beta-amyloid in several ways, one of which is by increasing its trafficking from within the cell to outside the cell, which is where it needs to be in order to get degraded. I think the way we conceptualize our studies in which we give high levels of insulin and then we see corresponding increases of beta-amyloid in the spinal fluid, one of the hypothesized mechanisms underlying that effect is that the insulin that we’re infusing that then crosses the blood-brain barrier and enters the CNS is promoting the trafficking of beta-amyloid out into the extracellular space in the brain, which then drains, of course, into the spinal fluid. If that were the case, then one could view this as potentially a positive effect of insulin (insulin getting beta-amyloid where it needs to be to be degraded so it can’t collect into these senile plaques). And then, interestingly, the enzyme that degrades beta-amyloid (one of the enzymes) that is a key player, is insulin-degrading enzyme, which is a member of a class of metalloproteases that-as its name implies-degrades insulin, but is also responsible in the brain for degrading beta-amyloid. Insulin can affect beta-amyloid through influencing this insulin-degrading enzyme, either by competing for the attention of insulin-degrading enzyme (such that it is not able to adequately clear beta-amyloid), or by regulating levels of insulin-degrading enzyme, so insulin is needed to increase the expression and increase availability of insulin-degrading enzyme. So there is this reciprocal relationship that exists, and very recent work by Bill Klein at Northwestern has actually revealed a fascinating side to this story in that beta-amyloid appears to be able to affect insulin function through regulating where its receptors are located. When a brain cell (a neuron in the brain) is exposed to beta-amyloid, the insulin receptors move off the membrane into the cell, where they are no longer available to be stimulated by insulin. This very interesting reciprocal regulation between insulin and beta-amyloid I think we’ve observed in our human studies with the techniques that you’ve mentioned, with the insulin infusion paradigms and more recently with administering insulin intranasally to get it directly into the central nervous system. Others now are using animal models to try to look more closely at the very specific mechanisms that are underlying the effects that we are seeing in humans. JB: Can we take that to the next step, talking about the genotypic sensitivity? From your early work (“early” means 2003, in this case, which is not that early-“recent” work, let’s call it), it would appear there might be some genotypic interrelationship to some of the sensitivities, so not all genotypes are affected equally by this relationship? The Significance of Apolipoprotein E in Insulin Sensitivity SC: I think the best way to describe it is that there is the apolipoprotein E, which is a lipoprotein that is very important for lipid distribution and has been associated with cardiovascular disease for a long time, and it comes in three “flavors” (three alleles) that are designated apolipoprotein E2, 3, and 4. The apo E4 isoform produces a large increase in risk for Alzheimer’s disease, so the E4 allele is associated with between something like a two-to-five-fold increase in one’s risk for developing Alzheimer’s disease across the lifetime. What we have observed is that when you have a group of patients with Alzheimer’s disease, about 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of them will have this E4 allele. That’s a much higher percentage than in the general population. But for the other 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} who do not have the E4 allele, they have Alzheimer’s disease, but they do not have a genetic risk fact that, as of yet, has been identified. But interestingly, these patients are much more likely to have insulin resistance. The patients with Alzheimer’s disease with the E4 allele do not typically have insulin resistance or, really, a potentially greater level of insulin resistance than the normal population. The way we think about this is that there are potentially two paths to Alzheimer’s disease, and probably more than that, but two main paths that we consider, one of which is driven by the physiological processes that are associated with the E4 allele, and then the second major pathway would be driven by factors that are related to insulin resistance. JB: That is really fascinating. What comes to my mind as I’m hearing you tell that story is knowing that there is some literature (as I recall) that relates high-saturated fat diets with an apo E4 double allele with increased risk to cardiovascular disease in indications of oxidative stress or free radical oxidative injury. It would suggest that maybe there is a diet connection or diet sensitivity to certain macronutrient distributions that might cut across different disease diagnoses associated with the process you are talking about, regulated through insulin and/or other oxidative processes. SC: I think that’s a very good possibility, and the way you’ve captured it I think is exactly right. That the E4 allele is promoting dyslipidemia and oxidative stress through an E4-related mechanism that I think we are just beginning to understand, and which-also-is likely very vulnerable to the effects of saturated fat in the diet. And analogously, insulin resistance is driving that same pathway, but through potentially other mechanisms that are also vulnerable to dietary influences, so the final common pathway may be these convergent dyslipidemia/oxidative stress effects that interact with beta-amyloid to produce the Alzheimer’s pathophysiology, and for one segment of patients they are getting to it through E4, and the other set are getting to it through whatever factors are predisposing them to insulin resistance. JB: Thank you. That really lines up so consistently with the message that we have been trying to communicate in Functional Medicine Update for many years: that these chronic age-related diseases are not monozygotic diseases. They are polygenic, and there are many different determinants, and to think that we are going to find a gene for Alzheimer’s is a little bit like chasing an elusive tail of frustration because there are going to be many different variables that couple together to give rise to sensitivity to certain environmental conditions that might, over decades of living, be seen as Alzheimer’s. That’s been our model, and it sounds like what you have said is consistent with that model. SC: I think so. When apo E (the apo E risk factor) was identified, which was not all that long ago (I’d say it was about 12 to 14 years ago), and then some of the causative gene mutations that cause early Alzheimer’s disease were discovered around this time as well, I think the field of genetics felt like they were going to wrap this disease up pretty quickly. But the truth is that those disease-causing mutations only affect about 1{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of all patients with Alzheimer’s disease (those who tend to get the disease earlier in life) and for the much more common late-onset disease that affects 95{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} or more of all patients with Alzheimer’s disease, we have had very little success. First of all, we haven’t identified any causative genes, and the only gene that has shown consistent, strong relationships as a risk factor is this apo E4 allele. I think the field has, over the last few years, shifted very much to the model that you are suggesting: polygenic, interacting with environmental factors, and the sort of incremental insults, if you will, that occur as a result of a poor diet and an inactive lifestyle causing some cumulative effect and potentially interacting with some genetic vulnerabilities, but in and of themselves having a very great influence on the ultimate expression of a disease. JB: The way that we have been talking about the etiology of chronic disease recently is to talk about metabolic disturbance through a systems biology impact on gene expression patterns within a network. We are trying very hard to get people to think about networks rather than pathologies and endpoints of a single process. That’s a very different way of thinking about disease than most of us were trained to think about it. It is kind of a mind-shifting paradigm. It seems like your work really speaks to that very nicely because it cuts across so many different aspects that we can’t just put our finger on one causative agent and say, “That is this disease.” SC: I think that’s very true. Even though my work has focused most closely on hyperinsulinemia and insulin resistance, that, in and of itself, is a system that affects so many different other systems that it is, by its very nature, a pleiotropic model, even though we are focusing on a single peptide as a key player in that ultimate web of causation. Absolutely, and that very much drives a different approach to therapeutics, I think-very much away from the “silver bullet” days of the cholenestrase inhibitor or the single molecular target as likely to be the therapy that will prevent or cure Alzheimer’s disease and moving more toward therapies that do have these pleiotropic effects on the systems that we now know are greatly increasing the risks of developing Alzheimer’s. JB: We’re calling that “network pharmacology.” It is interesting that if you look historically, that’s probably the way physiology has worked-as network interaction with our environment–throughout time. When we eat, we are eating complex molecules in our diet that influence, in a network pharmacological way, gene expression patterns that modulate function. It’s a whole different model, which then leads me to what I consider one of your landmark articles. To me, when I read it I just lit up. I thought it was beautifully written. It is your review article on “The Role of Insulin Resistance in the Pathogenesis of Alzheimer’s.”15 I think for many people, until maybe they read your article or heard about it, they might have thought about diabetes and Alzheimer’s as it related to Type 1 insulin deficient diabetes, but they may not have thought about insulin resistance, the more predominant problem that we are encountering in our society now with metabolic syndrome and so forth. I’m sure all of your colleagues didn’t rush to just say, “Yes, that’s exactly right, what you’ve got there.” There must have been some controversy. SC: Absolutely. I think for a long time this idea was very much considered on the fringe of possible important factors. I think what has really happened, again, over the last 10 years is the good epidemiology has definitely helped to point the field in the direction of metabolic factors as potentiators of Alzheimer’s pathogenesis. The idea that hypertension, and hypercholesterolemia, and diabetes…for awhile they were considered risk factors for vascular dementia, or for dementias that were what used to be called multi-infarc dementia. I think what has happened, with very good epidemiology, is it has become clear now that these conditions are risk factors for Alzheimer’s disease as well as for vascular cognitive impairment or vascular dementia. I think diabetes is a very easy disease for people to focus on. It’s very common. It’s very easy to understand. It’s defined very glucose-centrically. And I think what that did for awhile was that that did help raise awareness within the field of this class of factors as important, but I think now the progress is being made in understanding that the underlying these various conditions there is, in many cases, a convergent pathophysiology, which is insulin resistance. Insulin resistance, of course, is associated with nearly all cases of type 2 diabetes. Insulin resistance is observed in about half of all adults with hypertension. It is a main cause of dyslipidemia. Instead of viewing each of these vascular risk factors as independent or able to drive the Alzheimer’s pathogenetic pathway independently, I think we are now beginning to understand that there is an underlying convergence which focuses around insulin resistance and hyperinsulinemia. You’re right, that was not well-accepted as a potential mechanism when I first started studying this a number of years ago, but I do think now the field is much more receptive and good basic science work is really also helping now with some of the studies that I just described linking insulin and insulin resistance to beta amyloid and other pathogenic agents that are well known to play an important role in the expression of Alzheimer’s. JB: In your review, you raise some really interesting questions about modulators. I guess you might even call them in the human “reducible risk factors,” like HPA axis function, which we think of as related to how we are interpreting our environment and translating it through the neuroendocrine system into hormonal messages. Some people might even call these the stress/Selye mechanisms and how that relates then to insulin sensitivity. You’ve talked about the role that various nuclear orphan receptors have and how that regulates things like inflammation and signals over into vascular effects through PPARgamma and how that might have some effect. You are really laying out, in this article, I think, a very interesting different way of approaching pathophysiology from a-I guess I would have to use the term that we use-a “functional perspective” by looking at these modulators of function that then ultimately trigger processes that distort the web of physiology and produce what we ultimately see under the microscope as amyloid deposition. SC: I think that’s true. I do think when people begin to sort of appreciate the complexity of this web it is daunting at first. I think somebody has referred to it as “the morass of intermediary metabolism” or something like that because these effects-these modulators-are interrelated, but in a sense, I have come to view that almost as a positive aspect because I think it offers many portals for intervention. The truth is that intervening at one level of this web may likely have beneficial effects at many levels. I think an example of that might be the fact that certain treatments for hypertension protect against diabetes, and certain treatments for diabetes protect against hypertension. One might not have to be able to address the initiating cause, if you will; it might be enough to be able to find an intervention that can affect a number of these modulators and have a beneficial effect on the whole web. JB: I think you really stated that beautifully. As you are speaking I’m thinking in the back of my mind about the group that has been looking at bisphenol-A’s influence on insulin resistance and the relative risk to cardiovascular disease and diabetes, or the work that has been done on persistent organic pollutants (POPs) and their elevation of GGTP liver enzyme profiles and how that relates to insulin resistance and diabetes and how that could connect to the brain through this pathway that you are describing-through hyperinsulinemia, through what appears to be a distant effect, rather than just looking at the body as a collection of organs that are all isolated and compartmentalized. They are all interconnected through these pathways of signaling. SC: I do think that’s a clear message of this work and I think that is part of why it was difficult to make progress for a number of years because I don’t think that the neurologists think much about below-the-neck systems, and I don’t think that the endocrinologists think much above the neck (or at least above the hypothalamus). I do think this is an example of the way in which the central nervous system and the periphery are closely interrelated. I think each is capable of driving these pathologies, so an example would be the one that you cited where the exposure creating insulin resistance would affect the CNS, and then conversely we know that when there is insulin depletion specific to the CNS, or insulin inactivation that originates in the CNS, you get a compensatory increase in insulin secretion in the periphery. Beta-amyloid, as I said, is capable of causing brain insulin resistance, if you will, and that may drive insulin resistance and hyperinsulinemia in the periphery. JB: That leads me, then, to a series of papers that you have published that I think are-again-so interesting and provoke all sorts of thought. They have names like “Hyperinsulinemia Provoking Synchronous Increases in Central Inflammation in Beta Amyloid and Normal Adults.”16 This is looking at things like increased isoprostane levels and cytokine levels. And a companion paper: “Insulin Resistance in Alzheimer’s Pathogenesis: Potential Mechanisms” that talks about the inflammatory connection.17 And then in the Journal of Neurological Sciences, your paper “Insulin Resistance, Inflammation, and Cognition in Alzheimer’s Disease,” and you had the-I guess you call it-temerity or the boldness to then even have in that title “Lessons for Multiple Sclerosis,” God forbid that we cut out to another disease now with a similar mechanism.18 (I said that tongue in cheek, obviously.) These are really pioneering papers that when coupled together give rise to a body of knowledge that creates a different system of thinking about the etiology of diseases that fan out from a mechanism rather than just each individual disease being siloed. That’s how I read these papers. SC: Again, with insulin being a peptide with such pleitropic effect, I do think that it is related to a variety of types of neurodegenerative disease and CNS inflammatory states, and then the challenge becomes to determine why in one patient it might be associated with Parkinson’s disease and why in another patient it might be associated with Alzheimer’s disease. Is it insulin resistance driving some innate vulnerability otherwise determined, or are there types of insulin resistance? We know, of course, insulin resistance is a very heterogeneous condition, and so I think that is now one of the main challenges: to try to determine what particular mechanisms associated with insulin resistance may drive these different pathological pathways. Certainly inflammation is a set of responses common to a host of disorders. Almost anything that negatively impacts the brain is going to provoke some kind of inflammatory response. And the interaction of insulin resistance with inflammation, I think, is another complex topic. We are beginning to understand that insulin, in some ways, has anti-inflammatory effects. Again speaking to the issue of relatively lower levels and relatively confined time frame, when insulin becomes chronically elevated segues into a more proinflammatory response. So these are complex questions that will keep us busy for some time to come. JB: If our listeners want to pick out a recent paper of yours that kind of puts this together very beautifully, I think your review paper that you authored titled “The Role of Metabolic Disorders in Alzheimer’s Disease and Vascular Dementia: Two Roads Converged” that appeared in Archives of Neurology in 2009 is a very great place for people to start.19 I think it really is the most concise, extraordinarily well done summary of a large body of work (yours and many other investigators) that helps a person who is getting into this for the first time to understand the field. In our last few minutes together (obviously this conversation could go on ad infinitum, as far as I’m concerned, but with time being what it is…), could you tell us a little bit about whether you feel (and I think I know the answer to this question), from your discoveries, this opens the door for one of the therapeutic approaches towards these problems in the arsenal of tools being diet modulation? I am reminded of the epidemiological work of the patients that has been done on patients who comply voluntarily to Mediterranean diets versus those who eat a standard American diet and their rate of dementia over 10 years and their rate of mild cognitive impairment-those are published papers over the last few years. It would at least suggest, from epidemiological work, that diet probably has some role to play in this whole process. SC: I think that’s absolutely the case. One of the studies currently underway that we are just about to complete looks at that very question. Studies in which you query people about what they are eating and then relate it to aspects of dementia risk can be informative but suffer from not being able to control aspects of diet specifically. What we’ve done in a study that is going on now is we have participants who are either normal older adults or adults with very early cognitive changes characteristic of Alzheimer’s disease undergoing a dietary intervention where they receive 30 days of a high-fat, high-glycemic-index diet or a low-fat, low-glycemic-index diet. Before and after this 30-day period we’re carrying out a number of measures, including looking at their spinal fluid markers of inflammation and beta-amyloid, and looking at some changes in neuroimaging. We are attempting to address this very question. One of the things we are trying to do is model the early stages of diet-induced insulin resistance in a manner that’s very safe. We see, in our participants, all of the characteristic beginning changes of insulin resistance in terms of increased LDL, increased insulin levels, and all of these revert back to normal within just a couple of weeks after patients come off their diet. And interestingly we also see improvement in the folks on the low-saturated-fat/low-glycemic-index diet. One of the things we hope to do with this study-and we have been fortunate enough to be funded already by NIH to do the next version, so we’re going to continue on with this work-is to see how these very beginning changes in insulin function can provoke some of the pathological changes that we know happen with Alzheimer’s disease, and also to see if our patients who are already showing some signs of cognitive changes are particularly vulnerable to this dietary intervention. We’re thinking very much along the lines of what you’ve described. We’re just hoping to develop a controlled experiment that will, in a very safe manner, give us specific insights into how the diet is relating to the Alzheimer’s pathology. JB: Unfortunately our time has come to the end. I want to, once again, personally congratulate you. I think this is both pioneering and courageous work. This is not the easiest work and you are going uphill, often, against this dominant view that each disease is independent, one from the other, and we have these siloed effects. You’re really talking about a systems biology approach using a signaling molecule that has pleitropic effects (insulin), and it’s cutting across a lot of different subspecialties of knowledge, which always makes people uncomfortable (when you step on turf). There are a lot of things you have done very, very well as a scientist, and I’m sure also done well as a scientific politician because you’ve had to orchestrate through some sticky wickets and you’ve done it very well. I compliment you, and this is the kind of work that is going to change medicine for the better. We have an age-related burden of disease that is epidemic right now with our demographic transition. We need to find new solutions and this kind of work will help us do so. Thank you very, very much-both as a son of a mother who is growing older, and as a person who is also growing older, and for a generation of people who are trying to find better solutions to complex diseases. SC: You’re very welcome, Jeff, and thank you again for the opportunity to speak with your audience today. It was a pleasure. JB: My pleasure. Thanks so much, Suzanne.

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Bibliography

1 Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4(11):682-690. Review. 2 Bland J. The future of nutritional pharmacology. Altern Ther Health Med. 2008;14(5):12-14. 3 Zhang X, Crespo A, Fernández A. Turning promiscuous kinase inhibitors into safer drugs. Trends Biotechnol. 2008;26(6):295-301. 4 Chen ST, Dou J, Temple R, Agarwal R, Wu KM, Walker S. New therapies from old medicines. Nat Biotechnol. 2008;26(10):1077-1083. 5 Scarmeas N, Stern Y, Tan MX, Mayeux R, Luchsinger JA. Mediterranean Diet and Risk for Alzheimer’s Disease. Ann Neurol. 2006;59:912-921. 6 Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA. Mediterranean diet and mild cognitive impairment. Arch Neurol. 2009;66(2):216-225. 7 Bierhaus A, Nawroth PP. The Alzheimer’s disease/diabetes angle: inevitable fate of aging or metabolic imbalance limiting successful aging. J Alzheimers Dis. 2009;16(4):673-675. 8 Minich DM, Bland JS. Dietary management of the metabolic syndrome beyond macronutrients. Nutr Rev. 66(8):429-444. 9 Kong WJ, Zhang H, Song DQ, Xue R, Zhao W, et al. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation if insulin receptor expression. Metabolism. 2009;58(1):109-119. 10 Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci. 2007;27(50):13635-13648. 11 Hirsch IB, Boyle PJ, Craft S, Cryer PE. Higher glycemic thresholds for symptoms during beta-adrenergic blockade in IDDM. Diabetes. 1991;40(9):1177-1186. 12 Craft S, Newcomer J, Kanne S, Dagogo-Jack S, Cryer P, et al. Memory improvement following induced hyperinsulinemia in Alzheimer’s disease. Neurobiol Aging. 1996;17(1):123-130. 13 Watson GS, Peskind ER, Asthana S, Purganan K, Wait C, et al. Insulin increases CSF A&beta;42 levels in normal older adults, Neurology. 2003; 60(12):1899-1903. 14 Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology. 2003;28(6):809-822. 15 Watson GS, Craft S. The Role of Insulin Resistance in the Pathogenesis in the Pathogenesis of Alzheimer’s Disease: Implications for Treatment.” CNS Drugs. 2003;17(1):27-45. Review. 16 Fishel MA, Stennis Watson G, Montine TJ, Wang Q, Green PA, et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol. 2005;62(10):1539-1544. 17 Craft S. Insulin resistance and Alzheimer’s disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res. 2007;4(2):147-152. Review. 18 Stennis Watson G, Craft S. Insulin resistance, inflammation, and cognition in Alzheimer’s disease: lessons for multiple sclerosis. J. Neurol Sci. 2006;245(1-2):21-33. 19 Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol. 2009;66(3):300-305.

Welcome to Functional Medicine Update for February 2010. We have a wonderful issue in store for you that follows-up so beautifully from the previous issue with Dr. Suzanne Craft on Alzheimer’s pre-senile dementia and its relationship to insulin signaling. I think you are going to find this month a neuronal gem. Let’s move right to our Clinician of the Month.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jan Marino Ramirez, PhD Director, Center for Integrative Brain Research Seattle Children’s Research Institute 1900 9th Avenue M/S C9S-10 Seattle, WA 98101 www.seattlechildrens.org You know how much I look forward to this each month on Functional Medicine Update, our clinician/researcher of the month section. I have been so fortunate over the last several years to have remarkable people share their stories of what I consider to be cutting edge information at the frontier of where medicine is going. That is once again going to be the case this month. It is my opportunity and privilege to discuss with Dr. Jan Marino Ramirez the work that he is doing at the Department of Neurological Surgery, University of Washington School of Medicine and the Center of Neuroscience at Seattle Children’s Research Institute in Seattle, WA. I had the serendipitous opportunity to meet Dr. Ramirez on a plane flight coming back from Chicago when he was changing his place of focus/work from the University of Chicago to the University of Washington and was in that transition phase of taking on this new job as the Director of the Center of Integrative Brain Research at the Seattle Children’s Research Institute. We got talking, as is often the case when you have a four-hour flight. If you have a kindred soul next to you, you start a conversation, and as it materialized and evolved, it turned out we had so many points of contact in common. The excitement grew. The four hours of flight time flew by, literally, at supersonic speed. When we landed we recognized that we had been traveling a similar path, intellectually, for many, many years. It was a great privilege to have a chance to meet Dr. Ramirez, who goes by the nickname Nino. Dr. Ramirez has a background in biology and got his PhD summa cum laude at the University of Regensburg in Germany. He is a citizen of the world, having been born in Peru, educated in Europe, and working as an academic in the United States, now-fortunately for us-in the Seattle area. Probably his most notable accomplishment that you are going to be hearing about is the discovery that he and his research group have made in the area of epilepsy and seizure disorders. I’m going to let him tell you his story. From this specific example of the extraordinarily innovative and precise research that he has done I think you will see a more general theme about this whole nature of where we are going in basic research: to connect it in a translational way to clinical applicability and ultimately improve patient outcomes in very complex areas. Dr. Ramirez it is a treat and pleasure to introduce you to the listeners of Functional Medicine Update and thanks for being with us this morning. JMR: Jeff, this is really wonderful,this introduction. It’s a very hard act to follow, but I totally agree we were kindred souls. I never had such a short flight, I must say. The four hours went by like minutes and I learned so much. It is a great pleasure that we can now talk about this whole thing in a different way. JB: Before we get into the specifics, let me talk about-or let you talk about-your path. I’m talking about your intellectual path that led you to your position at the University of Chicago and, more subsequently now, at the University of Washington School of Medicine. Maybe you could tell our listeners about that and how you got into epilepsy research. Studying the Brain: From Invertebrates to Mammals JMR: It was really a crazy situation. I became a biologist because I was very interested in how the brain works. In fact, when I started off, I thought that we would never understand the human brain because it is way too complicated. I started to work, in fact, on insects because we thought these are very, very small brains, very clear-cut behaviors, and we will be able to understand it. We actually made really good progress in understanding the plasticity of those neural networks-the dynamics, how they adapt to behavior. At one point, I got kind of a midlife crisis because I thought, “The principles that we find here should also be applicable to the mammalian system and to my sense of humans.” I saw so many similarities that basically, mid-career, I switched my science from working on invertebrates to the mammalian system. It was a very high risk jump because I was kind of established in one field and invaded another field, but within one year we made huge progress in the neural control of breathing and, indeed, all of the principles that we learned in the invertebrates helped us, very much, to really go very deep into a better understanding of the dynamics of the mammalian brain. Nowadays, I think the mammalian brain offers huge opportunities because there is huge manpower behind it. There is so much known about how genes affect the nervous system that I think we are at the edge of a new wave of understanding of how the brain works. Really, my getting into the medical field was coming from the urge to understand how the brain works. I must say this urge is still there. I am learning so much more about the brain now that I am starting to interact with patients and with clinicians, and I think this partnership is something that helped me tremendously in this path. I have the feeling that right now we are going through an incredible change in how research is working. I say this because I’m just one example of many, many people. The basic scientists, for many years, started to work on the brain with the premise that at one point it would help patients. But really it wasn’t clearly meant. We knew that if we could better understand the brain we would help the patients, but it was such a daring step that we were all scared to go the next step to really help patients. What happens now is that people get a little frustrated. They put so much money into research, and at one point they want to have a return. There was a huge drive to say, “Hey, guys, now let’s go really to the next step and really try to translate the ideas into a cure or therapy.” That’s when this huge wave of translational research started. I think we’re in the middle of a change (a conceptual change). We are realizing that to understand the brain, working with clinicians will help us tremendously because for the children and the adult people with neurological disorders, all of these problems are related to brain function. If we work with them, we get a much better understanding of the underlying mechanisms. What I see as a conceptual change right now is that people have realized that it’s not bench-to-bedside work, it is bench-to-bedside-beside-to-bench interaction that has to be taken very, very seriously. Only if you really work together can you get to the next step. Here, for example, at our research institute, on the same floor we are working with clinicians and we are working with patients. So we work with neuroscientists, but also with patients. That is, I think, the key for a better understanding of brain function, and the cure, in the end. Grant Titles Indicate an Interesting Body of Work JB: I think that’s a fantastic description of the landscape of what’s going on now and what people are calling translational research and translational medicine. I wanted the listeners to get a sense as to what you, over your years of discovery, have been involved with. I’m going to read off, quickly, some of the grant projects that you’ve had funded. As I go through these titles, I bet our listeners are all going to say, “Wow, this is a very, very interesting area to be involved with.” Here’s a quick listing. Grants in: Hypoxic effects on mammalian respiratory neural networks; Role of substance P in controlling the central respiratory neural network; Integrated effects of chronic intermittent hypoxia; Pediatric epileptogenesis: from bedside to the bench; Aminergic uptake blocker and the treatment of erratic breathing in Rett syndrome; Neuronal control of pacemaker activity; Cardiorespiratory dysregulation in familial dysautonomia; Genetic analysis of congenital hypoventilation syndrome; Defining the domain of epileptiform brain electrical activity; Hypoxic effects on mammalian respiratory neural networks (ultimately resulted in a completed grant). When we go through this and we look at apnea and all the other things that your research has touched, it reminds us that you are really in a select group of people doing systems biology research. I bet you didn’t initially think of it as such, but you’ve found yourself in that, and oxygen is one of your principal discovery areas as it relates to controlling many, many functions in the system of these neural nets. Was this a slow, sequential discovery process? How did you get there? Studying the Brain as an Integrated System: Epileptogenesis JMR: No. I think from the get-go I was always interested in the systems level. I really wanted to understand how the brain works as a system and I think this integrated thinking helps you to better understand how it works. Just doing genetics or just doing single nerve cells will not get you very far unless you integrate it with a more systems level approach. I think this way of thinking is so much within a person that you cannot change it or learn it. Either you are like this or not. I love complexity, and because I love complexity I tackle complex issues and am able to solve the underlying problems. One of the grants is about epileptogenesis from bed to bedside. I think this is a very good example of how research brings you further if you interact with patients. We basically started to analyze brain tissue that was excised during a pediatric operation. There are lots of children-like up to 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}–that become intractable and the only way to treat them is to take out the epileptic focus (basically the center for the seizures). Instead of just throwing this brain tissue away, what we did was we used this tissue to better understand the reason. Why is this such an excitable piece of brain tissue? Why is it causing all these problems? In fact, we discovered that even if we take it out of the brain, we can replicate the seizures and that brain tissue responds to the anti-epileptic drugs very much like the whole patient did. We could do drug studies very precisely and we were able to predict what the best medication was for a given patient. That was a very, very rewarding finding for a group of scientists who really started off working on an insect. We were so gratified that we helped several of the patients find the right medication. But what happened then was after four years, several of those kids started to get seizures again. We realized that finding a new drug that helps to control the seizure is really just the first step and really hasn’t tackled the real problem of epileptogenesis. We were in a real big state of frustration because we did our best-these are like 36-hour, non-stop experiments-and we did this for several years, and then we realized the real problem is that this piece of tissue kind of wants to seize. It has this drive to be overheated, to be overexcited, and if you give it a drug that can temporarily abolish this overexcitation, after awhile–because the network or the neurons are set in a different way–you get a seizure again. We realized that what we have to understand is the whole thermostat of regulation in these nerve cells. It is kind of like you are working with a room that is overheated because the thermostat is set at 100 degrees Fahrenheit. What you do at that moment is you open one window to cool the room off, but the thermostat is working and after awhile it gets hot again. So you open the next window, you cool it, and then again. After the third drug, nothing actually helps anymore; the room will be hot and hot and hot. Instead of just opening windows and trying to regulate the excitability this way, we have to understand what is wrong within the cell. What is the homeostatic regulator that controls excitability? For several very complex reasons, we got into the inflammatory pathway. Inflammation changes the cell, itself, and we realized that basically this inflammatory process that seems to take place in the cell is causing this overexcitability. So we became very interested in the role of antioxidants and things that regulate intrinsic excitability. That’s a very, very big topic, as you said. The bottom line is, through the interaction with the patients and the clinicians we were able to change the paradigm of how we should go about studying epileptogenesis. This was a very, very rewarding journey that is a very good example, I think, of how translation works. You don’t work just on your bedside and try to understand why there is a seizure, you really work with a patient to get rid of the seizure, and only by doing this you see the whole challenge. JB: That’s a wonderful segue to the visit I had to your facility and talking to your post-doc collaborators and also your seminar that you gave to our research group in Gig Harbor. You made an extraordinary discovery–a model system–for studying the effects of things like oxygen tension and other substances. It is a systems biology approach towards understanding neurological function versus looking, as most neuroscientists do, one cell at a time and trying to understand each cell in isolation. Can you tell us what this discovery was? I know you got national media attention for it and deservedly so. It’s incredible when you see your preparation breathing and hiccupping. If you could just tell our group about that, I think it’s an extraordinary discovery. Studying the Effects of Oxygen on the Breathing Center of the Brain JMR: What you are alluding to is the fact that we can identify the center that controls breathing and isolate it. In isolation (and now we are talking just like a half-millimeter-thick piece of brain tissue), this brain tissue is still generating the principal drive for breathing. So it is generating arrhythmic breathing activity in the dish, and it not only generates breathing, but if you take away oxygen, it will start to generate sighs (like augmented breath that we would also do-when we snore we do this very strong augmented breath) This piece of tissue will not only do this, but if there is really no oxygen, it will go into a mode of gasping and basically this is the last step to get oxygen. So basically this piece of tissue mimics, exactly, what the whole organism would do, and it allowed us to study the whole mechanism-how this neural network that controls breathing reconfigures to adapt to changes in oxygen levels. That led us to very important insights into, for example, Sudden Infant Death syndrome. We realized that in hypoxic conditions when you do not have enough oxygen, your nerve cells depend on a single kind of mechanism, which is a sodium-dependent mechanism, and this mechanism depends on a certain modelatory environment, which depends on serotonin, norepinephrine, and other things. If you have a defect in one of those, you can breathe perfectly fine, but if you get into this hypoxic condition then your response is wrong. People might say, “Gasping? Why could this be deadly if you don’t gasp?” We have to realize that gasping and the breathing system itself is not just controlling our lungs. The breathing center controls, also, our whole state of mind, so to speak. If you sigh, you activate your norenergic system, you activate your neocortex, and it’s an important arousal mechanism. Ninety-five percent of the time when you wake up at night, you wake up with a sigh. It is kind of a wake-up mechanism. If you have a disturbance in those mechanisms, and you lay on your stomach and don’t get enough oxygen, then your system will not wake you up and you will basically get brain damage and die, which we think has to do with Sudden Infant Death syndrome. It is, of course, a very, very simplified manner in which I told you this. It is much more complicated, but this is kind of the principle behind this whole discovery that we made. Discoveries Related to Rett Syndrome JB: From that, you and I had this moment of “aha” where you had told me about some of the Rett children and you actually showed some videos. I think it was of a couple of young girls who were patients at the center. I then said, “It’s interesting because I was involved in the publication of a paper back in the late 80s on Rett syndrome girls, showing that when we looked at complex analysis of their neurochemistry, if we put them in rebreathing situations, we could normalize their neurochemical metabolites.” There was almost kind of a convergence between our two world views coming from entirely different perspectives. JMR: That was a very fascinating example. For the listeners who are not very familiar with Rett syndrome, it is a very devastating disorder that affects primarily girls because the boys basically die very early on. It is associated with a lot of problems, including seizures, but also huge breathing problems. It’s totally heartbreaking to see children with Rett syndrome and their breathing problems. At the moment we have no way to control their breathing. Jeff alluded that he was involved in the discovery that there is a problem with the amines, which are the biogenic amines that are present and control the state of the neural network. These children have deficits in this part of the brain. As a consequence, they start to have abnormal breathing problems. What we discovered is that this is kind of just the beginning of the whole problem. The beginning of the whole problem is that your breathing system is out of balance, and now the breathing system tries to adjust, but it gets—always–not enough oxygen, which then changes how you respond to neuromodulators. So a substance that under normal conditions for all of us would be a stabilizing substance, now suddenly becomes a disturber of brain function. In awake state we have very regular breathing, but for these children, in awake state, breathing will become very, very irregular because these substances that normally stabilize breathing become destabilized. That was, again, a very interesting interaction with patients that got us there. In the breathing system, when you isolate it, we were able to heal it right away, but in the whole child, we were not able to do that. The reason for this is that the phenotype of these children is really a complex one, resulting from this interaction that is involving, for example, hypoxia-inducible factors like EF-1alpha, etc. It is very complex research that is also related to obstructive sleep apnea, which is affecting a huge amount of people in the United States (with the crisis of increased obesity, for example). It is a major problem A lot of children (not even obese ones) have sleep apnea. It affects cognitive functions and all of this kind of relates to the stability of neural networks in the brain. JB: As I read your papers and had the privilege of listening to you talk about your work I was reminded of Glenn Doman and his group’s work at the Institutes for the Achievement of Human Potential, where they have been talking (for 55 years) about oxygen in children with brain injuries (that oxygen may be a limiting nutrient). Because oxygen is 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the atmosphere, it’s like free currency. But their view is if you look at these kids with brain injuries that they have seen over the 55 years that they have been in business and providing these services, many of these children have these temporal ischemic-type things going on, which then produces kind of an induced oxygen deficiency and makes it a limiting nutrient. They have talked about the whole nature of training these children how to breathe. This goes back, actually, culturally. Almost every traditional form of healing has had some way of improving breathing, from yogic, or dance, or exercise-some ways, before intubation, of getting more oxygen into tissues. It seems that you are really hitting on a fundamental mechanism that almost gets us to think that there is no such thing as free currency. We might think of water and air as being free, but yet they can be limiting factors in certain situations, particularly with regard to injury or maybe certain genetic uniqueness. JMR: You know, I love complexity, and oxygen is one example of complexity because I think one of the key factors of the breathing system is not only that it controls the lungs, but it also controls our neural network, essentially. I think you would always say, “I’m inspired,” but you would never say, “I’m expired.” It is tuned to inspiration when your respiration network actually drives a lot of neural function. So I think a lot of the healing that you get through controlling breathing is not only the oxygen, but also the central nervous system drive that controls your brain function intrinsically. Oxygen is another very, very complex system because you need a very, very fine balance between too much and too little oxygen. Both are bad, and it is very important that the brain is establishing this balance. I think what happens if you are in a situation where you don’t have enough oxygen is that the brain starts to get out of balance and basically runs into catastrophes. It suddenly doesn’t respond anymore to normal oxygen as it should. That’s why I think maintaining efficient oxygen is very critical to keep the network in balance (the brain). Inflammatory Processes and the Brain JB: That takes us back to one of the points that you made earlier: that your research, more and more, is heading down a road to look at certain inflammatory processes going on that relate to redox potential in the brain, and relate ultimately to things like mitochondrial function, and how that then has an influence on signaling, which then influences neural nets. Can you tell us a little bit about what that environment looks like for you? JMR: There are somewhat interesting things about it. Here’s the situation: The respiratory system is extremely sensitive to reactive oxygen species. You put on hydrogen peroxide (or whatever), and it responds very, very much. We thought, “Oh well, it is damaging the brain.” But it did not damage this part of the brain. It was just a signaling molecule, as a signal for changing activity in the brain, whereas, say, in the hippocampus in the neocortex, if you do the same thing, actual nerve cells die. Basically, in different areas, the role of oxygen is very, very different and there are very complex adaptations going on that play a role in regulating activity and we are trying to decipher this. JB: Last month in Functional Medicine Update we talked with Dr. Suzanne Craft, who is actually one of your colleagues at the University of Washington. Dr. Craft’s work is looking at what she called “type 3 diabetes” and its relationship to Alzheimer’s dementia and pre-senile dementia. The concept that is emerging from her work is that amyloid plaque, in part, relates to insulin signaling dysfunction that is associated with hyperinsulinemia and pre-diabetes (type 2), or even so-called metabolic syndrome. When I listen to her talk about her extraordinary work, the mechanism by which some of these things occur in terms of brain dysfunction, hippocampal apoptosis, and so forth, it seems to tie very closely together with what you’re talking about in terms of oxygen delivery and respiratory networks, and neuronal bioenergetics. It seems like the domain that is emerging from members of this community from multiple disciplines is starting to come to kind of a consensus as to how these things might interrelate through different signaling networks. Mitochondria and Neuroexcitability JMR: Absolutely. The importance now becomes much more recognized than it was before. We always thought neuroexcitability of a nerve cell was determined on the surface of the cell. There are these ion channels that change excitability, but we didn’t really realize the importance of the mitochondria within the cell-how they relate to excitability. And there is increasing evidence (and I think we don’t quite understand how it works) that the mitochondria itself has oscillations that actually determine the health of the nerve cell. People are thinking that a lot of the excitotoxicity comes through this oxidative stress that is produced within these mitochondria, and it might relate, for example, to Parkinson’s disease, because we still don’t understand why, in Parkinson’s disease, one cell particularly dies. These are cells that have intrinsic mitochondrial oscillations that seem to be critically involved. I think we are getting better and better insights into the role of energy metabolism in regulating the health of the single nerve cells and I think we totally underestimated this so far. JB: There is one other name that I am familiar with in the area of epilepsy research. This is an investigator from Montreal, Andre Barbeau. I’m not sure if you are familiar with his name. He worked a lot with his group on taurine as kind of a conditional nutrient that he was able to show (at least in a book that he published a number of years ago) could influence epileptic seizures in animals (this was an animal model) and then actually did some human clinical work showing that certain types of seizures, when taurine was supplemented as a conditionally essential nutrient, they had clinical improvement because of changing polarization and bioenergetics of the centers. It raises the potential that there may be therapeutic agents that focus on the cause rather than the effect of epilepsy that are yet to be discovered. Do you have some optimism that this could be the outcome? JMR: I think what we need to understand is basically how those channels for excitability and also the intercellular membranes are regulated. The membrane (the lipid bilayer, and all the surrounding ion channels, and kinases, etc.) is a system on its own. They are very, very complex. They are like these lipid rafts and all these interactions between the lipid bilayer and those really functional units depend on a lot of factors. We talked about omega-3, for example, playing a big role in stabilizing membranes, but also in regulating, in the end, excitability. I think we are just touching this area and realizing how much more regulatory processes take place in a nerve cell at this level that we took for granted. We thought, “Oh well, the cell has ion channels.” But we didn’t know that they are basically embedded in a very complex network of molecules, and if one of those molecules is not fed well (if it is missing something) then you have huge consequences. I think that is also an emerging field of research. JB: I can’t tell you how much we’ve enjoyed this discussion. Obviously we’ve prospected in all sorts of extraordinary areas that I think, in the traditional sense of neuroscience as it was seen 10 years ago, might have been considered risky, and so this has been kind of a courageous discussion that I have taken you into and I thank you for your willingness to go there. The courage is really your’s because you’ve moved your whole professional career from Chicago to Seattle, and you have started to assemble your team there at the center and decided that you wanted to do integrative neuroscience research, which illustrates your willingness to prospect new areas. Have you had much pushback at all from this, given that you are the guy in charge now and kind of assembling the team? JMR: If you make a decision full-heartedly, you cannot do something else. As soon as I realized that in order to do really good translational research I had to be much closer to clinicians and patients, I had basically no other choice than to come here to Seattle Children’s Research Institute because this was a great model for translational research. I must say I was very scared, but everything was like 10 times better than I expected (and I expected a lot). It is really an amazing environment in which to go for it. I think I have to tell anybody who is scared to go the next step. If you full-heartedly believe in something, that’s what you have to do. I’m extremely happy that I made that step. It invigorated my science so incredibly much, and I think we have made huge progress in the one year since I arrived. I must say, I am totally hyper about it. JB: I hope everyone who is listening feels that sense of inspiration. Each one of us, in our little island, carves out our trajectory in life. I think that what your model demonstrates to each of us-those clinicians who are seeing patients in their office-is that every day they are pioneers. They are creating new ground, and how they look at that patient and look at their work will create a sense of its outcome. I really want to thank you so much, both for the specifics of what you shared with us, but also for just the general concept of being bold and courageous about taking on new responsibilities and bridging the gaps that some people are very fearful to bridge between basic science and the clinical outcome. I think it’s a statement of the new age in the 21st century to create a functional medicine. Thank you, Dr. Ramirez, so much. JMR: Thank you so very much. It is always a great pleasure to talk to you. I hope you enjoyed that discussion with Dr. Ramirez as much as I. That was an unbelievable kaleidoscope of visionary thinking and translational research. Let me give you, my summary takeaways as to how, as a clinician, particular information that Dr. Ramirez shared might be of value to you. Summary of Interview Takeaways I think the first and most obvious takeaway is that to understand complex physiology, we can’t think of single cells working in isolation. His work on the brain slices he mentioned provides an understanding of how, even at a holographic level, a system of different cells working together kind of mimics and recapitulates that a whole organism breathes, gasps, snores, and hiccups is a very interesting part of our understanding. In fact, he didn’t mention it, but he connects these half-millimeter-thick cell slices across the tissue into a device that produces (from their electrical changes) a sound, so you can actually hear, as he said, these slices breathing, and you can hear them gasping, and you can hear them hiccupping. It’s a pretty remarkable metaphor to understanding systems and you can’t understand one cell type in isolation. For example, you can’t just take the nigra cells in the area that is associated with Parkinson’s and understand that without looking at the whole system. This concept would be the number one takeaway. The number two takeaway for me is the fact that there are a very important series of controlling factors for this system of neurochemistry that relates to oxygen delivery and powering up reduction oxidation through mitochondrial bioenergetics. We should not forget the importance of breathing and exercise and oxygen delivery to tissues. This is, of course, what Glenn Doman at the Institutes for the Achievement of Human Potential has been talking about for over 55 years. They train children to be more neurologically high performance. This process has to do with all sorts of technologies that might improve oxygen delivery (not just physical training and exercise), but also aspects of oxygen-carrying capacity in the blood, and even the CO2/O2 levels that help to use the bore effect to drive oxygen into tissues. That is possibly one of the reasons why rebreathing some exhaled air that has more CO2 in it can help to train brain centers to be more respiratorily active. This is, of course, one of the techniques that is used at the Institutes for children with certain brain injuries to improve their function. So oxygen could be seen as a limiting nutrient, and it could be a very important part of any therapy. Of course, there are all these traditional historic healing methods that are ways of improving oxygen delivery. I think that’s concept number two in the takeaways. Number three for me in the takeaways is the recognition that there are many structural components within the complex neural network that are regulated by aspects of nutrition that can improve depolarization and intercellular signal transduction and communication among complex cell types in the nervous system. Dr. Ramirez mentioned the essential fatty acids (DHA) that make up such a great percentage of the two position of phospholipids in the brain membranes. We must think about the important role that proper omega-3 fatty acid nutriture plays. We must think about the appropriate role that things like carnitine and taurine and lipoic acid play in modulating aspects of neurochemistry and oxidative reductive chemistry in the brain, which is the center of very high oxygen tension with very little antioxidant protection, so to speak, and that’s why it may so reactive-oxygen-species sensitive, as Dr. Ramirez talked about. The next and final area Dr. Ramirez talked about–the inflammatory process–comes back once again to the yin and yang of inflammatory balance. As we get into a place where we have too many proinflammatory mediators, we start shifting the sands of physiology into a different signaling network that is associated with depolarization of membranes and changes in ion transport and ultimately, in the case of epilepsy, different kinds of physiological phenotypes. I think of those characteristics that are all modifiable and all the things that we can think about when we are looking at patients with complex neurologic problems. Of course that ties back to Suzanne Craft’s work that was mentioned last month, with insulin signaling and how that affects bioenergetics of the brain and ultimately regulates certain aspects of oxidative chemistry. We are starting to develop a new functional medicine approach toward the understanding of the origin of a whole array of complex neurological disorders. I don’t think we are treating one at a time. In fact, as Dr. Ramirez pointed out, using drugs to treat one condition at a time leads to drug resistance because we didn’t ultimately treat the cause, we were treating the effect. You can see that in cell slices as well as in human beings. Epigenetic Side-effects of Common Pharmaceuticals These factors of resistance that occur to medications over time, in which the body adapts (probably epigenetically) to the exposure to certain medications, blunts their effectiveness and requires finding new molecules that are new to nature to modulate function. There is a constant concept of manipulating the therapeutic materials or intervention to keep up with the body’s ability to adapt or to modulate its function upon exposure to a foreign molecule. I’m reminded of a recent paper that was authored by Moshe Szyf and Antonei Csoka at McGill University (the Division of Pharmacology). They have been actively involved in looking at the role that various substances have on epigenetic modulation of genetic expression and this recent paper is titled “Epigenetic Side Effects of Common Pharmaceuticals: A Potential New Field in Medicine and Pharmacology.”1 In this article what they write about is that over time, exposure to new-to-nature molecules can induce, in the epigenome, modulation of epigenetic marks, so that ultimately gene expression patterns change. This could ultimately be seen as changing drug sensitivities, or changing drug tolerances, or even changing drug efficacy or safety relationships. DNA and chromatin modifications that persist from one cell division to the next occur as a consequence of these epigenetic marks and are related in part to exposure to foreign molecules like drug molecules. Over time, this may make an individual less tolerant and more sensitive to a drug. An example of this would be some of the anti-rheumatic drugs that are used for things like systemic lupus erythematosus and rheumatoid arthritis. Over time, some of these medications may actually start to become intolerant to the patient and induce toxic molecular effects, even though they may have had a better safety tolerance to begin with. I think this concept of a relationship between epigenetic marks and therapeutic foreign molecules is very interesting and may help us to better understand why drugs may lose effectiveness in the way patients respond to them. In the case of children with various types of neurological issues such as epilepsy, as Dr. Ramirez talked about, they have to have their medications constantly changed. The neuron, when it has these disturbed aspects of intercellular signal transduction and communication, really responds to a defect at the cellular level. Often what these drugs do is treat at the cell membrane level by blocking or inhibiting certain functions, but the real origin of the problem is a disturbed metabolism at the neuronal cell. As Dr. Ramirez talked about, neural networks are very responsive to reactive oxygen species and mitochondrial phosphorylation-type reactions. It is a bioenergetics story. When we start looking at the principal contributions to dysfunction, the functional medicine model once again holds true for neurological illness, I think, because what we are talking about is looking at the root causes of how the cellular pathology or cellular dysfunction ultimately promotes secondary adverse effects within the cell membrane such as gradient changes, transport properties, intercellular signal transduction and gene expression alterations. Each of those outcomes could be treated with different molecules that block or inhibit certain function. What factors might alter mitochondrial function? What type of functional changes increase reactive oxygen species and shift the redox potential into an oxidative mode with increased free radical pathology? I think these are important questions to be asking clinically. It leads us to things like coenzyme Q10, and N-acetylcysteine, and N-acetyl-L-carnitine, and taurine, and various types of conditionally essential nutrients that might be very helpful for modulating certain aspects of mitochondrial bioenergetics. We could use the term “antioxidants” in the broadest sense, but I don’t think “antioxidants” is really a specific enough term because in this case what we are really talking about is neuronally specific active substances that serve as cofactors or facilitators for proper mitochondrial redox function (reduction/oxidation function). Early Screening Tests for Dementia: Genetic Tests Don’t Tell the Whole Story Clearly, the earlier one can be involved in understanding the trajectory toward these problems and intervening at an earlier stage, the better off for the patient and the more likely that the intervention can be more physiologically based rather than focused on modifying symptoms by “hard-hitting” inhibition. To talk about early assessment, let’s use Alzheimer’s dementia as an example. There are useful assessment tools that can be used well before a tertiary stage of Alzheimer’s disease, where even with the best therapeutics effective outcomes are limited. Are there useful early warning screening tests? We have heard about lab tests like the apo E4-type genetic test to look for alleles that are associated with increasing risk to cardiovascular and Alzheimer’s disease. But a genetic test in and of itself doesn’t tell you about the phenotype of the individual because one might carry a specific genetic risk factor in his or her genotype, but it may not be expressed in the phenotype. Another individual may have a lower risk factor, but if it’s more amplified in its expression, it could have a more dramatic effect on the outcome of the phenotype. That means, in this case, Alzheimer’s disease. Although dementia is common with an expected prevalence of about 13 in 1000 people, aged 65 &ndash; 69, and 122 in 1000 of those over 80, only about half of those affected are diagnosed. We are always looking for new ways of getting early warning information that might then be more amenable to a more mild intervention. Various types of tests have been developed-psychometric questionnaires-to test things like short-term memory. A recent test that has been published, which I think has some very interesting opportunity to be used routinely in the clinic, is a pen-and-paper test that is a self-administered cognitive screening test. This cognitive screening test was first described in detail in the British Medical Journal.2This test was developed at the Department of Neurology at Addenbrooke’s Hospital in Cambridge. I think you’ll find this to be a very interesting type of pen-and-paper screening test. It is simply done. It seems to have a very good clinical sensitivity. It seems to move back the threshold for assessment to a much earlier age. This is the so-called TYM test, which stands for “Test Your Memory.” I thought the results of this study on the TYM tests were quite remarkable. Control participants completed the Test Your Memory questionnaire with an average score of 47 out of 50, whereas patients with Alzheimer’s disease scored, on average, 33 out of 50. They found that the Test Your Memory score showed excellent correlation with two standard tests, a correlation of about 42 out of 50 had sensitivity of 93{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} (when anyone had a score at 42 or less out of 50 of the questions they had a sensitivity of 93{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} on specificity, but 86{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in the ultimate diagnosis of Alzheimer’s disease). The Test Your Memory was more sensitive in detection of Alzheimer’s disease than was the Mini-Mental examination, which is often the test that is used clinically (TYM detected 93{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of patients compared with 52{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} for the Mini Mental State examination). The TYM test had a much higher level of sensitivity in picking up pre-and early-stage Alzheimer’s disease. The Test Your Memory test is available in the article (it can be printed out), and it is basically a simple type of memory test that a person fills out and does on their own (it is self-scoring). It is almost fun to do. (I guess it may be less fun if one has a very serious cognitive impairment; maybe then it is very challenging.) I think we are moving in the direction of having validated tests that can be used for earlier assessment of dementia, which would be very helpful in intervening with more mild types of interventions, and also for following and tracking the success of therapy. For those of you trying to find this questionnaire, it is the June 13 issue of the British Medical Journal, on page 1398. You can even Google “Test Your Memory” and probably be linked directly to it. The Brown paper (the specific article that has the Test Your Memory reference in it) is in that same issue of the British Medical Journal.3 I hope this questionnaire might be helpful for you as you are trying to develop some tools in the clinic for evaluating early-stage dementia. I have talked about two things, one of which is an assessment tool. The other is epigenetic effects and what happens as patients become tolerant to one drug (possibly by epigenetic modulation), which then changes the sensitivity to the medication, and may in some cases make them so sensitive that a drug that was previously tolerated now becomes toxic. This epigenetic correlation really links back to our emerging understanding of the etiology of Alzheimer’s. It would be a little bit premature to say that this is all linked together and we’ve got it completely nailed down and all aspects of this etiology is well understood. But certainly the map-or let’s call it the grid-of understanding is gaining more density and more degree of mechanistic understanding. Part of this emerging understanding has to do with the tau protein phosphorylation and how that relates to amyloid peptide aggregation, and ultimately the formation of neurofibrillary tangles and the tau hyperphosphorylation, which is a post-translational, kinase-modulated process that has to do with activation of inflammatory and oxidative pathways. It ties back, also, to epigenetic marks. It has now been found, for instance, that elevated homocysteine is a surrogate indicator for alterations in the tetrahydrofolate cycle, which is a methylation cycle. As that occurs, there are alterations in epigenetic marks related to methylation of the genome, and that then ties together with protein phosphorylation alterations and protein methylation alterations that ultimately create different expression patterns. There is a methyltransferase alteration that links homocysteine metabolism with tau and amyloid precursor protein regulation and tau hyperphosphorylation, and ultimately amyloid precursor protein aggregation the formation of neurofibrillary tangles. This is kind of-again-an emerging mechanism that ties together a precursor marker, which could be considered a surrogate biomarker (hyperhomocysteinemia with a mechanistic correlation with epigenetic alterations in methylation patterns), and how that ultimately transitions itself into different intercellular signaling processes through phosphorylation and regulation of various bioactive peptides, including tau, and how that then correlates to things like the triggering mechanism of oxidative stress and alterations of mitochondrial bioenergetics in the neuron.4,5 This pattern-this mechanistic understanding-fans out into a more functional medicine-based landscape, in which we have to look at many different variables and ask the questions: Is there a genetic underpinning? Does that person have a familial tendency toward accumulating homocysteine as a surrogate biomarker that relates to alterations in methylation patterns? Are the methylation patterns that that person has that are controlled by their genes or by the genes in combination with the environment, like drugs, or chemicals, or substances that might modulate the role of the body in its response to those exposures? Do they have adequate levels of specific nutrients to modulate the throughput of these intermediaries (in this case, folate, B6, B12, betaine), which we all know play important roles in the tetrahydrofolate cycle? And then ultimately, how does that relate to the exposure to even pharmaceutical agents that might be used that are potentially going to impact epigenetics and create different gene signaling processes that then alter methylation and phosphorylation patterns? I think you can start to see that we’re spreading our knowledge base into a broader landscape that allows us to better understand (possibly) the etiology in that patient, looking at their genes (their genetic architecture) and their environment to come up with a model as to where the modifiable factors might result in that individual’s specific history and tying that together with an assessment tool (like the Test Your Memory assessment tool) that allows us to track, clinically, how effective our intervention is being responded to by the patient. Insulin Dysfunction, Inflammatory Signaling, and Oxidative Chemistry One of the major environmental modifiers of this whole process is insulin, which we discussed in a previous issue with Dr. Suzanne Craft. I want to come back and remind us of the importance of this topic because one of the wild cards is the insulin signaling pathway and all the variants that are tied into it, which include things like inflammatory signaling and even oxidative chemistry, which are all tied through to the insulin axis of regulatory control and insulin-like growth factor 1 and all the various types of other intermediary molecules and enzymes that are involved in the regulation of bioenergetics through glucose metabolism. In tau hyperphosphorylation, one of the distinct mechanisms that comes up is not only the homocysteine connection, but also the insulin dysfunction connection. In the Journal of Neuroscience, there was a very interesting paper looking at Alzheimer’s disease characterized by this extracellular aggregates of the beta-amyloid peptide and how the intraneuronal neurofibrillary tangles are composed of hyperphosphorylated tau protein assembled in paired helical filaments, and that this tau hyperphosphorylation can induce aggregation and are thought to induce neurofibrillary tangles and neurodegeneration in Alzheimer’s disease.6 This has now been tracked to be precipitated (this whole process) by alterations in insulin signaling (so-called insulin resistance hyperinsulinemia). I’ve just come back into the environment or the domain of Dr. Suzanne Craft, our previous researcher-of-the-month. Insulin dysfunction can induce in vivo tau hyperphosphorylation and ultimately travel through neuronal function into the production of neurofibrillary tangles. Tau Hyperphosphorylation is Induced by Two Distinct Mechanisms of Insulin Dysfunction Data indicate that insulin dysfunction induces abnormal tau hyperphosphorylation through two distinct mechanisms. One mechanism was consequent to that of oxidative stress and relates to alterations in phosphatase activity and alterations in phosphorylation activity, which then results in this tau hyperphosphorylation and production of aggregates of beta-amyloid peptide. You might say that’s very interesting, mechanistically, but how does that tie, really, to the clinic? What’s the takeaway to the patient? Let’s first go to some recent studies done in animals that kind of-I believe-point us in the direction. The first is this paper that was out of the University of Oxford, Department of Experimental Physiology and Psychology, looking at the deterioration of physical and cognitive performance in animals after a short-term high fat feeding, in which this high fat feeding induced alterations in biochemical energetics, mitochondrial dysfunction, oxidative stress, increased ROS (Reactive Oxygen Species) production, and insulin resistance and hyperinsulinemia.7 Rats generally do not consume a lot of fat in their diet. This study involved force feeding animals into a high fat feeding regime for just 9 days, and the researchers then looked at the surrogate markers for mitochondrial bioenergetics: uncoupling protein 3 activity, mitochondrial oxidative stress, and also mitochondrial ATP production. They found that this high fat feeding over a fairly short period of time induced insulin resistance, altered the ATP-to-ADP ratios, enhanced the uncoupling protein 3 levels in mitochondria leading to more oxidative stress and more reactive oxygen species, and ultimately was tracked to reduce the cognitive performance of the rats in Mays tests. Within 9 days, these animals started having cognitive dysfunction; they couldn’t find their way through the maze effectively. What does that mean for people eating high fat meals and high sugar meals every day? Do the results of this short-term high fat feeding study in rats translate to humans? Are people consuming these types of diets like long-term high fat/high sugar feeding studies in humans where the ability to go through the maze of life is reduced, as well as the ability to make appropriate judgments and decisions and use the full impact of brain? Over time, does that track against people with certain genetic susceptibilities to increase loss of cognitive function by neuronal apoptosis and cellular suicide, all initiated by these alterations in mitochondrial bioenergetics? Diet and Cognitive Function I know I’m using some fairly broad language here. I’m speculating about many things that are not fully bolted down yet. However, as we recognize from some good epidemiological studies published in a whole variety of journals, there does appear to be something consistent that is emerging about diet and cognitive function in humans. Let me remind you all of a recent paper that appeared in the Journal of the American Medical Association titled “Adherence to a Mediterranean Diet: Cognitive Decline and Risk of Dementia.”8 This is a clinical outpatient study of 1410 adults greater than 65 years of age in France. The study authors looked at the influence that adherence to a low glycemic load, Mediterranean-type diet versus and ad lib diet had on change in cognitive performance and the risk to dementia over a period of time. They found that higher adherence to the Mediterranean diet, which is associated with better glycemic control, better insulin regulation, and lowered insulin resistance was associated with slower Mini-Mental status examination cognitive decline. Higher adherence didn’t necessarily associate itself with risk to incidence of dementia, but because this was a period of time that might have been too short to fully understand the long-term outcome of the effects of a low-versus-high glycemic load, Mediterranean-versus-non-Mediterranean diet, all we can do is suggest the trajectory is moving in the right direction for people who self-administered and self-complied with a Mediterranean diet. The findings from this study tie together with some other papers that have been published in the same area. One paper appeared in the Annals of Neurology in 2006 and was titled “Mediterranean Diet and the Risk of Alzheimer’s Disease.”9 This was an epidemiological study of 2258 community-based, non-demented individuals in New York state who were followed for one-and-a-half years, who either self-complied with a Mediterranean diet or just stayed on an ad lib diet. Researchers followed these individuals over a period of time, looking at the appearance of Alzheimer’s disease, and found a very significant divergence between the two groups relative to their prevalence of Alzheimer’s disease, with the ad lib diet group having a much higher prevalence over a period of one-and-a-half years than the individuals who complied with the Mediterranean diet. Similarly, there was a study published in the Archives of Neurology in 2009.10 In this case, the researchers were not looking at Alzheimer’s, but at mild cognitive impairment in individuals who consumed the Mediterranean diet versus ad lib diets (again, this is a population/epidemiological study). The adherence to the Mediterranean diet, in this case, was also associated with a trend for reduced risk of mild cognitive impairment. If you consider mild cognitive impairment as a precursor to later-stage conversion to Alzheimer’s disease, then the suggestion from this paper is that there is a lowered trajectory or risk toward Alzheimer’s disease. These three papers-the JAMA paper, the Annals of Neurology, and the Archives of Neurologypaper-all tie together with this concept of improved insulin signaling, improved neuronal mitochondrial oxidative chemistry, redox potential, and bioenergetics and lowered incidence of alteration of genetic expression, intercellular signal transduction, inflammatory markers that lead to neuronal injury. What happens if you go to humans, not animals, and you start a short-term overfeeding study, in which you start feeding high fat, high calorie density diets to humans? These studies are now being published and I think are also very illuminating. Let me cite one that I think illustrates the principle. This is a paper that came from the Department of Clinical and Experimental Medicine, Diabetes Research Center, at University of Linkoping in Sweden, looking at short-term overfeeding and its relationship to induction of insulin resistance in relatively lean human subjects.11 In this case, the researchers intentionally asked individuals to consume high fat diets, and then looked at various aspects of insulin signaling, like insulin receptor substrate activity. They looked at biomarkers of metabolic syndrome, and they looked at kinase signaling through map kinases and ERK 1 and 2, and how they related to this dietary change. This short-term overfeeding study in humans was found to produce an effect on reducing insulin sensitivity, increasing insulin activity, and altering insulin signaling that was comparable to the study that I mentioned earlier about deterioration of cognitive performance in animals that were administered a short-term, high fat feeding diet. I hope you can see there is some kind of a story that is emerging here that relates to signaling, and alteration of neuronal function, and insulin resistance, and oxidative stress, and inflammatory markers, and neuronal apoptosis, and hyperphosphorylation of tau, and beta-amyloid aggregation, and formation of neurofibrillary tangles. We are really talking about nutritional programming and how that may alter genetic susceptibilities in the expressing of phenotype that is associated with a trajectory toward Alzheimer’s. Our ability to understand this early may, in part, hinge on the appropriate types of evaluative instruments or tools that we use to establish functional impairment prior to the onset of a strict diagnosis. That’s why the Test Your Memory questionnaire might be one part of this story, as well as other types of neuronal functional challenge tests that allow us to assess neuronal memory reserves and how these functions at the whole organism are related to alterations at the cellular level. That truly is the functional medicine model, I believe, as applied to this area of neuronal dysfunction. Nutritional Programming and Metabolic Syndrome There is a very nice paper that talks about nutritional programming and its relationship to metabolic syndrome and to insulin resistance and intercellular signal transduction, which travels through different cell types as inflammatory signaling or alterations in epigenetic programming. This paper appeared in Nature Reviews of Endocrinology in the November 2009 issue.12 When we are in that moment within the exam room with a patient, these discussions that we’re having about early-stage memory loss and concerns about Alzheimer’s translate to the bottom line of looking at diet, looking at lifestyle, looking at how these variables influence dramatically (over time) aspects of the phenotype that ultimately regulate the potential risk to a later-stage disease for which the therapy is at best limited right now. Let me talk a little bit about this nutritional programming concept as it pertains to metabolic syndrome. As you probably all well know-we’ve talked about it at length within Functional Medicine Update over the years-metabolic syndrome, characterized by insulin resistance and altered insulin signaling and hyperinsulinemia, has a variety of hallmarks in the patient that you can see. One indicator is generally central obesity (but not always, I might add, because there are metabolic syndrome patients that are rather low in their BMI). We see a modest hypertension. We see some dyslipidemia that is generally associated with increased triglycerides and a lowered HDL level. And we often have a concomitant factor of increased inflammatory biomarkers like high-sensitivity CRP, which is often elevated. This is certainly true in those individuals who go on to have cardiometabolic syndrome, with a principal risks to cardiac disease. We also see altered vascular endothelial function, so flow-mediated dilation is often impaired in these patients and that in part relates to their marginal hypertension. If we look at the range of effects that these dysfunctions can have, obviously it ties itself together with all the vascularity, including vascular function as it pertains to central nervous system function. We have this dementia and Alzheimer’s connection to insulin resistance that Dr. Suzanne Craft was talking about. We’ve got the sleep apnea connection that’s very tightly tied to this. And we’ve got the erectile dysfunction family of disorders that are also endothelial dysfunctions and related to cyclic GMP alterations and G-protein signaling and how that ties to hyperinsulinemia. So a variety of different clinical presentations: sleep apnea, erectile dysfunction in males, memory loss, mood swings, energy problems, increased oxidative stress, problems of retinal function, even skin elasticity problems and alterations in skin, texture, tone, and integrity. All of these, with microvascular changes, are related to insulin resistance. Nutritional programming of metabolic syndrome, although it is a very esoteric title, really spans out into many different important clinical observations that you make in those patients. When you look into their eyes, or you look at their skin, or you look at their blood values, their biochemistry, their body shape-all of these things are tied, in part, to altered distortion of the metabolic web, which then creates this outcome of multiple presentations. It is obviously hard to see within their brains and to understand the neurological implication of this, but over time-not days, not weeks, not months, but generally years, if not decades-of altered insulin signaling, what can happen (particularly in individuals with specific genotypic susceptibilities) is it can induce these problems we are talking about that are ultimately related to neurofibrillary tangles and neuronal apoptosis and ultimately cell death with lowered neuronal reserve. If Your Patients Eat, You Are Doing Nutritional Therapy Nutritional programming is a conceptual approach that I think plays a very important role in our therapeutic decisions. Often I’ll talk to a physician and they’ll say, “I find this interesting, but I actually don’t do any nutritional therapy in my practice. I think it’s an interesting concept but I’m really not involved with nutritional therapy.” And my question is, “Do your patients eat during the course of whatever therapy you employ?” And of course if they are being honest their answer is, “Yes, my patients eat regularly.” And then my response is, “Well then you are doing nutritional therapy in your practice. You’re just not controlling it.” One of the more important variables that might alter the outcome and success of whatever therapy you select is diet. Nutritional programming alters the whole landscape or architecture of how a person is going to respond to whatever you decide to do for them. You are basically not controlling a variable that may have a dramatic effect on the outcome of their success. I think putting it in that context turns it around a little bit because in essence every physician does nutritional therapy whether they know it or not. It’s an ad lib part of an underlying variable that is modifying what they do. If you are really concerned about optimizing successful outcome, then it seems you would want to control diet and activity levels just as you’d want to control compliance and adherence with your primary pharmacotherapy. What this Nutrition Reviews paper really addresses is how metabolic syndrome, characterized by this clustering of clinical cardiovascular risk factors including hypertension, central obesity, dyslipidemia and inflammation, hepatic steatosis, oxidative stress, and insulin resistance ties together with proper nutritional programming of gene expression, and proteomic and metabolomic outcomes that translates into the phenotype. Different dietary personalities or different dietary constituencies play a very significant role in modulating those influences. In fact, what we really might start talking about when we look at diet and its relationship to neurological dysfunction, specifically, is that we are in an era of proteomics in which we are starting to recognize that these signals that we are sending through diet get translated, ultimately, through gene expression patterns into mRNA, which then gets converted in some fashion at the ribosome into native proteins and enzymes that control metabolic function. These then ultimately can be post-translationally modified by glycation, or oxidation, or phosphorylation into the final proteins that ultimately regulate our function. So when we are thinking about the clinical strategy toward the patient who is early stage and starting to lose their memory, we ought to really be exploring what it is that is altering the functional integrity of their web of neuronal function (bioenergetics) that is modifiable on the basis of our intervention, and, in fact, is possibly related and focused on the modification of those primary factors that translate into cellular dysfunction that creates the tissue dysfunction that ultimately is seen as this dementia problem (this loss of memory-cognitive decline). We are in an era of proteomics: understanding this complex matrix of how these proteins that come off our genes are controlled and regulated and how they ultimately regulate metabolic function. If we think of diabetes as a state of altered endocrinological function, we really need to expand that to talk about it as an altered state of physiologic cellular function at the bioenergetic level, at the level of second messengers, at the intercellular signal transduction level. Diabetes is really just a name that we have applied to a very dramatic distortion of the web of physiology that is really an energy deficit disorder if we think about it. Those cell types that are most dependent upon glucose for their metabolism are the cells for which the regulation of this function might be most dependent, so think of where those cell types are. We recognize that the brain cells are principally nourished by glucose. Only in states of starvation do they shift over into ketone bodies as a substrate for energy. So the brain, although it represents less than 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the body weight, consumes almost 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of its oxygen in glucose. It is a very voraciously hungry tissue for glycolytic reserve (glycolytic energy). When we start altering, then, the intercellular signal transduction, we distort this web. We have a stress put on the system , and the metabolism, and the gene expression, and the proteomic activity shift to respond to that stress and now we start moving into this era of what we call a disease. And it spreads out into all sorts of other companion diagnoses: renal failure, retinopathy, erectile dysfunction, NASH (non-alcoholic steatohepatitis), relationships to Alzheimer’s dementia. In other words, all of these conditions fan out from the central feature of distortion of this bioenergetic status. Link Between Telomeres and the Biological Aging Process Lastly, I want to emphasize these things tie together with increased oxidative stress and inflammatory markers, which then causes injury to our genome and can reduce the length of our telomeres. We recognize now that these telomeres that protect the ends of our chromosomes are tied very closely with our biological aging process. There are articles about the association between telomere length and mortality in people aged 60 years or older. In short, telomeres are found in patients with vascular dementia, which indicates low antioxidant capacity. Telomere shortening, as a consequence of these inflammatory oxidative reactions that come from dysinsulinism and altered insulin signaling are associated with cardiovascular disease and Alzheimer’s dementia and increasing genetic risk of people like apo 4s.13,14,15 I hope I have given you some clinical news-to-use with a patient when you are sitting in the exam room. How do we assess cognitive function? What do we think about in terms of intervention? What’s the landscape of modifiable factors that we have available at our disposal as a functional medicine practitioner? Thanks for being with us. We look forward to sharing with you next month.

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Bibliography

1 Csoka AB, Szyf M. Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Med Hypotheses. 2009;73(5):770-780. 2 Nicholl C. Diagnosis of dementia: the usefulness of screening tests varies according to the clinical setting. BMJ. 2009;338:1398-1399. 3 Brown J, Pengas G, Dawson K, Brown LA, Clatworthy P. Self administered cognitive screening test (TYM) for detection of Alzheimer’s disease: cross sectional study. BMJ. 2009;338:b2030. 4 Vafai SB, Stock JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer’s disease. FEBS Lett. 2002;518(1-3):1-4. 5 Sontag E, Nunbhakdi-Craig V, Sontag JM, Diaz-Arrastia R, Ogris E, et al. Protein phosphatase 2A methyltransferase links homecysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci. 2007;27(11):2751-2759. 6 Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci. 2007;27(50):13635-13648. 7 Murray AJ, Knight NS, Cochlin LE, McAleese S, Deacon RMJ, et al. Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding. FASEB J. 2009;23(12):4353-4360. 8 Feart C, Samieri C, Rondeau V, Amieva H, Portet F, et al. Adherence to a Mediterranean diet, cognitive decline, and risk of dementia. JAMA. 2009;302(6):638-648. 9 Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol. 2006;59:912-921. 10 Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA. Mediterranean diet and mild cognitive impairment. Arch Neurol. 2009;66(2):216-225. 11 Danielsson A, Fagerholm S, Ost A, Franck N, Kjolhede P, et al. Short-term overeating induces insulin resistance in fat cells in lean human subjects. Mol Med. 2009;15(7-8):228-234. 12 Symonds ME, Sebert SP, Hyatt MA, Budge H. Nutritional programming of the metabolic syndrome. Nat Rev Endocrinol. 2009;5(11):604-610. 13 Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003;361:393-395. 14 Von Zglinicki T, Serra V, Lorenz M, Saretzki G, Lenzen-Grobimlighaus R, et al. Short telomeres in patients with vascular dementia: an indicator of low antioxidative capacity and a possible risk factor? Lab Invest 2000;80(11):1739-1747. 15 Fitzpatrick AL, Kronmal RA, Gardner JP, Psaty BM, Jenny NS, et al. Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol. 2007;165:14-21.

Welcome to Functional Medicine Update for March 2010. This month we are going to address a topic that I believe many of us in functional medicine might consider to be outside of our normal discussion. We often think of function at the whole-organism level to be kinetic function: the movement of substances, the movement of molecules, the movement of tissues, one against the other, like fascia. We think about movement as stretching muscles. We think about movement as nerve impulses and electrolyte transitions and things of that nature. That becomes our stereotype of the word”function”-this kinetic concept of things in movement, things in transit, things in change, dynamic movement against gradients, membrane transport, and things of this nature. We normally don’t think of function as it relates to structural issues that appear to be static, or rigid, or fixed. We say,”Those are just kind of like the architecture upon which function (the process of change) occurs.” I think you know what I am speaking to now. I’m speaking about the skeleton. We have often viewed the skeleton as this grid-this template-upon which hangs the functional aspects of the body (the various organ systems that do the work to respond to environmental stimuli). In the world of science, the view of the skeleton and how it will impact medicine is dramatically changing. In this issue of Functional Medicine Update we are absolutely fortunate to have one of the world’s experts in skeletal dynamics and bone physiology as our clinician/researcher of the month, Professor Ego Seeman from Melbourne University in Australia. You are going to hear from him directly about the extraordinary work that he and his colleagues have been doing in redefining some of the aspects of skeletal dynamics and the whole nature of the remodeling of the skeleton. Although we think of the skeleton as a fixed mineral matrix, we are going to learn in greater detail how this matrix is really under change all the time. It is another functional part of the organism, responding to environmental stimuli just as all other organs do, and it is in communication (through intercellular signaling processes) with other distant sites in our anatomy and physiology. Differentiating Skeletal Dynamics from Bone Marrow This is a very new emerging view of the skeleton. I want to differentiate this discussion of skeletal dynamics from that of bone marrow. I think most all of us are familiar with the effect of bone marrow on the nature of our immune system–the origin of our red blood cells, playing a very active, dynamic, functional role in determining how critical nutrients like oxygen are transported, and how our body’s immune system works, and the site of various stem cells that have pluripotentiality. I don’t want to diminish our understanding of the functional nature of a component of bone, which is the marrow, but now we are going to be talking (in this particular issue) more about the structural component of bone-the cortical bone, the trabecular bone that relates to strength and the ability to stand upright against the force of gravity, and relates to being able to maintain structure that controls function over time. It’s that component that has often been thought of as being kind of rigid and fixed and not very dynamic. I think you’ll be changing your opinion of that concept (if you had it coming into this discussion) as you hear Dr. Seeman’s thoughts. We are starting to recognize that this organism that we each live in (our body) is very interesting in its ability to respond to environmental stimuli and to modify its function accordingly. Those responses are very individualized. This has been a theme that underscores the tenets of functional medicine: uniqueness, biochemical individuality, homeodynamics, the concept of things in transition and flux, and the concept of web-like interaction. There is this communication across barriers that lead to things working together as systems. You might once again ask the question: How do people ultimately develop their individual response to the environment, knowing that this uniqueness does exist in each individual? It is-again-a result of two factors that we have described so many times in functional medicine: the patient’s history, and the concerns, symptoms, and signs that have brought them into the office. These factors reflect an oral history of things locked in place from the genome (the inheritance factors–Mendelian–that they derived from the combination of the sperm and egg chromosomes), and it is also related to what’s happened from the moment of conception in the marks that are placed on those genome markers, which are called the epigenetic marks. We have spoken at some length over the last two years in Functional Medicine Update, and had some of the world’s experts telling us, about the emerging understanding of epigenomics and epigenetics, and the subordinate field that is emerging from that called nutritional epigenetics. What are these epigenetic marks? They are chemical modifications of certain regions within the chromatin, within the nucleosome, that modifies how our genomic message is read. As we have talked about at some length, it doesn’t mean that the genes in and of themselves have changed their composition-it is not like a mutation-but rather it is an imprinting of the genes with a specific…I call it a”paper clip” or”sticky note” that says either,”Don’t read this message,” or (in the case of a sticky note),”Read here, because this is a part of our book of life that should be read (this chapter or this story).” This imprinting process is very important in developmental biology because it allows an egg, which, once fertilized, has a single set of chromosomes to differentiate upon cellular replication into different tissue types. As you get these replications in embryogenesis, there is an imprinting of the genes that occurs as a consequence of regional differences in where that cell resides within the point of implantation, and all sorts of factors that probably influence the spatial nature of its own environment that causes imprinting to occur. That then results in differentiation of those cells into different cell types from the same chromosomal message. So the same genome gives rise to multiple cell types through this process of epigenetic imprinting and what we call developmental biology. The really remarkable discovery over the last decade or so is not that there are these alterations in the epigenetic message through methylation, or acetylation, or phosphorylation, or ubiquitination of various components of the nucleosome, but rather that some of these marks are labile. They can be put on, apparently, and taken off over the course of living as it relates to different environmental responses. I think this is where the story gets a lot more interesting related to what we call modifiable factors that relate to health and disease over the course of living. There are these marks that seem to be very fixed once put on (so a liver cell stays a liver cell, and a heart cell stays a heart cell), but then there are those marks at different regions of the genome that are more exchangeable and can be put on and taken off as it relates to different environmental situations in which that cell or tissue finds itself. These are the ones that then can lead to locked-in functional changes in the organism over the course of living. This appears to be most commonly apparent in the fetal stage and maybe in infancy, but there are now suggestions that these changes may occur throughout one’s life because of experiences they are exposed to in their environment. These could be nutritional experiences, toxic experiences, traumatic stress experiences, or drugs and other chemical agents. There may be many different early life environmental factors that change the epigenome and then have an impact over time (not maybe in the immediacy, but over the time of life of the individual) on health outcomes. There is a group that has been very actively involved in this work: the department of pharmacology and therapeutics at McGill University (Moshe Szyf and his colleagues). They have been publishing some fantastic papers looking at this whole concept of genomic imprinting and its effect on health outcomes. One of the interesting papers that they authored recently had to do with the influence that long-term pharmaceutical drug exposure might have on epigenetic imprinting and altering the set point for physiology as a consequence of altering imprinting.1 This has to do with people who become drug tolerant, or people whose physiology seems to change after they have been on a medication for some time (even after they take the medication away, their physiology seems to have changed). According to Szyf and his group, this may, in part, be related to the fact that these medications could alter genomic imprinting (epigenetic effects), which then locks in a different gene expression pattern and changes or alters the web of physiology. It is a very interesting concept about long-term effects of drug use (I’m talking about pharmaceutical, but it could also be recreational drug use as well) that alter physiology over the long term. There are many environmental factors that can create these changes in the epigenome as well. We heard from Dr. Michael Skinner in Functional Medicine Update in 2008. He talked about his research in animal models at Washington State University indicating that environmental exposures to various biocides led to genomic imprinting that was then actually hereditable and passed down through generations, increasing the risk to a whole range of diseases in the offspring that was not necessarily tied into their genes per se, but tied into their epigenome as it related to modification by these biocides. In a more recent paper, Dr. Szyf writes about the early-life environment and the epigenome and the fact that there are now several lines of evidence pointing to the early origin of adult onset disease that might go all the way back to infancy.2 The key question has always been: What are the mechanisms that mediate the effects of the early environment on our health? Another important question is: What is the impact of the environment during adulthood and how reversible are the effects of early life later in life? In other words, once imprinted, is it like you can’t do anything about it and you are just kind of stuck from then on with regard to whatever happened to you in infancy and you didn’t even have a choice, or are there ways that you can reverse and kind of take off some of these messages and put other epigenomic messages on in place? The genome, as we know, is programmed by the epigenome, which is comprised of chromatin, and we have talked a lot about that. A covalent modification, then, of DNA by methylation and also by non-coding RNAs modulates epigenomics and ultimately gene expression. All of these are, in fact, responsive to environmental pressures or environmental factors. The epigenome is sculpted during gestation, and it results in the diversity of gene expression programs and distinct cell types. The data that has been accumulating over the past year or so suggests that epigenetic programming of gene expression profiles is sensitive to the early-life environment, and that both the chemical and social environment early in life could affect the manner by which the genome is programmed by the epigenome. With this concept, I think the environment is broad in its scope of impact, both social effects as well as chemical and biological effects. This could be things like infection, drugs, and chemical exposures, as well as traumatic stress disorders, deprivation, a feeling of no love, attribution, or depression. All of these various things can have influence (apparently, based on the animal models that have been studied to date) on the imprinting of the genome into the epigenome, and how that then influences over time the expression of genes in terms of the phenotype. You might call it the”phenome” of the organism. Szyf has proposed that epigenetic alterations early in life can have a life-long lasting impact on gene expression, and thus on the phenotype, including susceptibility to many diseases. He discusses data from animal models as well as recent human studies that support the hypothesis that early-life social adversity leaves its marks on our epigenome and affects stress responsiveness, health, and mental health later in life. The interesting part of this that is emerging is that these factors appear to be somewhat reversible-that these are more labile epigenetic marks that seem to not only be put on but can be taken off or modified with different exposures. I think one of the ways we will see functional medicine applied in the future, as kind of a general and broad concept, is to learn how we therapeutically modulate epigenetic marks that have been put on under times of environmental pressure, and then restore expression patterns back to that which is consistent with a systems biology approach to health. Why would the body shift itself into a pattern of expression of disease? Maybe it doesn’t shift itself into a pattern of disease, but rather it shifts itself into a pattern that is consistent with response to that environmental pressure, and it is adapted (or let’s call it even”selected”) for that kind of response that is advantageous for the organism in the short term. The problem is once stuck in that physiology, when the pressure is removed, that new physiology-that new steady state function-is now a state function that leads to less optimal overall function, and we call that”dis”-ease, or a chronic dysfunction, that ultimately becomes an ICD-9 arterial atherosclerosis, or autoimmune arthritis, or type 2 diabetes, or inflammatory bowel disease, or dementia. In other words, the sequence of events that traveled downstream over time played out, once stuck in this physiology, into a disease that later can be patho-mnemonically identified. I think the work that is going on at McGill is very interesting both theoretically and also practically, because you can imagine over time that using, say, buccal cells from the mouth, one might be able to analyze epigenetic imprinting fairly readily to look at these labile sites, to put a person on a therapeutic intervention program, and to re-measure their imprinting patterns and see, in fact, whether they are being normalized relative to these genes that are associated with stress response, or insulin response, or oxidative stress, or bioenergetics. I think this is a whole new way of functional diagnosis at the cellular and molecular level that is tied into this epigenomic mechanism. We are going to be talking about that in much more detail, but I wanted to just get you to once again see, as we go into a discussion of bone remodeling, that some of these things get stuck early on in life, and then we have to restore function by altering the epigenetic marks. This model I have just described was further advanced in a very remarkable paper that appeared in the American Journal of Clinical Nutrition. I think this is one of those papers that has an”a-ha” associated with it because it really opens up our thinking about potential new routes for remediation of problems that have been historic, and I’m not talking about obesity. Obesity, as a word, almost inspires a Rorschach-like response (a visceral response), because it seems so pandemic and it seems like we can’t do anything about it. It’s coming on almost like a plague or an infection. In fact, those of you who have seen the maps produced by the National Institutes of Health each year that look at the prevalence of obesity state by state in the United States may recognize that when you go back and look at these annual maps that are produced, where the red colored regions of the country represent the rising tide of more than 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the population of a state having obesity, the spreading of that color red over the last 15 years looks almost exactly like that of an infection (like an epidemic). You can actually model it using the same mathematics that you would model an epidemic. Some people even say,”Well, that indicates that obesity is an infectious problem. That there must be an infectious organism associated with obesity because it looks too much like an epidemic-the slow, rising tide of an epidemic.” Whether it is caused by an infectious organism or not I guess is not as important for what I am going to be talking about: the nature of its spectrum of concern in the country. Does the rising prevalence of obesity cause the rising prevalence of things like type2 diabetes, and does it increase the relative frequency of a form of cardiovascular disease that is associated with hyperinsulinemia and insulin resistance? Does that ultimately result in kind of a new public health challenge that basically, in the future, will bankrupt the healthcare system? Let’s start looking at that model-the kind of epidemic proportions of obesity. Does obesity cause those problems or is there something that is causing the metabolic disturbance that then results in a concurrent increase in alteration of energy economy that we call obesity, and diabetes, and certain forms of cancer like breast, prostate, ovarian, and gastrointestinal cancer? And does it also relate to things like cognitive dysfunction and Alzheimer’s disease? Are these all covariables that interrelate with some central force of distorted functional physiology at the systemic level that then plays itself out as all of these things in concert? So it is not that obesity necessarily causes these, it’s that they are all cofactors that respond to the phenotypes as a result of the central features that are creating this problem. And could the central features that are creating this problem be related to things that are associated with epigenetic imprinting? Or associated with distortion of the metabolic web in such a way as to shift all the physiologies in these tissues, such as the adipocyte cells that associate themselves with fat and energy storage, or the hepatocytes, or the beta cells in the pancreas, or the myocytes, or the osteoblasts, or the neurons, or the cardiocytes? Are all of these cell types influenced by some kind of a distortion of the physiological process of the web of interaction by central features in the genes of those cell types? I didn’t talk about endothelial cells (those certainly would be at the head of my list as a cell type that could be influenced as well). All of these cells then have their physiology shifted to a different phenotype as a consequence of these genomic modulations as associated with an environmental pressure. Do these get imprinted and locked into a different state-a steady state-of chronic illness? I hope you can understand the model here. I think it is a very different model, conceptually, than the model of a disease that comes out of eating too much cholesterol in your diet. Or a disease that comes out of just having genes for arthritis. We are really talking about a much more complex interaction of environment with genetic pluripotentiality to express an altered or distorted phenotype that then later expresses itself as a disease and may be locked in to that pattern through epigenomic modulation. Let’s go back to this very interesting paper that appeared in the American Journal of Clinical Nutrition. The title of this paper is”Differential Epigenomic and Transcriptomic Responses in Subcutaneous Adipose Tissue between Low and High Responders to Caloric Restriction.”3Big title. A lot of words. What the heck does it mean? I think this paper really has some”below the water line” significance. The question the authors are asking is this: Does epigenetic modulation that is unique to an individual influence the transcription of their genes in such a way that it modulates or modifies adipose tissue physiology and creates, in a person, a higher risk to obesity that is less responsive to caloric restriction (meaning normal food intake modulation)? These are people who are, say, resistant individuals. These people-even on very extreme caloric restriction-have difficulty losing weight and don’t keep the weight off. Is there any relationship between these people considered to be low responders to caloric restriction and differential epigenomic and ultimately transcriptomic responses in their adipose tissue? Some of you may leap to the conclusion immediately that what I’m talking about here is this: These people, therefore, must be genetically inclined to be obese. That’s not really what I’m saying. What I am saying is there may be genetic uniqueness within the series of genes that control metabolism for which epigenetic marks placed on those genes (in certain family relationships of genes) create, then, a physiological distortion that makes these people more susceptible to obesity and resistant to caloric restriction. Simultaneously, those genes may be associated (when altered in their expression) with insulin resistance, and with inflammation, and with a state of physiology that is a state of alarm. Basically, what I am saying is those individuals who have resistant obesity are individuals who may be in kind of a physiological push-back to environmental factors that have created an alarm response in which the adaptation of the body is to store and to maintain an energy storage so that the whole physiology shifts into this insulin resistance/inflammatory”mount the guard and do battle” type of status. What did they find in this very interesting study? This was an intervention study done in individuals who had biopsy work done by taking their subcutaneous adipose tissue and measuring it using PCR (polymerase chain reaction)–kind of gene amplification–looking at various genes and then examining the epigenetic imprinting using bisulfite reactions to actually measure the methylation patterns in the genes. They looked at DNA methylation and gene expression as two variables in the subcutaneous fat. When they did this they found that there was a very dramatic difference between the low responders and the high responders to caloric restriction. High responders were people who, if you put them on a modest calorie restriction, lost weight and improved their body mass index. The low responders were individuals who, on a similar calorie restriction, would not lose weight; they would be resistant to that, and it would appear as if thermodynamics were not working on their side. What the study authors found is the low responders had a different methylation pattern and a different transcriptomic (or different expression pattern of their genes) than the high responders. Which Genes Are Epigenetically Altered? If you are mapping the epigenome between the two groups, can you define the genes that appear to be different in the way they have been epigenetically marked? The answer is yes, you can. It appears as if the genes that are likely altered between the low and the high responders are those genes involved in metabolic pathways related to things like angiogenesis, and things like insulin sensitivity, mitochondrial oxidative phosphorylation, and insulin secretion. The genes, once they were kind of personalized to their function, clustered around these characteristics that associate themselves with (in an altered state of function or expression) the diseases that are common today, like diabetes, and neuronal apoptosis/dementia, and inflammatory conditions, and cell replicative conditions that we ultimately associate with cancer. Why do certain people have a different epigenetic response to their environment compared to others? I think that’s a very interesting question. The question cannot yet be fully answered, but it may be that the response they are having to their environment in part relates to the slight differences in the environment that we don’t yet understand. The environment is a very complex situation, just as the genome is. We are exposed to many, many things, a number of which we still have very little understanding. Not only things like chemicals and radiation within the known short wavelength/ high frequency part of the electromotive spectrum, but we also are exposed to long wavelength energy, like radio waves and microwaves. We have psychosocial interactions that alter our function that you can’t even measure in EMF, really. There are different kinds of functional frequencies that modify our neuroendocrine immune function in such a way as to create different states of outcome. I would say that it would be very hard for us, in a controlled experiment, to really understand exactly what environmental circumstances influence what genomic imprinting and create what epigenetic changes. But I think we can say from the study (at least we can conjecture) that there is evidence that epigenetic changes do, in fact, account for part of the differences in outcome in things like obesity and resistance to dieting or proper calorie control, and inflammation and insulin resistance, and things of that nature. In monozygotic twins, there are often very different discordance between the body weights. If obesity was strictly a genetically controlled characteristic with a single allele-type locus, we would see a very strong concordance of obesity between twins. There is a relationship, but there is discordance. Although they had the same genome, the imprinting of their genes over the course of living between two identical twins was altered. The outcome was they had different patterns of weight and different body mass indices, and (I would offer at least as a hypothesis) different disease risks and different mediators that would be floating around in their bloodstream and in their tissues that would modulate function in different ways. This model of epigenomic imprinting and its influence on the trajectory of physiology over time and how it ultimately expresses itself in the phenotype is a very important part of our understanding of how to treat (in the broadest sense of the word”treat”) a patient. There may be certain loci of the genome that, when imprinted, are very difficult to change and require very aggressive intervention to result in lasting change and low recidivism. And then there may be other regions of the epigenome that are more labile and more easily changed by more mild intervention. Often the theme with drug therapy is if the patient doesn’t get a response in a couple of days or a week, somehow the therapy didn’t work. People are used to that”quick fix” mentality. But to really alter the epigenome in such a way as to recreate a functional state of less disturbance might take much more aggressive intervention, and for a much longer time. I think, therefore, our patients need to have patience. They need to be cognizant of the fact that to alter basic cellular biochemistry and genomic imprinting it may not just take a week, it may take months. And it may take a very aggressive therapy, not just a mild therapy, to reset some of these processes. By the way, some of these imprinting processes may require augmented doses of specific nutrients in order to overcome blocks, or to wipe out one physiology to be replaced by another. Knowing that many of these epigenetic marks are, in part, dependent upon nutrient status may be one of the extraordinary thresholds for understanding why certain high-dose nutrient pharmacology is beneficial in the short term to restore certain types of physiological functioning. I think that we are starting to see a new concept evolve here that gives rise to a different way of looking at origin of disease and how it can be modified–how to ask the right questions in the clinic, what kind of therapeutic agents are required to modify the function over the long term, and what kind of tests might we need to develop in order to really understand how we are shifting this epigenomic imprinting. I think this paper on the differential epigenetic and transcriptomic responses in subcutaneous adipose tissue is like the tip of the iceberg. I think we are going to be seeing many more of these papers and this kind of research being published over the years to come. This kind of work helps us to understand what genes might be the most labile, what types of things differentiate responders from non-responders, and what type of potential therapeutic agents might be necessary for a new pattern of imprinting that creates positive functional outcome With that in mind, and to get ready for the discussion with Dr. Ego Seeman about bone and recognizing that it also is a tissue in dynamic interrelationship and has its own epigenetic origin and imprinting, let’s talk a little bit about vitamin D.\ Vitamin D, as we know, is a bone-related nutrient (we all learned that early in school). We now recognize, with more recent work, that vitamin D is a seco-steroid hormone, as we talked about with Dr. Trevor Marshall recently in Functional Medicine Update, and has remarkable pleiotropic effects on many different factors of genome expression as a member of the nuclear orphan receptor family of modulators. It is a central factor in many of the processes that I am describing, pertaining to how genes get expressed into function. Vitamin D signaling plays a very important role in immune-mediated disorders. There is a wonderful paper that appeared in Molecular Aspects of Medicine in 2008 that is about the hormonal form of vitamin D, 1,25-dihydroxy cholecalciferol, and its influence on the vitamin D receptor to form this kind of heterodimer with things like T3 from thyroid hormone or the dimerization with vitamin A to induce certain gene expression patterns.4 The evidence seems to indicate that the physiology of vitamin D and its relationship with the vitamin D receptor is such that it plays roles in modulating stress response genes and genes that are related in the immune system to inflammation and inflammatory sensitivity. It may be as a consequence of these factors, which are many in their mechanistic origin, that we are seeing so many clinical impacts of vitamin D when properly modulated or properly normalized in a person by looking at their 25-hydroxyvitamin D level as a biomarker. We are starting to see so many different influences: type 1 diabetes, rheumatoid arthritis, neuromuscular disorders and MS, and aspects that are related obviously to immune function and infection, and even chronic pain syndrome. There was a recent report of women who are on aromatase inhibitor drugs and have chronic myalgia and arthralgias that had remediation of their pain syndromes when supplemented with high-dose vitamin D.5,6 I think that we are starting to recognize this from a mechanistic level as an example of how a modulator of genomic expression, in this case the seco-hormone 1,25-dihydroxyvitamin D3, can play such a significant role in modulating so many functions in the organism. So it is not just like one drug for one outcome. It’s like one biological agent to modulate a variety of gene expression patterns that control all sorts of functions in different cell types in unique ways. That would then raise the question: If it is so profound in its influence, would there be the possibility of too much of a good thing? That is, in part, what Dr. Marshall was talking about in his interview. There is a very nice article titled”The Yin and Yang of Vitamin D Receptor Signaling and Neoplastic Progression: Operational Networks and Tissue-Specific Growth Control.”7 This appeared in Biochemical Pharmacology in 2010. In this very well-written article, the authors write about the substantive evidence that implicates vitamin D receptor, along with 1,25-dihydroxyvitamin D3, in modulation of tumor growth. Both human and animal studies indicate that the tissue specificity is very high, and epidemiological studies have shown both inverse (meaning high vitamin D lowered cancer incidence) and also direct relationships (meaning high vitamin D and increased risk to cancer) between serum 25-hydroxyvitamin D levels and certain solid cancers. Vitamin D receptor, as we learned is very pleiomorphic; it controls many, many different genes. It has to do with carcinogen-induced tumorogenesis in tissue-specific model systems. It has to do with all sorts of things related to cell cycling and cell replication. The question is: Is there a place where too much vitamin D-in other words, too high a level of 1,25-dihydroxyvitamin D3-might, in fact, influence adversely some of the cell signaling properties that are associated with vitamin D? The conclusion that I can derive from this article is: We should be aware of that. Everything has a level at which it gets to be too much, including air and water, and that we ought to be in that safe range with the appropriate dosing so that we are somewhere in the 30-50 nanogram per milliliter level for 25-hydroxyvitamin D, but not assume that if a little is good, a whole lot more will be better. We ought to once again be mindful of the very subtle controls and metabolism that these bioactive molecules-these regulators-that regulate at what I call metabolic acupuncture points in this web of interacting physiology play very important roles. With that, let’s move to Dr. Ego Seeman, and really try to take this concept of structural integrity and functional integrity into a better understanding of bone and bone physiology.

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INTERVIEW TRANSCRIPT

Researcher of the Month Ego Seeman, MD Austin Hospital and Northern Health University of Melbourne Victoria Australia www.unimelb.edu.au Here we are once again at that section of Functional Medicine Update that I know you, like I, look forward to with such great anticipation. You’re not going to be disappointed this issue. We have the fortune of being telephonically linked with a person I consider to be the world’s leader in the area of bone mineral metabolism, bone integrity, and bone strength, and that is Professor Ego Seeman, who is at the University of Melbourne, Department of Endocrinology. I think his name (and reputation) precedes him. You probably don’t need me to say a lot about him other than the fact that he has won extraordinary recognition for his over 270 publications and 22 book chapters in the area of bone mineral metabolism. He has recently been awarded the IOF Medal of Achievement, awarded every two years by the International Osteoporosis Foundation. I think one of the things that strikes me about his work is it is both novel and integrates so much prescient information into an understandable package. This is very difficult to do as a primary researcher-to look at the body of the world’s work and to take your perspective and integrate it and come up with something fresh and novel that really moves a field forward. Dr. Seeman has done that. Dr. Seeman, it is really a privilege to have you as a guest on Functional Medicine Update. Maybe we can just start talking a little bit about the difference between bone integrity, bone mineral metabolism, and bone quality. I know that you have done extraordinary amounts of work looking at this kind of differential effect of osteolysis/osteogenesis, and then how that ultimately translates into the clinical sine qua non, which is bone quality. ES: Thank you. Thanks for saying those nice things. Only my mother would believe all of that sort of stuff you said, really. I guess that I do not distinguish the words”bone quality” or”bone density.” In fact, I think the word”bone quality” is actually quite a dangerous word, itself. From a historical point of view, the place that we have come to now is a product of many things, but the main one being, how could we measure those qualities (with an”s”) of bone that determine its strength? Or, in other words, its ability to resist breaking? Its ability, on the one hand, to tolerate loads and be stiff, so that it doesn’t bend too much, or it is sufficiently flexible so that when I’m running or doing a jump from a ladder down onto the ground, when the impact of my body weight is such that the energy that is conferred by my body weight to the bone is actually absorbed by the bone, where the bone functions a bit like a spring, so that it can bend a little, just to absorb the energy (and the energy is absorbed by the change in length of the bone) without it actually snapping? These are seemingly contradictory properties of bone. On the one hand it needs to be stiff, but not too stiff. On the other hand, it needs to be flexible, but not too flexible and bend too much, as it were. Bone is unique. It is amazing in that it can do these two seemingly contradictory things. And it does that by having different material composition. So on the one hand, it’s a rope, it’s a string, it’s like one of these big helices of big ropes that you see boats tied to at the end of a pier. But that’s not the only thing. These ropes can extend a little, compress a little, shorten a little, lengthen a little. Yet to confer the stiffness of the bone, the rope is then impregnated with crystals of calcium hydroxyapatite. Nature chose calcium hydroxyapatite for certain reasons. It could have taken particles of iron, or glass, or stones, but no, it took calcium hydroxyapatite. And it put just enough of this mineral into the rope to give it those special material properties that make it stiff yet still flexible. That’s one level. That’s the material construction, or the material structure of the bone. That material then is taken and threaded by God, if you will, through the eye of a needle. And then that needle is used to sew a material-a structure, a three-dimensional structure like a house, or a bridge, or a support for a light in a street-into this three-dimensional architecture that also has this property of strength. So when we talk about the”quality” of bone, I prefer to use the term that was actually first coined, I think, by Michael Parfitt, who is really one of my great heroes in the bone field, and that is bone”qualities”-the different material composition (the rope and the mineral), and then the three-dimensional structure of bone that confers its strength. Do you want me to go on? JB: No, I think that’s a very good way to set the tone. You’ve got many wonderful publications, one of which really struck me was back in…I think it was 2006…in the New England Journal of Medicine on bone quality and the structural basis of bone strength.8 You talked a little in that article about the heterogeneity in the pathogenesis of bone fragility because I think most people think about bone fragility being associated with increased bone resorption, but yet when you showed that diagram in the article it was quite fascinating because the heterogeneity between bone formation in the osteoblasts and osteoclastic resorption didn’t directly correlate with fractures. So it seems like there is something else going on. Could you tell us a little bit about that? “Flying” Through Bone ES: Okay. When bone is built…bone is built by a machine. It is built by what I like to refer to as a”cellular machinery.” Although people think of bone as like some hard”stuff,” I think it’s a wrong way to think about bone. Bone is a very complex structure that is made of these crystals, and if you could get a tiny space machine…You remember that movie? I can’t remember the name of it, where the guys got shrunk down and they were then injected into a vein… Fantastic Voyage, I think it was called…20 years ago, probably. Anyway, if you could get a tiny airplane, you could fly into the bone. You could fly into one of the canals, just like the many freeways in the Los Angeles downtown area. And you could fly around these corridors and canals of bone that contain vessels and nerves and then they branch off to the left and the right, and so this maze or myriad of canals that form the canals inside cortical bone. It’s called compact bone, but it’s not really compact at all; it’s just compact when you look at it from an airplane down. It really has all of these canals. These canals are made of surfaces. They have a surface, and on the surfaces, this is where the action is. The cells of bone that line those surfaces can become activated, so that when there is a tiny crack within the matrix of the bone itself and there is damage, that crack actually tears the nervous system of bone, which consists of osteocytes with their dendrites (with their tentacles). It is like the nervous system in the brain. These dendrites, once they are torn, they kill, they knock off the little osteocyte cells that undergo death by apoptosis. This is a very fashionable way to die. Anyway, so necrosis is out, apoptosis is in in the 21 st century, and these cells die. When they die, they send signals, and we don’t quite know what those signals are yet. They send signals to the lining cells that form the walls of these many canals. And then cells are recruited-the osteoclast and osteoblast cells are recruited. And the osteoclast cells start to dig down to find where the damage is. They target the damage, and nature has this way of repairing damage. The osteoclast cell, which is like going to the dentist, comes in, removes bone, removes the crack in the bone, then there is what is called a reversal phase (nothing much happens), then the osteoblast cells come in and they fill the cavity like a dentist, just filling the hole up with new bone, which undergoes primary and then secondary mineralization. In other words, crystals of calcium hydroxyapatite are deposited. These crystals then enlarge, and you reform the hole-you refill and reconstruct that hole that has been formed and fill it up. The problem is that after about 25 to 30 years of age, this cellular machinery that removes old bone and puts new bone back becomes sick. Something happens to it. Either the holes that are dug are too big, or not enough bone is put back in the bigger hole, or both of them. And that’s where the heterogeneity comes in. Some people dig bigger holes; other people don’t. Some people put less bone back; other people don’t. And you have a different pathogenetic mechanism from person to person that finally translates into fracture. We think,”Oh, everybody’s got fractures. It must be the same cause.” But it is not. And it varies from person to person. And we’re still not very good at identifying the specific abnormalities-the cellular abnormalities-responsible for making fragile bones in one person as opposed to another. And once we get better at doing that, and once we get better at identifying whether some people have a decayed cortical bone full of holes, or a trabecular honeycomb architecture that has been decayed and destroyed, we can better target treatment in accordance with the specific pathogenesis in that individual. And I hope that once we do that, we’ll be much better at preventing fractures than we are, because we’re not bad at it, but we’re not really great at it. And we’re not really good at preventing those bad fractures, like hip fractures and what’s called nonvertebral fracture (all of the long bone fracture-forearm fractures, pelvic fractures, upper humorous fractures, ankle fractures); we’re not that good at preventing those right now. JB: For me, as a non-expert in the field, that raises a very interesting question. This is truly a blank slate question. It sounds to me, as you so eloquently describe this architecture of bone-I felt like I was on the Invisible Voyage, with you, there, that was really fun, actually, as we went into the trabeculi of the bone-I’m wondering…these cells that line these surfaces-this sounds almost like a model that comes out of vascular biology with endothelial cells lining the vessels, one-cell-thick… ES: Exactly. JB: Is this partly analogous to an endothelial dysfunction of bone? ES: There are analogies. I agree that we could look at bone as a vascular structure. This is very complicated and I don’t understand it. I’m a clinician. I’m not a basic biologist. Forgive my ignorance, here. The process of bone remodeling is like the clotting cascade, but much more complex. It’s not just two cells. It’s not just a sort of two step with osteoblasts and osteoclasts. And it’s not even a three step, with osteoblasts forming bone, osteoclasts resorbing bone, and then the other cells I talked about (the osteocytes that are buried in the bone) forming the nervous or the sensor system. These three cells are the three big ones, but then there are lots of other cells in the marrow and within the blood stream. The T cells, for example (the immune cells), that participate in the cascade, which renders damage when damage occurs. There is a cascade of cellular events that lead to the production of osteoclasts (osteoclastogenesis) and osteoblasts (osteoblastogenesis). And those cascades involve lots of cells, including vascular cells. And so the coming together of vascular cells to the lining cells of the bone…these come together to form what is called a bone remodeling compartment. And there is communication between the vessel, which delivers precursors of both osteoblast and osteoclast cells to this remodeling compartment, which then targets the damage. It is very hard to discuss this without a blackboard and some slides, but I hope you sort of get this picture. But it is a very complex cascade of local cytokines, local cell differentiation, coming to remodel the bone to keep it new. But again, as we age, that remodeling machinery that is so vital and healthy and can repair bone in youth, starts to become abnormal as we age, and particularly in women. With bone remodeling, with the loss of female hormone, and with the loss of female hormone in men as well, incidentally (because testosterone is converted to estrogen in men and estrogen is important in both sexes), with this advancing age and the rapid decrease of female hormone (estrogen) after menopause in women, and the slower decrease of testosterone and estrogen in men, we have abnormalities in the intensity of remodeling-not just the balance in remodeling with either increased resorption and/or decreased formation in that resorbed or excavated cavity. New Drug Therapies Are Being Developed JB: Now you’ve raised all sorts of interesting questions for me. Let’s take this, if we can, one step at a time. First of all, cell signaling and activation through different altered gene expression profiles that are related to unhealthy bone. I know that Amgen is working on approval in the States of a drug that is a monoclonal antibody for receptor of NFkappaB ligand that is part of the signaling transduction pathway that you are describing. Do you have any sense as to whether this going to be a major breakthrough? ES: Yes, I think it is. I think it’s a great breakthrough. I’m a co-author on one or two of these papers, and I work and consult with Amgen, as I do with other companies, and they are a very exciting company. They are very innovative. When we start to understand the physiology and the pathways of bone, which I think has been one of the major contributions of genetic research (to identify novel pathways), the textbooks, as you and I knew them when we were kids, are being completely rewritten. It’s no longer that bone is bone, or the brain is the brain, or the liver is the liver. We now recognize that bone is regulated by brain, and that bone, itself, regulates insulin secretion, for example. And so, everything is being smashed to pieces, and it’s fantastic. You can either embrace this new information or be fearful of it and say,”Oh my God, I’ll never know anything.” Well of course we’ll never know anything. It’s infinite in its complexity. Coming back to RANK ligand, genetic research has recognized that this RANK ligand pathway, that a protein that is present on osteoblast precursors is like a key, and it fits into a keyhole on precursors on osteoclasts that switches these keyholes on, and these osteoclasts differentiate to become Pacmen, and they start eating up the bone. So here’s a drug-the antibody to RANK ligand-that in its essence, stops the key from going into the keyhole, and stops the synthesis of the osteoclasts, which is a very novel way of stopping bone resorption. Because the other way that we have is the family of the bisphosphonates, which kill osteoclasts once they are formed. Mind you it’s not the only way they work. They work in many, many different ways. But that is one of the main ways that the osteoclasts, that the bisphophonates…you take the bisphosphonate tablet, then it goes into the bone (it’s absorbed onto the bone). The osteoclast comes, resorbs some of the bone, eats it, then it takes in the bisphosphonate that essentially knocks it off. So we have different mechanisms of action. As we learn newer and newer pathways of the cellular biology, if you will, of bone resorption and bone formation, this gives us doors into finding drugs. And another one drug that is being developed is the anti-sclerostin antibody. Do you want me to go on about that? JB: Before you do that, let me just make sure we check in on your very eloquent discussion of RANK ligand monoclonal antibody. I think what that would suggest, obviously, is that there must be something going on in the bone remodeling unit that’s related to activation of the inflammatory cascade that is suppressed by RANK ligand antibody. And that that might then also say why when women lose estrogen or men lose estrogen that there is some different expression patterns of various cytokines and NFkappaB that relates to activation or, let’s say, taking the foot off of the brake and allowing this inflammatory process to occur. Does that, in part, say something about the mechanism of estrogen as an anti-resorptive agent? ES: Yes, maybe. This is a little out of my expertise. I’m a little reluctant to start talking about inflammatory cascades and so forth. That’s outside my training. But other than to say that there is no question that with estrogen deficiency, various inflammatory local factors or cytokines, interleukins are released, and they are part of this cascade leading to increased bone remodeling and bone resorption leading to the loss of bone. But I don’t want to go there. JB: That’s great. That’s fine. Does the 1,25-dihydroxycholecalciferol play any role in this process, as we are describing it? ES: Yes. It may be. There are systemic factors like parathyroid hormone, vitamin D metabolism that may be contributing. I don’t think that these are major factors because bone remodeling is time and space dependent. In other words, it is focally specific. You can take one point in bone, which is quiescent (quiet-nothing is happening), another point in bone, where there is resorption, another point where there is a different phase of resorption, another point where there is a different phase of resorption, another point where there is formation. These are locally regulated events, and the precise regulation of these local events is, again, very point-specific. I’m not sure that systemic factors would explain that very well. Controversy About Bisphosphonates and Necrosis of the Jaw JB: Okay. Let’s go back to your bisphosphonate. There has been-at least from my reading-some concern about the effects on osteoclasts and mandibular necrosis. Is that a real clinical concern or is this just an artifact? ES: With prolonged bisphosphonate therapy and repeated therapy, particularly in patients with cancer who are given lots of bisphosphonates, often to suppress hypercalcemia of malignancy, after prolonged therapy, there have been case reports of what’s called osteonecrosis of the jaw, which generally follows a tooth extraction. Is it real? Yes. Is it related to the bisphosphonates? Probably. Is it common? No. Is it common in the postmenopausal osteoporosis? No. Has it been exaggerated by the dentists? Yes. Is it causing problems for patients and doctors? Yes, it is. It is a real event, but it is very uncommon. It is doing more harm than good with this broad advertisement or discussions that are really disproportionate to the problem. The mechanisms are not understood; they could be effects of bisphosphonate actually on the endothelium in the mouth and altered healing within the socket of the tooth. SERM Connection to Bone JB: I think that’s very helpful. Let me move onto SERMs because this is another area, obviously. You’ve had some very interesting tissue seal activity, something like tamoxifen (its effects on ERalpha and ERbeta and its differential effects on breast versus bone). Could you tell us a little bit about the SERM connection, because that seems clinically very interesting? ES: Yes, it is interesting. The overwhelming problem with the SERMs is that they do not reduce non-vertebral fractures, okay? That’s it. There are now 8-year follow-up studies with raloxifene. The studies are very well executed and designed, and there is no evidence that the SERMs reduce non-vertebral fractures.9,10 More recently investigated SERMs confirm this. The great hope was that lasofoxifene and some of the other newer SERMs that have been studied would reduce non-vertebral fractures, but this has not been shown to occur. Why is that important? It’s important because in the community, the majority of fractures are non-vertebral. Our history came from the genius Fuller Albright, who first recognized vertebral fractures in postmenopausal women in 1941, about 70 or so years ago. Since that time (the next 30 years), there was enormous concentration on the pathogenesis of vertebral fractures. So much so that when you say to someone,”Do you have osteoporosis?” The immediate thought is,”Am I at risk for a vertebral fracture?” And that’s wrong. That is the 20th century view of osteoporosis and we have to change it. The burden of disease is non-vertebral fractures, and therefore we need drugs that reduce both vertebral and non-vertebral fractures. The SERMs are very interesting drugs, there is no doubt. But they do have these opposite effects: they reduce the risk of breast cancer, they do reduce the risk of vertebral fractures, and that makes them very attractive (and they also have very anti-lipid effects that have go some benefits but not others). So they are interesting drugs, but I’m not sure that they are the right drugs for this field. JB: Is the difference between the vertebral and non-vertebral fracture related to the differing trabecular versus cortical bone physiologies? ES: Yes. That’s a very excellent question. The short answer is yes. Eighty percent of the skeleton is cortical; 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} is vertebral. Some of the work that I have been doing that has been driven, actually, by one of my students (his name is Roger Zabaze-brilliant young man), has been directly looking at cortical bone and making the point that the loss of bone with aging is mainly cortical, not trabecular.11 A woman halves her skeleton during aging; she loses half of her skeletal volume or skeletal mass. Now only 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the skeleton is trabecular. There is no way that this can all be trabecular bone. Most of the trabecular bone that we have is lost by about the time that we get to 75-80 years of age. And after 65 years of age, most of the loss of bone is cortical, and it is coming from what is called the intra-cortical compartment. This is Roger’s work. He has shown that these holes-these cavitations within the cortex itself, which arises from the Haversian canals that I described to you before (all those canals we were flying through)-they are the source, and these holes enlarge, so you end up with a cortex called compact bone that, by 80, looks exactly like a sponge when you look at it in cross section. That’s why the orthopedic surgeons are having such a tough time keeping a hip prosthesis in when they replace the hip-keeping it firm-because there is nothing to hold onto anymore. That bone is a sponge. It ain’t compact bone any longer. JB: If we were to start looking at the clinical approach that you have to deal with everyday, given that we are still imperfect in our knowledge and probably will be for some time with the complexity of this field, how do you assemble this information in designing the program for the patient. ES: That’s a very good but a very tough question. I think firstly we need to think about bone as a structure, as a complex three-dimensional structure, and we need to have methods to define the abnormalities in it in specific terms. In other words: the size, the cortical thickness, the area, the number of holes, the number of trabeculi, the thickness of the trabeculi, the bone remodeling, the resorption markers, the formation markers, and whether a patient has a fracture or doesn’t have a fracture, and take the clinical and biochemical and structural features and put them together into a matrix where we can define risk. What we do in the 21st century so far is that we are using bone densitometry, which I think is a useful method, but it’s not the be all and the end all. For example, most fractures in the community occur in people with bone density above minus 2.5 T-score. In other words, in people who don’t have osteoporosis, as we define it using the bone density machine. We’ve got to take the red pill and get out of the matrix of the BMD machine. Many of these people who are breaking bone who have normal bone density actually have high porosity, or architectural abnormalities. We need to identify those abnormalities and we can then target treatment to those people who have it. We have to learn how to investigate patients more completely than we are currently doing, and then we will be able to target treatment to those, and, of course, avoid treating people who may have osteoporosis by the bone density machine, but that simply may be not osteoporosis at all; they’ve just got smaller bones that are measured by this silly machine and it looks like their BMD is low, but in fact their bones are just small. You follow what I mean? JB: Absolutely. ES: Okay. The machine we are using is okay. It was a good beginning, but it ain’t where it’s at. We need much better technology. And we are getting there, you know. We are getting this technology. And we are getting better measures of bone remodeling. I think that the future is bright. There are advances. And you can bad mouth all of these drugs like the bisphosphonates and so forth, but you know, they are pretty good drugs. And by and large, for the majority of people, they are pretty safe. We just need to learn how to use them better. JB: When you do your serological evaluation, is there a panel that you find most useful in pulling out some of these markers or is really there is no discreet biomarker panel that would be better than any others? ES: This is a little out of my area as well. I’m not an expert. My buddy, Pierre Delmas, was the king of that. You can use a range of bone markers. A bone resorption marker such as NTX, or bone formation marker such as osteocalcin, or better still, P1NP. And we are still on a learning curve with these markers. There are still problems with them. The blood has to be taken properly. It has to be taken fasting, first thing in the morning. It has to be separated quickly. There has to be a lot of meticulous care to get the reproducibility that we need (the within-patient reproducibility that we really need) to say,”Okay, we can use the marker. This guy or this woman is a high bone remodeler. Let’s treat her with drug X. This person is a low remodeler. She’s not losing much bone. Let’s leave her alone right now.” We are getting there, and we are better at it, but we’ve got to be much more meticulous about how we sample than is routinely done in day-to-day clinical practice. JB: Very good. There is one last thing. By the way, you have hit on so many extraordinary little bits of wisdom and we could follow each one of these, probably, for hours. I want to ask one follow-up on something you were speaking to earlier, which is this throwing out the physiology textbooks, where we have siloed each individual bit of our anatomy and physiology as if they are independent and separate and now we’ve looked at things more as a systems biology approach to physiology. There is an emergence in the literature that I have seen around bone, specifically, of the gut connection to bone physiology. Now we are seeing things on serotonin and the Wnt signaling pathway and through the lipoprotein receptor 5 polymorphisms. Is this something that looks like it is going to stand up? ES: Yes, it’s fantastic and the guy to talk to-you should ring him-is Gerard Karsenty. He’s at Columbia. I think he is one of the great-really a genius-in bone. You should talk to him. I think this is his shtick, you know. You should talk to this guy, not me. This is out of my league. JB: I don’t think there’s anything out of your league in this area from the reading of your papers, but you are being very kind. Links Exist between the Gut and the Brain and Bone Metabolism ES: It is out of my league. You talk to him. I mean, he’s the guy that has done the work, that has put it together, and he’s a visionary. He has found the link between this peptide (uncarboxylated Gla or osteocalcin-this particular form of osteocalcin) and that it increases the insulin sensitivity and secretion. He’s also found the link between the gut and the brain and bone metabolism. He’s the main man! Talk to him.12,13 JB: Obviously you hit on vitamin K indirectly, there, with the uncarboxylated versus carboxylated Gla. There is a lot of interesting nutritional endocrinology, it appears, in this field as well. ES: That’s right, and he’s actually done some work in that as well. This is the beauty of biology. As the world is infinite in its galaxies outward, it is also infinite in its galaxies inward. Either we embrace it and say we’re never going to know anything-and we don’t, we don’t know anything-but we’re going to see little bits of the magic of life. That’s what it is: magic. JB: Beautifully said. As we close, is there anything, to clinicians, that you would like them to have as a takeaway thought? It’s hard to summarize all of your work-270 plus papers and chapters… ES: To clinicians I would say,”Don’t believe anything. Don’t believe anything I’ve said. Don’t believe anything you read. Just learn to be skeptical and embrace skepticism.” I think it is the pathway to progress. That’s the fun of science: not believing your friends, and not believing anything in a conference. That is how critical reading is absolutely crucial to survival of science and medicine as a scientific method. Without that proper design-the proper execution of studies-we know nothing, and we can’t believe anything we read. And it doesn’t matter where it appears. It doesn’t matter the name of the person. It doesn’t matter if it is The New England Journal of Medicine. That does not make it right. What makes it right is reading the method section and saying,”Yes, these guys designed the study right, they asked the right question, they answered and executed the study properly, so therefore I can believe what they have said.” But if they can’t-if they haven’t done it right, if there are 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} dropouts in the trial, and you do calcium and vitamin D studies but everybody’s calcium and vitamin D replete-you can’t even test the hypothesis that calcium deficiency or vitamin D deficiency causes the disease much less test whether replacement of calcium or vitamin D has any benefit, because you have a population that wasn’t calcium- or vitamin D-deficient in the first place, you can’t make any inferences. And that’s an example where the calcium and vitamin D field completely breaks down. I’ve got a paper in press where I go through all of that. I think it is the American Journal of Kidney Diseases. I’ve gone through that literature pretty carefully. My message is critical reading is the future. JB: I can see why the International Osteoporosis Foundation president, Professor John Kanis, said about you,”Dr. Ego Seeman is among the most respected thought-leaders in the field of osteoporosis research and is renowned as a scientist, educator, scientific editor, and speaker.” I think you fulfilled all of those in this brief discussion. I want to thank you very, very much, Dr. Seeman. It is clearly obvious that medicine is built on the shoulders of people who have this critical thinking, as you have exemplified. Thank you very much for being available all the way down there in Melbourne. We really appreciate your work. ES: Thanks very much. Thank you for that. Goodbye.  

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Bibliography

1 Csoka AB, Szyf M. Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Med Hypotheses. 2009;73(5):770-780. 2 Szyf M. The early life environment and the epigenome. Biochim Biophys Acta. 2009;1790(9):878-885. 3 Bouchard L, Rabasa-Lhoret R, Faraj M, Lavoie ME, Mill J, et al. Differential epigenomic and transcriptomic responses in subcutaneous adipose tissue between low and high responders to calorie restriction. Am J Clin Nutr. 2010;91(2):309-320. 4 Baeke F, van Etten E, Gysemans C, Overbergh L, Mathieu C. Vitamin D signaling in immune-mediated disorders: evolving insights and therapeutic opportunities. Mol Aspects Med. 2008;29(6):376-387. 5 Waltman NL, Ott CD, Twiss JJ, Gross GJ, Lindsey AM. Vitamin D insufficiency and musculoskeletal symptoms in breast cancer survivors on aromatase inhibitor therapy. Cancer Nurs. 2009;32(2):143-150. 6 Khan QJ, Reddy PS, Kimler BF, Sharma P, Baxa SE, et al. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat. 2010;119:111-118. 7 Campbell FC, Xu H, El-Tanani M, Crowe P, Bingham V. The yin and yang of vitamin D receptor (VDR) signaling in neoplastic progression: operational networks and tissue-specific growth control. Biochem Pharmacol. 2010;79(1):1-9. 8 Seeman E, Delmas PD. Bone quality-the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354(21):2250-2261. 9 Hansdottir H. Raloxifene for older women: a review of the literature. Clin Interv Aging. 2008;3(1):45-50. 10 Goldstein SR, Duvernoy CS, Calaf J, et al. Raloxifene use in clinical practice: efficacy and safety. Menopause. 2009;16(2):413-421. 11 Borah B, Dufresne T, Nurre J, et al. Risedronate reduces intracortical porosity in women with osteoporosis. J Bone Miner Res. 2009 July 6. [Epub ahead of print] 12 Rached MT, Kode A, Silva BC, et al. FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest. 2010;120(1):357-368. 13 Yadav VK, Ryu JH, Suda N, et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 2008;135(5):825-837.

Welcome to the Functional Medicine Update for April 2010. What an issue we have in store. We have been so fortunate over the last year to have the ability to talk with some of the most remarkable founding figures of the field of functional systems biology medicine. You all heard iconic discussions with Dr. Linus Pauling and Dr. Abram Hoffer, both of whom I had the privilege of interviewing. In the case of Dr. Pauling it was back in the 1980s, and with Dr. Hoffer it was in 2009. In the 80s, Dr. Pauling forecasted where the field might go, and Dr. Hoffer assessed where it was, where it is, and where it might go as we move into the 2010 decade and beyond. We’ll continue that theme. We have a remarkable opportunity to discuss the future of this field with another of the iconic founding figures, Dr. Bruce Ames. Many of you know the name. He is a professor at the University of California at Berkeley, head of the department of biochemistry. The renowned “Ames test” was named after his development work and discovery. This is the test that is used by virtually every laboratory in the world for evaluating the potential carcinogenicity of chemicals by using a revertant salmonella mutant form of bacterial evaluation to screen chemicals and substances for potential mutagenicity/carcinogenicity. It has really become a standard for first-stage screening for almost every substance. Certainly all new drugs and all new chemical compounds are put through the Ames test. From there, Dr. Ames moved his career into what we would call orthomolecular (or metabolic) medicine, and the nature of how nutrients and various orthomolecular or natural substances that are native to human physiology influence function at the phenotypic level. You are going to hear from him about some remarkable new discoveries. This 80-plus-year-old/young individual still has his zeal for discovery and investigation I want to set the context for the discussion of how nutrients influence physiological function beyond prevention of nutrient deficiency disorders. We still carry a legacy from the turn of the last century, which was the age of the discovery of the “vital amines,” life-giving amine-like organic compounds (or vitamins, as we call them today). The first extraordinary discovery was related to rice polish, which had been taken off kernels of rice to make them more readily available for cooking and eating (to make white rice). This rice polish contained a life-giving amine substance that was able to both treat and prevent a very dreaded disease that had unknown etiology up to that point, which was called (by the Japanese) beriberi. Beriberi had neurologic and cardiologic implications and led to the death of many thousands of individuals, particularly in times of nutrient insufficiency or calorie restriction, like during war or famine or pestilence. This substance that was found within rice polish was thiamine, an amine that had to do with life. Thiamine (or thiamin-vitamin B1) was the first of the vitamins discovered, and from that, then, it was not too long before the discovery of riboflavin, niacin, paradoxine, and cobalamin. Later, with Roger Williams, vitamin B5 and pantothenic acid, and folic acid were discovered. The list started to rapidly increase as people started to recognize there were principals in food. These were small molecules whose absence could result in deficiency diseases that were, up to that point, unknown in etiology. This is a very remarkable chapter in the history and development of nutritional medicine if we think about it in the context of treating diseases with a small molecule that could rescue life very rapidly. This goes well beyond the calorie. Atwater discovered the calorigenic content of food through studies that were done on the heat-forming properties of various macronutrients. It was ascribed that protein and carbohydrate had calorigenic content of about 4 kilocalories per gram, and fat had about 9 kilocalories per gram of potential energy. These were measured as a heat unit-the calorie-which came over from physics. Identifying Cofactors that Activate Specific Metabolic Steps It was assumed that this was really going to answer the question of how people got energy from food. People eat calories, right? Heat energy was a potential source of metabolic fuel. But with the development of understanding of the vitamins, we recognized that there were other cofactors, or (as we learned later) coenzymes, that would activate specific steps within metabolism through their activity. These cofactors are things like flavin adenine nucleotide (FAD), or nicotinamide adenine dinucleotide (NAD), or pyridoxal phosphate, thiamine pyrophosphate TPP). These cofactors would bind with specific enzymes called apo enzymes to produce a halo enzyme (an active form of the enzyme), which then could participate with appropriate metabolic activity. I think the assumption throughout most of this history was that when the coenzyme derived from a nutrient bound to the apo enzyme to produce a halo enzyme, the process was about at saturation when individuals were consuming a diet of usual and customary composition, and that you wouldn’t get any more horsepower out of increasing the level of the vitamin-derived coenzyme because the enzymes were already fully saturated and working at maximal efficiency. Later, in the 50s, 60s, and 70s, work that was done in a variety of laboratories around the world found that in people who were apparently reasonably well-nourished and eating diets of variety in moderation, that, in fact, their enzymes were not fully saturated, and that in some cases they were underactive relative to the necessity they had for specific cofactors derived from vitamins. By increasing the vitamin intake one could activate enzymes more effectively and produce favorable metabolic outcome, i.e., manage symptoms like fatigue, hypotonia, mood disorders, issues of pain and myalgias, and things of this nature that were seemingly, once again, conditions without known cause. We call these functional nutrient deficiencies, as contrasted to acute nutritional deficiencies. We’re not talking about scurvy, beriberi, pellagra, xerophthalmia, rickets, kwashiorkor, or marasmus. We’re talking-in this case-about the level of nutrients that would optimize or promote proper functional outcome in the phenotype. Genetotrophic Disease: The Concept of Adequate Versus Optimal Intake All of this history precedes our recognition of genetic polymorphisms and the variety of differing types of single-letter alphabet changes in the alphabet soup of the genome that encodes for specific proteins. Prior to the double helix being described by Watson and Crick as the center of our genealogy, Roger Williams talked biochemical individuality more from a morphological and a historical whole-organism perspective. In his book, Biochemical Individuality (1950), he described the concept that there was something beyond adequate to relate to optimal nutrition that was unique to that individual’s need, not just nutrition for the average. This was a very important development, I think, in our whole formalism of how nutrients play roles in functional health in the individual as contrasted to the rule of the average. With this conceptual framework, Williams went on to define what he called genetotrophic disease. A genetotrophic disease is a disease that has a relationship, in that patient, between their genetic uniqueness and not eating levels of nutrients necessary to meet their specific needs. These disorders that are not truly vitamin deficiency disorders, but rather they are functional disorders of undermetabolism (or altered metabolism), with the development of non-end-product metabolites that might be considered intercellular toxins(they are not efficiently going into the final products that are necessary for powering up bioenergetics, and involved with membrane transport, and electrolyte regulation, and so forth. Dr. Linus Pauling and Revealing Research on Sickle Cell Anemia The genetotrophic disease concept was described in a wonderful paper authored by Dr. Williams in The Lancet medical magazine in 1949, which got people thinking: Is there something beyond adequate that relates to optimal?1 At that same time, Linus Pauling and his group at CalTech were working on aspects of mutations that appear within certain proteins in human physiology. In 1949, Dr. Pauling authored the landmark paper titled “Sickle Cell Disease, A Molecular Disease.”2 This marked the first time that this term, “molecular disease,” had been used in a title in a high profile, English-language journal. In this paper, Dr. Pauling and his post-doctoral student, Dr. Itano, demonstrated that in the heavy chain of the globin molecule of hemoglobin in a sickle cell patient there was a single amino acid substitution that led to a structural, functional change in the hemoglobin molecule. This substitution caused the molecule to pack into a more crystalline structure within the red cell to form kind of a crystal and latticework, so to speak, that deformed the shape of the red cell into what looked like a sickle. The sickled red cell can can cut its way through the vasculature and produce all of the problems that we associate, clinically, with sickle cell crisis. So it was really a structure/function deformation of a protein that affected, then, a cell architecture, that affected cellular physiology and whole-body disease. I think this is a very interesting model when compared to the Roger Williams concept of genetotrophic disease. Here we are clearly looking at a genetic uniqueness, but we know that not every patient who has this sickle cell genetic characteristic has sickle crisis. There are other variables that modulate the tendency or propensity towards having a sickle cell crisis. If you talk to sickle cell carriers, they’ll say sleep deprivation, or dehydration, or stress, or toxin exposure, or poor-quality diet all increase the relative risk of having a sickling crisis. Dr. Linus Pauling and Orthomolecular Psychiatry In the 50s, we start to see an interesting change in the understanding of the etiology of certain types of diseases because of this model of genetic uniqueness and genetotrophic disease, and a 1968 landmark paper in Science magazine authored by Dr. Pauling and titled “Orthomolecular Psychiatry.”3 I think these events are a very important part of the legacy of learning that takes us into the systems biology era and the functional medicine era of the 21stcentury, in which we start to look at the role that nutrients play (not just vitamins, but minerals and other conditionally essential orthomolecular substances, such as essential fatty acids, or carnitine, or coenzyme Q10, or taurine. These are substances that are biosynthesized by the body, but may not be biosynthesized at the level of need for a specific individual to optimize his or her function. We call these “conditionally essential nutrients,” in that we require augmentation of their levels in order to promote proper function beyond that which the person is biosynthesizing de novo. Cholecalciferol as an Example of a Conditionally Essential Nutrient A good example of a conditionally essential nutrient would be cholecalciferol (vitamin D). As we have discussed at length in Functional Medicine Update over the last couple of years, vitamin D is biosynthesized in the skin from dehydrocholesterol through a photolytic reaction. Photochemistry (a rearrangement) converts dehydrocholesterol into this unique different chemical structure through exposure to the appropriate wavelengths of light in the skin. This different structure, which ultimately becomes 1,25-dihydroxycholecalciferol (the hormonal form of vitamin D), gets hydroxylated by the kidney and the liver (first liver 25-hydroxylation and then kidney 1-hydroxylation) to produce the 1,25-dihydroxy seco hormone, vitamin D3. Vitamin D3 is not really a vitamin, as we learned from our marvelous interview with Dr. Trevor Marshall. Rather it is a seco hormone that modulates, in a pleiotropic way, through nuclear orphan receptor activities, multiple gene expression effects to influence cellular physiology through altered gene expression. This is probably why we see so many clinical symptoms associated with cholecalciferol insufficiency. Because of the multiple effects this hormonal form of vitamin D (1,25-dihydroxycholecalciferol) has on gene expression patterns, more than one sign or symptom can be seen. To come back to our question of conditionally essential, we say that this substance is biosynthesized in the body upon appropriate exposure to sunlight. But what if we are in different kinds of latitudes-say, a high or low latitude-in which we get a different exposure to the sun and more oblique exposure to the wavelengths of light that are important for doing this photochemical rearrangement of dehydrocholesterol to cholecalciferol? Now that person has a functional vitamin D insufficiency. What about a person who puts a lot of high SPF sun formulas on their skin and blocks most of radiation that is required to do this photochemistry? Or an individual who is heavily clothed, or who doesn’t go outside and is convalescing? Now vitamin D becomes a conditionally essential substance because it is no longer being synthesized at the level that is necessary to meet the body’s needs for optimal physiology, so now we have to have an augmented level by supplementation for its effect. This explains why vitamin D was called the antiricketic vitamin or the sunshine vitamin. This is why cod liver oil was given to children back in the 30s during the winter to help them form proper bones and immune function and so forth (vitamin A and D and fatty acids are in cod liver oil). Eventually, people began to wonder if there was more to vitamin D than just prevention of rickets, just as thiamin, riboflavin, pyridoxine, and niacin have different functional characteristics prior to the onset of beriberi, pellagra, or other kinds of vitamin-deficiency symptoms. Maybe, similarly, more subtle signs and symptoms associate themselves with insufficiency of vitamin D, as it relates to a conditionally essential nutrient or pro-hormone. I think this is a very good example of how we went from a state of understanding deficiency to a state of starting to understand biochemical uniqueness and sufficiency as it relates to an individual’s needs. “Nutrition is for real people. Statistical humans are of little interest,” said Roger Williams, at a seminar I attended that he presented in 1976. Let me say that again: Statistical humans are of little interest when it comes to nutrition. Nutrition is for real people. We can couple together the Roger Williams-Linus Pauling-Abram Hoffer work with the model of Bruce Ames, who takes this to the next level of understanding. Interesting examples have been published in the literature about this marriage of nutrition and biochemical uniqueness and genetic polymorphisms. I’m going to just do a couple of brain teasers that I think are clinically interesting that could be pulled from a sea of other examples, so please just take this as a very superficial example of the body of the whole. Most of us have learned that 25-hydroxyvitamin D is an analyte in the serum that is useful for evaluating vitamin D status to see whether a patient needs to be supplemented, as a conditionally essential nutrient, with additional vitamin D3. Levels in the plasma that are below 20 nanograms per milliliter for 25-hydroxy D are suggestive of functional vitamin D insufficiency. Although not yet in the ricketic range, these individuals are not in the optimal range of availability of this extraordinary nuclear orphan receptor agonist called 1,25-dihydroxyvitamin D3. Generally, the range of 30-50 nanograms per mL in the serum is recommended. With oral supplementation of vitamin D3, one can track the increasing levels in of the 25-hydroxy in the serum to monitor a patients sufficiency. It is generally recognized that 1,25-dihydroxyvitamin D3 ties to multiple different tissue targets, including vascular endothelial function, neuronal function, joint-space immune function, islet cells with the release of insulin function, insulin sensitivity at peripheral tissues, and the osteoblast-to-osteoclast equilibrium as it relates to bone formation and resorption and bone turnover. We would also couple it together with things like general immunity and anti-cancer effects that have been increasingly identified to be important to vitamin D sufficiency. One of the areas that is also interesting and takes us beyond the traditional insufficiency signs would be drug-related effects on physiology. This is an interesting wild card, isn’t it? Our population is heavily medicated. The population is using specific families of drugs: SSRIs for mood disorders, or statins for hyperlipidemia/hypercholesterolemia, or blood pressure medications to regulate hypertensive shifts, or even anti-metastatic drugs for managing cancer as a chronic disease. All of these families of drugs have some off-target effects on physiology and can induce what we call adverse side effects. Some of these effects can be life-threatening, while others may be more mild and just disturbing and discomforting, such as the myalgias that some patients taking certain forms of statin drugs experience. A Study on Aromatase Inhibiting Drugs and Arthralgias in Breast Cancer Patients What happens when women who have breast cancer are placed on aromatase inhibiting drugs? Some observations suggest that about a quarter of women on these families of medications have arthralgias, with symptoms that can be so serious they will actually discontinue the medication. In a recent paper in Breast Cancer Research Treatments in 2010, results from a clinical trial on women put on adjuvant aromatase inhibitor treatment (letrozole) for breast cancer were published.4 In this study, 42 women taking aromatase inhibiting drugs for breast cancer in which serum vitamin D levels were low were supplemented with 50,000 IUs of vitamin D3 weekly for 12 weeks. After 16 weeks, their serum 25-hydroxyvitamin D levels went up, on average, from below 20 to greater than 66 nanograms per milliliter (median level). And, interestingly, in those women who had the vitamin D supplements, increasing their vitamin D 25-hydroxy levels resulted in significant reduction of disability from aromatase inhibitor-induced arthralgias. We don’t have a specific mechanism of action that is derived from this. We don’t know exactly how vitamin D levels pertain to arthralgias in aromatase inhibitor-treated women, but, based upon this study, the clinical outcome looks very encouraging. Vitamin K: A New Study by Dr. Bruce Ames and Colleagues Focuses of this Nutrient There is another interesting nutrient that has not gotten the kind of attention it deserves, and that is vitamin K. You are going to hear Dr. Ames talk about a marvelous review paper that he and his post-doctoral colleague, Dr. Joyce McCann, recently authored in the American Journal of Clinical Nutrition5 They have developed what they call the “triage theory” related to micronutrient inadequacy that is associated with diseases of aging. The triage theory posits that some functions of various micronutrients are restricted during shortage and the functions required for short-term survival take precedence over those that are less essential. The body accommodates these insufficiencies by moving nutrients to the place that they are most critically important for maintaining function and giving up secondary functions. That leads to changes that accumulate as a consequence of those insufficiencies, which increases the risk of diseases for aging that have long latency periods before they appear. It is hard to pinpoint an etiological agent because the agent, itself, may not experience the disease in the phenotype for several decades. This long latency disease model was the focus of Robert Heaney’s McCollum Address that he gave when he won that prestigious award as the chief researcher in the United States. He talked about long latency versus short latency nutritional insufficiency disorders. For long latency disorders, insufficiency doesn’t show up within the phenotype immediately but rather decades later, such as in cancer, heart disease, diabetes, mental illness, and any number of other very interesting diagnoses for which the etiological agent was really insufficiency over years of duration. This is a different model of disease etiology than most of us learned as it relates to things like infectious disease, which is infection and then a full-blown disease occurring not too long after the latent period.6 In this review, Dr. Ames and Dr. McCann write about vitamin K-dependent proteins. This story sounds a lot like the emerging vitamin D story. They evaluated the relative lethality of 11 known mouse knockout mutants that are associated with these vitamin K-related proteins. We all know vitamin K is required for coagulation, so there is something about the blood coagulation matrix that has been very clearly understood. We also recognize that vitamin K-related proteins interact with bone matrix proteins like osteocalcin and matrix Gla protein, and they also have to do with things like growth arrest (specific proteins transforming growth factor beta inducible protein) and other gene expression-related proteins that–like vitamin K–have pleiotropic effects on modulating cellular physiology. Similar to vitamin D, if we start looking at the effects that vitamin K have in a pleiotropic model using gene knockout models in animals (where they have actually knocked out specific genes that are responsive to vitamin K), you find a very dramatic list of factors that cut across all sorts of potential symptoms that are associated with vitamin K insufficiency. This is what is described in this paper, and, in fact, in Table 2, the authors list in excess of 15 different vitamin K protein sensitivities that can be associated with various extraordinary symptomatologies beyond coagulation defects. What about vitamin K sufficiency in the diet, particularly in the diets of people who are eating very limited amounts of dark green, fresh, leafy vegetables, which is one of the major sources of vitamin K? Could there be issues related to vitamin K insufficiency that then alter these gene expression patterns and create increasing relative risk to a family of long latency disorders, including things like cancer, or aortic valve calcification, and is there, then, a public health problem? As a result of their research, Dr. Ames and Dr. McCann conclude: “In the United States, the average intake of vitamin K1 is about 70-80 micrograms per day, which is below the currently recommended adequate intake of 90-120 micrograms per day. Generally low intakes are also reported in Ireland and the United Kingdom.” They also point out that recommended intakes of vitamin K are based on amounts required to maintain coagulation function, not to promote proper enzyme function or gene expression patterns that associated with vitamin K sufficiency. Again, what is the benchmark we are using to evaluate optimal versus adequate levels of these nutrients, and particularly nutrients that have multiple signaling effects upon gene expression patterns? This is not just modulating a single enzyme activity, for example, a thiamine pyrophosphate does with an enzyme that it activates, like transketolase. We’re really looking at multiple pleiotropic effects upon gene expression, so what is the optimal range for the individual? These are big questions that are just emerging through the nutrigenomic revolution. As Dr. Ames and Dr. McCann point out in the conclusion of their article, vitamin K serves as an example to test the premise this triage theory-that the body shunts nutrients over to the most critically important parts of function and sacrifices other things that are not critical to the stability of the organism-and why modest micronutrient insufficiencies may cause age-related disorders such as osteoporosis, cardiovascular disease, and cancer over long latent periods. The evidence that they present in the article is consistent with a system that prioritizes the protection of vitamin K-related functions according to their essentiality for short-term survival at the expense of functions required to maintain long-term health. The analysis highlights what appears to be a primary mechanism that accomplishes this prioritization, which is the separation of coagulation factors from less essential vitamin K proteins by localizing the gamma carboxylation in the liver, where ingested vitamin K is preferentially distributed. The body has intelligence to know how to shunt vitamin K into critical functions like coagulation, while then sacrificing other functions like cell replication and bone function as a consequence of insufficiency. I hope I have set the stage for the discussion we’re going to have with Dr. Ames. The trajectory of the foundations and fundamentals from the last century to molecular, functional, and systems biology in medicine in the 21st century will be an extraordinary voyage. With that, let’s move to Dr. Ames

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Bruce Ames, PhD Children’s Hospital Oakland Research Institute (CHORI) 5700 Martin Luther King Jr. Way Oakland, CA 94609 www.bruceames.org I know you are all as excited as I am for the opportunity to speak and listen to Dr. Bruce Ames. I was just reflecting that it was 10 years ago-a decade ago-that we had the privilege of last speaking with Dr. Ames about his work in Oakland and at UC Berkeley about aspects of oxidative stress and the concept of metabolic tune-up. So much has happened in the last 10 years. This is a scientist who is a professor of biochemistry and molecular biology at the University of California, Berkeley; senior scientist at Children’s Hospital Oakland Research Institute; member of the National Academy of Sciences; and was a member of the board of directors of NCI from 1976-1982. He has every kind of award that can be given to an internationally esteemed chemist, and he has contributed to nearly 500 publications in his career. He is considered one of the most cited scientists. As I was a person who was very fortunate to have worked with Linus Pauling for a couple of years, I would have to say that Dr. Ames is really the Linus Pauling of this era. It is really a great privilege, Dr. Ames, to have you once again on Functional Medicine Update and to have a chance to talk about what has happened in the last 10 years in your very busy life. You have been credited-and I think justifiably so-in advancing this whole concept of mitochondrial aging and its relationships to bioenergetics and how that is influenced by specific kinds of nutrients or accessory biochemicals (“orthomolecular,” to use a term that Dr. Pauling coined). Tell us a little bit about this whole mitochondrial aging area that you’ve really opened up for us. Dr. Ames Explains the Concept of Mitochondrial Decay BA: I’ve been working in several…what I think would be “major” areas. One was mitochondrial decay and how that’s related to aging. I’ll talk about that. And then the other area is micronutrients (how much we need of each micronutrient). I think we are making big advances there. I think we’re really finally understanding putting micronutrient nutrition on a firm foundation, which it hasn’t been. I have been fairly active in all those areas. My main interest is preventative medicine: How do you prevent all these diseases before they come? I know the alternative medicine people are very interested in that, and they are interested in nutrition, which ordinary medicine has completely abdicated. All my physician friends tell me I’m out of my mind to go to alternative medicine meetings, and I tell them, “Look, they’re interested in the important things and you guys aren’t.” Why don’t I start with mitochondrial decay? I was interested in cancer prevention for many years. We did a lot of work on DNA damage, and what is causing it in people, and how to prevent it. More and more I became convinced that a lot of it was just built in. You look at cancer in mice, in rats, in people-it all goes up with about the 4th or 5th power of age. Mice have about a 2-year lifespan, and rats about a 3-year lifespan, and humans about an 80-year lifespan, and we all get cancer with this power of age. In 60 million years of evolution we have gone from a short-lived creature like a rat or a mouse with a high age-specific cancer rate, and now we are to people with a much lower age-specific cancer. So what’s going on? I became more and more convinced that cancer and many other conditions are degenerative diseases of aging, and that a lot of it is really coming from our own metabolism, which doesn’t mean you can’t influence it, but that a lot of it is built in. We’ve been working on that. When a post-doc, Tory Hagen, came to my lab some years ago (in the early 90s), he had a lot of expertise in mitochondria and I was more and more interested in mitochondria as a key factor in aging. Mitochondria, as you all know, are the power plants. All the fat and carbohydrate you eat is burned in the mitochondria, which means pulling electrons from them, and you add the electrons to oxygen in the mitochondria and generate energy. That burning process generates byproducts (the oxygen radicals) because you are adding 4 electrons to oxygen to make water (if you add them one at a time you get all these nasty compounds and nasty oxidants). Also, with age, they were getting less efficient. So we decided that working on the aging to get at the degenerative disease of aging. It’s hard to wait around 3 years while a rat gets older. We decided we’d look at mitochondrial decay, which one could get a biochemical handle on. It was known that with age, mitochondria are less efficient and putting out more oxygen radical byproducts. It’s like an old car engine: more black smoke and less efficient. Tory Hagen is a terrific experimentalist, and he figured out how to get at this problem: you want to look at a tissue that is not turning over rapidly, and yet you want to look at single cells. At first you think, “Let’s look at the white cells because you can get them and they are single cells.” But they are turning over so rapidly, so we decided to look at the liver. The brain would be good and the muscle-any tissue that’s not turning over rapidly-and the liver seemed to be a reasonable compromise. You can get single cells out of the liver (we figured out how) by perfusing the animals. And then you can look at all these functions that decay and see if you can reverse it. That’s what we did. We tried a lot of things, and n-acetyl carnitine had been shown by some Italians to improve mitochondrial function in various ways. We had set up all sorts of good assays, so we were able to repeat that work and show it was applicable for many things. In fact, 3 of the 4 functionalities we looked at were improved by feeding the rats n-acetyl carnitine. Carnitine is a normal mitochondrial metabolite that pumps fatty acids into the mitochondria to burn them. One thing it didn’t help was the increase in oxidants that occur with age. So we started screening compounds to see whether we could find something that worked there. We tried a lot of things, and the one thing that worked was lipoic acid, which is another mitochondrial metabolite that is used in mitochondrial function. Lipoic acid worked beautifully. And then we tried the two together, and made the mistake of telling some reporter the old rats got up and did the Macarena. They were more energetic, and the brain worked better, and all sorts of things. So we published a number of papers on that.7,8,9 The university took out a patent on this. I formed a company called Juvenon, which sells these pills over the web. I put all my stock in a foundation, so I have no financial interest in the company other than I’ll have money to give away to science if it’s successful, which it seems to be. That was my introduction-all this work that Hagen did-and then in the years after I had several terrific people who continued that work. And Hagen continued-he showed everything that we had shown in the liver was true in the heart, and we worked on the brain and showed the same thing happened in the brain. I’m fairly optimistic about that. It will be one way of improving mitochondrial function, and, in fact, it makes the animals look younger in all the ways we can measure (brain function, energy, biochemical measures). JB: In humans, knowing that these are conditionally essential nutrients because they are, obviously, biosynthesized at some level, what kind of levels must one take in to get mass action effects so you are driving it into the tissues in need? BA: There is some guesswork there. We have done all of our experiments in rats, and now some experiments have been done on mice, and some on dogs, but we really don’t have a lot of human data, though there are a few clinical trials (one on hypertension that worked and a few more underway). So there is guesswork, and that gets to mechanism: How are these things working? In a way we had the wrong idea when we started. We thought, “Ah, we’ll go for compounds that are known to be in mitochondria that might be possible antioxidants for lipoic acid or be useful in other ways.” We did a fair amount on mechanism, and it turned out we probably were barking up the wrong tree. It works, but it works for a different reason than we thought. Lipoic acid is the oxidized form; it has two sulfhydryl groups sticking out of an octanoic acid. You can make a ring, and that’s the oxidized form; the actual coenzyme is the reduced form. The reduced form is fairly unstable, so we fed the oxidized form, and we thought it was just getting reduced and acting as an antioxidant in the mitochondria. But it turns out it is a very effective inducer of Phase II enzymes. Phase II enzymes are about 250 enzymes that get turned on when you treat the cell with anything that damages sulfhydryl groups. With any oxidant or alkylating agent (heavy metal), you turn on these systems. It’s one of the body’s major defense systems. It turned out lipoic acid is very effective at inducing this defense system. People in Tory Hagen’s lab worked this out. When Tory Hagen was in my lab he had shown that glutathione synthesis goes down with age and lipoic acid kicks it up. It was known in the literature that glutathione synthesis is under control of these Phase II enzymes. They know all the circuitry; there is a transcription factor called NRF2 and a sensor called KEEP1. They know how you turn on all these defense systems. Anytime you get an oxidant into you (you radiate the animal, for example), you turn on the body’s major defense against oxidants. And that’s exactly what lipoic acid does, though it is quite non-toxic. But the body treats it as an oxidant. In fact, there is a compound in garlic that works in a very similar way, and there’s a compound in broccoli that works in a similar way. People have been discovering all these natural compounds that are sort of weak oxidants that turn on this system, and that’s what we think lipoic acid is doing. You are turning on your own defenses, which turns out to be a much more effective way of helping the cell than adding a little more of an antioxidant. Dr. Ames Explains “Metabolic Tune Up” JB: You then coined a term, which I think is a beautiful term: “metabolic tune up.” In a number of your papers over the last several years you have used that term and described it. For our listeners, could you kind of help us understand what you mean by that? BA: You have all of your metabolism going on, and it gets out of whack with age. There are ways of tuning it up, just the way you tune up an orchestra or tune up your car. I got chewed out by some eminent nutrition type because he can’t stand that word (“tune up”). I said, “Look, it’s not a bad word.” So there is disagreement on whether it is really a good concept. I think it’s not a bad metaphor because we know that all sorts of aspects of your metabolism go out with age. What I’ll talk about next is diet. Americans are eating such a horrible diet. They are fouling up all their metabolism, and that you really need to tune up because it’s aging you fast. Let me get into that now. There are about 40 micronutrients. To run your metabolism you need fuel, which is fat and carbohydrate. And you need about 40 substances that you have to get from your diet, otherwise you die. There are about 15 minerals: magnesium, calcium, zinc, iron…you know the list. If you don’t get any one of these you die, because you need these factors and they make certain enzymes work or there are other factors for proteins that make them work. We know iron is important for iron-sulfur clusters, it’s important in heme, and you really need these for your metabolism. Some sizable percentage(16{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}) of menstruating women aren’t getting enough iron by the standards they are using now. Those standards-as I’ll tell you in a minute-I think are not science-based; they are based on safety factors and intuition, all of that, and we think we know what the real basis is going to be. There are about 15 vitamins, and then there are some essential amino acids and two essential fatty acids (an omega 3 and omega 6). You need these 40 substances in your diet. The whole purpose of a balanced diet is to get all these substances in the right amount. What is the right amount? Nobody knows. We have two committees that have set up two numbers: the EAR and the RDA. The EAR is the level that the population is getting, where half of the population is inadequate and half is, they say, adequate. If you look who’s below the EAR (inadequate by what the committees say), we’re talking about 60{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the US population for magnesium; we’re talking about some sizable percent of the US population for calcium; practically everybody for potassium; and you go on and on. The omega 3s people are tremendously short of. Vitamin D everybody is short of, particularly people with dark skin. So you can make a long list of this. As I say, 16{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} seems small compared to 60{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, but 16{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of menstruating women are too low in iron. But nobody really cares much that the whole population isn’t getting enough magnesium. Where do you get magnesium? It is in the center of a chlorophyll molecule, just the way iron is in the center of the heme molecule in hemoglobin (it carries oxygen in the blood). Magnesium is in the center of a chlorophyll molecule; it is essential for photosynthesis. That’s a color cue. It means that anything you eat that’s green is giving you your magnesium, and also giving you your folate (foli is a Latin word for leaf-foliage), and it is giving you your vitamin K because vitamin K is used in photosynthesis in plants. If you eat your greens, you get those 3 micronutrients. But people don’t eat enough greens, so the whole population is very short of all 3 of these. They are all cheap. None of these micronutrients cost anything. A multivitamin mineral pill, which isn’t quite adequate (which I’ll tell you in a minute), is a few cents. You could give everybody all the micronutrients for a few cents. Why doesn’t anybody care? Because there is no pathology. And we think we have figured out the pathology. The RDA is at two standard deviations above the EAR. That’s what the population should be getting; that’s what’s on your food labels. Sixty percent or below the EAR for magnesium, and practically 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the whole population is below the RDA. We are eating all this refined food, which removes all the micronutrients. Every time you drink a sugary soft drink, you are filling yourself up with empty calories (40 grams of sugar and no nutritive value). That’s the leading source of calories in the United States. You go down the list of the 10 leading sources of calories in the US, that’s 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the total calories, and there’s nothing green on it. A balanced diet means eating fish a couple of times a week (more if you can do it), less red meat, and more fruits and vegetables, and some nuts and whole grains, and you need your fiber. All of these things you guys have been yelling about for years, but medicine just doesn’t get any nutrition training. They don’t have the time to ask people about their nutrition, so they have completely abdicated. I think a lot of the premature aging in the population is due to lack of micronutrients. Let me tell you why I think that. We were interested in DNA damage. Every time we made a human cell in culture old, we’d get DNA damage. And then if we made them short of micronutrients we got DNA damage. We did this on lots of them: in mice and in humans (human cells in culture). We were always getting DNA damage when we made the organism or the cell short of a micronutrient. I kept wondering, why the hell is nature doing that? One day it hit me: that’s exactly what nature wants. Animals have been running out of micronutrients through all of evolution. The minerals aren’t spread evenly through the world. There are red soils with high iron, soils with low iron, soils with high selenium, soils with low selenium. The vitamins aren’t spread evenly through the world. The essential fatty acids aren’t spread evenly, and the essential amino acids aren’t spread evenly. What does an animal do when it is running out of magnesium, for example? It turns out, built into our metabolism, is a way of dealing with all this, and I call it triage. Basically, as a micronutrient gets lower and lower, at some point what you do is you keep it in all the proteins that are essential for survival, and you take it out of all the proteins that are more long term (the things that normally come with age). So DNA damage shows up as cancer in 5 or 10 years. When you are going to die isn’t important. What nature wants you to do is survive so maybe you can reproduce a bit. Anything long term gets thrown overboard, basically. Your adaptive immunity goes out, your mitochondria start putting out more oxygen radicals, you get more DNA damage and cancer, and you get more heart disease. Basically, all of the degenerative diseases of aging are accelerated by being short of micronutrients. This was just a theoretical idea and we found some evidence in the literature, and now we are proving it for many different directions, though proving an evolutionary idea is kind of hard. I can’t say I’ve convinced the nutrition community yet, but we will. It’s going to be true. The implication of this is that some silent percent of the US is aging itself faster. When you pour out more oxygen radicals from the mitochondria, that’s linked to Parkinson’s and Alzheimer’s. You knock out your adaptive immunity, and that’s associated with all kinds of more viral infections and more susceptibility and less ability to take vaccines and all these things. We are hitting it from every direction, and I think everything we do sort of strengthens our ideas. Tuning everybody up for micronutrients is easy because it doesn’t cost anything. That’s where we are right now: trying to show that when we feed micronutrients to people it improves their immune system, it raises their HDL and improves their LDL and lowers their homocysteine, all relevant to heart disease. We are hitting this from every direction. I think there are things you can measure, but it is all insidious damage, and it is all long term. JB: I think this is obviously extraordinarily important, because it goes from the individual to public health and it really relates to burden of disease and ultimately even deals with issues related to healthcare costs and expenditures in an aging population. BA: I think it is relevant to obesity, too. My colleague, Marcia Shigenaga, has really started to understand obesity. It’s bacteria getting through your gut and causing inflammation that is driving all this. One of the important factors is we are getting too much fuel. You drink all this high fructose corn syrup and it punches holes in your gut and bacteria can get through it. Now you can measure this and all of the factors involved-fibers are important, we’re not getting enough fiber, and micronutrients are very important. I suspect that when you are short of micronutrients it makes you hungry because the body is trying to find that missing ingredient, and the food people are eating doesn’t have it. It makes everybody very hungry and they just eat this junk food that doesn’t have the same calcium and magnesium and things they need. That’s still hypothetical, but we are trying to prove that, too. There is some evidence in the literature that might support it. Shigenaga is working on neat stuff. Why not just take a multivitamin/mineral? It is not good enough, because a multivitamin/mineral is a good first iteration, but it doesn’t have enough magnesium, calcium, and potassium because you need a gram or two of those things and it would make the pill way too big. They put a token amount of calcium and magnesium in there, and practically no potassium. You need those. It doesn’t have omega 3s, which you get from deep sea fish, and we are really short of those. A third of the brain fatty acids are DHA, which is an omega-3, which you get from deep sea fish. You can go on and on. I think a multivitamin/mineral everybody should take as kind of a first approximation, but you need other things as well. You could take a calcium/magnesium pill, or you could eat more greens and more dairy (yogurt or whatever). If one’s knowledgeable you can do all these things, but I’m interested in getting the poor up to snuff because I think it is doing it in the brains, too. Joyce McCann, in my group, just had these 4 wonderful reviews about the developing brain.10,11,12 When you are a fetus and in the first two years of your life, you are making a trillion neurons, and each neuron has a hundred to a thousand connections. It is one of the most complicated things in the universe. If they don’t get enough iron, the mouse pups don’t do well, in IQ tests the rat pups don’t do well, and kids don’t do well in school. It’s irreversible. And yet we are talking about 16{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of American women being short of iron. And then you don’t get enough omega-3s (that’s some sizable percent of the population), and the brain doesn’t develop well. They weren’t even adding omega-3s to formula. There’s been an argument going on. The pediatricians could never get their act together. After Joyce McCann’s review came out on the omega-3s, one of the formula companies added DHA to formula. They are allowed to do it; they were just waiting for some official word and it never came, even though the Europeans were doing it. Obviously a baby sucks it out of the brain of the mother, and maybe a third of the brain is omega-3 fatty acids, and there wasn’t any in formula. This company added it to formula after our review came out (I don’t know whether our review had them do that, but at any rate, it was somewhat after the review). The sales went way up and all the other companies followed, so now it is in formula. She just had a review on vitamin D.13 Vitamin D is really interesting. It is a hormone. Vitamin D is converted to calcitriol, which is a hormone turning on 900 genes, lots of them in the brain. The whole northern tier of the United States is short of vitamin D. And one group in the United States is incredibly short of vitamin D, and it’s African Americans. If you have dark skin, you need 6 times as much sunshine as a light-skinned person to make your vitamin. The main source of vitamin D is the sun. Ultraviolet light converts 7-dehydrocholesterol to 25-hydroxyvitamin D, which then goes to make this hormone. If you have dark skin, it is much harder to get your adequate vitamin D. Ninety-five percent of African Americans are really low. It’s important in brain development. I think we ought to have a crash program to get vitamin D into everybody up north (Chicago, etc.). Skin color is all about preventing ultraviolet damage in the tropics. Dark skin is racially completely different in different people: Southern Indians, Africans, New Guinea. Very racially different, but they all have dark skin because otherwise you get burnt by the sun. A light skin…up in Sweden or Ireland you need every last bit of ultraviolet light to make your vitamin D. If you eat a lot of seafood you can get a reasonable amount of vitamin D. People who moved up north were eating a tremendous amount of seafood. I think that helped, plus a light skin. But now we have Irish people going off to Australia, burning themselves to a crisp, so there have to be campaigns in Australia (wear a hat and put on sunscreen) for fair-skinned people. But an African American in Chicago is in equally grave danger, and the solution is a vitamin D pill. And it’s cheap. I’ve gotten off on a little sidetrack. I think micronutrients are going to have a huge impact (if we tune everybody up) in lowering the degenerative diseases of aging. We’ll understand mechanisms. We will be able to do epidemiology better. Now, I think we’re putting things on a firm theoretical basis. I hoping it is all going to turn out to be true. At least so far everything points in that direction. It’s going to be a relatively easy thing to accomplish (fortifying foods). We’ve made a bar (a nutrition bar) that has everything in it. It really works. It helps raise your HDL, improves the LDL, it improves your immune system-everything we do to people, it improves it. I think it’s going to be a big thing to get micronutrients into the poor. JB: Can I ask a follow-on? Because I think you raised a very interesting point. I recall, in my pharmacology course way back when, the so-called “Tolman’s Law” of pharmacology that basically says everything is toxic at some level. You have these curvilinear, kind of parabolic dose-response relationships. You talked about iron. I want to use that as an example. Iron, on one side of the curve (in the insufficient side) has an adverse effect on function. But what about excess iron on the other side, knowing that it can be a free radical inducer? How do we gage what the appropriate level is? Iron: You Can Have Too Much of a Good Thing BA: People think, “Ah, if a micronutrient is good for you, more is better.” Mae West said, “Too much of a good thing is wonderful.” But she was thinking about sex, not micronutrients. You need to not overdo it, particularly for the minerals. Fernando Viteri, who is a professor of the nutrition department knocked on my door one day and said, “There are two billion women and children who are getting too little iron, and it’s a real catastrophe. The World Health Organization is giving them iron, which is a good thing, but they are giving them too much iron, and too much iron is bad thing.” I said, “Whoa, I didn’t know all that.” And so he said, “Would you help me-working on what too much iron does to you?” I said, “Sure.” One of my students and one of his students got together. We looked at the whole range of iron in mice (this we published some years ago).14 Too little iron fouls up your mitochondria and that was an unknown. And too much iron fouls up your mitochondria. I think we don’t quite understand the mechanism. So there’s a sweet spot, and that’s where we should be. You don’t want to overdo it, particularly for the minerals. We know that with hemochromatosis, which is a genetic disease where you absorb too much iron, that people die of heart disease and cancer; it is not a good thing to have. The same thing in these mice. When we fed them too much iron, it was bad for them. Iron accumulates with age, too. We have done a little work in that area that I’m thinking about (mechanism), but right now we don’t know all the answers. JB: One of the papers I know that you authored that came out of your group at Children’s Hospital Oakland Research was in Experimental Biology and Medicine on the daily supplementation of iron, looking at indicators of lipid peroxide formation in young women.15 That raises the question of what are the appropriate biomarkers that you feel have some usefulness in assessing this oxidative stress or free radical pathology? Do you think things like n-pentane and malondialdehyde are useful markers, or what would you suggest? BA: There hasn’t been a perfect marker for, say, somebody who is oxidizing too much. It’s a little complicated because it turns out that what we have shown for mitochondria is if you make human cells too low in iron, you pour oxygen radicals out of your mitochondria. If you make them too low in zinc, you do the same thing. If you make them too low in biotin, you do the same thing. If you make them too low in B6, you do the same thing. And we worked out that the mechanism has to do with heme biosynthesis in the mitochondria. But that, I think, is part of triage. When you are too low in all kinds of micronutrients, you are hitting the long-term things, and one of the long-term things is that your mitochondria put out more oxygen radicals. And what you need is not more vitamin C or vitamin E. It might help a little bit, but what you really need is getting the missing iron and the missing zinc and the missing magnesium-whatever is causing it. I think people have looked at oxidants and antioxidants in too simplistic a way, because all sorts of things will lead to oxidants being pulled out of your mitochondria (all sorts of deficiencies). What you need is the missing agent, not just more antioxidants. JB: That’s a very important point. Let me close with one last question. I remember very vividly the cover of Science magazine and your landmark article on “Dietary Carcinogens and Anti-Carcinogens.”16 I recall it created a groundswell of controversy and conversation. I think it really spurred the whole field on. Could you tell us a little bit about that? That was probably 20 years ago-I don’t remember the exact date of publication-but it was certainly in the early 80s (if not earlier). What has happened since then, Dr. Ames? I think that was one of those seminal articles. BA: Thank you. People were saying, “Ah, it’s those pesticides that are doing you in. If we eat organic food we’ll be fine.” And I just didn’t buy any of that because the amounts were way too small. There were huge amounts coming out of your own body. More and more I thought, “A lot of this has to do with aging and things that are accelerating aging.” And so, I got more and more interested in nutrition. What we are leaving out of our diet is way more important than what we are adding. You can get a part per billion of some pesticide, but it’s way too low to be important. It doesn’t sit with toxicology. It doesn’t sit with epidemiology. And the thing that is really important is eating a bad diet. That’s why the epidemiology is incredibly difficult. Epidemiology is just hopelessly difficult. It’s good for huge things like cigarette smoking, or not getting your micronutrients, or something like that, but it is just not good for small things. So if you understand mechanism, then you can measure something and really pin it down. But right now, it’s pretty hopeless, though the good people are making some progress. It’s always one guy says it is black, and the next guy says white, and they argue for years and they keep on getting more studies that say black or white, but it’s difficult to do. I got sidetracked. JB: No, I don’t think you did. I think that really defines the landscape of complication. It’s not like doing particle physics in a Wilson cloud chamber or something. We are really unable to control the parameters. That is one of the beauties of being human. BA: Yes, you have to be awfully smart to be an epidemiologist and learn anything interesting because you have to understand all the parts. You have to understand mechanism and work from mechanism on up. Otherwise, it is just way too complicated. Of course, politics is an order of magnitude worse, so people are always thinking, “Ah, we’re going to do this.” And they pass a law and it has all these unintended consequences. So I’m very cynical about if the politicians are going to help us very much. Part of that comes from all my experience in trying to understand mechanism and seeing how difficult epidemiology has been and how expensive. That’s why I’m hoping that working from mechanism on up is really going to help. If you have a few more moments, I would like to tell you about Vitamin K. JB: We would love to hear about vitamin K. Vitamin K and Triage Theory BA: Joyce McCann, who is a wonderfully smart woman in my lab, came to me one day and she said, “I’m a little skeptical of your triage theory. I think we ought to tackle it in a different direction.” I said, “Joyce, go to it.” She is really smart. She likes to do theoretical work. I said, “What do you want to do?” She said, “Well, let’s take about 10 micronutrients that are not too complicated. Vitamin D hormone is turning on 900 genes, and magnesium is in every possible kind of DNA repair enzyme. They are all too complicated. Let’s take those vitamins that are not so complicated and analyze them in depth, and see if it sits with your triage theory.” I said, “Sure, go to it.” So she started with vitamin K, and it’s a homerun. It’s just beautiful. It has all these medical implications. I’d like to just quickly run over vitamin K and what we learned about it. The review came out in the American Journal of Clinical Nutrition. I don’t think it has attracted a lot of attention, but it should. JB: Actually, if I could just give the citation for our listeners, I thought that paper was absolutely brilliant. It’s in the October issue of AJCN and it’s on page 889 or 2009 issue, the vitamin K review you are talking about. BA: Thank you. Basically, vitamin K stands for “coagulation” in German. It was first discovered as a factor needed for coagulation. Vitamin K is a quinone used in plants in photosynthesis (a phylloquinone). Animals have hijacked it for a different purpose. Basically there is an enzyme that takes vitamin K and takes a protein that’s been already made, and converts the glutamic to a Gla. Glutamic has one carboxyl group sticking out at the end of it, and what this does is add another carboxyl group right next door. So you have two carboxyl groups sticking out, and they combine to calcium. All the proteins that have a Gla in it are calcium-binding proteins, and that’s important in their function. To do that step, you need vitamin K. The first question Joyce asked was, “Can you set up a hierarchy among the vitamin K-dependent enzymes?” (Are some more essential than others?) She looked at the mouse knockouts. (They’ve knocked out half the genes in a mouse now so you can look and see what happens.) All the coagulation proteins hadn’t been knocked out because they are embryonic lethal. They are essential, so you just die if you don’t have those proteins. That makes sense because if you cut yourself and if you didn’t have coagulation proteins you’d just bleed to death. When you make the whole blood vessel system in a mouse when it’s an embryo, if you have any little imperfection the animal dies. It turns out that in a mouse, all these coagulation proteins are embryonic lethal; they are essential. But there are 5 proteins that turn out to be the interesting ones. When you knock them out you get heart disease or cancer (the long-term things). Those are the interesting ones. So how does the body work this? Well, when you eat green stuff you get your vitamin K. It is a lipophilic compound, so it goes on lipoproteins, gets the liver to the liver. And then the carboxylation protein converts Glu to Gla in all the coagulation proteins (they are all in the liver). But then, if you have enough vitamin K, you convert that phylloquinone to a menaquinone, which is a slightly different quinone, and that goes out to all the other tissues. There, these functions are all more important for long term. But the priority is to get the essential one for survival, which are the coagulation proteins, and you do that first in the liver, and then only if you have enough do you ship it out to the peripheral regions. Take the matrix Gla protein (Gla stands for this funny amino acid). When you knock that protein out in mice, they all die at 2 or 3 months of age of calcification of the arteries. We all know calcification of the arteries is an important factor in heart disease. If you look in the human gene, which she did next, what she found is there is a rare genetic disease called Keutal syndrome, where people die of calcification of the aorta. That fits. There are some polymorphisms where they are more susceptible to calcification of the arteries. One of the known consequences of vitamin K deficiency is calcification of the arteries. Ten million people are still getting coumadin (it’s also called warfarin), which interferes with vitamin K so they don’t get blood clots, and they die of calcification of the arteries (a lot of them die, not everybody). Everything fits, and on top of that, in Japan, there is a funny food called nato. Have you ever eaten nato? JB: Yes, we have. Nato: A Japanese Food that may have Protective Properties BA: It is a fermented soybean, and the people who eat nato get practically no heart disease. They don’t get bone fractures-that’s another one of these proteins (osteocalcin). And they may not get prostate cancer. Anyway, they have done all this epi in Japan, and that fits, because in nato is something called MK-7 (menaquinone vitamin K-7). That compound is delivered to all the tissues, not just to the liver. The MK compound is made from your phylloquinone that you get from greens. When there is enough of it in the liver it sends it out to the non-hepatic tissue. So it all kind of fits with the triage point of view. Two of these genes have to do with heart disease. One, you knock it out, you get calcification of the arteries. And another one has to do with acute coronary syndrome. Another one of the genes has to do with cancer; you knock it out, they all die of cancer. The mechanism seems clear: it is matrix protein interacting with integrin on the surface, which interacts with the microtubules, and so the animals get aneuploidy and all sorts of chromosome abnormalities. You are fouling up mitosis, and that’s why they get cancer. Once you work from this understanding of what each protein does, and what happens when you knock it out or knock it out by not getting enough vitamin k, then you understand mechanism and then you can do epidemiology. There is a lot of evidence on the calcification of the arteries, and very little on the cancer people (just people haven’t looked at that). But when they looked at prostate cancer in Japan-I think it was prostate cancer-what food seems so protect, the food that came out on the top was nato. We put all this case together, and it turns out that one of the consequences of vitamin D deficiency is calcification of the arteries. It turns out that vitamin D hormone is turning on the matrix Gla protein gene. So there is another micronutrient involved. I just got so excited by this review Joyce did. It is really a brilliant job. It has so many implications for medicine, because half the Brits are too low in vitamin K, and some sizable percent of Americans are too low in vitamin K. We’re not eating enough greens. Yet, none of the docs give you MK-7 or something like that when you come in with calcification of the arteries because they don’t even know about all this stuff. I think the alternative medicine people are at least interested and pick up on these things more quickly. JB: I want to thank you on behalf of all of the listeners and the world medical community. There are very few people who have the experience, wisdom, vision, and tenacity that a Dr. Bruce Ames has, and the ability to make that all high science and to do the work that you’ve done over the many years. You are obviously a treasure. BA: Well, I appreciate that, and while we’re at it, can I put in one more plug? JB: Sure. BA: It is impossible to get any of this stuff funded from the government. They are only funding 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of grants, and the minute you’re too innovative, it’s the kiss of death. Even though I have been an enormously successful scientist all my life and opened up new fields, I just can’t get funded for working on triage. It cuts across too many fields and it’s too innovative. By the time I’ve really finally proven it all, I’ll be able to get funded. So it’s all money limited. I’m doing it all out of my own pocket and I’m 81 years old and I don’t have too many more years to go. If you have a wealthy fellow who wants to do really good work, I’d appreciate it. JB: I like to think of you as 81 years young, because we expect many more years given the fact that you’re the model of living what you talk about. BA: Well, I have a lot of enthusiasm. My enthusiasm genes are undamaged but I won’t vouch for my neurons. It could be a disaster. But at the moment it is going well and I have wonderful people in my group. This is the most important work I’ve done in my career, I think. JB: We want to thank you. We will send out the message, broad and wide, that your group deserves a very strong consideration from people who are looking for philanthropic places to make a difference in society. BA: Thank you. I enjoyed talking to you and keep up the good work. JB: You do the same. Thanks, Dr. Ames. It is my hope that in hearing Dr. Ames that you came away with the same kind of “aha” that I had in this interview. This is the second time we have had the privilege of interviewing him on Functional Medicine Update, spaced in between by about 10 years. It is just remarkable for me to see how an individual who might say, “Well, I’ve already done all that I need to do in science. I can just kind of sit on my hands now and watch the world go by and enjoy my senior position in the field of science…” is still continuing to be vital and evolving the model and adding a contributory sense as to how we move ourselves away from the age of deficiency to the age of sufficiency: the nutrigenomics era of systems biology in medicine that really creates a different way of approaching the patient in terms of assessment and intervention-to focus, really on promoting optimal function, not just on the prevention of deficiency.

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Bibliography

1 Williams RJ, Beerstecher E Jr, Berry LJ. The concept of genetotrophic disease. Lancet. 1950;1(6599):287-289. 2 Pauling L, Itano HA, et al. Sickle cell anemia, a molecular disease. Science. 1949; 109(2835):443. 3 Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(825):265-271. 4 Khan QJ, Reddy PS, Kimler BF, et al. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat. 2010;119:111-118. 5 McCann JC, Ames BN. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr. 2009;90(4):889-907. 6 Heaney RP. Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr. 2003;78(5):912-919. 7 Hagen TM, Yowe DL, Bartholomew JC, et al. Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase. Proc Natl Acad Sci U S A. 1997;94(7):3064-9. 8 Hagen TM, Ingersoll RT, Wehr CM, et al. Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci U S A. 1998;95(16):9562-9566. 9 Hagen TM, Wehr CM, Ames BN. Mitochondrial decay in aging. Reversal through supplementation of acetyl-L-carnitine and N-tert-butyl-alpha-phenyl-nitrone. Ann N Y Acad Sci. 1998;854:214-223. 10 McCann JC, Ames BN. Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals. Am J Clin Nutr. 2005;82(2):281-295. 11 McCann JC, Hudes M, Ames BN. An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring. Neurosci Biobehav Rev. 2006;30(5):696-712. 12 McCann JC, Ames BN. An overview of evidence for a causal relationship between iron deficiency during development and deficits in cognitive or behavioral function. Am J Clin Nutr. 2007;85(4):931-45. 13 McCann JC, Ames BN. Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction? FASEB J. 2008;22(4):982-1001. 14 Walter PB, Knutson MD, Paler-Martinez A, et al. Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats. Proc Natl Acad Sci U S A. 2002;99(4):2264-2269. 15 King Sm, Donangelo CM, Knutson MD, et al. Daily supplementation with iron increases lipid peroxidation in young women with low iron stores. Exp Biol Med (Maywood). 2008;233(6):701-707. 16 Ames BN. Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Science; 221(4617):1256-1264.

Welcome to Functional Medicine Update for May 2010. We’re very privileged this month to have Dr. Jeanne Drisko, from the Kansas University Medical Center, who has been a true pioneer in our field for the last 20 or so years, during the evolution of what we might call the functional medicine model or the integrative medical model. In setting the tone for her interview, I thought we might talk about this confluence or convergence of different medical perspectives that is occurring right now. Hopefully we are going to create a catalytic event, which will transform medicine as we move into the later part of the 21st century. One of the common themes that you see among all disciplines–be it environmental medicine, or functional medicine, or the complementary/alternative/integrative medicine, or holistic medicine, or naturopathic medicine–is the recognition that by modulating aspects of the environment of the individual, the phenotype of that individual can be changed through this gene/environment interaction transduction process. All of us in these fields are trying to find ways to improve the tools in our toolkit to be better able to personalize a program to the needs of each individual. That translates into a form of medicine that is more participatory, more preventive-focused, more personalized, and more proactive or prospective. Modulating Environment Means Personalizing Therapy Therapies can be delivered that cut across all types of diseases, and can range from early stage prevention, into the various aspects of the wellness model, and ultimately into early stage chronic disease. Using just diabetes as an example, you could go from early stage insulin resistance/metabolic syndrome into pre-diabetes, and then right into type 2 diabetes, and into the more severe sequence of events related to type 2 diabetes. All of the stages that manifest as distorted physiology would be amenable to the model that I’m describing which involves trying to modulate the interaction of the environment with the individual to create a positive outcome. Another example of this would be the individual who has a gluten sensitivity. You can personalize that person’s environment by putting him or her on a gluten-free diet. For an individual who has a very strong reaction to a certain class of chemical exposures because they have an altered cytochrome P450 and Phase II detoxification system, personalizing their environment means eliminating that exposure so they will be less likely to have an adverse response. It may also mean improving the functional capacity of their detoxification systems by using certain kinds of nutritional support that might upregulate or modulate the expression of those enzymes that we call the cytochrome P450s and the Phase II conjugase enzymes. Or it might be such things as improving musculoskeletal function, improving lymphatic drainage with various types of physical medicine-body work, various types of movement therapies-that ultimately delivers better information and better release of toxic burden. All of these things may ultimately allow physiology to perform at a higher level. These would be considered rational therapies based upon a different model, a model that is not compartmentalized or siloed. This model does not look at each organ as an individual or separate part of the body with each organ that is diseased having its own disease family, treated by its own kinds of drugs, with its own diagnostic criteria and treatment options within a different subspecialty of medicine. Rather, this model looks at how these are all connected together in the symphonic orchestration that we call life. It is called our physiology. It’s called our body function. We are going to have the privilege of exploring this model in greater detail with Dr. Drisko. We will talk about how this model gets taught and how it gets implemented in clinical practice. Basic science underpins much of what we teach medical students and ultimately practice. The whole nature of thinking about pathophysiology, cellular biology, and molecular biology is undergoing a dramatic change. Let me, if I can, give you my thought about how I think this dramatic change in thinking affects every day practice and translates into the exam room (the relationship of the practitioner with their patient). It used to be that we thought these diseases were independent. If a person had heart disease, it was an independent disease from osteoporosis, and it was an independent disease from inflammatory bowel disease, which was an independent disease from rheumatoid arthritis. As people looked more significantly at the epidemiology of these different diseases, it was found that often they were linked. That there was a higher probability that a person who had heart disease might have diabetes and might also have osteoporosis. People started to ask, “Why would this be?” We had a weigh station of our thinking. We called these conditions “comorbidities,” meaning they shared commonalities in their origin somehow or they seemed to be interrelated, statistically, and we didn’t know how. We scratched our heads, but called them comorbidities. A person seeing a cardiologist might also be seeing an orthopedist and a rheumatologist simultaneously, and using three different classes of drugs treating three different sets of pathologies. As we move forward in our understanding of the mechanisms that underlie the appearance of these dysfunctions, we find that there are common immunological disturbances that relate to alterations in the balance of various types of immune cells, like the thymus-dependent 1 and the thymus-dependent 2 lymphocytes. These disturbances can influence regulatory functions at different tissue levels and lead to increased risk to a number of companion diseases. These comorbidities really are interconnected at the gene expression level and at the cellular physiological level. Treating the cause rather than the effect might help us to reduce the rather significant impact of more than one disorder simultaneously. This model is at the root of functional medicine, as it has been redefined for the last 20 years. The functional medicine concept involves trying to look at the origin of these situations at the level of disturbances in the gene/environment interaction. These disturbances can spread through the individual in a unique way to express as either pre-clinical or later-stage clinical diseases that need management. We have to have different reference points–different weigh stations along the road–to understand this. These become biomarkers and signs and symptoms that become hallmarks for these different conditions. Looking for the convergence of these signs and symptoms around central themes can help guide us as to the principal or primary treatment option to personalize therapy to that individual patient. That model-that functional medicine model-really differentiates itself quite significantly from the histopathology model of driving toward the disease that that patient has as the diagnosis and then treating it as an individual, unique, independent entity. With that broad brush reminder of the conceptual framework, let me talk about some interesting recent examples that I think illustrate how this plays out in our evolving understanding of basic biology, and why biological sciences and physiology and molecular genetics are all really rapidly changing. I have recently said that I got together with a number of my fellow alumni who graduated from undergraduate school with me back in the middle 60s. All of us were reminiscing on our molecular biology class that we took. Now this was not too many years after Watson and Crick had discovered the structure of DNA in the middle 1950s, yet we thought, 10 years downstream when we took (in the middle 1960s) molecular biology, everything was known that needed to be known. We were feeling pretty sophomoric, meaning “wise fool,” about the level of understanding of molecular genetics. We all mused (at this 40-year reunion that we had) that if we would take the same tests today that we took back then, with the same answers that we provided for those tests back in the mid-60s (for which we got high marks in these classes), that we would get Fs and none of us would be considered professionals in our disciplines today because those answers that we got As for back in the mid-60s now would be considered wrong. The one-gene-one-enzyme concept, for instance, now is not totally wrong, but clearly has been modified to a whole new conceptual framework as to how protein regulation is controlled at the transcription and translational level, and then post-translational modification by various types of secondary processes to give rise to active protein that then modulates cellular functions. These concepts–that genes and proteins are interrelated, and how they are acted, and how they are expressed, and how they function in cells–have undergone a tremendous change in the last 40 years. The very rigid system of the one-gene-one-enzyme concept now looks very ancient in terms of its conceptual framework. Now we see gene plasticity. Now we see epigenetics, which is the concept that genes are regulated in their expression by marks placed on the histone coats of the genome that then relate to how certain messages may be read, or how genes may be silenced. Some of these particular marks are labile; they can be put on and off as a consequence of different environmental exposures, including, as we have indicated in functional medicine, things like life experiences, traumatic stresses, and exposure to low levels of biocides. Things of this nature can modulate the epigenome in such a way as to change genetic expression and ultimately the phenotype of cells, tissues, organs, organ systems, and the whole body. These are dramatically changing landscapes as to how we view basic biology and the whole construct of what is known-what is factual-about biological sciences, from a rigid framework to this more plastic kind of interactive system, going from a deterministic model to an environmentally modulated model of biology is really a very profound change in our thinking over the last 40 years. Abscisic acid is a chlorophyll-related derivative. If you know anything about the past history of alternative cancer therapy, you probably know the name of Virginia Livingston. Dr. Livingston, in San Diego, pioneered this concept of progenitor cryptocides, which she felt was a microorganism that had something to do with cancer initiation. It was a very primitive organism, and its growth process could be arrested by abscisic acid. Her treatment approach was to use a lot of abscisic acid-rich vegetable products as part of the therapy for her patients. Since that time, which was back in the 50s and 60s, a lot has been studied on various phytochemicals, including abscisic acid. A report that appeared in 2010 in Clinical Nutritiontalks about the role that abscisic acid has in synergizing PPAR-gamma that then modulates cellular signaling through the protein kinase A/PPAR-gamma axis into altered gene expression patterns.8 If you go back to my previous discussion about how PPAR-gamma has a role to play in the CD36 nuclear receptor and how that, then, controls aspects of gene expression related to cellular proliferation and atherosclerosis, it might suggest that there is something interesting about this other phytochemical, abscisic acid, and its connection with diabetes, cancer, and heart disease. Clearly this is not exactly the same as what Dr. Livingston talked about as it relates to progenitor cryptocides, but it does suggest that there issome support for its activity. What we are really doing is enhancing, significantly, the level of various types of phytochemicals that may modulate these processes that I am describing (these intercellular signal transduction processes) that spread out, when disturbed, into a variety of diseases: cancer, diabetes, and heart disease. hese long-forgotten phytochemicals, which we thought were not that important in the diet (we could take them out and make foods white and stable for long periods of time), we’re now finding out may be very important in modulating cellular signaling and ultimately translation and trafficking of messages that relate to cellular function (cellular phenotypes). I don’t want to put too many eggs in one basket. There are many variables that can modulate these functions: environmental agents, radiation, stress, dehydration, ischemia, chemical exposures, alcohol, cigarette smoking. We know that all of these play roles in modulating reactive oxygen species, redox potential at the mitochondrial level, and intercellular signal transduction process. The point I am trying to make for our thinking as we move into our interview with Dr. Drisko is that there is a convergence from many historical lines of thinking, across many disciplines, as to how diseases in and of themselves are not the sine qua non of health care. What is the sine qua non is understanding the distortion of physiological processes from the mismatch of genes with environment that creates an altered sense of trajectory of function that then produces a disturbed state-a new emergent state of the function of the cell that becomes the cell, tissue, organ, or organ system that is now what we call dysfunctional. I think that model leads one to ask, what tools does the therapist/physician/healer of the 21 st century need to be properly prepared for managing the diseases of chronic nature that we’re now burdened with?

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jeanne Drisko, MD Director, Program in Integrative Medicine University of Kansas Medical Center 3901 Rainbow Blvd Mail Stop 1017 Kansas City, KS 66160 jdrisko@kumc.edu We’re at that place in Functional Medicine Update -the clinician/researcher of the month portion of our commentary. We’ve been so privileged to have some of the most remarkable contributors to the emergence of the new medicine. We’re moving in that same direction in this issue with Dr. Jeanne Drisko, who is the Riordan Endowed Professor of Orthomolecular Medicine at the Kansas University Medical Center and a medical school professor. Dr. Drisko is a woman who has been a leader in our field for many years, through medical education, clinical work, and her leadership in organizational development. She has been involved very significantly with the development of recent work on chelation therapy and an international clinical trial that is ongoing. She has also been a fundamental person in establishing, I think, academic respectability for the field of orthomolecular medicine. Last year I had the privilege of interviewing Dr. Abram Hoffer, who we would certainly say was one of the founding members of this concept of orthomolecular medicine. Jeanne is the next generation of the orthomolecular movement. Dr. Hugh Riordan, the namesake of the Chair Dr. Drisko is occupying, was an interviewee on Functional Medicine Update some 20 years ago. He was one of the founding members of the field or orthomolecular medicine, through the work that he did in his extraordinary clinic in Wichita, Kansas. Jeanne, it is really a privilege to have you representing the field, both as a leader in the field and also, I think, as a woman of influence in medicine, who is shaping what I think is going to be the medicine of our future. Welcome to Functional Medicine Update. JD: Jeff, thank you for such a spectacular introduction. I just have a question, did my mother write that? I also want to thank you for these many, many years of updates that you have done. I tell you, it is a wonderful way to re-educate and to re-tool when we are moving from conventional medicine into real medicine. JB: Thank you. That’s a really wonderful segue into the body of this conversation. You have just stepped down as the president of the American College for the Advancement of Medicine, originally AMPS and later ACAM, an organization that has been kind of at the frontier of bringing many of these concepts into practice and certifying doctors through their fellowship program in this field. Tell us a little bit about your experience with ACAM and how you saw the organization evolve over your tenure as president. The Four Pillars: Education, Clinic Care, Research, and Service JD: It was a very interesting experience. It was a two-year tenure as president of ACAM. It gave me opportunity to reflect and to participate nationally in the reshaping of medicine. But that was just one of the ways that I was able to dovetail with this change in health care. In any academic program you have four pillars: education, clinic care, research, and service. I see my service as being able to sit on committees, both locally in the medical center and for the state board of healing arts, but also nationally for many organizations, like Alliance for Healthcare Freedom, the IFM Faculty, the Consortium of Academic Health Centers for Integrative Medicine, ACAM, and on and on. Another organization that I am very excited about is our International Medical Consortium. That is a group of organizations. There are six of us, including IFM, ACAM, the International College for Integrative Medicine, the American Association for Environmental Medicine (AAEM) (the naturopaths are part of that organization), and the American Holistic Medical Association. We have all climbed out of our silos, so to speak, and joined forces and become, really, one voice, and we respond as one voice, with some help from the Alliance for Health Freedom, to answer politically charged questions. Yes, I sat as immediate past-president of ACAM, but I see this as a much broader focus, more of an international focus. JB: That is really a great platform from which to get your perspective on how you visualize where we are in this change, going through this recent very vitriolic (at times) debate about healthcare reform, and seeing what’s happened in the rising tide of chronic disease globally, and recognizing that in countries like China the increasing incidence of diseases that were considered Western diseases are now becoming absolutely pandemic. Tell us a little bit about where you think we are in this continuum of change. Changing Medical School Curriculum: Acute Care Versus Chronic Care JD: I’d like to back up at the very grassroots level of this, and that is in the medical school curriculum. There’s been a change in the way that the curriculum has been addressed during the first two years. You and I both recall the days when, during the first two years of medical school, you took the basic science-focused classes: biochemistry, pharmacology, microbiology. But now, curriculum has been changed to a systems-based approach. You may have 15 or 16 modules that you complete in the first two years, let’s say immunity, inflammation, genetics, neoplasia, GI tract, and nutrition (if you can believe that nutrition is now actually taught in medical schools). These are interwoven with these core foundational basic science underpinnings. And you have, woven through the modules, both clinical aspects as well as the basic science aspects. So those are the first two years, and the students are thriving in this model. But the second two years continues to be largely a hospital-based experience and focused on the acute care model. I don’t know if you recall, Jeff, but in 2004 you mentioned this wonderful commentary in your updates. It was in the Journal of the American Medical Association, and it was an editorial calling for change in the model, from the acute care model of education to more of a chronic care model.9 They discussed how chronic care has really become the main focus over the past 50 years, but our educational system still focuses on the acute care. So doctors are not being trained, really, in how to care for patients that have chronic, complex disease. We’re really failing in preparing our medical students for the future. And the patients are dissatisfied. We really need to change this model. JB: I think you are referring to the Halsted Holman article, “The Need for a New Clinical Education.” I was down at Stanford, where he is a professor of medicine, recently, and had a chance to talk to some of their students about, “Okay, is this advocacy that Dr. Holman talked about in that paper in JAMA really starting to be seen as something happening within the curriculum at Stanford?” You know, you get kind of interesting mixed reviews from the students themselves. I talked to third- and fourth-year medical students and some will say, “Yes, we think we are starting to see more focus on management of chronic conditions,” and then others will say, “No, really all of the drive is to go into specialty medicine and treat acute care-type problems because that is where the universal attractor for making a good living is.” So only 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of students going to medical school now are really focusing on the family practice/generalist kind of approach toward prevention and management of chronic disease, with most people (95{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}) heading out into the specialties. I’m not sure. I guess it is still kind of a mixed report card, it would seem. Insights on the Healthcare Reform Debate: Is the Government Becoming Too Intrusive? JD: It’s a very mixed report card and it’s because of the model. It is an apprentice-type of a model (apprenticeship), and that’s the way our attendings have been taught, and that’s the way they choose to continue to teach. It’s going to take a revolution. I want to tell you a little story about what’s going on. It’s on the internet, but it’s a little bit in the background. We’ve had, as you mentioned, this debate on healthcare reform, but I think what we are missing in this discussion is that we have moved into the era of government intrusion in healthcare freedoms. What has happened is…if you recall, in 2001, the Institute of Medicine report, Crossing the Quality Chasm.10 That really spurred change in Health and Human Services and in the Agency for Healthcare Research and Quality. Just for an example, the Agency for Healthcare Research and Quality received an enormous increase in their budget from this recent stimulus package. They received an almost 55{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} increase in their budget. Let me give you another example: the NIH only received a 2.4{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} increase. And preventive care only received a 1{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} increase. And education and health jobs received no increase in their budget. So this agency is now really the driving force in this change in health care. What they do is they collect data on health care in the United States, and they also fund studies. This information that they collate is then handed off to the National Quality Forum, and that can be found at nationalqualityforum.org. Their job is to take and collate this information from the Agency for Healthcare Research and Quality and develop new measures. Okay. Currently, this year, we have 70 quality measures that we have to follow in hospital-based medicine, and I’ll come back to that in a minute. They predict that by next year there is going to be 130 quality measures that hospitals have to follow. This is compared to 2006, when there were only 21 measures. This is an enormous growth in a very short period of time. What these measures do is inform us around, let’s say, hospital-acquired infection. If a nosocomial infection occurs while that patient is hospitalized, the Medicare funding, or even some insurance companies, will not be responsible for paying for that treatment. If that patient acquires that infection while hospitalized, it will be the responsibility of the hospital to pay for that treatment. This is a huge change, a huge shift. The National Quality Forum hands these measures off to the Hospital Quality Alliance. They receive electronic data from the hospitals around the country. What the Hospital Quality Alliance does-and this is part of Health and Human Services-is they compare hospitals on their performance, amongst themselves, one another, and by state. This is a very regulated experience, and we can only expect more from here. As I mentioned, this is for hospitals only. Currently there are no regulations for ambulatory clinics or clinics that many of us have in integrative medicine. There are no rules and regs as of yet, but this is expected to occur. How does this translate into how we care for patients? We may be mandated to do certain things. For example, when someone is signed out of the hospital here at KU Medical Center, we go into the electronic medical record and discharge that patient. We have to document, in that electronic medical record, every event that occurred during that hospitalization: Did the patient have pneumonia? Did they have congestive heart failure? Did they have a myocardial infarction? That info is then transferred back to the Hospital Quality Alliance Network, and what is mandated are specific instructions for that patient. They have to receive certain medications if they have had certain illnesses. And if they have had pneumonia, they’ll be required to get a vaccine before they leave, and they have to be given a specific set of instructions. Currently, there are very few core measures that are mandated and regulated, and this is the evidence-based medicine model. But we can expect that these measures are going to come more and more-there are going to be more and more of them for all of us, not just the hospital-based patients. I’m very concerned about this, and I think a lot of this-even though it’s transparent (it’s out there on the internet)-has been lost in the noise of the healthcare debate. JB: You said so many interesting things in that discussion. At the Institute of Medicine conference recently held in 2009 on integrative medicine, Senator Tom Harkin from Iowa was talking about the way we language things and how all of the motivations are to really have a disease-based economy; we don’t have a health-based philosophy in this country and then that determines the outcome. It is almost like a self-fulfilling prophecy. Just in the way these organizations are named I find interesting. “Hospital-based care” somehow fits under the rubric of “Health Quality Alliance.” I think most would probably suggest that “hospital-based care” and “health” are not exactly synonymous words; “disease care” might be more the appropriate term. How do we fight to get out of these linguistic boxes that we have been built into? It seems like sometimes the perceptions that come from words already predetermine an outcome. We have kind of been painted into the corner when we talk about health care, which is really disease care reimbursement reform. Integrative Medicine is Now More Accepted in a Hospital Setting JD: That’s exactly the problem. I don’t know if you recall what you spoke about, but you were here at KU Medical Center about 7 years ago. You showed a slide that had a profound impact on me. It was the slide of the tree, with the diagnosis up in the branches, so you’ve got hepatitis, or you’ve got pneumonia,t or pulmonary disease, or cardiovascular disease, up in the branches. But you told us to forget the branches and go back down to the roots. Dig down in the roots to solve the problem. That was such a startling awakening for me. I loved that model and I have used it repeatedly since then. And I use that model with my conventional colleagues here in the medical center. We have had a really revolutionary set of events happen here. I’ve been here 12 years. In the beginning I was shunned and a number of people tried to drive me out of the medical center, but with persistence and really knowing what I was doing was right, I hung on and grew and gained respect, and now work very, very closely with my conventional colleagues. So the students, the residents, and the attending staff all are very interested in what we are doing. In fact, we’re starting to get consults in hospital patients-patients in the ICU, patients that are very, very ill. I always claimed that we are really the chronic care model and that Western medicine is the acute care model, but when you see that these patients in the ICU really have underlying, very chronic complex disorders, it seems that we do have a place in this entire healthcare picture. Our conventional colleagues invited us into the ICU to see their patients. We almost don’t care what the diagnosis is because we look down at that fundamental root. We are digging down in the roots. We are looking at vitamin and mineral levels, essential fatty acid levels, how is the GI tract working, how is immunity faring? We’re looking for those fundamental abnormalities, and we make correction in a very straightforward, simple way. And those simple additions have such profound effects on these very, very sick patients. They are often better very quickly and discharged very quickly from the ICU as a result. These are not complicated tests that we are doing. We’ve worked out a panel of laboratory tests with our laboratory here at KU Medical Center, and we simply order routine vitamin and mineral/essential fatty acid levels off of this lab req. The lab comes up, draws the blood, and it gets done and it is back on the patient’s chart, just like a CBC or a metabolic profile. And then we can advise our colleagues. And we also support this with papers; there are wonderful papers in the literature about supporting essential fatty acid levels, for example. In that way we are able to really teach and train on a very exciting level. JB: Let’s go back to the four pillars that you started this conversation with (education, clinical, research, and service). In that little discussion you really hit on all four of those. I want to note-and you probably would not state this yourself-at KU Medical Center you were acknowledged as one of the top 10 researchers of the year. That suggests that you are building-in the way that you have survived against the critics-an edifice that incorporates these four pillars very, very effectively. I guess the question is, do we have, in our field, enough research base, enough stuff in the literature (the peer-reviewed literature), to hold the critics at bay, or do you think that’s still an area of deficiency? JD: Oh, it’s a horrible deficiency. I’m going to get on my soapbox here a little bit. We are on a merry-go-round that we can’t off of. There is a bias against integrative medicine. They say, “Well, there’s not enough research.” But then our research arms are not really set up for the real-world integrative medicine practices. Because of this bias…let’s use the NIH, for example. The NIH-the scientists at the NIH-really have bias against complementary and alternative medicine or integrative medicine, and they actually want to close the National Center for Complementary and Alternative Medicine. Periodically in the Journal of Science or somewhere you’ll see an editorial saying that that needs to be closed. In fairness to Steven Strauss, who was the previous director of NCAM, and currently Josie Briggs, they were intramural researchers at NIH; they’re not integrative medicine devotees, so to speak. So they really had to learn from the ground up. They’re really not interested (Steven wasn’t, and Josie is definitely not) in investigating the real-world integrative medicine practices. Josie has stated that her interest is in looking at the basic science-the underpinnings-of integrative medicine. That’s not going to answer the questions. And that’s not going to provide the research needs that the doctors and the other healthcare practitioners are demanding. So we’re really in a very bad state. For a number of us who do the real-world integrative medicine research, what we are dependent upon, then, is funding from private foundations. And I’m so thankful for these private foundations, because they see the need and they are willing to step up where the federal government hasn’t. JB: That’s a beautiful additional segue into your endowed chair, the Riordan Endowed Professor of Orthomolecular Medicine. I think I was first actually introduced to you when he invited me to speak…I think it was at his first congress, or first conference in Wichita in 1976. He was a colleague of Linus Pauling. He really took on this whole concept of looking at the web of metabolism in a way that had not been usual and customary in medicine. He really put a tremendous amount of energy into understanding things like intravenous vitamin C, had work published in the literature. You obviously-with your fellowship, your endowed chair-are continuing to keep that model alive. I know that there has been continued work being done on the vitamin C and many other things that we feel are kind of still in need of better science to support what we have seen clinically. Can you tell us a little bit about the whole Riordan Professor of Orthomolecular Medicine and how that interrelates with this proof of concept model that we’re describing? Ongoing Studies on Intravenous Vitamin C JD: Who would have thought that at a conventional medical center there would be a chair named after an integrative medicine doctor with the word “orthomolecular” appended to it? No one would have believed it. But, anyway, it has happened, and it was because of grateful patients that have been helped. They really pulled together the funds to establish the endowed chair. And I was so fortunate to have been trained by Hugh. I went back and forth between Kansas City and Wichita for over a year to sit with him and learn from him in his clinic practice. It was like nothing I had ever seen before, but it resonated with me. Hugh was a great teacher; he has taught a lot of people. And his son, Neil Riordan, continues on with research in his place, and the center in Wichita continues as well. I’m very, very grateful to Hugh and to the center. From Hugh, I learned about I.V. vitamin C. I also knew that very minimal research had been done. In fact, in my first trial that I wrote on ovarian cancer, I called intravenous vitamin C an “antioxidant.” Well, along came Mark Levine at the NIH, and Qi Chen, his post-doc, and the other members of his lab at the NIH and NIDDK. They started looking at intravenous vitamin C, both in a number of normal cell lines and cancer cell lines, and then translated that into basic science research in animal models, both healthy rat models and then a new mouse model of cancer (a number of different cancer types).11 I’ve been very fortunate to attract Qi Chen, after she’d finished her post-doc with Mark Levine, to come here to KU Medical Center, and she’s now an independent investigator set up in her own lab here, and continuing this research on the basic science of IV vitamin C. In fact, we are having our basic science research meeting today at noon. I’m always so excited. Once a month we do this and I get to hear the latest and greatest that Qi is finding in her basic science research. They’ve been able to advise us (all of us out in the clinical world) that indeed vitamin C is not an antioxidant when it is given in the veins; it is a pro-oxidant. It becomes hydrogen peroxide in the extracellular space (not in the blood space, but in the extracellular space), and that hydrogen peroxide diffuses, then, or crosses the cell wall, into the intercellular environment, where it impacts multiple pathways. We’re not even sure of all the pathways at this time. We also believe that besides its pro-oxidative effects, it has some immunoregulatory effects. I’m also doing a small clinical trial with a brain imaging investigator here at KU Medical Center, where we are giving I.V. vitamin C both to healthy adults and to adults with type 2 diabetes. We are imaging the brain after I.V. vitamin C infusion by MR spectroscopy to look at the peaks of the vitamin C in the brain and the differences between an oxidative environment brain (the diabetic patients) and the patients that are considered to be normal. Very, very exciting days for vitamin C research. JB: That is exciting. Are you collaborating at all (or have communication with ) John Hoffer? Because I know that John published that very nice clinical trial recently looking at intravenous vitamin C in a number of patients in Montreal.12 JD: Yes. I’m very good friends with John. I do miss Abram. I would receive these emails from Abram Hoffer in the middle of the night and it was always fun to hear from him. John and I are colleagues. We had the opportunity about 18 months ago or so to meet at the National Cancer Institute with Jeff White who runs the Office of Cancer, Complementary and Alternative Medicine, under NCI. Mark was there, and Qi Chen, and Mike Espy. We were able to have a really nice roundtable discussion with Jeff White about the future of vitamin C research and cancer care, so we are very close colleagues. An Important Clinical Trial on Chelation Therapy JB: I know you are involved in a very important additional large clinical trial on chelation therapy, and that is another kind of step along the path toward putting some scientific explanation/proof on things that people have observed, clinically, to be beneficial for some time. Can you tell us about the status of that trial? JD: Yes. You know, that’s a very interesting trial. That’s really, I think, the model of how integrative medicine should be structured. This is a partnership between conventional cardiology researchers. Tony Lamas is not an integrative medicine doctor. He’s the principal investigator. He is a conventional cardiology trialist, and he is connected nationally. What he did…he realized that there might be something to this chelation therapy. He approached the practitioners of this, so we were able to work with Tony in setting up how this trial might run. We had multiple phone conferences, and he had his statistical team from Duke on the phone calls. All of the events for the trial-whether patients had congestive heart failure or myocardial infarction-those events are being adjudicated at Harvard. This is really a partnership, nationally and internationally, now, because these study patients are not being run through academic centers. Some of them are in academic centers, but the majority of these study participants are coming through integrative medicine doctors’ clinics. So they are receiving chelation therapy as they would in a real-world setting. This is startling. Why hasn’t this model been replicated? It’s really unfortunate that it hasn’t. It’s because there was a strong push from Congress, and Congress told the NIH National Heart, Lung, and Blood Institute that they had to do this trial, so they were forced to do it. But because they were forced to do it, they wanted to do it right. They had a call for proposals, and they did the usual vetting of proposals, and they selected Tony’s trial. We’re very excited about this. I’m sure you heard about the bump in the road, where the trial was shut down temporarily. There was a group of…well, they’re not all physicians, but there is the Quackbuster group, and they attempted to close this trial for good. What had happened was there were erroneous accusations about patient safety, and this went to the Office of Human Research Protection. So because they had to investigate it, the Office of Human Research Protection asked the NIH to stop the trial until the investigation could be done correctly, so the Data Safety Monitoring Board at the NIH and the Office of Human Research Protection delved into every data point available, and at the end of the day, they found that there were no concerns for safety or further enrollment of patients, so they allowed the trial to continue. I think this is a victory for science, because it is not a political movement. This is about science. Either the hypothesis is correct or it’s not, and at the end of the day, we’ll know. JB: When is the study, you believe, likely to conclude? JD: There’s probably about another 150 or so participants that need to be enrolled. They are given their chelation therapy and then followed. So it’s probably not going to be over for another 2 – 2 1/2 years. This is a very large trial. There are almost 2000 participants enrolled in this trial. They are enrolled in the United States, Canada, and South America, so it is a very large trial. It is a Phase 3-a good, solid Phase 3-trial. JB: Obviously we are all waiting with bated breath. That sounds like a very, very exciting trial, and something that I’m sure we’ll have data beaucoup, and probably cohort analysis will prove all sorts of interesting things out of the trial. Congratulations. I know that that has been a very big project that you and many others have been dedicating time and energy to. Again, it’s a model for the kinds of things that need to be done in our field. JD: Absolutely. JB: I know that we’ve taken a lot of your time, but one of the questions that I’m sure is on the mind of the listener is, how does all this translate, in Dr. Drisko’s mind, to the future of medicine? And how is the family doc who is delivering care every day and organizations like the American Academy of Family Practitioners, which is the largest subspecialty organization in medicine, going to be affected? What will medicine look like? I guess I’m asking the crystal ball question, which is always an impossible question to really answer. Given that you have a vantage point that most of us don’t, maybe you could speculate a little as to how you see things moving forward. JD: I reflect on this question, actually, quite a bit. And I want to back up just a minute to talk about why I would even be reflecting on this question, and that’s because one of my four pillars is education. I have students that rotate through our clinic. I have a standalone, fourth-year medical student elective. I have nursing students visit. We have PhD students go through Qi Chen’s lab. We have residents that are rotating; I have a resident from internal medicine working with me currently. And then we started a fellowship and really, I think, built a wonderful fellowship that is probably not replicated anywhere in the United States currently; it’s really a fellowship that teaches real integrative medicine. The fellows come after primary care residency, so family medicine, or internal medicine, or pediatrics. I’m actually looking at possibly getting a pediatric fellow soon. How do we really point them to the future of medicine? What we try and teach them is that we’re here to serve our patients. If you think about that acute care model, there really isn’t a lot of time to spend getting to know that patient. In the acute care model, you have a problem: you’ve got bleeding, and you stanch the blood flow, and the problem is corrected, and the patient walks out. So it is really largely driven by the physician. But in the chronic care model, you’re now looking at a partnership, and this is one thing that Hugh Riordan taught me: that really you are learning as much about that patient as that patient is learning about themselves, so it is a partnership. What do we do? We need to listen. We spend a lot of time listening. And then we get down into the roots. We live down in the roots of the tree for that patient. We try and teach them how to get down in those roots, and to listen to their bodies, and to understand that the foundation is sleep and good nutrition. Then we try and correct the core deficiencies, and really clean up the terrain. I’ve been fortunate to be able to participate in the functional medicine module for detoxification and really helping to teach cleaning the terrain. What we are trying to do, then, is build a new model to show-to tell–the next generation of healthcare practitioners how they’re going to be taking care of patients. What is beautiful is all of the people that have come before me and standing beside me in the integrative medicine world that have taught me so much and continue to teach me so much. This is what we have to do. We have to pass it on to the next generation and they are so hungry. And even the attending staff, now-the people that are old and crusty like me-are also becoming more open-minded. They are saying, “Wow, this is working. This might be okay. This isn’t so wacky as we thought it was.” It’s this grassroots…just teaching in medical schools, I think that’s so critical. JB: Dr. Drisko, that’s about the most inspiring, enlightening, and hopeful message that I think we’ve heard recently on Functional Medicine Update. I think your leadership shines through by example. You’ve done the heavy lifting. You’ve gone through the appropriate academic training and credentialing. You’ve kept your search for knowledge and learning alive and well. You’ve inspired people by your enthusiasm and your sense that there is a better horizon that is in our future. All of things, to me, kind of focus on a central theme that seems to be true about all great social change, and that is the concept that truth wills out. It may take some time for truth to find its way through the tortuous path of selective interest and control, but eventually a truth will out. And it seems that there is a central truth to this field that you are describing. Maybe not all of the details are exactly i-dotted and t-crossed precisely, but the general construct…as my father would say, it fulfills a rule of reasonableness. There is something reasonable about what you are saying, and as we get more data, and more clinical information, and more young fresh minds that are really searching for the right answers, it seems that your model that you provided us here at the end, which is one of optimism and hope, is a very likely outcome. Thank you, you have given us all a big gift in your vision for our future. JD: You’ve been very kind and I appreciate the opportunity to speak with you. JB: Thanks and keep up the great work there. We are going to follow the studies and follow your work as part of the consortium very closely because these are the agents of change. Thank you very, very much. I certainly hope you had that extraordinary kind of “aha” experience that I had talking with Dr. Drisko as you were listening to her. If you calculate a takeaway value of this whole issue of Functional Medicine Update, there would be several takeaways, one of which is optimistic: that we are really seeing a confluence/convergence of education, clinical research, and service moving into a new medical paradigm. We’ll be speaking about that, actually, at some length in next month’s Functional Medicine Update. You’re going to get a two-part hit on this because next month we’ll be speaking with Dr. Halsted Holman, the individual who authored the article in the Journal of the American Medical Association on the need for a new clinical education. I think beyond there is also an implementation takeaway from this discussion, and it goes back to my introduction around antioxidants, and the CD36 receptors, and LDL oxidation, and the confluence or convergence among atherosclerosis and diabetes type 2, and cancer. When we look at things like vitamin C, should everybody be taking vitamin C? My answer would be yes. Clearly everybody should be taking it to prevent scurvy, but that’s a minimum expectation. I think what we should take away is the recognition that there is a level of vitamin C intake beyond that required to prevent scurvy that is optimal for individuals in a normal, healthy function to support proper redox potential and to modulate oxidative chemistry. Here we are talking about intakes of something like 500 to 1000 milligrams…I guess you call it nominally. Then if we talked about in case of infection, or a chronic illness, or ischemic events would there be required higher levels of vitamin C? The answer appears to be absolutely yes from the work of Mark Levine and Qi Chen and others that have been really looking at the role that vitamin C plays in these processes. What about vitamin E? Vitamin E, although it has been hit heavy in some of the negative press, certainly falls as an important member of this family of redox potential active nutrients. What about this rich array of phytochemicals that modulate along with minerals, like selenium, and zinc? Shouldn’t they also be part of the antioxidant arsenal? My answer is yes, if we think of these all as signaling substances-as things that modulate intercellular signal transduction (berries, and grapes, and the whole vegetable family that has carotenoids, and has the nature of these pigmented substances that modulate cellular function). What does it come down to? Again, almost the fundamental rules of logic that we’ve heard for so many years: diversity, minimally processed, high-plant-food-based diets, and things that we take in augmented levels that help regulate this complex interaction between our environment and our genes that gives rise to the expression of our health. A very interesting paradigm model that’s a very big shift from the way most of us were taught either nutrition or medicine. Thanks for being with us and look forward to Dr. Holman next month  

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Bibliography

1 Dod HS, Bhardwaj R, Sajja V, et al. Effect of intensive lifestyle changes on endothelial function and on inflammatory markers of atherosclerosis. Am J Cardiol. 2010;105(3):362-367. 2 Frattaroli J, Weidner G, Merritt-Worden TA, et al. Angina pectoris and atherosclerotic risk factors in the multisite cardiac lifestyle intervention program. Am J Cardiol. 2008;1010(7):911-918. 3 Mora S, Ridker PM. Justification for the use of statins in primary prevention: an intervention trial evaluating rosuvastatin (JUPITER)-can C-reactive protein be used to target statin therapy in primary prevention? Am J Cardiol. 2006;97(2A):33A-41A. 4 Kennedy DJ, Kuchibhotla SD, Guy E, et al. Dietary cholesterol plays a role in CD36-mediated atherogenesis in LDLR-knockout mice. Arterioscler Thromb Vasc Biol. 2009;29(10):1481-1487. 5 Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. J Clin Invest. 2009;119(1):136-145. 6 Abbadia Z, Vericel E, Mathevet P. et al. Fatty acid composition and CD36 expression in breast adipose tissue of premenopausal and postmenopausal women. Anticancer Res. 1997;17(2A):1217-1221. 7 Huang H, Campbell SC, Bedford DF, et al. Peroxisome proliferator-activated receptor gamma ligands improve the antitumor efficacy of thrombospondin peptide ABT510. Mol Cancer Res. 2004;2(10):541-550. 8 Guri AJ, Hontecillas R, Bassaganya-Riera J. Abscisic acid synergizes with rosiglitazone to improve glucose tolerance and down-modulate macrophage accumulation in adipose tissue: possible action of the cAMP/PKA/PPAR gamma axis. Clin Nutr. 2010. [Epub ahead of print] 9 Holman H. Chronic disease-the need for a new clinical education. JAMA. 2004;292(9):1057-1059. 10 http://www.iom.edu/Reports/2001/Crossing-the-Quality-Chasm-A-New-Health-System-for-the-21st-Century.aspx 11 Chen Q, Espey MG, Sun AY, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular in vivo. Proc Natl Acad Sci U S A. 2007;104(21):8749-8754. 12 Hoffer LJ, Levine M, Assouline S, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. 2008;19(11):1969-1974.

Welcome to Functional Medicine Update for June 2010. I’d like to start this issue with a quote that I feel exemplifies what we are going to be focusing on this issue: “It is axiomatic that medical education should prepare students well for the clinical problems they will face in their future practice. However, that is not happening for the most prevalent problem in health care today: chronic disease.” This quote is taken from a paper authored by Dr. Halsted Holman, Professor of Medicine, Stanford University, under the title “Chronic Disease: The Need for a New Clinical Education,” that appeared in the Journal of the American Medical Association in September, 2004.1 In this article, Dr. Holman eloquently describes how we are failing, both in terms of preparation of medical students for their practice of medicine, and later to support medical doctors in practice with appropriate approaches (both pedagogical approaches and implementation) approaches for the management of complex chronic disease. Dr. Holman states in this article that more than 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of our healthcare expenditures are spent on managing chronic disease, yet we don’t have a good clinical training program nor a system of thinking as to how to approach these ambulatory long-term care challenges. This is what we will be discussing in this issue of Functional Medicine Update: patient-centered care. This is a concept that Dr. Holman–himself and his group–has pioneered entry and application to through work first at the University of California at San Francisco School of Medicine, and more recently at Stanford University. When you hear this extraordinary interview with Dr. Holman, you are going to hear a doctor’s doctor. It’s immediately obvious the type of patient relationships that he has undoubtedly had over his years of practice. He is a seasoned visionary, highly thoughtful, conscious provider of health care, focusing energies on patient-centered chronic disease management. He points out in this article in the Journal of the American Medical Association that there are certain characteristics that really define an effective system for managing chronic illness. To presage the conversation, I want to describe those seven points. The first characteristic is caring for patients with chronic disease over time in the clinic, the community, and at home as an opportunity to teach the patient engagement in their own disease management process and what represents the elements of good care. This is the foundation of patient-centered medicine. Number two is educating patients in self-management methods. This is critically important because they will become the masters of their own disease, both managing it effectively and understanding how to deal with some of the uniqueness related to their specific situation. Number three-and this is a very important point that is not often seen in practice-is the participation in group visits of patients with similar chronic diseases or illnesses with the physician or the healthcare extenders in the office. Topics are often chosen by the patients. During these group visits patients learn from each other, and physicians learn from the experiences of the patients. A cooperative relationship with a healthcare extender provides a more cost-effective outcome. Number four is working with patients and other healthcare professionals in a manner that shares medical management responsibilities. This would be a collaborative process rather than a top down, command-and-control process: distributing skills among the exercise physiologist, or the nutritionist, or the individual involved in lifestyle management (the health coach). All of these become very important parts of a distributive system that makes more effective the self-management and patient self-care and ultimately patient-centered approach toward chronic disease. Next is the provision of care for patients without a physical encounter by the use of distance: telemedicine, and email, and website discussions. These types of interactions can lead to tremendous support when a patient is not in the office and provide the kind of overall experience that will improve outcome. Lastly, the final characteristic is using relevant behavioral science concepts and methods to understand the adverse effects of chronic disease on a patient’s life and how to reduce them. An approach based upon these characteristics frames a very different style of medicine. This is a medicine that is centered on the patient, not on the disease, and engages the patient in their own health process.It is cooperative, using group process among different individuals of different disciplines and the patients themselves to collaborate in solutions to individual health problems. A collaborative process. A distributive process. A process of engagement. And a process of self-regulation. Is this the medicine that we have all been taught? The differential diagnosis-drive to the diagnosis and drive to the treatment type of medicine? Or is this really a medicine that is built around functional medicine and what I have been talking about for years: a systems biology approach towards the remediation of chronic health problems? I read a recent paper that appeared in The Lancet medical magazine. It is a very profound paper by Dr. Andrew Scull, from the Department of Sociology at the University of California, San Diego.2 This article, to me, exemplifies a concept related to how we see the patient and how the patient is treated in an extreme example of differential diagnosis and driving to treatment: psychiatry. If you had the pleasure of reading this article, you probably got a very good “aha” about some things that we take for granted at the moment, only to later come back to re-evaluate them, and with 20/20 hindsight, ask the question, “How did we get there?” Dr. Scull is also the author of a book that I think you might find an interesting read, called Museums of Madness: The Social Organization of Insanity in 19th Century England.3 He also authored more of a consumer book titled Madhouse: A Tragic Tale of Megalomania and Modern Medicine.4 From the titles of those books, you can get the drift as to what Dr. Scull’s sociological view of psychiatric medicine is all about. The following quote is from the paper that appeared in The Lancet in 2010 under the title “The Art of Medicine”: “As I reach nearer the end than the beginning of my career, it still comes as something of a shock to realise that I have been at work on the history of psychiatry for some four decades now. I never intended that my early infatuation with disorders of the mind should turn into a life-long obsession. I began my exploration at a time when the museums of madness that were the Victorian age’s response to Unreason still loomed large in our collective conscious. The massive, ramshackle piles retained their hold, not just on our imaginations, but upon thousands and thousands of people with mental illness, still confined in what had been once proclaimed as a therapeutic isolation. It is hard to forget the sense of constriction and confinement that oppressed one’s spirit on crossing the threshold of one of these establishments. Above all, perhaps, I remember the smell, the fetid odour of decaying bodies and minds, of wards impregnated with decades of stale urine and faecal matter, of the slop served up for generations as food, the unsavoury mixture clinging like some foul miasma to the physical fabric of the buildings. My first encounter with the sights, the smells, the sense of despair that enveloped these total institutions, ought perhaps to have been enough to put me off any lingering attachment to research in such settings. Yet I remain as fascinated as ever with trying to understand the elaborate social institutions we have devised to grapple with, manage, and dispose of the ‘mad’, and with the intellectual puzzle that mental illness itself represents. To be sure, I have long since strayed outside the confines of the 19th century: initially into the Georgian age where the madhouse first came to the fore, and mad-doctors began to develop their claims to expertise; then into the therapeutic enthusiasms and uncontrolled experimentation on the bodies of patients in the first half of the 20thcentury; and, most recently, into the realm of hysteria from its origins in ancient Greece to the height of its fame in Charcot’s hysterical circus, its overt sexualisation by Sigmund Freud and his followers, and its official demise at the hands of the neo-Kraepelinians, who banned it from their Bible, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders. It is a history that has its charms as well as its horrors. But while I was busy in the archives, the contemporary psychiatric enterprise was undergoing a transformation as dramatic and fundamental as can readily be imagined. When I began to explore its past, psychiatry, at least in its American guise, was dominated by psychoanalysis. The Freudian movement had first risen to prominence during World War II, in the treatment of ‘war neurosis.’ Through the 1960s, its hold over the profession and the public imagination steadily grew. With scarcely an exception, the departments of psychiatry at the major medical schools were headed by psychoanalysts and psychoanalytical fellow-travellers. The ‘refrigerator mother’ was blamed for the seeming epidemic of schizophrenia. Although Freud himself had questioned the relevance of psychoanalysis in the treatment of psychosis, his more optimistic American epigones were undeterred. If they reluctantly began to use the first generation of antipsychotic drugs, they saw them merely as useful therapeutic adjuncts to calm down florid symptomatology so that the ‘real’ work of psychotherapy could proceed. Hollywood dramatised the miracles of the talk cure in movies like Suddenly Last Summer and I Never Promised You a Rose Garden. Anxious American parents turned to Dr. Benjamin Spock for enlightenment and were rewarded with bowdlerised version of Freud’s theory of child development. Best-seller lists saw the appearance of pot-boilers such as Robert Lindner’s The Fifty Minute Hour, titillating the masses with tales of secrets of the couch. Psychoanalysis ruled the roost. And then it didn’t. More swiftly and silently than the Cheshire cat, psychoanalytic hegemony vanished, leaving behind not a smile, but a fractious group of Freudians and neo-Freudians who squabbled among themselves. Professors of literature and anthropology tried feverishly to fend off the notion that Freud had turned into an intellectual corpse, but cruel realities suggested otherwise. Psychoanalysts were rapidly defenestrated, chucked out of their hold over academic departments of psychiatry and replaced by laboratory-based neuroscientists and psychopharmacologists. Psychoanalytic institutes found themselves bereft of recruits and forced to abandon their policy of admitting only the medically qualified. The very term ‘neurosis’ was expunged from the official nomenclature of mental disorder, along with hypothetical Freudian aetiologies for various mental disorders. The ‘surface’ manifestations of mental diseases that the psychoanalysts had long dismissed as merely the symptoms of the underlying psychodynamic disorders of the personality became instead scientific markers, the very elements that defined different forms of mental disorder. And the control of such symptoms, preferably by chemical means, became the new Holy Grail of the profession. It was a counter-revolution launched, not from the hallowed and ivied halls of the Harvards and the Yales of this world, but of all things, from St. Louis, from renegades at the oh-so-provincial Washington University Medical School, and from a renegade Columbia psychiatrist, Robert Spitzer. And its primary weapon was a book, or rather an anti-intellectual system published in book form: a check-list approach to psychiatric diagnosis and treatment that sought maximum inter-rater reliability among psychiatrists confronted by a given patient, with scant regard for whether the new labels that proliferated in its pages cut nature at the joints. Agreement among professionals was enough, particularly on those occasions on which a given diagnosis could be linked to treatment with a particular class of drugs. Indeed, soon enough the polarity would be reversed, and the creation of a new class of drugs would lead to the creation of a new psychiatric ‘disease’ to match, just one of the factors that prompted successive editions of DSM to proliferate pages and disorders, like the Yellow Pages on steroids. Drugs, of course, were the centrepiece of the new era. For some, they were the technological first cause of its most notable accomplishment, the emptying out of the old state hospitals and county asylums. Chlorpromazine and its derivatives gave psychiatry for the first time a therapeutic modality that was easy to dispense and closely resembled the magic potions that increasingly underpinned the cultural authority of medicine at large. Too bad that the phenothiazines were no psychiatric penicillin, and that they would be responsible for a long-ignored epidemic of iatrogenic illness. They reduced florid symptomatology, and for some patients, at least, provided a measure of relief. After centuries of therapeutic impotence, it was perhaps understandable that psychiatrists were so grateful for their arrival and so eager to hype the value of the new pills. In truth, antipsychotics played at best a secondary role in the demise of the asylum. Deinstitutionalisation was driven far more by fiscal concerns, and by conscious shifts in state policy. But for Big Pharma, psychiatric drugs were a bonanza, a major source of profits that ran into the many billions of dollars. Almost instantly alive to the profit potential of the phenothiazines, the multinationals were slow to realise the even larger rewards that could flow from exploiting compounds that changed people’s moods, but the belated success of Prozac changed all that. And changed as well the professional and public’s understanding of mental disorders. The US National Institute of Mental Health proclaimed the 1990s ‘the decade of the brain.’ A simplistic biological reductionism increasing ruled the psychiatric roost. Patients and their families learned to attribute mental illness to faulty brain biochemistry, defects of dopamine, or a shortage of serotonin. This biobabble as deeply misleading and unscientific as the psychobabble it replaced, but as marketing copy it was priceless. Meantime, the psychiatric profession was seduced and bought off with boatloads of research funding. Where once shrinks had been the most marginal of medical men, existing in a twilight zone on the margins of professional respectability, now they were the darlings of the medical school deans, the millions upon millions of their grants and indirect cost recoveries helping to finance the expansion of the medical-industrial complex. And so to scandal. He who pays a piper calls the tune, and to quite an extraordinary extent, drug money has come to dominate psychiatry. It underwrites psychiatric journals and psychiatric conferences (where the omnipresence of pharmaceutical loot startles the naïve outsider). It makes psychiatric careers, and many of those careers it fosters become shills for their paymasters, zealously promoting lucrative off-label uses for drugs whose initial approval for prescription was awarded quite other grounds. It ensures that when scandals surface universities will mainly turn a blind eye to the transgressions of those members of their staff who engage in these unethical practices. And it controls psychiatric knowledge in multiple ways. Its ghostwriters produce peer-reviewed ‘science’ that surfaces in even the most prestigious journals, with the most imminent names in the field collaborating in the deception. Researchers sign confidentiality agreements, and inconvenient data never see the light of day. The very categories within which we think about cognitive and emotional troubles are manipulated and transformed to match the requirements of the psychiatric marketplace. Side effects, even profound, permanent, perhaps fatal side-effects, are ignored or minimised. Fines may be levied when somnolent regulators are finally promoted into action, or damages paid where aggressive class action lawyers force hitherto suppressed findings into the public arenab but the profits already booked far exceed those costs of doing business. For a historian of psychiatry to live through such revolutionary times is remarkable indeed.” How Does the Example of Psychiatry Relate to Patient-Centered Care? How does this article relate to patient-centered care? Psychiatric disease is a chronic illness. It is something that stays with the patient. It is a psychosocial as well as a biomedical condition. It is a condition that Dr. Abram Hoffer talked about through his years of service as an MD/PhD psychiatrist. He was first involved with Freudian psychoanalysis, and later with electroshock therapy, and later with insulin shock therapy. He said the biggest and most important transition he made in managing forms of mental illness in his career, which spanned over 70 years, was in the implementation of a functional approach: looking at diet, lifestyle, environment, psychosocial connections, and interrelating that to genetic history, and, where necessary, therapeutic agents of intervention. He birthed the concept of orthomolecular psychiatry, looking at the molecular milieu from which physiological and neurocognitive function emerges. He and Dr. Linus Pauling birthed the concept of orthomolecular medicine: the life of the mind may be related to the patency or the physiology of the mind through not adjustment by new-to-nature molecules, but rather by adding into the environment of that patient specific nutrients and substances that are necessary based on their genetic need in order to promote proper neurocognitive function. This is a very profound, different model, and one that you are going to hear Dr. Halsted Holman speak to as it pertains to how to develop a chronic disease management system that truly addresses the needs of the patient. Not just disease-centric, but patient-centric. I think this article by Andrew Scull is very important because it really illustrates, using one specific example, the history of psychiatry, how we can tunnel ourselves into a specific isolated vision, which is a disease-focused type of model, always looking for the name of something to attach to it and finding the molecule that will modulate that outcome or that symptom. Rather what we are starting to see emerge is a different kind of perspective. It’s a perspective in which the patient is seen as a unique individual from which they bring their history, both genealogical history and their own individual personal history, to the time of the exam and the presentation of their signs and symptoms with different severity, different duration, and different frequency. It is that complex story that then defines the thumbprint or the uniqueness of that patient, for which then the construction of a program based on their need for long-term management of this chronic condition that they presented with can lead to an improved outcome What kind of information do we really derive on that patient? And how do we approach, then, actually constructing an effective long-term chronic care model that is personalized to that patient need? You are going to hear much more about that from Dr. Holman himself, but before we get to him let’s talk a little bit about the assembly of information that we call biochemical information, the so-called “biomarkers” that relate to disease of a chronic nature. I was once told-I think it was a very insightful comment-that it is hard to know what disease you didn’t get when you prevent it. It is much easier to know how you treated a disease and what its outcome was than to understand something about a disease that you didn’t get. I think that’s a very interesting insight because it speaks to why preventive medicine is so difficult. It doesn’t seem to have quite the juice associated with it that working in the emergency room does, where you have a person that has a very specific and life-threatening condition in the immediacy, for which you can then offer heroic intervention and “save their life.” For every patient that has an early marker that can lead to terminal cancer, or an early marker that may ultimately arrive as a fatal heart attack, or an early set of disturbed physiological functions that may later be seen as a life-threatening stroke–all of those particular situations are not nearly as heralded. They are more difficult to get your arms around. They are squishy, so to speak, in that you don’t know how you have actually influenced that patient’s life as dramatically as you might know in the emergency room when that person near death suddenly looks like they are going to survive. Yet the impact on the patient’s overall quality of life, and in fact even on what we would call their health span, may be more profound by early intervention in a chronic care model than the late stage intervention in heroically intervening to save a person from imminent death. I think that these constructs of how you find value, then, and understand how to assess a return on investment for the time you spend on a chronic care patient is a very interesting question, particularly in this age where everything is economically tied and we are always asking, “What am I getting in return for the time, energy, and money that I am putting in?” How do we quantify the value of a chronic care model in preventing an acute condition from occurring? I think part of that is related to understanding the concept of biomarkers. These are respected variables that we know have some relationship to outcome called health or disease that are identified in a risk category associated with many different chronic diseases. Let’s take an example. Let’s look the number one killer disease-a chronic disease-and that’s coronary heart disease and cerebral vascular diseases (as a family). And let’s ask, what about biomarkers that relate to these conditions? If you want to intervene early, while it is still a chronic care issue versus an acute care issue in an ICU, what types of information would you want to assemble? Validated biomarkers relate to our ability to understand the trajectory or the path that patient is on towards declining function and increasing risk to a crisis event, and also provides (if they are validated biomarkers that are sensitive, precise, and selective for that condition) some information about the success of therapy if we can modulate these biomarkers. Establishing the Definition of “Biomarker” The term “biomarker” was first introduced in 1989 as a medical subject heading in PubMed, so it is a fairly recent conceptual framework if we think about this. Rather than just a diagnostic marker, we are talking about a biological marker that assesses the trajectory towards a dysfunction that later becomes a disease. 1989. The definition was: “Measurable and quantifiable biological parameters such as a specific enzyme concentrations, or a specific hormone concentration, or specific gene phenotypes, which serve as indices for help in physiologically-related assessments, such as disease risk, psychiatric disorders, environmental exposures and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiological studies.”5 It was in 2001 that the National Institutes of Health, in a working group, standardized the definition of a biomarker as: “A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathological processes, or pharmacologic responses to a therapeutic intervention,” and defined types of biomarkers. Defining Subtypes of Biomarkers Defining the types was really the codification of biomarkers into various subtypes. A type 0 biomarker would be a marker of the natural history of a disease that correlates longitudinally with known clinical indices. That would be something like serum cholesterol, to use an example. It’s not tied to the diagnosis of a disease, but rather the trajectory of a dysfunctional physiological state that ultimately has a clinical outcome called cardiovascular disease. A type 1 biomarker would be a marker that captures the effects of a therapeutic intervention in accordance with its mechanism of action. So this might be to look at something like hsCRP after intervention with an anti-inflammatory substance. A surrogate endpoint type 2 biomarker would be defined as a marker that is intended to substitute for a clinical endpoint. A surrogate is expected to predict clinical benefit, or harm, or lack of benefit on the basis of epidemiological therapeutic pathophysiological or other scientific evidence. The most significant of these, obviously (for surrogate biomarkers) would be those that tie or correlate very closely with an outcome such as the diagnosed disease, or premature death, which is obviously the most discreet and least ambiguous endpoint. How do you validate a biomarker? This is a process of assessing performance characteristics, such as the sensitivity, specificity, and reproducibility of this specific thing we are measuring (this biomarker) and how it relates to the assay technique. And ultimately it would be quantified, looking at the evidentiary process that it is associated with a disease biology or a specific clinical outcome (either a diagnosis or a disease), or (as I said) the most unequivocal, which is death itself. These concepts of biomarker evaluation–the quantification of biomarkers, validation of biomarkers, and understanding the difference between a risk marker, a surrogate marker, and a marker of the natural history of disease–I think are all very important as we start looking at the things that we are going to test on patients who have chronic illness and try to understand how to use those data appropriately to both chart a course for therapeutic intervention in a patient-centered way, and for following the course of therapy or the success of therapy so it can be fine-tuned. Obviously biomarkers that we employ include a whole variety of different types of analytes. They may measure, for example, the exposure to environmental factors like heavy metals such as lead or cadmium, or xenobiotics-things like persistent organic pollutants, or things like gluten in a celiac patient. They may measure genetic susceptibility, particularly now that we are getting into genomic analysis, looking at various types of single nucleotide polymorphisms, or looking at things that relate to breast cancer risk, like BRCA-1 and -2. They also can relate to gene expression patterns related to risk, like we would have with insulin resistance and hyperinsulinemia. We might measure a specific gene expression patterns as seen either in mRNA or in protein levels that are associated with the clinical course of disease. And then we might think of markers of subclinical or clinical disease. One good example would be how we are using thyroid hormone panels, like thyroid stimulating hormone, along with T4 and T3, and how we are using 25-hydroxyvitamin D levels as a biomarker for relative expression into many chronic diseases, as it pertains to its mechanism as an agonist to nuclear orphan receptors that modulate gene expression. These analytes that we use in the screening can fall into various categories with different discriminative predictive abilities, different sensitivities, and different relative reliabilities, with the ultimate endpoint to connect these with some discreet and objectively definable outcome of disease, either the diagnosis of disease in and of itself, or the outcome of that disease in pathophysiology. These types of qualification of biomarkers require quite a detailed battery of studies, going from early studies of suggestive relative correlations (these would be correlative studies) to longer term outcome trials to see what happens to people at end of life or at the end of a disease process, and then backing that up into an understanding of how sensitive these various biomarkers are to understanding the disturbance of that chronic illness that is related to that specific patient. Some biomarkers would have much higher sensitivity to alterations in the course of disease than others. A family history, a personal health history, a good physical exam-all of these become very, very important, when coupled together with these biological markers, a functional status of the patient that then helps us to kind of have a look-forward view as to what the trajectory might be of that patient towards, ultimately, a more serious disease. When we take that, for a moment, into reality, let’s look at prostate specific antigen (PSA). We recognize the PSA level in and of itself in males may not be as important as a predictive marker as the rate of change of PSA over time. Those PSAs that rapidly change, it has been found, are much more indicative of carcinoma in situ and potential prostate cancer risk than just in the absolute value of PSA. This has something to do with changes over time of these biomarkers, and looking at alterations in the web of physiology as reflected in these biomarkers. This is serial analysis. It is one of the very important things for the electronic medical record, or good medical record keeping, to keep track of these various analytes over sequential visits, so that one can start looking at changes that occur over time to predict early warning signs of dysfunction. You probably recognize that when the original normal reference ranges were established for the standard analytes that are used in your multi-phasic screening serology it was found over the 30 or 40 years that those people were followed (the original cohort of individuals for which the reference ranges were established) that those individuals that had the greatest changes in their numbers over time were the ones that were most problematic in terms of relative risk and health problems. You might have a person who starts with a reasonably high level of some analyte, but if it doesn’t change over time, it’s not nearly as concerning as a person who started off, say, in “normal” range, but over time they had a very rapid increase or alteration in that level. The flux of change-the delta-is really what is most concerning. It has us measuring, over time, these markers and doing an analysis-a look back-all the time as to how that patient is traveling. Are things showing a sign towards more physiological distortion, or are they starting to harmonize and show a lower degree of physiological distortion over time? That leads us, then, into a better understanding of whether the intervention that has been applied is successful or whether it needs to be modified based upon that patient’s own individual response. I hope that what I have started to do is to get you to understand the concepts of both the strengths and weaknesses (or the limitations) of biomarkers as ways of evaluating physiological function. And not all of the tests that are available for analysis, be it the lipid test, or the glucose and insulin test, or the inflammatory test, or the cell replication test, or the autoantibody test, or the hormonal test, have the same degree of sensitivity, precision, and accuracy as it relates to prediction. There are varying degrees of confidence that we can put in these so-called likelihood of ratios of outcome based upon a biomarker. This field of biomarker evaluation is becoming a very dramatic evolving subset in medicine right now as we are trying to find better early warning ways of evaluating distorting physiology so that we can use milder intervention-even lifestyle medicine-to make changes early on. I was reminded of a recent paper that appeared in The Lancet in February 2010, titled “Statins and Risk of Incident Diabetes: A Collaborative Meta-Analysis,” in which the authors, by looking at outcome on patients who had been on statins and looking at the various biomarkers, found there is a slightly increased risk for the development of diabetes.6 Glucose levels often, in these patients, go up. Their fasting insulin levels go up. They become more insulin resistant. What they go on to write is that although this risk to diabetes on statins is low in absolute terms compared with the reduction of coronary disease, it may be that certain patients are more at risk as it relates to their own unique genotype. So here’s a way of not just focusing on one biomarker. We say statins and cholesterol, so maybe we would only look at serum lipids and we would forget to start looking at other variables like insulin signaling and its relationship to diabetes that might come in an individual as a relative risk factor. That leads me to the conclusion of this, and I want to talk about glycosylated hemoglobin. In the New England Journal of Medicine in 2010 an extraordinary paper that I think is a very nice piece of work was published on the biomarker called hemoglobin A1C.7 We all know about hemoglobin A1C. It has been used for years in following the success of intervention on diabetic patients to see if they are complying with their program or they are using insulin or whatever pharmacotherapy appropriately. This paper in the New England Journal of Medicinetitled “Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Non-Diabetic Adults” indicates that there is gradation of relative risk with glycosylated hemoglobin that occurs over time. This study points out that as we rise up from 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} above, starting at 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} and going up to 5.5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, going up to 6{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, going up to 6.5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, each of these are within what would have been considered the normal reference range, but they are all associated with increasing relative risk of cardiovascular disease. This is like the blood pressure story, where we have reevaluated, showing that there is a segmental increase in relative risk to cardiovascular and cerebrovascular disease with an increasing blood pressure well below that which we originally thought was a threshold . It is a sequential risk as you go up. Similarly with hemoglobin A1C. We would suggest, from this data, that as you get up above 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} (going from 5 to 5.5, still well within the normal) there is a small segmental increasing relative risk. And the as you go up from there to 5.5 and then to 6, you start seeing dramatic increases. When you get up to the highest level of 6.5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}–still at the upper limit of normal-there is a significant increase in cardiovascular disease risk associated with that high level of normal reference range of hemoglobin A1C. I think this tells us a lot more how to use biomarkers effectively for assessing relative risk and personalizing treatment programs to individuals and using target values. We are going to hear much more about this patient-centered approach toward chronic disease from the master, from Dr. Holman himself, so let’s turn to his comments.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Halsted Holman, MD Stanford University School of Medicine 1000 Welch Road, Suite 203 Palo Alto, CA 94304 In Functional Medicine Update over the years we have had the privilege of interviewing, as our Clinician or Researcher of the Month, very remarkable people. Women and men who have been making contributions to the growing frontier of knowledge and technology that relates to improving patient outcomes and improving the quality of care. We are certainly very privileged this month to interview someone who will continue this long rich tradition by sharing his experience in the area of clinical medicine, and that is Dr. Halsted Holman. The name is probably familiar to you because if you have been listening to Functional Medicine Update you have heard me quote his work for some time. In fact, his commentary in the Journal of the American Medical Association back in September 2004-an editorial article titled “Chronic Disease: The Need for a New Clinical Education”-was, to me, a landmark article in terms of bringing attention to the needs that we have to better address with regard to this rising burden of chronic disease. Dr. Holman has been a professor of medicine at Stanford University School of Medicine for many years. He did his undergraduate work there and his graduate work at UCLA and Yale University School of Medicine. He has been involved with teaching and clinical work in the area of rheumatology for…let’s say quite a few decades. He is a senior clinician. I can just tell by his writings and the things that he has accomplished he is one of those people that you probably go to if you are an aspiring physician to get the real story and the real information about how to be a good doctor. Dr. Holman, it is really a privilege to have you on this edition of Functional Medicine Update. Give us a little thumbnail history of your travels through medicine, in rheumatology and ultimately as a leader in curricular revision. Advocacy for the Chronic Care Model of Practice HH: Well, unfortunately I haven’t succeeded in leading any curricular revision here at Stanford. But in any event, in terms of background, I was an immunologist for many years and working in rheumatic disease, particularly with autoimmunity. But it became clear as we developed newer treatment methods, including corticosteroids, which radically changed the outcome for patients, that we were now transforming diseases that previously had not been thought of as chronic problems into chronic diseases. And what was absent, we found in our own work, was that we, having been trained to deal with acute disease, were now confronted with patient problems that could not be cured. Beyond that, it was difficult since we no longer had “Return to Normal” and “Death” as the usual outcomes, but rather chronicity spread out over years. We didn’t have a very good way of evaluating what was happening to patients and adjusting our treatments/approaches to managing their disease to something appropriate. Perhaps that can be said in the following way: With an acute disease, the patient is quite inexperienced and comes to the physician, and the physician can usually make the diagnosis, apply the treatment, and it is expected and usually occurs that the patient will return to normal. Well, of course, none of this applies to chronic disease. There is no cure. The patient lives with the disease and the efforts at treatment for an indefinite time period, during which the patient becomes very familiar with the disease and the treatments and becomes, in effect, the principal caregiver. That changes-it seems to us, at any rate-the way we have to deal with care of chronic disease. In specific, the strategy of treatment is no longer cure; it is maintaining the comfort and functional ability of the patient. The tactics are no longer just medicines or surgery or radiation, but all of the steps that are necessary to aid the patient to deal with the consequences of chronic handicap, and that, in turn, changes the pattern of medicine. The patient is very well versed in what’s happening to her or him. The physician’s role is not just the allocation of medicines or other standard procedures, but it is understanding what is happening to the patient and aiding the patient to function better. And aiding the patient to function better means teaching the patient how he or she can best adjust to the consequences of the disease or its treatment. That was one thing that we found was quite missing from what we were doing with the patients. We weren’t really helping them to be better caretakers. So in the process, we set up some educational programs along experimental grounds, and found that indeed you can teach the patients how they not only deal with the usual activities of clinical medicine, but how they can deal with the problems that arise as a result of their illness-problems in the social realm, in the economic realm, workplace problems, emotional problems, etc. And when you do that, surprisingly-and pleasantly, to us-the patient’s symptoms improve (usually). The patient’s are much more comfortable with their situation. And when you measure it, it turns out that they gain confidence, that they can manage their illness to the best extent possible. So out of this comes the question, how do we structure medical practice? And literally, people in Seattle, particularly Dr. Ed Wagner and others at the McCaw Institute, looking at this question devised they called the Chronic Care Model of Practice.8 The Chronic Care Model of Practice has now been tested in many realms, and it includes what we call self-management, education for the patient, but it has many other components, and it is a very fine way of altering your standard practice pattern that grew out of the history of acute disease care into a pattern that is much more effective and efficient for chronic disease. There are a number of features of that. I don’t know how far you’d like me to get into it, but the real issue today to my mind is the need for us to adapt our practices to more effective and efficient outcomes with the patients with chronic disease who currently (the chronic disease patients) are the main users of healthcare services, and their services consume 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of our healthcare expenditures. So it is a huge issue, and it means that we really have to remodel what we are doing in medical practice, and the Chronic Care Model gives very nice, relatively simple, concrete steps to move a practice in that direction. JB: That’s a beautifully eloquent introduction. In your article “Chronic Disease: Need for a New Clinical Education” that you authored in theJournal of the American Medical Association in 2004 you say many, many things. This is a very pithy, content-rich, short article. You talk about the fact that we’ve gone now to kind of inadequate situation relative to clinical education because of this changing nature of chronic disease now consuming 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of healthcare expenditures. You go on to quote from the Institute of Medicine Report titled Crossing the Quality Chasm that concludes (and you quoted): “Despite changes that have been made, the fundamental approach to medical education has not changed since 1910.”9 What’s the problem? I mean, clearly you made a very compelling argument here that seems almost irrefutable, but yet, even in your introductory comments when I talked about the success you’ve had achieving medical education you were a little bit reluctant to accept it. What’s the resistance? What is the Resistance to Changing Medical School Curriculum? HH: I wish I could give you a clean answer to that question. I can only hit around the target, perhaps, a bit. I’ll use Stanford as my model because that is where I have done most of my work, although I know the same thing is happening at many, many, many–if not all–of the medical schools. In a nutshell, at the end of the Second World War, the development of modern scientific technology began to accelerate, and the possibility of biological understanding rose in a way that had never been true before. The thinking was that since medicine had been a relatively subjective and not well-evidenced practice previously, the answer to making medicine more effective was to bring science into it. Many schools, Stanford among them, decided to place a very heavy emphasis on biological investigation. That was a starting point for the development of contemporary biomedicine, which in many, many schools is the principal activity of the faculty members. Now with that goal comes certain thinking patterns, which you might call ideologies, that say that the answer to the problems in health care is more biological understanding. People with that view became the leaders of contemporary medical education. Simultaneously with that development and all the emphasis on biomedical research, something else was happening, namely that the prior dominance of acute disease was subsiding and chronic disease was emerging. You see these two parallel developments of biomedical investigation and the transformation of patient problems from acute to chronic nature. My view-I told you I didn’t have a precise answer to your question-at least from here, at Stanford, is that the leadership of the institution was preoccupied with the scientific base of medicine (the biological/scientific base) and the money that could be generated from the NIH from pursuing that level of work, and was not at all concerned about this transformation and the nature of the health problems of the population. They were reluctant…well, reluctant isn’t the right word because that assumes they understood what was going on. The reality, in my opinion, is they didn’t care what was going on because of their preoccupation elsewhere. If you look today, for example, at the clinics at our hospital and at many, many other medical school hospitals, the character of the clinics hasn’t changed. Now that’s not true where there has been very intensive technology development, such as in cancer. But if you look at general internal medicine, family medicine, the usual specialties of endocrinology, and infectious disease, and so on, the way the clinics are run and the role of the patients and the doctors hasn’t really changes in the last 30-50 years. Many of the ingredients that go for good care of chronic disease, such as teaching your patients how to cope more effectively with the range of problems their disease creates, maintaining continuity of care for those patients, assuring integration of the different services that are given to the patients. None of these things really happen, or can even happen, because of the way in which we structure our clinics. In a nutshell, what the answer to your question is is a leadership failure, and the leadership failure, in my view, is the result of a focus of attention on only a part of the problem. Lord knows we do need more understanding in biology, but simultaneously we need a better understanding of how we apply whatever we know to the individual patients and to groups of patients with a particular diagnosis. I really fault the leadership very substantially. Now from time to time leaders have appeared who really understood this issue and wanted to induce change. They have been frequently, almost always (usually, at any rate), frustrated by the fact that it is very hard to change a large bureaucratic organization like a medical school. People are used to doing things in one way, and reluctant to change. Now, I know I’m talking a bit too long, here, but I’ll add one feature: When you do change your practice along the lines of the Chronic Care Model of Practice and become a partner with your patient and spend time helping that patient to cope with whatever the consequences are of the disease, and if you can develop your office so that you have an element of team care because good chronic care is a large task, and if you have a well-developed office along the lines of the Chronic Care Model prescription or some others, you find that the practice goes much better, so that the patients, if you are measuring outcomes, are better than you had previously accomplished, the patients are more satisfied, your practicing experience is more rewarding as your staff feels themselves much more involved in the active care of the patients. We do know that when you make the transformation along the lines of the Chronic Care Model, you will begin to experience outcomes that are much better than conventional practice usually yields. We haven’t been able to do that in the medical schools. There are almost no medical schools that have adopted their clinical training in that way, so we have moved, so to speak, “off campus” into the community, which is where the physicians, and the patients, and sometimes the administrations are much more responsive to this need to adapt medical practice to the prevalence of chronic disease amongst the patients. JB: There are so many things that go through my mind as I listen to your wisdom. It is almost like a Rorschach test of thoughts. I’m reminded of the book that Lewis Thomas wrote titled The Youngest Science, in which he talked about being a second generation physician at the turn of the last century. His father was a black-bag-carrying family doc who went house to house and didn’t have a lot of nostrums that really worked in his bag but got a lot of people well by being a good listener and really a good doctor, understanding the etiology.10 And I’m also reminded of Ivan Illich’s book, Medical Nemesis, in which he talks a little bit about the dialectic between medical technology and medicine, which is a caring principal of listening to peoples’ stories and managing their life experiences as it relates to their illness. It sounds like there is a whole different view of the diathesis of illness that you’re describing and how that weaves its way into the medical treatment experience and the clinical experience.11 In fact, I recall in your article in JAMA you talked about how maybe students will learn how the biology of chronic disease evolved, and then how that impacts the treatment, and these get integrated together rather than just looking at disease as this endpoint where we use drugs always to treat the patient that might be used for an acute disease in the chronic care setting and hope for the best. There is a lot underneath what you are saying, I think, that is very significant. Change is Inspired by the Practical Experience of Practitioners HH: You’re absolutely right. Writers like Lewis Thomas and Illich put their fingers on problems. I remember reading those materials and similar ones and wondering-noticing, first off-that they made sense, and then wondering what could be done to translate that kind of understanding into our practice (what we do on a day-to-day basis). It has been the evolution of thinking behind the Chronic Care Model and also, currently, the patient-centered medical home notion, of which the Chronic Care Model fits very well as a practice. But these have come more or less not by reading such good writings, as you mentioned, and then thinking it through, but through the practical experience of different practitioners who have tried to improve their care of patients with chronic disease, and in reality, as that has occurred. We now have, in our hands, a way in which we can mold our practices to combine the skill of the understanding of bioscience, the skill of biotechnology, and the understanding of the real patient needs in that setting, and how you go about applying the biological knowledge, the technology, and the understanding of the patient to get a synthesis that would be considered to be the essential outcome of good practice with chronic disease. We have it in our hands now. It’s not as though it is sort of an abstract wish that somebody else can bring in to practice a decade or two hence, but rather something that we can adopt at this time and that’s happening. Now there is some literature that actually recounts the experience of making these practice transitions. Developing Self-Management Programs for Chronic Care Patients: Group Visits Can Play an Important Role JB: That’s a wonderful segue, so let’s move over to that emerging literature that you and your colleagues are developing. I see you and Kate Lorig have co-authored a number of very interesting papers that are related to the implementation concepts-using a patient as part of their own therapy, this kind of medical self-care in some ways, as a patient-centered approach. This is true healthcare reform, by the way, versus reimbursement modulation that we call reform. You are really talking about reforming the system, not just reforming the way we pay for the system. I was very impressed. I read this report titled “Evidence-Based Chronic Disease: Self-Management Program for Older Adults” that you and Kate Lorig have developed at the Stanford Patient Education Research Center.12 What are the points of differentiation of this approach from that which one might see in kind of a traditional crisis/disease-care setting? HH: The fundamental principle would be that the patient is the primary caregiver living with the problem, both the disease problem and the treatments that are applied, 24 hours of every day. The point is to aid the patient to understand how to deal with that experience. The issues that are taken up in this self-management education are general issues that are experienced by patients with many different chronic diseases. For example, the education for a diabetic is not about how you use insulin or hypoglycemic medications, but rather how you adjust yourself to the impact of that disease on your life. How do you deal with the dietary changes that are necessary for the management of diabetes? How do you deal with the need to maintain physical capability? How do you address the problems that occur in your family when you have a handicap or some problem with children or spouse that can’t be readily addressed? How do you look at the fatigue that you experience? If you happen to have pain, which a diabetic may or may not, how do you deal with pain? The course takes those subjects as the focus. It is done interactively with the patients in the group talking with each other and talking with the leader. We found that the facilitator for the courses was actually better as a lay person with one of the diseases than a health professional because the participants (the patients who are participating in the class) related more easily to a colleague (meaning somebody with the same disease) than they did to a professional. We ran comparisons that showed that that was so. Out of these experiences, we found that the patients, after six weeks of two hours a week meeting together, had statistically significant improvements in their health status, and, most importantly, they felt more confident about managing their illnesses. When we asked them, “What was it in the class that you found the most important experience for you?” I think consistently it was that they learned from other patients. They learned through the discussions with other patients how they reacted to and took care of problems that arise. This is very similar to another format, which we have used but haven’t formally studied, namely group medical visits, in which the patients come together, you-as the physician-are present, but the patients set the agenda. When that occurs repeatedly over months, at monthly intervals of, say, two hours, you find the same things happen. The patients are much more satisfied with their medical experience. When I did them I certainly learned things about my patients that I had not known before-many important things that helped in caring for them. But here again, when we got done and asked them what was the most important thing, they said to me, “Well it wasn’t you or what you said. It was what I learned from the other patients.” We are being told by this experience that patients benefit from learning how to deal with their diseases, and they benefit particularly well from an opportunity to exchange their experiences with other patients. Think, for example, of how you run your clinics or your office. You don’t set up arrangements for your patients to get together and talk about how they cope with the problems they have. None of us do that as a routine part of our clinical practice, whether it is in the university clinic or in a private office. Here is a tool that is very inexpensive, but could aid significantly in the care of the care of the patients. If you can, be an eavesdropper in a group visit where you are present, so you, the physician, learn things that you hadn’t any idea about before you heard the patients getting into a discussion with each other about how they cope with a particular problem, whether that problem is buying the right kind of food at the right price for care of diabetes, or how they do exercise when it hurts, and so forth. I’m certain that we have fundamentally neglected the contributions our patients can make to their own care. There are a number of formats that can be used-different kinds of teaching experiences and the like. For example, there is one that is very interesting. It was dictated by reimbursement policies. Reimbursement, for most insurance companies, does not occur for patient education of the type we’re talking about. Some practices have devised a way of getting the benefits from group visits and patient education within the confines of the reimbursement system by running groups of patients. Let’s say 8 diabetics coming to the office for 2 hours at a specified time, and they are in the room with a physician and his or her nurse or other assistant, and the physician conducts a regular one-on-one visit with each patient for, say, 15 minutes, covering all 8 of them in 2 hours. But during the one-on-one, the other patients are all right there participating, so they pitch in, if you will, to the experience of a medical visit of the patient with a doctor. To everybody’s surprise, the patients really like this. And in that sense, because you keep notes on these interviews-or 15 minute interludes-with the patients, you can bill for them. It has been a technique that some creative physicians have developed in order to establish a working group relationship with their patients with a particular disease, like diabetes or congestive heart failure or asthma, where you combine the physician’s knowledge with the patients’ experience, to the benefit of everybody. JB: That’s a very, very novel and unique way of getting to this, and it sounds like you can also use health extenders to try to kind of stimulate that conversation. As you were saying, sometimes the doctor, herself or himself, is not the primary person. Maybe they engage in that conversation and kind of lead the biomedical part, and maybe a health extender might have that knee-to-knee thing about going to the store and buying fruits and vegetables and all that kind of real world stuff. It sounds like a very novel model. I had the opportunity to meet (in one of my trips recently down to Australia) Dr. Claire McGuiness. When I was talking to her she said, “We’re trying to really follow some of the things that Dr. Holman talked about in his article in JAMA.” I said, “Really?” and she said, “Yes, we just actually completed a study on chronic conditions self-management support groups that we are publishing.” It just appeared last year in the Journal of Chronic Illness. They report on patient outcome studies in a controlled environment for medical students in four different medical school situations in Australia demonstrating the proof of your concept.13 It is spreading. What you have described seems like it’s getting some traction, although probably not as quickly as you or the system needs. HH: Well, that’s true. And remember, it’s not just our concept. Many, many people have contributed to this in many different ways, but what is happening is it is converging into an understanding of how you can remodel a practice and make it work to the benefit of everybody, meaning the patient, the doctor, and the other members of the clinic staff. Healthcare Extenders and a Team Approach towards Therapeutic Lifestyle Change JB: I’m wondering, does this at all interface with the NIH recent publications on therapeutic lifestyle changes as a first line of therapy for various chronic diseases like dyslipidemia and diabetes type 2? It would seem that there is an interesting docking between what you are talking about in terms of managing chronic illness and this first line of therapy being a therapeutic lifestyle change. Do you see that interfacing, one with the other? HH: Absolutely. They are really converging. When you talk to patients-we’ve done these kinds of focus groups, as have lots of other people-about what they need, they really don’t understand, fully, what they can do to change their lifestyle. I mean almost everybody-I certainly know I do…I tend to be comfortable with things I have been doing and less comfortable with a new departure that I have to do in order to maintain my function, and capability, and my comfort. Patients are the same. When you can talk to them in a more leisurely way, and they can talk to other patients who have similar experiences, it’s a very real practical application of that general notion of lifestyle change. There are techniques that you can use that facilitate this. Let me back up one moment. For a physician to care for a patient in the way we are talking about, it requires more than just patient-initiated visits whenever there is a problem. It requires real continuity of care, and that is very demanding on the physician. One of the techniques that has evolved to address both the question of lifestyle change for patients and the need for more comprehensive care from the physician is the development of what are commonly called practice extenders of one kind or another. In this instance, I am talking about training your medical assistant to be a member of the care team, to meet together with the patient and the physician when the patient comes in. You develop a registry so you have a means of knowing how your panel of patients with a particular disease is doing. During the visit a decision is made about the next steps, which may be some behavior change, and then after the visit, this trained medical assistant (some people call them health coaches) maintains contact with the patient, so it is not as though you say, “Okay, this visit is over, I’ll see you in a month (or whatever).” Your extender-in this case a specially trained MA-contacts the patient to find out how he or she is doing, if there are any problems, and the patient can contact the MA at any time directly, and in that sense you have genuine day-to-day potential for continuity of care, you have supervision in a supervised way of the patient’s carrying out of the action plan of care, and this is done by having your team approach to care. There are now methods for training MAs to do just that kind of work. They are not very widespread and they are not without their problems, but it allows the issue of lifestyle change to be an active part of the continuing care process, without requiring the physician to do things that he or she either isn’t trained for or, more commonly, doesn’t have time for. Building a Data Set: Biomarkers and Patient Registries JB: Let me ask just two last questions. The first has to do with biomarkers. We are a number-driven society. We like some kind of quantitation. Are biomarkers an important part of setting goals, and benchmarks, and milestones for the patient or do they become confusing? I’m thinking of things like cholesterol levels, or blood sugar levels, or things of that nature. HH: Sure, I would say that they are definitely part of it. One of the issues here is the development of registries in which you have all of your diabetics, or all of your congestive heart failure patients, or all of your asthma patients grouped together and you have variables that are filled in there. For the diabetics it definitely would be their A1C levels, their LDL levels, their blood pressure-those variables that tell you about how they are doing. But you would also have other variables that you could put in there, for example, the exercise level the patient has achieved, or the alteration the patient may have made in a workplace or a leisure activity. You can put in variables that are easily quantitative like the A1C, or very difficult to quantitate but you can use words that have to do with behavior change where you don’t have a number. To me, the biomarkers are an essential part of the data set, but only a part of it. The other part of it is what is happening to the patient besides biomarkers. You know there has been debate recently about how far down you should push an A1C. There is evidence emerging that it you try to push it so far down that it is 6 in somebody who used to be 10, you are going to run into real problems, and isn’t it wiser to leave the A1C at 7.5 if you can get there from 10, hold it there, and address the other problems that are happening in the patient’s life? It gets to be a complicated interaction between biomarkers and the reality of the patient’s life, but that then becomes the essence of medical practice. How do you deal with those different variables? JB: Beautifully said. That’s really a systems biology approach to looking at medicine versus a histopathology approach. HH: Exactly. The trick for all of us is to figure out how to do that without having too much turmoil, and that’s where the Chronic Care Model comes in because you can apply the model pretty easily by just such simple things as developing a registry, getting your MA retrained, and making sure there are some education programs available-we call them self-management programs-for the patients to learn from. Those things can be done relatively inexpensively in an individual practice. Prospective, Preventive, Participatory, and Personalized: The New Medical Paradigm JB: I have one last question. This really plays off of the theme. You probably know Ralph Snyderman or are aware of his… HH: Right. I do know him. Not well. JB: …his colleague Leroy Hood. They have been talking about what they call the “4 Ps” of medical future. The “4 Ps” stand for Prospective, Preventive, Participatory, and Personalized, which is a whole different paradigm.14 It seems like it is very consistent with the model that you are developing for chronic disease management. Those four words-Prospective, Preventive, Participatory, and Personalized-seem to embody or encompass many of the things that you describe in your seven points of how to really develop a chronic care model in medicine. Do these seem consistent to you as it relates to terms? HH: They do. I have read about them. I really haven’t familiarized myself with what they think applies under each of the headings. It fits perfectly well. And, you know, nobody knows the best way to do this. It is an open question as to how the practices should be remodeled, but we have enough experience to know how to get deeply into the process and learn what works and what doesn’t. Their thoughts, I think, are quite accurate, but the real question to them becomes: How are you going to do that? That’s where, in the jargon of the day, the rubber hits the road. The healthcare model is, to my way of thinking, the most developed way to go at this time. Five years from now somebody else will have another way of looking at the problem, a new version of something resembling a Chronic Care Model, and that is as it should be. JB: You are a pioneer in this field and an eloquent spokesman for this model. I want to really thank you. Every person who has listened to this has benefited from it and in some way they’ll take away a piece of this into their practice. Your pioneering work and commitment to quality care over the years resonates through your voice and your advocacy. Thank you very much for taking this time. HH: You’re more than welcome. I’m please to be useful, and always like to discuss this with people so that we can learn from one another. JB: Well, you have infected a lot of people; you put a virus in their nervous system they can’t get away from. HH: I’m glad to be that pathogenic agent. JB: Thank you, Dr. Holman. HH: Thank you, Dr. Bland. Ever since I first had the opportunity to read Dr. Holman’s papers on patient-centered chronic care management I was impressed, but I have to tell you-I’m sure your feelings are like mine-having heard him personally, this is what medicine is all about. What he is talking about and how he contextualizes it (and I’m sure the way he and his colleagues have delivered it over their years of service) is the best medicine. It is amazing to hear, through the words of a thought leader, of a clinician’s clinician, how effective medicine can be if we just harness that which we already know. We don’t even need to discover a new drug, or a new surgery, or a new technology. We need to employ what I think we have been calling functional medicine-systems based medicine-that empowers a patient and gets them engaged in their own self-efficacy. Remarkable magic can happen. Thanks so much, Dr. Holman. What a remarkable contribution to our learning.

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Bibliography

1 Holman H. Chronic disease-the need for a new clinical education. JAMA. 2004;292(9):1057-1059. 2 Scull A. The art of medicine. A psychiatric revolution. Lancet. 2010;375(9722):1246-1247. 3 Scull, Andrew T. Museums of Madness. New York, NY: Palgrave Macmillan, 1979. 4 Madhouse: A Tragic Tale of Megalomania and Modern Medicine. New Haven, CT: Yale University Press, 2007. 5 Circulation. 2006;113:2335-2362. 6 Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 2010;375(9716):735-742. 7 Thanopoulou A, Karamanos B, Archimandritis A. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010;362(9):800-811. 8 Evidence on the chronic care model in the new millennium. Health Aff (Millwood). 2009;28(1):75-85. 9 Crossing the Quality Chasm: A New Health System for the 21st Century. Washington: National Academy Press, 2001. Print. 10 Thomas, Lewis. The Youngest Science: Notes of a Medicine Watcher. New York, NY: Viking Penguin, 1983. 11 Medical Nemesis: The Exploration of Health. New York, NY: Pantheon, 1976. 12 Chronic Disease Self-Management Program (CDSMP). Evidence-based Chronic Disease Self-Management Program for Older Adults. Stanford Patient Education Research Center. Stanford University, 2010. Web. 9 June 2010 < http://patienteducation.stanford.edu/programs/cdsmp.html>. 13 Pols RG, Battersby MW, Regan-Smith M, et al. Chronic condition self-management support: proposed competencies for medical students. Chronic Illn. 2009;5(1):7-14. 14 Snyderman R, Yoediono Z. Perspective: Prospective health care and the role of academic medicine: lead, follow, or get out of the way. Acad Med. 2008;83(8):707-714.

Welcome to Functional Medicine Updatefor July 2010. We’re going to be focusing our interest and intention this issue on successful (or healthy) aging and its relationship to functional medicine. We have a marvelous discussant interview this month”Dr. Pamela Smith”who will be sharing some of her extraordinary contributions, both as a clinician and as a curriculum developer and post-graduate educator in this whole area of successful aging and the implication to functional medicine. I returned, a month ago, from the Institute for Functional Medicine’s 17th International Symposium, which was at the La Costa Resort in Carlsbad, California. What a remarkable meeting of people/excitement/innovation/adrenaline those four days were, under the title “Confronting Cancer as a Chronic Disease.” This was a very interesting topic with extraordinary contributors looking at ways of managing malignant oncogenic disease successfully. This follows very nicely from last month’s Functional Medicine Updateand the extraordinary discussion we had with Dr. Halsted Holman about chronic disease. We talked about the need for a new clinical education, and how we need to look at various aspects of biomarkers to assess the soil of a person’s physiology, so to speak, as to the appearance of a disease, or the progression of a disease. I talked a lot about biomarkers last month. We recognize that biomarkers can come in many different flavors and be used in many different ways. Cancer biomarkers may differ slightly from those of what we might call cardiovascular biomarkers, or diabetes biomarkers, or arthritis biomarkers. But in some senses the biomarkers that reflect distorted physiological function have some confluence and convergence and they tend to overlap at principal fundamentals of distorted physiology that are shared among these different disease types”things like inflammation, and altered serum lipids, altered insulin and insulin signaling, changes in cell mitotic activity, changes in autoantibody levels. These are representative of alterations that occur across many different disease entities that share a common soil in their mechanisms (so-called systems biology). We might think of a biomarker as having a single disease focus, but sometimes it may have multiple comorbidities to which it is attached. For instance, rheumatoid arthritis can be connected to cardiovascular disease, which can be connected to osteoporosis, because they share common mechanisms that are associated with altered cellular signaling and proinflammatory mediators. We also see inflammation connected to type 2 diabetes. This web of interaction makes biomarker analysis very, very important as we start to try to understand how we can assist individuals to lower the risk to disease and improve their function (i.e. engage in successful healthy aging). What type of data would we like to assemble in patients to start to evaluate serially, or longitudinally, how they are changing over time at the physiological level? This could include things like cognitive tests. This could include memory tests. It could include things like peripheral neurological tests, reaction times, gait disturbances, balance, visual acuity, hearing acuity, skin elasticity, and cardio/respiratory parameters, including things like pulmonary testing like FEv1, pulse rate, blood pressure. All of these become part of a collection of observables that tell us something about the functional capacity of an individual. Those observables can then be coupled with genetic markers. We’re now looking at various SNPs that cluster themselves together as relative risk factor markers for the susceptibility to certain conditions. Or more importantly (maybe), we’re even looking at how these genes are expressed into genetic expression patterns in RNA, or through the transcriptome ultimately into the proteome. We measure, then, the connection between altered gene expression patterns that ties to gene susceptibility patterns. That then ties to altered proteomics. The presence of certain proteins like hsCRP (high sensitivity C reactive protein in the blood) are a connection to gene expression associated by TNFalpha-modulated inflammatory gene expression, which then may tie back to certain susceptibility SNPs that pertain to increased or heightened sensitivity to inflammatory initiation. We are asking, “What are the inflammatory initiators?” Are they things like substances in food, air, and water; chronic infection; bacterial cell wall debris? What are the precipitants? Are they heavy metals, toxic xenobiotics? This conceptual framework–to understand at the earliest level possible where the confluence of these various distorted parameters arise, both symptomatologically and biochemically–becomes the kind of teaching system, or evaluation system, of functional medicine. It is ultimately incorporated into what is called the functional medicine matrix. It is requesting or querying these various areas within the patient’s physiologic function that cut across different diseases to correlate with poor outcome and unsuccessful or unhealthy aging. All of these questions really become part of collecting information using tools likemolecular imaging or whole-body imaging. Radiology has now become part of functional assessment: using CAT scans and MRIs, and using various types of NMR data to evaluate functional capacity of various organs. We look at things like stress testing–going from the exercise EKG test into thallium scans and into electron beam, looking at calcium foci in the arterial wall, and looking at heart wall motion studies, and looking at insulin clamp, or things like vascular endothelial function using flow-mediated dilation or carotid intimal media thickness as a measure of potential atherosclerotic progression. All of these become a new arsenal of tools that the physician can use to assess aspects of this trajectory towards disease. We were talking about in this June issue of Functional Medicine Update. What about inflammatory biomarkers that seem to be related to so many chronic diseases? These would include the use of blood cytokines as biomarkers, which are now undergoing preclinical safety assessment and sensitivity evaluation to see if, in fact, these things–IL-1, IL-6, interferon gamma, and tumor necrosis factor alpha–can be used as effective assessment biomarkers for evaluating onboard inflammation along with things like C-reactive protein or fibrinogen. C-reactive protein is considered a late-phase reactant. It is produced by the liver in response to a message that occurs upstream from activation of cytokines, particularly IL-6. By understanding more about the upstream mediators that are the initiators of the downstream effects, we can get an earlier warning understanding of the general shift in physiology towards an inflammatory state. We can look at things like metalloproteinases and MCP1, or the difference between IL-4 and IL-6 as a contrast between activation of the thymus-dependent-1 and thymus-dependent-2 trees of the immune system. It gives us much more differential assessment opportunity in understanding where the distortion is occurring in that individual patient’s physiology. This is all fairly sophisticated discussion. We are probably still a few years away from completely nailing down how, for instance, serology of cytokines could be used. There is one reactive molecule that is getting a lot of attention recently, myeloperoxidase (MPO), which is produced by white cells in response to an inflammatory insult and is also activated within the HDL particles to produce oxidant response. The activation of MPO is part of the microbiocidal killing response of the body in immune defense. But myeloperoxidase, when overactivated, also increases oxidant stress, and it associates itself with hypochlorite formation and oxidation. Once again–as is so often the case–we have this U-shaped curve (this parabolic dose response curve): too little is not good, too much is not good, in the middle of activity is where we want to be. Can MPO, myeloperoxidase, be used in serum or in red cells as a surrogate marker for looking at inflammatory status and function? These are the kinds of questions that are now being discussed and evaluated.1,2 There are some laboratories doing studies on yet-to-be-fully-validated biomarkers and indicating a need for more presumptive testing. Use A Variety of Biomarkers to Compile Information We shouldn’t put all of our eggs in any one biomarker basket. An example would be phospholipase A2 , which has been used for evaluating endothelial inflammation and unstable plaque inflammation. It’s a very useful serological tool. Apo B and apo A-1 are apolipoproteins that we also associate with vascular function. We say too much of apo B and too little of apo A-1 is a shift towards atherogenesis. All of these become an extended group of biomarkers that have been used in some ways for compiling relative understanding of a person’s functional status. Again I emphasize that no one biomarker in and of itself answers all of the questions. It is really compiling these biomarkers as a pattern”a system”to look at interrelationships. Homocysteine would be a good example of this. We know that elevated homocysteine can be sometimes seen just as a consequence of inflammatory disorders, in which altered methyl group physiology occurs and you start to get an activation of the folate cycle at an increasing level of homocysteine, and when that person has managed their inflammation their homocysteine comes down, independent of their need for folate B6, or B12 supplementation. These are complex relationships to physiology. How we use these tests “again” shouldn’t be an all-the-eggs-in-one-basket approach. One test cannot provide a complete understanding of the patient’s physiological status. Rather, we need to compile multiple snapshots that we weave together to form a total picture of the patient and their trajectory toward health or disease. That’s what I think the more advanced functional medicine practitioners are doing: assembling this complex data set of information, doing pattern recognition, focusing this through the functional medicine lens to understand the individual status of that patient and develop a personalized program for their intervention. I think I’m speaking to a very different model than using a single analyte (biomarker) for a single diagnosis for a single drug for a single outcome. This is a very, very different model. We learned about this model, very eloquently, at the 17th International Symposium from Dr. Dean Ornish, who was a keynote speaker and actually won the Ava Helen and Linus Pauling Award in 2010. As you probably recognize, Dr. Ornish’s contributions have been multi-fold. He is one of the first people to really do the heavy lifting to demonstrate that lifestyle intervention with an appropriate and minimally processed diet with exercise and stress reduction programs done in cooperation with one another has a tremendous impact on outcome of gene expression, of proteomics, and of metabolomics, and actually can result in the regression of existing things like atherosclerotic plaque, and can have a positive effect on prostate cancer and on insulin signaling.3,4,5 Dr. Ornish has done the hard studies, with humans, to really demonstrate that what Pritikin talked about many years ago, which was more anecdotal and observational, when put to the more rigorous test of study and proof of concept can be demonstrated to be true. Lifestyle medicine, as we are seeing it emerge, is becoming an extraordinary “re-found” tool. It’s like learning old things in new ways, and is probably the most effective and certainly the safest way of managing many of these chronic disease entities. In fact, Dr. Ornish announced at the Symposium that after 16 years of developing the literature and the studies to prove the concept, the Office of Medicare Reimbursement has now agreed to reimburse for these lifestyle medicine intervention trials or programs/therapies for individuals with cardiovascular disease. I think we are really starting to see very, very significant progress being made in understanding how to promote healthy or successful aging by asking the right questions and then intervening with the right personalized therapy, much of which may be at first initiated through modified lifestyle, diet, exercise, and stress management programs. Dr. Ornish said a series of very profound takeaways. One is that “diet” is a four-letter word, and if you talk to people about putting them on a diet there’s going to be a pushback and almost a reflex reaction towards noncompliance. If you talk about an eating plan, a food plan, about eating healthy, about eating in abundance, eating with joy, and eating from this list of good stuff, it is amazing how much better the compliance and how much the attitudinal adjustment of the patient improves. They become part of their own program rather than feeling it has been forced upon them because they are being punished. I think those are very interesting things that we learned from Dr. Ornish’s presentation. He also made the very important point that awareness really is the first step in healing. If you don’t have a self-aware patient, if they are not conscious of the fact that they are in control of their own physiology to some great degree, it’s going to be a real uphill grind to get them to truly subscribe to healthy aging. They may still be looking for the proof in the bottle”what pill will be the answer to all these problems, make it simple, and they can continue to do whatever they have been doing that is self-destructive and anti-evolutionary? Awareness that they are the master of their own universe is actually the first step in their own healing process. He also made a very, very interesting”I think”visual contribution to our sense as to how this field works. He said, “Let’s look at the difference between illness medicine and wellness medicine.” Looking at the spelling of illness medicine-“i-l-l-n-e-s-s””as contrasted to the spelling of wellness medicine””w-e-l-l-n-e-s-s””he said, “Illness medicine is “I-ness” medicine, and wellness medicine is “we-ness” medicine. Wellness involves the group support. It involves collaboration. It involves a different environment. It involves normative behavior patterns within your peer support group”your family and friends. That’s a “we-based” medicine”wellness medicine”as contrasted to “I-based” medicine, where it is treating disease, fighting the battle, you against the onslaught of this disease in isolation. I think that’s a very, very interesting metaphorical differentiation between illness, or disease-based medicine, and wellness, which is the functional approach towards improving outcome (not just treating a biomarker, but really enhancing the functional quality of life of the individual; that’s so-called healthy aging). Genotypic Stratification and Individualized Risk In the course of these discussions, we recognize that the whole field of health risks is changing, as Dr. Nancy Emenaker talked about in her presentation at the Symposium. Epidemiology, which has been kind of the guiding force to look at variables in our life that create potential relative risk to disease, is giving rise to things like genotypic stratification, where we are looking at individualized relative risk, or individualized risk, based upon the genes and their interrelationship with the environment of that patient. This concept gets away from the 70 kg human”one size fits all, everything is about averages”to actually looking at this cohort stratification around individuals that share common genetic propensities or susceptibilities. I think that’s a very, very important step. Think about what Dr. Bernadette Healey gave us, through being the director of the NIH a number of years ago during the Women’s Health Institute work, and really taking the Women’s Health Initiative and moving it forward to try to evaluate the gender differences between men and women. This was kind of the first big cut of stratification–seeing that men and women do differ physiologically and that women need to have different intervention. Women have a different type of heart disease than men. They have, obviously, more prevalence in endocrine-related dysfunction, especially with breast, endometrial, and ovarian function. They have different relative risk to osteoporosis and so forth. These are characteristics that relate to gender stratification, which then can be taken beyond that to stratification at levels of other specific genotypes. Public Health versus Individual Risk At the Symposium we also heard from Dr. Gina Solomon, who talked about the difference between public health and individual risk to diseases like cancer. We have these public health messages”seat belts, and pap smears, and immunization, and cholesterol screening, and blood pressure screening”but then we need to take it down to the individual relative risk. I talked a little bit about the fact that individuals are exposed to different things in their environment and they may have different relative susceptibilities based upon their genes. In fact, we are going hear from Dr. David Jacobs on Functional Medicine Update in the August issue, next month, who will be talking about the pioneering work that he has done with Dr. Duk Lee, looking at the relationship between environmental xenobiotics and type 2 diabetes in susceptible individuals, which I think is a very fascinating story that really talks about individualization of relative risk. Vitamin D as an Example of Balance and Consideration of Complex Variables At the Symposium there was a discussion of vitamin D, this very interesting, complex, regulator of gene expression and cellular function. Once again, too little is not good, but too much may not be good either. I think we need to keep these things in balance”there is always this nature of the push and pull, yin and yang. What do we know about vitamin D? We know that vitamin D is converted ultimately into its active hormone form, 1,25-dihydroxyvitamin D3, and it interacts with the vitamin D receptor (VDR) to heterodimerize, ultimately, with nuclear orphan receptors at the nuclear envelope to then regulate promoter regions of genes (probably more than 50 genes). Vitamin D, in its hormonal form, regulates gene expression that ultimately alters cellular function. Some of these activities are involved with immune function and cellular proliferation. High levels of 1,25-dihydroxyvitamin D3 might be considered an immunosuppressant in terms of certain arms or components of the immune system This is why it might lower relative inflammatory disorders. But too much suppression of the immune system by excessive 1,25-dihydroxyvitamin D signaling, as we heard from Trevor Marshall in Functional Medicine Update a number of months ago, could actually compromise immune integrity against viruses and bacterial infection, so you might have increasing risk to opportunistic infection. It might also increase risk to proliferative disorders like cancers. This is the yin and yang of vitamin D: taking it in the appropriate amount and converting it into the appropriate levels of 25- and 1,25-dihydroxyvitamin D3.6 What happens in cases of inflammation if that individual has a proliferative disorder or a proliferative situation? Probably the most common example of a proliferative situation is that of pregnancy. In pregnancy, there is obviously a growing tissue mass (a differentiated fetus). Because that fetus is a foreigner in the mother’s body, there is an obvious alteration of the immune system to allow that fetus not to be rejected. Part of that process is to convert more 25-hydroxyvitamin D into 1,25-dihydroxy. So there is alteration in vitamin D chemistry that occurs in the case of pregnancy. Low levels of 25-hydroxy are associated with small for gestational age children, whereas adequate vitamin D levels are associated with gestational age births.7,8 It has been suggested that there are some things about vitamin D deficiency or insufficiency that might be altering pregnancy. One needs to be in that mid-range and not assume that the more the merrier as it relates to these fat soluble hormonal stimulators. You may have heard recently about this tragic situation with Gary Null, the well-known nutrition devotee who basically was in a life-threatening situation as a consequence of eating some of his own food that unfortunately had been inadvertently contaminated with excessive vitamin D. Rather than 2000 IUs they had 2 million units. He ended up with extraordinary hypercalcemia, and cardiac calcification, and immunological suppressive disorder, and was very seriously ill. He is recovering, but it is probably going to be a long time back from this acute vitamin D toxicity.9 I’m using an extreme example here just to try to remind us that these things have very profound effects. These are very biologically active molecules, these hormonal forms of vitamin D. It is not just low levels we should be concerned about, but excessive levels as well. In fact, there is a suggestion that 1,25-dihydroxyvitamin D3 could be very useful in mothers that are deficient to prevent spontaneous abortion because, as I said, it produces a modulation of the immune system that is desirable for patency of the fetus.10 Too little not so good; too much obviously not so good either. That’s kind of a watchword for all of the things that we use”intervention agents”when we are trying to promote improved health or healthy aging. What about all of the biomarkers that are associated with vitamin D physiology? What would those be? Let me give you my opinion. Those include things like serum 25-hydroxyvitamin D (that’s the analyte you normally measure to determine vitamin D status), but what about the hormonal form, serum 1,25-dihydroxy? It has been said, “That changes so rapidly that it might be not a very fixed number.” But that’s part of what we want to know: how vitamin D is being converted into its hormonal form. Making serial measurements at the same time of the day on a fasting blood sample of 1,25 along with 25-hydroxy might be very useful. We don’t want the ratio of 1,25 to 25-hydroxyvitamin D3 to be greater than 1.5 to 2.0 to 1. If it gets above 2 to 1 then you start asking, “Is there inflammation onboard? What’s promoting this increased conversion?” Often what might happen is the person would say, “Their vitamin D is low because their 25-hydroxy level is fairly low.” They keep supplementing and the person’s 25-hydroxy vitamin D doesn’t go up. You ought to be looking for the 1,25 level to see if it is being driven or converted into the 1,25 hormonal form due to agents on their physiologic function that increase or stimulate the conversion. Generally these are substances that activate cytochrome P450 27B1 in the kidney that is associated, then, with increasing conversion of 25 into 1,25-dihydroxy. There are many environmental factors and inflammatory factors that activate the expression of SIP27B1 and increase the conversion of 25 to 1,25. We also look at things like parathyroid hormone levels. Is it possible that secondary hyperparathyroidism is a consequence of vitamin D insufficiency? Could we use PTH levels to evaluate relative functional need for vitamin D? The answer is yes and no. Studies have suggested only a moderate correlation between PTH (parathyroid hormone levels) and vitamin D levels, undoubtedly because PTH really varies as a consequence of a number of components, only one of which is related to vitamin D directly.11,12,13 There is also, of course, total serum calcium and ionized serum calcium. We recognize that calcium can elevate dramatically. In the cases of vitamin D toxicosis, calcium may be low. In cases of vitamin D insufficiency, the serum calcium-to-phosphorus ratio may increase as a consequence of vitamin D insufficiency. It may also increase as a consequence of vitamin D toxicity. I think that’s the paradox. Are we on the deficiency side or are we on the insufficiency side? And then lastly is the vitamin D receptor story. There are different polymorphisms of vitamin D receptors and some are much more sensitive to binding to 1,25-dihydroxy than others. There may be receptor genetics that would be helpful in understanding the relative sensitivity that that person has to their own vitamin D by transport by the VDR into physiological function. Those are some thoughts about the vitamin D story. One of the things, clinically, you should probably be aware of as we talk about the vitamin D story is the hyperparathyroid/vitamin D/gastric bypass story. We recognize now, with obesity on the upswing as rapidly as it has become and with more and more people having gastric bypass surgery, that as they get into things like Roux-en-Y gastric resection there is very often found to be malabsorption of vitamin D and a low level of 25-hydroxyvitamin D, and this can present a negative outcome for the patient. I think in cases where there is a malabsorption syndrome present, as might be the case with Roux-en-Y or maybe even gastric banding, that we be very mindful of the vitamin D levels and make sure that adequacy is achieved.14

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INTERVIEW TRANSCRIPT

Clinician of the Month Pamela W. Smith, MD, MPH 1900 S. Telegraph Road, Suite 102 Bloomfield Hills, MI 48302 (313) 884-3288 pepper4@sbcglobal.net I think I have been on a very, very remarkable roll over the last couple of years with the types of people that we’ve been able to interview, who are really the pacesetters, the leaders, the vision tenders of this new medicine. Certainly that is the case this issue with our interviewee, Dr. Pamela Smith. The name “Pam Smith” probably is very familiar to many of you if you’ve been in this field for some time. She is a clinician’s clinician, and has extraordinary accomplishment in building a practice in Michigan (actually several practices, several different offices). She was graduated from the Wayne State-affiliated hospital group, and became internal medicine board certified. She spent time first at Meharry Medical College, and later became committed to getting her Master’s in Public Health at the Medical College of Wisconsin in the 90s while she was running her practice. This is one of those universal energies that you find in some people. You wonder, how do they do all of these things? How do they form their life in such a way as to create this kind of driving continuity of growth, and development, and constant expansion of understanding? Pam is certainly that kind of person. She has most recently (over the last decade) been extraordinarily involved in the development of curriculum and teaching and training. You are going to hear much more about that. I don’t want to steal her thunder, but she has really been instrumental in moving physician education into this whole area of functional and, I guess you’d call it, integrative and complementary and anti-aging medicine”the real tip of the spear”developing a very high quality education program/certification program to help people move their practices into what we think is right way to do medicine (good medicine) in the 21stcentury. With that introduction, Pam, it is just such a treat to have you here today in our studio in Gig Harbor, Washington, coming all the way from Michigan and Florida, which I know you spread your time between. Tell us a little bit about your extraordinary run over the last 25 years. How did you get started in this field”I mean moving from maybe a very traditional medical view into now becoming really a leader in our field? How Insomnia Led to a Change of Direction PS: I was very happy being an ER physician at Detroit Receiving Hospital, which was a trauma center, until one day I could not sleep. I had never had any insomnia whatsoever, and for an ER doctor that’s a problem because you have to change shifts between night and day. I went to 11 physicians, and they all said the same thing: “Take a sleeping pill.” The last one was psychiatry. After two sessions the psychiatrist said, “This is not psychiatric. Please just take a sleeping pill.” I was very lucky. Dr. Shelby-Lane, who was my ER partner, saw that there was going to be an interesting conference on anti-aging medicine featuring hormones. We thought we’d just go see what it was about. There I was. Second slide, second sentence saying, “Women without progesterone frequently have insomnia.” I did the very first saliva test in the Midwest. I was very lucky that the pharmacist at the end of my block where I grew up was a compounding pharmacist. I had no progesterone at all on my saliva test, so what I did was I worked with my compounding pharmacist, started taking progesterone, and within 48 hours slept like a baby. Of course this got me very interested in looking at the concept of why we never look at the cause of the problem. We just write out the golden prescription, which is fine, but it doesn’t really answer a lot of questions. And fortunately, the science is now here to look at the cause. JB: I think you have done something that is very complicated for most individuals, and that is bridge the gap between the mechanistic world and the clinical world (you know, where the tire meets the road”patient management). And this area of”I guess we call it functional endocrinology, or bioidentical hormones, or managing the web of physiology”is probably the most complicated place to jump in because you’ve got so many different components that are all interacting one with the other and with the patient’s past (antecedents, triggers, mediators, signs and symptoms). Trying to figure that all out in this milieu is not an easy job. How did you go about kind of teasing apart and gaining the mastery that you have? Was it through experience with patients, education, reading? For those who may be on their path, what was your path of discovery? PS: It was a little bit of everything. I went to a second anti-aging conference and learned a lot more about hormones, but I discovered that wasn’t the only answer. I was very fortunate at that time to become involved with IFM, and really learn that there was a whole other facet to what we did. It wasn’t just prescribing hormones, because that would be just the golden prescription again. I really discovered that most people, honestly, don’t need bioidentical hormones. If we are never stressed, then our body, after menopause or andropause, really does make an adequate amount of hormones to maintain function. However, I don’t really know a lot of physicians that are never stressed. Because all of us do stress our adrenal glands probably to the max, many of us do need bioidentical hormones. But it was a fascinating road to go down with IFM and learn the web”everything is a web, including the hormones”and then go on to look at structure, spiritual health, and all the other facets. JB: When you are in your practice…you know, we kind of self-select patients that affiliate with our world view. Have you watched your patient type or population change over the years as you have been on this path? How would you characterize, now, the types of people that seek out your care and your practice? PS: When I first started this kind of medicine 14 years ago, I ended up mostly with patients looking for bioidentical hormones, I think because that was my area of expertise, plus my first book, HRT: The Answers, was on hormones.17 However, now my practice has really evolved. It’s about 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} bioidentical hormones and 60{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} functional medicine. It has now changed from what was originally an all-female practice, because women seek health care more than men, to now being 45{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} male, 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} children, and 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} women. Treating “Walking Wounded” Executives JB: In that distribution”which, by the way, that’s a whole textbook in and of itself, writing about the diversity of challenges for care”I would presume you probably are seeing people who might be considered executive health clients who are kind of in that walking wounded state (stooped shoulders and shuffling feet), saying, “When am I going to get sick enough that someone knows what’s wrong with me?” kind of mentality. They are probably in the rat race of time compression, the picosecond we live in. Do you see these kinds of executive females and males coming to your practice asking, “What is going on with me?” PS: All the time. And their universal statement is, “I feel like my body is divorcing myself.” In fact, we took an attorney, and I always ask the patient, “What brings you in to see us?” His complaint, at 63, was, “I lost my first trial.” I wasn’t really sure what I was going to do with that, but what he really meant was he had never lost a trial, but now his memory was not as sharp, he couldn’t smooze the jury, and so we worked with him and we got him nutritionally and hormonally sound, and he brought us into his law firm in Ann Arbor, Michigan. We worked with all of the attorneys, ages 50 and above, and increased all of their IQs at least 7 points. JB: That’s exciting. In your bag of tools…that’s one of the nice things about this field, it seems to me: we don’t have to give away any of our tools; we just can open up our bag and put more tools into it so it is expanding the number of opportunities that we have and diversity for intervention. What would be some of your “go to” areas? You’ve talked about hormone replacement. Are there other things you have found over the years that really seem to be little gems or pearls in managing some of these problems? PS: I truly wish I had understood initially in the practice of medicine how important gut health was. I now really understand (I hope!) most of the ramifications, but early on I didn’t realize that if the gut wasn’t healthy, the patient wasn’t healthy. I really encourage people to go back and look at the idea of gut health. When a patient had GERD, reflux, IBS, constipation, diarrhea, this really needs to be addressed. Obviously they are not going to make serotonin well. They are not going to make their nutrients well. The immune system is going to be compromised. But also they won’t be able to take on any medications (or nutrients, as well) if their gut is not healthy. JB: Now we are doing a very interesting little dance because it seems once we move into this arena we start crossing boundaries. There is this kind of siloed thinking in medicine, where you want to stay in your sandbox, and you don’t want to go in anybody else’s sandbox because you’ll tread on their sacred territory. Now we are into gastroenterology. We could be in neurology. We could be in endocrinology. These “ologies” sometimes hold us rigid. Do you have challenges traveling across these boundaries from some of your colleagues, or does it happen fairly smoothly? PS: Initially we did have some major challenges, particularly from endocrinology. Gastroenterology was a little more open. But the good news is, because we are so science-based in functional medicine, if you have the opportunity to present to the other clinician the science, most people will understand what we are doing. JB: Let’s talk about the lab, because for a lot of individuals, knowing something in a number helps them to understand the state of health they are in. They kind of deny their own feelings until they see a number. Or it might be useful for that person in tracking their performance because we are kind of a quantitative society; we like to see numbers improving. It could be a batting average if you’re a baseball player, or your average bowling score, or your cholesterol level. Where does lab play roles in the practice of your health care? PS: Because I’m a physician, it’s really important that we can document what we’re looking at in the patient, that they do have a process that needs augmenting or fixing, and it’s also important to document that they are doing better (that they are improving), not just for the legal aspect, but the patient likes to see that they are improving as well; it’s good encouragement. I always tell my patients, I’m there for 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. I’m there for information. They’re really 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of this, and my goal is to guide them, but they have to really do what they need to do to be healthy and stay healthy. JB: Is there a standard kind of portfolio of evaluative tools that you use, or do you tailor the individual test that you might select (the panels of tests) based on the history and physical and your acumen as you look at the patient and talk with them? Delivering Individualized Treatment in Practice PS: Really every one of the patients in my personal practice has totally individualized and personalized care. I don’t go in with a preconceived notion. You’ve read the book, as have I, about how doctors think. I think a lot of us have a preconceived notion and I’ve turned that part of my brain off. I literally listen to the patient, and I think that’s the most important thing that most clinicians have forgotten about. Fortunately, in functional medicine, we do listen to the patient. The patient will tell you what needs to be done. You have to address why they are there, but in addressing their key component”for example, depression or insomnia”you do go through the entire functional medicine matrix, and before that person is really healthy, you will have fixed all of those modalities; it just varies on which one you start with first. Dialogue: A Lost Art in Medicine JB: Let’s talk about that extraordinary kind of dialogue, hearing the patient’s story, which I think is, as you are indicating, kind of a lost art in medicine. If you go back to the turn of the last century and read some of the great medical figures, you’ll find that they were great story listeners and great kind of “synthesizers” of information. But one of the things they had was time, which seems to be the most lacking part of our world right now (adequate time). How do you find enough time in your practice? How do you structure the way that the office visits go to get the amount of time to have this dialogue and to hear the story? PS: Probably the most important thing is we don’t take insurance in our practice. Insurance is a contract between the patient and the insurance company, and so we give them a super bill and they bill the insurance company, and the insurance company sends them a check. What that does is it stops me from worrying about the fact that I’m not being paid to see them. My goal is the healthy patient. And the insurance company pays me 5.2 minutes to see the patient. I cannot do individualized care in 5.2 minutes. So we have removed that issue from seeing the patient. Many times my initial office visit will be an hour, even not having done the physical yet, in just talking with the patient and taking a really good history, listening to the patient. Most patients want to talk; they want to tell their story. JB: It is very interesting. There are themes that probably reoccur as I have the privilege of talking with leaders like yourself. I am reminded of last month when I had the privilege of talking with Dr. Halsted Holman from Stanford. We were talking a little bit about the same theme”about listening and spending the time to really be present with a patient’s story. I brought up Lewis Thomas, who was at one time one of the editors for The New England Journal of Medicine and has written a number of best-selling books (one is The Medusa and the Snail), and was very, very much into describing medicine in a very allegorical way. One of his books that was not as well read as others I found fascinating. It is called Medicine: The Youngest Science, in which he really talked about the fact that his father, who was a physician at the turn of the last century, didn’t have nearly the tools that we have today”the science-based pharmacopeia”but yet his patients got a lot better.18 He wasn’t constrained by insurance, he wasn’t constrained by Medicare, he wasn’t constrained by a lot of the kinds of institutional things. What he had was a black bag. He would travel to homes and he would sit with people and he would listen to them. Through that process of engagement of dialogue often came solutions. As you were indicating before, maybe people often really know the solutions; maybe they just need to have them reinforced. They need to have a guide. They need to have a wisdom authenticity factor. As you structured your practices (being spread across the multiple clinics), you obviously brought in other people into your practice to assist you. How do you train them? How do you communicate to them the importance of what you have learned over the years so there is a consistent theme of quality? Because it seems like that’s a central feature to this success. An Angel Donor Leads to Functional Medicine Training Programs PS: What we discovered is that a lot of times we would all learn the science, and we would come to very interesting conferences. But we didn’t know how to apply everything on Monday morning. We really had to develop a system”a curriculum”for everyone to learn and be able to reproduce the information. We still had to provide customized and individualized care, but have the same core basis of knowledge. Ten years ago I was very fortunate. I had a patient that we helped, and the patient was very wealthy and wanted to know what she could do to help us. She became an angel donor to us, and we started looking at how we would develop curricula. We did focus groups, etc. And we developed the Fellowship in Anti-Aging, Metabolic, and Functional Medicine, which has now become a Master’s program in Metabolic and Nutritional and Functional Medicine at the University of South Florida College of Medicine. The good news is that it is open to all kinds of practitioners. This is the exciting part: Yes, we have MDs and DOs, but in the program we have 1700 people who are also pharmacists, chiropractors, naturopaths, PhDs, exercise physiologists, PAs, nurse clinicians. It’s been a lot of fun because we all learn, and we all have new ways to help the patient, and we are able to put all those areas of knowledge together. So people can now literally get a master’s degree in this field from a major medical school. JB: I hope the people who are listening to this are really…I mean, you say this so easily”it flows off of your tongue as if it is something we can all do simply, just stepping off the curb and here you go, we produce a curriculum, and we produce a degree, and we get an affiliation with an accredited medical school, and, voila, it all happens. But having been in medical education myself for my first 13 years as a professor, I recognize that what is said easily is not so easy behind the scenes to accomplish. There are all sorts of barriers, and there are obstacles, and there are belief systems, and there is a long-standing sense of self-importance. You’ve got to kind of rise above all of this and find a common thread that ties people together to a bigger vision. Obviously this would be a conversation that could go on for hours, but can you kind of give us a succinct sense of how you traveled this terrain to be successful? This is quite an accomplishment. How the Master’s Program in Metabolic, Nutritional, and Functional Medicine is Structured PS: I do really believe, honestly, that there was some divine intervention that was involved. Because there are a lot of talented people, we are the only accredited program right now for a master’s degree. We are able to have the professors who literally are the leaders in their particular area of expertise. Because all the professors really want the patient to be healthy”that is their goal, we all have different ego structures”we were able to take that one core thought about a healthy patient and bring it together to provide a master’s program for people who are out of their training. It’s done in a fashion where it is three days at a time so that you can leave your practice and come back without having a big issue. You also have webinars every Monday evening, which are archived in case you can’t be present for the webinars. There are eight core courses and there are two electives, and then the eleventh course is an online ethics course that the state of Florida requires for anyone getting any degree from any medical school in the state of Florida. The eight core courses are endocrinology; the second course looks at hypercholesterolemia, hypertension, diabetes; the third course looks at gut health, neurotransmitters, neurology; the fourth is amino acids, fatty acids, spiritual health, and looking at nutritional depletions caused by medicines. What a key component that we have not looked at that is just really turning out to be very major. The fifth course is what we call clinical intensives, where we go over hundreds of case histories. The sixth is introduction to functional medicine and neurology. The seventh looks at brain fitness, autoimmune diseases, chronic fatigue, and fibromyalgia. And number eight looks at psychiatry, an integrative approach to cancer therapies, sleep modalities, etc. JB: Wow! That’s an omnibus. That’s intense. How many hours, in total, does this represent when a person goes through this curriculum? PS: There are 24 hours of actual basic core course that you learn, plus you have to do (for each course) 10 webinars. Then in the master’s program there are 2 quizzes, which are open book (we don’t want to stress the adrenals), but they are timed, so you don’t have 30 years to take them. And then you write case histories; you write 3 of them. That’s really where the professors that are grading material understand whether you connect the dots or not. We can all learn material, but in functional medicine it is important to connect the dots. JB: I think that is really where the tire does meet the road: seeing how this all integrates in the system of patient management. I mean there are many, many things that are wonderful little…I call it cocktail talk. They are little vignettes of knowledge that you can use to stimulate conversation, but then how does it all integrate within a system that ultimately delivers value to the patient? That’s where the real value arises. Tell us a little bit about what you learned, because often–I have found over the years as a teacher–you become the best student because your students become really great teachers. That reciprocity is what can really drive the vitality of programs. Have you experienced that? PS: Absolutely. We have, twice a month, what we call “Professor Day,” where one’s professors (and usually one of the two times it is me)…I sit by my computer and for 12 hours people can email me any question in the world that they want. It has been amazing. The more I learn the more I realize I don’t know anything and I need to learn a whole lot more. JB: When you look at how this has been received, because obviously your have gotten visibility not only within our medical community but certainly probably within the education system, what have been the reviews so far? PS: It’s been fabulous. All of the clinicians”their comment is this has reignited their love for medicine. This is why they went to medical school, or any other professional school that they went to. And from the viewpoint of the public, I literally could spend every day going to a different city, being asked to speak to the public on functional anti-aging medicine. There is that much of a need. People really want to know this information. JB: When we look at healthcare reform”I know this almost sounds like an oxymoron in the way that it has been discussed, here, the last few years (and particularly the last few months) because it doesn’t seem so much as a healthcare reform discussion as a reimbursement reform discussion”have you found that there is, both within the health professional and the patient, a real interest in “health” reform, not just universal access and reimbursement reform? PS: I do think more and more people are wanting to be healthy. The problem has been that (at least from a physician viewpoint) we’ve never spent the time to help the patient be healthy. Part of that is we never learned how to be healthy ourselves first. That’s the most important part: you work on yourself first (you get yourself healthy) and then you can help others. JB: Very well said. Example is the best teacher, isn’t it? There is no question about it. As you’ve developed your curriculum, because this is such a remarkable changing field, how have you been able to kind of keep pace with changes that occur? It just seems like every week a new bit of understanding starts to develop. Let’s use the vitamin D story. Five years ago, it was the outlier that talked about vitamin D beyond that of an anti-ricketic vitamin. Now, if you’re not really up to speed with regard to all of the multiple activities that 1,25-dihydroxycholecalciferol has, you seem like you have been left behind. How do you keep pace in your curriculum with these rapidly changing events? PS: Unlike most kinds of curricula, ours changes every time the course is given. Most of the courses are given twice a year. Next week we are about to give another course. I just went through all of the seminars. They are drastically different than they were even six months ago. The good news is our professors, because they are cutting edge and leading people in their fields, are able to impart that information and change it on a very rapid basis. JB: Do you have to take your curriculum for annual review? Is there a curriculum committee? Is there somebody at the university that says, “We’d like to pass our eyes over what you are teaching,” or have you become both a combination dean and curricular development person in one? PS: Oh, no. I have had great amounts of help from the University of Florida College of Medicine. The Senior Dean, Dr. Klasko, is just phenomenal. He is almost 60 years of age. He’s a gynecologist/obstetrician; he still delivers. He is very cutting edge and really allows you to be able to work on things without micromanaging. Dr. Michael Barber, who is my counterpart, is a PhD biochemist. He has been phenomenal to work with. He’s the one that goes over the curriculum. I couldn’t ask for a better team of people to work with, along with the other people at USF; they’re great. JB: Now let’s talk a little bit about how you bridged this extraordinary gap. You talk about taking care of ourselves and being good examples, but it sound to me like you are stretched in time, stretched in distance, and stretched in responsibility. Tell us a little bit about how you manage the clinical world, the teaching world, the advocacy world, and all the other parts of the world in real life that connect to your being. PS: I really do think I am stretched thin. The thing is, right now the time is here for a functional medicine approach. I really thought it would probably be 5 to 10 years from now, but medicine is moving so quickly that the time is here, so I don’t mind being stretched a little bit thin. I do keep the things that help me stay not stressed. I like to hike and bike. I like to needlepoint and quilt. Those are the kinds of things that calm me and keep me centered. I’m also married to the nicest guy in the world, who also helps keep me centered, which is part of the phenomenal things that I think have to happen in life for you. JB: Fantastic. This whole concept of a support system I think is, for all of us, critically important. It can be your office staff who can be a team that really provides nurture and support for one another. It can be your family. It can be your principal partner. It can be the community in which you live. I think we need to form those connections. When you read The Blue Zones you probably saw that one of the characteristics that was associated with long and healthy life was being part of a tribe. We define our own tribe: people that understand us and give us that support. Obviously that’s something you give back to your patients as well, as they are a member of your practice and your teaching. They are part of your tribe. PS: I’ve learned as much from my patients as they will ever learn from me. I learned that, very fortunately, as an intern, so I’ve been very blessed in over 30 years of practice to really work with my patients on a one-on-one equal basis. It has been phenomenal. I’m also blessed to truly have a fabulous staff that I work with, from my receptionist, to my nutritionist, to my PA, to the people who work with me in the fellowship. They are all a key component as important as I”or more important”to make this all work. JB: Let’s talk a little bit to the person who is listening who may be new to this field and is either trying to transition into the field from where they have been in their medical practice previously, or maybe just starting out into their world. Is there some early guidance from your experience that you would provide or offer to people saying, “How do we make these first steps?” What are some of the things that you’ve learned that might be helpful to take this first step toward changing their practice to this style? PS: The first thing is someone can come into this field from really any background. In the fellowship and master’s program, we literally have clinicians from every field of expertise. In fact, we even have a pathologist, who, after 22 years in pathology, is now going to open a practice next month in Traverse City, Michigan, and see patients for the first time in her life. It is also a key component, when we look at all of this, not to take insurance in this kind of practice. What I usually suggest that people do is they keep their family practice (internal medicine practice, or OB/GYN, or whatever basis they have), and then set up a separate corporation, and on separate days they see their metabolic/functional/anti-aging patients. That way you don’t mix the two. When people say, “Don’t you feel extreme guilt if you don’t offer functional medicine to your primary care patients that you’ve had before?” And my response is, “No.” Because the initial practice for me was internal medicine. Internal medicine has certain guidelines, and that’s the care that I provide to those patients. Yes, now that does include vitamin D, but it would not have 5 years ago. I don’t, however, go through looking at nutritional depletions caused by every one of their medicines unless they are in my metabolic/functional/anti-aging practice. Now my practice is just anti-aging/metabolic/functional medicine, but initially people can have two practices”separate tax ID numbers”and then just don’t mix the two. Just let people know that you have additional training in this field of expertise, and that on Thursdays, for example, you are going to see your functional medicine patients, and if they are interested in that kind of approach that you would be happy to see them on Thursdays. JB: That’s a real pearl. Thank you. That’s real news-to-use”a very, very wise suggestion. Obviously over the years that you’ve been doing this, just from what you have said, you’ve built more and more interest in this other thing that used to have occupied maybe a part of your time, which now is occupying more than 100{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of your time. Have you done this through advertising? Have you done that through public speaking? Have you done that through radio shows? Have you done that through promotion of certain types? How have you built that reputation, or is it just word of mouth? PS: The two best things that have brought us patients are, number one, word of mouth, which I think, hands down, in medicine is always the best way, and number two is really public speaking. And you don’t have to be a great public speaker. The first time I did a conference there were only four people there. But every Tuesday night we did a conference in our first office in Canton, Michigan, and it just grew and grew and grew. There are also other people that you can work with. For example, in my community, the compounding pharmacy helps promote our practice. We also work with other practitioners; we have a plastic surgeon that we do conferences with together. The chiropractor down the street from me”we do conferences together sometimes for patients. My style is a little bit different. I don’t do PowerPoint. I take open questions during the seminar that I give. It’s a lot of fun. People really want to be able to talk to the clinician as opposed to necessarily looking at a PowerPoint presentation. We usually have about a 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} success rate: when we have a seminar, within a year 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the people will want to see us. That part is very exciting. Again, it doesn’t take a lot of people being there. One of my friends owns a quilting shop, and when one of my books came out she wanted me to do a book signing there because she was having a sale on her quilting material. It was the worst storm there has been in Detroit for years; it was an ice storm. Two people came. One person who came owned ten home healthcare stores, and that’s all it took. So sometimes it’s not about the numbers; it’s really about how you are going to help people, because if you do it really does come back to you. JB: That’s a beautiful lesson, thank you. Let’s turn it slightly here and talk about what you perceive as barriers. We’ve been very uplifting, I think, in this conversation, to this point, and very kind of high level, but obviously there is always a yin to a yang. What are barriers or what things that are obstacles”things that one should be aware of that make life a little bit more complicated? PS: I think one thing that is really difficult for people to understand is that you never criticize someone else. Other practitioners will criticize me. I never criticize them back. My response is always, “I’m sure your other doctor is an excellent physician or you wouldn’t be seeing them, but this area is my area of expertise. If your other clinician has a question, please have them call me, email me, fax me. I’ll be glad to fax them a medical article that is a clinically controlled trial showing them why we are going down this pathway with you.” And I think that’s really the important aspect. I just keep giving back, to the other clinicians, the science. Then they realize that no one can read it all; we can’t either. We really have–now–a pretty good interchange with most people. JB: You’ve given us extraordinary news-to-use in this discussion. It is interesting how you’ve woven together philosophy and experience with real pragmatism. I guess that’s what really separates high achievers from dreamers. We can all dream”and hopefully we all do”but then somehow translating that dream into a pragmatic action plan, and a list of achievables, and standards of internal control, where you say, “Okay, am I making progress along my list?” is probably what establishes performance. You have been very successful, I would imagine, throughout your whole life, being a person who establishes those milestones, benchmarks, measuring sticks for performance. Are there things that you would guide someone getting involved with this? Do you write a lesson plan? Do you have a business plan? Do you do journaling? Or is it just something that you have inherently developed in your daily routine? PS: I think one of the things that makes good leaders is failure. I’ve not always been successful in everything I have done. But everything that has been a failure, I’ve been able to have my glass be half full. I have turned it around to learning something, and then turning that into something that will progress into a better way to help patients. That has been a key component in my own life. We do encourage everybody to become involved in the fellowship and the master’s. As we go forward as one group, we will be able to help people much more than if everybody kind of has their own little separate connections. We are all about the patient”all of us, all clinicians are, that’s what we are here for. Even the PhD’s that work in the labs”they are still there for the patients, they just do it in a different fashion. We hope people go forward in taking the master’s. I’m sure other master’s programs will develop, but if people are interested they are certainly welcome to email me. My personal email is pepper (just like the spice) @ sbcglobal.net, so that’s pepper4@sbcglobal.net, and I’m happy to answer some questions and really look at other ideas, different ways of training. Right now we’re involved with different medical centers and looking how we can impart this to residents and in medical schools. JB: Anyone listening who is motivated is probably in awe of what you have been able to accomplish over your years of both practice and curricular development. This is really an amazing next step for the field. On behalf of the people that are listening I want to thank you for taking the time to be out here with us in Gig Harbor, and for sharing this and really motivating us. I think all of us need inspiration at times. Sometimes the daily routine of just getting up and making it through the day with all the compression of responsibilities seems overwhelming, so to have someone of your bright light giving guidance tends to lift us all up. Thank you, Dr. Smith, and we look forward to following your contributions and your program very, very closely as we move forward. PS: Thank you, Jeff, and I’ve really been very privileged to have you as one of my mentors. That has been one of the nicest things in my life. JB: Thank you, Pam. For those of you who are listening, this is a year in which we have had some very, very strong clinicians that have been speaking to us. Maybe those of you who have been long-standing Functional Medicine Update subscribers have recognized that we’ve drifted off into the esotericism of primary science. But I think over the last several months you can see that we’ve really tried to focus on bringing clinical acumen from people who have done this successfully into the body of understanding, because as Dr. Smith said, it is really through what we do with patients that makes this all real. The rest of it is kind of interesting intellectual fodder, but until we can really deliver better outcomes, it is pretty much just an intellectual enterprise. Dr. Smith, once again, absolutely fantastic motivation for us to keep the vigilance and keep proceeding forward. PS: Thank you. It’s my hope in having listened in this July issue to the really sage and insightful comments of Dr. Pam Smith concerning the curriculum, the study, and ultimately clinical implications related to successful aging, and coupling that together with what you learned in the June 2010 issue of Functional Medicine Update from Dr. Halsted Holman, that you started to emerge a fairly interesting way of approaching, in your own practice, the delivery of health care that will lead to healthy/successful aging. Obviously there are a lot of devils in the details and there are many more things we can and will be studying, but I hope that you got the general drift of how to use biomarkers: what kind of information to assemble, how that gets put into a lifestyle medicine program, and what that might mean in terms of following the trajectory of the patient and using the patient as the center of their own universe and teaching them something about self-reliance and self-efficacy, and using orthomolecular substances where necessary to augment and support proper physiology. It’s a whole new paradigm. It’s the paradigm that we have been discussing for 20 years that we call functional medicine. See you next month.  

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Welcome to Functional Medicine Update for August 2010. In this issue we’re going to explore a subject that I think for most of us is acknowledge as very important in understanding the etiology and management of chronic disease, but it is also fraught with a lot of confusion and misunderstanding and lack of specificity. I’m now talking about the environmental relationship to chronic illness. I recall an Institute for Functional Medicine Symposium that occurred in Tucson, Arizona, more than a decade ago, where one of the world-renowned experts in the area of chemical carcinogenesis and mutatgenesis, Dr. Bruce Ames, spoke. Now Professor Emeritus at the University of California, Berkeley, Dr. Ames was Researcher of the Month just recently, talking about the work he has been doing in the area of long latency nutritional disorders associated with things like vitamin K deficiency. You’ll recall this very powerful interview we had with Dr. Ames on micronutrient deficiencies and metabolic tune-up. This Symposium presentation that Dr. Ames gave years ago made a lot of the attendees quite upset. He made the comment that environmental chemicals were a fairly small contributor–in fact almost insignificant–to the rising tide and prevalence of chronic disease and specifically cancer, and that there were many other factors that played much more principal roles in the induction of chronic disease than environmental chemicals. I think ire was expressed by many of the participants at that meeting because of the perception of the environment and of the literally tens of thousands of new chemicals that have been introduced into it through the developments in petrochemical synthesis that have occurred since oil became the fuel powering the economic engine back in the early 20th century. The perception is these chemicals are the root culprit of many diseases as they have gotten into our environment and become persistent, get concentrated in lipophilic tissues, and ultimately adversely infect organ systems like the nervous system or the immune system. This then leads to regulatory signaling difficulties on all of function and produces a variety of different diseases based upon the individual’s genotype. That’s a model that has been held as a presumption within the field for some period of time, for which Dr. Ames’ comments seem to be contradictory. This very complicated question about the relationship between the environment and our health opens up some important landscape principles that we need to define before we can really understand whether these connections are real or not). Those connections have to do with things like genetic variability and susceptibility, and the recognition of the diversity of genomic characteristics that relate to how we respond individually to our environment. Single Nucleotide Polymorphisms Affect Variability and Response The age of molecular genetics, which is now upon us, has really rapidly and dramatically changed since Dr. Ames made his comments more than 10 years ago. The human genome project has concluded. They are now starting to look at the number of single nucleotide polymorphisms present in the human genome (recognizing that there are over two million different SNPs that have been identified) and what effects they have on variability and response of an individual to their environment.. That would be number one. Toxicology: Low-Level Exposure Over Time Can Have Subtle Effects Number two is the difference between what I would call a toxicological view of environmental exposure (one chemical at a time, looking for a specific mutational injuries), and how exposures can induce alteration in the mechanics of the cell (the hard wiring of the cell) to actually produce disease later. There are now very significant emerging suggestions that the role of chemicals, taken multiple at a time at very low levels, may be much more subtle on physiological function than the traditional toxicological injury model. In fact, the analogy to this is a little bit like the analogy between looking at drug effects (pharmaceutical drugs) on physiology versus nutrient effects: we say drugs hit single metabolic steps very hard, so they have a jackhammer effect, versus nutrients that influence each step maybe very mildly, but the complex nature of modulation of systems biology by nutrients may produce a more remarkable effect over time than a drug which is influencing one step very hard and locking down that physiological function. It is a different kind of effect. It is a systems effect versus a step-wise effect. It is a web versus a pathway effect. That may be what we are looking at here as it relates to low-level exposure to multiple chemicals in the environment and how they influence cell signaling. This whole question of intercellular signal transduction-how outside environmental messages get transduced into intracellular function and finally into the phenotype of the cell-is only now emerging as a well recognized component of biomedicine. The tools that come out of informational science/computational biology are allowing the large amounts of data that is required to be assessed, compiled, and analyzed to evaluate systems effects to now start to be approachable. We are starting to see more and more studies that are looking at systems-wide influence on function as a consequence of exposure to a complex array of different environmental signals and chemicals. That is the context for the discussion this month. By the way, I’m very excited to say we will actually carry over this discussion into September. We are going to follow on from our interview with world-renowned researcher this month, Dr. David Jacobs, from the Division of Epidemiology and Health at the University of Minnesota School of Public Health, and speak with Dr. Randy Jirtle next month, who I’m sure is familiar to many of you who have beenFunctional Medicine Updat subscribers for awhile. Dr. Jirtle is at Duke University Medical Center in the Department of Radiation Oncology. Two years ago we discussed the work he had done on the Agouti mouse, showing what happens when you supplement the pregnant mouse with high levels of methylating nutrients. He was able to produce for the first time what is called a pseudo-Agouti mouse. The fur color changed, but more than that, the physiochemistry of the mouse changed. This Agouti mouse, which is known to be diabetic, obese, and get heart disease and cancer suddenly didn’t get obese. Not only was its fur a different color, but it also didn’t get diabetes, it didn’t have the same incidence of cancer, and it lived longer. This was done without changing its genes, but rather just changing the environmental signaling of its genes through epigenetic imprinting. We’ll talk more about that, obviously, in September with Dr. Jirtle, but I just want to alert you to the fact that this topic that we are describing-environmental modulation of intercellular signaling-will be kind of a two-part series, starting this month with Dr. Jacobs and moving next month into a subsequent discussion with Dr. Jirtle With that in mind, let’s talk a little bit about what we mean by environmental signals influencing the cellular phenotype. There’s probably no better example of this than the role that low level chemicals seem to be having on signaling that associates it in the phenotype with diabetes, cardiovascular disease, certain cancers, and even obesity. We have discussed this in previous issues of Functional Medicine Update over the last several years. We started discussing this because of the recognition that there seemed to be some connection between persistent organic pollutants (POPs) and later stage onset of metabolic syndrome, insulin resistance, hyperinsulinemia, obesity, and even type 2 diabetes. Connecting POPs to Later Stage Onset of Disease: The Research of Dr. David Jacobs and Dr. Duk-Hee Lee This construct of correlation-epidemiological/statistical correlation-was seen through an analysis that was done of the NHANES III (the Health and Nutrition Examination Survey III data) by Dr. Jacobs and Dr. Lee. They showed that there was no direct relationship between body mass index and diabetes (meaning fat people didn’t correlate well with diabetes), but they did see an association when they included another variable, which was elevated plasma levels within the normal range of activity of an enzyme called gamma-glutamyl transpeptidase (GGT). Gamma-Glutamyl Transpeptidase (GGT): An Enzyme Involved with Glutathione Recycling In clinical chemistry, most of us know this enzyme, GGT, is used for evaluating drug or alcohol addiction and for sobriety programs. Generally we differentiate it from ALT and AST, the traditional liver test enzymes, which are related to things like hepatitis and cirrhosis. GGT is more related to alcohol and drug-related functions. Not to get too deeply into biochemistry, I just want to remind you that gamma glutamic acid is a very unusual amino acid. It actually doesn’t appear in normal protein synthesis, where we have alpha amino acids that are involved with protein synthesis and the poly peptides that we call proteins. Gamma glutamic acid is connected to its neighbors in a different kind of configuration-a gamma linkage versus an alpha linkage-and in this case, there is really only one place where gamma glutamic acid is seen in prevalence in human physiology and that is in the tripeptide that we call glutathione. Gamma-glutamyl transpeptidase is an enzyme that is involved with glutathione recycling/resynthesis, and therefore, in part, GGTP may have a functional significance related to the synthesis of a very important biomolecule in cellular physiology: glutathione. The Functions of Glutathione in Cellular Physiology Glutathione has three general principal functions in cellular physiology. First, it has a role in antioxidation; in the redox control it is the most prevalent intercellular antioxidant in human physiology. It shuttles itself between glutathione disulfide (the oxidized form) and reduced glutathione. There are enzymes, glutathione peroxidase (selenium-containing enzyme), and glutathione reductase (requires FADH2 which is a riboflavin-related cofactor-stimulated enzyme). Glutathione reductase and glutathione peroxidase work as a shuttle to keep glutathione in the right balance between the reduced and oxidized forms. Generally we say that in a cellular milieu we have more reduced glutathione (GSH), than we have of the oxidized glutathione disulfide (GSSG). As the oxidative reductive chemistry changes and that individual’s tissues or organs are under more oxidative stress, the ratio of the reduced glutathione to the oxidized glutathione goes down, so they get a reduction in the reduced and an increase in the oxidized glutathione. That’s one role of the glutathione molecule: establishing proper intercellular reduction/oxidation, particularly in mitochondrial bioenergetic oxidative physiology. The second role of glutathione is as a conjugating nutrient in xenobiotic detoxification. It forms mercapturates as a consequence of Phase II conjugation with glutathione-S-transferase as the principal detoxifying enzyme that connects glutathione to a detoxified Phase I xenobiotic to then render it into this more water soluble mercaptuate form. When a glutathione molecule is used, say in a hepatocyte for detoxification of a xenobiotic molecule, it connects itself to that transformed molecule in a covalent way, making it unavailable in the cell. In fact, it ultimately gets excreted in the bile or in the urine as a mercapturate. That depletes the glutathione stores in the cell. A combination of oxidant stress and inflammation that requires more glutathione in the reduced form coupled with the detoxification through mercapturate formation can produce, then, a temporal insufficiency of intercellular glutathione that could have adverse effects on bioenergetics and oxidative chemistry. The third role of glutathione is that of conjugation with partially oxidized long chain polyunsaturated fatty acids. These could be derivatives of linoleic acid, or derivatives of arachidonic acid, or derivatives of eicosapentaenoic acid (omega-3 fatty acids). The formation of these oxidized derivatives and then their conjugation with glutathione produces molecules that we call leukotrienes, like leukotriene b4, the most proinflammatory molecule known in pulmonary physiology, or leukotriene d4. So this also removes glutathione out of the intercellular milieu. Glutathione as a Xenobiotic Detoxifying Nutrient Let’s go back to our discussion of glutathione as this second phase reactant (that is, as a xenobiotic detoxifying nutrient). In this particular role, as glutathione is reduced in its abundance by conjugating with an oxidized transformed pollutant molecule, or xenobiotic, or drug, it then has to be replaced–it has to be regenerated–and that is where the glutathione recycling becomes important, and where activation of inducible enzymes like gamma-glutamyl transpetidase starts to play a role. Now, doyou start to see a potential association? You might say, “Does that mean that the higher activity levels in the plasma of GGTP in a person who is not an alcoholic or abusing a drug substance is a consequence of the body trying to accommodate by upregulating the activity of this enzyme, or the abundance of this enzyme in the plasma, to try to accommodate the need to get more glutathione available and to activate detoxification of things like drugs and alcohol, or things like persistent organic pollutants?” Could it be, going back to the observations of David Jacobs and Duk-Hee Lee, that the elevated normal levels of GGTP that are associated with those people with elevated BMI who have diabetes is a surrogate marker for the fact that they are suffering from some type of metabolic poisoning from xenobiotics that is requiring their physiology to upregulate detoxification, and therefore what we are really looking at is the connection between an xenobiotic exposure and obesity and later diabetes? Meaning that diabetes does not necessarily come from obesity, but there is a metabolic disturbance that results in the outcome in the phenotype of both obesity and diabetes that happens to occur concomitantly, and that this connection, then, renders the person at higher risk to conditions that we say are obesity-related conditions (or obesity-risk-related conditions) like diabetes, heart disease, and various forms of cancer. So really the effect is below that and the symptom is above that, which is obesity.” That’s a pretty long-winded introduction to what you’re going to hear from Dr. Jacobs today in much greater detail. What I would like to say is that there is increasing evidence that connects together these persistent organic pollutants with obesity, and in fact these have even been given the name “obesogens,” as substances that can induce and modify the function. One of the really interesting recent papers that describes this very nicely is a paper that appeared in one of the Nature magazine journals, titled Obesity. This occurred in the June of 2010 issue. I think the title alone gives you a sense as to the topic. The title is “Obesity and Persistent Organic Pollutants: Possible Obesogenic Effect of Organochlorine Pesticides and Polychlorinated Biphenyls [PCBs].”1 Now let’s take this from the esoteric down to kind of the ground level of language and understanding. What we are talking about are persistent organic fat soluble or lipophilic toxins that, at low level, could accumulate in tissues, and, in so doing, can modify physiological function in such a way as to set in motion a process that leads to obesity and to type 2 diabetes. We know that persistent organic pollutants are endocrine-disrupting chemicals; they are sometimes called xenohormones. They are associated with the development of metabolic syndrome and type 2 diabetes; increasing numbers of papers about animal studies and in epidemiological studies in humans seem to indicate this. Unfortunately, in humans, little is known about the role and the potential origin of obesity. Recently this topic has come under much more exact review, looking at the correlation between serum levels of persistent organic pollutants and the prevalence of obesity in cohorts of obese and lean adult men and women. In this paper in Obesity they studied 98 obese and 47 lean participants, aged greater than 18 years, men and women. Serum samples were analyzed for the presence of polychlorinated biphenyl and various congeners within that family, as well as organochlorine pesticides, and dichloro-diphenyl-dichloroethylene, and beta-hexachlorocyclohexane (these are metabolites of organochlorine pesticides). What was found is a significant negative correlation between BMI, waist, fat mass percentage, total and subcutaneous abdominal adipose tissues, and the serum levels of PCBs, and the sum of PCBs. There was a positive correlation, however, with BMI, waist fat, fat mass percentage, and total and subcutaneous abdominal fat with the chlorinated hydrocarbons. Also, the chlorinated hydrocarbon persistent levels in the tissue correlated significantly with HOMA scores (the homeostasis model for insulin sensitivity). So what you see is people that have the higher levels have lowered insulin sensitivity, meaning more insulin resistance. These results suggest there is a diabetogenic effect of low-dose exposure to these persistent organic pollutants, and it is more complicated than just that of producing body fat alone (an accumulation of body fat). There are many subtleties of this metabolic disturbance that cut across different potential disease states Does that also relate to things like Agent Orange and herbicides? To answer that question, maybe we want to go back to Vietnam and Cambodia and Laos and start looking at people now 50 years downstream from the experience, from the Vietnam War and the use of defoliants, and ask, “Is there any evidence of increasing prevalence of diabetes?” In Cambodia, as you probably know, the population works very hard. It is still reasonably non-industrialized. There is still a lot of family agriculture to produce the foods of need, and the people are generally very lean. We don’t see central adiposity, we don’t see obesity, so you might say, “We would expect there to be very low prevalence of type 2 diabetes because it’s just not seen in very lean highly active people.” Yet there is rising epidemic of type 2 diabetes in Cambodia.2 People have scratched their heads and said, “Why? I don’t understand it. It doesn’t follow with our traditional identification of risk factors for diabetes. These people are lean, they are hard acting, they are eating principally vegetarian diets, they don’t have McDonald’s on the street corners. What’s going on?” Studies on Agent Orange Exposure Decades After the Vietnam War The variable could be exposure and accumulation of these fat soluble biocides. In fact, there are now papers that are being published on individuals and population groups that have been exposed to these defoliant materials, including US veterans that were exposed during the Vietnam War to Agent Orange, showing how their levels in fat tissues of these POPs (persistent organic pollutants) were correlated with a variety of chronic diseases, including type 2 diabetes and cardiovascular disease, as well as neurological conditions and other problems, including potentially cancer.3,4 There is more and more evidence that these POPs really play roles in inducing metabolic disturbances that result in kind of mitochondrial poisoning, and alteration in bioenergetics, and accumulation of body fat, and having a neuroendocrine effect as endocrine disrupters. The data confirm, then, the lifelong accumulation of POPs does occur in the human body, and as we are exposed these things get into our tissues and our tissue levels rise. Studies say plasma concentration over time can rise in kind of equilibrium with that of our fat soluble levels within fat tissues. Studies have clearly demonstrated that the capability of persistent organic pollutants can accumulate in the body throughout lifespan and there is a relationship between age and serum levels of POPs that’s been observed in lean, obese, and severely obese people. In fact, Nichols, two years ago, presented age-specific reference ranges for PCBs based on the United States Health and Nutrition Examination Survey 2001-2002.5 Is there a threshold where the level of these persistent organic pollutants starts triggering certain metabolic disturbances that are seen clinically? Or asking it a different way, could this be one of the factors that lead to increasing prevalence of chronic disease with age? Are these accumulating levels of a potpourri mixture of biocides increasing the relative risk to metabolic poisoning? When I use the word “poisoning” I’m using it here very advisedly because we’re not talking about traditional toxicological effects; we’re talking about subtle effects on intercellular signal transduction, gene expression modulation, and ultimately effects on things like insulin signaling and inflammatory pathways, and cell replication, and things that are much more subtle in their influence. I think that there is a case that is emerging to support the fact that body fat accumulation may be more than just eating luxurious calorie-rich diets, and that it is also potentially associated with factors that modulate our cellular physiology. These obesogens that are in our environment may be partially contributing. There is a very interesting article that appeared recently in Molecular Endocrinology, about the case for obesogens and how there is now very significant research that is accumulating indicating that the conventional wisdom that obesity is primarily the result of a positive energy balance (meaning too many calories in and too few calories burned), is not the full explanation for the story of the rapid rising tide of obesity, not just in the United States, but elsewhere in the world.6 What are the bioenergetics of food being used as fuel, and how does it ultimately get released from the body as a non-polluting form of energy which we call heat, and water, and carbon dioxide versus stored for a rainy day that never comes? That particular process is all mitigated through bioenergetics related to mitochondrial function. What we are saying, here, in this story that is emerging, is that lipid accumulation may be the result of blunted metabolism, and it occurs while other things are happening at the gene expression level that are associated with rising risk to inflammatory disorders and to risk of diabetes and cardiovascular disease. I think these are really dramatically frame-shifting principles that set a new stage as to how low-level substances in the environment could participate in altering metabolic function. In animal models it appears as if this concept is correct. You can induce some of these factors that we are talking about through low-level exposure to these “obesogens” in the animals’ environment and watching the effect it has on adipocyte size, adipocyte cellularity, and adipokine profiling after exposure. If you do DEXA scanning on these animals you find that their intra-abdominal fat increases as a consequence of low-level exposure to these persistent organic pollutants. Expansion of this research may help us to understand why we’re seeing such a rising tide of various chronic diseases in the developing world that we can’t correlate directly with obesity. It’s not like the United States, where there is a direct link between obesity and some of these metabolic disturbances; it’s more of an indirect relationship. Even in the United States, as was pointed out by Jacobs and Lee, the association between diabetes and obesity is only seen when focused through the lens of the GGTP level. The person has to have an elevated normal quintile of GGTP couple with their elevated BMI to have a strong correlation with type 2 diabetes There is a wonderful review that just appeared in Nature Reviews of Endocrinology. Ana Soto and Carlos Sonnenschein did a very nice job reviewing the connection between endocrine disruptors and cancer incidence.7 Again, this is a different kind of model than what Bruce Ames was talking about at the Institute for Functional Medicine meeting over ten years ago. In this case we are talking about subtle effects-not mutagenic effects, but subtle effects-on intercellular signal transduction, signaling that relates ultimately to gene expression patterns that associated with cellular proliferation and the oncogenic process. We call this oncogenic potential or oncogenic burden. It is now recognized that environmental endocrine disrupting chemicals, including pesticides and industrial chemicals that have been released into the environment, have bioconcentrating effects on wildlife, and ultimately get into our food supply, get concentrated up the food chain, and ultimately are delivered to humans. The effects that have been observed in animal models after exposure to these substances correlate positively with increased incidence of malformations of the male genital tract, with neoplasms, and with decreased sperm quality (observed in both the European and United States populations in independent studies). We now also see changes in the female reproductive system and changes in neuroendocrinology, including alterations in the phenotype of behavior, obesity, prostate cancer, and thyroid and cardiovascular endocrinology. These are all unequivocal and multiple-study-documented cause-and-effect relationships. In fact, even things like plasticizers like bisphenol A, at very low levels, have been found to modulate signal transduction in such a way as to increase this endocrine-mediated pathway that increases the risk to obesity, type 2 diabetes, and other chronic diseases. What’s the impact of endocrine disruptors on endocrine targets? Do we have a specific ligand agonist understanding of how these things fit together? You have to get the signal from outside the cell inside the cell. There must be some antennae sitting on the cell that picks up that signal (that environmental disruptor signal), and that is now also starting to be well-understood. There is a paper that was published in Hormone Metabolic Research in 2010 that looks at endocrine disruptors in human health from this structure/function relationship: how these chemicals have mimic effects on modulating receptor sites for various hormones and influencing (through signal transduction, right to the genome) the production of messenger RNA, and altered proteins in the cells, and altered metabolism.8 There are a whole series of substances that are on the hit list of concern: phthalate esters, you’ve heard about; pesticides, I mentioned; dioxin, obviously; bisphenol A; diethylstilbestrol; heavy metals, including lead and cadmium and mercury; various types of polychlorinated biphenyls, I’ve talked about PCBs; even things that are benzene derivatives have been demonstrated to be xenohormones (xenoestrogens, so to speak). I think that we are starting to see heavy metals, persistent organic lipophilic toxins, secondary metabolites, and biocides all playing roles, as well as substances that are used in home products that may result in things like precocious puberty, delayed puberty, fertility-related problems, structural reproductive tract abnormalities, endometriosis, or mammary gland developmental problems that may be associated with increasing risk to breast cancer like proliferative breast problems. These are not insignificant issues. What we are starting to recognize is the environmental connection to our function is symphonic, rather than hard-hitting, single-agent toxicology. The neuroendocrine targets of endocrine disruptors, as pointed out by Andrea Gore in a recent review in Hormones, are the same receptor sites that modulate subtle function within the development of an organism from fetal development all the way up through adulthood, and maintain a homeostatic function in the organism.9 The combination of all these chemicals put into our environment at low level, along with differing metabolic susceptibilities, genetic uniqueness, and detoxification abilities among people, makes this area very complicated to study, and to lockdown, and to demonstrate a clear cause-and-effect relationship. I think as you hear Dr. David Jacobs describe the work he is doing you’re going to understand much more why this topic is rising into prominence and why we are starting to get a read on methods for evaluation, The research is focusing on how detoxification processes (through enzymes like gamma-glutamyl transpeptidase, and glutathione synthesis and conjugation) play roles in detoxification and lowering burdens of these chemicals, and why persistent organic pollutants are being seen much more now as possible contributors to the rising tide of chronic disease, not just in the United States, but in these developing countries where you don’t see the kind of anthropomorphic changes that are often associated with chronic disease in the United States. People in these countries don’t necessarily look like they are obese. Rather they are lean, they are active, they are eating fundamentally similar diets to that of their ancestors. But the variable that they are exposed to might be these persistent organic pollutants. With that in mind, let’s hear from a person with a great deal of knowledge. He is one of the discoverers of this area, and a person whose work I have followed very carefully over the last fewyears as he has had multiple publications in top-tier journals, Dr. David Jacobs.

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INTERVIEW TRANSCRIPT

Researcher of the Month David R. Jacobs, PhD Mayo Professor of Public Health Division of Epidemiology and Community Health University of Minnesota School of Public Health 1300 South Second Street, Suite 300 Minneapolis, MN 55454 Here we are once again at that section of Functional Medicine Update. I know you look forward to it like I do, and that’s talking with the experts, the clinicians and researchers who are creating the field of 21st century medicine, which will hopefully help us to address better the rising burden of chronic age-related disease, give us new ways of looking at the etiology of disease, and ultimately provide new ways of intervening, both preventively and therapeutically. You’re not going to be disappointed this month. The researcher this month is a person whose work I’ve been following very carefully and closely. Every time one of his publications comes out I can hardly wait to read it. I think this work is really creating a whole new paradigm. I’ve cited his work on several instances over the last few years on Functional Medicine Update. I’m speaking about Dr. David R. Jacobs. Dr. Jacobs is a Mayo Professor of Public Health, Division of Epidemiology and Community Health, at the University of Minnesota School of Public Health. He has what you might consider a fairly interesting background, not one that you’d immediately connect to an investigator in the type 2 diabetes area. He is a mathematician from his undergraduate training, and then later earned a PhD in mathematical statistics at Johns Hopkins. Working in epidemiology means he’s a person looking at associations, and he has done an extraordinary amount of work in a whole variety of areas. Let me give you kind of a thumbnail of some of the areas that he has had interest during his professional career. I think where I first became familiar with Dr. Jacobs’ was with regard to the work he has done on whole grains and refined grain intake and the relationship to chronic disease. This is some epidemiological association work that I’m sure we’ll touch upon in this interview. He’s also looked at inflammatory processes, oxidation, and how that relates to chronic disease. The area that we’re going to be speaking to quite a bit in this interview is related to pioneering work in type 2 diabetes and its relationship to xenobiotics and persistent organic pollutants and how that translates into function. And then there is this other area, which I know we’ve talked about in Functional Medicine Update, and that’s periodontal disease and its relationship to the etiology of cardiovascular disease. That’s just kind of a tip of the iceberg when it comes to the areas that Dr. Jacobs has been involved in, but we’re going to focus, in this discussion, principally on xenobiotics and the emerging understanding of their relationship to type 2 diabetes. With that long-winded introduction, Dr. Jacobs, thanks so much for being with us. How did an undergraduate degree in mathematics translate ultimately into looking at the epidemiology and the association between persistent organic pollutants and type 2 diabetes? DJ: Thank you, Dr. Bland, for that really nice introduction. I don’t know if you want to do the whole biographical course or not, but population science is basically, in a certain way, a branch of applied mathematics. It’s very applied. An interesting little story is that when I was doing mathematical statistics, which is really heavy-duty math, the mathematical statisticians kind of said, “Well, the biostatisticians, they’re just applied, they don’t really know the answers.” But it turns out that the substance, of course, is so important, and I have striven throughout my career to really understand the substance and I’m much more interested in the substance than in the mathematical principles. That’s the short answer. JB: I think that’s a good one. I think one of the things that has been a hallmark of your work is this collaboration that you have had with Duk Lee at the Medical University in South Korea, which is looking at this xenobiotic connection and how you went back and looked at NHANES II and III data. Maybe you could take us through that whole story because it sounds just fascinating how this whole hypothesis emerged. I’d love to know where it came from. Complementary Skill Sets Leads to New Research Ideas DJ: Okay. Actually the story with Duk-Hee Lee is really a fun story because I had written three papers with her before I met her. She is just an incredible vigorous and bright scientist. I got to know her through colleagues. You know, we English speakers control literature, for better or for worse. I am often called on for my English language skills, to help people who have written in a foreign language or have a native language other than English. We hit it right off because I not only fixed the English but I made a few comments on the first paper that we worked on. Ultimately she came to Minnesota and she’s been here several times and worked with me for months to years at a time. We’ve had a relationship in which we actually talk to each other by email now over the past eight years or something probably at least once a week. I think we have written something like 50 papers together. The way that the science came about is that she was interested in a variety of things and it turned out that our skill sets were complementary. I depend on her very heavily for ideas and she has depended on me heavily for logic of expression and various different ways of critiquing different ideas that she has, which are in epidemiologic or medical principles. I would have to say she is the leader of the team as far as this kind of work with the pollutants goes. Examining the Association Between GGT Elevations and Health Risks JB: Let’s go back to…it’s probably not the beginning because I’m sure I don’t really know the beginning, but I’m going back to my beginning in reading your literature, which is extraordinarily prolific. I want to compliment you just on the volume of extraordinary publications that you have authored with her over the last 10 years; it is quite amazing. Talk a little bit about gamma-glutamyl transpeptidase to begin with. That’s some of the first work that sealed this association between GGTP elevations in the normal range and health risks.10,11,12 It sounds like you must have had some presumption, or did that just jump out of the literature unexpectedly? DJ: You know, it has been a learning experience for me, and as I said, Duk-Hee is really the person who has motivated the specific scientific ideas. When I first met her she was dabbling in studies of hypertension and sort of things not being exactly the way you expect them to be. And when she came to Minnesota the first time, which must have been…I don’t know, 2002 or 2003 or something…she was very interested in oxidative stress. Now, we’ve had a study on oxidative stress-myself, and my colleague Myron Gross at the University of Minnesota, and Michael Steffes, again at the University of Minnesota-which is attached to our study, CARDIA, that is an NHLBI-funded study that’s been going on since 1985.13 We’re currently following people for their eighth examination. That’s been a big part of my life, and we have, as I said, an RO1 NIH grant to study oxidative stress. So I had some knowledge of oxidative stress. Duk-Hee was very interested in the possibility that GGT-I call it GGT rather than GGTP, I’m just used to its older name-was actually somehow or other involved in oxidative stress and was involved somehow through glutathione. So the function-sort of the biology-of GGT is that it sits on the surface of cells widely distributed through the body, and it facilitates the breakdown of circulating glutathione, which is three proteins, and then the transfer of those components back into the cell. The GST (glutathione) is reassembled and it serves as a primary antioxidant in the intracellular environment. So it seems as though somehow or other GGT would be important in that. We started studying iron, which is a very difficult area because free iron is so fleeting that you almost never see it, or perhaps never actually see it in vivo. But anyway, we went from the iron over to the possibility that GGT might itself be a pro-oxidant or might be somehow or other indicating a very high level of oxidation because of a lot of glutathione activity. Duk-Hee did the work on that (the preliminary/primary biologic reading). It was very interesting because GGT has primarily been thought of in two respects: one is a marker of alcohol abuse, which is really happening secondary to something like cirrhosis or fatty liver disease caused by high alcohol intake; or liver disease itself, and GGT is then thought of as a liver enzyme. Actually GGT, as I said, is scattered widely throughout the body, and it has these very important functions in maintaining one of the most important body systems, namely the intracellular antioxidant or oxidative balance. That was how we got into it, and, sure enough, when we started looking at the data, the data really perked up the epidemiologist’s eyebrows because it was a very strong finding and it seemed to go beyond the alcohol idea. It wasn’t just liver because there were other more specific liver enzymes (ALT and AST), and they didn’t behave the same way as GGT. So that’s really sort of our first findings and how we got started with that. JB: For those listening that may not be looking at their recent biochemistry, what I would want to remind you is that when you talk about an amino acid/glutamic acid (that’s the “G” in “GGT”), that most amino acids are alpha amino acids, so when we put a prefix “gamma” in front of “glutamic acid (gamma-glutamyl),” it raises the question: Why is a funny amino acid like a gamma linked? Of course, as Dr. Jacobs pointed out, in human biochemistry the only place that you have prevalence of a gamma glutamic acid is in that tripeptide called glutathione. This is what I think was a very skillful perception that Duk-Hee came up with because it seems that (having been a clinic biochemist for 30 years) there has always been this presumption that GGT is shed from a damaged liver just like ALT and AST in the case of an alcohol and drug abuse relationship. Now suddenly we start talking about the functional nature of that enzyme, GGTP (gamma-glutamyl), and its connection to glutathione. I think that was a really brilliant connection. And then you go to your epidemiological evaluation of NHANES. Can you tell us a little bit about that? And how did you come up with the POPs concept, to start looking at the correlation between persistent organic pollutants and levels in the serum of GGT? Connecting GGT Data to Persistent Organic Pollutants DJ: Right. I really appreciated that addition about the amino acids. There is another issue (just before I get to the POPs). When we measure just about anything in the blood-I mean even if we measure things in hair, toenails, urine-we’re looking for the lost penny in the best light. It’s hard to get to the cell surface and measure GGT or anything else (soluble ICAM is another great example that we are working with a lot). It is hard to get it in its natural environment where it is really working, so what we are working with is the circulating element, and why is it circulating? You know, it should be sitting on the cell surface doing its job. Nevertheless, I really do agree that Duk-Hee Lee is just brilliant and this was an amazing connection to make and it has been so much fun for me to watch it work and then look at the epidemiology. She was sitting around in her office in South Korea and thinking about GGT. We had another study which was prominent in the thought process, and that was that she was the biostatistician/epidemiologist/physician working with a steel company called POSCO in South Korea. So they had eight years of observations, and that included GGT.14 I think it was between ’96 and 2003, something like that. And what we showed was about 180{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} increase in GGT graded over time and independent of age during that time period. So the mean level of GGT in the beginning of the period was about 8, and I think it went up to a mean of about 25. Those are activity units for the enzyme. This was really surprising. At the same time in Korea, in the same people, the serum cholesterol went up by about 8{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, so the GGT was really changing fast. And she was wondering, now, what could it be that would cause such a rapid change and such a profound change over time? She was looking at various different delivery sources of some kind of a provocateur for this, and she finally came to, “It must be in the diet.” It had to be something that was changing rapidly and that was very commonly eaten or commonly exposed, so everybody in the population would get a fair exposure. She thought, though, that it probably was not the food itself because the records on that seemed to indicate coffee, meat, and fruit as the main factors that affect GGT. So it just didn’t seem as though it could be the food itself. The other thing which might have changed a great deal was these pesticides and other industrial chemicals, and then especially the ones that were persistent. Persistency in a chemical like this-we’ll take PCB, polychlorinated biphenol, or something (the abbreviations are easier to remember than the long words), or organochlorine pesticides, which have now all been banned since the late 1970s, and among this group also is dioxin (dioxin is the most famous of them and was used in Agent Orange to defoliate Vietnam, which was another unfortunate story)-these things enter into the body and then they sit there. They are difficult to metabolize. They are difficult to clear. They probably cause oxidative stress. They probably cause hormone disruption. But they just sit there, especially in fat tissue, and their half-life may be on the order of 10 years or more. Duk-Hee had done independent reading about those things, and she thought that they might somehow or other be connected to the GGT story. She’s very good at going back to the basic biochemistry textbooks and trying to understand the way that things work, far better than I am or will be. She drew a picture of another action of GGT, and that is in forming conjugates of xenobiotics with glutathione. It turns out that within the cell, in that particular reaction where you have some kind of a xenobiotic and have glutathione as transferase, which is a really important constituent of this whole antioxidant system, and GGT plays an important role, again, in disassembling the glutathione so that it can be conjugated with whatever xenobiotic it is. The xenobiotic conjugate, then, becomes water soluble and can be excreted in the urine. Now whether it would be the POPs themselves that would be so conjugated, which seems less likely, or they wouldn’t be persistent, or, say, the reactive oxygen species, which are developed because the POPs are sitting there and the body is complaining about it and trying to react to it, it sort of doesn’t matter. So we finally came to the theory after several years of working with this that the GGT is actually working not only as a marker of oxidative stress, but more specifically as a marker of the activity of the attempts of the body to clear some of these xenobiotics. Connecting Obesity and Type 2 Diabetes to Previous Research JB: This, to me, is such an amazing representation of discovery. This whole process of how you two collaborated along this path is fascinating because it takes us into part of the next chapter. Maybe it’s not the next chapter in your lineage, but in my thinking it is the next chapter, and that’s the connection between obesity and type 2 diabetes. If there is anything that had rocked perceptions about the origins of the relationship between type 2 diabetes and obesity it would be, I think, your sieving of epidemiological evidence from NHANES and looking at that connection and finding (I believe) that it was not a strong connection in the absence of a marginal elevation within normal range of GGT. Can you tell us about that next step, because this is just a fascinating journey into discovery? DJ: At least in our preliminary cross-sectional study of NHANES we had 2000 or more people, and I think we had 218 cases of diabetes that were prevalent (in other words, they existed at the time of measurement of the different POPs, persistent organic pollutants). There were 463 (I’m quoting these numbers by memory, so I may not be exactly right), but I think there were 463 people in the lowest quartile of the POPs. We actually took six POPs and we put them together, statistically, and so when I said a quartile of POPs that means that these were the people who had the least exposure to some combination of these six POPs, each of which had a pretty powerful relationship with diabetes. Among those 463 people, about one-third of them were obese, so a BMI (body mass index) over 30. There were only two cases of diabetes in those 463 people. One of them was in the middle BMI group (in the 25 to 30 group) and the 30-plus also had one, but that was a half a percent of the people who had diabetes, and overall, 218 people over about 2000 (it was about 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}). So in the top three quartiles, actually, I think we had 13{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} percent versus a half a percent in the bottom quartile of the POPs. As I just said, there was no gradient of the diabetes within that particular group of people who did not have very much in the way of POPs. Obesity has always been a difficult and an interesting thing to understand. The history of obesity and total mortality is a strong U-shape. And the history even with cardiovascular disease is sometimes on/sometimes off depending on the data set. For many years at the beginning of my career, we really thought that obesity was not a factor because if you regressed, say, cardiovascular disease on obesity and the triad of blood pressure, smoking, and cholesterol (sort of a Framingham score), the obesity would drop out of the model. Then over the years people got a little more sophisticated and they started to think that there are these secondary paths. So obesity causes hypertension. Obesity causes hyperlipidemia. It’s related to smoking in that the smokers are thinner, and when they quit smoking they tend to gain quite a bit of weight. So it is really, in a certain way, a marker of all these things. It is an indirect player, and similarly (perhaps) with diabetes. The third line of thought was that the obesity was actually sometimes leading to hypertension and hyperlipidemia and sometimes it was not. It’s a little hard to know, and now with this added concept…there are two added concepts, which are really important with obesity. One is that adipose tissue is not only adipose cells. The adipose tissue also contains adipose cells that have died, and those will then be quickly surrounded by macrophages, a similar mechanism for body defense as happens in atherosclerosis. The macrophage colony will be throwing off IL-6 (Interleukin-6) and a variety of other cytokines, so actually the adipose tissue is pretty interesting because it is more than just the adipocytes and the fat storage; it’s also storage of some decaying and inflammatory matter. The other thing is that there are lots and lots of fat soluble substances that we encounter, and so where are they going to sit? Well, besides the fat in the adipocytes, there are going to fat soluble substances, and the pollutants that we have been talking about are basically fat soluble. There are a lot of reasons for thinking that sometimes funny things are going to happen with obesity. I’m not a proponent of obesity, but I’m a little more skeptical, perhaps, having done some of this work. If people are actually burying POPs in their fat tissue, there may be a penalty for losing weight. It would be better to be thinner to begin with, to be lean all the way through your life, but if you do get heavier, maybe there is some penalty phase that you have to go through as you’re losing, and you would actually, then, be releasing these fat soluble substances. JB: For the clinician, as they start to make this kind of “aha” connection between the potential, let’s call it, “surrogate” biomarker of this relationship between xenobiotic accumulation and physiological function, it seems that your work would point us towards the direction of looking at what the normal range is. Because the elevation of these GGT levels that were associated with increasing risk of type 2 diabetes were within the upper quartile, I think, of normal, so what is normal range? What does it really mean? How Can Clinicians Apply GGT Data in Practice? DJ: We do have to be careful with GGT because, as with any lab measure, it has its range and its laboratory-specific value. Cholesterol, for example, is extraordinarily well-standardized across virtually every lab in the US, but there are different tests for GGT and different ranges, so absolute numbers are a little bit difficult, although I was citing some earlier. People typically talk about values such as 40 for women and 50 for men as being the end of a normal range. If you send a participant in a research study to a physician with a GGT of 60, they are going to say, “I don’t really know what to do with this. It’s got to be 2 or 3 times the upper limit of normal.” And then they are going to be thinking of treating liver disease, so they will be doing other liver tests and that kind of thing. What should you do with all this stuff in the normal range? I think that in many ways this research points to the connectedness of life and the connectedness of the organs within the body equally well. When I say connectedness of life, we really enjoy…say the flame retardants, which are brominated chemicals much like the chlorinated ones that we’ve been dealing with. And we enjoy the ease of eradicating mosquitoes, which might carry malaria. We enjoy the PCBs in out computers. We are so dependent on all of these things. The oil spill in the Gulf is directly related to all of this and how industrial we are. But it is not without a penalty; it is not without its risks. One of the risks is that the chemicals that we use are not necessarily compatible with life. We should be suspicious when we use a pesticide. If we have a chemical that is noxious to one form of life, then it also is going to do some kind or other of subtle damage to you. If we are going to put humans in a special place, let’s not forget that we are life forms and we have a lot in common with bacteria, for example, in that way. So this connectedness of life, we really have to be careful, politically and socially, about what we do. Maybe the physicians can be raising a hue and cry about this and saying, “Look, we have to be really careful about the way that we develop the technology and the way we use things. We do like our nice cozy lives, but we better be careful about how we are doing things.” I mean, I don’t know a medical solution to this. As far as the connectedness of organs, well, we were thinking liver, but what about the kidney? And what about blood vessels? And what is it exactly that insulin resistance is and where is the defect? Is it just in the pancreas or in the insulin receptors throughout the body? And so on, and so on. I’m not so sure what to say to a clinician. One thing I should mention-I think maybe we are running short on time at this point-but I want to mention that in our studies of GGT, it has not been as predictive, and maybe even not predictive, say, of cardiovascular disease and diabetes in the elderly. Once you get above 65 or 70 years old, the GGT seems to stop with its very powerful predictive capacity. Duk-Hee’s idea about this (not well substantiated, but she has a pretty good history of making really clever guesses), is that as we age we lose the capacity for good Phase II enzyme systems and clearing of xenobiotics and that sort of thing. Maybe that’s the case. So clinically, the GGT might be very helpful if you have a sort of standard measurement scale, and you have a 40-year-old person, and that person comes in with, say, a 45 or a 50 GGT. That might be something that you should be thinking about as a warning sign that this person may be on a path towards diabetes, or towards hypertension, or towards heart disease. If you saw the same thing in a 70-year-old person, maybe you would not and even say, “Why am I measuring this thing. It’s not really relevant.” That would be sort of the current status, I think, of the way that a clinician might use GGT. Does the Data Indicate Ethnic Variability in Relative Risk? JB: Let me, if I can given just the few minutes we have remaining, ask kind of a combination question. The scope of your involvement in looking at the field in a broader sense has been very, very large. Recently you were one of the authors on a paper, along with Dr. Lee, that looked at the association between certain genotypes that are associated with type 2 diabetes and how that might relate ultimately even into ethnic risks, the GWAS studies and type 2 diabetes Is there any ethnic difference looking at Koreans versus Caucasians? Do you feel that there are ethnic specificities of relative risk from what you have seen so far? In other words, certain individuals might have a higher susceptibility?15 DJ: Mostly I think that the differences among human beings are trivial compared to, say, the differences between our neighbors, the noble apes and chimpanzees. As a human species we are pretty alike. Nevertheless, when you look at the genetic information, you see lots and lots of single nucleotide polymorphisms that vary depending upon who you mate with. I like the term “mating pool” better than “race,” actually. There are some differences, and I think that they are mostly overblown. One of the interesting differences, though, is obesity and its relation to diabetes in Asians versus Caucasians. It seems as though, at a level or a body size that would not look particularly fat, the Asians are already developing diabetes at a much higher rate than we are. So far, the Asians have not been getting the level of obesity that we have in the West. But that does seem to be a difference. Now, could that have something to do with the POPs? I mean, that is very difficult to know. Duk-Hee has been starting to do some of these studies in Koreans. But the POPs take two or more mLs of blood, which is a huge amount in the world of covert studies that I live in. We save half mL vials. Sort of the money in the bank for these cohort studies is the vials-the blood vials-that are in the blood bank, and who wants to give up four of them to measure POPs? And then the other problem is that you need very specialized equipment and tandem mass spectrometry to measure the POPs, and it is like at least $300 a shot to measure these things. So it makes them rather difficult to study, and we are kind of waiting for the field to catch fire, where people reserve special aliquots and they say, “Yes, this is important enough to do it.” And maybe other breakthroughs are made and analytic methods so we can study them. But they are in very low concentrations. That, itself, is a big warning: that they could be apparently causing quite a bit of damage at very low concentration. So that’s that. Research on Whole Grain Consumption JB: Good. Let me ask one last follow-on question. You have also been very actively involved in looking at the relationship between whole grains versus refined grains and things like cardiovascular disease.16,17,18 Do you think there is any connection that you’ve seen in your work that might correlate dietary persuasions of whole versus refined grains plants, POPs, and diabetes? In other words, these diet persuasions, could they also translate into relative risk of exposure or something related to metabolism of these POPs, putting people at higher risk with increasing GGTs? DJ: Well, I said earlier that POPs are delivered by food, and I didn’t emphasize that very much, but they are in the fatty tissues, and since they are persistent, when an organism is slaughtered or it is carrying pesticides as a plant for us to eat, that is still there and it in fact perpetuates itself through the ecologic cycle. That means if POPs are delivered through food, even though they’ve already been banned, they are stuck in the food supply and that really messes up nutritional epidemiology. We used to think that nutritional epidemiology could be done with a table of nutrients, a list of food names, and you would know an apple is an apple, a piece of pork is a piece of pork, and you could study what you were eating. But now, with the recognition that POPs are in the food supply, and mercury and heavy metals are another really good example of the same kind of thing, or bisphenol A is another one that we are getting through plastics so it is in the containers that our food is contained in, it makes it very hard to know exactly what you are getting when you eat a food. Having said that about this sort of unfortunate disjuncture between POPs and nutrition, the work that I’ve done with whole grains led me in another direction, and that is to the concept of nutrient-rich plant foods in general. I was trying to think: what could it be about the whole grains that, in study after study, independent of who was looking at it, independent of the nature of the population, the people who were eating whole grains were having a lower risk? Of course, it turns out that whole grain consumption-the act of going out and looking for the whole wheat bread, or eating the oatmeal, or not eating the breakfast cereals that are made with refined grains, looking for brown rice, that kind of thing-it indicated a person with a high level of health consciousness. So you see all of the popular behaviors like if you would say to me or say to any random scientist, “What’s good for you?” The people who are eating whole grains are also, for example, taking vitamin supplements. Now I don’t think vitamin supplements are a good idea at all, but popularly it’s believed that they are. So they are also better educated. The women are taking hormone replacement, which is another thing that, in the past years, there have been questions raised about it, but say in the 1980s it was strongly believed that that was a good thing to do. They are more physically active. There are less smokers. So is it really the whole grains? I think it is the whole grains, and I think that it has to do with this rich layer of bioactive substances that the plant uses for its own survival, which is sitting on the outer layers-the aleurone layer, which is right under the bran in the grain. I think more generally that you have many of the same kinds of substances and you have the same idea of mechanical benefit should translate into human consumption benefit. So there are lots and lots of plant foods that work like that. Not among those plant foods is sugar. Why not sugar? There’s nothing wrong with sugar in a plum, for example, because that comes with everything else in the plum, and so it has been naturally organized by evolution for the virtue of the plum and the plum tree’s survival. That sugar is probably great, the same as everything else that comes with the plum. But the sugar which is just poured in great mounds into water and then served up as sugar-sweetened beverages provides a lot of calories and it provides none of these other nutrients that you would get, and the same thing would hold for refined grains because you’ve laboriously gone through and chopped off all the good stuff and you are left with a starch, which is not in itself bad, but it is not in its natural proportion and it is missing an opportunity, I say, to maximize nutrients per bite. It’s missing the opportunity to actually give the person a bunch of extra nutrients. And then another bad category would be something like french fries, where the cooking method is such that you are oxidizing the oil. You just heat it and heat it and heat it, and you get changes in the chemistry of the oil, and those changes are not necessarily so good. The margarine thing was another example of this preparation thing. It is kind of akin to the pollution chemicals in that we wanted to have margarine, we thought that saturated fat was bad for us, so we engineered something so we would still have the nice solid feel of butter, but, you know, it would be all vegetable oil. Unfortunately the hydrogenation doesn’t occur to any extent in nature, and we had a whole lot of isolated trans fats, which have become everybody’s whipping boy these days. So those are a few of the principles of nutrition that I’ve been thinking about in the last couple of years, and actually doing all that work in connection. The work on POPs has been very illuminating and a mind-opening thought process. JB: I think you said that beautifully. I’m struck, as I listen to you, thinking about all of the various secondary metabolites in plants and whole grains that modulate gene expression associated with these enzymes that you discussed earlier that have Phase II detoxification effect: quinone reductase, glutathione s-transferase, and so forth. This web that you described–this interconnectedness, these systems of biology–really argues for all of these variables you’ve been describing having some interesting symphonic orchestrated relationship. I think that’s a whole different view of the biology of life than probably many of us grew up with in our training, which was more compartmentalized, isolated, insular, and reductionistic. I want to compliment you. This work you are doing is just very pioneering. I’m hopeful that as you heard Dr. Jacobs’ story told by him and had a chance to let this process over your frontal lobes, you’ll recognize that this is not an esoteric topic. This is a very important clinical topic with really important clinical outcome potential. And when we tie that together with what we are going to be discussing in the September issue with Dr. Randy Jirtle, it frames a whole new step forward in the evolution of functional medicine  

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Bibliography

1 Dirinck E, Jorens PG, Covaci A, et al. Obesity and Persistent Organic Pollutants: Possible Obesogenic Effect of Organochlorine Pesticides and Polychlorinated Biphenyls. Obesity (Silver Spring). 2010 Jun 17. [Epub ahead of print] 2 King H, Keuky L, Seng S, et al. Diabetes and associated disorders in Cambodia: two epidemiological surveys. Lancet. 2005;366(9497):1633-1639. 3 Carpenter DO. Environmental contaminants as risk factors for developing diabetes. Rev Environ Health. 2008;23(1):59-74. 4 Fujiyoshi PT, Michalek JE, Matsumura F. Molecular epidemiologic evidence for diabetogenic effects of dioxin exposure in U.S. air force veterans of the Vietnam war. Environ Health Perspect. 2006;114(11):1677-1683. 5 Nichols BR, Hentz KL, Aylward L, et al. Age-specific reference ranges for polychlorinated biphenyls (PCB) based on the NHANES 2001-2002 survey. J Toxicol Environ Health A. 2007;70(21):1873-1877. 6 Grun F, Blumberg B. Minireview: the case for obesogens. Mol Endocrinol. 2009;23(8):1127-1134. 7 Soto AM, Sonnenschein C. Environmental causes of cancer: endocrine disruptors as carcinogens. Nat Rev Endocrinol. 2010;6(7):363-370. 8 Diamanti-Kandarakis E, Palioura E, Kandarakis SA, et al. The impact of endocrine disruptors on endocrine targets. Horm Metab Res. 2010;42:543-552. 9 Gore AC. Neuroendocrine targets of endocrine disruptors. Hormones (Athens). 2010;9(1):16-27. Review. 10 Lee DH, Silventoinen K, Hu G, et al. Serum gamma-glutamyltranferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28,838 middle-aged men and women. Eur Heart J. 2006;18:2170-2176. 11 Lee DH, Silventoinen K, Jacobs DR Jr, et al. Gamma-glutamyltransferase, obesity, and the risk of type 2 diabetes: observational cohort study among 20,158 middle-aged men and women. J Clin Endocrin Metab. 2004;89(11):5410-5414. 12 Lim JS, Lee DH, Park JY, et al. A strong interaction between serum gamma-glutamyltransferase and obesity on the risk of prevalent type 2 diabetes: results from the Third National Health and Nutrition Examination Survey. Clin Chem. 2007;53(6):1092-1098. 13 Lee DH, Jacobs DR Jr, Gross M, et al. Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Clin Chem. 2003;49(8):1358-1366. 14 Lee DH, Ha MH, Kim JR, et al. Gamma-glutamyltransferase, alcohol, and blood pressure. A four year follow-up study. Ann Epidemiol. 2002;12(2):90-96. 15 Son HK, Kim SA, Kang JH, et al. Strong associations between low-dose organochlorine pesticides and type 2 diabetes in Korea. Environ Int. 2010;36(5):410-414. 16 Jacobs DR Jr, Gallaher DD. Whole grain intake and cardiovascular disease: a review. Curr Atheroscler Rep. 2004;6(6):415-423. 17 Murtaugh MA, Jacobs DR Jr, Jacob B, et al. Epidemiological support for the protection of whole grains against diabetes. Proc Nutr Soc. 2003;62(1):143-149. 18 Pereira MA, Jacobs DR Jr, Pins JJ, et al. Effect of whole grains on insulin sensitivity in overweight hyperinsulinemic adults. Am J Clin Nutr. 2002;75(5):848-855.

Welcome to Functional Medicine Update for September 2010. We have been traveling together-those of you who are Functional Medicine Update listeners or readers-on a very interesting journey over the past year and a half. And that journey is looking at what previously would have been considered almost antithetical to good science, that is, that our characteristics are totally controlled by our parentage through the traditional Mendelian genetic mechanisms (this dominant and recessive pattern of ancestry that we are all so familiar with). Laid on top of that now is this “new old” concept that there is this imprinting of genes that we call epigenes, resulting in epigenetic changes that then regulate the way that our book of life is expressed as a consequence of exposure in the environment, starting at the moment of conception (and maybe even pre-conceptionally) and continuing all the way through the fetal development period and then into life. These particular marks that we call epigenetic marks-the methyl groups on the CpG islands–regulate the way the genes are expressed (the so-called “silencing” of genes), or the acetylation of our histone proteins. The book of life is opened at certain chapters, which are read as an expressed pattern. I’m laying out a fairly broad platform, philosophically, as we get into this issue of Functional Medicine Update. What I really want to talk about, from this platform, is how nutrition, lifestyle, and environment can influence developmental epigenomics. I want to talk about how that ultimately may give rise to increasing relative risk to certain diseases, and how those diseases may cluster much more rapidly in populations than we would have predicted on the basis of not having to wait for selective natural selection occurring over long periods of time. Could disease prevalence change very rapidly in a population over time as a consequence of epigenetic changes? I am talking about things such as autism, or attention hyperactivity disorders, or atopy that leads to asthma, or other conditions where we have seen very dramatically significant changes in prevalence that we can’t really account for on the basis of the genes changing. Epigenomics Applied to Metabolic Disorders With that platform in mind, let’s apply this concept to metabolic disorders. Metabolic disorders are probably the most rapidly rising family of age-related disorders that associate themselves with chronic disease and burdening of the healthcare system. These are disorders that used to be found only in older-age individuals and are now starting to be seen in younger-age people. The classic example is what we used to call adult onset diabetes. It was called that because only older people seemed to get it. As the condition started to be seen more frequently in adolescence, the name changed from adult onset diabetes to type 2 diabetes. It is now a condition with rapidly increasing prevalence in younger people. Why? Have genes changed to the extent that we have undergone mutational injuries? The answer is probably “No.” But maybe has there been an epigenetic modulation of the way genes are expressed? That answer is possibly, “Yes.” If that is the case, can we do anything to correct the epigenetic marks, and silence the genes that we don’t want expressed, and open up for expression those genes that lead to proper insulin signaling, and inflammatory signaling/glucoregulation? Research Indicates Chronic Disease Can Start in utero Those are very interesting broad questions of health in the public. What about genomic-related issues in the individual and how nutrition he or she is exposed to actually starts in utero and may influence the rest of the course of his or her life? What we are starting to see suggested from some research is that a lot of chronic age-related diseases may actually start epigenetically in utero. With this in mind, we might consider a condition like type 2 diabetes to be a conditionally essential nutritional epigenomic disease that has a long latency period. The latency period is decades, not months like you would have in some infection diseases, or weeks or even days with some very virulent types of infection. But the onset of the disease occurs over decades; slowly but progressively the person becomes type 2 diabetic and may develop cardiovascular disease at a later stage. Not only are metabolic disorders among the fastest growing health problems worldwide, they also have a tendency for manifestation at earlier ages. There seems to be a higher rate of these metabolic disturbance-related issues in women than in men. By 2020 the number of patients with diabetes is expected to increase to 350 million people worldwide. Obesity now affects between 30 and 80 percent of adults according to a recent World Health Organization European Region study. Also according to this report, up to one-third of children were already classed as early-stage obese. Unfortunately, more than sixty percent of children who are overweight before puberty will be overweight in early adulthood. Women with diabetes and obese women are sub-fertile, and we know the frequency of polycystic ovary syndrome and anovulation and fertility issues (reproductive biology) is adversely affected. And women with diabetes have a higher risk for spontaneous abortions and congenital malformations in their offspring. Looking at data, increased BMIis associated with adverse effects on lactation and mammary tumorigenesis. Set against this context of a worldwide epidemic is the increasing rate of overweight individuals who have imbalanced nutrition in women of childbearing age. According to the WHO report, in a recent study 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of women in France and 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of women in the United States were found to be in a nutritional status that could predispose a fetus to subsequent metabolic and epigenetic misprogramming, and thus lead to common adult disorders that includes things like metabolic syndrome, type 2 diabetes, and cardiovascular disease. This is almost like an epigenetic nutritional epidemic that we’re talking about.1 The developmental origins of adult health and diseasepotentially tying back to fetal origins was actually first hypothesized in the 1990s. According to the same article featuring the WHO data, there is compelling evidence that specific ontogenetic changes, such as prenatal development and early childhood could be an obesogenic environment. This environment could then program children to go on to express obesity and obesity-related metabolic disturbance disorders like type 2 diabetes in their phenotype. It’s not that these children have the genes, per se, for obesity, or the genes for diabetes. Rather it is that the obesogenic environment in utero created a milieu that then altered genomic imprinting to result in the expression patterns, postnatally and over time, of a sequence of events ultimately associated with obesity, heart disease, and diabetes. These trends are continuing and that is bad news. The good news is that if this model that I have just proposed is correct, this is a reversible trend. By doing the right thing, you can alter the epigenetic marks that are put on the genome during fetal development at these labile regions that interrelate with disturbances that we call metabolic diseases, and prevent these diseases from being manifest. Some research has indicated that epigenetic effects induced during the perinatal period produce persistent development adaptations in structure physiology and metabolism. Animal work in this field has been published over the last decade. How does an adult organ’s genome retain the memory of the intrauterine (or early life) exposure long after the exposures have been taken away? I have discussed bisphenol A as a potential obesogen that may have effects on imprinting the genome epigenetically in the fetus in such a way that it alters, in the fully developed organism, expression patterns of various physiological or metabolic functions that are associated with disease. It could be the chemical environment. It could be the nutritional environment. For instance, women, if they are folic acid deficient/methyl deficient upon conception and during pregnancy, can undermethylate and that can lead to increasing risks to the silencing of various genes. When expressed, these genes can lead to increased malformations, like spina bifida cystica, or anencephaly, or altered kinds of conditions related to the expression of oncogenic potential that could lead to increasing risk to cancer. These methylation patterns play roles in regulating, epigenetically, the expression of function in the adult after birth. And those methyl groups are, to some extent, dependent upon the availability of s-adenosylmethionine, which, in turn, is dependent upon the adequacy of the methylating nutrients (folic acid, B-12, B-6, betaine) in the periconceptual woman’s diet. All of these things are potentially starting to cause us to change our view of changing disease patterns occurring in our population at a fairly rapid rate, not just in the United States but globally.2,3 The important thing, as I mentioned, is that these epigenetic marks are flexible; it is possible both to put them on and to take them off. By altering environmental, nutritional, social, cultural, and hormonal factors, and by changing drugs and toxins, you can alter the epigenetic landscape during this spaciotemporal window in which tissues are being formed and differentiated, and ultimately leading into a sex-specific phenotype. This is why females might have possibly higher sensitivities to some of these epigenomic regulators than males; it is a consequence of the differentiation of their developing endocrine system. Alternatively, other alterations of epigenetic marks can lead to irreversible changes in lineage specification in the deviation of a cell type determination, which could lead to oncogenic potential and increasing risk to cancer. It could also result in, as I said, long-term latent periods that don’t express until late teens, 20s, or 30s as a disease that has come from that dysfunctional phenotypic expression pattern. I think these are very remarkable concepts that are more than theories. There are adequate information and data to support doing evaluation of the epigenome and looking at aspects of methylation or promoter regions of genes. Researchers are looking at histone acetylation in genomes and actually correlating, in animals and humans, altered states of methylation with health outcome.4,5 I believe that those individuals who are holding on to believing the fixed mechanism of disease causation is locked inextricably in the genes are making specious presumptions and are way too rigid in their views. As I said, as we learn about systems in life more and more, things seem to be in-between two polar opposites. Rather than being black or white, we’re most often in some degree of gray, and that gray can vary in shade depending upon the environment. How do we appropriately regulate the epigenome? Many of the epigenetic marks that are laid down during fetal development actually appear to be transmissible into the next generation through reproduction. So regulating the epigenome may not just be about influencing the initial generation. There may be a transmissibility factor that moves into the next generation in the absence of something changing those marks. I am reminded of Lucille Hurley’s work at the University of California at Davis that was done some 30 years ago. Epigentics might have played a role in her work on zinc. In her study, which was an animal model, she deprived the mother of zinc during the early stage of pregnancy (not to be frankly zinc-deficient so that the mother would be in serious compromised/imminent death, but marginally deprived).. The offspring of that mother that was marginally deprived of zinc had immune dysregulation; they were more allergic and they were more atopic. If that was continued on for another generation, it got progressively more severe. This sounds a lot like the Pottenger cat studies, doesn’t it? In the 1930s in California, Dr. Pottenger was rearing cats on cooked meat and milk and showing that they developed allergic phenomena. He was able to produce, actually, the first arthritic cat by subsequently feeding three generations of this-what he called-“devitalized” food to the animals. Lucille Hurley’s work seems reminiscent of Pottenger. I In her controlled experiments it took three generations of repletion of zinc to bring those animals back to the same immune competence as the initial mother.6 How long does it take to correct epigenetic marks that are laid down? I don’t think we have a simple answer because it depends on the mark, its location, in what tissue it is found, and in what period of development it was altered. There are myriad complicated variables that might change, to some degree, the way we answer that question. I think what we can say is that certain marks that are laid down can be taken up, and other marks can be laid down over time. That would be things like altering the environment, wouldn’t it be? This concept is about asking different questions to get different answers, not just rearranging the deck chairs on the proverbial metabolic Titanic. It is about making the appropriate changes by changing the exposure to certain xenobiotic chemicals (for example, moving away from some of the xenoestrogens like the dioxins and some of the bisphenol-A-like compounds that influence hormonal development epigenetically), and changing dietary exposure to obesogens, the environmental epigenomic nutritional programming agents. It is also about improving the presence of adequate nutrients that are necessary for control of proper epigenetic programming, like the methylating nutrients and also things that control histone deacetylases and acetylation, such as butyrate in the gut.. Clinical Utility: Asking Different Questions Could Lead to Different Answers What I’m really saying is that asking different questions could lead to different answers, which could then alterepigenetic programming. From a functional medicine perspective, I think this is quite an interesting topic that has clinical utility. We talk about function being the result of the interactions between genes and the environment. The environment could be things like exercise, work, stress, toxin exposure, lack of life fulfillment or love, lack of attribution, poor quality diet, or it could be exposure to cigarette smoke or lead. All these various factors are modifiers (maybe we should call them biological response modifiers) that alter the way that gene pluripotentiality is converted into the phenotype (either the healthy phenotype or the not-as-healthy phenotype). But now we have a weigh station, or a weigh point, along the road. We’re saying it is not just modulating the metabolism, in and of itself. It is actually modifying the way that the book of life is read into metabolism. We have to look at the genomic, proteomic, and metabolomic factors all working together to give rise to the phenomics-the outcome of that individual-that is expressed over time as they grow older, and go through their developmental cycles. We can have long-latency chronic diseases where the root origin started at much younger age and we just didn’t know it. This is a concept Robert Heaney talks about. He is the professor of endocrinology from Creighton University Medical School, who recently received the McCollum Award from the American Society of Nutrition, the United States’ most prestigious nutrition investigator award. Dr. Heaney talks about long-latency nutritional inadequacy diseases, like osteoporosis. You don’t get osteoporosis overnight if you don’t get vitamin D and calcium, but over time it expresses itself. Similarly, you don’t get diabetes immediately as a consequence of altered insulin dysregulation; you get type 2 diabetes over a period of time. Similarly with coronary heart disease. Maybe even similarly with certain forms of cancer that may take 20 years from the root origin of change at the cellular level to be finally expressed as a diagnosable cancer. All of these things, to me, are very important. The vitamin D story is a good example of this concept. Vitamin D, as we have talked about in previous issues of Functional Medicine Update, influences nuclear orphan receptor effects and the expression of many genes. People have been in debate about exactly how many genes are turned on as a consequence of 1,25-dihydroxyvitamin D3 activity, but it is certainly tens of genes that are modified in their expression when 1,25-dihydroxy D3 hybridizes with things like triiodothyronine, or the retinoic acid receptor, or even retinoic acid itself. It then activates specific genes, that then produce mRNA (messenger RNA), that then are converted into certain levels of active proteins, that then undergo post-translational modification to form active proteins, and then alter metabolic function and cellular phenotype. That particular sequence of events that I’ve just described is ultimately tied back to an environmental factor called the sun. Photobiology. Lack of exposure to the appropriate wavelengths of light in the skin (and depending upon the skin color) converts dehydrocholesterol ultimately into 25-hydroxyvitamin D3, which is produced by hydroxylation in the liver, and then that gets further hydroxylated to 1,25-dihydroxy. It can either happen in the vascular endothelium, or it can happen in the kidneys and brain, and then ultimately has this hormonal regulatory effect on gene expression. We might consider, then, that the environment-in this case, exposure to appropriate wavelengths of light so that the skin can make this material (this vitamin D material)-coupled together with the fact that that material ultimately regulates both gene expression and has effects on epigenomics as well, may set in motion a new set point in physiology that is passed on (a transmissible factor) to the next generation. You might have one generation that has a temporal vitamin D insufficiency that has increased risk to, say, certain neurological disorders or autoimmune disorders (for instance, multiple sclerosis, which has been connected with vitamin D inadequacy).7 But that effect, if it occurred in pregnancy, could then influence the epigenome of that offspring, which then maybe sets in motion a different regulatory effect upon the offspring. It is my belief that these conditions that we often see that seem mysterious, where disorders pop up with greater frequency, are not solely a consequence of better diagnosis. I’ve often heard people talk about the increasing frequency of autism being because we are more attuned to it and we have better diagnosis, but I think it is also a consequence of these epigenetic changes that are occurring that can regulate over time how genes are expressed. This field is so complicated because we are talking about low levels of environmental chemicals that might have influence. We are really talking about levels that are at the threshold of our ability to even analyze them in materials accurately. How do these levels interrelate with levels of other things? Is there an orchestration effect on epigenomics, so it is not just one chemical at a time, but it is multiples at a time? In systems thinking, it is very difficult to unequivocally answer the question of one agent against one outcome. That in itself is challenging, but when you add two agents against an outcome, or three agents, the relative complexity of proving a hypothesis goes up exponentially. It becomes virtually, in atomic theory, impossible to solve unequivocally the three-atom story as to exactly understand the energy of interaction among three atoms together through fundamental theoretical chemistry background. I think we have the same problem when we start looking at chemicals in the environment at low level coupled with altered photoreactivity because of the use of high SPFs in sun formulas, coupled with increasing exposure to heavy metals, coupled with altered stress patterns. I could go on and on with this story. How do you tease out all those variables but still, as you tease them out, keep the integrity of the system because it is an interacting system in your study so that you actually have something that is realistic, when you’ve actually concluded your study, about what’s going on in life? These are the complicating factors of unequivocal proof of concept, but I think that even in the absence of a complete understanding of how to prove that the system of these interacting variables has a different effect than each individual variable we’re able to start understanding that the impact of a changing environment is much more profound, not only in the immediacy of function of that organism, but on the subsequent generations than we previously ever understood. We’re going to have the privilege, in this month’s clinician/researcher-of-the-month interview, of going back some two years after we had an “aha” on Functional Medicine Update by interviewing Dr. Randy Jirtle, who, with Bob Waterland, was credited-and justifiably so-with making the principal first discovery in the field of nutritional epigenomics. Dr. Jirtle’s research group did folate and B12 high-level supplementation experiments in Agouti mice (white fat mice). If they did the supplementation early in pregnancy of the mother, the offspring of those mice, for the first time, didn’t have white fur (they had a mottled pseudo-Agouti fur color). And the other interesting thing is the offsping-although exposed to the same ad lib animal chow of their parents-didn’t get fat, they didn’t get diabetes, they didn’t get cancer like their parents did frequently, and they lived longer, without changing their genes, just changing the epigenetic marks due to methylation changes. That observation, and the photographs of those animals, and the reproduction of that work by many labs around the world has virtually revolutionized our thinking. All the things that I’ve talked about came out of this “aha-ism” from Dr. Jirtle’s group. Dr. Jirtle was one of the principal people described and interviewed in a recent Time magazine article on epigenetics published in January 2010.8 How long does it take to understand and accept the implications of this kind of a paradigm-shifting discovery? That’s what we are going to be discussing with Dr. Jirtle. It’s wonderful to go back and revisit with him at what should be the richest time of his life, the most fulfilling time, a time where this field, with Michael Skinner, who we also interviewed, looked at the effects of pesticides on epigenomics, or looking at the work that hormesis plays on epigenetics (very low levels of substance that produced much higher outcome than we would have expected in terms of changing biological function. That was Dr. Edward Calabrese, you recall, that we interviewed on hormesis (the kind of father of hormesis). How has this all evolved over the last couple of years as the field has virtually exploded in interest? I’m very privileged to have a chance to go back and revisit with Dr. Jirtle about his extraordinary contributions

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INTERVIEW TRANSCRIPT

Researcher of the Month Randy Jirtle, PhD Jirtle Laboratory Environmental Safety Building Duke University PO Box 3433 Durham, NC 27710 www.geneimprint.org Here we are once again at our Researcher/Clinician-of-the-Month section of Functional Medicine Update. Some of you may remember Dr. Randy Jirtle. The chance to speak to him exactly two years ago, in September 2008, concerning his pioneering work on epigenetics, and how it is shaping much of what is happening at the frontier of biomedicine today was, I thought, a “goosebump” experience. He and I were speaking briefly before we got into today’s interview, and I was saying that these interviews with people who are shaping the new medicine is like being in school for me. I’m challenged by the best minds, the people who are really thinking out of the box, the people who somehow have the courageous ability to cross lines despite the possibility of people saying, “Well, you’ve just stepped out of your discipline, and now you are stepping on somebody else’s turf and you should know better.” Randy Jirtle is certainly one of those individuals. As I look at his background, I’m quite amazed that he started out with a BS in nuclear engineering. He then moved to his MS in radiation biology and his PhD in radiation biology with a minor in statistics. Now he is a professor in radiation oncology at the Duke University Medical Center and a world-renowned expert in epigenomics/epigenetics. How does this all fit together? I think that’s probably where we want to start. Dr. Jirtle was the principal person featured in a 2010 article in Time magazine that was titled “Why You DNA Is Not Your Destiny.” That was the January 6, 2010 issue. I’m so vicariously proud to see Dr. Jirtle, himself and his work, so prominently displayed in that article. Dr. Jirtle, let’s start. Maybe you can help us understand. How does a person who goes down the track of nuclear engineering into radiation biology ultimately get into epigenetics? RJ: To me it makes sense because, you know, I’ve lived it. But I know to a lot of people it wouldn’t seem to make very much sense. In 2006-it was a big honor-I was given a “Distinguished Achievement” award back in the School of Engineering at the University of Wisconsin. Because of that, actually, some interesting things happened. For one, my daughter is now a student at the University of Wisconsin because of going back there and seeing the university. If I would have told her, “You might want to consider going there,” I have a feeling I probably would have been told, “No.” So that’s a positive thing. I said to a friend of mine, “You know, this is very interesting because I never practiced a day in the field of engineering.” I was changing already when I was at the end of my career. I did well in engineering, but I knew I didn’t want to stay in engineering to do research as a standard type of research. And at that time, there was no such thing as bioengineering. And my friend said, “If you really think about it, what you really did is you actually did do bioengineering before it ever was around.” He said, “That more than likely is why the engineering school finally recognized what you have done and maybe why you have done it because now most engineering schools have very big strong bioengineering departments.” That make some sense to me, and how we got into epigenetics is another one of those “Ys” in the road. When you come to them, Yogi Berra said, “Take it.” We took that road back in the early 90s and we identified the IGF-2 receptor as being a tumor suppressor gene. I think it was 1991, and Denise Barlow, who was at Vienna at that time, identified that gene as being the first one shown to be genomically imprinted. That imprinting process involves epigenetic silencing, so it was at that time that I decided we would move our whole research program into the field of epigenetics, because it was clear to me that we were essentially talking about programming of a computer, and I have always liked computers, so I finally felt like I had gotten home. JB: To me that is the definition of courage: following your intuition, shrugging off convention and maybe even recommendations from your colleagues, and staying the course. You know, you push everything up on the board of life and then you make it happen. Thank goodness for all of us that you made that decision. What has followed, as we described briefly in our discussion back in 2008, is quite remarkable. In this recent article in Birth Defects and Research in Clinical and Molecular Teratology (this was in the June 21st issue) that you co-authored with Bernal, you really, I think, in the introduction of that article, say some things that are not just exciting, they are truly paradigm-shifting.9 So many of the things that we thought were facts and immutable–things that we took tests on when I was back in molecular biology and molecular genetics in the 60s-are now being set aside. I’m going to quote from the article: “Through DNA methylation, histone modifications, and small regulatory RNAs, the epigenome systematically controls gene expression during development, both in utero and throughout life. The epigenome is also a very reactive system. Its labile nature allows it to sense and respond to environmental perturbations to ensure survival during fetal growth. This pliability can lead to aberrant epigenetic modifications that persist into later life and induce numerous disease states.” I’ll stop there. That collection of words, to me, represents a landscape of change that is truly remarkable. Can you summarize for our listeners what’s meant by that? It’s just profound to me. RJ: First of all, when you read it back to me I was thinking that I should have put a period in there somewhere! JB: It may be the way that I read it! The Epigenome as a Programming System RJ: As I said, it’s a programming system. We have one genome, half of it comes from the mom and half of it comes from the dad. I think of that as sort of like being the hardware of a computer. That’s the analogy I always use. But we have 250-300 different cell types, so how do you get those different cell types? You have to tell each cell how to work, and that working system, which we collectively call the epigenome, that’s the software that tells those cells how to behave and work once that developmental process has occurred. A liver cell doesn’t have to have tissue bumping up against tissue to make it into a liver cell every time it divides; the program has been set during that very early developmental stage. As a consequence, you can even take a liver cell and put it into culture and it still remains a liver cell. So you have a programming system, just like you have in your computer, that allows that to occur. But once you start using-in effect-software to control cell type and what a cell does, now you’ve got a system that is intrinsically more labile than the physical hardware of your computer. It doesn’t mean, for example, that a hard drive couldn’t go out or even a chip couldn’t go out, but it is much less likely that that is going to be problematic and cause problems for your ability to use your computer than when you get a glitch, or a bug, or something (a virus, for example) in your software. So it is a labile system. That labile system has pluses and minuses. It also allows that cell, now and during development, to respond to early environmental changes. You don’t have to rewire something hardware-like to change the way it works; the environment can do that to a certain degree. I’ll stop there because often I talk sort of in a run-on way. I want to have you add your comments to that. JB: I think that the takeaway that I’m starting to better appreciate and understand from your work is that there are many variables that early development can be exposed to (early fetal development can be exposed to) that can modulate or imprint and result in different functional phenotypes that may last a lifetime. We had the opportunity to interview Dr. David Jacobs recently about his collaboration with Dr. Duk Lee. I know you are very familiar with their work around environmental exposures and the influence that they have on later-stage chronic disease. It seems that much of what they are observing, to me, is really overlapped with the epigenomic imprinting that you have discovered. Do you feel that there is kind of a convergence between these two schools of research? Overlap of Research with Dr. David Jacobs and Dr. Duk-Hee Lee RJ: Yes. These systems didn’t evolve to give us problems. You know, scientists…I guess this is maybe a negative…we think somewhat critically and therefore you think always negative about the bad things that happen. But this system, when you are allowed to, for example, respond to the environment, it enables the developing offspring to potentially set itself up to better function in the world that it perceives it is going to be living in. The problem that we see now, particularly-and this happens with all species because any time you have differentiated cells you’ve got to have some sort of programming going on-is that there is a perception in many societies when you are in utero that you’re going to be in an environment of low amounts of nutrition, etc. But we’re finding now that we’re in the land of plenty, so what is becoming epidemic throughout the whole world, not just in the United States or Western culture, are the problems of obesity, diabetes, and increased incidences of cancer. It is a mismatch that appears between what was perceived to be the environment that we are going to live in and the environment we find ourselves in. It is probably one of the first times–or maybe the first time–that’s ever happened because usually an overabundance of food is not what our species has encountered. JB: Let’s take a specific example. I know you have authored a number of papers that have discussed this, and this subject is also related to things that Jacobs and his group with Duk Lee have looked at, and that’s environmental exposures to things like bisphenol-A, which is an epigenic-marking substance, and it would be an epigenotoxic effect with BPA.10 But you’ve also found, at least in your animal work, that you can ameliorate some of that effect of BPA on the epigenome by supplementation of the pregnant animal’s diet with methylating nutrients or with genistein from soy. Could you tell us a little bit about that? RJ: To me, this is the hopeful part of this whole story. Hippocrates said two millennia ago, “food is medicine,” and that’s what we, in effect, have shown, at least with these doses of exposure to bisphenol-A and the doses of supplements that we used in this animal model. I say all of that because epigenomes vary greatly between species, so the ability to potentially extrapolate between species is going to be a little bit more difficult, I think, than extrapolating mutational effects between species. I really think that this whole field of epigenetics is very positive because it demonstrates that there is the possibility of preventing many of these problems, and that’s an extremely hopeful situation because if you have a mutation and you inherited it, you can’t change that mutated base back to normal, whereas we potentially can alter epigenetic programming, or even potentially, when the programming is there, reverse it. This is prevention, and I think this is what we are going to start seeing people think about and do much more than they have done in the past. JB: Let’s take an example in an area that I know you’re a world expert on, and that’s the whole oncology area. Let’s look at Mary-Claire King and BRCA1 and 2. I’ve had the privilege of speaking with her as well. I think she’s a quite remarkable person on a lot of levels, both as a molecular geneticist and also as kind of a scientific philosopher. She made the observation-I think she even stated this in one of her papers in Science magazine a few years ago-that in the late 60s/early 70s, women who had the BRCA1/2 homozygous recessive “bad luck of the draw” would go into the phenotype of having the probability of breast cancer somewhere around 50-plus percent.11 RJ: Right. Can Epigenetics Be Altering Disease Penetrance? JB: But with that same genetic characteristic now in the 2000s (the early 21st century), the expression and penetrance into the phenotype is like 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. So the genes have remained constant, but their expression patterns have changed dramatically. I know you’ve looked at some of the epigenetics. Do you think there is a factor of epigenetic silencing that controls the expression of things like BRCA1 and 2, which we consider almost immutable deterministic cancer genes? RJ: Yes. I get this often, but the way you stated that is really beautiful because you get goosebumps truly thinking about this. We always think about the percent of the people that get (or have) the problem from inheriting these mutations, but we often don’t think of the other side. In other words, there is a certain percentage of people that, for some reason, don’t have these problems even though they have the mutations. People have thought (scientists have thought) that there have to be “modifying” factors that in effect, as you say, reduce the penetrance of the mutation. In other words, you have the mutation but you don’t see the phenotype. I think many people thought that these modifiers (again, why they worked or didn’t work) was because of mutations. In other words, there is something else that is modifying the effect of having the mutation in the BRCA1 and BRCA2 genes, and that something else (let’s say a gene product or something like this) that, again, is mutated or not mutated and that’s why you have this variation. But the other possibility is whatever these modifying factors are, they could literally be controlled epigenetically. So now you have the potential of altering penetrance not by changing at all the BRCA1 and BRCA2 mutations, but changing the expression of the modifying factors, and you could do this very rapidly, and with high probability through a population, through epigenetic phenomena. Whereas you would never be able to see that with that great degree of effectiveness by causing mutations in those modifying factors. You just wouldn’t see it because you’d have to inherit, again, and usually these mutations are recessive, so you would have to have two of them come together to have an effect. You can see what I’m saying. It doesn’t fit very well with Mendelian inheritance. With epigenetic phenomena, particularly if you can even pass that forward from generation to generation through the gametes, you could very rapidly cause a very marked effect on the ability of this BRCA1 and BRCA2 mutation as causing a problem. JB: Now you’ve really opened Pandora’s box with me, so bear with me. I’d like to follow-on several of the thoughts you just left us with. You very gently and graciously talked about what I guess we would term “transgenerational epigenetic transmission,” which in the face of strong Mendelian thought sounds a little like what I would call an adaptation. Or it sounds like things that we were told in genetics just didn’t happen. Is there evidence supporting this transgenerational epigenetic transmission? Evidence for Transgenerational Epigenetic Transmission RJ: Definitely in plants and in insects. It is very clear that this is the case where things have been through for tens to hundreds of generations: variegations in plants, structure of the flowers, eye colors, and different types of things that you see in fruit flies, for example. These are epigenetic and they are passed forward from generation to generation. There is no doubt about that in these species. The problem is it is not quite as clear whether you can have these types of inheritances occurring in mammals. I think, for example, with the Agouti mouse model that we used, where you have this coat color change, there is evidence that even in this model that this information is passed forward from generation to generation. But it is not as clear, I don’t think right now, at least not at this point, that you have this transgenerational inheritance in mammals as you see in other species. JB: Looking back just historically for a moment, I think Jean-Baptiste Lamarck and Darwin were contemporaries, or at least close in age or close during the period. Why did Darwin so predominate in his concept and Lamarck look like an artifact? RJ: I’m not really sure. I’m not an expert in evolution, but I don’t believe that Darwin totally dismissed Lamarck’s theories back when he was writing, but for some reason they just didn’t catch on as readily. Maybe it was because of Mendel’s work at that time and that people focused more on the mutational aspects of things rather than these programming changes. You’ve got to remember, 30 or 40 years ago when you didn’t know how something worked you’d say, “It must be epigenetic,” which basically meant, at that time, that you had no clue what it was so you just threw it into that box. That gave sort of a bad name to the whole field, plus there were political things that occurred, too, that went against Lamarck-type theory that people didn’t like. But now that we have much more information about how these programs are controlled by DNA methylation, histone marks, etc., this field has gone forward very strongly, and I think that has helped a lot; it is not discredited quite as much. JB: If we look at this imprinting that you are talking about, and let’s go specifically to methylation for a second, one might consider silencing of genes, if it is an oncogene, to be possibly a good thing. But then one might say, “But hold it. If you methylate and silence the promoter region of a tumor suppressor gene that might be bad.” How does one address that philosophical conundrum? RJ: Yes. The problem with everything in this whole filed is dosage and timing. In terms of what might be good at a low dose, I use the analogy of a glass of wine or two a day might be good for your cardiovascular system, but a gallon a day probably isn’t. And the other thing is that there are particular times in our lives when we are more vulnerable to changes that could be deleterious than other times, and particularly, I think, from the standpoint of tumor suppressor gene inactivation in cancer. This is a disease of the aged, primarily, so as a consequence, having high levels, let’s say, of folic acid in our flour has been shown to be very good from the standpoint of reducing neural tube defects. But at the same time, for another population of people that are here which is people that are older, it could potentially increase their chances of getting cancer by epigenetic silencing of the tumor suppressor genes. I don’t know how you get out of this problem because not one set of clothing, basically, fits all people. JB: That raises a question for me. You and I just touched upon this two years ago in our interview, and that was that the fetal genome is very susceptible (open) to epigenetic imprinting, so in the first trimester it is critically important to make sure you prevent bad exposures to the fetus, and get the right nutrition and the right balance. But then we talked about the question, “Are there labile epigenomic marks that later in life can still be manipulated by an altering environment, or is it that once set in the fetus it is locked in and immutable?” I know you have come quite a ways in the last two years in the field in understanding what is and what is not labile as we get into a fully developed offspring. What is the status today? RJ: From the standpoint of the Agouti mice, the question I get often is, “Can you affect coat color, let’s say, after an animal is born?” In other words, if an animal is born yellow, which means that little bit of DNA that is upsteam of the Agouti gene, during early development, wasn’t methylated, and as a consequence the Agouti protein is produced all over the body and gives rise to a yellow coat. In those animals, if you continue them on a high-methylating supplement in the diet, could you gradually change that coat color to brown, for example, in this model system? We have not done those studies, but I have talked to a colleague of mine about it. I don’t think this has been reported. He asked, “Have you ever done that?” and I said, “No, because 21 days after they are born those animals are gone because animal care costs are high so we don’t keep them for long periods of time.” But he said, “We did.” And he said, “I’ve taken pictures of them.” And he said, “When you keep them on these high-methylating diets, you can see that the coat colors gradually start becoming browner and browner,” suggesting that you can alter these epigenomes even after birth. That hasn’t been reported and I have not personally done it, but that is one set of observations that suggests to me that you can change things even later in life. Whether you can change it with the kinds of things that we can ingest or if you have to use different types of compounds that are much more effective in doing this I’m not sure. But we know we have epigenetic therapy for cancer, so there we are causing changes in the methylation patterns after the tumor has developed. You can release those methyl groups and, in effect, induce tumor cells to commit apoptosis and die. So I think it is probably true that one could do these types of things also in a normal individual. Maybe it is one of the reasons why we do have increased incidences of cancer. If we’re not maintaining our epigenome properly, we might ultimately have problems. All of these issues just have not been addressed yet very well. We’re just starting. I think with the tools that we have right now for looking at the epigenome-the sequencing tools, basically-a lot of these questions are going to start becoming resolved, but we don’t have these issues resolved at this point. JB: I think you’ve really done such a superb job of laying out what the present state of our understanding is and the potential significance of this playing field, of this whole filed. I think one of your colleagues at Duke Medical Center has done quite a bit of research on…I can’t remember the name of the drug, you can help me with it, I’m sure…a drug that alters methylation. I think you were just referring to it. It is used in chemotherapy for specific tumor types. Maybe you could tell us a little more about that, because to me that is seemingly an interesting example of adult modulation of the epigenome.12 Epigenetic Cancer Therapies RJ: They are able to treat certain types of leukemias with what they call epigenetic therapies. Many of the tumor suppressor genes are hypermethylated (or they have many methyl groups in front of the tumor suppressor gene). When you expose them to these compounds, what happens is those methyl groups gradually are released, and as a consequence, now the gene functions and you induce that cell to either be a good citizen and stop growing, or usually what happens is it undergoes what is called programmed cell death and they die. So you are trying to make them good citizens. That is different from most therapies. Chemotherapies that we are using now are cytotoxic and they just literally sort of nuke the cell. The same thing with ionizing radiation; I mean, they just blast the cell. So this is a very different approach. Lower doses of compounds are used (of these therapeutic agents), and for longer periods of time. And you don’t see, in these patients, the negative effects that you would often see with the cytotoxic agents. It’s a whole different field. If there were epigenetic changes, for example, that gave rise to autism, or let’s say schizophrenia and other neurological disorders, it is potentially possible we could use compounds that would alter the epigenetic states of genes that are very important in giving rise to this and therefore block this problem, and as a consequence, get people through a developmental stage to the point where they would never have that problem at all? I think this the exciting part of the epigenetic therapy and the epigenetic field of scientific research. Again, it is prevention. Even though what we were talking about initially with cancer is therapeutic, I really think the big thing is going to be ultimately the use of compounds, and nutrition might be one of those types of things to prevent these problems from ever occurring. JB: To me that’s obviously really the exciting frontier. Is it appropriate to call those alleles that might be modifiable something like “metastable epialleles”? Or is that not appropriate language to define them? RJ: That’s the terminology that was coined for these Agouti genes that can be methylated or unmethylated. They are referred to as metastable epialleles. There are only-to my knowledge-three genes that we now know of in different strains of mice that are regulated by this type of metastable effect. In humans-to my knowledge, again-we don’t know any. That doesn’t mean that there aren’t some, but it’s going to be a little more difficult to find them because every individual also varies in his or her genome, so it is going to be harder to determine whether an effect that you see is because of a genetic change or difference or because of an epigenetic change. So they are harder to find but I believe they are there, and we now have the tools that I think we should be able to find these things. One thing that is really interesting that is coming out of a lot of this work now is copy number of variance. In other words, you have areas where there are microdeletions or microamplifications. It’s possible these are occurring in areas where one allele or one copy of a gene is silenced (in other words, these imprinted genes). They can be either imprinted genomically, so you have parent-of-origin effects of the expression, or they could be caused by mutations and could be altered in their expression because of genetic sequence that is close to them, but it gives rise to a lot of genes, I think, that are expressed only from one copy. If you end up deleting that one copy, you can see very clearly why you would have an effect on phenotype. JB: Yes. RJ: It’s really interesting because I feel we’re going to find a lot of diseases are mapping into these regions where we have genes in which only one copy primarily functions normally. JB: Yes, and I think that’s a part of genetics that many of us, in school, didn’t really consider the implication of. We get something from our father, we get something from our biological mother, they code together. Which of those two sets of characteristics get expressed? How do they get mixed and matched? What do the promoter regions look like? Which are silenced; which are activated? And do they change in changing conditions so that one gets turned on and the other gets turned off in its expression? It’s a lot more genetic variability potential into the expression, it would appear, than maybe we first recognized. RJ: Right, and that information is coming out now because we can do this massive sequencing and look at not only methylation differences between the two alleles, but you can very clearly quantify expression of the two copies if you have some sort of a mutation or polymorphism, as we call it, between the two copies. So you can see whether one copy or the other copy is expressed more prevalently, or if they are basically expressed sort of equally, which is was most people thought (if genes were on, both copies worked). Hypermethylation versus Hypomethylation JB: Two last thoughts here. We could go on-at least I could go on-for hours on this. Your work just opens for me so many interesting thoughts and questions. Let’s come back to the word that you used earlier, which is “hypermethylation” as contrasted to “hypomethylation.” There is this view, I think, that if you don’t get enough methylating nutrients that you put at risk regions of the various CpG islands and the promoter regions of genes to be hypomethylated and to not have proper silencing. And then the alternative to that is people might say, “Well, if not enough is not good, what about too much?” So let’s say we stimulate too much methylation by giving too high levels, as you were implicating, of folic acid or B12 or B6 or a combination there of, and you get into hypermethylation? It appears to me now, from what I’m reading, that when you have a state of hypomethylation in specific regions of the genome, you have hypermethylations in others. It’s not just a one-size-fits-all, too low levels leads to always hypomethylation. So it sounds like altered methylation occurs in the genome as a consequence of factors in the environment that modify the methylation pattern. Is that what’s emerging? RJ: Yes, it seems like it. In particular, that ends up being the case in cancer formation. The first thing that was defined, back in the 80s probably, that you saw in cancer formation was horrible hypomethylation. But then the whole emphasis went towards the fact that some of these tumor suppressor genes are silenced because of hypermethylation. Now we know it is exactly what you said. In this sea of hypomethylation, you do have certain areas that for some reason become hypermethylated. So you have all of these combinations. Basically what it is is a deregulated epigenome, and it is causing a lot of different changes, of which some of them, then, ultimately are selected for because of the growth advantages to those cells and they ultimately are what we see as a tumor. JB: What I’m starting to better understand is that maybe these patterns are really reflections–the shadows of the image of altered cellular regulation from different environmental perturbations. RJ: Right. They are deregulated in general, and then you get variations of regulation. Why do we look at cancer and see these? Because they grow bumps and they kill you (not all of them; at least some of them do). So you have natural selection for certain genes being turned off and certain ones being turned on, sometimes through mutations, but also sometimes because of alterations in the epigenomes that are controlling the expression of these genes. When you select for something that gives you a net inappropriate growth that’s not controlled the way it should be, you end up with cancer, and it is natural selection for these different alterations in gene regulation. JB: Let me, if I can, close with one last question, which maybe is an overarching question that ties a lot of this together. You’ve talked, in some of your recent papers, about epigenetic biosensors that then control regulating genes. Often these are in the non-coding regions of genes-very interesting-in the entrons that are the regulatory regions that we used to call junk DNA, which I find kind of interesting just from a historic perspective (be cautious what you call junk). RJ: Right. JB: One of the things that struck me as I looked at this, is that this imprinting that occurs in fetal development implies, as you have shown in your work,, that for many diseases that we get in later life, the clock started ticking with our fetal epigenomic imprinting: diabetes, CVD, and cancer might come many years later. So they are diseases of long latency from epigenetic modulation. As you looked at this, do you have a sense as to whether most chronic diseases are a consequence of the epigenetic imprinting at the fetal stage, or is it not yet known how much of this is modulated later in life? RJ: I don’t think we know because we really just don’t know very much about it. This is a guess, now. People say, “What’s more important, mutations or epigenetic changes in disease susceptibility?” And I say, “You really can’t ask that question. You can ask it, but you can’t answer it.” Because if you use the analogy that I have used about the hardware-the DNA-being comparable to the hardware of your computer and the software being comparable to these epigenetic programs, and if you are typing on the computer, you could ask, “What’s more important to you right now, that physical computer or the software program that you are using to type that information into the computer?” They are both important. But the other question that you just asked is what gets messed up more readily and potentially gives rise to problems? I think that we’re going to find that what’s causing the vast majority (or at least a goodly amount of these problems), are not going to be just these mutational effects, but frankly will be these epigenetic changes. They are more labile, and therefore as a consequence it is more likely that you can change in a bad way. So that’s my guess. JB: I’m obviously just an armchair observer of what you are doing as the expert, I’ve looked at what’s going on with Mike Skinner and the work that is going on at McGill with the stress-related factors and the epigenetic imprinting in animals and the relationship to later-stage disease.13,14 Now that these tools are available, this seems to be growing exponentially to give much more weight to this plasticity that is regulated through the epigenome, as contrasted to the hard-wired change of mutation in the traditional kind of Darwinian/Mendelian sense. This is a whole field that is emerging, which I think has a good news component to it because if we, as you said, can identify where these loci of alterations are and look at how you can modify them favorably by regulating the environment, it may lead to reversibility, which is, of course, what everybody is searching for as we have this rising tide of chronic disease. Identifying Epigenetically Labile Targets Difficult Due to Species Variability RJ: Right, but the problem right now is that we don’t really know what the epigenetically labile targets are. There are going to be a lot of them probably, but there are probably some that are going to be much more important than other ones. This, I think, brings in a big issue here, and that is that the species vary in their epigenetically labile targets. They’ve got to because if we have software that is telling how an individual species develops, and that’s the programming that is going on, and it’s not really totally the genes that are involved, but how they are regulated. You have to have different programs running in a mouse, for example, versus a human. With bisphenol A, we showed (and I think other people too) that it reduces the methylation that one normally sees, at least in the model system we used. And in that system we get all of these different effects: yellow animals, obese, diabetes, all that type of thing. But I can’t really even extrapolate that to another strain of mice because other strains of mice don’t have that transposable element-that little viral set of DNA-upstream of the Agouti gene. What I think we can extrapolate is that this tends to cause a reduced ability to methylate. But what effects it has and what the targets are that it is effecting will vary-I believe-between species. That is going to make extrapolation more difficult between species. This is important because we use animals as surrogates for humans to determine treatments and also to determine what compounds are problematic (risk assessment). JB: Wow, that’s a very insightful comment. Again, we could go on and on. I guess the best thing I can say right now is if the environment we are in influences our epigenome in positive or negative ways, then these minutes that you have spent with me have definitely created a healthy epigenome for me. This conversation is sending the right messages to my epigenome. So, thank you very, very much. Your continued diligence, and leadership, and very articulate and what I would say “news-to-use”-type of approach to this very complex topic is really refreshing. I really appreciate you spending the time with us. RJ: Well, thank you very much for talking to me. I do love this field of research. It is gratifying to see the field grow as rapidly as it is growing. I was asked one time about the field, and it looks, right now, like the papers that are being published in this area are doubling every one-and-a-half to two years. We’re in the vertical phase, basically, of the epigenetic rise, which means the present, past, and future are merging. What does this mean? It means it is very difficult to predict what’s going to happen. JB: It is my deep hope that when the awards are given for the first pioneers that brought this concept into the 21st century vision that the name Randy Jirtle will be at the head of the list because you certainly deserve it and we thank you very much. RJ: You’re way too kind. Thank you very much  

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Bibliography

1 Attig L, Gabory A, Junien C. Nutritional developmental epigenomics: immediate and long-lasting effects. Proc Nutr Soc. 2010;69(2):221-231. 2 Doolin MT, Barbaux S, McDonnell M, et al. Maternal genetics effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida. Am J Hum Genet. 2002;71(5):1222-1226. 3 Chiam K, Tilley WD, Butler LM, Bianco-Miotto T. The dynamic and static modification of the epigenome by hormones: a role in the developmental origin of hormone related cancers. Biochim Biophys Acta. 2009;1795(2):104-109. 4 Barth TK, Imhof A. Fast signals and slow marks: the dynamics of histone modifications. Trends Biochem Sci. 2010 Aug 2. [Epub ahead of print] 5 Wallace DC. Bioenergetics and the epigenome: interface between the environment and genes in common diseases. Dev Disabil Res Rev. 2010;16(2):114-119. 6 Beach RS, Gershwin ME, Hurley LS. Gestational zinc deprivation in mice: persistence of immunodeficiency for three generations. Science. 1982;218(4571):469-471. 7 Hanwell HE, Banwell B. Assessment of evidence for a protective role of vitamin D in multiple sclerosis. Biochim Biophys Acta. 2010 Jul 30. [Epub ahead of print] 8 Cloud J. Why your DNA isn’t your destiny. Time. 2010 Jan 6. 9 Bernal AJ, Jirtle RL. Epigenomic disruption: the effects of early developmental exposures. Birth Defects Res A Clin Mol Teratol. 2010 Jun 21. [Epub ahead of print] 10 Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Sci U S A. 2007;104(32):13056-13061. 11 King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643-646. 12 Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794-1803. 13 Skinner MK, Guerrero-Bosagna C. Environmental signals and transgenerational epigenetics. Epigenomics. 2009;1(1):111-117. 14 Szyf M. The early life environment and the epigenome. Biochim Biophys Acta. 2009;1790(9):878-885.

Welcome to Functional Medicine Update for October 2010. This month we are going to deal with a topic that I know has been discussed at length over the last several years in Functional Medicine Update. This month we are going to take a slightly different spin (a different look, a different perspective, a different part of the matrix or the lens upon which we focus information to ultimately arrive at clinical decision-making). The focus this time will be taking the concept of metastatic disorders-proliferative cellular disorders-and sieving it through a different way of looking at the origin, the management, and the progression of cancer. The Institute for Functional Medicine Symposium titled “Cancer as a Chronic Disease” held in May 2010 dealt with this new context of cancer as a chronic disease. Why would we say it is a chronic disease? As a consequence of a number of the major breakthroughs in therapeutic tools that are available for the treatment of cancer, many people who would have previously not survived from the initial diagnosis are now either in remission or in states of chronic management. What this means is the disease that had a reputation of being a lethal disease, one that leads always to a terminal event, now is a condition that in many cases may be managed more as a chronic disease. What is the origin of cancer? Why would cancer undergo this transition from a disease with a certain reputation of pathophysiology leading to mortality to that which can be managed? What does that mean about the future as it relates to the management of this condition and maybe its prevention? Those kinds of questions were the focus of the 17th Annual Symposium of the Institute for Functional Medicine, and it’s those types of things that I would like to focus on more in this issue of Functional Medicine Update. Our clinician of the month this month, Dr. Jeanne Wallace, was one of the most highly rated presenters at the 17thInternational Symposium. Dr. Wallace will be talking about her experience in consultation and patient management in the area of cancer, but I thought I might set the context for her discussion and raise some difference perspectives about how we’re thinking of this disorder. Let’s first talk a little bit about the nature of what signals a cell-a fully differentiated human cell, a eukaryotic human cell somewhere in the body in a state of developmental biology that is static–to undergo this transformation into a dedifferentiated state that is cell proliferative in nature, invasive, and ultimately has a metastatic potential. The cell is also angiogenic (sending out new blood vessels to nourish the mass as it grows). What would be the process that would trigger that? The Role of Carcinogens, Both Environmental and Endogenous Historically, we’ve talked about the role that carcinogens or mutagens play in mutating or altering genomic messages causing nicks (or damage) and chromosomal instability that ultimately produces mistakes. These mistakes cause a regulation of expression factors of this dedifferentiated primordial state of the cell that we call a cancer cell. For much of the past 30 years, this concept of carcinogen-induced cancer has dominated the thinking in the field. Of course, there are also in situ carcinogens, for instance, estrogens and estrogen byproducts. These may be in situ carcinogens as a consequence of their influence on DNA. We have twice interviewed, on Functional Medicine Update, Dr. Eleanor Rogan from the University of Nebraska. She received a Linus Pauling Award from the Institute for Functional Medicine for pioneering work she has done on the oxidative metabolism of estrogens into the hydroxy estrogens and finally into the quinones. These quinone-like estrogens, the 3,4-quinones, can react very rapidly with electrophilic regions of the genome (DNA) to produce these mutational adducts, which then interpolate in such a way as to cause potential misreading of the genomic message and start neoplasm. Dr. Rogan has been at the forefront of understanding how an endogenous hormone, estrogen, undergoing specific types of metabolic transformations (in this case to 4-hydroxy estrogens), then can become oxidized into these 3,4-quinones and initiate a cancer. It begs the question: How do you prevent the formation of these endogenous carcinogens? That leads us into the discussion of things like detoxification. How does estrogen get detoxified and ultimately eliminated as a glucuronide or as a sulfate in a non-toxic form that can be excreted either in the feces or in the urine? Dr. Rogan has pointed out that these particular metabolic transformations of estrogens are facilitated by a group of cytochrome P450s, one of which is cytochrome P4501B1, one of the isoforms in the more than a hundred different members of this family of cytochrome P450 enzymes. And that cytochrome P4501B1 not only resides in the liver in its activity, but also it resides in the breast and it can be activated in breast tissue to increase the production of these 3,4-quinones (estrogen quinones).1 What do you do to prevent the activity of cytochrome P4501B1? One thing is to increase the conversion of estrone and estradiol into agents that would not be allowed to become 3,4 estrogen quinones, and that’s by the 2-hydroxylation pathway, to form the 2-hydroxy estradiol and estrone. The hydroxylation by cytochrome P4501E2 and 1A2 produce these other estrogen metabolites, which then prevent the conversion by 1B1 into the carcinogenic 3,4 estrogen quinones. And we know that cruciferous vegetables that contain the class of phytochemicals called glucosinolates (things like indole-3-carbinol, and 3-hydroxy-2-butanone, and phenylisocyanate, and even including sulforaphane) activate gene expression in the liver and other tissues of the enzymes that are responsible for the formation of the 2-hydroxy estrogens. That’s the explanation for the epidemiology that shows association between women who consume more crucifers and a lower incidence of female hormone-related cancers.2,3 One even sees intervention trialsin which women were given placebos or given supplemental doses of these phytochemicals, particularly I3C or diindolylmethane (DIM), a polymeric conjugant of I3C, and have demonstrated an increase in the excretion of 2-hydroxy estrogens. In the case of I3C one clinical trial showed that approximately 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of women with biopsy diagnosed CIN II-III who were supplemented with either 200 mg/day or 400 mg/d I3C for 12 weeks had remission, as compared to placebo, in which none of the women showed remission. This suggests there is a reversion of the cellular architecture back to normal, at least in this study of women diagnosed with CIN II-III. This study also showed a favorable effect in the 2/16 estrogen ratio, further suggesting the impact these estrogen metabolites on DNA injury.4 We are starting to witness a possible connection between epidemiology and cellular mechanisms of action in how this all relates to environmental factors such as diet, aimed at understanding what may induce or prevent specific cancers. We also recognize that cytochrome P4501B1 is activated by certain types of the conjugated equine estrogen B ring unsaturated estrogens.5 For example, these types of compounds are found in pregnant mare’s urine, but the same compounds are not found in human women. These B ring unsaturated estrogens that are found in equine estrogen hormones can activate cytochrome P4501B1, and therefore may have a preferential metabolism into the 3,4 estrogen quinones, which we’ve said are more carcinogenic. There are probably a variety of different routes of contribution to changing the balance of metabolism of estrogen. Dioxin is another one that is known to enhance the activity of cytochrome P4501B1 and may increase, then, the burden of these carcinogenic estrogens. As we learn more about the story, we learn more about both what things to avoid and what things to women should be exposed to improve the hormonal balance. This is very similar to what Dr. Sidney Baker has said so many times when asked, “What is the difference between a functional medicine approach towards the patient and a traditional diagnostic, pathophysioloical approach?” His answer is brilliant: “The functional medicine approach is to ask two questions. (1) What is the patient getting too much of? and (2) What is the patient not getting enough of?And to remove those substances that the patient is getting exposed to in excess, and to add back those things that the patient is not getting enough of. ” This is personalized medicine based on a very simple conceptual framework that has patients being asked different kinds of questions about their histories. This is the concept of antecedents leading ultimately to triggers, producing mediation of various signaling substances that ultimately work on target tissues to produce signs and symptoms. This is a different model than the drive for the name of the pathophysiology and putting a diagnosis on a condition. It is more about asking how you got there rather than what it is that you finally got to. Cancer may derive in part out of this endogenous and exogenous exposure to carcinogens (as I have just described with the estrogen story), but it goes beyond that. I think this next step is where the world gets both more interesting and probably more confusing. I owe Dr. Barry Boyd, a medical oncologist and integrative oncologist from Connecticut who is associated with the Yale University Medical School program, for starting me down this path of thinking in terms of oncology and oncogenic burden from this perspective. A number of years ago, Dr. Boyd was asked to speak at the Institute for Functional Medicine Symposium. During his talk he alluded to the fact that insulin signaling plays a very important role in the potential oncogenic risk that a patient might have, and also to the progression of tumors.6 At that point in time I really hadn’t thought much about insulin as being a hormone that had anything to do, principally, with tumorigenesis or oncogenesis. Since that time, however, thanks to Dr. Boyd, I have come to recognize that this is a very, very active area of research, one that has enormous potential, clinical implications, and one that is, fortunately, something that you can intervene against. You can measure insulin signaling and you can manage insulin signaling, so it is not just an esoteric concept that we say, “Oh there’s a risk factor, but there is nothing we can do about it.” In this case, we would say, “Hey, there is a risk factor. Once we understand it, we can do something about it and we can intervene with the appropriate diet and lifestyle, and, if necessary, pharmacology program.” Kinases Play a Complex Role in the Relationship between Insulin and Cancer So what’s this all about? What this is about is the recognition that insulin is much more than just a glucose-modulating hormone. I think we have all started to recognize, in this field, the pleiotropic effects that insulin has–the multiple personalities that it has as it regulates a complex set of genes and their expression. It does so by binding to the insulin-binding site (the insulin receptor), and then triggering, through a very complex signaling mechanism, through insulin receptor substrate 1 and down through a variety of interrelated kinase signaling molecules, including Burton tyrosine kinase (BTK) and spleen tyrosine kinase (SYK), and ultimately down through phosphatidylinositol 3 kinase and through MTOR, down through glycogen synthase kinase 3. This is, I know, sounding very esoteric and biochemical-ish, so let me just summarize what I’ve just by providing an analogy. There is this complex pachinko game, if you know the Japanese pinball game, where you hit a little ball up to the top and then you are able to create, from that, a multiple series of hits of these balls as they move down from the top to the bottom and ultimately you rack up a score. One ball can create multiple actions if you are lucky and you play the game right. That’s very similar to the way kinases work. We learn in school about biochemistry as linear paths, and we call them metabolic pathways. But really these metabolic pathways are just like tendrils in a web of a network of physiology. We kind of freeze-frame one tendril, which looks linear. A substrate goes to product, and we memorize that, like glucose goes to glucose-6-phosphate, but yet that is embedded within this very complex web of interacting pathways that forms this network. The network of signaling substances within a cell that translates the outside world to the inside function that ultimately regulates things like mitochondrial function, endoplasmic reticular stress, oxidative phosphorylation, and genomic expression is a series of more than 300 different enzymes that have names (kinases), and I have spoken about these at length in previous issues of Functional Medicine Update. These kinases are phosphorylating enzymes that modulate and modify the function of enzymes in the cell by sticking a phosphate group on something like a serine or a tyrosine residue on the protein chain to slightly modify its structure, which then modifies its function. So they are regulatory. It is like the fine-tuning knob of the body. As we think about the fine-tuning knob analogy, these are things that can be modulated, by the local environment. The kinase regulation of gene expression is, in part, controlled by the local environment of the cell, which is controlled by the environment of the host. So times of ischemia, or times of dehydration, or times of hyperthermia, or times of toxic exposure, or times of malnutrition, it modifies the expression of this relay race that we call the kinases, That then influences differential expression of the genes. Let me discussan example of this so it sounds a little bit more reasonable. We’ve all heard recently about the important role that the phytochemical, resveratrol, found in peanut skins and grape skins, has on modulating what are called the sirtuin (silent transduction) genes that are associated with longevity (Sirt1). Sirt1 is an NAD-dependent deacetylase family of enzymes that are modulated in their activity by resveratrol. What has been found recently is if you look at various kinds of compounds that are found in nature, it is not just resveratrol that modulates sirtuin1 in eukaryotic mammalian cells, but also other polyphenols and other phenolic phytochemicals are found to play roles in modulating sirtuin. So it is a symphonic modulation of sirtuin function. If you start looking at the roles that these sirtuins have on cell function, what you’ll find is that the roles, through NAD-dependent deacetylase activity, are to alter gene expression of some of these kinases. And the kinases ultimately go on to alter the phosphorylation patterns of various proteins and enzymes in the cell, which then modifies its function to make it a cell that is more insulin sensitive; a cell that is more energy economical relative to mitochondrial oxidative phosphorylation; a cell that has lower proliferative potential; a cell that has more apoptotic potential if it has become a transformed cell; a cell that is less prone to inflammatory signaling. These multiple effects-I call them pleiotropic effects-that come out of modulating the sirtuin gene expression, are related to the role that certain environmental substances (in this case dietary polyphenols) have on kinase signaling. How does such a long-winded explanation connect back to the insulin story? Because insulin is a very powerful modulator of principal intercellular signaling kinase processes that are associated with a whole array of cellular phenotypes/cellular outcomes, not just glucose transport alone. That’s certainly an important part of this (getting the energy molecule-glucose-into cells efficiently). Beyond that, there are many other roles that this alteration by insulin of these signaling pathways has on cellular phenotype. This include things like inflammatory status, cell proliferative status, apoptotic status, cellular architecture (the cytoskeletal structure), and even the effects on mitochondrial oxidative phosphorylation and bioenergetics. If you have a dysfunctional insulin signaling regulatory pathway and you overdrive some of these kinase mediators, what can happen is that you actually change the phenotype of the cell into a personality that can be more prone to transformation into a proliferative cell, (a cell that becomes more relatively angiogenic, a cell that ultimately may become metastatic). The hyperinsulin state associated with insulin resistance has now been found to overdrive specific kinase-modulated pathways that can, in part, increase the relative risk of a metastatic disorder. There are a whole series of new kinase-inhibiting drugs that are used in cancer treatment. These are profitable blockbuster drugs that are very hard-hitting inhibitors of specific kinases associated with growth of cells and proliferative phenotypes. The challenge with some of these drugs, however, is that because they are so hard-hitting and they are so efficient in locking down specific kinases, you get collateral damage because there are other places where the activity of those kinases may be considered important for housekeeping function of cells. So you can potentially get off-target effects and some fairly severe adverse side effects from these kinase-inhibiting drugs. Most Well-Known Cancer Diets Have Recommendations in Common This is to be contrasted with the modulation of kinases more mildly or moderately through insulin signaling and ultimately through the dietary regulation of things like polyphenols or other phytochemicals. When we talk about a diet that may be good for cancer, it is very interesting that many of these diets (be it the Kushi diet program, or the Ornish diet program, or the minimally processed high fruit and vegetable-type diet program) all of these share the characteristics of having a low glycemic load (meaning low insulin stimulating) and having a high phytochemical concentration in terms of modulating, with these phytochemicals, specific kinase-signaling processes. There is undoubtedly something very important buried in this emerging science that is starting to come to light that correlates to the influence that a low glycemic load diet in combination with a phytochemically dense diet may have in regulating the intercellular signal communication process that leads to the outcome of either a quiescent cell or cell division causing proliferation. Can Insulin Therapy Lead to Greater Risk to Cancer? This subject ties back to our previous discussion of various endogenous hormones that are converted, like the estrogens, into potential mutagenic or carcinogenic substances. We wouldn’t necessarily call insulin a carcinogen, but we would call it a modifier of gene expression function that can correlate with proliferative disorders. Those of you who have been following the literature know that this story has taken a little bit of an interesting twist in 2010. In 2010, what was found and reported in a number of journals was that individuals who are insulin-requiring diabetics receiving specific forms of insulin therapy appear to have a higher statistical prevalence of cancer.7,8,9 Do certain forms of insulin or certain types of insulin administration actually increase the relative risk to cancer by an overdrive of these signaling pathways? There is quite a debate going on now within the field as to whether this relative risk is highly significant, moderately significant, or insignificant, but I do think that the data are quite clear that certain types of insulin administration in diabetes do appear to be statistically associated with increased incidence of cancers. Some people seem to want to put labels on molecules and say, “It’s a bad molecule or a good molecule.” Many times I’ve heard the term “arachidonic acid” associated with being considered a bad molecule as a fatty acid metabolite. Yet if you didn’t have any arachidonic acid in your cells, you would have very dysfunctional immune system protection that would put you into an immune-compromised state. So you need adequate levels of arachidonic acid. It is not a good molecule or a bad molecule; it’s a molecule that has important roles to play when in proper balance. We could have the same conversation about insulin, this polypeptide protein molecule (this peptide hormone). It is not a good or bad molecule; it is a functional molecule in the range of concentrations and activities that leads to healthy homeostatic function. If insulin is too low you get pathology, and if it is too high you get pathology. This is the classic example of Tolman’s Law of pharmacology for all substances: parabolic dose response curve. Everything, including air and water, has a dose too low that leads to death (dehydration for water or hypoxia and oxia for oxygen). But on the other side, there is a dose that can be considered toxic. For water, hyperhydration can be lethal, and for air,hyperoxygenation can be lethal. It is really the challenge of the functional medicine practitioner to help the patient be in his or her zone of optimal function, at the top of the parabola. Whatever concentration that of substances that induces or supports proper function would be the ideal state. So you are getting optimal function versus concentration. This network is so complex, with literally thousands of things going on in each cell in real time and with each cell type being different from every other cell type. The complexity of this seems overwhelming. That’s why we choose certain kinds of biomarkers to assess the smoke rather than the fire. We look at the shadows on the wall of the cave. We often can’t look at the direct processes going on, so we have to look at the artifacts or the secondary byproducts and we call these biomarkers. In terms of insulin, because we can’t analyze all the insulin signaling pathways in all the cells and know how it’s turned on and turned off, the biomarkers we use are related to overall insulin signaling processes. These may be things like hemoglobin A1c. Hemoglobin A1c, or glycosylated hemoglobin, is a surrogate biomarker for the relative effectiveness of insulin. There are many other variables and many other factors that are involved in this, so we are oversimplifying to say it is just a measurement of insulin activity, but it is a surrogate marker for insulin. You might ask, “What is a good level for hemoglobin A1c if we are trying to balance the patient and monitor and manage their insulin signaling?” It used to be we would say that hemoglobin A1c, or glycosylated hemoglobin, was principally useful for following the success of compliance in a diabetic patient in trying to keep their hemoglobin A1c levels below a certain percent of total hemoglobin. Patients with glycosylated hemoglobins of a high percentage were people undergoing this non-enzymatic reaction of glucose with their globin portion of their hemoglobin molecule to glycosylate. The more glycosylation, the more injury to the hemoglobin, but also the presumption of the more injury to many other proteins by this non-enzymatic glycosylation. The suggestion is that this measurement is like time-lapse photography of glucose physiology in the whole body over the life of the red cell (about 120 days). In medicine, glycosylated hemoglobin was principally being used as a way to monitor compliance and control in a diabetic patient. Over the last decade, however, many more detailed studies have been ongoing looking at glycosylated hemoglobin levels in individuals who have marginal insulin resistance, or what might be considered metabolic syndrome patients (people with refractory insulin resistance with elevated triglycerides and low HDLs and increased abdominal circumference).10 In these cases these patients may not yet be diabetic, but what has been found recently is that their hemoglobin A1c start drifting up. It is not the case that there is a threshold, above which you are suddenly in trouble and below which you are completely safe. It is more of a gradation, as we have seen often in almost all variables that we measure. This is consistent with the parabolic dose response, because a parabola is a continuous curve; it is not a discontinuous curve. You go up one side of the parabola and go to the top, and then down the other side. It is a continuous line. What does that really mean in terms of following the patient? It means that the serial analyses of biomarkers like glycosylated hemoglobin become very important. It’s not just taking one data point and then trying to make a decision. It is rather trying to follow the patient over time and see what the relative delta (the rate of change) is. Is it going up? Is it going down? Is it staying the same? Going up is not good. Staying the same or going down is considered desirable. We’re using this surrogate biomarker to track the success of therapy and to try to define the environment-let’s call it a “molecular milieu” in the cell-that would reflect proper cellular signaling and proper gene expression patterns. In the patient who is not a diabetic, necessarily, but who has an elevated glycosylated hemoglobin, who may have other family histories of cancer, who may have other risk factors, you might, as part of therapy, direct intentionality towards modulating glycosylated hemogloblin (lowering it) as a biomarker for the influence you are having on insulin signaling and its ultimate influence on cell proliferation. This is an example of a different strategic approach towards both susceptibility to and the management of cancer. These are the kinds of things that we use as a snapshot to track the patient and to engage in personalized intervention. Another-I would call it adjunctive-biomarker that can be used is high sensitivity CRP as a surrogate marker for inflammatory potential. We know from past experience and discussions we have had in Functional Medicine Update that CRP is a relatively problematic biomarker for inflammatory assessment because it is a pretty downstream marker (C-reactive protein). What happens in the cascade of inflammation is that upstream there is the production of inflammatory cytokines, triggered by tumor necrosis factor alpha, which then produces interleukin-6 (IL-6). IL-6 then travels systemically and ultimately triggers the liver to induce gene expression of a protein called C-reactive protein. C-reactive protein is kind of a second-signal messenger of inflammation. It is the second guard. It’s not looking at the primary modulator; it’s looking at a secondary effect. But even with that limitation, we see that drifting upward with hs-CRP levels in serology is reflective of chronic inflammation. I want to put a caveat on that by saying that hs-CRP is very susceptible to outside “noise” in that test. If a person has a cold or the flu, hs-CRP will be elevated for that time period. If a person has an injury, like a musculoskeletal injury, it will be reflected in an hs-CRP test. If a person has a chronic state of some type of a trauma, that can elevate hs-CRP. I think we have to be aware of the fact there can be spikes in hs-CRP that are temporal, and the levels will come back down once the patient has have gotten over that immediate insult. But it is a good marker for inflammatory burden if a patient that has, on a regular basis, with no underlying infection or trauma, an increased level of hs-CRP. In combination, using the glycosylated hemoglobin test with the hs-CRP test can help us start to develop an understanding of the landscape related to potential risk to various kinds of chronic conditions, one of which-and we are speaking of it here specifically-is that of cancer, a proliferative disorder. What I’m really trying to get you to understand is that as we look at the cancer as a chronic disease question, we’re lead into a using a different lens for assessing information; we’re throwing the net a little broader for collecting information. We’re not just looking at tumor markers, which are the traditional way that you follow a diagnosis of a cancer, but we’re really looking at the molecular milieau and at the intercellular environment, to try to appreciate what is going on at the gene expression level that might, in fact, encourage these metastatic problems. The last marker that probably should be put on the list-and this list could be fairly long, but one last big pillar that I’d like to add-is genomic instability. We know that oxidative stress induces genomic instability by inducing genomic damage, both at the mitochondrial DNA level and at the nuclear DNA level. Measurements of oxidative stress, like TBA-active materials (TBARS), or looking at 8-isoprostane levels, or looking at 8-hydroxydeoxyguanosine levels in the blood, are surrogate markers for oxidative injury to various biomolecules, including fatty acids or DNA, that reflect the potential for oxidative stress. This is another correlation with genomic instability/genomic damage and ultimately to the oncogenic potential of that cell. If you were to group together these tests–hemoglobin A1c, hs-CRP and other inflammatory biomarkers, and oxidative stress markers–you would start to observe a landscape that is associated with the potential that we call oncogenic potential. I think it is that type of model that you are going to hear much more about from Dr. Wallace, as it relates to how she counsels physicians and patients who have malignancy in trying to develop the proper physiological environment so that it is less selective for cells that are transformed having a friendly opportunity for proliferation, angiogenesis, and metastases. This is a very, very different model, I think, than the traditional diagnosis and treatment model in oncology. It is not in place of. That model can still be consistent to a traditional treatment model, but I think what we are looking at is a functional approach towards oncological burden that is hopefully going to be adjunctive and amplify the success of positive outcome in a patient who has early stage malignancy, or is being treated for cancer, or is managing malignancy as a chronic disease. It gives some new tools-some new rules of the road-upon which one can navigate. You might say, “What’s new about this?” I think what is new about all of this is that this is assembling some of the more recent (and when I say recent I mean within the last decade) understanding of the cellular and molecular physiology of cancer (the whole cancer biology). And then trying to take that cancer biology understanding and apply it clinically, knowing that we are still in a house that is under construction, that we don’t have all of the architecture worked out. It is a very complex network, as I have described, for which much of it is still a mystery, but that doesn’t mean we can’t act. That doesn’t mean the information that we have at hand won’t provide valuable approaches that will augment and improve successful outcome. With that in mind, I hope I have laid a context for what we are going to be hearing from the expert, the highly ranked presenter at the 17th International Symposium on Functional Medicine, Dr. Jeanne Wallace.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jeanne Wallace, PhD, CNC 1697 East, 3450 North North Logan, UT 84341 www.nutritional-solutions.net I know you’ve heard this said by me many times: this is the part of Functional Medicine Update you and I both look forward to. Each month, I wrap around our clinician or researcher of the month a little narrative that hopefully explicates and supports and enriches what they have to say. The voice they bring is really the premier reason for being (the raison d’etre) for Functional Medicine Update. Once again we are very privileged to have an extraordinary presenter/clinician who is going to talk to us about a very complicated but important area. This was the focus of the 17th International Symposium on Functional Medicine in May of 2010, which was on titled Cancer as a Chronic Disease. As we start to learn more about the etiology of cancers, and we learn more about how to put together a comprehensive care program, and as patients now start to survive through the primary therapy into years of life after, the question really becomes, what the best management? How do we manage cancer on the front end, during, and after? Questions of compassionate care become very, very important. This discussion goes beyond buzzwords such as “integrated cancer therapy” or “integrated oncology,” to really look at the whole milieu-the ecos-of this unique condition of cell replicative disorders that we call cancers. We’re very privileged to have Dr. Jeanne Wallace for today’s interview, who, at the 17thInternational Symposium, was the top-ranked speaker out of a very remarkable portfolio of experts in the field that presented over the four days of the Symposium. Dr. Wallace has pioneered what she terms is a “multi-modal” approach that targets multiple aspects of cancer pathophysiology. We’re going to learn from her directly more about what that means. It all relates to this dysregulated cell signaling and gene expression, how that turns into things like angiogenesis and metastatic processes, and how one then goes about selective apoptosis of transformed cells. How do you redifferentiate cells to their normal architecture? And how do you support, properly, whole organism immune function? These are all parts of different strategic thinking about cancer as a chronic disease and how one might design a program to manage it. Dr. Wallace is a certified clinical nutritionist. She is a PhD. In 2001, she submitted a Best Case Series of 101 glioblastoma multiformae stage IV brain tumor patients to the National Cancer Institute’s Center for Complementary and Alternative Medicine, and the data was updated in April of 2004 to include 325 cases that were favorably reviewed. She is a member of the Society of Integrative Gynecology and the National Association of Nutritional Professionals, and is just a remarkable and dedicated professional counselor, guide, and presenter. With that introduction, Dr. Wallace, welcome to Functional Medicine Update and thanks for being with us. Maybe I should start with this first question: What was your path that led you to this extraordinary…I would say both demanding but also fulfilling occupation? JW: Thanks, Jeff. Thanks for the introduction. It’s nice to be here. I often describe my path here as having been drafted because I didn’t volunteer to work in the field of cancer. I grew up with a large family history of cancer, and watched grandparents and my uncles pass away, and my mother and my sister are both survivors, so I knew as a fairly young person that I wanted to work with cancer patients. I started out doing that in psychology in my training and didn’t feel right there and looked at some other ways of going. It was when a friend of mine developed a stage IV brain tumor that I decided. I was working in the field of nutrition and we couldn’t find anyone to help her, and I decided, “This is it. I have been drafted. This is my calling.” And I really turned the focus of my practice at that time toward a look at primary brain tumors and nutrition. I had been working with some other types of cancer for a couple of years. That really became my full focus at that time. And I’m happy to say she is still alive. It is 13 years later and she is a survivor both of primary brain tumor (a glioblastoma) as well as advanced breast cancer. Should “Survivors” Actually Be Called “Champions”? JB: You used a word there that I know we’ll come back to discuss in some aspects over the course of our conversation and that’s the word “survivor.” It has always struck me that that word is kind of passive. It is used quite a bit in this field for people who go through the process and come out the other side successfully. In my experience, “survivor” sounds a little bit…almost weak, because it sounds as if the person was lucky to have survived versus what often happens, which is a very aggressive victory. I have almost wanted to change the common language to say rather than “survivor,” these are “champions” or “victors” or something of that nature. What has your experience been with how patients go to the other side relative to their whole outlook and emotion and approach towards their disease? JW: I have to agree with you. Certainly it reflects the way the field is sort of set up. We have the oncologists with their single-minded focus (not all of them, but a great number of them) on the cancer cell, and they really view this as a war that they are having difficulty winning with the tools that we have–the weapons of radiation and chemotherapy and surgery–and the idea of the patient just coming in and submitting passively to the treatment. This is not at all the experience I have in working with my clients. These are individuals who see their role very much as being on a team, and that the work that they do-with nutrition, with mind/body medicine, with their attitude, with guided visualization and other complementary therapies-they are very aggressively pursuing this. I agree that “champion” or a “victor” is a much better name for how they would see themselves. JB: Tell us a little bit-maybe you can use an example of how a patient would, as a client, come to you, and how you might see them and walk through the relationship with them with their disease. What to Ask. What to Test. Advice from Dr. Wallace JW: I’m lucky in that the great majority of my clients come because they are referred by oncologists. This certainly wasn’t true 10 years ago. When I work with a client, I put together for them a very lengthy report and some materials that sort of guide them through an understanding of what I call the “oncometabolic milieu.” It is sort of an understanding of the underlying processes in their body, and I focus on the terrain of the environment in their body that is promoting or fostering the progression of the cancer. So I really want to empower those clients so that they understand that there is much they can do to address the cancer in addition to going through the conventional medical treatments. We’re lucky. We get referrals from cancer centers all over the country and outside the US as well. The clients come and they often don’t have a sense of what we are going to do, so we do some orientation time and give them a sense. One thing that we like to do is we like to look at the environment of their body with a series of tests. We have them fill out extensive intake materials about their medical history, their medications, their diet, and their social life. We collect as much data as we can. Sometimes we don’t use it until later when we get the “aha,” but we do like to collect a lot data. And then we run some tests, because I want to get a sense of what’s going on inside this person’s body. I want to come back to that term that I coined-that “oncometabolic milieu”-I really have taken that from the idea in cardiovascular disease over the last 10 years that we have come to understand that metabolic syndrome is this antecedent or precursor of events going on in the body that foster and favor that cardiovascular disease process. I think the same thing can be said in cancer. We have had such a narrow focus on the cancer cell, as if it were an island existing in isolation. And what we really see now is that many events going on in the body, such as systemic inflammation, and hypercoagulability, and incompetence of the immune system and dysregulation in hormones, and also metabolic syndrome-these are factors that favor aggressive cancer growth, metastasis, invasion, angiogenesis, and cancer progression. So there is much we can do with nutrition, and also with many of the other complementary therapies, that address this oncometabolic milieu and give the client a way to really be a team member in the care of their cancer. So we run testing. We, for example, will look at metabolic syndrome. We like to look at the A1c (glycated hemoglobin A1c). We’ll run a high-sensitivity C-reactive protein, fibrinogen, vitamin D levels, sometime different hormone levels, and we’ll look at these to get a sense of where should we put our focus in our counseling with this client. Each cancer patient has a different fingerprint of this syndrome. We might have some clients who have elevated inflammation and elevated fibrinogen, but the immune system actually looks fairly okay, and maybe their blood sugar regulation looks really okay. And for another client, perhaps with the same disease and diagnosis and other similar characteristics, the underlying terrain looks very different for them. They are maybe not in a state of hypercoagulability and inflammation, instead they have metabolic syndrome and deficiencies in vitamin D and other nutrients, elevated copper, for example. We do that testing and then we sort of individually tailor our consulting for the client based on that testing. JB: You have-in that very extraordinarily condensed, articulate, rapid delivery-covered a huge landscape of important information, so I’d like to go back and pick up a few of the details because that was brilliantly stated. The term that you’ve coined, which I really like, is “oncometabolic milieu.” I wrote a couple of articles that appeared this year on…I’m using a slightly different term but I’m amazed as to how convergent our thoughts were… JW: I hadn’t seen your articles until I was at functional medicine. I was interesting to see our brains were going along the same pathway and trajectory. “Oncometabolic Milieu” JB: They really were. I talked about “oncogenic potential,” but I really like your term better. I think it is a more robust term. Let’s go through some of the subtypes that you just described: the hypercoagulability, the hormones, the metabolic syndrome, hyperinsulinemic condition, the inflammation, oxidative stress, and relationships to nutritional imbalance. You probably use as a surrogate marker–obviously, fibrinogen–to look at coagulability. Tell us a little bit. How does the coagulability component connect to your oncometabolic milieu? JW: This is really like 10 years of my research sort of coalesced into one theory. What I have done is surveyed the literature for different markers where modulating them, or reaching a certain threshold, can alter the progression of the cancer or alter response to treatment. I have maybe four dozen of these different markers, and I’ve really narrowed it down to five or six markers because they seem the most robust. If fibrinogen is elevated, a couple of things happen. It increases the metastatic potential of the cancer. This probably happens through several different mechanisms. It may be that the fibrin is sticking to the cancer cells and helping them evade the immune response. It might be that the fiber in fibrinogen is enhancing metastasis directly. It might be that it decreases the circulation and the delivery of oxygen to the tumor site, and those hypoxic areas are then resistant to treatment. Or it may be that chemotherapy doesn’t perfuse out to the tissue because the blood is sort of thick and sludgy because of the high fibrin. There are multiple mechanisms of action, here. If you look at the literature, there are some different cut-off points. Some studies have suggested that, for example, in lung cancer patients, fibrinogen above 350 is associated with poor survival/poor response to treatment. Some studies have used 310. We use 310 as our cut-off, and so when we measure the fibrinogen, if a client is elevated quite a bit above that, we will advise them on diet and nutritional supplements/botanicals that lower their fibrinogen, do an intervention, say, for 3 months or 6 months, come back and repeat the test to ensure what we are doing in terms of dietary nutritional support is actually effective at altering that particular parameter. Inflammation-and we use the C-reactive protein, here-and hypercoagulability go sort of hand in hand. Often times when the fibrinogen is elevated, you also see high C-reactive protein. There is such a large body of data and research studies linking systemic inflammation to all types of events in the oncostatic process or oncogenic process. You have increased growth rates, and you have increased rates of infection, and increased weight loss during treatment, and increased metastases, and increased angiogenesis when there is systemic inflammation. The prostaglandins and leukotrienes that are inflammatory-those coming out of COX2 and 5-drive the active growth messengers and they drive the invasion, metastasis, and angiogenesis. When we have an elevated inflammation, we can get a direct benefit from decreasing the inflammatory state, so there is definitely nutritional things and botanical things (dietary things) that we do to try lower the C-reactive protein, and we look at those hand in hand (those two). JB: It strikes me, as I’m listening to your very wonderful explanation, that it was 1979 in my life. My colleague, Jay Johnson, and I were both associated with the Bellevue-Redmond medical facility. Dr. Leo Bolles was the principal medical doctor there. We had visits from people all over the world that were in the field of nutritional medicine. We had this visit from an oncologist from Australia. He described a very simple in-office procedure that was looking at, basically, how fast blood coagulated, and he had a certain range. And he actually had studied vitamin E and showed that vitamin E could have a positive effect on these cancer patients and it had an impact on this test, a surrogate marker. It is interesting how old things get learned better and better over time and we get more precision. I give him a lot of credit because he was under a lot of criticism from his oncologic colleagues in Australia at the time. They said that this didn’t seem reasonable because there was no mechanism of purported action. You know, 30 years can make a difference in our understanding. JW: Yes, when your focus is just on the cancer cell, these types of markers of the environment or the terrain in the body don’t make any sense to you. It is one of those things. Ten or 15 years ago, when I talked to oncologists, they really thought that I was out there in left field, or out there in right field, or not even on the map. Not now, especially since I’ve been very careful to document, scientifically, where my approach is coming from. When the client gets a report and they take that to their oncologist, they have 140 pages. It is very well-referenced-some 300 to 500 scientific references-all from the mainstream literature. It can be very eye opening. On the information side of this, there is a study that just stands out so much for me, and it really-if you haven’t thought about how the environment in the body might be influencing the course of disease for a cancer patient-this study is just such an eye-opening one. It is Donald McMillan, and it was published in Nutrition Cancer in 2001.11 It is a study of 772 cancer patients-predominantly breast, gastrointestinal, and lung cancers. In the beginning of this study he measured the C-reactive protein. There is no intervention, and he waits about 3 years (1000 days), and looks at survival based on the C-reactive protein. And what he found is that using a cut off of 1.0, those patients who had low C-reactive protein, 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of them were still alive at the 1000-day mark. Those patients whose C-reactive protein was elevated above that level, none of them had survived that long. This C-reactive protein correlation was stronger than stage of disease, extent of disease, and many of the other factors. So it is sort of saying, “Here we are thinking about our cancer patients in terms of stage II disease or stage IV, it was actually a better indicator of survival-overall survival-whether or not they had inflammation.” I really spent quite a bit of time thinking about that. I thought, “This might explain in part why sometimes you have a person with stage II disease whose disease is very, very aggressive and doesn’t survive as long as one of those outliers with stage IV who becomes a long-term survivor. Maybe it has more to do the environment than the characteristics that we are currently using to assess whether or not the cancer will behave aggressively.” JB: That’s beautifully said. Let’s move next on this list to hormones, because that is a big topic, obviously, with a lot of different molecules under the title “hormones.” Are there some that you find are more problematic or of more importance when looking at those that stand up for clinical evaluation? Evaluating Cortisol and Estrogen in Cancer Patients JW: Yes. I’ll test on just two here, those being cortisol and estrogen. We’re very interested in normal pattern of cortisol regulation throughout the day, looking at that Spiegel and Sephton work out of Stanford.12 They showed (and this sort of follow-up to their breast cancer support group study that is so well known)…they are looking at that pattern of normal cortisol secretion throughout the day and finding that dysregulation in that cortisol rhythm was associated with poor survival in breast cancer. We certainly see that in our clients. I think that is probably mediated by many different events in the body. Cortisol, of course, increasing blood sugar and blood sugar dysregulation, we find-in our clinic-a very important factor. So there is the cortisol blood sugar issue. There is probably also elevated cortisol immune suppression going on. Although I haven’t touched on it with you, there is also a relationship when adrenal function is low; it can drive copper up. The adrenals are needed to stimulate the synthesis of ceruloplasmin, a copper-binding protein. Copper is a cofactor for many of the angiogenic enzymes, like VEGF, and basic fibroblastic growth factor, and HIF1. So when copper is low, it can slow the process of angiogenesis. When you have elevated cortisol or cortisol dysregulation, hyporadrenia, then what you see is copper is elevated and it favors angiogenesis. High glycemic response (metabolic syndrome) also favors angiogenic response. We’re very interested in cortisol and because of that we do a lot of adaptogens and counseling about reducing stress to normalize that. That is one area where hormones are of great interest to us. Another is estrogens. You know, there is the straightforward “Are-you-looking-at-estrogens-to-say-You-are-positive-for-breast-cancer?” (Or another type of cancer where estrogen drives it, such as with some types of brain tumors, many types of head and neck cancers, and many of the other gynecologic or reproductive cancers?) So that’s an issue, but for us, what we are really focused on about the estrogens is, again, back to angiogenesis. Estrogen drives copper up, so often when we have elevated copper we work very hard to decrease the copper as an antiangiogenic strategy. When you are looking at your free copper (so you have measured a serum copper and a ceruloplasmin), you need both of those numbers to get a sense of the free copper (what will diffuse into the tissues and act on angiogenesis). You are using a simple formula where you take your ceruloplasmin and multiply that by 3 and subtract it from your serum copper to get a free or unbound copper. When you are looking at that, if your serum copper is elevated above 130, you are probably looking at somebody with the estrogen-dominant situation, and you’re not going to be able to address the copper without addressing the hormone balance. On the other hand, if the ceruloplasmin is suppressed, especially below 22, you are probably looking at hypoadrenia and you’re going to need to nourish the adrenals and use some adaptogens in order to successfully get the copper down in your antiangiogenic strategy. In terms of hormones, those are two that are standouts. Sometimes we look at others, but those are probably the two most predominant places we are looking at. JB: That’s very, very helpful. Again, as I am listening to you I am kind of reflecting back. Years ago-this was probably the early 80s-I did a series of grand rounds at the University of Arkansas School of Medicine, and I met a professor there by the name of John Sorenson. If you do a search PubMed on his name, he published a lot on copper, and particularly as it related to both vascular disease risk and to cancer.13,14 He was one of the first people that I had ever heard to talk about molybdenums and antagonism of copper, and he was actually studying molybdenum salts in animal tumor models, showing that you could prevent angiogenesis. I know there is some work on molybdenum that has occurred since then. JW: Yes. That’s George Brewer’s work out of the University of Michigan, and he has now three or four preclinical trials (pilot trials) on cancer patients where they have used the off-label drug-it is a drug developed for Wilson’s disease, tetrathyomolybdate. They’ve used that quite successfully in cancer patients to drive the copper levels down.15 JB: Amazing how these things all interconnect when you start looking at a broader picture. Let’s move-this is a good segue, obviously, talking about insulin and its influence on cortisol-to hyperinsulinemic syndrome, which we call metabolic syndrome. Tell us a little bit about how you look at that, how you assess that, and then maybe what your thoughts are about the appropriate kind of food plan or diet plan for patients in that situation. Cancer and Metabolic Syndrome JW: Going all the way back to Warburg perhaps, where there was the first acknowledgement that cancer cells are sugar feeders, and there has been such a controversy about that in the literature, and certainly the oncologists have a lot of resistance to that. Moving forward, is it really the sugar itself that is the problem? I don’t think that it is. I think what we are looking at, here, is that we get this metabolic syndrome where we have increase in the insulin and insulin resistance at the same time, and that sort of drives a huge cascade of events. For example, insulin resistance is then going to increase the secretion and production of insulin-like growth factors and decrease their binding proteins, so you have more active insulin-like growth factor that acts as a cascade. And then you have the adipose sites and the different hormones that they make and that is increasing angiogenesis. And then you have the insulin increasing the activity and signaling of aromatase, so you get more free estrogen. It’s like this huge cascade of events that can impact the cancer in many different ways. You look at the literature and you see for breast cancer patients, colon cancer, and many other cancers, those who have signs/symptoms of metabolic syndrome have greater risk of recurrence, have greater rates of metastases, have significantly shorter survival.16,17 There is also some research showing post-op complications in colon cancer patients are much higher in those with metabolic syndrome. Patients undergoing bone marrow transplant have greater risk of infection. There are several different ways that this can impact the cancer process. We screen for metabolic syndrome. We don’t use a fasting glucose. We really look at the glycated hemoglobin A1c (so you’re not getting a single snapshot of where the sugar is with the glucose; you’re looking more over a two- to three-month process). And then we are also looking at waist circumference, for example, and HDL cholesterol levels, and just, you know, the whole kit-and-kaboodle. I want to remember to say: I think it’s really important we (most of us who work, I think, in the integrative medicine field) have this knowledge of metabolic syndrome. You are looking for waist adiposity, and you want to remember that cancer patients in chemotherapy and radiation undergo sarcopenia; they lose muscle mass. So the number on the scale when they step on may be the same, and they may still fit into their clothes, and they may still look “fit” or have a lean body weight, but they may be metabolically obese as a result of having lost that muscle mass. So you want to remember to screen not only those with extra waist circumference, but you want to look at these markers if a person has been in treatment, because certainly they have metabolic syndrome even though they don’t necessarily look apple-shaped, so to speak. So that’s a good point. And then in terms of the diet, this is just huge. I think a lot of people have approached the diet about “What diet should we give a cancer patient?” based on politics, and dogma, and all different kinds of ideas. I grew up a vegetarian. I was a vegetarian for a very long time. I was wedded to that idea, but when I started having the idea that my clients with cancer needed to have a diet that lowered inflammation, was not high in copper, and did not raise the blood sugar, I really began to look very differently at what I should be suggesting for diet. And instead of coming from the “this is the diet that everybody says is the right diet for cancer patients,” I end up individually tailoring diet for each person based on “How can we get their blood sugar down and the C-reactive protein down?” So I often find, when I have clients who come in who have been on a vegan diet (and often but not always a vegetarian diet), that they’re having a lot of difficulty regulating their blood sugar on that diet. In particular, the vegan approach, we find, elevates the copper, predominantly because the best food sources of zinc are meat foods. We end up doing a very low refined carbohydrate, very low carbohydrate (almost no starchy carbohydrates-we limit that very strongly), so that the client is getting their carbohydrates predominantly from vegetables and legumes that are low glycemic, and letting them eat, yes, meat, as long as it is organic and pastured or grass-fed. Poultry and eggs, which are often not included in those diets, we find that that is often the best way to regulate the blood sugar. We look at other things. Do they have digestive incompetence? If you have trouble with your digestion you are not digesting your fats and proteins, and then regardless of including them in the meals you may only be getting your carbohydrates and that causes a spike in your glycemic response after your meals. We look at muscle mass. If they are sedentary then they need to be put on an exercise program with some weight training to build some muscle mass back. We look at stress levels, and cortisol, and nutrient deficiencies like chromium and zinc, magnesium, vitamin D. All of those are involved in the insulin resistance or in blood sugar regulation. Cancer and Antioxidants JB: Beautiful response. Let’s move to this concept of free radical oxidation, which often accompanies inflammatory conditions. And we have this whole big thing out there about antioxidants. I know at the Symposium virtually every presenter spoke, or at least touched partly in their discussion, on this antioxidants conundrum. Do you have an opinion or thought about this antioxidant connection with oncogenesis? JW: I could probably talk your ear off about for several hours. Yes, I definitely have some thoughts about that. And certainly looking at the literature, one thing that really stands out for me is the genetic stability. You know, when the oxidation is increasing you get a lot of genetic instability. In terms of maximizing the treatment, and preventing more aggressive behavior of cancers after tumors, you don’t want that genetic instability. I think a big part of the “controversy” has sort of been a focus on antioxidant supplements. I grin when I say that because I think the antioxidant power of vitamin C, or vitamin E, or some supplement, pales in comparison to a whole food. If you are looking at those charts on the ORAC values, for example, and you see vitamin E comes in at 125 ORAC, says research out of Tufts, and then you look at any respectable fruit-take blueberries-and the ORAC value is 3,250, it’s like you’re not really talking about antioxidants when you are talking about a single nutrient that you are taking as a supplement. Many of the oncologists who perhaps have not studied antioxidants use that term as if it was an umbrella of one or two things and don’t understand the different types of free radicals. And they are telling their patients not to have any antioxidants, not realizing that if a person goes out and eats a chocolate bar, they are getting antioxidants. As something that we look at, we know with the diet we are recommending, and we are trying to get our clients to eat 8 to 10 (bare minimum), half-cup servings of fruits and vegetables every day, we can see a big change in oxidation when they are doing that. Cancer and Vitamin D JB: That’s a beautiful recommendation. Let’s talk briefly about this vitamin D controversy. There is this concept that 1,25-dihydroxyvitamin D as a seco hormone that has great effects on multiple gene expression patterns, and overdrive can increase oncogenic potential, but then underdrive can also increase oxidative potential, suggesting a parabola of optimal levels in tissues of 1,25. But we are measuring the 25, so people, I think, assume that if 25 is low then 1,25 must be low, but we have actually seen, and I’m sure you have as well, there are some cases where people’s 25 are low but their 1,25 are high and the more 25 you give them the more they convert it to 1,25. Do you have a thought about this whole conundrum of vitamin D? JW: Yes, and that was sort of new for me, something that I got as a gem out of the conference, because we were not measuring 1,25 often. When 25-hydroxy was not going up, then we would come and look at the 1,25 and then we were limiting vitamin D supplements, since we said, “Okay, that’s where it is going and we don’t know how to stop it from going there.” We set our range of optimum vitamin D for the 25-hydroxy between 60 and 80, and I ended up setting that range based on several different studies and my work with autoimmunity, which runs in my family. We were aware, having worked with some autoimmune clients, that when we get the vitamin D to 80, that works sort of as an immune suppressant. That works sort of to induce immune tolerance. When that worked so well, my thinking was, “Well, I probably don’t want to drive the blood level of 25-hydroxy over 80 or I may be suppressing immune response instead of benefitting it.” I think there is still quite a bit of basic research that needs to be done on vitamin D to answer some of these questions. In our brain tumor group, certainly there is a lovely study out of France by Paul Trouillas in which they used high-dose vitamin D supplements in patients who had completed and failed all other therapies (or more likely those therapies had failed them).18 The chemotherapies, radiation surgery–they had had the maximum of those treatments and their tumors were still growing. They had a fair response rate. I think it was 27{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the patients in that trial had a response, including several complete regressions, and there is a four-year, a five-year, and now a seven-year survivor in that study, which is still ongoing. This is for glioblastoma muliforme, where six months is sort of a median survival and if you make it to a year, in the literature that is considered quite good. Vitamin D having such a strong response as a differentiating agent in that study, we’re still very enamored of using vitamin D for our clients. I think there is an interplay between vitamin D, vitamin K, vitamin A, and perhaps vitamin C that has not yet been looked at. Having been wedded to the scientific approach of “study this one thing individually,” we really miss a lot in nutrition where there is such an important synergistic effect and interplay of many different nutrients together. I’ll be holding out until we get a clear picture of what those interactions are and what to do. JB: Very well said. My last question has to do with this digestive incompetence that you referred to. I know there is a big body of literature that is emerging right now about the gut microbiome and how the physiology of this highly diverse community of bugs we have in our gut influences our immune system and cellular function. There is some work suggesting that certain supplements, pre- and probiotics, might be useful in either pre- or post-treatment cases in cancer. What is your experience with pre- and probiotics, if any, at this point? Cancer and Pro- and Prebiotics JW: We definitely use them for many reasons. Our clients are on all types of treatments that kill off the great majority of flora in the intestines, and obviously those are so important in helping with immune competence. There are several other things that are important for that healthy eubiosis in the gut. Maybe key among those is when you have those healthy bacteria and you are eating a diet high in soluble fibers, your intestines become a butyrate-manufacturing facility. And butyrate is a histone deacetylase inhibitor. It is a differentiating agent. It is really important for cancer patients. We really want to ensure that our clients have those healthy bacteria at least for that reason, if not also to crowd out unfavorable bacteria, which would, for example, in a breast cancer patient, those bacteria would be using beta-glucuronidase enzyme to reassemble estrogens that had been broken down from the liver. There are several different pathways from which that is really important to do. It is definitely part of our protocols to do that. JB: Obviously we have just touched the tip of the iceberg. You are a dense treasure-trove of extraordinarily useful information. I guess I’d like to close by asking to look out at the horizon for a moment, and with your experience that you are having both at the evolving frontier of the interface between science and patients, and also with the changing way that patients respond to their own disease, what is your view of the future? How do you see things unfolding? JW: I’m really excited about where we are right now. Speaking at the Symposium was really exciting to me. I met many oncologists who were there. I’m just thinking ten years ago that kind of discussion-friendly discussion-between where we are with nutrition and complementary medicine, and the integrative field and oncologists, that may not have been possible. I feel like I’ve climbed a mountain, I’m standing at the peak, and I can see out over the field, and I’m actually very excited about where we are. I also think that this approach, I’m happy to be able to share this with people Many practitioners keep all of their secrets very carefully guarded. I don’t feel that way. It is such a big field and I’m happy to share my information. I think one of the pearls of this particular approach is it really allows you to individualize the support for those cancer patients. Whereas often new clients come to me and they’ve seen four or five practitioners and they have the same little bag of 30 supplements that this practitioner gives to every cancer patient and how do I know which ones are actually useful for me and which ones might be doing me harm? This kind of exploration-using some testing to explore the terrain and then individualize the protocol-I’m hoping that the entire field of oncology will move more in that direction, not only the integrative/nutrition/holistic approach being individualized, but also I’m seeing with a lot of the mainstream and conventional treatments that we are moving in the direction of individualizing cancer treatments. I think we are just at the beginning of that, and that’s what we will begin to see over the next five years. I’m excited about it. JB: Well, I think you are both a very articulate spokesperson for this evolution and also, obviously, a dedicated clinician/professional really assisting people at times that are very challenging in their individual and their family lives. I applaud you. It’s very courageous of you. For our listeners, if you want to be reached, I presume it is through your group, Nutritional Solutions Consulting. JW: Nutritional Solutions, that’s right. JB: Which is at nutritional-solutions@comcast.net? JW: That’s correct. JB: We’ll put that on the summary. Again, it is nutritional-solutions@comcast.net. People who want to contact you by email. Dr. Wallace, thank you so much for spending the time with us. Again, I am so in admiration for what you are doing. It is a big job, and as they say, you need big people to do big jobs and obviously you are one of them. Thank you so much. JW: Thank you very much. What has been the ultimate objective of this month’s Functional Medicine Update? I hope it became very clear to you hearing the eloquent and very, I think, well-framed conversation with Dr. Wallace of how she approaches cancer in her consultations that there is something here, in the functional medicine area, that really deserves much more attention, that deserves much more focus to try to improve outcome and to reduce unnecessary burden of disease and prolong life, if not prevent the disease to begin with. I think that this is a very, very exciting part of the functional medicine story. When we started down this road some 20+ years ago, little did we know where the journey might take us. It was my belief, probably at the onset of our functional medicine model, that we wouldn’t have much to say about oncology. But because we are all connected by the same web-this same web of physiology that connects cancer together with heart disease, with arthritis, with dementia, the functional medicine matrix and that method of thinking provides an insight that can be applied to virtually every state of pathophysiology. So I hope there are some tools and news to use out of this extraordinary discussion with Dr. Wallace.

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Bibliography

1 Zhang Y, Gaikwad NW, Olson K, Zahid M, Cavalieri EL, Rogan EG. Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Metabolism. 2007;56(7):887-894. 2 Mulvey L, Chandrasekaran A, Liu K, Lombardi S, Wang XP, Auborn KJ, Goodwin L. Interplay of genes regulated by estrogen and diindolylmethane in breast cancer cell lines. Mol Med. 2007;13(1-2):69-78. 3 Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007;55(3):224-236. 4 Bell MC, Crowley-Nowick P, Bradlow HL, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol. 2000;78(2):123-129. 5 Spink DC, Zhang F, Hussain MM, Katz BH, Liu X, Hilker DR, Bolton JL. Metabolism of equilenin in MCF-7 and MDA-MB-231 human breast cancer cells. Chem Res Toxicol. 2001;14(5):572-581. 6 Boyd DB. Insulin and cancer. Integr Cancer Ther. 2003;2(4):315-329. 7 Hernandez-Diaz S, Adami HO. Diabetes therapy and cancer risk: causal effects and other plausible explanations. Diabetologia. 2010;53(5):802-808. 8 Hassan MM, Curley SA, Li D, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer. 2010;116(8):1938-1946. 9 Gerstein HC. Does insulin therapy promote, reduce, or have a neutral effect on cancers? JAMA. 2010;303(5):446-447. 10 Lipska KJ, De Rekeneire N, Van Ness PH, et al. Identifying dysglycemic states in older adults: implications of the emerging use of hemoglobin A1c. J Clin Endocrinol Metab. 2010 Sep 22. [Epub ahead of print] 11 McMillan DC, Elahi MM, Sattar N, Angerson WJ, Johnstone J, McArdle CS. Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer. 2001;41(1-2):64-69. 12 Sephton SE, Dhabhar FS, Keuroghlian AS, Giese-Davis J, McEwen BS, Ionan AC, Spiegel D. Depression, cortisol, and suppressed cell-mediated immunity in metastatic breast cancer. Brain Behav Immun. 2009;23(8):1148-1155. 13 Crispens CG Jr, Sorenson JR. Evaluation of the anticancer activity of CuDIPS in SJL/J mice. Anticancer Res. 1988;8(1):77-79. 14 Sorenson JR, Wanglia GW. Co-treatment with copper compounds dramatically decreases toxicities observed with cisplatin cancer therapy and the anticancer efficacy of some copper chelates supports the conclusion that copper chelate therapy may be markedly more effective and less toxic than cisplatin therapy. Curr Med Chem. 2007;14(14):1499-1503. 15 Gartner EM, Griffith KA, Pan Q, Brewer GJ, Henja GF, Merajver SD, Zalupski MM. A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer. Invest New Drugs. 2009;27(2):159-165. 16 Shen Z, Ye Y, Bin L, Yin M, Yang X, Jiang K, Wang S. Metabolic syndrome is an important factor for the evolution of prognosis of colorectal cancer: survival, recurrence, and liver metastasis. Am J Surg. 2010;200(1):59-63. 17 Rose DP, Haffner SM, Baillargeon J. Adiposity, the metabolic syndrome, and breast cancer in African-American and white American women. Endocr Rev. 2007;28(7):763-777. 18 Trouillas P, Honnorat J, Bret P, Jouvet A, Gerard JP. Redifferentiation therapy in brain tumors: long-lasting complete regression of gliablastomas and an anaplastic astrocytoma under long term 1-alpha-hydroxycholecalciferol. J Neurooncol.

Welcome to Functional Medicine Update for November 2010. “Function.” What does it mean? That’s a very interesting question. It’s one that we have been talking around, through, up and down, and examining and microscopically dissecting for the better part of 30 years. In this issue, you are going to be exposed to a real fundamental understanding of what we mean by function. This may be a paradigm-shifting experience. In fact, I would say strap on your intellectual seatbelt. I would even go so far as to suggest that if you are listening to FMU for the first time, you need to find a quiet place to do it. Distraction really would be a disadvantage in fully absorbing what our clinician/researcher of the month has to say and how he says it. Without further ado, let’s move right to one of the most extraordinary interviews that I have had the privilege of having in my 28 years of doing Functional Medicine Update.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Moshe Szyf, MSc, PhD Department of Pharmacology and Therapeutics 3655 Promenade Sir-William-Osler Room 1309/1310 Montréal, Québec H3G 1Y6 Canada Those of you who have been following Functional Medicine Update for many years are probably very used to me saying this each issue, and that is what an exciting opportunity we have to hear from the voice of someone who is creating a discipline that is changing the whole paradigm of medicine and health care. We’re not to be disappointed this issue because I’ve been very, very privileged to be able to get Dr. Moshe Szyf to tell us about his work. I’ve been following it now probably since about 2006. I think it is some of the most pioneering and impactful and paradigm-shifting work that I’ve had the privilege of reading in that period of time. As I look at it, probably in retrospect, for the last couple of decades. Let me tell you a little bit about Dr. Szyf. He has a fascinating background. He got his original degree at Hebrew University in Jerusalem. He went on and did a post doc in biochemistry, and then went on to do a post doc at Harvard Medical School in genetics. For the past three decades he has been focusing on understanding how DNA methylation plays roles in genetic transcription and gene expression patterns, and ultimately phenotypic outcome of cells and function of organisms. As you know, we have been spending a reasonable amount of time over the last couple of years trying to get our intellectual arms around this concept of epigenetics, and Dr. Szyf is certainly one of the pioneers in this field. Looking at how that work emerged and evolved in his lab, he has developed various ways of looking at DNA methyl transferases and how they regulate gene expression patterns, and how that ultimately translates into understanding factors within the environment that might modulate or influence DNA methylation and demethylation in these epigenetic marks that alter the programming of genes and how they express their function. He has published widely. He is I think what I would call a translational researcher. He has been everything from a microscope to a telescope, looking all the way down, using gene arrays, to examine how genes are expressed and epigenetic marks, and looking all the way up, at whole-organism phenotypes through behavioral studies in animals and trying to determine how this all fits together. Dr. Szyf is at McGill University. He is in the Department of Pharmacology there. Most of us are very aware of the history of McGill Medical School and McGill University. This was the birthing place of the term “stress” in physiology-by Hans Selye. I think “stress” is now the most cited English word in medicine (a single word being appropriated from physics). If Dr. Selye was alive today, I think he would be celebrating Dr. Szyf’s work, saying, “I can’t believe how this has evolved since my early observational years with adrenalectomy of rats and how far we’ve come in understanding some of the more detailed mechanisms of how these factors in the environment translate into function.” With that long-winded introduction, Dr. Szyf welcome to Functional Medicine Update. I just can’t tell you how much we appreciate you being with us today. Let me start with the first question. From a biochemical/genetics background, what led you into this whole field of epigenetics? DNA Methylation Patterns Can Tell the Story of a Life MS: I started my career with epigenetics, and actually the first experiment I did was to look for mutants of E. coli that don’t have the enzyme that methylates DNA. I’ve been doing this for 30-something years. When we started, we looked at phages that infect bacteria, and there was one phage we looked at-it was called Phi X 174-and it has one methyl group and we tried to understand its role. I was fascinated by DNA methylation because philosophically it is a very interesting creature. On the one hand it is part of the chemistry of the DNA. So if you, for example, take a mummy that died 5000 years ago and take its DNA and sequence it you get the ancestral information. You can also sequence the methylation pattern. You get information of DNA methylation, which we now know tells the whole story about the life of that individual. So we have, in between the very fixed DNA structure that is copied by very strict rules, something that is, on the one hand, dynamic, and on the other hand very stable. So it was very clear from the early days that this was something really fascinating, something very different from what we knew about in genetics, and that’s why I was attracted to it. JB: My first contact with your work was, as I mentioned, back in about 2006 when I happened onto an article that you had been a principal author on, on targeting DNA methylation in cancer and how these regulatory mechanisms might play a role.1 Let’s walk down your history. For me, that’s where it starts. DNA Methylation and Cancer Research MS: Right. After maybe 10 years of working on DNA methylation, it seemed to me to be a great mechanism to explain what happens in cancer. Cancer is characterized by numerous changes in gene expression. Essentially a cell changes a program from one state to the other state. In thinking about what can do that, DNA methylation was a perfect candidate. Our first studies looked at the regulation of the enzyme that methylates DNA and if it changes with cancer. The first discovery was that the enzyme that methylates DNA goes up when the cells replicate faster. The second discovery was that all of the known cancer pathways turn on this enzyme. Third came a question: so what if it turns on this enzyme? How does it transform a cell? We discovered that what happens in cancer is it turns it on at the wrong time of the cell cycle. So if it is normal for this enzyme to methylate DNA as it is dividing, it is not normal for it to methylate DNA when it is not dividing, because when it does that it adds methyl groups that should not be there. Then we noticed that in the bottom of the methyl transferase gene there is a regulatory region that was conserved in evolution. When you have that region, the methyl transferase works perfectly well with the cell cycle and cannot change the fate of cells, but when you remove it and put it in a cell, it transforms the cells. It changes the methylation organization of the cell. That led us to the question: what kind of proteins regulate that? We’re still working on how this is connected to the cancer pathway. S-Adenosylmethionine, Methylation, and Cancer JB: Let me take that, if I could, to an area that I know a lot of our listeners who are clinicians have been following, and that’s the interface between methylation and the tetrahydrofolate cycle and the universal intercellular methylating agent, S-adenosylmethionine. There have beeninteresting reports recently that I’m sure you have seen on things like adenomous polyps and folate supplementation and does that prevent or does that increase the relative risk to malignancy? What have you-if anything-seen as it relates to the interface of the folate cycle with these things that we are talking about in cancer replication? MS: We were most interested in S-adenosylmethionine, which is kind of the bottom end of this folate cycle. S-adenosylmethionine is the donor of the methylation reaction. What we found was that many of the metastatic genes get demethylated in cancer-lose methyl groups in cancer-and if we treat the same cancer cells with S-adenosylmethionine, we can methylate those genes, silence them, and block cancer metastasis, both in human cancer cell cultures in vitro and when you transplant into mice in vivo. One important connection is it seems that deficiency of S-adenosylmethionine (SAM) could enhance cancer metastasis. There is a body of literature that connects S-adenosylmethionine and cancer in rodents, especially in the liver. When rodents are fed a diet that is deficient in the methyl donors, and therefore reduced SAM, they will develop liver cancer at a much higher frequency. And vice versa. You can protect animals from cancer by providing them with S-adenosylmethionine. So this is the positive side of S-adenosylmethionine. We also discovered that S-adenosylmethionine actually blocks the process of DNA demethylation, the opposite of DNA methylation, where enzymes remove methyl groups. So we think there is a big hope for S-adenosylmethionine intervention in preventing cancer metastasis. Another example where S-adenosylmethionine might be important is in diseases like lupus, where again there is a global loss of DNA methylation and perhaps in those situations there is a need for upregulating the methyl donor facility in the cells. You know, there is a good connection between S-adenosylhomocysteine, which is the opposite of the unmethylated form of S-adenosylmethionine, and cognitive decline in Alzheimer’s disease. There are multiple examples of health problems that are a consequence of lack of S-adenosylmethionine. That is a downstream consequence of lack of either folic acid or vitamin B12. However, there is the opposite side, which is increased methylation can also cause cellular transformation. There was a fear that folate supplementation might do the opposite, which is increase the risk for cancer. I’m not sure about how strong this data is. My inclination is that actually high levels of SAM would be, overall, protective from cancer and cancer metastasis. The big question is: Are these accidents that happen because you have too much SAM or too little SAM and then some stuff happens and some genes get methylated and some genes get demethylated, or the body responds to the signals that come from low SAM or high SAM by resetting programs? I kind of tend to believe in the latter in that both during development and later in life we have mechanisms that sense how much SAM we have and reset, essentially, the entire program of the cell, including the way DNA is methylated, to respond to this environmental challenge. We don’t know yet how much folate is sending a signal that is protective from cancer, and at what point that signal will be kind of facilitating the development of cancer. JB: That was beautifully stated. Very nice summary. It reminds me, as you are speaking, that years ago on Functional Medicine Update we had the privilege of interviewing Dr. David Heber from UCLA, in the medical school there, and he was talking about work that they had done looking, as you say, at liver cancer in folate-deprived animals and the increasing relative risk of carcinogenesis as a consequence of exposure to chemicals.2 One of the things that I’m abstracting from your discussion is that there may be multiple variables that together orchestrate this expression alteration that we see as cancer. It’s not just a single hit or a single agent. Thinking Of Cancer as an Adaptive Program MS: Oh no, I think it’s an entire program. And I think we still don’t understand what this program is telling us, because I think if we understood why the program is turned on, we would have better ways of dealing with it and preventing it or treating it. I think there are really two concepts in the way cancer develops. One is the Darwinian concept, which is that bad things happen by accident and then if a cell gets a mutation that makes it replicate faster it would be selected and then eventually another mutation happens and you get more selection and then another mutation. This is to look at cancer as a sequence of random events that somehow are selected because of the growth advantage of a cancer cell. And there is the other perspective that I tend to subscribe to more now, looking at the kind of changes that happen in cancer (that really cancer is a program). It’s a program that is part of the adaptive programs that our genomes have, and it finds itself in the wrong context and then it becomes a disease. I think there is a very strong connection between these programs and the methyl or mono-carbon cycle in the cell. These send a signal to the cells, reset your program this way or that way, and that program can lead, in certain contexts, to cancer. JB: That really brings to mind an enigma that I’ve had in my thought process ever since developmental biology in undergraduate school: What about stem cells? How do they get deprogrammed and reprogrammed into ultimately becoming differentiated cells? Obviously methylation programming plays a big role in that. It strikes me that these are some things that we are really just at the frontier of trying to understand, thanks to your work and others. By the way, for our listeners, on the bibliography that we’ll be supplying along with this, which will list Dr. Szyf’s articles, there are a couple of other papers that I think fall into the light of this DNA methylation/cancer. One is titled “DNA Demethylation and Cancer: Therapeutic Implications” that was in Cancer Letters, and another that is a very nice review paper that you put together in the Annual Reviews of Pharmacology and Toxicology in 2009 on “Epigenetics, DNA Methylation, and Chromatin-Modifying Drugs.”3,4 It really, I think, is a pretty forward-looking review of where this field might go, therapeutically. Let me move to autoimmune disease, because you’ve also touched upon that and you have a wonderful article in Clinical Reviews of Allergy and Immunology that I think is one of those landmark, “aha” articles titled “Epigenetic Therapeutics in Autoimmune Disease.”5 Can you give us a little bit more thinking about how this epigenetic methylation model fits into the autoimmune constellation of disorders? Methylation and Autoimmune Disease MS: There is evidence that the methylation machinery is effective in autoimmune disease. One of those is, for example, lupus, where the evidence is strong. We know that demethylating drugs can induce lupus. For example, people treated with either 5-Azacytidine or other drugs that are known to be hypomethylating drugs, are at high risk of developing lupus. If you look at the DNA of T cells from lupus, it is hypomethylated–it has globally less methylation–so it is a dramatic change in methylation levels. It seems that they have a defect in their methylation machinery, which results in activating genes that are the pathway of T cell activation that are normally shut down and only activated in response to specific antigens. In this case they are hyperactivated in a very promiscuous way, resulting in an attack of the immune system on the body itself. The question, of course, is why does this happen? Why do T cells lose their methylation level and become these kinds of cells? Is this some sort of an adaptive response that probably has some sort of physiological role in the proper context and now is out of context? Again, I think there is a program out there. To decipher this program one has to look at not one or five genes to change, but entire circuitries of genes to change, and ask the question, why do they change? Another interesting thing is that in lupus there is a high level of an alpha protein called MED2 that we found is responsible, in part, for demethylation, suggesting that resetting the regulation of demethylating enzymes results in a whole resetting of the pattern of how the DNA is methylated. I think we can ask the question at many levels, what’s the relevance of that? There are ways to deal with lack of methylation. The big question is can we supplement the missing methylation by pharmacological or dietary tools? I think it is worth it. Can we inhibit the demethylating enzymes and remethylate the DNA to make those T cells normal again? And I think we can ask the question at a different level: What is the physiological purpose of this kind of response of T cells? Why does it happen? What does it tell us? And what kind of environment were these cells exposed to that they responded in this way and how can we prevent that? DNA methylation allows us to ask these questions at many levels, from the therapeutics to the diagnostics to the prevention. JB: In your review article-your article titled “Epigenetic Therapeutics and Autoimmune Disease”-you also introduce a concept that I hadn’t thought much about, which is quite interesting, and that’s the counter-current communication (or cross-talk) between histone acetyl transferases and histone deacetylases, the acetylation of the genome as contrasted to the methylation if you think of the methylation as “stop” function and the acetylation as “read here” function. And then that ties into things like, “Does this have any relationship to phytochemicals like resveratrol that influence independent histone deacetylases?” MS: Absolutely. JB: And so is there a SIRT1 longevity relationship here of cells? I’m sure you’re thinking about all these things, but it sounds fascinating that there is a circuit, possibly, of epigenetic programming and with methylation tied to acetylation that is a very important switching point. The Relationship between Histone Acetylation and DNA Methylation MS: Right. As you recall, we published several papers showing that if you change histone acetylation you also change DNA methylation, so these things cross. And that has significance both for the impact that wine can have on humans, as well as drugs. A good example is valproic acid. It’s a drug that has been used in the past (for decades) as an anti-epileptic drug. Nobody thought that it was an epigenetic drug, but now it is quite clear that it is a histone deacetylase inhibitor. But again, nobody thought that it changes DNA methylation, and now there is very strong evidence that it changes DNA methylation. So now you can ask two questions: What is the toxicology of valproic acid that is associated with changing DNA methylation? We never thought about it. As well as: What are the pharmacological therapeutic utilities of valproic acid in certain cases where we actually want to change DNA methylation? Can we use it? For example, can we use it in cancer? Or can we use it in certain psychiatric situations where actually demethylation could be useful? These questions are being asked now. I think the other implication is that almost every chemical that we are exposed to has to be tested, as far as its impact on the epigenome and the connections. The fact that one chemical changes histone deacetylation doesn’t mean that it only changes histone deacetylation; it also can change DNA methylation, and therefore histone methylation, etc. etc. Epigenetics and Pharmacology JB: You’ve authored at least two papers that I’ve read that really were kind of mind-bending in this area for me. One is titled “The Dynamic Epigenome and Its Implications in Toxicology,” and then the more recent one is “Epigenetic Side-Effects of Common Pharmaceuticals: A Potential New Field in Medicine and Pharmacology.”6,7 I think very few people that I’ve ever spoken to have conceptually thought about what would happen with long-term use of specific drugs that modulate epigenomic methylation patterns. Maybe you can speak to your thought here because I think it is pretty powerful. MS: I think the classical tests that we give drugs are very short and intense. Essentially we test whether they work in animals, and whether they cause genetic mutations and if they don’t we are very happy. The thing about epigenetics is epigenetics is a memory for the genome to an exposure. It can hit you many years down the line. So you are treating with a drug that gives you whatever effect you think it is acting on-blood pressure, or GABA receptors, or something like that-assuming that that is what you want to do, and then you inject it into rats, and you figure out the toxic BLD50, and you are happy because you are well below that and it doesn’t change blood pressure and other things, and off you go. The drug is approved. But at the same time, it modulates one of the enzymes that controls the epigenome, and there are dozens and dozens of those enzymes. The scary part is that they are all connected, so if you change one you will change the others. And if you change DNA methylation, you essentially change the memory of the genome; you change the way the genome is programmed. And the impact might not be immediate, but it might be down the line. The other scary part is that we thought in the past that DNA methylation is only of interest to cells that divide, because there was a dogma that you cannot lose DNA methylation because it is such a strong chemical signal unless the cells divide without an enzyme that methylates DNA. And since most of our body doesn’t divide, we’re not worried about effects like this. That was the general concept. But now we realize that neurons that don’t divide-and as you know, we did quite some work on behavior-are highly affected by methylation and demethylation. So you give somebody a drug that is supposed to be lowering his blood pressure or acting on acne in his skin, and they demethylate genes in the brain (or hypermethylate genes in the brain), and the consequence of that will be felt long after. What if it changes the methylation pattern of germ lines or germ cells? And then these effects will go to the next generation and to the third generation? Essentially we are starting to reexamine a lot of those safe things that we did-how safe they really were. JB: There are so many fantastic things that you are bringing up. My mind…every neuron is firing because it’s just raising all sorts of interesting questions. Let me, if I can, focus on revisiting the autoimmune story as a model. There has been a long anecdotal history suggesting that certain dietary approaches can improve autoimmune disease. These are diets that are generally low in animal products, richer in vegetables, and lower in processed foods and sugar and so forth. But there has never been really a mechanism to explain why this might be. I know I’m over-extrapolating here, but in listening to you, it sounds like it would be at least possible that these very phytochemical-rich diets that have been associated with lowered autoimmune disease could have influence on-because of the role that we know that some of these phytochemicals have (we’ve talked about resveratrol, but there are many of them)-these methylating enzymes and on the acetylation enzymes, that maybe you are really modulating some of these things in immune cell lines that you are describing with these diets in a much more profound way than we previously understood. Is that at all possible? MS: It is possible and it is testable. I mean, that’s the beauty of DNA methylation; you can actually measure it. You can measure it at a global level. You can measure it at a gene-specific level. You can measure it at a whole-genome level. You can measure it at the resolution of every CG in the genome. I think what I’m really saying is that we have to examine these things scientifically, both the positive and the negative things that we are doing. Positive biases, as we know, epidemiologically have a positive effect. It is worthwhile examining what impact they had on the epigenome and vice versa. They are all testable hypotheses and they could be easily modeled. The immune system is actually one of the best ones to test because it is relatively accessible. You’re not talking about deep brain structures; you are talking about the cycling, itself, that you can access. What is needed is a controlled experiment where you can actually follow the epigenetic states of different kinds of T cells, for example, before and after the intervention and compare it to a control group. JB: A clinician listening to your extraordinary story might distill this down to when they are sitting with a patient in the exam room and say, “Gee, does that mean that I should-because these are methylation defects in these autoimmune patients-see homocysteine plasma elevations in these patients as an indication of their methylation defect?” I think what I’m hearing is we shouldn’t jump to the conclusion that this necessarily always would be translated as something that we see as elevated blood homocysteine. MS: No, not at all, because there are so many ways to change the methylation pattern. Homocysteine is probably one way; I’m not sure it’s the strongest way. It could be all of the things you’ve mentioned-drugs the person has taken-and you would not see homocysteine differences. It will be a response of the machinery of the DNA methylation and epigenome machinery to whatever signal that exposure is given, and it might not be seen in homocysteine levels. However, you can examine epigenetic levels. That’s doable and that should be done. JB: One of your many papers-and I know I’m just hitting spots along your very remarkable and productive scientific life here-was in the Journal of Medical Primatology and had to do with organ and gestational effects of maternal nutrient restriction on global methylation.8 I think this is work done in baboons. Can you tell us a little bit about what happens when you restrict nutrients on the methylation patterns that were seen in primates? Effects of Nutrient Restriction on Methylation Patterns MS: There are dramatic global changes in DNA methylation. Obviously there are dramatic changes in health and that is manifested later when these animals become adults; we know that. But we didn’t know what the possible mechanisms are. One mechanism is an overall change in the way the DNA is methylated, suggesting kind of an overall response of what we call the methylome (the entirety of the DNA methylation signals around the genome in critical tissues). The question is, why is it happening? You can have a mechanical explanation: that when you deprive animals of amino acids you also deprive them of donors of the methyl group that goes into S-adenosylmethionine, eventually inhibiting the methylating enzymes and stimulating the demethylating enzymes. That’s one way of explaining it. The other explanation is that what we are seeing in these animals is essentially an adaptive response-that life under nutrient deprivation is a different life than life under nutrient excess. What the mother is doing by the nutrient deprivation is sending a signal to the developing fetus. “You’re going to have a tough life, and therefore you need to reprogram your genome to deal with that.” If you are under nutritional deprivation, any piece of food you eat has to be stored as fat because you never know when the next meal is coming, therefore you have to push all the enzymes (the genes encoding these enzymes) to deal with metabolism towards fat storage and towards insulin resistance. Whereas if you are in a world where there are high nutrients, you need a different genome. You need a genome that takes every piece of food and just turns it into energy and doesn’t store it as fat. There are two ways to look at it. Is this DNA methylation change an accident that happened because of a mechanical defect in the enzyme because they were not supplied with whatever they needed to work? Or, is it a signal that the environment of the mother, through the amount of food, is sending to the developing embryo on how to program the genome? I believe in the latter, as you can guess from what I have told you before. I think that all these things, from autoimmune disease to type 2 diabetes, to depression and stress, are all adaptive responses, many of which are programmed early in life by signals that come from the environment. These signals could be nutrients. They could be the maternal stress. They could be the social environment early in life. All of these signal to the developing genome what kind of world you are going to live in. They can result in disease when there is a disconnect between the program and the real world that the animal or the human is finding themselves later. This monkey was nutrient-deprived as an embryo, and then he is provided a rich cafeteria diet in the American way of raising primates. There is a total misfit between the programming early in life and what happens now, and that monkey will become obese and will develop type 2 diabetes. However, if he was in the jungle, probably that genome was perfectly adapted to the kind of world he had to live in, where there is no food. JB: I think we need to take-the listeners-an intellectual deep breath, here, to re-oxygenate the brain. What you’ve just said is unbelievably profound as it pertains to the etiology of chronic age-related diseases, of morbidity patterns, of the birthing of pharmacology, of how medicine is constructed. The spreading effect is both sociologically and technically and medically profound. This is why we have called this “functional medicine,” because at some level what you are really describing to me is how things function. Not the predetermined kind of hard-wired sense that we were born with the set of genes that were rigid and would play out their orchestration regardless of what we did, but rather this a more plastic model of the environment/genome interaction that creates a functional outcome. It’s a very different model than many of us learned in medical school that we are talking about, it seems to me. MS: I think so. I think we are undergoing this transformation from the genetic determinism to a much more dynamic way of looking at things. It might change the way we do medicine, and we understand medicine, and even the kinds of drugs we’re giving our patients. I think the main problem that our genomes have, if you think about it, is that our genomes are very, very static machines. DNA is replicated by very strict Watson and Crick rules. It’s not very adaptive. And I think what the methylome does-the methylation pattern-is it confers upon that fixed genome the dynamic that it needs to deal with the kind of world we are living in. The world is changing, and the genome is not changing fast enough to deal with it, and so you have this interface. JB: Yes, the way that I’ve actually described this when I’ve been asked by docs, “Can I put this into a sound bite or elevator speech?” is I say that the genome, as we have thought about it-the code, the linear string of nucleotides-is like the course tuning knob (natural selection mutation followed by natural selection course tuning). But we need a fine tuning knob to tune into the frequencies of the moment to get the right station that we want to play, and that’s the epigenome. MS: Absolutely. Very good. The Role of the Social Environment on the Epigenome JB: Let me just close with two very important last parts of what could be almost a continued (almost ad infinitum) discussion. You related to the work that you’ve done, which I think is also extraordinarily pioneering, about the role the social environment has on the epigenome. A couple of articles that you have authored are titled, “The Social Environment and the Epigenome” in Environmental and Molecular Mutagenesis in 2008, and then a very interesting review paper that I really like that you authored with Mike Meaney on “Environmental Programming of Stress Responses through DNA Methylation.”9,10 This is where I got to thinking about Selye and McGill and your work and “Life at the Interface between a Dynamic Environment and a Fixed Genome.” Just the title alone is enough to bring goosebumps to the reader. Could you tell us a little bit about how that translates to things like maternal care of the epigenome and phenotypic differences in behavior? People almost would say, “I don’t believe it. You can’t tell me that there are signals coming from behavioral aspects of the environment that are kind of marking the genes. It just doesn’t seem reasonable.”11 MS: Right. The thing is we needed to find a mechanism that can link things. Actually doctors knew and psychologists knew for a long time that the early environment and the early maternal environment (or family environment early in life) has a profound impact on the health of the individual later in life. One of the strongest determinants of health is, for example, socioeconomic status early in life. And also what epidemiologists have noticed for decades is that if, for example, people shift from adversity early in life to life of privilege later in life, it doesn’t have as much of an impact as being privileged early in life. So early in life privilege and lack of social stress and social adversity has a profound impact on health, and the question is why? We did a series of rodent studies, and then we looked at humans and monkeys as well, to look at a connection between what happens early in life and perhaps DNA methylation mediating it. The way we think about it is like this: The maternal environment results in activating pathways in the brain that respond to that. For example, serotonin responds to so-called reward pathways. And that pathway activates a series of sequence events in critical cells, like in the hippocampus, that eventually result in epigenetic programming of a set of genes (now we know it is not just one gene but the entire circuitry of genes is methylated differently in response to the maternal care). It doesn’t sound as magical once you understand that. When there is maternal care, the animal responds with high serotonin. The high serotonin acts on receptors that trigger, on what we call signaling pathways, a series of phosphorylations that eventually activate transcription factors that can read addresses in the genome and take to the genome a load of chromatin- and methylation-modifying enzymes and program the genome accordingly. Does it make sense? We think it makes sense, because this is the way the mother programs the child to the kind of world they need to live in. If it is a stressful world, and the mother, through her behavior, sends the signal to the offspring by lack of maternal care, there is going to be lack of firing of serotonin and that will give a signal that life is bad: “There are a lot of bad guys around and you better be stressed and anxious because otherwise you’ll be shot.” On the other hand, if the mother sends a signal that life is privileged, serotonin goes up, that turns on the right enzymes, that programs the genome to say, “Life is good. There is no reason to be overstressed.” Again, I believe this is an adaptive response. This is a beautiful way nature allows our fixed genomes to function in the world. I also tend to believe that this signal is not limited to the brain, but the entire body is reset to respond to it. Recently we have been doing studies where we are looking at blood cells-for example, T cells-in response to social adversity early in life and seeing the DNA methylation differences in adults that we can associate with early social adversity. Why would T cells respond? Because I think the immune system and the brain are highly interactive, and perhaps in evolution it was a package deal. If it was a bad world, there were also a lot of microbes around that you needed to take care of. So stress and the immune system always went hand in hand, and the social information and the immune information are together packaging the young child to deal with the world. JB: I’m amazed, actually. Even if I look at the title of your program there at McGill, I think that the title alone is so epic in this shifting paradigm: The Program for the Study of Behavior, Genes, and Environment. It maybe would have sounded almost like an oxymoron 10 years ago. Your work is just to be applauded. Could you just briefly tell us about that extraordinary experiment you did where you separated the grooming mothers? I think the results are just fascinating. Animal Studies Document the Effects of the Early-Life Environment on Stress Response Later in Life MS: The things you can do with rodents you obviously can’t do with humans. We are limited with our human studies although they are the most interesting. We can’t really randomize children to be with a good mother or a bad mother, but we can randomize animals. Michael Meaney, who worked on this system for a decade, noticed that there is a nice correlation between the amount of maternal licking and grooming, which is the way a rodent mother takes care of her pups, and stress responses later in life. The big question was, why? We offer this epigenetic mechanism. We can show that the pups that were licked more also had a very different epigenetic program than the pups that were licked less, and you could see that difference in adult pups and adult offspring. So now the big question was, was it genetic or was it epigenetic? Because you can argue that maybe the pups that were licked more also had better genes and that’s why their mother licked them more, because they had those better genes and that’s why they are doing better in stress response than the others. Or was it the maternal licking that actually did that–it was not her genes, but it was her behavior that programmed the offspring to have a different stress response? The way to do that is what we call cross-fostering. You divide the pups of one mother to two different kinds of mothers. Now, the pups that come from the same mother are split to two different mothers. One is a high-licking and grooming mother, and the other one is a low-licking and grooming mother. Now there is no genetic transfer of information between the caring mother and the child; the only information of this transfer is the behavior. What it seems is that the behaviors of the mothers serve as a vector of inheritance. This inheritance doesn’t go through the germ line, it goes through the behavior of the mother. We were doing similar experiments with Rhesus monkeys, where you can separate monkeys (some are reared by mothers and some are not), and show exactly the same thing: that it is not the genes that they inherited, but it is the behavior that they are exposed to early in life that actually defines how the genes are programmed, and how they will behave as adults, and how they will sire their own offspring. So you can have, really, a transmission of a phenotype without having germ line transmitting it. JB: I’m sure you’ve been asked this question more times than you ever wanted to answer, but I’m obligated to ask it. We are a world-historically, it’s not just right now-of war. We have all sorts of things that produce what we call (in this country, at least) post-traumatic stress syndrome and post-traumatic stress disorder (PTSD). What I am sure you have been approached by all sorts people with-returning veterans and all the implications of war around the world-what is the message? This must be a complicated question for you to have to deal with. Philosophical Questions and Social Policy Implications MS: I think the message is that war has an impact well beyond the point at which the war has ended. Populations of children that were raised under the stress of war will become different kinds of adults. That is how, probably, an aggressive behavior is perpetuated from one generation to the other. That is a negative side effect, but the cross-fostering experiment suggests that you can easily erase it by changing the environment early in life. JB: The implication of that is so profound, but it is also quite optimistic. It gives us some thought of how to reconstruct society-re-engineer it-in light of what appears to be maybe just very fundamental mechanistic science can extrapolate up, like this microscope/telescope argument I was talking about before, to become a profound motivator for a positive change in society. MS: It has important solid policy implications. Because you can extrapolate from what you are seeing in your experimental paradigms, or small samples, a mechanism that makes sense, and you can test it by a policy intervention. I was asked once, by a group that was working for peace in Afghanistan, what is the best intervention you can have? And I said, have women teach the kids at a very young age and break the cycle of aggression. Because if you pass aggression to the young children, it is going to be very hard to change them when they become adults. If you ask yourself, “Where should I spend the billions of dollars? Should I spend them on UN troops or should I spend them on supporting early life education?” Perhaps boosting early life education in some of these areas could have a profound impact, if we take the rat and the monkey animals as a good example. JB: In the bibliography we’re going to supply some of Dr. Szyf’s more recent articles, like the one that you had, I think, in Biochim Biophys Acta recently on the early life environment and the epigenome.12 And then one that I really liked was in Trends in Molecular Medicine, this review you had on “Epigeneitic Mechanisms of Perinatal Programming of the HPA Function”-the hypothalamic/pituitary/adrenal function.13 This is, I would say (and I hope I’m not being disrespectful; I’m trying to be complimentary), like Hans Selye revisited at a much more profound level of genomic expression modulation. And then lastly I’ll just ask you (and we’ll close on this one), the article that you authored in Nature Neuroscience, “Epigenetic Regulation of the Glucocorticoid Receptor in Human Brain Associates with Childhood Abuse.”14 That was, to me, another really profound implication. Could you describe that study? MS: In this study essentially we wanted to translate what we saw in the rats to humans. It’s impossible, obviously, to translate it perfectly well. The question we asked is, can we see in brains of adults the methylation patterns that we would associate with early life child abuse? In the rats we saw differences in the way the glucocorticoid receptor was programmed based on maternal care, and in humans we asked if we can see whether early life abuse ended up in a different methylation pattern in the brain when these victims died. We had three groups of brains: we had victims who died from suicide who were abused as children (this was quite a large group); and then victims who died by suicide who were not abused as children (so we could actually test whether it was suicide that caused the methylation changes or whether it was the child abuse that did that); and, of course, the control group of people who died accidentally and were not abused as children. We saw some distinct DNA methylation differences in glucocorticoid receptor genes. Since then, we expanded this to other parts of the genome and there are profound differences all over the genome that we can associate with early childhood abuse, suggesting that what you do to children early in life is actually memorized in the brain, and can affect their behavior years and years later in life. Why does this happen? I still believe it’s an adaptive response. Child abuse is a signal. The child is getting a signal–“This is really a bad world”–and he or she programs the brain to deal with this kind of world. And if that child is found in a civilized world, there is a tremendous disconnect between the programming and the kind of world that person is living in. I think the major implication of it is that whatever we do counts, and is memorized, and nothing is really transient. There are mechanisms that kind of print those things in our genome and program our genome to respond to those signals. JB: Well, in close, I know that you have received tremendous accolades for your work and acknowledgement of both the high science that you’ve done and the implications of the science, but I just want to add my note to probably the hundreds that you’ve gotten. Hopefully the people who will listen to this interview let it kind of work over their nervous systems and start to see many things that come out of what you said, one of which is the power that basic research can have in ultimately creating a different sense of our reality. It moves us beyond what we thought were facts to a whole other landscape of what may be the real facts, at least facts as we know them at a different time. That, then, translates and maps itself ultimately into the social milieu, and produces-hopefully-a stickiness for us to reevaluate how we’ve actually looked at dysfunctions at many levels, from histopathology to social pathology, and those things that we might have thought were determined indelibly and could not be modified which now give, through your work, a much more optimistic potential for plasticity and modification. And lastly, the implication that structure and function are intimately interrelated and that structure is constantly changing-morphing-and being altered through its interaction with its environment. This is a duality, and that extraordinary dance-that orchestration-is what plays out in peoples’ lives that ultimately gives rise both to their own health and disease patterns, and might be even transmissible without changing their genes, but rather the epigenome into that of their offspring. Very profound concepts here. As just one of probably thousands of people admiring your work, I want to thank you for the diligence that you put into it and the way that you describe it. MS: Thank you so much. JB: It has really been a privilege. Highlights from Dr. Szyf’s Interview and Connections to Other Researchers I’m sure your impression of Dr. Szyf is the same as mine. Once you’ve heard this story from him, you are never the same. This is absolutely one of those paradigm-shifting moments in the history of biomedicine, science, and the sociological and cultural aspects of it. We’ve been building up to this point for the better part of a couple of years now on Functional Medicine Update, with the remarkable opportunities we’ve had to speak with the people who are defining this domain, creating this space, and moving the ball forward, so to speak, in our understanding of the mechanisms of disease, and where dysfunction arises, and this whole context of gene/environment interaction. We’ve had Randy Jirtle speak to us twice, now, about his pioneering work in epigenetics. We’ve had Michael Skinner speak to us. We’ve had the extraordinary discussion about hormesis and how low levels of effects at the right metabolic and epigenetic pressure points can create more profound influences on function than we would have predicted (this nonlinear dose response relationship that we’ve talked about). We’ve had presentations that relate to environmental aspects of signals that influence, then, gene expression, like the gut biome discussions we’ve had with the group from Louvain University in Belgium, Dr. Cani and Dr. Delzenne. We’ve looked at the effects that the oral cavity has through gut microbial activity in the peridontium, and how that can send signals to modulate expression patterns in the immune system that are associated with diseases such as cardiovascular disease. The list goes on; I won’t do an exhaustive review. But just to remind you of this landscape that we’ve been describing that really paints a different picture to the origin of disease than that which most of us learned in our organ-system-specific, histopathology-oriented educational background. This is the time of tremendous change. This is the time where the dominant view as to how illness emerges is starting to really take this more plastic view that was so eloquently described by Dr. Moshe Szyf in his interview. I’d like to follow up with a few of the points that he made just to make sure that we didn’t lose some of the substance, because there was so much density, wasn’t there, in his discussion? It was like, “Oh my word, I’m going to just capture that idea for a moment. I’ve got to let this settle in.” Each one of those was almost iconic as we went through the discussion with him. Let’s backtrack and review. We started off with Dr. Szyf talking about targeting DNA methylation and how it relates to malignancy, and the fact that there is alteration in cancer cells in their methylation patterns, both hypomethylation and hypermethylation, and that relates to the dysregulation of genes and their dedifferention and embryonic transition into this replicative state. He then went on to say that this might explain why, in animal studies where you prohibit the exposure to proper methylating nutrients (folate, B12, B6) and expose them to low levels of carcinogens, that their relative incidence of carcinogenesis and cancer goes up dramatically over the animals that are properly nourished with regard to these folate nutrients. In fact, he even went on to talk about studies that have been done about its relationship to low folate sufficiency (low one-carbon pathway of sufficiency) and relative production of cancer, and even drugs that induce demethylation and how that can encourage cancer. Dr. Szyf then also led us to recognize that the methylation patterns don’t work in isolation, they crosstalk with other genomic regulators of expression such as acetylation. And acetylation takes us into a different family of enzymes (these are the histone deacetylases that remove acetyl groups from the genome and the histone acetyl transferases that put acetyl groups on the genome). So we have the methylating and demethylating enzymes, and we have the acetylating and deacetylating enzymes, and those interrelate in terms of their crosstalk, one with the other, so if you modulate histone acetylation/deacetylation, you also influence methylation because you may open up the genome to a place where methyl groups can then be delivered or removed. The SIRT1 gene (the so-called longevity genes) are associated with NAD-dependent histone deacetylase activity, and we know there are a variety of phytochemicals that activate these acetylation/deacetylation activities, like resveratrol that has gotten a tremendous amount of attention, and EGCG (epigallocatechin gallate). We recognize that curcumin plays roles in these pathways, so there are a variety of phytochemicals (plant-derived materials) that modulate, in a very subtle way, these epigenomic patterns and can then lead to the expression of different chapters in our book of life, so to speak, like those relates to the SIRT genes, which are signaling information genes related to insulin signaling, and inflammation, and cellular cycle regulation, meaning they have roles in prevention and management of things like diabetes, heart disease, inflammatory disorders like arthritis, and dementia, and cancer. These are very fundamental mechanisms that cut across many different disease families. Recently I was at a very interesting meeting at Harvard University Medical School that was attended by a variety of leaders in the field of basic and clinical science, including the CEOs of a number of the major pharmaceutical companies, and the presidents of a number of the major medical schools, and the CEOs of large insurance healthcare providers. One of the principal speakers on the podium who was talking about what we have learned in the last ten years in basic science said, “What we have learned is that the blockbuster agents of the future are not blockbuster drugs to treat a disease, but blockbuster agents to modulate the mechanisms of disease.” He said that we should be treating blockbuster mechanisms, not blockbuster diseases. I thought that was a profoundly functional medicine-esqe statement. It really shows that this concept that we in functional medicine have been talking about for 20-plus years is really starting to have a general sense of traction within the nature of medical education and ultimately medical logic and treatment. Another of the presenters at this meeting was Dr. Jeffrey Flier. Jeff Flier is the Dean of Harvard Medical School and is revamping the curriculum there and went on to say that they have, at this point, pretty much done away with the traditional method of teaching medical students the organ-specific type of organ-systems approach, where you studied an organ system, shut the textbook, took a test, and then moved on to the next one, as if they were isolated, one to the other. He went on to say that they have abandoned that approach and they are now integrating their approach in such a way as to talk about systems biology, and cross-functional activity, and shared aspects of mechanism that ultimately give rise to dysfunction that become disease. That was a pretty exciting moment for me to hear the Dean of Harvard Medical School talk about principles that we’ve been trying to promote and discuss within Functional Medicine Update for 28 years. Dr. Szyf presented information to us about folate cycle, and methylation dependency, and how S-adenosylmethionine may serve as a very powerful therapeutic agent for the management of metastatic cancer. He described how it both assists in methylation and blocks demethylation, and how that interrelates, then, with regulating gene expression and keeping certain characteristics, like oncogenes, silenced, so you don’t get into this dedifferentiated proliferative state for a cell. These were very, very interesting and profound new ways of thinking about cancer and some of the modifiable aspects. He went on from that to talk about autoimmune disease. I thought that was a very nice and fascinating step over because you might think this is a whole departure from talking about malignancy. But really if you think about it, with autoimmune disease we get clonal increases in various components of the immune system. Various types of T cells are clonally increased and we get an overactive number of cells. You start to have an immune system that has kind of gone into overdrive, so to speak. Is there a shared connection between malignancy and immune hyperactivity that relates to clonal increases in cells of the immune system and their heightened vigilance? He talked about the fact that in an autoimmune disease (particularly, he was referring to systemic lupus erythematosis), demethylation is a common feature in the genome of the immune cells in patients with SLE. He also talked about drug-induced lupus. Most commonly the family of drugs that do this are demethylating drugs. To me, it was very gratifying for him to say that because it was about ten years ago that I did a seminar series on the autoimmune disease/environment connection, in which I used as an example the fact that an alteration in genomic messaging associated with demethylating drugs was one of the precipitating factors in drug-induced arthritis, and particularly in SLE. I think-again-the body of the understanding of these things is starting to gain visibility. We are starting to get a higher degree of resonance, so to speak, around these ideas. Dr. Szyf also went on to talk about valproic acid, this anti-epileptic drug which now may have off-label use for things that are related to methylation/demethylation defects, like things pertaining to Alzheimer’s dementia, or things pertaining to arthritis, which were not in the initial approval of the drug, but because of the mechanism of action having this effect on epigenetics, this may prove to be a very useful secondary application for certain medications. I asked him: “Can you diagnose this solely by looking at blood homocysteine?” He responded: “No.” Obviously this question of methyl dynamics within cells is much more than just the homocysteine outcome as it relates to plasma or serum levels, and what we are really looking at is mechanistic effects inside cells, not the “smoke” that falls outside cells that is the homocysteine level. He thought that was not a really sensitive biomarker for derangements at the molecular and cellular level that are related to epigenomic methylation. Dr. Szyf also made a very nice point in talking about how agents of diet can possibly, in a complex diet, have a very different orchestrated set of signals that influence the epigenome, versus those in a diet that is very simple, has been chemically modified, and may influence altered epigenomic patterns. He also talked about the effects of various drugs and the role that they have on epigenetic modulation. We didn’t have time to go into it in great detail, but this article that he authored titled, “Epigenetic Side-Effects of Common Pharmaceuticals: A Potential New Field in Medicine and Pharmacology,” is pretty profound. In this article, he talks about how the epigenome that refers to the overall epigenetic state of a cell serves as an interface between the environment and the genome, and it is dynamic and responsive to environmental signals, not only during development, but throughout life. We used to think these epigenomic modifications were only occurring in embryonic life, but now it is being seen there is some plasticity throughout all of our life. It is becoming increasingly apparent that chemicals can cause changes in gene expression that persist long after exposure has ceased that appears to relate to epigenetic marks that are laid down through chemical exposures. This includes things like bisphenol-A, for instance, and other low-level environmental chemicals that may have hormetic effects on altering cellular signaling, well below what we consider traditional toxicological effects. These are the more subtle orchestrated effects-the fine tuning knobs-that may influence function over long periods of time. Drugs may alter epigenetic homeostasis also-direct effects of drugs could be influencing chromatin architecture or DNA methylation. Examples include such things as the anti-hypertensive medication Hydralazine, that is known to inhibit DNA methylation. An example of an indirectly acting drug is Isotrienin, which is a transcription factor activator, and therefore that two-tier mechanism could be involved with both indirect and direct effects that influence drugs’ influence on that individual’s function well after the person has even stopped taking the drug. They have modulated the epigenome in such a way as to kind of freeze a certain functional structure in place that follows them. These could be epigenetic side effects that have long memory effects, basically, of pharmaceuticals. Dr. Szyf goes on to say that if this model is looked at seriously, this could lead to a new approach to pharmacology, which would be called pharmacoepigenomics, the impact of which might be equal to or greater than that of pharmacogenetics itself, and that we have to look at these kind of longer term potential implications on modulating peoples’ epigenome and what influence that could have on off-target adverse side effects or other things that appear later in life. I think that was a very interesting part of his story-things that, again, we might not immediately think of that come out of this conceptual framework. Also, he talked about the extraordinary influence that behavior and environment have. These could be environmental chemicals, like I mentioned such things as pesticides, herbicides. Or in the case of bisphenol A, plasticizers that at very low levels that we might think of as normally having benign effects might influence, subtlety, the epigenome in such a way as to regulate function downstream and lock a person into a different physiological state of function. We transitioned from that into what is considered by many to be the “I don’t believe it” part of the story, which is that behavior can modify the epigenome, that experience in life can modify the epigenome, that laughter, fun, joy, bliss versus rage, anger, fear, and isolation can set epigenetic marks that create a whole different way for cells-not just in the immune system itself, but other cells within the body-to express their function. That conceptual idea is so powerful that it almost rivets you in your place. This is when he starts talking–from a fundamental basic science and then later an animal science, perspective–about the rearing of the rat pups by their mothers, and the translocation effects, and how these effects are transgenerationally transmissible through breeding. He says it may take three or four generations to breed out these characteristics to bring them back to their F0 generation of genomic methylation. These are almost heretical thoughts compared to the way that many of us learned genetics, embryology, behavioral science, and even medicine. It really attacks the functional concept at a very dynamic, kinetic, real world way that puts us all in the center of our own life experience. And it gives the relationship between the provider and the patient a much more…I would call it dynamic environment to engage both in discussion and therapy as it pertains to modulating the patient’s environment and reconstructing an epigenome that will send the signals of success rather than the signals of being at war. When Dr. Szyf was talking through this extraordinary story, he mentioned that from his work, he has a different view about the origin of disease than what has been historically accepted. His view is that rather than these diseases being hard-wired into our genes, that our responses that give rise to disease are adaptive responses to an altered environment, in which the outcome over time, through the epigenetic modulation, becomes a disease. In other words, we don’t have diseases wired into our genes, we have physiologic responses to environmental modulation wired into our genes that then creates an outcome that’s later called our phenotype of health or disease. You might think that this is just word-splitting and I’m just playing an intellectual exercise with you, but I believe this is a profoundly significant conceptual difference from the way that we have thought about the origin of disease that leads to a profoundly different way of managing the origin of disease, and ultimately treating disease in and of itself. I’m not talking so much about emergency room or acute care. I’m talking about ambulatory care with chronic age-related diseases, where you have the time to really create different signals that could influence positively the reconstruction of the epigenome and regulate the gene expression away from the signals of alarm to the signals of being at peace. I think these are really dramatic examples of how we would contextualize this form of health care, because it’s not like taking an antibiotic from a gram-negative bacterial infection in which you expect to block that cell wall synthesis of the microbe and the next morning that person is going to be over their fever and feeling better. In this case we are reshaping the way that our book of life has been guarded in our vault called the genone, and reshaping how it is going to be expressed, and signaled, and modulated into its pattern that we see as a phenotype (the collection of cells to tissues, to organs, to organ systems, to the whole organism). Dr. Szyf talked about the fact that, yes, we know about the genome’s influence on the immune system, we know about its effect in the central nervous system, but we now recognize that these epigenomic influences are occurring in all cells-not just the rapidly dividing cells, but also in cells that we might have considered to be post-translational, like neuronal cells, where you might have said, “Well they are way over the time where epigenetics will have any influence on them because they’re not dividing.” Now we see that these marks (these enzymes) are still active in these cells. Even if the genes are not in and of themselves dividing in mitosis, the genes are being regulated in their cellular biochemistry as a consequence of the activity of these enzymes (the methylating/demethylating, acetylaying/deacetylaing, and so forth-enzymes that are modeling and remodeling the epigenome. These are really, really profound concepts that marry and dock directly with the whole fundamental patient-centered medicine constructs of functional medicine. They really represent Roger Williams’ biochemical individuality concepts at even a deeper level, because it’s not just the genes in and of themselves, but it is how they have been epigenetically marked that might influence the function of that organism. It takes the molecular medicine concept of Linus Pauling and it moves it into an even more robust kinetic environment. The life of a cell becomes this dynamic dance between the pluripotentiality of the genome and its outside environment. And then we take that and we start applying it to conditions like neuropsychiatric conditions, and we think of Dr. Abram Hoffer’s extraordinary work in orthomolecular psychiatry, and how nutrients, as members of the B complex vitamin family, can alter certain neuropsychiatric disorders in individuals who may have been suffering from conditional insufficiencies of epigenomic modulation. It’s a whole new frontier of explanation at a mechanistic level of what we have observed phenomenologically for some time, but has been dispelled, or dismissed, or said is not true because we don’t have a mechanism to rationalize the observation. We have seen published studies that have dismissed folate in large clinical intervention trials, saying it really has not been proven to be effective. You have to ask the question: “Have we been able to segment and stratify these studies correctly, so that those individuals with the most dynamic responsiveness of their epigenome to that principle, knowing that there are multiple factors that regulate these pathways, that we have selected the right people because maybe what happens if by not segmenting we lose the ones that are most responsive in the noise of those that don’t have that unique contribution to their etiology?” It’s a different way of looking at the way we design research, at how we evaluate outcomes, and actually how we would even set up studies to look at responders and discriminate from non-responders. Dr. Szyf said, as you heard, that these are all testable hypotheses. Using a different model, we can now start to karyotype the epigenome. We can start looking at these different methyl patterns, and promoter regions in the CpG islands of cells where methylation occurs, and look at how these CpG islands are methylated and demethylated under certain principles, and start to tie together certain genetic characteristics with environmental modulators that then produce outcomes that could lock a person into the physiology of alarm. And then lastly, of course (and not least in this discussion) was the social science implications, the societal design, the nature of us as real people in a complex world-our political and economic structures and the way that we relate to one another in tribes, so to speak. Or the feeling of isolation, the feeling of no attribution, the feeling of no love and how they translate through these signaling systems into what might be considered altered epigenomic regulation and ultimately physiological response of alarm, which tracks back with inflammation, and heart disease, diabetes, cancer, osteoporosis, and dementia and so forth. What are we doing with our children as we have exposed them to this environment of fast-paced life environments that are associated with violence and with lack of respect? What are all of the messages that we are getting and how are they imprinting epigenomic methylation, demethylation, acetylation, and so forth, the architecture of the epigenome that then regulates how the pluripotentiality of the genes of that individual would be expressed in their life. These are very, very profound concepts and topics that are really at the forefront of this tree that functional medicine set up years ago to try to understand, in the complexity of a systems biology approach to medicine, the ultimate etiology of chronic age-related diseases in a way that you can do something about it at the origin rather than just at the symptom and sign level up in the high order of the tree. Instead of how the leaves get brown, we should be treating the roots and the trunk of the tree. With that, we thank Dr. Szyf. What a profoundly moving, paradigm-shifting, bias-altering experience we’ve all just been exposed to thanks to not only his extraordinary work, but the way he described it. I look forward seeing you in December, next month.

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Bibliography

1 Szyf M. Targeting DNA methylation in cancer. Bull Cancer. 2006;93(9):961-972. 2 Zhang J, Henning SM, Heber D, Choi J, Wang Y, Swendseid ME, Go VL. NADPH-cytochrome P-450 reductase, cytochrome P-450 2C11 and P-450 1A1, and the aryl hydrocarbon receptor in livers of rats fed methyl-folate-deficient diets. Nutr Cancer. 1997;28(2):160-164. 3 Szyf M, Pakneshan P, Rabbani SA. DNA methylation and cancer: therapeutic implications. Cancer Lett. 2004;211(2):133-143. 4 Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol. 2009;49:243-263. 5 Szyf M. Epigenetic therapeutics in autoimmune disease. Clinic Rev Allerg Immunol. 2010;39(1):62-77. 6 Szyf M. The dynamic epigenome and its implications in toxicology. Toxicol Sci. 2007;100(1):7-23. Review. 7 Csoka AB, Szyf M. Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Med Hypotheses. 2009;73(5):770-780. 8 Unterberger A, Szyf M, Nathanielsz PW, Cox LA. Organ and gestational age effects of maternal nutrient restriction on global methylation in fetal baboons. J Med Primatol. 2009;38(6):219-227. 9 Szyf M, McGowan P, Meaney MJ. The social environment and the epigenome. Environ Mol Mutagen. 2008;49(1):46-60. 10 through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci. 2005;7(2):103-123. Review. 11 Szyf M, Weaver I, Meaney M. Maternal care, the epigenome and phenotypic differences in behavior. Reprod Toxicol. 2007;24(1):9-19. Review. 12 Szyf M. The early life environment and the epigenome. Biochim Biophys Acta. 2009;1790(9):878-885. 13 Meaney M, Szyf M, Seckl JR. Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health. Trends Mol Med. 2007;13(7):269-277. 14 McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M, Turecki G, Meaney MJ. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12(3):342-348.

Welcome to Functional Medicine Update for December 2010. What an epic issue we have this month. I’m so excited about it because it’s an area that we have hit upon on a number of occasions during our 28 years of existence, but today I think we are taking a different approach. The subject this month is psychiatry-the history of psychiatry. We’ve got a magnificent expert to help guide us through the labyrinth of history of psychiatric conditions, psychiatric management, and the profession of psychiatry. I think it is a very interesting case study for the general evolution of medicine. I hope you’ll be able to extrapolate beyond psychiatry to other areas of medical innovation, thinking, paradigms, and how concepts are shifted. We’re going to have the chance to speak with Dr. Andrew Scull in a moment, who is the author of some extraordinary publications on the history of psychiatry. I’ve read a number of his books and papers, which are fascinating reading. He is a marvelous writer. One book is titled Undertaker of the Mind: John Monro and Mad-Doctoring in Eighteenth-Century England(University of California Press, 2001).1 His work, Museums of Madness: The Social Organization of Insanity in Nineteenth Century England was published by Allen Lane Publishers in 1979.2 And his most recent book is Madhouse: A Tragic Tale of Megalomania and Modern Medicine.3 I think all of these are extraordinary reading. By listening to my discussion with him I think you are going to connects to the evolution of thinking and how it translates into medicine and the standard of care.

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Interview

Researcher of the Month – Andrew Scull, PhD University of California, San Diego Department of Sociology, 0533 9500 Gilman Drive La Jolla, CA 92093 Here we are once again at our clinician/researcher of the month section. This section really sets the tone for the whole issue, as you may have noticed over the last several years. The context of each issue is framed by these people who are remarkable. They are defining visions, perspectives, technologies, or procedures that relate to the direction of medicine: creating a more effective, patient-centered-based medicine as we move into the 21st century. I’m so excited that we have the chance to talk with Dr. Andrew Scull, who is a professor of sociology at the University of California at San Diego. That might sound, at first blush, to be a departure for me. You might say, “Sociology department? That doesn’t seem to fit into the kind of Jeff Bland-left-hemisphere-of-the-brain-reductionistic-analytic-Newtonian model of trying to understand the piece parts. It seems like that’s a broad brush, bigger picture perspective.” The answer is “Yes. It is and it fits together beautifully with our whole concept of function-function at every organizational level.” Dr. Scull got his undergraduate degree at one of the colleges in Oxford University, and then came to the states and got his PhD at Princeton in sociology, and then went back and did a postdoctoral fellowship in medical history at the University College in London. Now he is a distinguished professor of sociology and social science studies at the University of California, San Diego. Books by Dr. Andrew Scull I wish I would have known of Dr. Scull earlier, but it was only as a consequence of reading his article that appeared in The Lancet (April 10, 2010) that I became acquainted with his work. The article that he authored was titled “The Art of Medicine: A Psychiatric Revolution.”4 I did cite this article in a previous issue of Functional Medicine Update in 2010. Since then, I have become a “Scull-ite.” I’ve been reading everything I can find that Dr. Scull has written, including Madhouse: A Tragic Tale of Megalomania and Modern Medicine, which reads like the greatest thriller novel that you’d ever imagine. You can’t believe that it is actually a true story. We’ll be talking more about that. His book Museums of Madness: The Social Organization of Insanity in Nineteenth Century England was, I think, one of his first books, published in 1979. And then I most recently read Hysteria: The Biography(Oxford University Press, 2009).5 Dr. Scull has to help us understand-through the lens of the past-what the future of medicine might look like as we as we try to ferret out systems improvement. With that as a long-winded introduction, Dr. Scull, thanks so much for being part of Functional Medicine Update. We really appreciate it. AS: Thank you so much for that awesome introduction. It’s most kind. I’m very pleased to be able to talk with your listeners. The Significance of the Diagnostic and Statistical Manual of Mental Disorders JB: Let me, if I can, start down the path. There are many ways to get into this hologram of understanding the things that you have been investigating and talking about for these many years. Let’s start with psychiatry, because that is one that you have done such in-depth work in (the history of psychiatry). In one of your publications you talk about the use of medicines in anglo-American psychiatry, and how that really interrelates to the Diagnostic and Statistical Manual of Mental Disorders (DSM4), and what is a disease? Those questions are all tied together. Maybe you can help us by guiding us down this path. AS: Yes, let me try to talk a little bit about that situation. American psychiatry, in particular from World War II onwards for about a 20 or 25 year period, was heavily dominated by psychoanalytic ideas. During that period there existed two editions of the Diagnostic and Statistical Manual, but they were neither very large nor terribly important, in part because those diagnostic categories didn’t mean much to psychoanalysts; that wasn’t something that concerned them. During the 1970s, the American Psychiatry Association put together a task force to re-write that manual, and it turned out to be a very groundbreaking document, something that I think reoriented not just the field in the United States but all across the world. By way of context, of course, psychiatry had already experienced a tremendous shift in therapeutics with the advent (beginning in the mid-1950s) of so-called antipsychotic drugs, the first of which was Thorazine and the whole category of phenothiazines. Subsequently, as we know, the category of anti-depressant drugs came to the fore as well. There is actually a synergy between the DSMIII as it appeared in 1980 and the subsequent edition, DSMIV. Four has been revised and there is a fifth edition in the works; it will be out in a couple of years. When that manual was rewritten for the first time in 1980, it really began to…it is often referred to as a “neo-Kraepelinian” kind of document, after the famous late 19th century German psychiatrist, Kraepelin, who would distinguish between dementia praecox (later relabeled “schizophrenia”) and manic depressive illness. The dividing up of the mental illnesses that occurred in that manual really, to some degree, reflected the drug revolution, and then as the manual has evolved over the years, it has continued to be a central focus of the way in which disease is being conceived by psychiatry and the way, increasingly, it is treated. So it has helped to cement the re-biologization of the field: the attempt to claim that mental illness is a primarily biological event that can be treated by specific classes of drugs, so that those diagnostic categories in turn link up with different forms of therapy. But it turns out, as the manual evolved, we see new drugs in a sense creating new diseases, if that makes sense to you. That is, the advent of a class of drugs that potentially has some effects is then a search for ways reconfiguring the way we think about mental illness and to link those two things together. I think in general if we look at the evolution of psychiatry over the last four or five decades, what we see is a shift away from a period where social and psychological factors were considered as central parts of the picture to one where increasingly we move towards biology. If you look at the pattern with psychiatric training programs in major medical schools, in 1970 virtually every major department in the United States, with the exception of Washington University in St. Louis, was headed by either a psychoanalyst or what we might think of as a psychoanalytic fellow traveler. And if you look now, none of them are. Everything has moved in the direction of neuroscience. Everything has moved in the direction of biological research and drug-related research. So the field has moved very sharply away from where its center of gravity was three or four decades ago, and that’s not unprecedented in the history of psychiatry. If you look to the 19thcentury, when the large asylums first come on the scene, the logic behind them is the notion that a therapeutic environment (largely a social psychological environment) will be the primary mechanism of cure. But by the end of the 19th century (by the last third of the century), we’d moved to an era where a much more pessimistic, hereditary account of mental illness is abroad. Mental patients are largely seen as people whose biological mechanisms have gone awry. Oddly enough, from 1870 to past 1900 you have this very strong emphasis on the biological roots of mental illness, and then almost exactly 100 years later we see exactly the same phenomenon emerging. It all depends, of course, I suppose, how one assesses that. It depends on whether one believes: A) the science is sufficient to justify that engagement, and B) that things aren’t being lost when the social and psychological dimensions of mental illness get diminished attention. I think, in lots of ways, the DSM is both a symbolic event, and, practically, tremendously important. It marks a decisive move within psychiatry. It has not just been an American event. It has been something that has had worldwide significance. JB: That’s a wonderful platform and context. I think you were very politically gentle and gracious in the way you described that, because there seems to me-and I may be over over-reading this, so I will stand corrected if you think so-that there is an interesting bifurcation that occurs from this concept of psychiatry as focused on the mind to psychiatry focused on the body. It seems like this body/mind duality got kind of shifted over. Rather than looking at it as body/mind or a mind/body as one whole, we went from one part which was the mind (psychoanalytical Freudian psychology), over to another part which is the psychobiology of psychotropics. Am I exaggerating, here? It seems like we missed something in the middle, which was the connection of the holograph of mind/body. Psychoanalysis versus Biology: Shifting Perspectives AS: Yes. Well, I think largely not. I mean, there’s always danger, of course, when one is describing a complex reality and you paint in broad brush strokes, but I think it’s fair to say that overwhelmingly we’ve had exactly that kind of shift occurring. It was always difficult for me to comprehend, as I looked at the history, the sense that psychoanalysis could be an effective therapy for schizophrenia, for example, although there were Americans who claimed that it was. Likewise it is hard for me to imagine we can move into a world where we ignore the mind side of the equation and the contextual part of mental illness. As I read the literature, at least, the etiology of most of the major mental disorders is still very much up in the air. We have some suggested hypotheses. We have some clues. We have some hints. But part of the discord is not only do we not have much more than palliative therapy for these conditions, but our level of understanding of them is really quite primitive. Yet, when these enthusiasms take hold in either direction, there tends to be a neglect of the limits of our knowledge and we get carried away with enthusiasm for what, at best, are partial solutions. And those enthusiasms, in the longer lens of history, can come to seem rather odd, if not downright bizarre. Since physicians are trained predominantly to think of illness as a biological event, there is always a tendency to move back in that direction. And certainly during the time when psychoanalytic perspectives were dominant, it is clear that the relations between psychiatry and the rest of medicine sometimes got quite strained because the notion of talk therapy for illness seemed a very odd one to most doctors, not to mention some of the details of psychoanalytic theory that many of them found difficult to swallow. You know, the same tendency to pull back towards the body in the past has led to some really-what is seen after the fact-very odd kinds of intervention. Not that some of them don’t sometimes seem to have had purchase. One of odd things about the history of 20th century psychiatry is there have been two Nobel Prizes awarded to psychiatrists. One was the invention of fever therapy for tertiary syphilis, which produces a multitude of psychiatric problems. And the second was for lobotomy in 1949. Oddly enough, no prize for any of the drug therapies that now would dominate psychiatric practice. If we look at the 30s, for example, you see a period of extraordinary drastic sorts of physical therapies that are introduced on a very casual kind of basis, things like insulin comas, and metrazol to produce seizures, and ECT, which still survives as a treatment modality (almost alone among these things), and of course lobotomy itself. Not to equate modern therapies with those, but it is important to understand that with psychiatric drugs there are limits. We often forget (unless we’re on the shop end of these things) that these drugs can, in many instances, carry severe side effects along with them. There are many patients who fail to respond to the drugs, and even for those who do, what they do is control symptoms. I don’t mean to minimize that. That’s an important accomplishment. But they certainly are not a psychiatric penicillin. They don’t make any of these conditions go away. One of the things that troubles me about the way in which we seem to lurch from one extreme to another is that we lose perspective, and we get overly enthusiastic about whatever the fad of the day is, and that is certainly a concern I would have in the present climate. JB: Yes. You said many, many things that are very interesting. I want to follow up on one that I think spawns many other issues. I may not be quoting exactly what you said, but something like, “New drugs create new diseases.” You can think of agoraphobia, or you can think of attention deficit hyperactivity disorder, which didn’t exist as a disease entity decades ago. I even think of-and I may be stretching the envelope a little bit, here-cholesterol. Cholesterol is almost seen like a disease. The number one selling drug in the Western world is a cholesterol-lowering drug for which the drug is being used to treat no disease. It’s being used to treat a number, which has a relationship-in statistical association-with a disease, but once you start to define cholesterol elevation as a meta-disease, it takes on a life of its own and creates its own mythology, it creates its own technology, its creates its own standards of care, it creates its own economy. It seems, if you use psychiatry (what you’ve observed) as kind of a model, that that same phenomenon of new drugs creating new diseases…I mean, look at erectile dysfunction-there’s an interesting one. It just springboards down. So it raises the question: Do we use biology as a stocking horse for the sale of drugs? AS: Yes, I would think so. And if you look actually at the statistics on the larger-selling categories of drugs, both anti-psychotics and antidepressants rank in the top five in terms of sales and profit. It is fairly obvious there is a huge incentive there. If any of your listeners have been following the medical journalism that has been emerging and the lawsuits, a lot of evidence of the drug trials being manipulated in ways that are quite alarming so that findings that Big Pharma doesn’t like get suppressed and those trials don’t see the light of day-we see only a very selective sample of what’s going on-and that’s not something confined to confined to psychiatry, obviously. So these are deeply troubling events. On the one hand, whether it be the misery of psychiatric illness or the degradations of other kinds of illness, we’re desperate for cures, but in the search for them, what we fail to realize is that interventions always come with a price, and sometimes that’s a price worth paying, but we do need to be cognizant of that fact. To use a famous phrase from another social science, “There’s no free lunch here.” One does worry that indeed it seems like that with the statin situation. Frankly, for healthcare budgets at a time when, in the United States, healthcare is now absorbing .17 of every dollar, the explosion of those new things-constantly one wonders where that’s going to lead down the road. To come back to the point you made at the outset of that question, though my work is largely focused on matters psychiatric, psychiatry is not so different after all from much of the rest of medicine. It’s different and it’s not. Some of the things we see in the psychiatric realm do carry over into other realms of medicine. JB: Let’s pick up on that, following on that train of thought. Let’s look at the DSM and this concept of the primacy of disease. As we get into more granularity of differential diagnosis and start defining specific conditions as diseases-let’s use autism as an example, which really, mechanistically, is a variegated presentation of all sorts of different distortions of neuronal function that we try to lop into one diagnosis and then hopefully make that so it could be treated with one drug. This construct of what I call reductionistic medicine seems like it drives us into a model that is very, very limiting, relative to the way that the new biology talks about networks and talks about connections. In fact, it even drives us into the organizational structure of medicine of guilds, which become specialty boards that do standards of care, in which everybody is sitting around speaking the same language and patting one another on the back, saying “This is what we believe to be our truth for the reasons of expediency.” It seems that there is a whole social nexus that derives out of this conceptual framework of taking complex issues and reducing them to simple diagnostic criteria and calling that a disease. Am I wrong? The Politics of Establishing Psychiatric Categories AS: No, I think that is absolutely right actually. What we have learned about DSM-V, which has yet to appear, is that there is an attempt to broaden the diagnosis of autism to talk about autistic spectrum disorders, which potentially sucks many, many thousands of new patients into this ambit and with that label, which has obviously very profound consequences for people who are given it and for parents who are struggling with children whose maturation may be different than the norm. That’s certainly a valid observation. And I think if you look at the construction of the DSM, it purports to be a scientific document, but in fact the construction of those categories was often a heavily political enterprise, where horses were being traded to get to a consensus that really was relatively artificial, but then once it exists, it is ratified. It acquires a significance in all kinds of ways that perhaps its creators neither fully intended nor anticipated. That, too, is a big, big problem. The difficulty of defining the boundaries of disease-and particularly a psychiatric disease-goes back a very, very long way. There was a time in my nominal home discipline of sociology where sociologists talked about mental illness as the product of labeling, which I think was romantic nonsense. But at the margins, you can see what those people were getting at. I think all of us encountering somebody who is completely dissociated with reality-whose cognitions, whose emotional reactions are far beyond anything we’ve experienced-as competent members of the culture, we don’t need to be experts to know there is something radically different about those sorts of people. But where do we draw the line between eccentricity and madness, for example? That’s been contested all through history, and the problem with these diagnostic categories is when you get the blurring at the boundaries. For example, if you start talking about-as has happened in the past and is again about to recur with DSM-V, depending on how the final negotiations go-preventative intervention, that is, looking for the precepts of the psychosis and treating patients before they actually become unhinged, that is a real slippery slope and potentially something that creates the very thing you want to avoid. If you start treating people differently because of what you assume may be the developmental path in the future, you’re creating a situation which can kind of rebound on them and on you. The Social Context of Disease JB: Yes, and I think you said earlier something that’s really an important takeaway from this discussion, and that is the social context of disease. I think in psychiatric disease, the social context becomes very probably more obvious than maybe other diseases, but they all have a social context. We live up here in the Pacific Northwest in Seattle, andthere is an ancient tribe of first nation people in British Columbia called the Haida Indians. The Haida Indians were the carvers-they did the totem carving. A lot of people wonder why the faces of many of the figures in these totems seemed so distorted. What I have read is that in their culture, individuals who were born that might today have what are called psychiatric disorders or diseases were considered unique in their insight. You know, they were speaking closely to a spiritual being and therefore they were more revered. And they were actually carved not as disfigured human beings, but as unique features in their society. What would have been their DSM back in that time? I know you have written on this-you’re actually an expert on this in your book Hysteria: The Biography -the word “hysteria,” in language, has an interesting context because I believe, if I’m not mistaken, it comes from the Greek root that has something to do with the womb. The History of Hysteria AS: “Hysteria” is the Greek for womb. It had, for much of its history, a kind of gendered context to it. It was seen, perhaps peculiarly, as a disease of women, and then at times not. Beginning with Thomas Willis in the late 17th century when you get a neurological account of hysteria’s origins, when once again it’s a real disease and the root is in the nervous system, That opens up the disease as something that both men and women can experience. At various times in the history of hysteria we see that kind of rediscovery of male hysterics from many people, including physicians at the time. Shell shock in World War I was often seen as a form of hysterical disorder. That was certainly true among German physicians, and it was true among the French, and for some British, who were coping with this epidemic of apparently psychogenic disorders in the troops. That was a huge military problem. And, of course, now anticipated because of what we have seen in every industrialized theater of war. Fortunately, in my view, the appalling things that people witness and sometimes have to do on the battlefield are things that most of us recoil from in normal times and have a very hard time processing and dealing with. That, I think, well may have something to do with all the psychiatric troubles that flow from war. In World War I it was shell shock. In World War II, it was combat fatigue or combat exhaustion. And, of course, by Vietnam it had become Post-Traumatic Stress Disorder. And that concept which began as something applied to these military casualties has spread to victims of trauma in civilian life and it has acquired a life of its own, as categories tend to do. How the Gut has Factored into the History of Psychiatry JB: I think you really described this-historically–very beautifully in the book, Madhouse: The Tragic Tale of Megalomania and Modern Medicine. You talk a little bit about the turn of the last century, with Pasteur and the infectious disease revolution, getting to Elie Metchnikoff, the father of immunology (winning a Nobel Prize in medicine in 1903), and how Metchnikoff talked about prolongation of life through this gut connection to the body. There was a dominant theme that the gut had something to do with systemic health through infection and endotoxemia, which then spread into psychiatry and became a dominant theme for abdominal surgery in the 20s and 30s in America. All of this history tends to point me in a direction that says something about our tendency to medicalize changes in functional status. Without looking at cause, we jump into medicalization by quantifying, naming and blaming (as Dr. Sid Baker calls it), and then producing a procedure before we understand where the dysfunction really originated. AS: Yes, I think you can actually push that even further back. It is very much the case that with the rise of bacteriological models of disease the gut became very suspect, not just among some psychiatrists. A lot of other fields of medicine looked at this, and particularly the notion of what was called focal sepsis: chronic, low-grade, untreated infections producing illness at a distance, so to speak, and the connections not being made. But you can push that back even further if you move to the two millennia or more of Western medicine where Galenic and Hippocratic notions of the four humors were dominant. That was a period, as well, where notions of defects in the digestive system and the bowels were obviously the focus of a lot of attention-bleedings, and purges, and vomits very much the central remedies against disease. In some ways, that notion of kind of inner cleanliness–you can see it exploited by ads for constipation remedies today–it’s got a resonance both in folk belief and in medicine that sometimes can produce a pretty gross effect. There were a number of major figures, like Franklin Billings, who was the Dean of the University of Chicago Medical School back in the nineteen teens, who became general advocates of this notion that much of ill health could be traced back to problems in the bowel and the digestive system in general. So when Henry Cotton comes along and applies those notions in psychiatry, you know, in a certain sense, they are part of the air almost at that time. We develop models of disease and we sort of push everything to fit in. At the time of bacteriology, it was assumed that pretty soon disease would be amenable to intervention and many of them would cease to be very problematic. Unfortunately, that has turned out not to be true, not to minimize the importance of that revolution. It has given us some purchase on disease we didn’t have before, but it by no means is it a panacea. JB: Let me close. This has been-by the way-a fascinating discussion for me and I think the listeners are really getting a whole conceptual framework. What we often focus on is the moment of what we should do rather than the context in which we are doing it, so I think you are really helping us to see, contextually, some of the ways that we ultimately are directed into what we do. I’d like to have you talk about your views on what I see as a paradigm shift that is occurring (or recurring-I think it occurred at the turn of the last century to some degree, but it’s now gaining a lot of momentum)-and that is this genes/environment connection: that we carry with us this pluripotential in our genes that is expressed as a consequence of the environment in which we find ourselves-the psychosocial, the chemical, physical, molecular, and electromagnetic environment where we find ourselves. That, to me, produces a different kind of thoughtfulness about medicine, because rather than single diseases existing individually, what this does is it connects together different dysfunctions so that diseases become less important and the origin of the dysfunction becomes more important. We are moving from isolated points that lead to specialization in medicine to looking at connectedness, and networks, and how normative behavior influences these. Do you see this as an issue? AS: I think what you are painting is what one sees in one’s optimistic moments perhaps. Obviously it is what one hopes will happen. I think these would be the growing interests in genomics and genetics in relationship to medicine. This is often fueled among the public–and to some degree the earlier enthusiasts–with much too simple a model of how genes and disease might be connected, so that there would be a simple one-to-one correspondence between some kind of genetic abnormality and the appearance of a particular kind of disease. I think increasingly we are realizing-rather along the lines that you were suggesting-that it is not just one site on the genome, but a bunch of things may contribute. And what they provide is a context within which disease may or may not materialize depending upon a host of other factors, including environmental ones. And as long as we keep that in mind and don’t assume that there is going to be some simple-minded kind of unlocking of the key of disease that excludes those factors, then that indeed could be a very positive development. JB: So let’s go back 360 and finish with the last question. Given all of this landscape that you’ve taken us across, coming back to psychiatry, what’s your vision as to where psychiatry is going as a discipline? How do you see it changing-if at all-over the visible future? Thoughts on the Future of Psychiatry AS: You know, most of us turn out to be pretty bad at forecasting the future, so you are asking me to go out on a limb here. What I think will happen probably over the next two to three decades is that what I see as a swing of the pendulum too far in a single direction will probably exhaust itself, and we’ll see a revival of a more complex picture of mental illness that brings some of these other elements back into being. Part of what’s happened is that the psychotherapeutic part of the enterprise, for lots of reasons (including what insurance companies are willing to reimburse and so forth), has tended to move into another professional arena: into the hands of clinical psychologists using cognitive behavioral therapy and the like, and psychiatric social workers. So that end of things, within psychiatry, has tended to be minimized. I don’t think that’s sustainable over the long haul. I would guess it will prove not to be sustainable. But we shall see. It’s always impossible to predict what kinds of research breakthroughs may occur. We talked earlier about how autism is sort of spreading and becoming much more amorphous as a category, and I think a lot of the categories we use to think about psychiatric disease don’t really cut nature at the joints, so one of the things we may see is we may discover some things that allow us to move beyond creating diagnoses by committee, which is basically what DSM has done for some fraction of mental disorders. After all, in the past, if you lived in 1880, people thought of what they call general paralysis of the insane as simply a subtype of insanity, and only in the early 20thcentury did we definitively begin to understand that it had its roots-in this case-in tertiary syphilis. So I don’t know whether those things will be forthcoming. None of us, I think, is able to peer that clearly into the future. But I think looking at the way, over the past couple of centuries as medicine has consolidated its interests in mental illness and has striven to cope and understand it, we have seen these kinds of broad oscillations between emphasizing the mind, emphasizing the brain, and we are presently in the midst of one of those brain moments, but I suspect that the underlying reality is so much more complicated that eventually the profession will be forced back to recognizing that. JB: That’s very, very interesting. When your students come to you and say, “Dr. Scull, I really enjoyed being your student. I’ve enjoyed this whole field, and somewhere along the line I’m going to have to make a living and I’d like to do it in the social sciences. Where do you think I ought to put my footprint?” Is there a place, as you see it, where in the immediacy this model of thinking is going to have applicability in social work, or social sciences, or in medicine? AS: That’s a hard one to call. A number of my students with that orientation have ended up going into public health programs, actually. Others, off to medical school. I had an absolutely wonderful student about three or four years ago who is presently at Stanford in an MD/PhD program, but before he went to Stanford he said to me, “I really want to do more medical history. I think it’s going to make me a better researcher and a better clinician.” And he went off to London and did a master’s in medical history before he went off to medical school, and I think many of his science professors-because he is a quite brilliant student-thought, “What on earth are you doing? Why don’t you jump straight in?” But, in fact, he came back from that experience, won the William Osler Medal for writing the best essay on the history of medicine after simply one year of graduate training, which was extraordinary, and students like that give me hope about students going into medicine more directly, but with a more contextualized understanding of disease and its history, may be the ones that help us move in a more balanced direction. JB: That’s a beautiful way to finish this discussion. What a great optimistic perspective. Thank you so much, and, again, I’m going to follow everything you write. I encourage our listeners to. If they want to start with a spellbinding book, Madhouse: A Tragic Tale of Megalomania and Modern Medicine is that kind of book. I couldn’t put it down myself. It’s such a fantastic history of psychiatry from this perspective of the anatomical/physiological relationship of infectious disease to neurological function. Keep doing what you are doing. It’s really a good guidepost for us and I appreciate it so much. AS: Thank you so much. I’ve really enjoyed the conversation. I hope your listeners will find something of value in it and I much appreciate you getting in touch with me. Thanks again for the kind words. JB: Thank you. Dr. Linus Pauling’s Writings on Psychiatry I hope you enjoyed that discussion with Dr. Scull as much as I did. What an amazing personality, teacher, historian, and communicator. As I listened to him and had a chance to read his books and papers, I was reminded of the extraordinary journey of psychiatry, even in the area of molecular medicine, and the pioneering, almost-paradigm-shifting paper that appeared in Sciencemagazine in 1968 titled “Orthomolecular Psychiatry. Varying the Concentration of Substances Normally Present in the Human Body May Control Mental Disease.”6 Of course, the author of that paper was none other than Dr. Linus Pauling, two-time Nobel Prize-winning laureate. It is interesting to note that when I talk about Dr. Pauling now to some of the younger people coming into the profession, they are not actually familiar with his name, which I think is a tragedy. He still remains, today, the only person to have won two independent solo Nobel Prizes in different disciplines, one in chemistry and the other in peace. He was the father of so many ideas that come into our culture now as kind of well-accepted paradigms: the mechanism of anesthetic drugs, and the concept of immunology that he developed with Delbrook while he was at Cal Tech, protein structure (i.e., the structure of collagen, even the Watson and Crick double helix was born in part-as you know, if you read The Double Helixby James Watson-through exchanged communications from his son, who at the time was in England with Watson and Crick, about his father’s x-ray crystallography work on what later became known as the double helix (Pauling thinking at the time that it might have been a triple helix).7 These impacts he has had, and then going on into the area of peace and the nuclear atmospheric test ban treaty that he and Albert Einstein and Albert Schweitzer, which was a very fundamentally important step for scientist’s advocacy in getting the ban on atmospheric testing. All of these are historically interesting parts of the social fabric of our society and the great mind-the social mind, the mindfulness-of our society. The article that appeared in Science really set a tone for reviewing the nature of mental illness-where it came from-suggesting that concentrations of various substances within brain biochemistry that are unique and normal to human physiology could help explain the origin of schizophrenia and other mental diseases, and that by modulating the environment using natural substances one could restore improved function. In the article, Pauling wrote: “The functioning of the brain is affected by the molecular concentrations of many substances that are normally present in the brain. The optimum concentrations of these substances for an individual may differ greatly from the concentrations provided by his normal diet and genetic machinery.” This would be what we call the biochemical individuality concept that Roger Williams spoke about in the 40s and 50s. “Biochemical and genetic arguments support the idea that orthomolecular therapy, the provision for the individual person of the optimal concentrations of important normal constituents of the brain, may be the preferred treatment for many mentally ill patients. Mental symptoms of avitaminosis sometimes are observed long before any physical symptoms appear.” It has been said that neuropsychological effects are some of the first signs of chronic vitamin intake below the levels necessary for optimal function, well before you get into the deficiency symptoms of scurvy, , or pellagra. Pauling also wrote: “There is a possibility that for some persons the cerebral spinal concentrations of vital substances may be grossly low at the same time that the concentration in the blood and lymph is essentially normal. A physiological abnormality such as a decreased permeability of the blood-brain barrier for the vital substance or increased rate of metabolism of the substance in the brain, may lead to a cerebral deficiency. Diseases of this sort may be called localized cerebral deficiency diseases. It is suggested that the genes responsible for abnormalities (deficiencies) in the concentration of vital substances in the brain that may be responsible for increased penetrance of schizophrenia. The so-call gene for schizophrenia may itself be a gene or a series of genes that leads to a localized cerebral deficiency in one or more of the vital substances.” Dr. Abram Hoffer and Orthomolecular Psychiatry That was Dr. Pauling’s contribution in 1968 on the orthomolecular environment in the mind. It is another chapter in the history, explanation, and understanding of the etiology of neuropsychiatric disorders. Following up on that is the other founding member of this field of orthomolecular psychiatry. This is a person I interviewed and his interview was in the December 2009 issue of Functional Medicine Update. I’m talking about Dr. Abram Hoffer, now unfortunately deceased, but certainly one of the individuals who is credited with birthing this concept. If you go back and look at Dr. Hoffer’s work, he talked about orthomolecular treatment of schizophrenia back in the 1970s, and was actually a colleague of Dr. Pauling in the development of this concept. We can go well back before the 1970s, however, back into the 1950s, when he first observed the role that niacin had in modulating schizophrenic symptoms in some patients. In fact, if you go back to the Acta Psychiatrica Scandanavica, you’ll find articles by Dr. Hoffer and Dr. Osmond, his colleague, about the treatment of schizophrenia with nicotinic acid, a 10-year follow-up in the early 60s, from the work they did in the 1950s.8It’s a very interesting chapter in understanding the etiology of neuropsychiatric disorders. If you listened to Dr. Pauling and Dr. Hoffer in the December 2009 issue, you recall they both said that these concepts are not good for everyone. In other words, there is this genetic heterogeneity, and schizophrenia has multiple causes with multiple molecular mechanisms that can contribute to it. Some of these causes may be related to this preclinical, pellagrous condition that we call schizophrenia. Niacin therapy may be a useful tool in modulating the intramolecular environment of the brain and stabilizing critical neuroregulatory substances and improving function. In fact, it is not only niacin. Perodoxine, cobalamin, and ascorbic acid have all been found, in different individuals, to play potentially important roles in the orthomolecular environment of the brain.   The Research of Dr. Michael Maes With that in mind, let’s move to a more contemporary view of this. Another colleague I’ve had the privilege of meeting and spending some time with is Dr. Michael Maes. He is an MD, PhD psychiatrist and a molecular geneticist from Belgium. Dr. Maes has an amazingly productive background in terms of his both clinical and research work, publishing well in excess of 100 papers over the last several years. I think if you trace through Dr. Maes’ work, it gives another context of understanding the development and origin of neuropsychiatric disorders and the connection of systems biology to the brain. In medicine, we often tend to isolate organ systems as if they are compartmentalized from other organs and they have their own pathologies that are separate from other pathologies. Therefore, they have their own diseases, and their own treatment regimes, and their own molecules that are using those treatment regimes, that are owned by certain subspecialists in that medical discipline. Psychiatry has its own drugs to treat its own diseases, as if the brain was really isolated from the rest of the body. As we move forward in our understanding of systems biology, we recognize that what we used to consider to be comorbidities, where disorders would serendipitously line up together and have similar overlap, was maybe actually related to the fact that these comorbidities share common mechanisms of distorted metabolism. As an example, the arthritis connects to the osteoporosis, which connects to the heart disease through alterations in mechanisms of the immune system that trigger inflammatory response that can be seen in different patients as different degrees of presentation of either heart disease, osteoporosis, or arthritis (or a combination thereof). Rather than call these comorbidities, they really should be called outcomes of the same altered metabolic system. By a similar token, if we look at the DSM (the direction as it relates to the diagnosis of mental illness), those diagnoses tend to be very broad and descriptive diagnoses that are more related to presentations than they are related to molecular distortions that lead to the individual presentation. So there may be multiple paths towards those different diagnoses. What we call them may be the same, but how we got to that name may be very different from patient to patient. It is that differentiation–that cohort kind of compartmentalization–helps us to better understand not just what we call it, but how the patient got to that state of signs and symptoms on presentation. It also helps to guide us as to how to individualize or personalize the treatment to the specific need of the patient. Rather than treat the name of the disease, we’re treating the individual situation in that patient. Research on Functional Deficiencies and Cerebral Metabolism That is the model characterized by Linus Pauling and Abram Hoffer with the orthomolecular concept, but it now goes into other themes, beyond that just of the traditional vitamins-these functional insufficiencies or deficiencies-in terms of cerebral metabolism. That is what Dr. Maes and his colleagues have been helping us to better understand. It has been his observation that these conditions such as depression, or dysphoria, or various types of schizophrenias, or even autistic types of diagnoses, really relate, in part, to alterations in the neuroimmune system of the individual, and better understanding of the origin of distortions in neuroimmunology helps us to tailor a program of treatment to the individual needs of the patient. This cuts across into a whole family of companion comorbid situations that we consider related to alterations in neuroendocrine or neuroimmune function, including such things as fibromyalgia. I think it is very interesting that the drug LyricaTM, which has recently been approved for the treatment of fibromyalgia, works as kind of a gabapentin activator of function, which suggests an immune-neurological connection that is central rather than peripheral. So the trigger point pain found in fibromyalgia patients may have a central-mediated problem at the connection between the nervous, immune, and endocrine systems (this neuroendocrineimmune dysfunction). As we learn more about neuroendocrine dysfunction, it helps us to understand how that interrelates with immunity and immunological function, and how it then goes out into a wide variety of diagnoses that are both in the psychiatric as well as in the immunological categories. Dr. Maes and his colleague, Dr. van West, first wrote about this in an article they published in BioDrugs in 2001, in which they said that fibromyalgia is “a form of nonarticular rheumatism characterized by long term and widespread musculoskeletal aching, stiffness, and pressure hyperalgesia at characteristic soft tissue sites called soft tissue tender points. The biophysiology of fibromyalgia, however, has remained elusive.”9 Now there is increasing evidence to suggest that there are various serum activities of neuroendocrineimmune disturbance that is then seen as muscle energy depletion, as it relates to altered mitochondrial function that is related to altered immunological function that is tied to inflammation. These concepts that we would go upstream and start actually looking at the origin of why you would have these interruptions in mitochondrial function that produces pain, some of which may be related to the social environment and others relate to the physical environment, is a different way of approaching the etiology and ultimately the treatment of fibromyalgia. Dr. Maes has followed up on this concept of the neuroendocrineimmune system being a kind of combined system for regulating all sorts of intercommunication among centrally mediated processes, immunologically and peripherally mediated processes, and endocrine-related processes, and it ties together through the inflammatory response. He has published papers showing that the inflammatory response is amplified in women who previously suffered from major depression, suggesting that depression is accompanied by sensitization of the inflammatory response system.10 This could be like a dog chasing its tail: there may be something that starts the depression moving, that then alters the immune system, the immune system becomes more proinflammatory in its response to a perceived hostile environment, that then further circles back and causes more alteration in neurological function, which then sets more depression in place. In his work, inflammation markers have been found to be associated with altered cognition and altered affect in aging populations. This was published in the Journal of Neuroimmunologyback in 2003. The suggestion is that if you start looking at things like high sensitivity C-reactive protein, and do testing of word learning tests and word recall tests in individuals, you will find there is a very close correlation between increasing inflammatory markers and decreasing memory and cognition, suggesting, again, that there is this interrelationship between nervous system function, and immune system function, and inflammatory signaling. The Metabolism of Serotonin: Neurotoxins As you probably know, serotonin is derived from the amino acid tryptophan, through metabolic conversion through kynurinic acid. These intermediary molecules in the metabolism of serotonin can be considered neurotoxins in their own right, and can have-in animals-effects on their mood and their nervous system activity. If you had an alteration in the metabolism of neurotransmitters coming up from the precursor tryptophan into serotonin and its byproducts, it would be possible to induce autotoxicity, which then could activate the immune system. This is very similar to what Dr. Hoffer talked about back in the 1950s with his constructs of orthomolecular psychiatry. He talked about the alteration in metabolism to produce hallucinogenic substances that could induce, endogenously, schizophrenia. The chemistry at that time was not sophisticated enough to allow complete understanding of the various intermediary metabolites and all the orthomolecular environment. But today, as a consequence of multi-analyte testing and all of the high throughput screening we can do, and the ability to do analyte testing at a very low level of concentration, some of these intermediaries in this alteration-the web of physiology-are starting to be understood. This autointoxication concept is getting more traction, and that’s what Dr. Maes talks about as it relates to how these substances may interrelate with immune system activation and then be like a circular effect on depression, anxiety, mood changes, and inflammatory mediators all working together. It is not just in the mind; chronic fatigue syndrome, fibromyalgia, and depressive disorders all swim together, work together, through the inflammatory pathways. You’ll see increased NF-kappa-B activities as a gene transcription agent for activating the genes that are associated with proinflammatory cytokines. There is this sense that agents that amplify the inflammatory pathway may be aggravant substances for depression, mood, and behavior dysfunctions, for which we then treat the effect rather than treat the cause. In fact, if you look at some of the hallmarks of activation of gene expression of inflammatory mediation, like the activation of genes that regulate nitric oxide synthase and prostaglandin E2, you find that there is an activation of inducible nitric oxide synthase and cyclooxygenase 2 in chronic fatigue patients, and fibromyalgia patients, and depressed patients. This was actually published in Neuroendocrine and Endocrinology Letters in 2007.12 This model is another part of our evolving understanding of the origin of neuropsychiatric and neurophysiological disorders. If you start looking at tryptophan metabolites along the pathway of ultimate excretion of indoleamine metabolites from the metabolism of tryptophan through the serotonergic pathway, you see there is some relevance in individuals to the autointoxication concept that was first born out of work from the middle of the last century. By modulating the metabolism of these substances and improving their throughput into serotonin and their exit ultimately out of the body through detoxified intermediates, we improve the molecular milieu (the orthomolecular environment). Eosinophilia Myalgia Syndrome: Tainted Tryptophan Resulted in Autoimmune-like Reactions For those of you who feel this sounds like it doesn’t have anything other than theory behind it, let me remind you that we had a condition called eosinophilia myalgia syndrome that was of extraordinary concern some 20 years ago. EMS led to the death of a number of individuals-more than 10-in the US, and literally thousands were adversely affected by this autoimmune-like reaction that had neurophysiological, neuropsychiatric, and neuromuscular relationships, symptomatically. The origin of EMS, which was virtually epidemic for awhile in its prevalence, was the consumption of tainted tryptophan that was manufactured by the Showa Denko Corporation in Japan by fermentation using microbiological production. These organisms that they were using were genetically modified, and unfortunately the final tryptophan was not cleansed of a small contaminant called peak-E, which was a tryptophan-type of dimer that with formaldehyde produced this very toxic effect on the immune and nervous systems that ultimately led to what we diagnosed and called eosinophilic myalgia syndrome, leading to death and very serious disability (sometimes lifelong disability) of people who consumed this tainted tryptophan. The amount of this peak-E amount of tryptophan dimer was very, very small. In fact, it was missed in the first analysis because it wasn’t high enough in concentration until they went to a more detailed chromatographic analysis to find material in it. It was almost like a trace contaminant that had this very dramatic effect on immune and neurological function. This tryptophan contaminant demonstrates, I think, that there are substances that even in very small amounts may have very profound influence on neuroendocrine immune function. The autointoxication concept is not so far away from what we observe factually, from clinical experience, to be thrown out as ridiculous. In fact, if you look at another condition called hepatic encephalopathy, I consider that an interesting example of autointoxication as well. This is often seen in hospitalized geriatric patients. They develop hallucinations and psychoses. The treatment of choice for that condition has historically been something like lactulose oral therapy, which causes diarrhea. It’s a gut detoxification, and basically by reducing the load of toxic metabolites from the gut, which are often protein byproducts from bacterial fermentation in the gut, it lowers the load on the liver. The liver of an older-age person that is hospitalized may not be able to completely remove these substances, and therefore they are delivered to the blood and then ultimately to the blood-brain barrier, where they have this effect of producing hallucinations and psychoses. Hepatic encephalopathy should really be called gastrointestinal hepatic encephalopathy, in which the gut and bacterial debris that comes from metabolism of various food stuffs and protein amino acids into secondary metabolites are not properly detoxified or regulated at the hepatic level, and then travel to the brain where they can have an adverse effect. I think if we look at a little bit broader view of neuropsychiatry as it relates to the concept of autointoxification and take a more contemporary and modern view of it, it doesn’t look quite as strange as it did back in the early 1900s. In fact, I think it is also interesting to note that the management of this is not gastric resection, as was discussed in Madhouse by Dr. Scull (how this was managed in psychiatric hospitals by surgery-by shortening the bowel), nor by giving antibiotics, but rather by regulating proper metabolism, and proper barrier function of the gut (the so-called gut mucosal barrier), and proper hepatic detoxification function. So the strategy-using the orthomolecular model of Pauling and Hoffer-would be to provide adequate levels of orthomolecular substances to manage the natural processes of regulating these substances. I think this is a very interesting conceptual shift, from a surgical invasive intervention that was being used in psychiatric hospitals in the 1920s and 30s to a more orthomolecular modulation of the molecular milieu. Dr. Maes, in some of his more recent work, has looked at this gut connection to things like chronic fatigue syndrome and fibromyalgia. I’m very pleased about this because it was back in the early 1990s that our group first started talking about and publishing papers on the gut-brain connection and the gut-immune connection and its relationship to chronic fatigue syndrome and fibromyalgia. At the time, it was considered totally heretical thinking. I recall presenting at a number of meetings where it was considered absolutely ridiculous to consider the fact that there would be some connection between the gut and the immune system that would been seen as either chronic fatigue syndrome or fibromyalgia. Yet, in 2008, in Neurology and Endocrinology Letters, Drs. Leunis and Maes published an article titled “Normalization of Leaky Gut in Chronic Fatigue Syndrome is Accompanied by Clinical Improvement: Effects of Age, Duration of Illness, and Translation and Translocation of Lipo-polysaccharide from Gram-Negative Bacteria.”13 That’s a very interesting title and I don’t know if it completely resonates with you, I think it is a very important title, clinically. We have this barrier function called the gut mucosal membrane. That gut mucosa is not only actively involved in excluding the translocation of bacteria, but also in engaging in detoxification and selective transport of nutrients while excluding toxins. So there is a detoxification process going on in the gut mucosa, as well as (obviously) in the liver. When you get a breakdown in the gut barrier function and you get this paracellular leakiness, it can lead to translocation not only of bacteria, which can induce immunological effects, but also to middle molecular weight molecules, things that were previously excluded and had to be detoxified before they were passed into the blood. This leakiness, which can be measured clinically in patients with things like the lactulose-mannitol oral challenge test to look for gut permeability, is a very interesting concept that ties to endotoxemia and relationships to quality of diet, environmental agents, stress factors, all of which can alter the integrity of the gut mucosal membrane. These portals of entry through a leaky gut to the gastrointestinal associated lymphoid tissues of the gut-immune system allow exposure to foreign molecules, which then initiates various types of immunological responses, including the production of proinflammatory mediators. I think that what Dr. Maes and Dr. Leunis are talking about in this Neuroendocrine and Endocrinology Letters article is the fact that if you look at chronic fatigue syndrome patients and examine inflammation and gut function, you find there is a very strong interrelationship. What they found is that by administering agents that help to improve gut immune function and gut mucosal integrity, such as the amino acid L-glutamine given therapeutically, N-acetylcysteine, and zinc, in conjunction with a low gluten diet and a diet that is not high in solutes, like salt and sugar and saturated fat, that you can actually restore proper gut immune integrity (mucosal integrity), lower inflammatory mediators, and reduce the symptoms of chronic fatigue syndrome. This has been re-studied by a number of other investigators and we’ve spoken to some of these studies in previous issues of Functional Medicine Update. We have talked about how one high fat, high sugar meal in apparently healthy people has been demonstrated to increase post-prandial bacteria lipopolysaccharide in their blood, to increase pro-inflammatory cytokines like TNF-alpha and IL-6 in their blood, and to activate immunological response.14That’s just one high fat, high sugar meal. What happens if a person eats that day in and day out, meal in and meal out? They are-to use kind of a descriptive term-driving holes through their GI mucosal membrane and increasing the exposure of their gastrointestinal immune system to these immune active substances that can then generate more proinflammatory mediators. All of these things, I think, are very interesting as it relates to a systems biology process of looking at how the gut, the diet, the environment may interrelate to various psychiatric diagnoses. We’re not-again-talking about the necessity for gastrointestinal resection or surgery. We’re talking about appropriate orthomolecular provisions for function at the gut immune level, the hepatic level, and circulating white cells in the blood-brain barrier. How would you compare this type of an approach? We call it the 4R approach-remove, replace, reinoculate, repair therapeutic approach. Removing the offending agents that are causing alteration in gut mucosal integrity, things that would be considered like parasitic organisms, or food allergens, or toxins. The second “R” is that of “Replace” (replacing digestive enzymes and acid where necessary to stimulate proper digestive function). The third “R” is “Reinoculate” (adding pre- and probiotics-symbiotics-to stimulate proper friendly bacteria and push out the toxic parasitic bacteria. And lastly “Repair” is the fourth “R” (to add those nutrients like glutamine and zinc and essential fatty acids of the omega-3 family that are necessary for repairing proper gut mucosal integrity). How does this 4R approach contrast to the generally accepted approaches to chronic fatigue syndrome, things like cognitive behavior therapies? There is a nice paper that has been published-again in Neurology and Endocrinology Letters -in 2009, in which the effect of cognitive behavioral therapy in chronic fatigue was examined and it was found that although a lot of people feel this is the standard of identity and the standard of care, in this treatment trial, there was no significant benefit of the cognitive behavioral therapy, and managing, in the long term, chronic fatigue syndrome symptoms and severity.15 In fact, in a study in Current Opinions in Psychiatry in 2009, volume 22, it was found that people with chronic fatigue syndrome actually did best when they were placed on a program that was lowering inflammatory burden, improving gut mucosal barrier function, and reducing things like cyclooxygenase II activities and inducible nitric oxide synthase activities, and that that had an effect also on their mood.16 This not only improved somatic symptoms like aches and pains (muscular tension and fatigue), but also it had a very positive effect on reducing irritability, sadness, and a subjective feeling of depression. Again, this is the body/mind connection through this kind of a systems biology approach. I think this cytokine hypothesis of depression and its relationship to inflammation and oxidative and nitrosative stress and leaky gut really represents a new target for adjunctive treatments in depression. I think the concept that there are secondary metabolites of various biomolecules that may be considered neurotoxic is not an unreasonable thing to consider given the expanding body of understanding we have about the molecular milieu of the mind. We’re starting to see much more of the interconnection between the gut-brain barrier in major depression, how intestinal mucosal dysfunction is associated with increased translocation of lipopolysaccharide from gram-negative entero bacteria and how it plays a role in the inflammatory pathiophysiological role seen in depression and maybe other behavioral and psychiatric illnesses. So I want to go back and give credit to the founding figures upon which this field is being built, Dr. Pauling and Dr. Hoffer. Dr. Maes’ work continues to extend this concept, and also-I think-the 4R program, a therapeutic concept we developed in the functional medicine model some 20 years ago. People now see that this really has a tremendous opportunity to advance successful outcome in patients with these chronic neurochemical, neuroimmune, endocrine dysfunctions, like chronic fatigue syndrome, fibromyalgia, and other depressive disorders. I want to once again thank Dr. Scull for his extraordinary history lesson that gave us a timeline upon which we viewed advances that are being made in this field and recognize that we shouldn’t throw a baby out with the bathwater. We ought to look at the best that exists and assemble new information into new therapeutic tools that will help alleviate these very complex disorders of the mind.

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Bibliography 1 Scull, Andrew and J. Andrews. Undertaker of the Mind: John Monro and Mad-Doctoring in Eighteenth-Century England. Berkeley and London: University of California Press, 2001. 2 Scull, Andrew. Museums of Madness: The Social Organization of Insanity in Nineteenth Century England. London: Allen Lane and New York: St. Martin’s Press, 1979. 3 Scull, Andrew. Madhouse: A Tragic Tale of Megalomania and Modern Medicine. London: Routledge, 2006. 4 Scull A. A psychiatric revolution. Lancet. 2010;375(9722):1246-1247. 5 Scull, Andrew. Hysteria: The Biography. New York: Oxford University Press, 2009. 6 Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(825):265-271. 7 Watson, James D. The Double Helix. Denver: Mentor Books, 1969. 8 Hoffer A, Osmond H. Treatment of schizophrenia with nicotinic acid. A ten year follow-up. Acta Psychiatr Scand. 1964;40:171-189. 9 fibromyalgia. BioDrugs. 2001;15(8):521-531. 10 Maes M, Ombelet W, De Jongh R, Kenis G, Bosmans E. The inflammatory response following delivery is amplified in women who previously suffered from major depression, suggesting that major depression is accompanied by a sensitization of the inflammatory response system. J Affect Disord. 2001;63(1-3):85-92. 11 Teunissen CE, van Boxtel MP, Bosma H, et al. Inflammation markers in relation to cognition in a healthy aging population. J Neuroimmunol. 2003;134(1-2):142-150. 12 Maes M, Mihaylova I, Ruyter MD, Kubera M, Bosmans E. The immune effects of TRYCATs (tryptophan catabolites along the IDO pathway): relevance for depression-and other conditions characterized by tryptophan depletion induced by inflammation. Neuro Endocrinol Lett. 2007;28(6):826-831. 13 Maes M, Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008;29(6):902-910. 14 Erridge C, Attina T, Spickett CM, Webb DJ. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr. 2007;86(5):1286-1292. 15 Twisk FN, Maes M. A review on cognitive behavioral therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30(3):284-299. 16 Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009;22(1):75-83.

Welcome to the January 2009 issue of Functional Medicine Update. It is the start of a new year, the start of a new age, and the start of a new period of opportunity. Let’s start this new age with a very interesting concept, one that I think makes functional medicine stand out clinically in a way that we probably would have never dreamed possible. I’ll start with this: Unspecialized loose connective tissue forms an anatomical network throughout the body. We recognize now that connective tissue functions as a body-wide, mechanosensitive signaling network. Three categories of signals are included, including electrical, cellular, and tissue remodeling, each potentially responsive to mechanical forces over different time scales. I am paraphrasing from a paper authored by Dr. Helene Langevin, Department of Neurology, University of Vermont College of Medicine, titled “Connective Tissue: A Body-Wide Signaling Network?”1 You are going to have the pleasure of hearing directly from Dr. Langevin about her work in the area of extracellular matrix physiology and looking at the mechanistic and cellular roles that mechanical and electrical stimulation have on whole-body physiology. Before we get to Dr. Langevin and her pioneering work, I’d like to set the context for what-to me-is emerging to be one of the most remarkable stories that gives substance to the concepts of functional medicine, which we have been describing for over twenty years. It is the story that surrounds an aspect of this connective tissue, the collagenous matrix that holds us together. We have thought of connective tissue as being a structural component of the body, but now we recognize it is a composite not only of structure, but also function because it participates in transduction of signals. Signals from the environment are transduced into the interior of cells, to the very heart of the cell where our book of life resides within the library called our genome. These signals then unlock portions of our library, and certain chapters in our book of life are read to create the stories that become the phenotype of those cells and alter function as a consequence. This mechanism of mechanical transduction of signals to the interior of cells to produce different function is now an extraordinary new component of the evolving understanding of what we have really meant by a systems biology approach to medicine that we call functional medicine. With that in mind, we are going to focus on extracellular matrix physiology and connective tissue in this month’s issue of Functional Medicine Update. The place I want to start this discussion is with a condition that we all think we know quite a bit about: osteoporosis. I would like to cast the term “osteoporosis” through the lens of the functional medicine matrix to produce a different sense of what is emerging to be understood about osteoporosis, the relative loss of bone over time with increased risk to fracture. Osteoporosis as Viewed through the Lens of the Functional Medicine Matrix Let’s start with the presumption that osteoporosis is partly related to things like calcium nutriture, vitamin D status, vitamin K status, and the relationship to estrogens and other hormones. We know these factors play a role in maintenance of bone integrity, but we also recognize that bone loss, leading to decreased bone mineral reserve and reduced integrity of the bone mineral matrix, can occur as a consequence of inflammatory conditions. Let’s consider post-menopausal osteoporosis. Could it be more than just the loss of estrogen that then induces some kind of an anabolic change in the bone remodeling unit? Could it be considered, in part, an autoimmune disease? Why do I bring that up? I bring that up because it is now being recognized that there is a role of T-cells and the relationship of their secreted inflammatory mediator, tumor necrosis factor alpha (TNF-alpha), along with other cytokines, in the pathogenesis of bone loss that occurs in systemic inflammatory diseases. The relevance of these T-cell activities in bone loss due to estrogen deficiency has been investigated now by a number of different groups that have shown in recent years that the increased presence of TNF-alpha-producing T-cells is essential for the changes in bone metabolism during estrogen deficiency.2 The lack of estrogen increases the secretion of interferon gamma by helper T-cells, through which complex class 2-related expression of major histo-compatibility class 2 antigens then enhances the activation and proliferation of the TNF-alpha-producing T-cells. Is osteoporosis an autoimmune disease, or is it a problem related to an isolated difficulty in the bone itself? In other words, does it have a systemic connection, or is it a localized problem that is seen only in bone? Those are very interesting questions that move us beyond looking at individual organ parts (in this case the skeleton) in isolation from the rest of the body, to looking at the body (the skeleton) in the context of what we call systems biology (from a functional approach). In order to better understand the connection of estrogen and mechanical stress or exercise (weight-bearing exercise, as it is often said, or resistance exercise), or nutrition of calcium, or magnesium, or phosphorus, or vitamin D on bone metabolism, we have to know something about the cell biology of bone metabolism itself, and that’s really advancing dramatically in terms of our understanding of how the bone remodeling unit works at the cellular and even molecular level. Let’s dig a little deeper into this question of the cellular biology of bone metabolism. There is a wonderful review that was just published in 2008 in the Journal of Clinical Pathology titled “The Cell Biology of Bone Metabolism.”3 Bone (in the macro look) is a specialized connective tissue that is hardened by mineralization with calcium phosphate in the form of hydroxyapatite. We know that it has rigidity and shape and it protects and supports the body, but it’s more than that. Contrary to popular belief, bone is a highly dynamic structure undergoing constant remodeling throughout the whole of our life, and, in fact, is an integral part of the neuroendocrineimmune system. Now, you heard what I just said. Let me say it again: bone is an integral part of the neuroendocrineimmune system. That’s a different perspective on looking at skeletal health and integrity. We’ll come back to talk much more about why I think that position is now justified in light of what we’ve learned about bone metabolism and the cellular biology of bone. Regulation of Bone Status: Osteoclastic and Osteoblastic Activity To make a simple story out of a much more complex topic, bone status is regulated, in part, by the activity of two different cell types: the osteoblast, which produces new bone, and the osteoclast, which is involved with bone resorption. In youth we have osteoblastic activity exceeding that of osteoclastic activity, and we have net skeletal growth. In mid-life, we’d like to think that our bone resorption equals that of our bone reformation and so we have a long period of skeletal homeostasis under constant remodeling. It’s a little bit like the hummingbird flapping its wings. It looks as if the bone is staying in the same state, but actually if we were to look at it with time-lapsed photography, what we would see is remodeling of the bone occurring all the time with new bone replacing old and maintaining that skeletal equilibrium. And then in older age we know osteolysis exceeds that of osteogenesis and we start to get skeletal loss. That can occur, however, even at younger age with specific types of disorders that are associated with osteoclastogenesis, where you actually see the osteoclastic activity exceeding the osteoblastic activity, so we have net skeletal resorption. What causes this to occur, be it either in the alveolar bone of the jaw (or the mandible), or the trabecular bone of the spine, or the cancellus bone of the wrist? What is it that results in this dynamic equilibrium and the shift between osteoclastic and osteoblastic activity? I think that is really the theme of this new emerging understanding of the cell biology of bone. If we look at the ultimate activity at the bone remodeling unit at the osteoclast and at the osteoblastic cell, what we’ll find is there are many, many different signal transduction agents that are involved in signaling to the book of life-the genome-within those cell types, what they are going to express in terms of proteins that then regulate their function. This intercellular signal transduction process within the bone remodeling unit is regulated by exposure to environmental factors, as well as the genetics of that individual. And that signal transduction process is emerging to be much more complex than we ever would have believed, in that it is influenced by, and it also influences, activities within the nervous, immune, and endocrine systems. Factors that would be considered hormones, or inflammatory mediators, or even mechanical signals can all influence the regulatory signal transduction within these cell types that make up the bone remodeling unit. Those activities of the bone remodeling unit cells secrete (into the plasma) substances that have influence downstream on other tissues and influence the neuroendocrineimmune system in other places of the body, so it is a feedback process. Once again, it is a system of biological function. Bone doesn’t work in isolation. Signal Transduction Agents Influencing the Phenotype of Bone Let’s look a little bit more in detail at these signal transduction agents that regulate the expression of genes that ultimately control the phenotype of bone and may have influence on other functions of the body. One of the principal processes in the signal transduction process related to skeleton and bone formation is the so-called Wnt/beta-catenin system that connects with bone morphogenic protein pathways and modulates key transcription factors within the regulatory units of the genome of these bone cells. The Wnt/beta-catenin signal transduction process becomes a very important part of the process that regulates, then, osteoblastic activity and its interrelationship with osteoclastic activity. I’m going to talk about this in more detail and I want to make this fairly complex story as easy to understand as possible. I will ask for a little poetic license, here, in that there are very significant levels of detail below what I am going to be speaking about, but I’m going to take kind of a higher level view. What I am really saying is that the nuclear regulatory factors that control the expression of genes within the osteoblastic and osteoclastic cells are influenced by environmental factors that then signal through the Wnt/beta-catenin signaling pathway. Therefore, if we wanted to understand something about ultimately what is seen clinically as a bone demineralizing situation, we’d want to know something about its upstream regulatory effects on these signal transduction processes. We’re going to be focusing both on the Wnt/beta-catenin pathway and we’re also going to be looking into the osteoclastic cell (the bone resorption unit) at another interesting signal transduction pathway, the NF kappa B pathway. On the surface of the osteoclastic cell resides receptor sites that then signals into the osteoclastic cell, down through a signal transduction process that ultimately causes either NF kappa B to translocate to the nucleus and upregulate, in the osteoclastic cell, the production of factors that lead to bone resorption, or RANK-RANKL to lead to osteoclastogenesis, where you actually increase the activity and number of the osteoclastic cells at the expense of lowering the activity of the osteoblastic cells. The Wnt/beta-catenin signaling pathway regulates, to some extent (or to a major extent), the osteoblastogenesis, which means increasing bone reformation, whereas the RANK-RANKL signal transduction pathway activates osteoclastogenesis, which primarily regulates bone resorption. I hope this is becoming at least somewhat understandable now. Environmental factors that activate the RANK-RANKL system are involved with bone loss, whereas those that activate the Wnt/beta-catenin system are more related to bone reformation. The RANKL system (the Receptor of NF kappa B ligand) is an inflammatory mediated pathway, down through NF kappa B, translocation to the nucleus of the osteoclast and upregulating the expression of genes that then regulate osteoclastogenesis and bone resorption. The Wnt pathway is a pathway that is regulated by many environmental factors that I’m going to go into and discuss, including weight-bearing exercise and mechanical stimulus, including various hormones like vitamin D in its hormonal form (1,25-dihydroxyvitamin D3) and estrogen, and including a variety of other signal transduction agents that may be nutritionally derived, for which we have only recently started to recognize play a role in bone maintenance (in fact, they would not be on the short list of most people who think of various nutritive factors that are associated with bone regulation). These other agents are phytochemicals that might favorably influence the Wnt/beta-catenin signaling pathway in osteoblastogenesis. It is further important to understand that the osteoblast and osteoclast equilibrium is just that: an equilibrium. You can shift the teeter-totter toward more osteoclasts and higher activity resorption by activating the RANK-RANKL system. You can also shift the teeter-totter the other way, toward more osteoblastic formation and more bone formation by activating the Wnt/beta-catenin system. This is a regulatory intercellular signal transduction pathway that then is influenced and communicates with the outside world and environmental factors, both endogenous substances like hormones and exogenous substances, activities, or functions, including things like mechanical transduction or energy medicine. With all of that as kind of a summary background, let’s now talk about what this skeletal remodeling unit that is composed of the osteoblasts and osteoclasts does, both locally and systemically. Locally it is going to regulate the structure and function of both cancellous and trabecular bone. The formation of this spongy bone is porous and forms a very high tensile-strength structure that is actually very lightweight compared to its strength. This architecture of the bone is regulated not just by calcification with hydroxyapatite, but by the bone mineral matrix itself, as supported by the protein that is the structural protein (the connective tissue protein) that regulates the ultimate structure and function and strength of the bone. This is the local effect of this process on bone strength and function. Endocrine Regulation, Energy Metabolism, and the Skeleton Beyond that, however, it has been recognized now that healthy bone or unhealthy bone is secreting substances that go into systemic circulation as a consequence of the bone’s response to its environment, and that then influences tissues at a distance. What am I really speaking about? If you recall, last year in Functional Medicine Update I talked about a remarkable paper that appeared in the journal Cell in the August 2007 issue, titled “Endocrine Regulation of Energy Metabolism by the Skeleton.”4 This was work that came out of the department of pathology and genetics at Columbia University College of Physicians and Surgeons looking at the role that various factors secreted by bone could have on things like the endocrine pancreas beta cells, the Islets of Langerhaus cells that secrete insulin, or the adipocyte cell that secretes adiponectin. What was found was that a substance called osteocalcin that was secreted by the osteoblastic cell (in an uncarboxylated form), upon stimulation by the Wnt/beta-catenin intercellular signal transduction process, had positive impacts on the adipocytes secreting adiponectin, which is, as you know, anti-inflammatory and insulin-sensitizing. It also had positive effects on the beta cells of the endocrine pancreas in secreting more insulin. In fact, it leads to proliferation of the beta cells. That leads to what? Improved insulin stability, improved glucoregulation, improved appetite regulation, and improved weight. People started saying, “Just a minute. Are you saying the skeleton has a role to play in energy regulation of the whole body and has an endocrine-like effect by regulating influences on beta cell activity within the pancreas, and adipocytokine production that then influences things like appetite?” The answer is yes. That is what has been seen. In fact, it is now recognized that the signal transduction process that controls the secretion of osteocalcin by the osteoblast is regulated by a gene called esp, and that gene, then, ultimately is controlled by various types of environmental factors. If you have esp gene activities either up- or downregulated, it then has an influence on whether osteocalcin will be produced more or less by the osteoblasts, which then has an effect on either improving or decreasing insulin production and sensitivity, and increasing or decreasing adiponectin production by the adipocyte. These are really profound, new thoughts about systems biology in medicine, and we want to talk about structure and function. We’ve moved now to an understanding of cellular physiology that has a whole-body context. We’ve moved beyond seeing the bone as a structural unit sitting in isolation, to seeing bone as an active contributing member to the overall neuroendocrineimmune system, regulating far-ranging functions such as appetite, insulin sensitivity, glucose, and even anti-inflammatory proteins such as adiponectin. By the way, a very nice review of this whole concept of energy regulation by the skeleton authored by George Wolf from Berkeley appeared in Nutrition Reviews in 2008 that I think you might find very helpful if you want to read more about this topic.5 It seems like a different view of how the skeleton is part of an overall systems biology relationship is starting to emerge. What we might see as unhealthy bone (bone that means we have increased osteoclastogenesis with increased bone resorption) is reflective not only of increased risk to osteoporotic fracture, but also of maybe systemic problems related to difficulties with regard to insulin sensitivity, to difficulties related to appetite regulation and adipocytokine production, and to difficulties related to inflammatory conditions. It is a push-pull: inflammation increases osteoclastogenesis, and increased osteoclastogenesis then has a feed-forward effect on supporting increased inflammation, so we are into a chronic cycle of inflammatory disorder. To follow up on this and to show you that extraordinary work is continuing in this area, I want to point out there was a very interesting additional paper published in the August 2008 issue of Nature. This came from the Section on Obesity and Hormone Action at the Joslin Diabetes Center at Harvard, and this was titled “New Role of Bone Morphogenic Protein 7 (BMP7) in Brown Adipogenesis and Energy Expenditure.”6 You’ll remember I talked about two signal transduction pathways playing very important roles in osteoblastogenesis. One was that of the Wnt/beta-catenin pathway, and the other was this bone morphogenic protein pathway and its relationship with transforming beta. This whole process of osteoclastogenesis versus osteoblastogenesis is regulated by the way these signals are transduced at the cellular level. What does this paper in Nature tell us? It follows on in the energy-regulation-by-the-skeleton theme. As we all know, adipose tissue (or the adipocyte mass) is central to the regulation of energy balance. It is what fat supposedly is there to do, to kind of store energy for a rainy day in the form of triglycerides. Two functionally different types of fat are present, we know. One is called white adipose tissue, which is the primary site where fats as triglycerides are stored, and also we have the brown adipose tissue, which are more metabolically active forms of fat cells that are specialized in energy expenditure related to thermogenesis and may counteract obesity. Factors that specify the development and fate of the function of white and brown adipose tissue still remain poorly understood, however, it is now recognized that the family of bone morphogenic proteins support white adipocyte differentiation and that bone morphogenic protein 7 singularly promotes differentiation of brown pre-adipocytes, even in the absence of other hormonal inductions. Bone morphogenic protein 7 coming from bone activates a full program of brown adipogenesis, including induction of early regulators of brown fat, increasing the thermogenic activity and influencing energy economy of the body, so the skeleton can regulate energy expenditure. Healthy bone is healthy body. A healthy body is a system of biology that produces high function. It’s impossible in light of what’s emerging in the basic clinical sciences to look at disease as organ-specific in isolation. We have to start looking at things as networked, as interactions, and as systems where we get these interactive components that then set up new cycles of harmonics, and those harmonics become steady states that we call (for the lack of a better understanding) a disease Let me go back now to where we started this discussion: intercellular signal transduction. For those of you who are not cellular biologists or molecular biologists, let me try to take another run at this, just so we all are on the same page. When I say signal transduction, what I’m speaking to are processes within a cell that take outside information in the form of agents that signal to the cell. These could be mechanical signals, electrical signals, or chemical signals. They are picked up by receptors sites or signal transduction proteins that are generally involved with a family of proteins that we call kinases, which are phosphorylating proteins. The kinases modulate the signals like a relay race: runners passing the baton from one to another from repetitive phosphorylation cascades. A signal gets transduced from outside the cell, then, to the inside of the cell through the cytoplasm, ultimately through the nuclear envelope into the nucleus where the genome resides, and even into the mitochondria (the energy powerhouse of the cell). These transduction processes that are mediated or modulated through these kinase enzyme signaling relay racers (I guess we’d call them) result in altered structure and function of the cell. Wnt and beta-catenin constitute an important signaling transduction pathway to regulate (as nuclear regulatory factors) the expression within the nucleus on the cassette of genes that regulate osteoblastic cell function, a specific constellation of proteins that then cause bone reformation. The Wnt genes encode a highly conserved class of signaling factors required for the development of musculoskeletal and neural structures. There is increasing evidence that Wnt signaling is critical for bone mass accrual, bone remodeling, and fracture repair. Wnt proteins bind to cell surface receptors and activate signaling pathways which control the nuclear gene expression, and this Wnt-regulated gene expression controls cell growth and differentiation. With all of that in mind we might ask, “How can you alter Wnt function and what role does Wnt play in this process?” Wnt is going to stabilize (once it is produced this pathway is activated) a process within the osteoblastic cell that is going to engage osteoblastogenesis (increased osteoblastic activity) and increased bone formation activity, so we’re going to actually see a positive influence of Wnt stabilizing the target genes (or activating the target genes) involved with osteoblastogenesis.7 What this means is if there is no Wnt activity (or there is inhibited Wnt activity) the result would be reduced osteoblastogenesis, where activated Wnt would lead to increased osteoblastogenesis. So you might ask, “Are there people who are born with increased Wnt signaling pathways and what influence does that have on their bone?” The answer is yes, there are genetically unique individuals, and they have very dense bones. What about people on the opposite, who have low Wnt signaling pathways as a consequence of their genetics? Those people also have been identified and are associated with early-onset, very serious bone demineralization issues-things like osteoporosis pseudoglioma. These genetic outliers do exist to confirm the importance of Wnt pathway. The Wnt pathway regulates, at the cellular level, the expression into the phenotype of these particular aspects of osteoblastogenesis and how that then interrelates with osteoclastogenesis. Serotonin has Stabilizing and Destabilizing Effects on Signaling Pathways With all of that in mind, now the question is: what regulates the Wnt pathway? Are there things upstream that we should consider? Here is where the story gets unbelievably interesting. After publication of a paper that appeared in Cell in November of 2008, this has to be considered one of those “I can’t believe it” kind of responses by the scientific community. It turns out that within this complex signaling pathway, one of the things that stabilizes Wnt or destabilizes Wnt signaling is a hormone that we are very familiar with that has to do with mood; that hormone is called serotonin. Serotonin, we know, is synthesized within the central nervous system; it’s a neurotransmitter. The principal place where serotonin is synthesized in the body happens to be in the enterochromaffin cells in the small intestine, in the duodenum. In fact, almost two-thirds of the body’s serotonin comes from the gut. We learned this years ago from Dr. Michael Gershon in his classic book The Second Brain, which talked about GI hormonal function. Serotonin synthesis in the gut contributes significantly to the level of serotonin in the blood. In fact, the majority of blood serotonin doesn’t emerge from the central nervous system; it emerges from the gut. Gut serotonin does not cross the blood-brain barrier, so it doesn’t lead to mood elevation, but it does have impacts on cellular function beyond that of mood. This is where the story gets extraordinarily interesting, because in the November 28th, 2008 issue of Cell, an article was published (again out of Columbia University-collaboration amongst researchers in the departments of genetics, neuroscience, psychiatry, and pharmacology)-that was titled “Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum.”8 What is that all about? This is a very, very extraordinary part of the story. Let me, if I can, show you how it connects to our Wnt/beta-catenin regulation of osteoblastogenesis. Loss and gain of function mutations in lipoprotein receptor 5 (Lrp5), a broadly expressed gene, have been known for some time to affect bone formation. There is a wide body of literature from molecular genetics and animal biology to demonstrate that it causes osteoporosis and the loss of function, or it can result in high bone mass and the gain function. Although Lrp5 has been viewed as a Wnt coreceptor, an osteoblast-specific disruption of the beta-catenin does not affect bone formation. In this paper, however-the one I’m just describing in Cell-the authors demonstrated that Lrp5 inhibits the expression of another interesting gene: Tph1. Now what does Tph1 do? Tph1 controls the biosynthetic enzyme tryptophan hydroxylase that then results in the formation of serotonin in the enterochromaffin cells in the duodenum. What am I really saying to you? I’m saying that when you have elevated serotonin production at the gut level, you have increased bone loss by activating osteoclastogenesis and reducing osteoblastogenesis because you block the Wnt/beta-catenin signaling process. Serotonin produced by the gut has a very dramatic effect, then, on increasing the potential for bone loss (that’s serotonin production in the enterochromaffin cells within the small intestine). The editorial that follows this article points out that “gut talks to bone.”9 Does this sound at all familiar, relative to the functional medicine and systems biology discussions we’ve been having over the last many years? In this particular editorial, the author talks about these mutations in the Lrp5-this co-receptor of Wnt protein-that then can result (through the serotonergic signaling pathways) in reducing bone reformation). What is it that activates serotonin production through this process of the Lrp5? That’s where we get to a very interesting connection to clinical medicine. Also in 2008, in Neurogastroenterology and Motility, another journal, it was reported that inflammatory signals associated with IL1-beta and lipopolysaccharide-induced serotonin secretion was shown in the enterochromaffin cells derived from patients with Crohn’s disease.10 When we get into chronic inflammatory bowel diseases, or conditions where the immune system of the gut is upregulated, we get increased production of inflammatory mediators that activate this regulatory pathway that is associated, then, with what? With suppression of Wnt and osteoblastogenesis, with increased systemic serotonin production, and increased risk to bone loss. Here we have a condition of gut inflammation connected to bone loss, which is then connected to unhealthy bone, which is connected to lowered osteocalcin, lowered adiponectin, lowered insulin sensitivity, lowered insulin output, and increased obesity and type 2 diabetes. These are very profound and new types of network thinking. Let’s couple this together with a paper I described to you last year titled “A High Fat Meal Induces Low-Grade Endotoxemia: Evidence of a Novel Mechanism of Post-Prandial Inflammation.”11 This paper appeared in the American Journal of Clinical Nutrition in 2007. The authors pointed out that if you take apparently healthy people and feed them a high-fat/high-sugar meal, and then you measure bacterial endotoxin in their plasma, you will find it circulating after the meal, indicating gut permeability and an upregulation of their inflammatory pathways at the gut-immune level. You can actually measure the increase in the inflammatory cytokines that occur after giving a person a high-fat/high-sugar meal. What happens if people constantly activate the inflammatory pathway of their gut, increasing gut enterochromaffin cell production of serotonin, and bathe the bone remodeling unit with increased serotonin that influences the Wnt signaling pathway and shifts the balance of osteoblastogenesis and osteoclastogenesis toward osteoclastic activity and bone loss? Lowered osteocalcin production, increased inflammatory potential, lowered adiponectin, increased regulatory storage, blunting of thermogenic effects on the brown fat, and now we shift that whole-body archetype systemically into a person with central fat deposition, insulin resistance, metabolic syndrome, high triglycerides, cardiovascular risks, and so forth and so on. The treatment of choice in medicine has generally been to treat each of those outcome variables independently, as if they were isolated, rather than to look at the web of interacting variables. We can say it another way: is there not a co-morbidity between gut inflammatory conditions, autoimmune disease, osteoporosis, cardiovascular disease, and type 2 diabetes? That’s a new way of looking at a systemic problem with a functional medicine lens. With that in mind, let’s move to what you’ve been looking forward to-an extraordinary visit with Dr. Helene Langevin.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Helene Langevin, MD Associate Professor of Neurology University of Vermont College of Medicine 89 Beaumont Avenue Given C423 Burlington, VT 05405 Once again we are at that place in Functional Medicine Update that I know you, like I, look forward to with great anticipation: our clinician/researcher of the month. This month we are fortunate to have a person I think we could call both clinician and researcher. I have looked forward to this interview for probably the better part of three years, as I have been reading her work and becoming more and more fascinated with the way she and her group are approaching this very complicated area; the work is very high level. I have probably peaked your interest. I’m speaking to Dr. Helene Langevin, who is associate professor of neurology at the University of Vermont College of Medicine and has a very remarkable background. She got her MD at McGill University, did neuroanatomy and neurochemistry at Cambridge, went on to a residency in internal medicine at Johns Hopkins, and then was an Endocrinology and Metabolism Fellow at Johns Hopkins. That’s no small background in academic medicine and clinical medicine. Since then, Dr. Langevin has been very actively involved in a research area that I think might lead many “traditionally trained” physicians to think, “Wow, that’s something I never thought about.” Her area of interest is the extracellular matrix and connective tissue, and how that interfaces with various therapies that are mechanical and mechanical/electric, like acupuncture. These are really very interesting questions that have sat for thousands of years in the Traditional Chinese Medicine literature, but maybe have suffered for lacking some of the Western intervention or mechanistic concepts. This is really where Dr. Langevin has made some extraordinary and very precise measurements with her group. With great pleasure and privilege, Dr. Langevin, I’d like to introduce you to our listenership at Functional Medicine Update and thank you so much for spending some time with us. HL: Thanks for having me. It’s a great pleasure. JB:Let’s jump right in. With the background I just described, which is formidable, one might ask, “How did you move from that background to the perspective of wanting to look at this whole area of connective tissue, the extracellular matrix, and (I guess you’d call it) the systems biology that connects the nervous system and the immune system to the extracellular matrix-how did that happen?” Studying the Interface between Needle and Tissue in Acupuncture HL: Well, it was kind of an interesting path for me. I was practicing medicine (internal medicine and endocrinology), and I had a lot of patients who had chronic pain. I was finding myself quite powerless to do a whole lot about it. A lot of people were asking me about whether they should be having alternative types of treatments, like acupuncture. This was in the 1980s, and there were already quite a surprising number of people who were interested in that. I met some acupuncturists and I became interested in it, and I decided to study acupuncture. I went to acupuncture school part-time, and I was intrigued by the whole completely alternative approach to looking at a patient, looking at the problem. It seemed to me that they were looking at the human being from a completely different point of view. I thought that was very interesting, so I started practicing acupuncture. One of the things that really intrigued me when I was an acupuncture student was that they would teach you how to manipulate the needles, and then they would say that you had to feel what was happening at the interface between the needle and the tissue. They would say you have to wait until something happens and then you know that you have manipulated the needle enough and you stop. I could really feel something happening under my fingers. The tissue seemed to be tightening. Something was changing–mechanically–the interface between the needle and the tissue. When I asked my teachers-my acupuncture instructors-what was this due to, they would say it was probably muscle contracting. That didn’t make sense because there were some acupuncture points on the body where I was inserting needles and there was no muscle there at all. The idea kind of trotted around in my mind that if this phenomenon was truly some kind of tissue contraction that was not due to a muscle, then what could it be? The skin is not supposed to contract, and the connective tissues underneath the skin are not supposed to contract either. I then moved to Burlington, Vermont and one thing led to another. I sort of finally decided that I needed to really investigate it and I got a research grant to simply try to measure the force that it takes to pull the needle out. That was our first study and we found that there was indeed something going on. After you manipulated a needle, it took more force to pull the needle out. At that point I had no idea what was causing this. We did some studies in animals that showed that it was, in fact, the connective tissue that was winding around the needle and changing the mechanical interaction between the needle and tissue, and then I really got interested in connective tissue because we also kind of looked at the acupuncture points and found that there was a lot of connective tissue there. A lot of these acupuncture points and meridians are located in between muscles in sort of intermuscular fascial planes. It seemed like maybe this acupuncture map that people were drawing thousands of years ago was maybe an indication of where to put the needle if you wanted to your needle to interact with connective tissue. And then I got completely fascinated with connective tissue, and now I am really studying connective tissue-many aspects of it-way beyond acupuncture, at this point, but acupuncture was kind of what got me into that. So that’s the story. JB:It’s just an incredible story. You know, I’m always reminded when I have the privilege of speaking to people like you (seekers), that there is some unique characteristic that defines people like yourself-people who make observations and are willing and courageous enough to follow the process of inquiry to the next level, against what sometimes might be considered barriers that hold other people back. Many people ask these questions, but then they just say, “Oh well, no one seems to be interested in these questions so I’ll just move on.” Somehow people like you stop and use their resources, their experience, and their wisdom to really dig deep and find things that are unexpected discoveries, and, of course, you’ve done that. The first two papers I read of yours’ were the paper that was in FASEB journal back in-I think it was-2001 on “Mechanical Signaling through Connective Tissue, the Mechanism for the Therapeutic Effect of Acupuncture,” and the other was, I think, a paper in 2002 in the Anatomical Record on the “Relationship of Acupuncture Points and Meridians to Connective Tissue Planes.12,13 When I read those papers, something just dawned on me. You helped guide me to this kind of “a-ha-ism” that maybe the primacy of the cell that we use within biological thought that ultimately directs and focuses its energy into medicine is really not the right fundamental unit. Maybe we ought to be looking at this extracellular matrix as a fundamental unit of organization. I think you have opened a lot of eyes through your work. HL:I need to sort of specify one thing that’s important, I think, for listeners to realize. We think we identified many important things, physiologically: that connective tissue is mechanically responsive, including to acupuncture needle manipulation; and that fibroblasts within the tissue (the extracellular matrix) constantly remodel and they respond to the mechanical stimulus. However, at this point, we still don’t know the cause of the mechanical effect of the needle on the connective tissue. What does it have to do with the therapeutic effect? I think it’s important to realize that that is still a work in progress. That first paper that you mentioned in FASEB was kind of the original paper where we laid out the hypothesis that, in fact, there could be mechanical signals that could be transmitted by the needle to the tissue via cellular mechanisms. People call this mechanotransduction, which is basically the transformation of a mechanical signal into a biochemical response or cellular response. I’m still very much in the dark about how this could translate into a therapeutic response. I think it is very important for people to realize that. JB:Thank you. I think that’s a really good caveat to put in. Maybe you can tell us a little bit–in summary-about the techniques that you’ve been using to dig down into this very complex area and try to tease out some of these answers because your experimental methods, I think, are very, very novel and&hellip;it’s not easy work, it looks like to me. A Stepwise Approach to Studying Connective Tissue and the Extracellular Matrix HL: Yes, we have to really go stepwise, and I think right now we have kind of, I would say, a three-pronged approach to this. The first thing is we have identified these really very interesting responses of connective tissue to the needle. That almost has become a cell biology project. As a matter of fact, one of the grants that I have right now is to study the effect of mechanical stimulation on the fibroblasts, and we’re just looking at cell biology, almost purely. What are the fibroblasts doing? What are the mechanisms by which they are responding to the mechanical stimulation? What are the responses in terms of cytoskeletal remodeling, gene expression, protein expression, and changes in connective tissue physiology? That is just stuff that is basic research. We’re just trying to understand: how does the connective tissue interact and respond to the mechanical forces? At the other end of the spectrum, we are looking at chronic low back pain, because the idea is, “Well, okay, if the needle is doing something to the tissue that is going to be translated into a therapeutic response, what is it that that would be fixing? What is the problem that this mechanical stimulus would help correct?” The important thing right now (the reality) is we don’t really know very much about what causes chronic musculoskeletal pain. We are still very much in the dark about the pathophysiology of the problem. A lot of people have musculoskeletal pain and people have looked into the nervous system in terms of hypersensitization, psychological responses to pain, but the tissues themselves&hellip;we don’t really know what is it in the tissues that could be contributing to the pain, and in particular, connective tissue has been looked at very little. We have a study that is ongoing right now where we are looking at a group of subjects with chronic low back pain with ultrasound. We are looking at the structure of the connective tissue to see if it’s abnormal. People who have chronic low back pain&hellip;they have pain and say they have an initial injury, they will change how they move, or they will move less, or they will change their movement patterns because it hurts to move. Because connective tissue is so exquisitely responsive to mechanical stimulation-it remodels, in good ways and bad ways-if we stop moving or if we change the way we move, the connective tissue changes. For example, if you have an arm in a cast or a shoulder injury and you stop moving your shoulder you can get a build up of connective tissue such that you lose your range of motion. We are hypothesizing that the same thing occurs in the back-that in low back pain, the connective tissue essentially fibroses, or becomes thicker, and that impairs movement and further contributes to the chronicity of the pain. We are also looking at how tissue, if it is abnormal, responds to the acupuncture needle mechanical stimulation. Are the responses different in people with low back pain versus people without low back pain? To link these two projects, we have an animal model where we actually induce connective tissue abnormalities under control conditions using a combination of inflammation and movement restriction, and then we see how we can impact that with mechanical stimulation. JB: I was reading the very interesting paper that you co-authored with Karen Sherman on “The Pathophysiological Model for Chronic Low Back Pain: Integrating Connective Tissue and Nervous System Mechanisms.”14 This appeared in Medical Hypotheses last year, and I was kind of struck-and I’m sure you’ve been asked this question before-that not only does it seem like this argument (or story) connects to acupuncture, but to other manipulative (or physical) forms of medicine like deep-tissue therapy, Rolfing, and other things that may send signals through the fascia that implicate remodeling. Studying Mechanisms that Apply to All Manual Therapies HL: Yes, absolutely. I think that’s very important. The mechanisms we’re studying are not restricted to acupuncture or to manual therapies. I think they might be common to a lot of manual therapies-types of treatment even beyond that, even movement therapies, like yoga, for example. Anything that stretches the tissue may have an effect on the connective tissue. The acupuncture needle is an interesting way to mechanically stimulate the tissue because it is focused. The needle, first of all, can penetrate quite deep. When an acupuncturist manipulates a needle, they can impart, actually, some very high forces, but in a very, very focused manner to the connective tissue because the collagen fibers are actually winding around the needle and then the needle becomes mechanically coupled to the tissue. With everything you do-when the acupuncture needle is manipulated up and down or sideways-it transmits a mechanical signal that can affect the deep connective tissue layers, very, very precisely. On the other hand, manual therapies, where you are applying your hands, or fingers to the tissue, applying a combination of pressure and stretch, there are some differences, obviously, as to how these mechanical forces are applied to the body, but they still have something in common. And then, of course, movement-based therapies, like yoga, or Feldenkrais or Alexander technique, or techniques that show people how to move differently also apply mechanical forces to the tissue, although this time it is the person, themselves, doing it. We think some of the mechanisms we are studying in terms of connective tissue responses could apply to all of these. JB:You know, we want to talk about a model of integrative science. You authored a paper (as the lead author, I think) along with a variety of your colleagues, and it included not only your work at the department of neurology, but the department of mechanical engineering and the department of pharmacology, all at the University of Vermont’s College of Medicine. This paper was published in the American Journal of Physiology and Cellular Physiology in 2005 and was titled “Dynamic Fibroblast Cytoskeletal Response to Subcutaneous Tissue Stretch Ex Vivo and In Vivo.”15 This is a very interesting model for a different kind of research than we have seen in the past. HL:Yes. We think it is important for several reasons. First of all, from the point of view of cell biology, I would say the overwhelming majority of the work on mechanotransduction in cell biology is being done in cultured cells. These are cells that are fibroblasts or other types of cells that are grown on plastic dishes or collagen matrices-artificial environments. There are a lot of very interesting signaling pathways that are known to be activated by mechanical stimulation in cells, gene expression, all sorts of stuff that we know that cells do when they are mechanically stimulated. We can look at fibroblasts in their own tissue environment in an ex vivo model, which is where we take a piece of connective tissue out of the body (we use a mouse model), but it’s the whole tissue with the fibroblasts in it. They are excised from the animal and they are kept in an organ bath, sometimes for as much as a couple of days, sometimes for just a few minutes or a few hours, but they are still in their environment, and we look at how the fibroblasts respond to mechanical stimulation. We also look at them when the mechanical stimulation is applied in a live animal, then we sacrifice the animal and look at the cellular response (the mechanical stimulus is applied when the animal is still alive). We had a lot of surprises, there, when we compared how our fibroblasts were responding, and how they even looked. The morphological appearance of the fibroblasts looked quite different from the fibroblasts in the dish. We think that when you are studying the effect of mechanical stimulation, it is really important that the mechanical environment of the fibroblast or the cell is maintained because the fibroblasts growing in the dish are not necessarily going to respond the same way as if they were in the real tissue. We think, from a cell biology point of view, these are important models. And, of course, from a translational research point of view, we think they are important because they will allow us to understand the effect of the dose of the mechanical stimulation. Obviously, it is really important how much and how long, for example, tissue is stretched. Physical therapists know this in their practices. If you have somebody who has, for example, a contracture, or connective tissue adhesions following an injury, a scar or something like that, and you stretch the tissue just enough, that can cause the connective tissue to remodel and the range of motion to improve, but if you stretch too much, you can actually injure the tissue more, and cause inflammation, and the person has more pain and that can worsen the problem. We don’t really understand the mechanisms by which all this happens, and we don’t know the dose-these are all things that people do by experience, empirically. Each practitioner knows what enough is and what is too much. But there is quite a lot of controversy. Sports medicine, for example, is very interesting now. Everybody used to stretch before sports events-athletes and trainers would recommend a lot of stretching-and just recently there is starting to be a whole bunch of publications saying that stretching actually sometimes can impair sports performance and does not prevent injury. There are even more recent studies that have begun to really look at how much people should stretch because stretching too much can be detrimental. I really think this points to the importance of understanding the correct dose of mechanical stimulation that the tissue requires to be healthy, and also what could be a therapeutic dose. If somebody is in a situation where their tissue is not healthy, what is the right dose to promote a healthy response and healing of an injury? Or in chronic pain, for example, what could be helpful to the patient? JB: That’s a beautiful segue, actually, into kind of a translational question. Being a person with a multiple personality-type of background (all the way from your board certification in endocrinology and metabolism and internal medicine, to your being a licensed acupuncturist), you’ve got your world view on many different planes. What do you think the operator dependence is, and/or the practitioner-dependent component of being successful in implementing these? From what you’ve said, it sounds to me like there is a lot of art in the skill of understanding how to be part of this process with a patient, and the touch and the feel and the skill that comes from years of experience, or whatever those characteristics are, must be very important in outcome. Creating Tools to Record Acupuncture Techniques HL: Yes, absolutely. That’s one of the things that fascinate me, actually. What is the difference&hellip;For example, what makes a good acupuncturist and a not-so-good acupuncturist? Acupuncturists typically and traditionally are trained by apprenticeship for generations and generations. In China and in Asian countries, acupuncturists typically learn from their families-from their parents, father, mother-and the art and types of techniques would get transmitted along the generations. There are so many different ways to practice acupuncture. If you look at, for example, Japanese acupuncture versus Korean and Chinese acupuncture, people will use different depths of needle penetration, different amounts of simulation. Some people turn the needle one way, some people do up and down combinations. We don’t really know what works better for what condition. We’re just beginning to scratch the surface, really, and trying to understand what works and what doesn’t. One of the things I’m interested in, actually, is developing some tools to record the needle technique that an acupuncturist employs during treatment so that at least we can document what people do and try to understand, quantitatively, what is more effective in terms of acupuncture techniques. The same, really, is true with manual therapies. I think there are a lot of efforts right now in the chiropractic community and massage to develop techniques to actually measure the forces that are applied during chiropractic manipulation, for example, to try to understand, first of all, what happens during a treatment. We do research to be able to standardize the practices in order to do controlled clinical trials. I think it is very important that we do that and that we pay a lot of attention to what is being done to understand what works better. JB: When we start looking at the mosaic of your extraordinary work–now many, many papers and many, many different studies–there is something that kind of stands out to me. I’m sure you are probably way ahead of me in seeing this. The landscape tends to suggest that when we look at the body-and, in fact, I think you even spoke to this very eloquently in a paper you wrote not too long ago, I think it was back in 2006 on connective tissue, a body-wide signaling network-that somehow there is this signaling capacity, from a mechanical stimulus, through the fascia, that has a whole-body effect that more suggests, then, systems biology or network signaling type of phenomena, which is a very different context for physiological response than we have previously been thinking about, which has been point of action and point of response. This is more of a general network change in physiological state function. Can you give us some insight on how you see this information that is emerging relating to this whole network and systems biology concept? HL: Yes, that’s a great question-something I am very interested in-but, again, that is something that is still at the hypothesis level right now, but I think a very interesting hypothesis level. Connective tissue is a network; there is no doubt about that. It’s an anatomical network because it goes absolutely everywhere in the body. I think there is sort of analogy-this kind of image-that you could draw a line from any point of your body (a continuous line) to any other point of your body via connective tissue because it actually surrounds every muscle, every nerve, every blood vessel, every organ, so it is an anatomical network. And, in addition, it’s a cellular network because the fibroblasts are connected to each other. They make contact with each other, and that’s another thing we found by looking at our whole tissue using different microscopy techniques–we are able to actually see the processes of the fibroblasts touching each other. Of course, the question is, “Well, if they are making so many contacts and they reform the cellular network, are they talking to each other?” So far, we have not been able to identify (with certainty, anyway) any signal that gets transmitted over a significant distance-I’m talking about, you know, more than just one cell to the cell immediately adjacent to it. It is a very tempting hypothesis that there might be some kind of a body-wide signaling network and that’s the hypothesis I put forward in that paper. So far we have not conclusively tested it one way or another-I can’t say there is or there isn’t at this point in time. But we’re still looking, and I think that one of the things that acupuncture theory kind of suggests or proposes is that the network of meridians in the body, in effect, connect the various parts of the body functionally. Because we found this relationship (interesting relationship, anatomical relationship) between the connective tissue network and the acupuncture meridian network, I think it raises the interesting possibility that what the acupuncturists refer to as “qi,” which is what they call a life force. People struggle as to how to describe qi as some kind of active principle, but you could think that it is perhaps some form of signaling, or information exchange, or something like that, through the acupuncture meridian network. That was really the hypothesis I proposed-that perhaps this signaling network does exist. We’re still trying to find out what this qi could be, but right now we don’t know. JB: That segues into something I’m sure you’ve had discussions about. One of the people who worked in the medical school at University of Maryland, in the integrative medical department, was kind of a methodologist/biostatistician and authored a book that appeared last year called Snake Oil Science in which he was reviewing the clinical trials that had been on CAM therapies. As I recall, in that book, he took exception to acupuncture as having any demonstrated proof of outcome when you start looking at it from RCTs. I have some thoughts about those studies and the way he evaluated them, but I’d be interested in your thoughts about translating some of your mechanistic work into the outcome trials in humans. What is your thought about those who criticize and say there is no demonstrated proof of concept? Randomized Controlled Trials are Problematic for Studying Acupuncture HL: Yes, this is a very important subject that acupuncture researchers are, right now, obviously very concerned with. Acupuncture research has reached a point where it is kind of a paradoxical situation. There are really three big types of acupuncture studies. One is people do trials where they compare the effect of acupuncture to no treatment or to standard care, and they find there is an effect of acupuncture (that acupuncture really helps people). But then in clinical trials that compare acupuncture to a sham procedure, very little difference is found between the acupuncture and the sham acupuncture. And then, on the other hand, when we look at physiological studies, where we look at the effect of acupuncture on the brain using neuroimaging, or what I’m doing in connective tissue, or what other people are doing looking at, for example, inflammatory response in peripheral tissues, we find that acupuncture does have very clear physiological effects. What we don’t know is this: what is the relationship between the physiological effects and the therapeutic effects? That’s one thing we don’t know much about. And the other thing we don’t understand is: what’s the role of a needle in the therapeutic effect? If you can get the same effect with some kind of sham needle, then does that mean that the needles are not doing anything? I think part of the answer to this sort of paradox is that part of what the sham control trials are doing is they are really asking a very, very specific question. They are saying, does it matter if we put the needle in one place versus another place? Or, does it matter if we manipulate the needle or not manipulate the needle? It is very important to understand that these particular trials are really asking a fake question and maybe some of these trials are showing us that, as far as the therapeutic effect is concerned, maybe some of these factors (for example, where you put the needle) maybe don’t matter that much. If the control-the sham control-is putting the needle in a non-acupuncture point, for example, and you find just as good an effect, well maybe it doesn’t matter. Maybe the needle position is not that important. I think we have a long way to go to understand this, but the field of acupuncture is working very hard right now to try to solve these questions. You know, I think that within a few more years, hopefully, we’ll have some answers. The relationship between the mechanisms that we are uncovering, in terms of the physiological effects of acupuncture and the therapeutic effects, also, I think we have a lot of work to do there to try to better understand that. JB: I’m going to follow-up with a philosophical question. There is no obvious right answer to this question, but I’d just like your opinion. Let’s just take, for a moment, as a thought, your proposed argument (or hypothesis) that appeared on connective tissue as a body-wide signaling network and the role that acupuncture and other mechanical therapeutics might have on that network, and then ask the question: could it be that the methodology of the RCT is really suspect because, in part, we have this whole Heisenberg uncertainty principle about what is changing, what are the variables? You know, the RCT wants to look at univariant-type of processes, and it doesn’t sound like this falls nicely into univariant analysis at all. I’m just wondering, are we painted into the corner with the way that the RCT is done to get a certain negative answer? HL: That’s possible, of course, but I think there are probably some other really (perhaps) more basic explanations for why the RCT is not giving us statistically significant differences between the sham control groups and the real acupuncture groups. For example, it could be there are components of the acupuncture treatment, such as the attention and the time the acupuncturist spent with the patient, the teaching (the reframing of the problem, the traditional Chinese diagnosis), the education that takes place during a real acupuncture treatment that really kind of supplements the effect of the needle. It’s very possible those effects are overpowering in magnitude compared with the effects of the needles themselves. It is really the combination of all of this that causes the therapeutic effect, and if you are trying to isolate the effect of the needle by itself, you are looking at an effect that may be important, but is small compared with the nonspecific effects of the treatment. I think we need to really look at all the components of acupuncture treatments besides the effects of the needles. There may be a synergistic effect, obviously, between all of these things. We would need to really start looking at what happens during an acupuncture treatment, as a whole. The sophistication of the methodology that needs to be developed in order to investigate complex interventions, such as acupuncture, is quite formidable compared with doing a placebo-controlled trial of just a pharmacological agent. I think we are leading the way here-the alternative research, the CAM complementary and alternative medicine (CAM) research community is really at the forefront, I think, of research methodology for developing placebo controls. I think we are doing that out of necessity because these modalities are so complex, and I think we’re going to really improve our understanding of how to do clinical trials, in general, via these problems that we’re facing. JB: I want to really compliment you. The answer you just gave to my very diffuse and somewhat nonspecific question was extraordinarily eloquent. You answered that question better than I could have. Thank you very much; that was very nicely said. Let me close with one last thought. We’ve been talking about systems, which is a very extraordinary and complex concept. It is sometimes hard to get our heads around this, but I’d like to move it down the ladder now into smaller and smaller units of functional control (regulatory control), to the cellular level. One of the things that struck me in your 2001 FASEB paper was a diagram that showed how matrix deformation could transmit signals through cells by way of membrane-related conformational changes that then would influence intercellular signal transduction through things like kinase signaling through ERK and other kinase pathways that ultimately would modulate things like inflammatory potential, or cell replication, or gene expression. Do you think there is any evidence accumulating now to support the model that there are potential mechanical changes at the cell cytoskeletal structure that then can be translated through intercellular signal transduction in the cell to gene expression patterns that alter its physiology? HL: Absolutely, yes. There is a very solid body of evidence in favor of this in cultured cells. There is no doubt this takes place and we are starting to understand the pathways involved in mechanotransduction using cultured cell models. So far, what we have done in our ex vivo models is we have confirmed that there is no question this occurs in tissue in response to the mechanical stimulus, whether it’s stretch or using the acupuncture needle. The cells are receiving the mechanical signal. They are changing their cytoskeletal morphology in an active, dynamic manner that can be inhibited using specific cytoskeletal inhibitors or cytoskeletal signaling molecules such as Rho kinase and RAC that involve actin and microtubules. Our results are supported by a large body of literature in cultured cells that suggest that applying a force to a very specific part of the cell surface where there are protein complexes that contain integrins (these are molecules that are thought to form a mechanical bridge between the cytoskeleton of the cell and the extracellular matrix). An integrin acts a little bit like a sensor in that it allows the cytoskeleton of the cell to respond to the mechanical force in a direct way, and then that can trigger cascades of signaling events. Obviously we have not tested all of these in our system, but we have tested some of them and, yes, our results are very consistent with what has been described in cultured cells, with some differences, however, as I mentioned earlier. The morphology, for example, of the cells in whole tissue is different, in some ways, to that of the cells in the dish. I think it’s important to compare our results to those in cultured cells and see the similarities and the differences. JB: I knew before we started that this was going one of the most provocative, interesting, and mind-expanding discussions that I’ve had the privilege of having and it has certainly lived up to that. Your work is just amazing. I think it’s really at the cutting edge of developing a new science as it relates to systems biology and how it pertains to what we used to think of as unproveable hypotheses. I want to really commend you. It’s courageous to be involved in this field and I think you are bringing the best of science with the best of tradition together. Thank you very much. We’re going to follow your extraordinary work closely because I think it is opening the door to the next generation of evolution in medicine. HL: Thank you. It was a pleasure speaking with you. We’ll see what happens next. JB: We certainly will. We’ll stay tuned. Best to you, Dr. Langevin. Wasn’t that a treat? What an amazing journey we just were taken on with Dr. Langevin in this area of a systems biology look at the interaction between mechanical forces and cellular signaling. That was extraordinary. It reminds, in the 26 years. I think you can probably see that what she was addressing is a new methodology for evaluating, at a basic level of scientific inquiry, things that for millennia were just considered kind of experientially correct but we didn’t know the reproducibility, or the variation, or how technologies could be employed with greater senses of positive outcome. Now those new methodologies-the systems thinking-are connected together with historical records of experience in such a way as to, I think, optimize the translation of this into future clinical. What an extraordinary experience we had. I look forward to talking to you in the February issue. Thank you.

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Welcome to Functional Medicine Update for February 2009. As you probably recognize, the world is changing at a remarkably rapid rate. This is the case as we watch the evolution of the new medicine and healthcare system the Obama administration, and his new health policy directors and Secretary of Health and Human Services are defining. We are going back and reevaluating a lot of things that have been thought of as facts. We’re looking at new things that might be part of a new information system that describes a new reality for health care. That’s going to be the theme that you’ll hear woven throughout Functional Medicine Update in 2009 and beyond. A principal tenet in the field of functional medicine is based on the ability to modify various environmental agents that have effects on expression of genes and, ultimately via gene translation, on the phenotype (the health and disease patterns of the individual). This gene-environment interaction is a fundamental and conceptual component of the functional medicine model: the nature of a patient-centered personalized approach; looking at etiology from an antecedent-trigger-mediator-sign-and-symptom perspective; and examining fundamental underlying processes that lead to the disturbance of the network of physiology that we call dysfunction, which ultimately give rise downstream to pathology that we label as disease. All these components become the framework upon which the functional medicine process of thinking has evolved. This does not necessarily lead to specific therapies, but more a process of thought as to how we evaluate the patient, work up the patient, and understand the etiology of his or her specific condition (what types of factors lead to that condition and how they can be modified). We really focus on modifiable factors. One modifiable factor, obviously, is diet and its constituent nutrients. In functional medicine, quite a large amount of focus and time is spent on examining the role that diet plays on gene expression. Over the course of 2008, a number of Functional Medicine Update clinicians or researchers of the month spoke about the role that various principles in diet play in modulating gene expression or influencing the epigenome (with methylation, acetylation, and phosphorylation of histone proteins). In addition to what we have historically known about diet and the regulation of metabolomic factors, we’ve started to evolve a molecular understanding of how diet (and the nutrients it provides) is the signature upon which the information from our genes will be expressed. These are things like the coenzymes that are derived from the B vitamins-for example, flavin adenine dinucleotide (or FAD) that comes from riboflavin, or nicotinamide adenine dinucleotide (NAD) coming from niacin vitamin B3, or thiamine pyrophosphate, or pyridoxal phosphate that come from vitamins–that then ultimately serve as cofactors in coenzymes and specific metabolic processes that activate apo enzymes into halo enzymes (the active form of these enzymes that then do their work at specific places). With all of that as a context, people have wondered for years about doing randomized placebo-controlled trials against specific disease endpoints using specific nutrients. What would happen? Would you be able to demonstrate, under these controlled conditions, that these vitamins, when given in supplementary doses, could either treat an existing condition or provide secondary prevention, or prevent a primary condition? This has been a longstanding debate, certainly in the 30+ years that I’ve been in the field. The National Institutes of Health National Center for Complementary and Alternative Medicine (or NCCAM) has been sponsoring a number of these intervention trials over the last several years. The unfortunate thing about these trials (for those who are of the belief that they would demonstrate positive outcome), is that most of them are not positive in their outcome. The results are either ambiguous, neutral, or maybe even (to some extent) there are some negative implications of these vitamin intervention trials that have been published. This has caused a rude awakening for some of the strong proponents of giving single nutrients at high doses for the treatment or prevention of disease and has made it difficult to rationalize some of the observations made in these clinical trials. Basically, attacks have been made on the study designs: not stratifying to the appropriate patients; or the wrong doses; or the wrong formulations of these substances, be it either phytochemistry or botanicals (things like St. John’s Wort for depression, or Gingko biloba for memory, or even looking at things like Echinacea on immune system function). The results of these clinical trials have not been uniformly positive; they have been either kind of neutral or maybe even showing no effect. Study Results Have Led to Disillusionment With all of that in mind, one might start to be somewhat disillusioned and maybe even come to the conclusion that nutrients don’t play a role in prevention of chronic, age-related degenerative disease. Perhaps nutrients are just there to prevent nutrient deficiency disorders like scurvy, beriberi, pellagra, xerophthalmia, rickets, kwashiorkor, or marasmus, and beyond that–if you have proper hemoglobin levels and proper total protein in your blood–you really don’t have risk or concern about malnutrition or undernutrition relative to these nutrients. We can cite some recent studies that pertain to this disillusionment. There was a paper that was recently published looking at the long-term use of supplemental multivitamins (vitamin C, vitamin E, and folate) with regard to the risk to lung cancer. The results of this study were published in the American Journal of Respiratory and Critical Care Medicine in 2008.1 This particular study, which was a cohort of 77,721 men and women, aged 50 to 76 years, all living in Washington State, was called the VITAL study (VITamins And Lifestyle study). Cases had been identified through surveillance epidemiological registry in the Seattle, WA area. These individuals were looked at for their incident lung cancer and their voluntary use of supplementary multivitamins over an average of 10 years. A total of 521 cases of lung cancer were identified. The researchers adjusted for smoking, age, and sex and found there was no inverse correlation with the use of a supplement in these individuals. They concluded supplemental multivitamins (vitamin C, vitamin E, and folate) were not associated with a decreased risk of lung cancer and supplemental vitamin E was associated with a small increased risk. The conclusion of the study was that patients should be counseled against using these supplements to prevent lung cancer. Another study result that shares some of this negative theme was published in the Journal of the American Medical Association in 2008 (the November 12th issue). This study was titled “Vitamins E and C in the Prevention of Cardiovascular Disease in Men.”2 This was the Physician’s Health Study II randomized controlled trial. In contrast to lung cancer prevention in the previous study I mentioned, this was a randomized double-blind placebo-controlled factorial trial of vitamin E and vitamin C that began in 1997 and continued until August 31st, 2007. In the study there were 14,641 US male physicians enrolled who initially age 50 years or older, including 754 men with prevalent cardiovascular disease at the period of randomization. They received 400 IU of vitamin E every other day and 500 mg of vitamin C as a supplement daily. They looked at a composite endpoint of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease death. During this mean follow-up of 8 years, there were 1245 confirmed major cardiovascular events. Compared with placebo, however, vitamin E had no effect on the incidence of major cardiovascular events, and there was also no significant effect of vitamin C on major cardiovascular events. By looking at all the data and the relative risk factors from this large long-term trial of male physicians, the authors of this study conclude that neither vitamin E nor vitamin C supplementation at those doses reduced the risk of major cardiovascular events and there is no support for the use of these supplements for the prevention of cardiovascular disease. Should We Be Disillusioned or Should We Ask More Questions about the Studies? With these papers, I’m just giving two examples from what has been a fairly long list (over the last few years) of published randomized intervention trials that have failed to demonstrate significant positive health outcomes in the study populations that were used, under the conditions of supplementation, and the endpoints that were examined across a wide range of conditions. In the past we have discussed familial adenomatous polyposis with colorectal cancer risk and folate and B12, lung cancer, breast cancer, and now cardiovascular disease with these supplements. One starts to ask the question: are we at a point of disillusionment about this whole model? Is the use of high doses of specific nutrients really specious? Was it a great concept that really doesn’t wash? We are going to be talking more about ways that information from the environment and from nutrients translate themselves through the genomic message into the phenotype later in this issue of Functional Medicine Update. I think we need to-again-ask the following question: are we sure there are not buried, within these specific data sets and these large randomized trials, cohorts of individuals, who as a consequence of their unique genetic characteristics, are high responders, but they get washed out or they get lost in the sea of non-responders that do not carry those characteristics? The reason I bring this up is fairly simple. Let’s assume that constituents within diet are reasonably low potency in terms of their impact on specific functional characteristics at the metabolic and physiologic level. This is in contrast to drugs that have been developed, designed, and screened for their very high affinity binding constants with specific substrates and have very low IC50s in the nanomolar or sometimes the picomolar levels, and they have been hand-picked/selected for their extraordinary affinity for the endpoint. If you do a test of these particular molecules on an outcome (let’s say hypertension, in which you are looking at an antihypertensive molecule), it may wash out among different SNPs with differing levels of sensitivity within any one of the various genotypes. Some maybe get more effect than others, and those may be the people who have (at low potency) a high effect. On the other side of the bell-shaped curve, there may be those individuals who have very low affinity, who have to go to a higher dose to get response. Everybody gets some response. By the way, this probably also defines why there is (with these potent drugs), a very high risk to adverse drug reactions. Where one person is getting a favorable effect, those potent molecules at that same dose in another person with a high affinity may be getting an adverse effect. The drugs are designed specifically for this very high activity (very high potency, low IC50 characteristic), and they do what they are supposed to do in the emergency room. There is no ambiguity. They come in and they don’t allow a lot of room for conversation, in terms of the substrate and how they ultimately influence that function at the cellular level. Nutrients, however, operate with a much more mild substrate-binding relationship for a much more benign effect (maybe wild-type SNPs). In a randomized trial of those nutrients, you may get (at best) ambiguous results because the cohorts that are most able to have a higher response to those nutrients at that dose that may be small. Remember a SNP is defined as a single letter alphabet change in the genetic code for one percent or more of the population. If you have low penetrant SNPs and you start looking at those individuals who have a higher response as contrasted to people without those SNPs, they may be lost in the noise of the study (washed out) by the average of the non-responders. I think we have got ourselves into a little bit of a conundrum here as we start to try to study the responsiveness of specific nutrients in human populations with a double-blind placebo-controlled randomized trial for all genotypes. The people who go on to get heart attacks may be those individuals who have unique characteristics in their genetic lineage that make them more at risk to certain things. For those individuals, nutrients may be more responsive, but they get lost in an overall study. Saying it another way, if we look at things like methylmalonic aciduria or phenylketonuria, these represent genetic metabolism diseases of infancy that are very low in penetration in the genes of the human population. If we put those people on diets of average (diets of adequacy for the average individual) they might be inadequate or toxic for these genetic uniquenesses. In the case of phenylketonuria, we may want to, obviously, restrict phenylalanine in their diet. If we gave them the same amount of phenylalanine that would be considered adequate for the wild-type individual genes and good for their nutrition, it would produce a potential toxic effect, leading to neurological and hepatic injury in the children that consumed diets with that same level phenylalanine in their protein. By the same token, methylmalonic aciduria is a little bit of the other side of the equation. If we feed diets to those children with the level of B12 that would be considered adequate (and maybe even good) for the average wild-type genotypes, those individuals would be vitamin B12 insufficient based on their need and would develop high levels of methylmalonic acid in their urine and have acidic pH changes intracellularly. Those things will sustain neurological damage and these individuals would have irreversible pathologies associated with this nutrient inborn error of metabolism. Given very high levels of folate and B12 (relative to the average person), these individuals can lower their homocysteine levels and their methylmalonic acid levels and achieve much better function. For them, the level they need is dictated not by their genes, but in the overall gene penetrance. If we just did a gross study of the role of vitamin B12 in neurologic function of the population at large, there are a small number of those individuals we might lose in the average That’s the rub, I think, when we have nutrients that we are studying with a pharmacological model because it is a model that is really designed for high potency molecules that can penetrate through the wide variety of different genotype responsiveness. A person who really understood this very, very well, way back when (“back when” means back in the 1940s), is a psychiatrist who grew up in Sascatchewan, Canada. He is a very remarkable guy who I have had the privilege of knowing for many years-actually several decades now-with whom just recently I had an extraordinarily warm and rich moment. I sat down with him and we talked about his 50 years plus of experience in this field, his views, and how this concept emerged for him. You probably know who I’m speaking about. I’m speaking about the father of orthomolecular psychiatry, Dr. Abram Hoffer. Dr. Hoffer grew up in the plains of Sascatchewan in a farming family. He is a guy who knew something about the soil and growing things. He went on to get his PhD in food chemistry. He recognized that things were being discovered (I want you to recall that Abram Hoffer is in his 90s and is still practicing orthomolecular psychiatry). In his earlier years, Dr. Hoffer was right at that interesting phase of understanding vitamins and their role in health and disease. Early Years Influenced Future Study of Schizophrenia He was a student of pellagrous dementia (the “3 Ds” of pellagra are diarrhea, dermatitis, and dementia. When people have vitamin B3 deficiency, clinically (or phenomenologically) they go through a schizophreniform stage of mental alteration in their function. and so he had always had in his mind, From the time of his PhD in nutritional sciences, Dr. Hoffer had always had it in his head that there was something about vitamin B3 and brain function and the manifestation of a condition that resembles schizophrenia. Later, Dr. Hoffer went to medical school. He became a board certified psychiatrist, rose to great prominence in Canadian psychiatric circles, and is in decision-making and opinion-leading positions in high-order institutions. He was one of the first people to really learn about electroshock therapy and to be very skilled in it. Certainly he was very skilled in the dominant theme at his earlier age: Freudian psychotherapy; he was a very skilled psychotherapist. But he was very frustrated because many of the things he was trained to do and became an expert in really weren’t producing very good outcomes. The results he was getting with schizophrenic patients were very marginal. Adventures in Psychiatry: 2005 Autobiography Always thinking back to his PhD in nutritional sciences and food science chemistry, Dr. Hoffer wondered if there could be some kind of a connection between what he learned about pellagrous dementia and what he was seeing in some people with schizophrenia. All of this is described in a wonderful autobiography Dr. Hoffer wrote and published (I treasure the copy he gave me). The book describes many years of his journey in understanding the role that vitamins play in mental health and neurochemistry. I would almost call Dr. Hoffer one of the progenitor pioneers of the whole field of neurochemistry and how it interrelates with metabolism in the neuron and nutritional factors. Adventures in Psychiatry, his autobiography, was published in 2006.3 The book describes the journey Dr. Hoffer has been on and that we (those of us who have been fortunate enough to come along in this field after him) have followed. In this discussion with Dr. Hoffer, I found that not only is he a gracious, warm, caring man and a person who is thoughtful about everything, but he is also a warrior. He is a willing participant in carrying his ideas against criticism-asking the right things, but willing to sustain the criticism of his peers who often don’t understand. Dr. Hoffer teamed up with Humphrey Osmond to form the Hoffer-Osmond duo back in the 50s and 60s. This was extraordinarily fortuitous because they brought the best of their energies and their intellect to this field and moved it ahead. He met Linus Pauling, the father of molecular medicine, and, with Dr. Pauling being very interested in the chemistry of the brain, this was an impactful meeting. Ultimately Dr. Pauling published what had to be one of the landmark papers in the history of medicine, I think, in 1968 in Science magazine titled “Orthomolecular Psychiatry.”4 In 1968, this article really shocked the medical world. It talked about vitamin binding constants and sluggish enzymes, and also about the principle of pushing an enzyme to function by increasing the substrate (by mass action) with the substrate as a cofactor. It represented a very remarkable thought about how to promote function out of a genetic uniqueness; that is, you can’t change the enzyme, but you can change the concentration of the coenzyme to force more of the coenzyme/enzyme-binding complex to get more activity out of that enzyme. These constructs and how they relate to function marry themselves beautifully to Dr. Hoffer’s practice of orthomolecular psychiatry, in which he was using niacin at high dose and pyridoxine and vitamin C in his schizophrenic patients for the modulation of schizophrenia. As Dr. Hoffer points out, not all schizophrenics respond to this therapy because schizophrenia, like so many diseases, is polygenomic and multiple etiologic; it doesn’t have just one cause. Schizophrenia is a term that is a descriptor for a collection of signs and symptoms. It doesn’t tell you, specifically, what is going on in the etiology of that condition. We often think a name tells us what something is, when a name actually just describes a set of symptoms. Dr. Sidney Baker calls this medical taxonomy, and it is the way that many of us learned: clustering conditions, signs, and symptoms that have similarity and calling it a disease, which assumes that when individuals have these common characteristics they are sustaining the same physiological disturbance at a molecular and cellular level. That turns out not to be true. At the mechanistic level, there may be more connection among different diseases than we previously ever recognized. These connections are called comorbidities. I find that interesting: looking at them as being manifestations of the same dysfunction at the cellular level that then express themselves in different ways in different tissues, and organs, and organ systems. How does the orthomolecular psychiatry argument help us to understand better why some vitamin intervention trials have come out as not being positive? These are expensive, randomized, clinically controlled placebo trials. Orthomolecular psychiatry helps us to recognize that there may be, within any disease condition, various manifestations of that disease based upon different presentations at the cellular level, some of which may be more responsive to individual therapies than others. This is wonderfully described in a review article that appeared in the Israeli Journal of Psychiatry and Related Science in 2008.5 This paper was actually authored by someone who shares a common last name to that of Abram Hoffer: Leonard John Hoffer, MD, PhD, professor of medicine at the McGill University Lady Davis Institute for Medical Research and the Jewish General Hospital in Montreal, Quebec, Canada. Leonard John Hoffer is Abram Hoffer’s son (one of his two sons) and he has become an extraordinary researcher in his own right and carries a lot of these questions forward in his own work as a strong academic medical researcher. This article is a review of vitamin therapy in schizophrenia, going way back to the earlier discussions and observations of Abram Hoffer and Humphrey Osmond. The article states that we still, today, recognize schizophrenia as a devastating and poorly understood disease, for which the only accepted therapy is nonspecific anti-psychotic and anti-seizure medication. However, there is this other interesting history of vitamin therapy, and Dr. Hoffer summarizes evidence. There are some forms of schizophrenia that may really be latent nutrient insufficiency or deficiency based upon the genetic uniqueness of certain people, and in some cases, vitamin therapy can worsen the symptoms of schizophrenia. There is also evidence that large doses of certain vitamins can improve the core metabolic abnormalities that predispose some people to develop schizophrenia. This is a different model of schizophrenia that is still not generally accepted within the body of psychiatric medicine, even though there are now over 60 years of experiences in many clinical and scientific reports that tend to justify this model. Dr. Hoffer recounts the history of controversial, vitamin-based therapy for schizophrenia, which later got named-as you heard me mention before-orthomolecular psychiatry by Dr. Linus Pauling. This therapy advocates a process for discovering promising new schizophrenia therapies that involve small, carefully controlled clinical trials of nutrient combinations in appropriately cohort-selected patients with specific genotypes. Here, again, we are looking at stratification. How do we do the studies? Let’s look at the right people so we can examine those who are more likely to show a response based upon their genetic uniqueness and responsiveness. This same theme that I am describing with orthomolecular psychiatry and B vitamins could also hold true in the application of vitamin C and cancer. Years ago, Ewen Cameron, a Scottish surgeon, made an observation in the Vale of Leven Hospital that patients who had malignancies and got vitamin C therapy seemed to do much better, and even have prolongation of life; their energy levels and vitality seemed to improve. Dr. Cameron then co-authored a paper on this topic with Dr. Pauling.6 In fact, when Dr. Cameron came from Scotland to become the medical director at the Pauling Institute in Palo Alto, CA, I had the privilege of having the office next door, in between he and Dr. Pauling. I was engaged in many discussions about the vitamin C-cancer relationship back in the early 1980s. Some of you may recall, Dr. Moertel, a well-known oncologist at Mayo, who then took very strong umbrage about this vitamin C-cancer connection. He published a paper in which it was supposedly proven that intravenous vitamin C did not have a positive impact upon malignancy.7 However, now some 25-26 years later, work is going on to reevaluate this whole connection. New Studies on Nutrients Focus on Select Individuals Dr. Mark Levine, an endocrinologist at the National Institutes of Health has done in situ kinetic studies looking at the adequacy of vitamin C to promote proper enzyme function. Dr. Levine has also been working in conjunction with investigators at the Linus Pauling Institute (now at Oregon State University), Dr. Balz Frei and Dr. Steve Lawson. Together they have been looking at this vitamin C-cancer connection in a revisited fashion and showing that high levels of ascorbate can induce and participate in certain kinds of free radical pathology that may be specific to the physiology of the cancer cell (the kind of hypoxic, acidic environment of a cancer cell). There may be, at a fundamental mechanistic level, some usefulness of intravenous vitamin C to induce hydrogen peroxide in these cells in situ, which cause selective tumoricidal effects. This was published in the Proceedings of the National Academy of Sciences in 2008.8 Two phase I clinical trials of cancer and vitamin C have recently been published demonstrating remarkable tolerance and safety for high-dose (up to 1.5 grams per kilogram of IV vitamin C) in patients screened to eliminate hyperoxaluria and glucose-6-phosphate dehydrogenase deficiency (that’s G6PD deficiency), which is a genetic condition that is associated with increasing susceptibility to vitamin C toxicity. Case reports also have been published indicating that high-dose IV vitamin C was associated with long-term tumor regression in three patients with advanced renal cell carcinoma, bladder carcinoma, or B cell lymphoma. These findings were published in the Canadian Medical Association Journal in 2006.9,10 More recently, clinical plausibility has been repeatedly suggested with studies by Chen, et al, that have appeared in the Proceedings of the National Academy of Sciences, one of which looked at pharmacological doses of vitamin C as a pro-oxidant that decreased growth of aggressive tumor xenographs in animals.11,12,13 These types of reports all tend to support what Ewen Cameron saw clinically in his Scottish patients and what Dr. Pauling was supporting back in the early 1980s. There is a lot yet to learn about the pharmacology of specific nutrients at high dose, particularly in different disease states and in specific genotypes. I think that we should be very cautious not to throw the baby out with the bathwater. There is a very nice collaborative study co-authored by John Hoffer and Mark Levine that appeared in the Annals of Oncologyin 2008 looking at high dose intravenous vitamin C and its safety (this is up to 1.5 grams of vitamin C per kilogram body weight, 3 times weekly, given intravenously).14 What this study pointed out was that high-dose intravenous vitamin C, even at the high dose, was well-tolerated, but they could not demonstrate yet any anti-cancer activity. However, the promise to the approach, they say, may lie in the combination with cytotoxic or other redox-active molecules (so, a combination of chemotherapy with vitamin C may induce elective tumoricidal effects due to the participation of ascorbyl radical). I think you can see there is a lot yet to learn. We are still really developing the tools to examine some of the tenets that were observed clinically and phenomenologically, and we’re trying to look at them in select populations of individuals that are more likely to respond. Let me give you one other example of this. It is a paper that appeared recently titled “Intensive Nutritional Supplements: Improving Outcomes in Stroke Rehabilitation” inNeurology.15 This particular study was a randomized prospective double-blind single-center study looking at intensive nutritional supplementation in 116 patients admitted to a stroke service. This group of researchers looked at individuals who received a high dose vitamin supplementation program after a stroke, and at those who were not supplemented. They evaluated if there was any improvement in motor function as measured by motor sub-scores or 2- or 6-minute time lock tests. All of these were found to be highly significantly improved at a p<0.002 level in those stroke patients that had the vitamin supplements post-stroke versus those that did not. Again, I think we need to be very open-minded about how we evaluate the role of supplements, whether it is one supplement at a time in the population at large or multiple supplements given together for specific cohorts of individuals. We have to name the specifics of what we are trying to do so we can understand better the outcome. In this particular paper in Neurology, the authors conclude: “Intensive nutritional supplementation, using readily available commercial preparations, improves motor recovery in previously undernourished patients receiving intensive in-patient rehabilitation after stroke. That leads us to ask the question: how do you clinically apply this information? We apply it in the context of improving, overall, the diet and lifestyle of the individual. We know that the complex array of the signature of a good diet coupled with a good lifestyle and regular exercise gives an amplified outcome of benefit. Ralph LaForge-he was at Duke University, Division of Endocrinology and Metabolism and Nutrition-writes in a Duke University Newsletter about applying these things within the context of a therapeutic lifestyle change.16It is not just giving a pill for an ill, and not just using a green medicine (replacing a drug with a nutrient and saying we are getting the same results but less toxic). Really, we ought be looking at the fact that this is a whole different strategy. It is a functional strategy that is based upon implementation with an array of agents that modulate the expression of genes in such a way as to create a different outcome, a different expression pattern, and a different functional phenotype (the healthy phenotype). This lifestyle change-type intervention produces pleiotropic (multiple) benefits across a wide range of function. It’s not like a drug against a single endpoint. It helps to reestablish the frame of reference of the physiology. It influences the network of physiology. As a consequence, therapeutic lifestyle change intervention–along with selective supplementation–can induce, in individuals, a much more positive outcome than just a single substance as an alternative to a single drug. I think the combination of a physical activity, coupled with a dietary regimen (or you may call it a food plan), coupled with selective supplementation based upon the need of the individual, frames the context and strategy of an effective functional medicine intervention. It does so by looking at the whole system. This whole concept of homeodynamic balance, or homeostasis, is really achieved in an individual as a consequence of an equilibrium of various things that are going on in real-time, like a hummingbird’s wings. A hummingbird may look like it is stationary at a flower getting nectar, but if you do a time-lapsed photograph of its wings, you will see they are beating very quickly; that’s homeodynamics. The bird’s homeodynamic activity maintains that static position, and that’s the same thing that happens in physiology with a therapeutic lifestyle change intervention program and selected complex nutrient supplementation: you are balancing the web-like activities-what I call metabolic redundancy or the ability to maintain function against a changing environment. You have to look at the whole system, things like the digestive system, where we know much of the immune system is clustered.. If you have a dysfunctional immune system, maybe you ought to be thinking about the gut. The gut is more than just plumbing; it is more than just a conduit that takes food from the north to the south and excretes it, digests it, and assimilates the nutrients from it. It is part of the gut enteric immune system and part of the second brain: by producing neurotransmitters and speaking to the body through these intercellular regulators, we ought to be looking at normalizing gut immune function, which leads to things like accessory types of nutritional support agents, like pro- and prebiotics. There is more and more evidence now that probiotic supplementation can have a very favorable effect on systemic immune system function. A paper that appeared in the journal Clinical Gastroenterology in 2008 talks about the use of probiotics in allergic disorders by improving gut mucosal activity, or so-called GALT (gastrointestinal associated lymphoid tissue), activity.17 Intestinal microbiological function can then communicate with the gut immune function in such a way as to lower inflammatory potential and to improve signaling through the immune systems of the rest of the body. Allergic problems and atopic disorder in children and neonatal problems of immunological dysfunction may all be very responsive to improving the gut floral environment by probiotic and prebiotic supplementation. The next step is removing from the diet things that might be considered offenders-things that activate inflammatory reactions of the gut, like gluten, which is receiving much more attention recently. Literally hundreds of papers have been published over the last two years on the clinical concerns about gluten and its interaction with genetically susceptible individuals’ immune systems. We’ll talk about that more in a subsequent edition of Functional Medicine Update. I hope I have set the tone for where we are going to go with our researcher of the month discussion. We will look at how signals from our environment are functionally modulated through the genome into the phenotype. There are myriad ways that epigenomic and genetic information gets translated into our health and we can change it with things like a therapeutic lifestyle change program and nutritional support. Let’s move to our researcher of the month.  

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Brian Berman, MD Professor of Family Medicine University of Maryland School of Medicine Kernan Hospital 2200 Kernan Drive Baltimore, MD 21207 Here we are again at that part of Functional Medicine Update that you and I both look forward to with great anticipation, our clinician/researcher of the month section of the edition. As our visitor this month we are very fortunate to have with us someone I would consider to be one of the top luminaries in integrative medicine as a clinician, Dr. Brian Berman. Let me just tell you a little bit about Dr. Berman. This is certainly a truncated biography of his very, very rich background. Dr. Berman is a professor of family medicine and the founder and director of the University of Maryland Center for Integrative Medicine, which was the first center for research, education, and clinical care in complementary and integrative medicine in a US academic medical center. I think that just shows something about Dr. Berman’s initiative and also about his political savvy, because as we all know it is not easy to start something new and try to carve out a domain and have affiliation and understanding. Dr. Berman is very, very prolific in his writing, with over 200 peer-reviewed publications and 7 books to his credit. He is heavily funded through the NIH, and his focus is on traditional Chinese medicine (TCM) and its relationship to acupuncture. He is certainly a world authority in the whole area of acupuncture. I think we have to contextualize this within the background of Dr. Berman’s expertise as a family medicine specialist and also as an associate professor of medicine at the University of Maryland School of Medicine. Rich background. Tremendous successes. And, of course, in November 2005 Dr. Berman’s was awarded the Bravewell Foundation Award for his contributions; the Bravewell Award is considered to be one of the most prestigious awards in the area of integrative medicine. Dr. Berman, it is wonderful to have you as a contributor to Functional Medicine Update. Also, I need to say it’s wonderful to have you as a colleague in the field. Your work has been a shining light, and the excellence that you have brought to your center at the University of Maryland has really been a beacon for many of us. Welcome to Functional Medicine Update. BB:Thank you very much, Jeff, and it is really a pleasure to be here. I feel the same way about following your work over these many years and the impact that it has had on so many physicians out there. JB:Thank you. Let me start with a question (always kind of the first question I have of a person who has been a leader and innovator such as yourself. You have a very solid background as a family physician and also as an academic physician. And with some-probably-risk, you moved into the area of TCM and acupuncture. (When I say risk I really mean professional risk because people start asking questions.) What was it that drew you into these fields? Lack of Answers Leads to Journey BB:It was many years ago-it was really in the late 70s-when I finished my internship and my residency in family community medicine. I worked in the Shock Trauma Center here at the University of Maryland, which is one of the real leading lights in trauma care in the country, and my training was excellent for acute care. But when it came to a lot of chronic diseases (a lot of the things that people came into me on a daily basis for in my primary care practice), I found that I didn’t have all the answers that I was looking for my patients. I was just getting frustrated with that. You know, I could either continue to tell them that the tests are normal and everything seems to be in order and they would say, “But why do I feel so terrible?” and I would basically say, “Well, maybe you need to see the psychiatrist.” I just didn’t have the tools and a way of relating to my patients in a way that was that effective or satisfying. So I really got into it more by looking for better ways to help my patients. Back then, as you know, there wasn’t a whole lot going on as far as training programs, so I kind of began a journey back in early 1980, 81, 82–during that time–and eventually started to look into things like how the mind affects the body (acupuncture, in particular). I spent a lot of time educating myself, first in this country (I was actually in the first class that Joe Helms–when he was doing his UCLA acupuncture continuing education classes-did; it has grown a lot since then). One thing began leading to another. It has certainly been a journey. It took me over to the UK (England) for most of the 80s, in fact. There wasn’t much that I could find (in terms of people willing to take you on) in this country back then. JB:It is very interesting when you talk about the timing. It seemed to me that the late 70s/early 80s was a really fertile time for birthing what has now matured over the last 25-30 years as this field. I was fortunate to be at some of the founding meetings of the American Holistic Medical Association with Norm Shealy back in La Crosse, Wisconsin back in the late 70s. Joe Helms, obviously, was one of the speakers on the podium in those early meetings, as were a lot of the people who have now kind of grown up to be the leaders in the field. What do you think it was back then that kind of started this movement going? Was it the disillusionment coming out of the 70s? What do you think actually was the germ seed of getting this thing started? The Start of a Movement BB:Probably if we looked at that timeframe, a lot of us were from the 60s (I was at Columbia University in the late 1960s). We were certainly taught to question and, you know, not to just accept the status quo; I think that was part of the education that we received. It was also part of the times back then to do that–I think that was true with everything we were doing, including those of us who went in to medicine. We started to really look at questions like, “What did this really mean for the way I related to my patients?” and not just saying “Well, this is how it has to be.” So I think there was an element of that; if we kind of trace everybody’s paths back then there was a lot of that kind of searching that was going on. It was certainly a fun time to be involved in it. Probably you had no idea what you were getting into. It was a real sort of pioneering feeling at the time. There wasn’t sort of a path. There was not a way that you would go on to become a professor in your particular field. If anything, it was sort of the anti-tenure factor, following that path, but it was also an exciting time. There was certainly a group of people in a number of different disciplines that have emerged that were involved in that. JB:Since you made that career decision to allow your seeking personality to prevail and have become really a leader in this field, what kind of resistance have you confronted from your colleagues (if any)? Establishing an Integrative Center at the University of Maryland BB:I came back to the United States in 1991, and I really did that because I had trained extensively in things like mind-body acupuncture and homeopathy (I trained at the Royal London Homeopathic Hospital and worked with a colleague who had 25 years experience) and I had incorporated that into my family medicine practice. In a way I made a mental shift: it wasn’t so much the tools as much as the relationship. It was really, in a way, getting back to good family practice. So that was the mindset that I had in coming back. The University of Maryland, where I did my internship and residency, said, “Okay. We are willing to travel down this road together if you will do this in a scientifically rigorous way.” In fact, the deciding moment was when the head of the cancer center (I was in a meeting with the dean, the head of the cancer center, and the fellow who came from the foundation that gave me my original funding in Great Britain) said, “Do you think you’ve got all the answers?” And I said, “No, not by any means. I have a lot more questions than answers. I just find it a more satisfying way to practice, and I think the results I am getting are better, but I have no idea what is working for what, or why it is working, or when it is working.” And he said, “Well good, because we don’t feel like we’ve got all the answers either, so if you are willing to collaborate together&hellip;” That was a very open-minded person, and at that time I thought, “This is great. We’ll just get started,” not really realizing all that goes into getting involved in an academic center. There were many different things. There was a lot of skepticism. This was 1991. The NIH had not opened up an Office of Alternative Medicine or-as it was actually called-the Office of Unconventional Therapies, when it first got started (OUT was the first acronym). That hadn’t even occurred yet. We started in the Pain Center at the University of Maryland, through anesthesiology, because that was where I had had a lot of patients coming to me for unresolved pain problems in my practice. We eventually developed it into a very interesting multidisciplinary center, which had the usual anesthesiology, psychology, nursing, and physical therapy, but in addition to that, had many other modalities, including acupuncture, different types of relaxation techniques, mind-body approaches, homeopathy-a wide range of things. It took us years, working together, to begin to really see where the strengths, limitations, and weaknesses were and how we could actually work together and communicate well. There was a lot of skepticism. There was not a lot of research going on back in 1991, and the skeptics would certainly hold up the first thing saying, “There is no evidence here.” And they weren’t far off; the evidence that did exist at the time was not very strong, methodologically. We began to see who we could collaborate with, who was willing to work together, and eventually created a small team on the research end. Continuing with the clinical care, we began to get ideas about where we might put our best foot forward in doing research for different pain syndromes, acute and chronic. Ideas were emerging about what we might be able to tackle, and then we began to work with our colleagues in methodology and biostatistics, as well as experts in particular diseases and experts in the therapies that we were studying, starting with acupuncture and then eventually branching into mind-body therapies. That has continued to this day. There is still skepticism out there, but I think it is a lot, lot less and there is a sea change in the people willing to collaborate with us. For example, this past year, a new colleague joined us from the NIH, Dr. Margaret Chesney, who was the deputy director of the National Center for Complementary and Alternative Medicine. I wanted to introduce her around to potential collaborators, so we met with the head of the genomics institute here. They were very, very willing, and really thoughtful, about how we could use the full array of what they have to offer in a big genomics institute to explore some of these therapies. Same thing when we went in to meet with the head of molecular biology and biochemistry-the same willingness to apply some of their approaches (or techniques they have) to really looking at the cellular level at some of these therapies. This experience carried all the way through to the dean of the dental school, who is a real leading expert in imaging techniques in pain, as well as to the Shock Trauma Center and looking at some of these therapies in the acute care setting. These are world-class researchers and people who were really willing to look at what these therapies have to offer. So I think there is a shift that has been occurring over this past 17 years. JB:That is really an exciting history. Congratulations. It seems to me from my kind of outside-looking-in experience that a lot of this interest is driven by patient response. I presume that on the other side of this question of how your professional colleagues responded, we then have the question: how did the patients respond? That sometimes seems to be the driver. What has been the patient response to your center? Patients Vote with their Feet BB:I think the patients are always voting with their feet. When I was in England I was outside of the National Health Service and had an extremely busy practice because people really wanted this type of care. They didn’t want to forego their conventional care, but they really wanted to have a combination and a reasoned approach. Certainly in the United States I have found the same thing. In the beginning I think it was more people who were very desperate who would come to us. They had tried many different things and still had their particular pain problem. And then over time it was really shifting-there was a lot more referring. The patients were saying, “We want this type of care. We want to find ways where we can help ourselves and take on more responsibility, and offer good information, as well as to undergo certain types of treatments.” That might be a particular block, or it might be acupuncture, or homeopathic treatment, but it would also be very much the self-help approaches related to lifestyle changes: diet, exercise, nutrition, things like that. The patients are very much there, and I think are looking more and more for this type of an approach. JB:That leads me to a follow on to your previous point, which I thought was a really well-stated point, around the research methodology and the kind of evolution of research methods and strategies for trying to define some of these things in a reproducible epistemology. We’ve had the privilege, on Functional Medicine Update, actually just last month-our January issue of 2009-of interviewing Helene Langevin, from the neurology department at the University of Vermont on what I think is pioneering work on the evaluation on the mechanism of action at the cellular level (the physiological level) of acupuncture. Also there is Dr. John Longhurst, who I know you are familiar with, at the University of California, Irvine, Medical School, who has been a highly funded NIH grantee on his work as a cardiologist in acupuncture as it relates to vascular compliance in hypertension. These investigators kind of represent to me, from a pure science perspective, some of the crème de crème of what’s happening in the field. But on the other side, then we see things like the book Snake Oil Science by Bausell, who I think at one time was a methodologist within the University of Maryland, and who-from his universal wisdom-has come to the conclusion there is nothing to any of these techniques that is beyond that of sham or placebo. As an expert in the field, can you help us to kind of balance between those two paradoxical and contradictory world views? Addressing the Skeptics BB:Well, there are always personalities, and in this country everybody can have their opinion, so we wind up with a lot of opinions. What we would say to the skeptics is that it is important to look at the science and to look at the evidence. I think the first two people you were talking about are really immersed, particularly in the basic science of acupuncture. They are really grappling with some of the issues, as is Dr. Lixing Lao from our own center, who is also really pioneering some of the very interesting breakthroughs with acupuncture research. We are also doing the same approach that we have taken with herbal medicines (with Chinese herbal medicines)–so a formula of 11 herbs for arthritis–and really taking that same sort of stepwise approach. At our center, we go really from the bench all the way to the bedside, and then to the Cochrane systematic reviews. We have been coordinating that field since ’96. We really believe in the idea of taking a phase I small study, seeing if there is some activity there and if it is safe, and then from there, building on that and going to a phase II study where you are adding in a control group, making sure it is still safe and looking at some efficacy, and then going to more of the phase III clinical efficacy study (so a large-scale, multi-center trial) like we did with our acupuncture/osteoarthritis-of-the-knee study. And then actually doing a systematic review of all the other studies. We feel that it is not one study that is going to be everything, but rather you are building up (like a mosaic) evidence, and that’s really an important way to go. I think some of the skeptics-certainly Arthur Bausell would be included in that-are not really looking at the evidence. I know in his book he said there is just nothing there, but I know (because he published some things with us) that he is aware of the Cochrane Collaboration. He is aware (or should be aware) that there are now over 20,000 randomized controlled trials, as well as over 500 systematic reviews. Everything in his book that he said about complementary therapies you could say about conventional medicine. There are gaps and there is small-effect science usually, and what we need to do is to keep building on the evidence and see where it is relevant (where it is clinically relevant), where it isn’t, or where it is just not working. That’s how science sort of builds upon itself. The sort of mindless approach to say, “Well, there is nothing there,”-it’s hardly worth commenting on. JB: I really appreciate you saying that. When I read the book (Snake Oil Science), I was offended because I thought it was a very selective, biased appraisal of the literature. I then went back and really looked at all of the articles that he had cited as negative articles, and then the ones that were either not cited (or not properly cited) as positive articles, and it lead me to write an article that appeared in Alternative Therapies that was kind of reviewing his review.18 I came to the same conclusion as you: that it seemed that there was an a priori set of assumptions that were trying to be proved rather than really having an open-minded methodological evaluation of the strengths and weaknesses of the field. I don’t know where that was derived from, but it didn’t seem like it served well to leading to clarity. BB: No. Maybe it sold books-I don’t know. If you look at some of his articles in the past&hellip;he actually published one article with an investigator at our own center and found opposite to what he was saying-that it’s not all placebo. You know, it’s hardly worth commenting. There are so many more important things. We have been doing a lot of clinical trials, a lot of bench science and Cochrane reviews, and what we are sort of also grappling with now is&hellip;I don’t quite know how to say it, but you’re putting this ladder up with all of the studies, building up one at a time against this building, and then you get to the top and, you know, you want to make sure that you are on the right building. Some of the approaches that I think people are starting to say we really need to look at (and this is not necessarily complementary and alternative medicine, this is just good, whole-person care, preventive medicine-what I really feel integrative medicine is about)-people are talking about, “How do we evaluate that?” Bringing in some of the things that we already know about behavioral medicine and its effect on some of these chronic diseases and then the effect of, say, adding health coaches, and then maybe judicious use of some particular therapies to that-those are the type of changes that we might need to be looking at and seeing the results of going forward. JB: That really is a very nice segue into a question that I think is an affiliated question, which has to do with what has evolved in the field since its inception, and that’s the development of various organizations to support both the research and also the dissemination of information clinically. I’d like to ask your opinion (being at a high level of oversight in your position): what is your impression of how the NIH Center for Complementary and Alternative Medicine has contributed to the development of this field over the last, say, 10 years? And then I think a companion to that is your involvement with the Consortium of Academic Health Centers for Integrative Medicine, and also the Bravewell Foundation-how do you see the three of those all making contributions? Organizations Making an Impact BB: Well, the NIH NCCAM I think has had a major impact by just existing and having a funding source and sort of a national agenda. Really the different leaders there have tried to set a very high bar, both for the basic science and the clinical trials. As they have gone on, they have been learning as well. They have had, certainly, a number of clinical studies recently that have not shown any effect, and I think they have said, “We are learning that the dose is a critical piece. Or the stabilization of a particular herb is very important.” You know, there are different issues that they have found, which kind of gets back to that sort of very stepwise approach. But just the fact that they are there and holding some methodology meetings or meetings on placebo or bringing people together from different points of view I think is very, very important, so you get a lot of the universities involved. They also had an emphasis on drawing together some of the different therapies, whether it is chiropractic, or naturopathic, or massage therapy and some of the academic health centers to collaborate together. I think all of those things encourage new ways of really doing research when you have the right people at the table. I think they have had a big impact. We had two NIH center grants-one working with people in Hong Kong-and the impact of NIH over in Hong Kong has really led-really encouraged-some of the health authorities to take things more seriously. The Consortium of Academic Health Centers for Integrative Medicine I think is a wonderful thing. I was involved with it when it first started (I think our first meeting was in 1999 at the Fetzer Institute in Kalamazoo). It was really the idea of Jon Kabat-Zinn, who saw back then that a number of places were starting to emerge in the field and it would help if we just got together (especially with some of our deans or presidents so we could let them experience what some of these therapies were about), and really to talk about some of the challenges that we were facing, and some of the opportunities. We started with, I think, six or seven places, and I was just recently at the last meeting in Texas and I think there are 43 universities now that are involved in the consortium, including some of the Canadian schools. What I was really struck by (this is the part that I really appreciated) was that there was so many young people there. It wasn’t just the old ones-like myself or you-that were standing around; there was like a whole generation of people who were really finding a path and a passion for doing good work in this field, whether it was in education and looking at new models of education and how you bring mind-body skills into the schools, or certainly a wide range of discussions about research, including complexity science and the meeting that is going to come up in Minneapolis in May of 2009. It is just sort of exciting. It is good because it gives people a place where they can really share experiences, maybe some places are, you know, maybe one or two or three years into the game at their own institutions, and other places have more years-you know, everybody is willing to learn from each other and share. I think it is still maintaining, although it is harder as it gets bigger to maintain that certain spirit, but I think there is a real willingness to share and collaborate. And then the last group you mentioned was the Bravewell organization, which is a different type of organization. That is a group of philanthropists who are really doing good by coming together and raising the awareness of what integrative medicine is about, such as through their PBS series that they did a couple of years ago, and now they are hosting an Institute of Medicine summit meeting in February, I think it is. JB: Sounds like exciting times. What an evolution, just in the last few minutes of your summary. If you think back 25 to 30 years, who would have guessed, right? A Great Time (and Future) for Integrative Medicine BB: Absolutely. Even in our own organization. I took that funding from the Bravewell Collaborative and seed funded an institute outside the university, one that could complement the hands-on work that different universities are doing, but to be able to take a step back, and to bring people together from very different disciplines to look at some of these healthcare questions and say, “Okay, maybe somebody from anthropology and social sciences, or somebody from the business world, or somebody from public health or medicine, and to really come together and grapple with some of these questions, and then to have some demonstration projects to really test out what people think is maybe a way forward with it. It’s a great time, and it is certainly a needed time right now to make some changes. And I guess the last thing I would say is that a lot of what we have been talking about (medicine and disease), certainly at the institute that we formed and I think a lot of people are saying, is that what the real focus (and maybe the real leap forward) is going to be more of the focus on health and well being. With the Greek gods (one was Asclepius of medicine and then Hygia of health), they knew the difference, and we kind of lumped it together. But we haven’t put so much influence on the health side. JB: That’s a beautiful segue to really my last question (we could go on in this conversation for hours with the rich history that you have brought to this field). I’d like to close by just asking you, from your perspective, given that we are seeing a rising tide of certain chronic illnesses in our society, where do you think family medicine is going over the next, say 4 to 6 years? We have a new age coming up in 2009. What is your position as to where we might be going? BB: My hope is that family medicine and primary care medicine will really focus on more of the prevention side. I think that we sort of give it lip service. What is it-2 or 3 percent of the total budget goes to that? So taking a whole-person approach-the biocycle, social side that people always talk about in family medicine, as well as not just taking people back to a neutral place, but really looking at a more proactive way of looking at health, and health across the whole lifespan. That’s where I think it has to go. I think people are talking about some of the medical models and home models and where that fits in to maybe extending that with electronic records and also the health goal-different ways of extending things. That is where I think things are going to go. That is my hope about where they will go because I think that will make a difference. JB: Do you see any signs that third-party providers and institutional kind of assignments of fee-for-service are sympathetic in changing in that regard so that there will actually be an incentive to be able to keep the lights on by doing this kind of medicine? BB: That’s a key question. You know, I think there is certainly hope with the new administration. There are certainly newspaper articles (New York Times, Washington Post) saying that we really need to look at realigning our financial incentives towards keeping people well and out of hospitals. It’s not going to change that easily from the insurance companies. I think it will need to come from people voting with their feet with their flex accounts and their health savings accounts, and then also maybe from the top saying, “We really do need some real change at this point in time.” JB: Dr. Berman, I want to thank you so much for what you have provided in the way of leadership and courageousness, really, to be the initiator, founder, and director of the first center of integrative medicine in an academic medical center in the United States. That sets a tone for the whole field. I bet you are very proud of seeing, now, those 43 medical schools that are part of the consortium. It certainly started first with your program. It is really a privilege to have you as part of the field. BB: I really appreciate that. It is great to see a lot of people getting involved. I think it is what the people are demanding, and I think a lot of people who have gone into practicing this way are really enjoying more the practice. We just have to figure out some the ways to make sure-as you said-that it keeps the lights on and keeps people well. JB: I’m with you. Thanks a million and best to you in 2009. We’ll talk to you soon. BB: You, too. Thanks very much. I’m sure you were all as impressed as I was in listening to Dr. Berman recount this journey that he has been on in the development of what I might consider the new medicine-the medicine that takes the best from the past and couples it with the best of our future to create the new solutions to this rising tide of chronic disease. I think this thoughtful approach and the willingness to open minds, to be a recipient of information from different sources, to filter that and to see how it fits into the paradigm is all a very, very important part of developing clinical acumen and being a good evaluator (not being a sponge, but being a filter). I think if we try to be a sponge-with the weight of new information coming out-we are logged completely full so quickly. So we have to learn how to filter that information, information about the perspectives that we use to evaluate quality of information and how it has stickiness in our practice to create improved patient outcomes.  

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Welcome to Functional Medicine Update for March 2009. Functional medicine, like all other disciplines within the health sciences, starts with good observation. What does the patient tell us about the nature of the intervention? What does the patient tell us about their interaction with their environment and how that presents itself into their phenotype or their health patterns? These are the kinds of questions that challenge every health practitioner no matter what their discipline, and have historically been the challenges that have confronted the development and evolution of making a more efficacious, more outcome focused, healthcare delivery system. New Therapeutics Are Dependent on Information Being Developed at the Cellular Level In this issue of Functional Medicine Update, we are going to have the opportunity to speak with a person whose literature you (maybe) would not come in touch with if you are a clinician because it appears very, very esoteric relative to the daily practice of health care. Articles with titles like “Small Interfering RNA-induced Transcriptional Gene Silencing in Human Cells” don’t seem like the kinds of things you’d probably include in your everyday reading.1 But as you will learn over the course of this issue of Functional Medicine Update, what we are starting to recognize through articles by investigators like Dr. Kevin Morris from the Scripps Institute, is that the nature of the decisions that we make in the clinic–the observations we make and how they are sieved into new therapeutics–are dependent upon new information being developed at the cellular level in understanding how the environment influences gene expression. One of those areas, which we will learn in more detail in this issue, relates to what are called small interfering RNAs (ribonucleic acids). RNAs can exist in a variety of different forms in the cell: they can be messenger RNA, they can be ribosomal RNA, or they can be related to transfer RNA. Each one of those RNA forms has a very important role to play in the transcriptional process of taking information from outside the cell and converting it into inside information, in terms of the proteomics of the cell converting that information into specific proteins and enzymes that ultimately regulate the function of the cell, tissue, organ, or organ system. What we are starting to witness is the fact that these epigenetic factors (the factors that occur within the scope of not changing the genes in and of themselves but regulating the expression of the genes at promoter regions and transcriptional element control) are, in part, controlled not only by things we’ve discussed such as methylation, acetylation, phosphorylation, and ubiquinitation, but also by the appearance in the cell of these small interfering RNAs (now recognized to be in the thousands). These RNAs were previously thought to be kind of junk, but are now recognized to have very critical roles to play, epigenetically, in modulating how cells function, day to day, and respond to their environment. This recognition ultimately weaves itself into a better understanding of the individual response a patient has as we evolve a personalized medicine approach that includes looking at the symptoms, signs, antecedents, history, and genotypic variables within a patient start to better understand the complex nature of their chronic illness Let’s take that high-brow, blue-sky introduction down to the ground level of clinical observation. Over the course of years, we all probably have thousands of anecdotal stories from practice. This anecdote is about a 19-year-old young man that came in to visit us who had had cystic acne for many years. From the age of about 14 on, he had had this disfiguring acne. He reported that in junior high school and then later in high school there was always at least one kid whose face was worse than his, but by the time he got to college it looked like he had the worst skin and he was very, very embarrassed about it. His skin attached a stigma to him relative to his socialization. He said he made absolutely no friends and he was too self-conscious to approach anyone. He would stay up late at night so he could do lengthy skincare routines when his roommates were asleep. He took virtually everything, and had visited dermatologists/specialists to try to find answers to this question. He had been to a number of doctors and had been unsuccessful with treatments, including taking Accutane. He eventually found his way into one of our functional medicine research projects at the Functional Medicine Research Clinic in Gig Harbor, WA, and was evaluated for his relative history. Could Skin Problems Originate in the Gut? Asking different questions can often get different answers. As you know, a functional medicine provider often throws a broader net in looking at the ecology of an illness, the home of where that thing might have originated. In discussing this situation with this young man, it turned out that he had a considerable amount of digestive problems in his history, which he had never really been asked about. The question was: could the origin of his skin problem have originated by immunological dysfunction in the gut? This was a fairly simple hypothesis, but one that had never been asked before. The concept was that maybe this patient needed to be put on a 4R-type intervention program. “Remove,” “Replace,” “Reinoculate,” and “Repair” are the “4Rs” of the gastrointestinal restoration program. The first “R” involves removing the foreign agents that might be altering the immune system (this could be antigens, allergens, toxins, or heavy metals). “Replace” means to replace digestive enzymes and/or bile acids as necessary. The third “R” is “Reinoculate,” which has to do with the pre- and probiotic supplementation to reinoculate the gut with friendly symbiotic bacteria. And then the fourth “R” is “Repair,” which refers to the addition of nutrients that are necessary for support of proper mucosal repair (pantothenic acid, zinc in a non-irritating form, the amino acid arginine, vitamin E, and essential fatty acids). With that as a strategy, he was put on a probiotic high potency along with a prebiotic daily containing arabinogalactans and fructooligosaccharides and non-fermentable carbohydrate. The combination of the prebiotic and probiotic was accompanied by nutritional supplementation with omega-3 fatty acids in an enterically coated form (about 3 grams a day), and good support with regard to the nutrients necessary to support mucosal repair. His diet was also evaluated to see if it contained potential antigenic or allergic substances. It didn’t appear as if that was a major offender in his case. According to blood tests, there didn’t appear to be any major sign of an IgG- or IgE-related problem, so his diet was modified very little (in fact, I would probably say none at all). Yet on the addition of the prebiotics, the probiotics, and the other nutrients, he had a remarkable response within a period of just a few weeks. What was his response to the program? I am paraphrasing his words: “About three days after starting the program I realized that my skin looked much less red and that it seemed some of my cysts that I had had for six years seemed to be calming down. Everyday I thought my face looked a little better. It has been now over three months and for the first time in the last nine years I don’t have acne. I couldn’t believe that I wasted so much time trying different types of treatments and seeking different doctors’ opinions who couldn’t do anything for me when all I had to do was just to consume the appropriate nutrition.” This is an example of taking a very complex etiology and condensing it down to a fairly simple intervention using a functional medicine conceptual framework. You might ask: what was going on in his environment (the local environment) that would have created an immunological problem that was seen as a symptom of this acne vulgaris? I don’t think we can answer all those questions. I think that’s probably a very complicated set of associations. I do think we can postulate that this complex relationship that we have with our gastrointestinal-associated lymphoid tissue–how it picks up information from the gut, and how those messages are translated through our enteric bacteria ultimately into our GALT–is becoming a more well understood component that relates to this environmental connection to our health. I believe that this is a very important takeaway from what you are going to be hearing about with regard to molecular genetics and cellular biology around small interfering RNAs. What is it that the environment does that then modifies the cellular milieu in such a way as to create different expression patterns of our genes and ultimately, then, lock us in to these cycles of chronic illness for which we then take therapeutic agents to treat the effect, not ever having really appropriately identified nor treated the cause? Let me give you another example of this that goes back to our discussion with Dr. Michael Skinner from Washington State University. We talked about environmental epigenetics with Dr. Skinner, and about the brilliant work he has been doing in looking at the role that low-level environmental chemicals can have on epigenetic marks and transmission effects through the generations of these alterations in epigenetic signals. An interesting paper was just published in the January 28, 2009 issue of Human Reproduction Advances titled “Maternal Levels of Perfluorinated Chemicals and Subfecundity.”2 I think this paper is kind of another step in understanding this emerging frontier of how environment plays roles in modulating function through conception, fetal development, and infancy. In this particular study, the plasma levels of perfluorinated chemicals were evaluated at weeks 4 &ndash; 14 of pregnancy among 1240 women from the Danish National Birth Cohort that were recruited from 1996 to 2002. For this pregnancy, women reported time to pregnancy in five categories. Infertility was defined as having a time-to-pregnancy of greater than 12 months, or receiving infertility treatment to establish pregnancy. What was found from the study? There was a very strong association between longer time to pregnancy and higher maternal levels of the perfluorinated chemicals and also the relationship it had to infertility. Compared with women in the lowest exposure quartile, the adjusted odds of infertility increased by 70 to 134 percent among women in the higher three quartiles. Fecundity odds ratios were also estimated using so-called Cox statistic discrete time models, and it was really found that there was a high impact of the exposure of these chemicals and body burden of them on lowered ability to conceive and have children. The findings suggest strongly that exposure to this class of chemicals, and exposure to them for some period of time with increasing plasma levels, in the general population reduces the ability to conceive. These exposure levels are very common in developed countries, which may allow some explanation for the rising incidence of infertility among couples. This all goes back to the question: are we putting epigenetic marks on our book of life in such a way as to alter the expression of processes that are related to conception and to appropriate term births and deliveries? These are subtle questions that talk about our understanding at cellular levels as to how these signaling processes actually occur. Again I’ll come back to our discussion about small interfering RNAs because we might say, “Well, these are part of the story. These are part of what’s going on in the cell that can mask or uncover specific regions of our genome that are modified by the environment that create different expression patterns.” Managing Early-Stage Symptoms of Cognitive Decline Let’s take another example. I think this is another interesting emerging story, and that is the story of dementia-let’s call it cognitive decline in older age and then later Alzheimer’s dementia. We are all on the search for the Holy Grail: what is it that causes Alzheimer’s disease and leads to these neurofibrillary tangles and the beta-amyloid deposition and the loss of hippocampal function that we ultimately associate with memory loss and Alzheimer’s disease? What can we do to prevent this from occurring, and what are the therapeutic agents that might be useful in managing early stage symptoms of cognitive decline (this period where we might do what is called neuroprotective therapy, where you can intervene early and prevent the course of continued loss of cognitive decline)? In order to answer that question, one might ask this question first: is Alzheimer’s disease strictly a genetic disorder? If we go to the literature and look at the genetics of Alzheimer’s, there are certainly certain gene loci (like the apoE4 genes) that have a strong linkage, but I don’t believe there is any data to indicate that Alzheimer’s dementia is a homozygous-type of tight-gene-linked genetic disease. It rather is one of those disorders associated with the altered function or expression of many genes that ultimately regulate neurological function. It is one of those disorders that we would tie together with genetic uniqueness and environmental exposure. When we start looking at various types of environmental exposures or environmental features that might associate themselves with either the protection against or the increased prevalence of Alzheimer’s disease, we are obviously led to questions surrounding the diet. In an earlier issue of Functional Medicine Update we discussed this paper by Dr. Mattson at the NIH on neurohormetic chemicals that are found in our diet. Neurohormetic chemicals are actually phytochemicals (food-derived materials) which he postulated (from animal studies) might have a positive impact on the prevention of Alzheimer’s-like etiology through the emerging mechanism of productions of these neurofibrillary tangles.3 These phytochemicals-these neurohormetic protective phytochemicals-include things like sulfuraphane from cruciferous vegetables, and EGCG found in green tea, things that were related to red wine and peanut skins, like resveratrol polyphenols, and alpha-acids that come from various foods that relate to the root vegetable family. These, he was suggesting, are chemicals that in animal models, when the animals are dosed with higher intake of these in their diets, were found to actually slow the rate of what might be considered the animal model of Alzheimer’s dementia. It raises a question as to whether diet might play a role in both the prevention and even the relative prevalence because the alternative of a diet rich in phytochemicals is a diet that is devoid of phytochemicals and rich in sugars and fats and other types of neurotoxic substances that activate the NMDA receptor sites and increase glutamate transport in the brain and increase oxidative mitochondrial injury. These would be foods that are associated with what we call type 3 diabetes, which is the new term that has been associated with the blood sugar insulin dysfunction that we think is an etiological agent in Alzheimer’s disease. This was also a topic that we have discussed in previous issues of Functional Medicine Update. The emerging literature is supporting the fact that dysinsulinism is not only associated with diabetes and cardiovascular disease (breast, prostate, and colon cancer), but it is also associated with Alzheimer’s dementia through this type 3 diabetes. If we were to ask, then, “Has our diet been moving in the way that the environmental signals that come from it are signaling through cellular receptor systems two different things? Number one is reducing the neuroprotective chemicals that are within a complex minimally processed whole foods diet, and number two is increasing the dysfunction of insulin and other signaling molecules that activate neuronal oxidative injury and apoptosis,” the answer could likely be ‘yes.’ That is the way our culture has drifted, and therefore it is not just that we are getting older, alone, that is the explanation for an increasing prevalence of age-related dementias, but it is also getting older in a suboptimal environment: setting dysfunctional signals in our neurons. With all of that as an introduction, let’s talk about three interesting papers that were just recently published. The first is a paper that appeared in the Archives of Neurology very recently in 2009 that describes the Mediterranean diet and its relationship to mild cognitive impairment.4 Having spoken to this concept of the low glycemic load Mediterranean diet for some time within Functional Medicine Update, I think we all recognize this is a diet that contains considerable amount of phytochemicals through the colored foods and the minimally processed foods that are found in the traditional Mediterranean diet. The Mediterranean region is a very diverse region with many different diets that really fall within that theater of influence, but that there are characteristics that tie these diets together. Meat is generally considered kind of a secondary component of the diet. Fish is eaten more frequently than in America. There are a lot of colored, minimally processed vegetables. Fruits are consumed. These are generally what we could consider to be more organic. There is a lot of olive oil (generally first-pressed type olive oil with a lot of rich phytochemicals in it), and of course there is the wine component as well, with one to two glasses of wine a day often consumed. So you have all these characteristics-a type of pattern of eating-that is low-glycemic load, complex and phytochemically rich. What is this article that appeared in the Archives of Neurology in 2009 say to this? These researchers looked at an ethnic community and evaluated people that were consuming the Mediterranean diet by choice (this happened to be a community in New York, not in Sardinia, or Corsica, or southern Italy). These were people of Mediterranean extraction who continued to consume their traditional diet, but were living within New York, so you can’t just say this is solely a consequence of living in a different place in the world. They were in a very high-density urban environment. The researchers looked at things like age, sex, ethnicity, education, apoE genotype, caloric intake, and body mass index as variables. In this prognostic study, they followed 1393 cognitively normal participants over an average period of time of about four and a half years (the range was from 1 to 16 years), of whom 275 developed mild cognitive impairment. They then looked at those individuals who had very high adherence to the Mediterranean diet versus those who had low adherence (they broke them into cohorts). The results were quite stunning. The data separates itself out with a high statistical significance, and they found that the higher the adherence to the Mediterranean diet, the more association there was with a trend for reduced risk of developing mild cognitive impairment and a reduced risk of the conversion of mild cognitive impairment to Alzheimer’s disease. There was a pretty dramatic separation of the two data sets. Obviously this is an association study. I want to be very cautious that we don’t go from association to proving causality. Other studies that have been published, for instance, a previous study looked at the Mediterranean diet and the risk for Alzheimer’s disease and was published in the Annals of Neurology.5 This study looked at a community of 2258 non-demented individuals (again in New York), who were evaluated every one and a half years for their cognitive performance. It was found that of those who adhered to a Mediterranean diet, it was the main predictor of all the variables they looked at, including apoE genotype, for determining the trajectory towards whether they were going to get Alzheimer’s disease in later life or not. In fact, it was more powerful a predictor than apoE genotype.Those who adhered very strongly to a Mediterranean diet over the period of time of study had a much lower incidence (in fact about 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} lower risk) of Alzheimer’s disease versus those that were in the lowest tertile of compliance with a Mediterranean diet. Again, we ask, how could this actually work? What are the values of a Mediterranean-style diet and its relationship to function of the brain? To fully answer that question it is going to take years of research. We have to look all these signaling processes of how the various components of the diet would work their way up from the gut, to the plasma, to neurochemical signaling, and ultimately we look at glial and neuronal function. I mean, it is going to be a fascinating exploration into this connection between environment and neurological function. But we can say, I think, at the whole-organism, kind of broad-brush level, that what’s going on is that the Mediterranean-style diet is a lower glycemic load. It stabilizes insulin levels; it has lower postprandial blood glucose effects. We know those people have lowered hemoglobin A1C, or glycosylated hemoglobin levels, so you are having less glycation of proteins. Less inflammatory biomarkers are produced, hsCRP levels are lower, and as a consequence of all these immunological effects — cooling off the immune system, and lowering inflammatory potential– and favorable effects on glial cell function (knowing that the glial cells are kind of brethren, or close relatives, of the macrophages, and the Kupffer cells in the liver and the GALT cells in our gastrointestinal tract), that that communications system is kind of put at rest. And so our model would be the combination of the phytochemicals that modulate function of the signaling process in conjunction with the lowered glycemic load, results in a very dramatic effect, over time, on neurological function. And then you lay that on top of genetic susceptibility factors and it expresses itself finally as this reduced incidence of Alzheimer’s disease. These are very profound new chapters that are being written as it relates to how, at the molecular, cellular, and tissue, organ, and organ system level, that actually our environment can influence a very large constellation of diseases, including things like Alzheimer’s dementia, which some people have just kind of relegated to say, “Well, it’s because we’re getting older and everybody will get Alzheimer’s eventually, and those with the most genetic susceptibility get it first.” That’s a very simple deterministic model that I think neglects all this other emerging literature that is really coming to light. Even things like mid-life coffee and tea drinking have been found to influence the risk of late-life dementia. A recent paper was published in 2009 that I thought was quite fascinating, out of the department of neurology in Kuopio, Finland.6 This group of researchers looked at the role that caffeine has on central nervous stimulation and also some of the other flavonoids that are found in tea and coffee, and other phytochemicals, and how they modulate function. They looked at the consumption of coffee and tea drinking and its relationship with various types of Alzheimer’s disease risk factors, including apoE4 genotype and depressive symptoms and other lifestyle and vascular factors. According to their data, the lowest risk (in fact, 65{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} decreased incidence of Alzheimer’s disease) was found in people who drank 3 to 5 cups per day of coffee. Tea drinking was relatively uncommon and was not associated with dementia or Alzheimer’s disease. Drinking these phytochemically-rich beverages at midlife was associated with a decreased risk of dementia later in life. The researchers go on to say this finding might open possibilities for the prevention of dementia. Again, this is just part of the story. It is not that we’re going to have a magic bullet: just increase your consumption of tea and coffee 3 to 5 cups a day and there will be no more Alzheimer’s. What we are saying is that there are many different contributions to a phytochemical matrix that might have neurohormetic effects in lowering the incidence and risk of the mode of action, or the etiology, of Alzheimer’s disease. The combination of the Mediterranean diet composite and how that signature of nutrients influences gene expression as well as these other phytochemicals that are found in tea and coffee-a different story is emerging. By the way, this was in the in the Journal of Alzheimer’s Disease, the first volume of 2009, if you want to follow-up on this mid-life coffee and tea-drinking study and the risk to late-age dementia. Again, diet is a very complex modulator of environmental signals that has influence, then, on things like small interfering RNAs, and methylation patterns, and phosphorylation patterns, and acetylation patterns of the genome and how that translates itself ultimately, epigenetically and nutrigenomically, into messages that then wash their way through a person’s genetic uniqueness into their phenotype and how they specifically look, act, and feel. With all of that as kind of a presage, you probably know that there was a study that was just published in the Archives of Internal Medicine in 2009 titled “Multivitamin Use and the Risk of Cancer and Cardiovascular Disease in the Women’s Health Initiative Cohorts.”7 This was a study done at the Fred Hutchinson Cancer Research Center at the University Washington School of Medicine in Seattle, WA. I think it is a very interesting study. This study included 161,808 participants from the Women’s Health Initiative clinical trials. These were 68,000 women in three overlapping trials of hormone therapy, diet modification, and calcium and vitamin D supplements. What they did is collect detailed information on multivitamin use, baseline and follow-up time points, and the study enrollment was between 1993 and 1998. A total of 41.5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the participants used multivitamins, so it was a fairly good penetration of individuals who self-selected to supplement daily with multivitamins. After a median of 8 years of follow-up in the clinical trial cohort and about 8 years in the observational study, there were 9619 cases of breast, colorectal, endometrial, renal, bladder, stomach, lung, or ovarian cancer; and 8751 cardiovascular events; and 9865 deaths. They then looked at multivariate-adjusted analyses to see if they could tease out whether those individuals that took multivitamins daily had any difference in incidence of any of these health conditions versus those that did not. They came to the conclusion that there was no impact on any of the parameters measured (in any of the diseases measured) by taking multivitamins. They went on to say, after a median follow-up of 8 years in the clinical trial and observational study cohorts in this Womens’ Health Initiative group, there was no convincing evidence that multivitamin use had influence on the risk of common cancers, cardiovascular disease, or total mortality in postmenopausal women. Here is another study in the kind of litany of studies that have been published recently that tends to argue that vitamin supplementation doesn’t have any positive benefit. So what can we say about that? There are a number of features which keep coming back to the story that I have been developing over the last several years about these intervention trials (this is actually an epidemiological trial-self-supplemented epidemiological trial, so it is not a true cohort-controlled, intervention-type of blinded trial, but, again, it tends to suggest that supplements don’t have any long-term health benefit). The model that I’m trying to get people to understand is a model that may be very different than that which was espoused some 25 years ago in the book Life Extension.8 Some of you remember that book by Pearson and Shaw, in which they propounded that as long as you took an appropriate number of supplements you could neutralize the effects of any bad diet or bad lifestyle; it was all about taking very large amounts of supplements to kind of get the best of all worlds against whatever decisions you might make in your diet and lifestyle. At that point in time, 25 years ago, I made a very strong statement on Functional Medicine Update that I felt this was going to be proven to be inappropriate, that supplementary nutrients were not the primary feature that modified our function, but rather we had to consider our lifestyle variable first. We had to be on an appropriate diet, we had to consider our stress and our exercise, environmental pollution, smoking, all these things were very big tuning knobs for influencing our health outcomes that we couldn’t just neutralize easily by taking doses of multivitamins. But for those places where there are nutrient gaps in which specific kinds of nutrients like B6, or calcium, or iron, or antioxidants like vitamin E might be in less than optimal levels, the insurance policy of a good multivitamin/mineral high-potency bioavailable formula would be helpful in filling in those nutrient gaps. It would be kind of the combination of dietary, lifestyle, and nutritional supplement on a preventive feature that would be proven valuable. Well unfortunately, these aren’t the kinds of studies that are generally done. We don’t control the diet and lifestyle of these individuals, we just take the luck of the draw and then we say the vitamins didn’t work. Sometimes the signals of the supplements are lower intensity than the adverse signals of a poor-quality lifestyle and diet (it swamps that information). If you did cohort analysis within the full data set, you might find people who really regulated their lifestyles very well, and by the addition of supplements they got added advantage, but they would be kind of washed out of the data set by all the kind of “luck of the draw” individuals that were just eating whatever they want and taking a vitamin supplement, hoping that that is going to be the insurance policy. I think what we are emerging is to recognize it is the composite signals that come from our lifestyle and our environment, our diet, that then give rise to the expression of our genes and puts epigenetic marks on our genes and modulates things like the small interfering RNAs that may be affecting, then, our gene transcription processes and regulating both somatic and germ cells. We also recognize that this environmental toxicology issue is not inconsequential, starting at the moment of conception and moving through our whole life, and how it influences cellular function. My thought about this recent published paper in the Archives of Internal Medicine is that it is not really a big surprise that there was no direct link upon reduction of cardiovascular incidence or cancer incidence in a large cohort of people who are doing the common things that we see our society doing, that is, eating high-calorie, low-nutrient density, poor-quality depleted foods and having the sense that maybe they can, by taking a multivitamin, ensure good health in the absence of making good decisions. It’s really just kind of once again affirms the complex nature of how we are influenced by the signals in our environment. The Council for Responsible Nutrition, which is an organization, as you know, that represents the science of the nutritional supplement industry, released a press release in response in response to the Archives of Internal Medicine article.9 In this press release, they say that multivitamins, like all other dietary supplements, are meant to be used as part of an overall healthy life and are not intended to be magic bullets that will assure the prevention of chronic diseases like cancer. As I have already said, the key to good health is a commitment to an overall wellness approach that includes the daily use of a multivitamins, and that’s also the position of the Council for Responsible Nutrition. With that in mind, you might say, “Is there a difference between nutritional prophylaxis that would be, say, generally everyday maintenance of a good, healthy set of signals going to your genes, and that of therapeutics? Is there a place for nutritional pharmacology?” That term was first used by Dr. Spiller in the book titled Nutritional Pharmacology that he authored back in the late 1980s.10 I think that there are, obviously, places where we would use therapeutic doses of specific nutrients to get beneficial effects, like the vitamin D story that is starting to emerge. Continuing Discussions on Vitamin A and D Supplementation I was very pleased that one of our long-term Functional Medicine Update subscribers, Dr. Warren Levin, who has been a very noteworthy expert in this field for more than four decades, shared with me a paper that he had received back in the 1970s from Dr. Arthur Alexander Knapp, who was practicing medicine in New York City and had an idea to use higher therapeutic doses of vitamins A and D in patients that had various types of ocular and ophthalmological problems, including myopia, and was able to publish work that is very interesting.11 This paper Dr. Levin sent me authored by Dr. Knapp looks at 40 years of his research with the supplemental dose of nutrients in people that had certain ophthalmologic problems, showing that supplementation had a very distinctive benefit in helping protect against things like macular degeneration and also improve eyesight beyond that just of wearing glasses, that there was improvement, overall, in vision. There is a difference between nutritional therapeutics and nutritional preventives. That leads to some interesting recent papers that just appeared in the literature around this vitamin D and vitamin A story. There is a very nice paper on cod liver oil, vitamin A, respiratory infections, and vitamin D that was coauthored by Reinhold Vieth and Walter Willett, and really a whole list of individuals, all of whom have all been looking at the association between vitamin D and immunological problems.12 What they find in this paper and suggest is that omega-3 fatty acids and vitamin E coming through cod liver oil historically used by our grandparents or great-grandparents for tonics have very dramatic effects on improving immune function in children and lowering the risk to frequent respiratory infections, so maybe there is something very interesting about the flu, for instance, and relative risk to the flu as a consequence of vitamin D and vitamin A status. There actually is a very nice review on the epidemiology of influenza that was just reported that actually discusses this whole connection to vitamin D status and increasing incidence of infection with the flu. This appeared in the Virology Journal in 2008.13 The authors of this article point out that the epidemiology of influenza swarms with incongruities, but one of the things that seems to be central is that many times epidemics of the flu are associated with periods of either nutritional insufficiency or poor solar radiation, giving rise to lowered vitamin D associations and potential increasing risk of infection. They go on to say that we ought to be looking at the vitamin D connection to influenza, and that adequate vitamin D levels may be very important along with vitamin A for support of the immune system and defense against viral infections. Similarly, as you probably know, we’re seeing more and more evidence come out supporting the fact that vitamin D may be very helpful for things like immune inflammatory disorders, like multiple sclerosis (MS), which appears to have a susceptibility gene that is a vitamin D metabolite, 1,25-dihydroxycholecalciferol-responsive gene. In certain people who have this genetic risk, they require higher levels of vitamin D in order to promote appropriate function.14 What are we really speaking about? We are speaking about the nature of individuals who have expressed risk that is different than other people, that is encoded within their genes, and their environment is going to be unique to them, and the response to it is going to be unique to their gene sieving process. That particular translation process occurs through both epigenetic and genetic mechanisms, and we are going to be very fortunate to hear a little bit about what this emerging story is around small interfering RNAs and how they are another part of this complex milieu within the cell that translates messages into gene expression patterns. Let’s now share this story with our researcher of the month, Dr. Kevin Morris.  

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Kevin V. Morris, PhD Assistant Professor Department of Molecular and Experimental Medicine The Scripps Research Institute 10550 N. Torrey Pines Road, MEM 131 La Jolla, CA 92037 www.scripps.edu/mem/rheum/morris/home.htm We can hardly wait to get to our clinician or researcher of the month every month because we know that’s where the cutting edge is going to be exposed. That’s where we’re going to look at where the field is going. That’s where we’ll find new tools and new opportunities to contextualize that private moment in the exam room with a patient and ask, “How did they get here? What is the etiology of their condition and how might I frame it in a different way to get improved outcomes?” You are not going to be disappointed this month. I’m very fortunate that we are going to have Dr. Kevin Morris as our expert. Let me just contextualize this because it may be a little bit of a stretch for some of you, but I’m asking your patience and your indulgence because I think you are going to be very pleased to see the outcome. You might even be surprised at how far you’ll come in this discussion in understanding how much you really already know. Dr. Morris is a leader in the field of what I guess you would call post-translational/post-transcriptional gene silencing (or TSG, transcriptional gene silencing). This really falls in to the scheme of things that you have heard about on Functional Medicine Update over the last year, which had to do with epigenetics and how the gene expression is modulated through the environmental factors, both intracellularly and extracellularly. We have had Dr. Michael Fenech from CSIRO in Adelaide, New Zealand talk about genomic instability. We had Dr. Randy Jirtle talk about nutritional epigenomics from his work at Duke. We’ve had Dr. Michael Skinner talk about environmental epigenomics and genetics from his work at Washington State University, and Dr. Edward Calabrese talk about hormesis and the effects that small concentrations of agents can have on modulating cellular function.You are developing kind of a comfort level with the language of where this field is going, and you’re going to take another very important step today with Dr. Kevin Morris. Let me give you a little bit of a background on Kevin. He has had very, very rich productivity for an investigator. I hope it is not sounding pejorative, but I would call him a young investigator (in that anybody less than 60 years of age these days I call young). He started off at the University of California at Davis, and after his PhD went on to a postdoctoral fellowship at UCSD. From there he went to the Beckman Research Institute at the City of Hope in Duarte, CA, where actually he was the co-author/principal author on a paper that appeared in Science magazine in 2004 titled “Small Interfering RNA-induced Transcriptional Gene Silencing in Human Cells,” which turned out to be, I think, a very pivotal discovery in that up to that point (as far as I know) there had not been the proof that the small RNAs could silence genes in mammalian cells. So this was kind of an interesting step that you are going to hear more about from Dr. Morris. He has now achieved, I think, very notable distinction as an Associate Professor in the Department of Molecular and Experimental Medicine at the Scripps Institute in La Jolla, CA, where he oversees post-doctoral students and is engaged in very active studies. Last year-2008-was a very productive year for him and his group, with some very important published studies coming out that help us to understand this post-transcriptional gene regulation through these interfering RNAs. With all of that as kind of a very complex introduction, Dr. Morris, welcome to Functional Medicine Update. It is really a pleasure to have you as an expert on our audio magazine. KM:Thank you, Jeff. It’s a pleasure for me to be here, as well, and be honored with an interview and discuss my work further with the medical community. JB:We are dealing, here, principally with clinicians, who might say, “What in the heck are small interfering RNAs, or what are micro RNAs, and from that, what do they have to do with medicine?” Maybe we should start with the basics, here. Maybe you could just describe the whole concept of micro RNAs and small interfering RNAs and what we have learned because it is a fairly new concept, really, within probably the last decade that has become more understood. Definition of Small Interfering RNA KM:Right. Initially I’ll just go into a brief summary of the history. In 1987, some folks doing plant genetics found that small double-stranded RNAs could turn off a gene (the expression of the mRNA). As we know in basic biology, your DNA makes mRNA, which then makes a protein. And they found, in plants, that these small interfering RNAs could direct transcriptional gene silencing. What that means is that these small interfering RNAs are double-stranded small RNAs that are 21 to 27 nucleotides long and they are double-stranded pairs. They enter into a complex in plants and they match the corresponding DNA of the gene promoter, and what they do is they cause epigenetic changes at that promoter that lead to downstream silencing of that gene. The important part of transcriptional silencing in small interfering RNAs is that it is inheritable-it is passed on to daughter cells. siRNAs and Post-Transcriptional Gene Silencing In the late 80s they figured out that this was occurring in plants and that it has been shown in yeast. In 1998, Andy Fire and Craig Mello showed that small interfering RNAs could also direct post-transcriptional silencing, and what that is these small RNAs target the transcript that is making the protein and they cut it. And then in 2004, my lab was able to show that you could take these small RNAs and design them-knowing the sequence of a gene promoter-design them, make them, in the lab and put them into cells, and that they would go to that promoter and turn that promoter off in human cells. With small interfering RNAs, I think what opens up the whole medical area is that we can design them a priority, knowing the sequence of whatever we want to target. We can target a gene either post-transcriptionally (like Andy Fire and Craig Mello did and they received the Nobel Prize for this in 2006) and that cuts the transcript-it cuts it and it no longer makes a protein, however, you still get the transcript being made, and over time you’ll regain the expression of that gene. Or you can target it transcriptionally, which is the way my lab does it. You target the gene promoter, and that works mechanistically through a different sort of paradigm. In that paradigm, it causes epigenetic changes: histone methylation and DNA methylation at the gene promoter, and that causes that promoter to be less accessible to the transcription machinery, and it can result in long-term silencing, where the gene is turned down in a more permanent manner. Now, we design these small RNAs knowing the sequence that we are targeting, but up until this point it was not known whether this was an endogenous mechanism in human cells. We knew that we could do this (we could put the small RNAs into the cells), and we knew the machinery was there to turn off the gene transcriptionally, but we didn’t know whether there were RNAs doing this endogenously. There have been microRNAs that have been reported, and piRNAs-other different species of small RNAs have been reported-but none of them have been shown to work to transcriptionally turn off a gene. It was in 2008, where we recently published, that we found that noncoding antisense, which make up (presumably) 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of all genes that are being expressed can actually do this. JB:First of all, congratulations on summarizing a huge body of information in a very concise way. You have obviously said that before; that was very, very well done. And secondly, this kind of little haiku-this little pearl-that you dropped at the end, which is in 2008, your work and that of others has now defined that these small RNAs are produced endogenously and can serve as post-translational modulators and that that constitutes maybe 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of expression patterns, is a pretty profound concept, it would seem to me. What Regulates the Production of RNA to Begin With? KM:Let me clarify that. There are microRNAs being made, and they are post-transcriptional modifiers; they inhibit the mRNA from being made into a protein. But what I am talking about is even further upstream of that and saying, “Can we even stop the mRNA? What regulates the production of the RNA to begin with?” So to think about it in terms of snow on a mountain, we want to stop the snow from even falling onto the mountain as opposed to melting and flowing into a river, etc. The post-transcriptional targeting…it’s like damming up a river; it is stopping the water flow that way, whereas transcriptional targeting is stopping the snow and rain from even occurring. And so what we work on is the transcriptional targeting, which is upstream in the gene promoter. What has not been known was what is controlling this. Are there RNA species controlling this? What we found out is that there are non-coding RNAs that do this. I think it is 1.2{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the entire human genome is making proteins. That leaves about 98{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the genome with what we traditionally used to call “junk” DNA. Nobody knew what that was doing and some people speculated that it was involved in spacing the genes out so they could be expressed and controlled, etc., and there may be some aspect that the DNA does that. But it turns out that a lot of that junk DNA is actually made into RNA, and nobody has understood what those RNAs are doing, and those are called non-coding RNAs; they don’t make a protein. What we showed in 2008 in this PLoS Genetics paper is that there are non-coding RNAs that can regulate the gene’s transcription.15 That was sort of a big “a-ha” moment, where it is like, “Oh, small RNAs can do this, too.” And that is how we found that we could even do this in human cells. Now we are actually on the tip of the iceberg, figuring out the RNAs that are inside our cells that are doing this. The interesting thing to point out is that several of these non-coding antisense RNAs have been documented in tumor suppressor genes, and tumor suppressor genes tend to (in cancers) become epigenetically silenced, and so that fits in with this whole discovery where the non-coding RNA is involved in this regulation. The notion is what happens over time is that these non-coding RNAs become uncontrolled or overexpressed, and they lead to silencing of the promoter for, let’s say, a tumor suppressor gene, and that tumor suppressor gene gets silenced and that can be sort of the epigenetic prelude to developing into a cancer sort of state. Obviously cancer is far more complex than a single gene, but this is the notion we are working with. JB:Let’s take an example of an environmental factor that influences the non-coding RNAs, like a viral infection. I know you have done quite a bit of work in your history with HIV. If you have a viral infection, how does it impact expression of non-coding RNAs? Research on HIV Infection and Non-Coding RNAs KM:Well, HIV is a particularly interesting example. What happens is HIV can impact the microRNA pathway; that’s well-known. How it impacts non-coding RNAs, which we have just now recently started to understand…I mean, there is so little work right now in the non-coding RNAs and there is not a lot of emphasis on it, so I can’t go into the details of mechanistically how it impacts non-coding RNAs (and I’m talking about larger species of RNAs), but when we talk about microRNAs, which are smaller RNAs that are involved in regulating genes in a post-transcriptional manner, there is much more known about that, and HIV does impact that. When HIV infects a cell, it uses the proteins that are involved in the microRNA pathway and pulls those proteins away from the endogenous microRNA pathway. It uses them for its own production, and by doing that, it causes a cell to become less regulated, less controlled, because it no longer has the proteins it needs for the microRNA pathway to regulate all of the endogenous genes so genes start to get out of whack. But the virus is coming in there, it uses that protein and it makes more of itself. The virus doesn’t initially care; it wants to make a lot of virus, right, and produce more virus? But HIV will actually go into a latent state-it will become hidden-if the cell survives and it makes enough virus, it goes into a latent state, and that’s why we have this chronic infection that never goes away. We suspect, and we have some evidence that there are non-coding RNAs that HIV makes, itself, to regulate its viral latency, but that’s not been published yet. JB:So if we were to then ask a kind of a teleological question…I know this is an unfair question, but I’m sure you have a speculation. In the development of our biology, what advantage is there to have these non-coding RNAs in terms of their ability to regulate? Because clearly it appears like one might say, “Well, this sounds like a random, kinetic, molecular modulation of gene expression because you’ve got all this sea of small RNAs floating around, hitting on specific portions of the genome; it sounds like it would be a fire drill.” KM:Exactly, and we don’t know where the non-coding RNAs come from. But the notion would be that…we’re just going to talk about it on a cell level, but obviously the human organism, the human body, is an amalgamation of cells, but on a cellular level, the notion is a cell gets placed into an environment, it has certain interactions with that environment, and it causes a certain gene regulation. If that gene regulation is selected for (is positive), the cell out-proliferates the other cells. That cell would putatively have a particular non-coding RNA profile that is going downstream and regulating genes in a differential manner, and if that is selected for, those non-coding RNAs would then lead to epigenetic modifications that become sustained and kept, and that cell outcompetes the other cells and becomes the dominant cell. The thought is that the non-coding RNAs are involved in differentially regulating gene expression to allow for sickness to occur. There is absolutely no evidence on this; this is all speculation at this point. JB:So now you have touched on something that has a lot of, kind of, sense within our listening group about what they call the folate cycle in intermediary metabolism, because we’ve discussed methylation and silencing and promoter regions of genes by the cytosine methylation patterns, and I think there is this sense that nutrients that support methylation, which would be folate, B6, B12, and betaine, for instance, can help to maintain proper methylation patterns, but we also know-as you’ve already alluded to-that there are promoter regions of genes that are hypermethylated, and does that occur as a consequence of, say, a person consuming too much folate, B12, or B6? It sounds to me, from the way you are describing this, that the regulation of methylation patterning is more complex, obviously, than just the available of s-adenosylmethionine. It is regulated, in part, by these small interfering RNA’s communication that maybe direct methylation patterns. Am I moving in the right direction? Small RNAs and Directed DNA Methylation KM:Yes, sort of. If we design the small RNAs in our lab and put them into cells, we can see directed DNA methylation at the site we are targeting. It is not found upstream of that site, it is found downstream in the orientation of transcription. So it is as if the RNAs guide a complex that contains DNA methyltransferase 3A and Argonaute-1 and histone deacetylase-1-those three we know are involved. It is as if small RNAs guide that complex to that target site and it moves downstream in the orientation of transcription, causing changes in the nucleosomes (epigenetic changes-histone methylation, and eventually DNA methylation). We see DNA methylation-it occurs-and certain promoters are more susceptible to DNA methylation and they become silenced when they are methylated. But no one has really understood what is guiding the methylation to this site. Obviously the folate cycle is involved in methylation, and there are certain nutrients that are involved in maintaining the ability for methylation to occur, but the guiding mechanism, or the endogenous infector molecule that is telling the cell, “This gene needs to have methylation at this loci,” has been sort of missing. We suspect, with the evidence that is mounting in our lab as well as in others, that non-coding RNAs do this, and when they become dysregulated, or differentially regulated, they can lead to robust DNA methylation that can lead to long-term silencing, and that is sort of what you see in cancers, you know, with tumor suppressor genes that are turned off. JB:So then that leads, obviously to a companion question, and, again, I’m coming back to our field in which the clinicians may be everyday asking, “Gee, am I influencing, somehow, the regulatory pathways through the way that this person is living their life that ultimately expresses itself through the phenotype?” We’ve heard a big story that comes out of David Sinclair’s lab at Harvard: the resveratrol connection to histone deacetylation and the sirtuin gene family. It would suggest that there are maybe phytochemicals, or let’s call it small molecules in the diet, that might actually have some influence on these regulatory pathways, but they way I’m interpreting what you are saying is that the impact of some of these might be much more complex in terms of their regulatory effects, mechanistically, going through small RNA-directed pathways. Is that a possibility? KM:Yes, certainly there are small molecules and compounds found in our diet that can affect histone methylation and DNA methylation. The notion would be that the non-coding RNAs are guiding epigenetic changes to particular gene loci, but then it’s the diet that is there to revert those changes, and that’s functionally beneficial to the cell, then what you would expect is that that gene would be selected to be turned on, even in the presence of the non-coding RNAs. We don’t know where the non-coding RNAs are coming from, but I would suspect that if a particular gene has been selected to be turned on based on the diet and it being beneficial for the organism, then I would suspect that you would find those non-coding RNAs where they are emanating from, their promoter, if you will, would probably become epigenetically modified. I think it’s a balancing act in transcription, where you have the sense and antisense transcripts. The sense becomes and makes the mRNA, which makes the protein; the antisense is the non-coding RNA, and that’s the 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the transcripts I was talking about, and those antisense non-coding RNAs are functionally involved in regulating the sense transcription. So I think there is a balancing act between the two, and I think diet and environment is the regulatory mechanism, but that hasn’t been shown yet. We are headed that way. I mean, this is getting real complex real quick. JB:Thank you. You are taking us exactly in the right direction that I think many of our listeners want to go. It seems like these discoveries you and your co-investigators are making can be applied maybe in two different ways, one of which is (you’ve already alluded to), we could conceivably see the construction of synthetic derivatives of these antisense RNAs that could be used therapeutically to interfere in specific ways with gene expression that would be favorable to a disease state, so that would be a pharmacological application, and there are many small biotechs that are kind of taking that concept up to develop these new molecules through the I & D process. And then the second would be to look at how the environment (diet, lifestyle, chemicals, xenobiotics, and things of that nature influence the regulatory pathways through these small RNAs and ultimately find out how to personalize nutrition through the appropriate kind of screening device. Do you see the latter, in the future, is going to be a possibility? Potential Applications of Small RNA Research KM:I think you hit the nail on the head, right there. There are two potential areas, here. I will start off with the synthetic potential, here, in terms of making compounds that can specifically target gene expression. What is important about the most recent PLoS Genetics paper that we published is that it shows that if you find the non-coding RNA that is involved in regulating a particular gene and involved in turning that gene down, and you target that non-coding RNA in a post-transcriptional manner, you can inhibit the inhibitor (silence the suppressor, if you will), and that causes a gene to be turned up. Conversely, if you target a gene’s promoter in the transcriptional manner, or you target the gene’s mRNA in a post-transcriptional manner (most of the biotech companies are actively targeting post-transcriptional silencing), that’s a transient approach versus transcriptional, which is more permanent because it involves epigenetics. But either way, if you target a gene’s promoter, or the mRNA, you can turn the gene down. So what is really remarkable about this RNA-based technology (this antisense RNA technology is what it really is–small interfering RNAs, single strand and antisense RNAs), is they can both drive transcriptional silencing. What is really fascinating about this is that we can specifically turn up or down a gene. You basically pick it: what do you want to hit? That’s the notion. We can do that on a cellular level. Obviously delivering it inside the human body to the target regions…that’s where the trick is. How are we going to get these small molecules into the cells that need it and not the cells that don’t need it? What is fascinating about the ability to be able to specifically turn up or down a gene’s expression is that it allows (in my mind-I can see the light at the end of the tunnel) for the first time, where we can take and make personalized approaches. We can say, “Right. Patient A comes in. Patient A has a certain pancreatic cancer, let’s say. They have a certain genetic profile (genetic expression mark, if you will) in this particular tumor area in the pancreas. These genes are up and these genes are downregulated and they are all known to be involved in pancreatic cancer.” We can go in and design molecules that would cause to turn down those genes that are overexpressed and turn up the genes that are underexpressed. We have the potential ability to do that. The question would be, how would you deliver it to the area where you need it, specifically, and not hit all of the other cells? That is the same problem we have right now with current chemotherapy. Now, you could do the same sort of approach dietarily. If you understood how diet works, and the small molecules that are being produced by a certain diet, and how that affects gene expression, you could tailor a diet to fit with what a person is needing in terms of gene expression (if you understood the diet on a gene expression level). Each person is different, right? There are different diets, there are different genetics, and there are different environments that they are dealing with, but certainly I see medicine moving (at least, in the next 20 years in developed countries) into a personalized sort of arena, where we can draw somebody’s blood and a week later tell them, “Here’s what the situation is. Here’s what we can to amalgamate the situation (or ameliorate it, if you will).” JB: So when we look at this future application that will come out of these discoveries, it sounds to me like we are into a whole, really different field of investigation that takes us beyond Mendelian genetics, takes us beyond the deterministic model that really medicine grew up around Mendelian kind of cross-overs and dominant and recessive characteristics, and it moves us in to a field of genomic expression plasticity, which is pretty empowering for a different kind of medicine than that which just treats rigidly defined disease that appeared as if it was a legacy of bad genes. KM: Right. You are exactly right there. I mean, the Mendelian genetics still apply. We’re not saying anything of what science has done over the past 200 years is not appropriate; it all fits in. And proteins are still involved in gene transcription. We are just saying, “Hey, there’s another layer of complexity that is going on, and we’re just now getting to understand that because we have the technology that allows for us to go there and to figure these sorts of things out.” I think the dogma in science is ridiculous because many folks are still stuck on this, “No, proteins control gene transcription.” Well, RNA does, too. There are other factors playing out and it is shortsighted to think it is so simple. But maybe that is the way we want to be because it makes it easier to think about it if it is simple in sort of a Mendelian genetic approach. But yes, you are absolutely correct. There is a plasticity that is going on, and that’s different for every individual. Diet affects that, environment affects that, and the body and cells respond according to a particular situation. JB: Do we know if the telomeres have any influence on compaction of DNA such as to make the nucleosome more responsive to small RNAs? KM: Telomere and telomere shortening…I don’t know the exact specifics of that, but that probably does have a role to play in nucleosome structure, but see, the telomeres are at the end of the chromosomes, so I would imagine there might be accession points there for RNA polymerase and other transcription factors that may bind in there and start moving down the chromosome, so it might have to keep it relatively open. We haven’t gone and tried to target telomeres to see if we could modulate their local nucleosomal structure. It was something we thought about doing with another group, but you know, resources are limited right now and we have to focus on what we can do. Small RNAs and Telomerase Activity JB: The reason I kind of went off on that sidebar is if you look at the Hayflick’s number in replicating cells and you assume that that has something to do with shortening of the telomeres and the telomerase activity is important for maintaining the integrity of the telomeres, and now we look at this recent paper that appeared in Lancet-I’m not sure if you saw it-that came out of the UCSF Medical School group with Dean Ornish being one of the investigators…16 In this paper they showed that by intervening in people who had prostate cancer with a lifestyle intervention (this was a vegetarian diet, stress management, and exercise), they actually got enhanced telomerase activity, suggesting that they were possibly changing the integrity of chromatin, increasing genomic stability through increased telomerase activity, and that actually correlated with lowered LDL levels. It starts raising at least a question as to whether this would influence, then, expression activators (or modulators) of expression like small RNAs? KM: I don’t doubt it at all that doing those sort of lifestyle changes would affect your body, each cell, on a genome-wide scale. I would imagine it is a fantastic study that could be done to just take some patients and, you know, have the before and after and take the cells and do chip-on-chip sort of assays and look at where the nucleosomes are positioned. I mean, I can see doing an experiment in this manner. I would be willing to bet that there are significant changes that are occurring; it doesn’t phase me at all. Now, how it is working…I think it is a complex scenario. I’m sure RNAs are involved. I’m sure non-coding RNAs are involved to some extent in the changing of the nucleosome positioning. JB: One of the important takeaways that I have from what you have said-and by the way, you’ve said it brilliantly, at a level that we as non-specialists in this area can understand-is the question that has been floating around, and that is, if something is deficient and you increase the intake of the precursors to modulate that deficiency (now I’m thinking of something going back again to methylation of the genome with folate-related nutrients), it doesn’t necessarily mean excess of those same substances would cause a hyperfunction because there are so many regulatory steps in what does and does not get, in this case, methylated, other than just the availability of the methylating agent s-adenosylmethionine? So if you don’t have the methylating agent there at all, then it is hard, no matter what the regulatory mechanisms are, to methylate. But if you do have the methylating agent there in adequate levels, there are many other factors that will control and regulate regions that might be hypermethylated or hypomethylated. Am I saying that correctly? KM: Right. JB: So when that comes back, then, to your “a-ha” for us-25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the genome related to these non-coding RNAs-it would suggest this is a fairly important regulatory conserved feature of mammalian physiology. KM: That’s the notion. As I said, there are very few of us working in this area. I suspect more and more folks will start working on it as it becomes more realized. Getting into the methylating agent and having…it’s a substrate versus enzyme, right? And if you have a lot of substrate there and no enzymes, that could also impact the ability to methylate, if you will. I suspect there is a balancing act that is required. As is always the case, the middle road is probably the best one to take for a healthy individual and a balanced sort of expression profile that allows itself to deal with environmental stresses and strains and to evolve accordingly to the selective pressures placed on it. JB: Let me ask one last question about these siRNAs (the small interfering RNAs, these antisense RNAs). If you were to do some speculation here and kind of look forward five to ten years, how do you see this translating into a clinic? Do you think we are actually going to see some leverage of these discoveries at a translational science level? Looking Ahead to Clinical Applications of siRNA Research KM: Yes. Like I said, I’ve been doing science for several years and I used to think, “Oh, we wrote another paper, published it, no one will read it.” I never saw any sort of translational aspect of what we did. It is just now that I’m saying, “Wow, this can really go.” In my lifetime I can see the work I’m doing, and several thousand other people are doing, actually becoming developed into a drug, into compounds that are useful. As I said, delivery is an issue. But delivery is always an issue in every drug you develop. But I do see that we are headed that way where we can design these compounds-small interfering RNAs, small antisense RNAs, and small non-coding RNAs-we can develop this sort of technique to turn off or turn on a gene. It just is a matter of what genes need to be turned off and what genes need to be turned on. And we can figure out what genes need to be turned off and turned on based on our genome-wide screening capabilities that we have, and then once we have that, it is a matter of finding the small RNAs that will work to turn off or to turn on the gene, depending on what you need to do. Once you have those, you have those banked in a library. Data is data, and you make the molecule. And then the last question is, how do you get it in to the cell? If it is pancreatic cancer and if they are doing surgery, you can get it into the local environment that way. That has always been sort of the issue (the delivery), but I really do believe that we will see this in the next 10 to 20 years. I’m optimistic, though. JB: I think your optimism is well-framed, and I think this concept that some of these are heritable and how that will be seen as another way of modulating the health of future generations-these are very powerful concepts that you are discovering. Congratulations, I saw that for 2009 you have been awarded an Astor Fellow at Oxford. That is certainly another indication that your work is being seen as meritorious and having value. It sounds like your future to make real contributions in this area is very rich. KM: Well, let’s hope so. I mean, I take it day by day. Yes, the Oxford Fellowship is very nice. There are some great folks over there and it will be a nice time to go over there and visit and teach about some RNA-based regulatory mechanisms. We’ll see. As the Chinese proverb says, the future is difficult to predict. JB: We wish you the very best and we thank you so much for spending some time with us. This has made available to a large group of clinicians a topic that otherwise they might have been pretty intimidated about, so thank you so much. KM: Thank you, Jeff. We thank Dr. Morris very much for his extraordinary job in making a very complicated topic understandable. As you know, I was talking (as an example) of environmental agents that can modulate epigenetic and genetic signaling in an earlier section of this issue, the vitamin A and vitamin D connection. I was talking about the necessity for providing adequate levels of vitamin D to meet the needs of the individual such that the blood level is somewhere in the range of about 40 &ndash; 50 nanograms per milliliter of the 25-hydroxyvitamin D, kind of a standard test that we should be doing to evaluate vitamin D status in our patients. We also recognize that excessive levels of either vitamin A or D can tip us on the other side of the curve and produce adverse effects. We can’t assume that just because it is a nutrient that if a little is good more is better. We need to be in that zone of proper optimal function, and for vitamin D that is somewhere around, apparently, the 40 to 50 nanograms per milliliter level of the 25-hydroyvitamin D in the serum.

 In Closing: Articles on Coenzyme Q10 Supplementation and Statin Mypopathy

One of the other interesting associations between supplementation of nutrients and function that is emerging is the coenzyme Q10 association with statins. Recently, there was an article in the Harvard Health Letter (in their September 2008 issue) about the coenzyme Q10/ubiquinone relationship to mitochondrial function, the powerhouse of the cell.17 It is recognized that taking a statin lowers coenzyme Q10 as a consequence of interruption of its biosynthesis. In this article, the author says taking a supplement increases blood levels of coenzyme Q10 if it is a bioavailable form of coenzyme Q10, but the effect inside muscles is inconsistent. Whereas one study showed an increase of co-enzyme Q10 in muscles after supplementation, another showed a decrease, indicating that the form of Q10 may be very important in establishing its efficacy. More to the point, they go on to say that only two trials of co-enzyme Q10 for statin-induced muscle problems have been published up to this point [in 2008]. Since then, we have seen a number of other studies that have been published that once again reaffirm the value of supplementation of coenzyme Q10 when people are taking statins as a conditionally essential nutrient, meaning that it is essential on the condition that they were interrupting the synthesis in their bodies of co-Q10 due to the taking of statins, and that this seems to correlate with lowered Q10 levels and increasing risk to myopathy, one of the major side effect of statin supplementation. Recent studies that have been looking at this in greater detail include a very interesting paper that was published in 2008 in Current Opinions in Rheumatology titled “Genetic Predisposition to Statin Myopathy.”18 In this particular paper the authors ask, why do some people appear to be more susceptible to statin myopathy than others? And they did find a genetic analysis for variants and disease-causing mutations relevant to statin myopathy seem to provide a better understanding that there are some people who are more likely to get myopathy from statins as a consequence of the effect it has on mitochondrial energy metabolism, and that they are these kind of yellow canaries who first show apparent functional Co-Q10 insufficiency. The concept is finding the right patients, giving the right dose, and making sure it is a bioavailable form. In a more recent paper, researchers looked at the effect of ubiquinone/co-enzyme Q10 on myopathy in statin users.19 This was published in Current Opinions in Lipidology in 2008. Here was kind of a meta-analysis of looking at studies that have been published on supplementation of coenzyme Q10 showing that bioavailable forms do increase blood levels, tissue levels can vary from patient to patient based upon their individual absorption and transport properties, although the overall evidence from the literature does not support coenzyme Q10 supplementation in statin-induced myopathy, says the paper, there are those notable exceptions where people seem to have had a very remarkable response to co-Q10 given at several hundred milligrams a day of a bioavailable form in the reduction of their myopathy. And then lastly, the most recent paper is one titled, “Coenzyme Q10: Is There a Clinical Role and a Case for Measurement?”20 In this particular paper in Clinical Biochemical Reviews, the investigators go on to say that coenzyme Q10 is an essential co-factor in mitochondrial electron transport, and that measuring blood levels of Co-Q10 might help us to understand those patients with myopathy that would be potentially candidates for Co-Q10 supplementation, and then supplementing them in a dose-response relationship, titrating their need with a bioavailable form of Co-Q10 to bring their plasma level up, their tissue levels up, and to monitor their symptoms, might the best way proceeding on therapies. So they come to the conclusion that there is individual variation in Co-Q10 absorption and utilization, but correlating the clinical symptoms with the plasma Co-Q-10 levels might be very helpful in defining those patients more likely to respond to Co-Q10 supplementation. In closure, what have we said this issue? We have said that there is genetic variability, there are environmental modifiers, and that one size doesn’t fit all. When we are doing a supplementation program, it should be more of a therapeutic intervention, individualized to the person, but we need to start with a good diet that is rich in an array of phytochemicals and delivers low glycemic load and has an effect on normalizing these hormones that are involved with inflammation signaling. I think with all of this packaged together, we can now start to explain some of the molecular interactions at the cellular level that give rise to gene expression patterns and emerge the first steps towards, really, the definition of a personalized functional medicine. Thanks for being with us. See you next month.

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Welcome to Functional Medicine Update for the April 2009 edition. In this issue, we are going to be focusing on what has been termed “integrative functional medicine,” a concept that may be coming into its own as we move through this extraordinary period of healthcare revolution that we are in as we witness the opening up of the next chapter in the history of health sciences and healthcare delivery. In 2005, in the Textbook of Functional Medicine, I wrote a preface, which I think–as I look back now–embodies much of the conceptual framework that we are now describing and discussing pertaining to how the future might look for health care.1 I said clinicians who focus on the management of complex chronic disease have not chosen an easy path and we all know that. It is a complex field that requires diligent work and it is not easy. In the Textbook of Functional Medicine, we describe an approach to improving patient outcomes across a wide range of chronic health conditions through careful analysis of common underlying pathways that interact to produce disease and dysfunction or health and vitality. Outstanding is the content that has been contributed by many experts in the development of this concept-this systems biology approach towards health care. The approach to disease management and health promotion described within the concepts of functional medicine represents the evolution of this model over the past, now, nearly 18 years, through the voices of its leaders. In this preface I wrote, “Functional medicine reflects a systems biology approach to health care: a comprehensive analysis of the manner in which all components of human biological system interact functionally with the environment over time. Over the past century, biology and medicine have focused heavily upon understanding the physiology and biochemistry of individual organs, cells, and molecules. Traditionally, researchers and clinicians have explored one component of various biological systems at a time. In clinical practice, this process usually leads to the differential diagnosis [the driving force for much of our medical education to become a better diagnostician]. In drug discovery, it helps us to understand how individual, new-to-nature molecules, or new compounds, interact with a specific drug target to modify human physiology. From these investigations has emerged an exceptional knowledge base [that we call the medicine of our past–certainly the patent medicines of the past 70 years]. We are now poised to comprehend the common underlying pathways of health and disease as never before.” The new tools of molecular biology, and molecular science, and ultimately cell physiology examine what we call energy and medicine. Looking at things like nuclear magnetic resonance and various types of very sophisticated imaging has given us a new view of the body. In the Textbook of Functional Medicine, I continue, “We can acknowledge that most diseases that we diagnose are rarely the result of a single physiological problem localized to a single organ. Rather, most chronic disease results from the complex interactions of multiple organ systems and multiple physiological and biochemical pathways with the environmental influences and genetic predispositions.” This knowledge demands a new clinical approach to prevention and treatment that is framing where we are going in 2009 and beyond. Two challenging questions have stimulated the development of functional medicine: How are the body’s physiological systems linked together and how is their function influenced by both environment and genes (the interfacing of those two)? The recognition that these two questions are inextricably linked to each other has become much clearer with the discovery that the human genome contains far fewer genes than expected, and that much of our biological uniqueness is related to the “non-coding” region of the genome-the region that controls systems of gene expression. In essence, we’ve learned that our complex phenotype cannot be adequately understood by exploring one gene at a time (although we recognize, now, that exploiting one gene at a time can lead to a drug development process for remediation of a specific endpoint, but it doesn’t apply to a systems biology understanding of the dysfunction). Systems of genetic expression give rise to our biological complexity, and they need to be understood from an integrated perspective, hence integrative functional medicine, as a term. Health care is an enterprise focused on the alleviation of human suffering caused by disease and dysfunction. Disease, at the start, is a functional impairment (we call it a dysfunction) that, if left untreated, becomes a diagnosable disease that later can become the cause of death. Each disease has a past, a present, and a future tied to the progressive loss of function and vitality. In 1980, Dr. James Fries, professor of medicine at Stanford, authored his landmark article that appeared in the New England Journal of Medicine titled “Aging, Morbidity, and Natural Death,” and the loss of function was what he called the loss of organ reserve.2 This functional systems biology approach to understanding the origin of disease is now being encouraged by the National Institutes of Health under a program that was started by Dr. Zerhouni, the NIH Roadmap, as a route to accelerate discoveries that will improve health.3 We are now starting to see cross-disciplinary work recognizing that the only answers that will really be meaningful in solving these complex chronic diseases are those of a systems approach that integrate different knowledge bases and different experiences. Three characteristics define the systems biology approach to medicine: emergence, robustness, and modularity. Emergence represents the specific characteristics that are displayed in a complex system that are not demonstrated by its individual parts. In functional medicine, we call this web-like interconnections of physiological processes and biochemical pathways that give rise to networks. Robustness is the ability that complex biological systems have to maintain homeostasis in the face of changing environmental conditions; in functional medicine, we call this homeodynamics: the greater the degree of physiological freedom within an individual, the more robust their health and the more ability they have to accommodate change. Modularity refers to a system that is comprised of functional units working together to produce an outcome that cannot be produced by any of the units working independently. An example of this concept of functional medicine is a view of the immune, endocrine, and nervous system as one super system: the neuroendocrineimmune system. Only by working at the system level as a whole, and not at each of its units in isolation, can the practitioner fully understand the complex presentation of multiple signs and symptoms that a patient often exhibits upon presentation. We now recognize in excess of 75{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of healthcare expenditures are for the treatment of chronic disease and most physicians are not adequately trained to deal with these complex problems.4 In functional medicine, it is the conviction that developing a healthcare system that effectively manages and prevents chronic disease will depend upon our ability to apply this systems biology approach to medicine. Functional medicine incorporates many aspects of this approach, each of which plays a vital role. Identifying and following biomarkers of function that can be used as indicators of the onset of disease and also as markers for the success of intervention is an extremely important activity in functional medicine. Using a patient-centered rather than a disease-centered model emphasizes the importance of eliciting the patient’s story and incorporates mindfulness in the narrative tradition. Recognizing that the extent and severity of chronic conditions in middle to late life are, to a large extent, the outcome of environmental insults received at any point from conception forward, allows for a focus on long-term prevention to be integrated into clinical practice. Harnessing the healing power of the mind-body interaction is also important to functional medicine clinicians, as developed from scientific progress in the field of psychoneuroimmunology. The Origins of Functional Medicine In looking back at the history of medicine in the 20th century, the origin of the concept of function can be credited, in a large degree, to people that we have talked about over the years in Functional Medicine Update, such as Dr. Hans Selye. His pioneering work related to the functional endocrinology of what he termed stress and its relationship to chronic disease as diverse as peptic ulcer, hypertension, and heart disease, carried a new medical model for a disease arising out of dysfunction, rather than from infectious organisms or inborn errors of metabolism. He put a physiological mechanism behind the concept that “it is more important to know what kind of a person has a disease than what disease a person has,” as was so really beautifully stated by William Osler.5 Voices from all aspects of our society are now merging into a unified call for this new model to address chronic health conditions. In a 2005 article in the New England Journal of Medicine, it was pointed out that children being born today may be the first generation in the history of the United States with a lower life expectancy than that of their parents. This prediction comes at a time when the United States spends nearly 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} more per capita on health care than any country in the world, but is now seen-as a World Health Organization outcomes measure-as 37th in the world in terms of health outcomes.6 Functional Medicine is an Effective Response to Call for a New Model: An Epic Week of Healthcare Policy Meetings We are living in a very interesting time. Functional medicine is an effective response to this call for a new model of care. It was born out of collaboration among clinicians of many disciplines and specialties-clinical laboratory specialists, health science researchers, health educators, health policy professionals, and healthcare administrators-to address the rising incidence and cost of chronic disease. Over the past 15 years, functional medicine has become an experienced voice in these discussions. As we move into this issue of Functional Medicine Update, we have just completed, in late February of 2009, an epic week of healthcare policy meetings on Capitol Hill in Congress, and at the executive branch of our government. Reforming the United States healthcare system–implementing an effective approach to chronic disease–has become a very, very big call to action. One of the meetings in Washington, DC the Summit on Integrative Medicine and the Health of the Public, was sponsored by the Institute of Medicine, a branch of the National Academy of Sciences, and co-sponsored by the Bravewell Collaborative. This summit took place February 25-27, 2009, and was chaired by Dr. Ralph Snyderman, President Emeritus from the Duke University Medical School.7 At this three-day colloquium and summit, extraordinary discussions were held among people from a whole variety of backgrounds. The singular mission of the meeting was to find more effective ways of delivering health to the country. The keynote address by Senator Tom Harkin from Iowa, the third-ranking member of the health committee in the Senate, gave us a call to action in which he quoted from a speech given by Dr. Mark Hyman earlier in the week at the Senate Committee hearing Dr. Hyman said, “It is time to change not only the way we do medicine, but the medicine we do,” which is a wonderful quote that Senator Harkin picked up on and incorporated within his talk, with appropriate attribution to Dr. Hyman. We are at that interesting cornerstone-that nexus, that inflection point, that opportunity point-when great things can happen. Some people say these things occur only once in a century (these moments of great opportunities for change) when everything is poised for a tipping point. It is certainly the case right now, given all the various events that we have seen in our world community over the past year, and certainly it focuses on healthcare reform as well. Many years ago, Lewis Thomas, ex-editor of the New England Journal of Medicine who was a wonderful medical writer as well as a clinician/doctor, as you probably recall, authored a Pulitzer Prize-winning book that talked about the nature of medicine and the nature of biological sciences: The Medusa and the Snail.8 Another book that he wrote in 1983 didn’t receive quite as much attention, but I though was an extraordinarily important book and was titled The Youngest Science, in which Dr. Thomas described how medicine was evolving from a descriptive science where a disease diagnosis was the most important feature of medicine, to a preventive science based upon understanding the etiology of disease.9 He predicted in this book that by the end of the 20th century or the start of the 21st century, biomedical sciences would have discovered enough about the origin of chronic disease to treat early causes of the disease and not just its late-stage effects, based on understanding the mechanism of disease. Dr. Thomas’ prediction has proven to be largely correct. Over the past 30 years, the underlying physiological dysfunctions that give rise to later disease have been discovered and we are witnessing a transition in medical thinking from that which is reactive (i.e. pathology-based medicine) to that which is proactive (i.e. prognostic-based medicine) and based on an understanding of the early alterations in physiological function. The emerging understanding of the origin of chronic diseases is that they result from a complex interaction, as I have said, between the genetic uniqueness of the individual and their lifestyle and environment. Chronic disease is, therefore, the translation of an alteration in physiological function in the individual that reflects the translation of genetic susceptibilities through exposure to specific lifestyle and environmental factors. Statement by Senator Edward Kennedy We are really at a very interesting time of change. Senator Edward Kennedy, who is the chairman of the committee of the senate that looked at the relationship of health for the future of the country (this is the United States Health, Education, Labor, and Pensions Committee) issued a statement about integrative medicine as a vital part of the new healthcare system.10His statement covered much of what we have just been talking about. The American healthcare system urgently needs repair and reform. As a nation we are spending 16{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of our gross domestic product on health care (more per capita than any other country in the world), yet health outcomes of Americans, as Senator Kennedy points out, are ranked 37th in the world. Our system is often called a sick care system, not a healthcare system because it is designed to treat disease and illness instead of promoting good health. Paraphrasing from Senator Kennedy’s statement, he said, “Genuine health reform, therefore, requires a major transformation in our national mindset of how we care for ourselves and others. It must incorporate and encourage disease prevention activities and lifestyle changes that promote long-term health and well-being. The current incentives in our health system that lead to overtreatment and mistreatment must be changed to promote high quality, appropriate, and coordinated health care. The nation’s alarmingly high and growing rates of obesity and chronic disease today are a clear call to action. By preventing diseases before they start and adopting a broader approach to medicine we will actually reduce costs in the long run, and will extend and improve the quality of life as we do so. To achieve this fundamental shift in the nation’s healthcare mindset, it will be necessary to reform how medicine is practiced. Low cost or even free health screenings and vaccinations will encourage individuals to take part in preventive medicine. Patient-centered and coordinated care that addresses the whole person, from genetic predisposition, to lifestyle choices, to potentially harmful conditions is essential for treating acute diseases and managing chronic conditions. We must adopt a more integrated approach to medicine through health care that addresses the mental, emotional, and physical aspects of the healing process.” This is just a small part of Senator Kennedy’s statement. We are at that extraordinary time where these great changes can occur, it is necessary they occur, and integrative functional medicine may take its seat at the table and make contributions to this healthcare change. Our clinician of the month this month on Functional Medicine Update could not be a better choice for carrying this message. You’ll hear, from his own voice, about his years of experience in developing what I consider a true integrative functional medical practice, and about his advocacy as an academic medical person in charge of a department that is delivering this at the University of Texas Medical System. The concept of genetic polymorphisms (or the diversity that Roger Williams talked about in the late 1940s and early 1950s) is now starting to gain a foothold in not only pharmacogenomics and how different people respond to drugs, but also relative to how people with differing genotypes respond to environmental exposures and to diet. In fact, there are so many papers being published in the area of nutrigenomics now that it is virtually impossible to keep up each month with the expanding body of literature. As an example, a paper was recently published looking at the role of various genetic variants in how methylenetetrahydrofolate, or a form of folic acid, and choline are metabolized as it relates to their impact on blood homocysteine levels.11 In this paper that appeared in theJournal of the American Dietetic Association in 2009, it was reported that certain single nucleotide polymorphisms (SNPs) in the phosphatidylethanolamine N-methyltransferase enzyme (the genes that control the production of that enzyme), and also methylenetetrahydrofolate dehydrogenase SNPs, influence the biomarkers of choline metabolism, and particularly are seen when folate intake is restricted, with much more significant increases in the blood levels of homocysteine. This is not simply treated by giving folic acid supplements; one needs to also give higher levels of choline, as well, in order to overcome these metabolic, I guess you would call it, “tight spots” that relate to these single nucleotide polymorphisms of the phosphatidylethanolamine N-methyltransferase genes. I think we are starting to witness that one size doesn’t fit all in nutrition any more than it does in drugs. When we start to really look at various patterns of response and susceptibilities, we have to take into account these families of genetic uniquenesses. The so-called genome-wide association studies (or GWAS) studies that are being used now for evaluating SNPs that might be associated with increasing susceptibility to disease are starting to help us understand that it’s not that genes in and of themselves cause disease, it is that the genes in and of themselves determine the response that we might have to our environment and how genes are expressed that give rise to their phenotype. We can’t change the genes, but we certainly can change the environment that the genes pick up the message from Let me, if I can, take this to another step of clinical application, and that has to do with statin therapy and one of the adverse effects that is seen of statin therapy, which has to do with muscular signs and symptoms, neurological issues, and, in the extreme case, severe problems of muscle atrophy (rhabdomyolysis). As we recognize, the extreme case is very infrequent, but there are much more mild cases of adverse response to statins that are seen. They are not seen in all individuals, and, in fact, by changing from one statin drug to another, you often are able to modify response in that patient with the adverse symptoms. This suggests that the concept of a class effect of a drug may be a little bit of a misunderstanding–that different molecules have different effects of gene expression, and therefore we can’t say that because it is a member of a class called statins that it has the same exact physiological response in the body, depending upon that person’s own genetic uniqueness. However, we do know that one of the potential adverse effects that statins (as a family of HMG-CoA-reductase inhibitor molecules) has, is lowering the sterile biosynthesis that goes through isoprenoid polymerization and biosynthesis that has, ultimately, to do with other molecules that are being built by that same pathway, such as coenzyme Q10 (or ubiquinone). Low Levels of Coenzyme Q10 as a Contributing Factor to Statin Myopathy There have been longstanding questions as to whether the low intracellular and plasma levels of coenzyme Q10 that are seen in patients who take statins are, in fact, the contributing factors in some of the musculoskeletal problems that are associated with adverse response to statins. A number of papers have been published over the years trying to make some kind of a correlation between statin use, coenzyme Q10 levels in plasma, and the clinical adverse effects of statins. Recently there have been many more studies published on this that help to enlighten us as to this relative interrelationship. I’d like to take you through some that I think are quite fascinating. Genetic Predisposition to Statin Myopathy The first paper has to do with genetic predisposition to statin myopathies. It now appears that these conditions of adverse effects to statins are not seen in all people, but rather there may be certain genotypes that are more susceptible than others. In a recent paper that was published in Current Opinions in Rheumatology titled “Genetic Predisposition to Statin Myopathies,” the authors say that technological advances have now made it possible to identify genetic variations in the human genome through GWAS (genome-wide association studies) that reveal disease-related mutations in single nucleotide polymorphisms that are associated with more risk to specific diseases.12 More than 30,000 individuals in the United States, this article goes on to say, suffer from severe life-threatening symptoms of statin-induced myopathy that may, in some cases, persist long after the secession of therapy. That was a number that was quite surprising to me-30,000 individuals suffering from severe life-threatening symptoms of statin-induced myopathy. Genes of interest include those involved in the pharmacokinetics of statin response (muscle atrophy, exercise intolerance, pain perception, and mitochondrial energy metabolism). These researchers have just completed a genetic analysis for variants that relate to this station myopathy that provides some understanding of predispositions that might then lead to individuals being at higher risk to adverse effects to statin medication application. This has to do with things like carnitine palmitoyltransferase 2 deficiences and a range of other SNPs (single nucleotide polymorphisms) that go on to potentially define individuals that may have increasing risk to myopathic outcomes. Is it one gene or is it a family of genes? The answer is obviously the latter. The genes that they have defined in this particular paper that seemed to come out with higher prevalence include various types of cytochrome P450 polymorphorisms of cytochrome P4502C8, 2D6, and 3A5, as well as metabolic muscle-related genes like CPT2 and AMPD1. And then other things like nitric oxide synthase 3 and APOE4. So there are a whole series of genes that appear to be associated with the increasing risk to statin myopathies; these are the various SNPs (the single nucleotide polymorphisms). In screening for patients who might be at risk to myopathies as a result of statin therapies, one would then form a cluster of gene SNPs that you would analyze to determine a relative risk factor. I think this is the way we are starting to see pharmacogenetics infiltrate its knowledge base into that of clinical practice and clinical medicine. The Issue of the High Cost of Screening At this point, one would ask, what is the relative prevalence of these SNPs that are associated with increasing susceptibility to adverse effects to statins? Is it very miniscule prevalence, or is it prevalence of high enough impact that we would be concerned across the board and want to do screening? In other words, is it cost effective to do screening? (Because it is an expense, obviously, to do SNP testing.) Or do we just take it as an outlier that is such a small frequency of individuals that we can’t really justify the expense? These are very, very complicated questions in medical decision-making, aren’t they, when we start asking how much expense is a system willing to bear to screen for those individuals who might have an adverse response in or to protect those individuals? We don’t really have hard and fast rules as to how to make those decisions, and that’s part of the uncertainty as we start developing this understanding of genetic variation and individual response as to what is justified in terms of cost for doing screening. Once we ask that question, then the next question (which further complicates the issue) is, does coenzyme Q10 intervention play any useful role in either preventing or even managing myopathy in statin users? Of course, this is another controversial area for which no hard and fast rule has emerged either. There is, however, some interesting recent research that has been published in this area that I think is noteworthy for consideration. One of these papers appeared in the Current Opinions in Lipidology journal in 2008.13 This paper looked at the effects of coenzyme Q10 therapy on myopathy in statin users. This was a review summarizing the current evidence on coenzyme Q10 supplementation. The conclusion was that present evidence did not support supplementation in statin-induced myopathy because they could not find statistically significant meta-analysis justification for Co-Q10 oral supplementation to ameliorate statin-induced myopathies. One can be a little bit-I would say-confused in how to interpret this data because the question is did doing a meta-analysis stratify for the appropriate people who might be most sensitive to Co-Q10 supplementation? Did it look at the right levels of Co-Q10 supplementation, knowing that these studies have a variety of different dosage levels, from 100 to as much as 600 milligrams a day? We know that in patients who have various types of mitochondrial encephalopathies, like MELAS (Mitochondrial Encephalopathy Lactic Acid Syndrome), that these individuals have low muscle Co-Q10 concentrations. Supplementation with 250 milligrams per day of Co-Q10 was found to have some positive influence on clinical symptoms in these patients with this metabolic inborn error of metabolism that we call mitochondrial encephalopathy. These patients can end up with various types of myopathies that resemble rhabdomyolysis, although they have slightly different etiology. One might say, “Well, gee whiz, then giving doses of 200 milligrams a day of Co-Q10 with a patient on statins should be adequate.” Studies did not seem to show a positive effect when patients were given simvastatin and got 80 milligrams of Co-Q10 a day; there wasn’t a clinically significant improvement in reduction in myopathies. Maybe 80 milligrams is the wrong dose, maybe we need a higher dose, or maybe we need to look at individuals with unique types of sensitivity because maybe myopathies come from a variety of different mechanisms, only some of which are related to the statin issue. Let me go to another review paper. This is titled “Coenzyme Q10: Is There a Clinical Role and Case for Measurement?”14 The question is: how low is the serum or plasma level of Co-Q10 that would be correlated with the therapeutic dose required to modulate myopathy? This appeared in Clinical Biochemistry Reviews in 2008. I think this is another interesting contribution to our advancing knowledge in this area. We consider coenzyme-Q10 to be an essential cofactor in mitochondrial electron transport that has to do with establishing proper redox control (reduction-oxidation control) within the mitochondria. It is also known to be an intermediate that is biosynthesized in the body. Coenzyme Q10 is not considered an “essential nutrient,” but might be considered a conditionally essential nutrient, meaning that if a person has insufficient biosynthesis to meet their needs, that they might need augmented levels from the diet in order to make up the gap (fill in the gap). That is the justification, then, for Co-Q10 supplementation in times where a person is consuming statins and inhibiting Co-Q10 biosynthesis. Being endogenously synthesized via the mevonalate pathway, we now recognize that although some is obtained from the diet, most Co-Q10 in people is synthesized directly in situ from the same pathway that goes on to produce squaline lanosterol and ultimately into cholesterol itself. If an individual, then, has a low plasma level (or serum level) of Co-Q10, does it then indicate that they have a poor synthesis of Co-Q10? This paper really looked at that correlation between serum levels of Co-Q10 and whether that is an indicator of low intracellular Co-Q10 levels, meaning it is a surrogate marker for a reduced mitochondrial sufficiency of Co-Q10. The authors of this article went on to say that it appears as if (from the data accumulated to date) that there is a correlation of some reasonable significance between low serum Co-Q10 levels and that of insufficient Co-Q10 in mitochondrial functional states to regulate redox potential within the mitochondrion. These can be further aggravated, obviously, through specific polymorphisms of genes that have to do with the electron transport chain, like Factor 2, where Co-Q10 plays a very important role, or cytochrome oxidase, in the mitochondrial oxidative chemistry. So some individuals may be at much higher risk than others, and a number-a plasma level or serum level of Co-Q10-may not give the full story, depending upon that individual’s own sensitivity and how that reflects oxidative stress at the cellular level. With all of this in mind, what it leads us to recognize is that Co-Q10 certainly seems to have a suggested benefit when orally taken as a supplement during times of statin therapy, somewhere between, say, 100 milligrams or 200 milligrams a day. One needs to be concerned a little bit about the bioavailability of the Co-Q10 formula. Some formulas have been found to be much more bioavailable than others. Clearly it has to get into the body in order to do some good. If it is a non-absorbable form, it won’t promote the appropriate improvement in plasma and cellular levels. Co-Q10 can be measured in the body, so bioavailability studies can be done and should be done to demonstrate the increase in plasma levels after oral consumption. The better brands of the product have this kind of data associated with it. I found it interesting that in the question and answer section of the Harvard Health Letter in 2008 (the September issue), a question was posed: “Why don’t you tell readers that everyone who takes a statin should be taking coenzyme Q10 as well?”15 The response says that taking a statin lowers coenzyme Q10 because it is carried through the bloodstream in LDL. Lowering LDL-the main job of statins-means less Co-Q10 in circulation. It has been hypothesized that statin effects of Co-Q10 might account for muscle aches and pains from these drugs, however statins don’t appear to affect Co-Q10 inside cells or mitochondria. Taking a supplement increases blood levels of Co-Q10, but the effect inside muscles is inconsistent, with one study showing an increase in Co-Q10 after supplementation, and another a decrease. More to the point, the only two trials of Co-Q10 for statin-induced muscle problems contradict each other. It is possible that Co-Q10 supplements may prevent statin-associated muscle problems in people who don’t take enough Co-Q10, or who are at risk for muscle damage due to hypothyroidism or pre-existing muscle disorders It is hoped that clinical trials will be conducted to explore this. For now, though, there is no credible evidence that everyone who takes a statin should also take Co-Q10. That’s the position that the Harvard Health Letter has taken and I think it probably summarizes my point. There is one other fat soluble vitamin that I think we should also be thoughtful about that relates to this heart healthy connection, and that’s vitamin K (menaquinone and phylloquinone) . A very interesting series of papers has been published over the years about vitamin K and its relationship to cardiovascular disease. The most recent paper I am aware of appeared in Nutrition Metabolism and Cardiovascular Disease in 2008 and is titled, “A High Menaquinone Intake Reduces the Incidence of Coronary Heart Disease.”16 We often think of vitamin K as a blood clotting nutrient helping to regulate blood clotting factors, but it also seems to have impact on other aspects that relate to vascular calcification and heart health thereof. I would put vitamin K as an important part of our assessment of nutrients and cardiovascular risk. Obviously, I would also still continue to put vitamin E on that list, knowing that vitamin E (as an antioxidant) does have effects on mitochondrial oxidative chemistry. It (along with Co-Q10) helps to protect against free radical injury, and there are studies that have at least suggested that a combination of vitamin E and Co-Q10 might produce benefit in protection against myopathies of statins beyond that of Co-Q10 itself. I think we are starting to see some very, very interesting clinical clarity being brought to this question about the pharmacological effect of statins on Co-Q10 biosynthesis and that influence on myopathies. Again, the concept of genetic uniqueness, and polymorphism starts to play a role. Let me, if I can, summarize what I’ve tried to give you here in this rapid-fire introduction. What I have tried to say is that we are undergoing a transition in basic biological sciences and our understanding of how it relates to medicine, health, and disease, that is second (probably) to the revolution that occurred at the turn of the last century. This paradigm shift is really a remarkable sea change as it pertains to how we understand physiological function as a network of differing interacting variables that give rise to cross-organ changes in function, ultimately expressing signs and symptoms that we categorize as diseases that are all interconnected through similar mechanisms. I went on to say that genetic polymorphisms (or a variety of these kinds of SNPs) may determine relative risk to certain types of conditions, either both gain in function or loss in function types of responses. We often think of SNPs as only being harmful, but actually the maintenance of single nucleotide polymorphisms in our genome may reflect the legacies that we have within our genetic diversity that have helped certain populations to protect themselves against certain conditions in the changing of their environment, like starvation or infection, where certain SNPs were selected for in times gone by. So what we might consider today to be a disadvantageous SNP, might (at one time) have been actually advantageous for survival for the people carrying it. We recognize that SNPs can impart either gain in function or loss in function depending upon the environment to which they are being exposed, and we start to see that SNPs express themselves in families (it is generally not one SNP at a time, but it is rather these nucleotide polymorphisms that cluster themselves together to give increasing risk). I also talked about the homocysteine connection. Maybe homocysteine is just a marker for a whole family of different uniquenesses that relate B6, B12, choline, phosphatidylcholine, and folic acid and its conjugers that, then relate to regulation of vascular dynamics and immune function. Lastly, I’ve kind of finished this up by talking about what happens if you pharmacologically modulate or modify normal function (like the statin examples with myopathy), and can you then use a conditionally essential nutrient to back fill in the area of function, knowing that different genotypes may respond differently with different relative susceptibilities? This medicine that we are seeing emerge today is much more complex than that which we probably learned as a memorized list of diseases and presenting signs and symptoms, with a specific drug to treat each of those diseases. What we are really being given is a chance to look at a variety and how it influences the function of organisms in a positive way-this is a new functional medicine model. With that, we are going to have one of the pioneers in functional integrative medicine talk about their clinical reality, Dr. Victor Sierpina

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Mont Victor Sierpina, MD Professor Department of Family Medicine The University of Texas Medical Branch 301 University Blvd Galveston, TX 77555-1123 Many of you ask me about this section of FMU, which is our clinician/researcher of the month section. You’ve made comments like, “Wow, we’ve been so fortunate to get these opinion-leading, pace-setting, visionary researchers who are really charting the new biology that is underpinning medicine.” But then the parenthetical question is: why can’t we have a little bit more of the clinical how-to, or the people who have their fingers in the exam room more, who really are the people doing the work? It is a balance between the biology of the new medicine as well as the practice of the new medicine. I’m honoring that by having someone who I would consider, from my experience, probably the top of the class in this area of delivering the medicine in a humanistic, compassionate, intelligent, wise, and balanced way, and that is Dr. Victor Sierpina. Let me give you a quick introduction to Victor. If you are in our field, you probably already know the name or even know him personally; he is very noteworthy. Quickly, to just review his background: Dr. Sierpina has a BS in biology from Arizona State and then later an MD from the University of Illinois. He went into a family practice residency, and then ultimately went on to do all sorts of postgraduate work, including body/mind training and acupuncture training. He went through many years of work, academic study, scholarship, contribution, and clinical work, and now is at the Department of Family Medicine at the University of Texas Medical Branch at Galveston. He is a professor-the WD and Laura Nell Nicholson Family Professorship in Integrative Medicine. He is one of the leaders and has just come off the Chairmanship of the consortium of medical colleges that are dealing with integrative medicine in some fashion in their curriculum. More than that, I would say Vic is just a doctor’s doctor. He is really very, very balanced and very capable of doing what we call integrative medicine and finding the right tool for the right application. With that introduction, Dr. Sierpina, it is wonderful to have you as a guest on Functional Medicine Update. Let me ask, I guess, the question that always starts any one of these interviews: what is the path that ultimately led you to your integrative medicine interest from family practice? VS: Thanks, Jeff, for that kind introduction. Early on my family was always interested in nutrition and home remedies and such. As a child of the 60s, and growing up in that era (I was in high school and college during that period of time), there was a lot more focus on natural remedies and things that were kind of outside of the mainstream. As my friend, Mark Blumenthal, said, “We went through the 60s and never exhaled,” which is one of the ways that we changed our minds about how the world looks. During that period I started to become more interested in realms such as mind-body and spirituality, as well as more natural approaches to health care that I had kind of been exposed to as a child. JB: As this happened, and knowing that your path has been really not only clinical but also academic medicine, I’m sure you probably raised the eyebrows (or looks) of some of your colleagues. When was your first sense that you were going to be put under a different level of scrutiny, or maybe you haven’t had that experience and it’s been a smooth transition? VS: Well, it has had its rocky points, that’s for sure, but it hasn’t been nearly as bad as people might have expected. I was in private practice for about 15 years prior to coming to academia. I worked as a medical director at an urgent care center in the Chicago area, did home births, worked at a holistic center there, and then ultimately started a solo practice in the mountains of Colorado. During this time I did acupuncture, mind/body work, and herbs/supplements/nutrition as part of my practice. When I came to the university and decided to go into the teaching field it was because I enjoyed teaching so much (in Colorado I taught the ambulance crew and the ski patrol crew, both of which I was medical director of, and I realized how much I liked that). So when I came to Texas I thought, “Well, I’m going to just keep practicing like I did, and this is what they hired me to do.” And nothing was too exciting until people started noticing that I was doing acupuncture; all the rest of my armamentarium of treatments wasn’t nearly as exciting, apparently, to people as acupuncture. That seemed to be a marker that let a lot of people here in Galveston (which is actually a very liberal community) kind of come out of the closet about their interest in everything from Reiki, therapeutic touch, traditional Chinese medicine, botanical medicine, etc. The fact that a physician was doing these practices… people that were researchers, nurses, other physicians, felt like they had somebody kind of as their point person to talk to and say, “Well, he’s doing this and we want to hear more about it.” So that was back, gosh, in ’97, ’98, and so I kept getting invitations to talk about the range of things, so although there were certainly some skeptical faculty, by and large people recognized this was a trend among the public and there was some validity in some of the services that I was offering that they weren’t doing yet. JB: So as you have moved forward, obviously you have been very successful in building a team and also in getting funding. I know that you have been a recipient of at least two NIH grants supporting what is going on there in integrative medicine at the University of Texas Medical Branch in Galveston, and I think you’ve got a couple of very fine colleagues, Susan Gerik and Julie McKee, who are part of your integrative healthcare center. Tell us a little bit how you built this. Funding for Integrative Medicine Research VS: Well, the first thing was an intramural grant (the President’s Cabinet Grant, here, which is a grant that is meant to seed small projects that might not get funding otherwise). I applied for that to set up a website at UTMB-this is back in the late ’90s-that would serve as kind of a clearing house for information about complementary medicine. We had faculty, peer-reviewed websites; anything that we posted on there went through our process of vetting the websites that were on our websites, so that people linked to quality materials. We licensed some databases, such as Health Notes Online, natural medicine’s comprehensive database that students would use. So that was a small grant (like $25,000), and that was kind of a nice crystal, I suppose, around which other activities were built-a journal club, a course on spirituality and healing (we got another $50,000 grant from the George Washington Institute of Spirituality and Healing-it was a Templeton Fund grant at that time). So several of those kinds of activities started to move, and then when the National Center for Complementary and Alternative Medicine said, “We’ve got to start developing curriculum in medical schools in this area,” we had a track record of several years, so we were awarded, in the first round, 1.6 million dollars over a 5 year period to initiate curriculum across not only medicine, but nursing and our allied health schools here. JB: The question that I think a lot of people have always raised is, in a very crowded medical curriculum (when people are in medical school everyone is vying for another moment of mind space of the student), how have the students responded to your opportunities? Including Integrative Medicine into Medical School Curriculum VS: The students are very open in this area. In fact, I’m kind of in a situation right now where I’m having to retool the curriculum because it is a constant maintenance project, so curriculum changes all the time. What we were able to do (you mentioned our team, like Dr. Gerik, Dr. McKee, Kara Geary, others that we have had over the years-Dr. Frenkel), that we were on various curriculum committees. When you’re on the curriculum committee, you can’t be a one-focus, one-issue person; you pitch in, but you see the opportunities. Rather than adding a whole additional course, we would take, for example, the clinical reasoning course and add cases on integrative medicine/alternative medicine topics. We’d bring in the librarian and have her drive the students in a lecture hall demonstration on how to get to websites that they could look things up if a patient came in on a number of supplements, where they could find reliable science-based information about that. We added cases (web-based cases) that the students could go through. We had some demonstrations, as well as electives and selectives later in their third and fourth years. We haven’t done as much, obviously, as I’d liked to have done, but it is that hydraulic effect, and the best approach to it, I think, and the greatest compliments we have, is that the students feel like they get enough material, but not too much, and sometimes they don’t even recognize that it is integrative because we’ve integrated it. JB: You’ve authored two recent papers, and I think just the titles alone kind of describe your skill in putting these things together and making them stand up and be valid. One is titled (from Academic Medicine last year), “Integration of the Biopsychosocial Model: Perspectives of Medical Students in Residence,” and the other was from 2007 titled “Barrier Strategy and Lessons Learned from Complementary and Alternative Medicine Curricular Initiatives.”17,18 Both of those kind of define a domain, so if we kind of take an away point, here, looking at the academic side, would you say that curriculum has shaped up enough now that it is starting to stand up and be looked at by people who may not understand it, saying “Wow, there’s really something here that we should pay more attention to?” VS: I think so. It is somewhat institutionally based. We try, through the LCME, which is the Licensing Commission for Medical Education, and our Consortium of Academic Health Centers for Integrative Medicine, to create some standards in which all medical schools would have to incorporate certain integrative medicine content into their curriculum. We were partially successful in that; they listed this area as one of the areas that medical schools now have to catalog and describe what they are doing in that area. In reference to those two articles, for example, that you referenced, the mind/body area is really an area of non-evidenced-based practice and teaching, which is to say that there is plenty of evidence for mind/body therapies, but we don’t act as if they are evidenced; they don’t fit into the medical culture. If someone comes in and they are depressed or anxious we give them a pharmacological treatment rather than some self-actuated self-care strategy that they can do (deep breathing, or meditation, or visualization). It is still outside of the culture of medicine, although when you expose students to it, particularly through personal practice, they get it and they will start using it with their patients. Some of the strategies, like I say, are just embedding curriculum within courses rather than having it as separate courses. For example, we just started (this year) a pilot program for our family medicine residency with seven other residency programs. This is hosted through the University of Arizona as a distance learning program. Residents are even busier than medical students because they take care of patients in the hospital and clinic, but we have been able to integrate 200 hours of training in integrative medicine, which includes prevention, self-care, chronic disease and acute disease management, motivational interviewing, behavioral science objectives, botanicals, nutrition, physical fitness, and so forth, across the board in the residency, relatively painlessly through online modules and short lectures, and it fits with their need to learn what they need to learn for their board exams and in training exams. So that is a strategy, and certainly the time barrier/resource barrier is always there, but if you are persistent you kind of get things done. I’ll add, too, Jeff, that we are doing a survey right now of the 42 centers that are part of our Consortium of Academic Health Centers for Integrative Medicine, of what curriculum they are all doing as far as medical school and residency. So that survey should be out sometime within the next month or so, and we are going to really have, then, a very comprehensive catalog of what people actually have been able to implement at their various schools. The Consortium of Academic Medical Centers JB: That’s a really interesting segue, Vic, because I wanted to get your, kind of, insight. I know a number of people have heard of the Consortium of Academic Medical Centers, but probably don’t know the root origin of it, or what its principles are, or what its objectives are. Could you tell us a little bit about it? VS: Back in, I think it was ’99, eight schools decided that they had some interest in this area and they had a retreat. Jon Cabot Zinn, the founder of mindfulness-based stress reduction; Andy Weil from Arizona; Jim Dolan, who was the Dean (I think) at Massachusetts at that time (although it could have been Arizona); Ralph Snyderman; and some other folks from these different schools sat around with deans of their schools and had a discussion on how this area might proceed. And during the discussion (according to the folklore, at least) the lights went out, so they had to sit around with candles and Jon said, “Well, let’s just have a meditation session.” So they left with that idea that they would try to build a sufficient number of schools with projects and interest in research, clinical, and educational areas in integrative medicine so that we would have a voice within the medical establishment. Arbitrarily, they picked somewhere around 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the schools (there are 130 medical schools now–17 in Canada, 130 in the US, plus the DO schools). We have exceeded, now, over the years, that 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} metric, so we’ve got a substantial voice in the academic setting. The schools are not only in Texas and Arizona-we have many of the Ivy League schools, such as Harvard and Yale, Duke, Stanford, and really some of the top schools in the country are part of our Consortium, as well as four in Canada. It gives us a chance to look at policy, we look at educational initiatives to research collaborations, clinical models, as a larger group, and not feel like we’re out there rowing upstream in a single boat, but it is really a rowing team. JB: I know you just finished up a tenure as…you know, probably you give the new jobs to the person that is most busy…so you got the job of being the Director of this Consortium over the year. What was the learning curve for you? VS: I’m still in that position until the end of this year, and then Adam Perlman, who is my vice-chair is going to take over; it was a two-year term. The learning curve for me is somewhat personal. When you are working with people in a very large context like this it is very important to be inclusive. I have always been a bit of an impatient, non-procrastinating person. When I see something that needs to get done I just like to charge ahead and do it. But when you are leading a large group like this, it is very important to get input from the largest number of people; to get buy-in and cooperation, otherwise you end up do everything yourself and it doesn’t go very far. JB: I notice that you’ve got some support from the Bravewell Collaborative, which is another interesting, really, I think, innovative group. Maybe you can tell us a little bit about Bravewell and the connection to the Consortium and this whole evolving movement. The Bravewell Collaborative VS: This group started, as I said, with 8 schools and then maybe grew to about 10 or 12 by 2001. At that time it was called the Bravewell Philanthropic Collaborative for Integrative Medicine; now it is just called the Bravewell Collaborative. This was a group of wealthy people who were highly committed to integrative medicine: Ken George and Bill George, who was the founder of Medtronics; Christie Mack and John Mack (he’s the CEO of Morgan Stanley; and I think about 20 other philanthropists, similarly placed across business and industry, with wealth that they really wanted to commit towards integrative medicine’s development. So among their projects-and they have a number of projects, including seeding some clinical sites, and helping, actually, with the recent Institute of Medicine Summit-was a project to support this Consortium of Academic Health Centers, which at that time was 12 schools. With their support for infrastructure (for maintenance of an office, a website, some travel, and so forth), we’ve been able to grow very quickly, now (over the last 8 years), to 42 schools from 12 schools. They have been enormously supportive-very, very beautiful people that have just strong hearts about the need to change medicine, and they really want to use the Consortium as a tool to really change the educational culture, and the content, and the process of delivery, and the way that doctors are trained at pre-doctoral and residency levels. They are most concerned about the medical school curriculum. They continue to be our partners, and we are so grateful for the Bravewell Collaborative. The Institute of Medicine JB: You’ve done a beautiful job of taking us down this path because you mentioned the Institute of Medicine Summit, which I believe is, by all accounts, kind of an epic meeting that was just completed in February of 2009, in that we were told it was the largest Institute of Medicine meeting ever held at the National Academy of Sciences. You were one of the principals in developing the curriculum and organization of the meeting. Tell us a little bit about how that connected to Consortium, Bravewell, and this whole evolving movement, and this time of great change. VS: Sure. That definitely was a capstone meeting. As you know, Jeff, there has been a series, over the years, of symposia. The original conference in this zone was the Chantilly Conference in Virginia back in the early ’90s. That seemed to be one of the things that led up to the formation of the Office of Alternative Medicine. Under the Clinton administration, the White House Commission on Complementary Medicine Policy worked to develop a report. The Institute of Medicine also published a report on complementary medicine in the United States about 4 or 5 years ago. So there has been a number of these kinds of major, state-of-the-field initiatives. It was felt to be necessary now (given the current change in political opportunities) that in changing health care, there could be some kind of a major focus that not only looked at integrative medicine from an educational standpoint and practice standpoint, but really from a potential policy change standpoint. So this was a brainstorm of the Bravewell group; they approached the Institute of Medicine-I think it has been, Jeff, a couple of years in the making-and said, “If we put together a summit on integrative medicine and public health, can we partner with the Institute of Medicine?” The Institute of Medicine, for those who aren’t familiar with it, it is a part of the National Academy of Sciences. It is not part of the government. It is purely a scholarly group. It is highly prestigious; if you are a member of that academy, you are respected by your peers throughout the world (lots of Nobel Laureates and top scientists and so forth). So the Institute of Medicine is a subgroup of that, which just focuses on medicine. Other academies, like engineering, and so forth, are there. The Bravewell folks funded (or co-funded) this with the Institute of Medicine, planned it over this period of time, and actually still has a lot of planning and outreach media follow-up in process. But the general idea was to bring people together from all areas of health care (stakeholders). They included physicians, people like us from academia (we had over 50 attendees from the Consortium, for example), people like you, Jeff, that are in the research and education realm, certainly people from insurance, from business, researchers, and we tackled about 5 major areas of health care with panels and white papers. They had kind of a vision for what health care might look like: issues of research and the science behind integrative medicine, clinical models, workforce and education, and, finally, economics. So over the two-and-a-half days, we had people from all over the world. Over 600 people attended; it was free to attend, but you had to register in advance, and they had over 200 people on the wait list because they were just oversubscribed. It was extremely well organized. I was on the planning committee. I say it was organized not because I was on the planning committee, but I saw it start from ground zero and it was just amazing how it became very interactive. The audience had a chance to participate. There were a number of breakout groups. And there will be a proceedings published in November. For people that have an interest, if you go to the Institute of Medicine website (just dial up the Institute of Medicine on Google and put in “integrative medicine”), there is a list of the commissioned papers there, the agenda, and, as of tomorrow, there are video tapes that will be posted of all of the sessions, so you can watch any of the sessions. So the Consortium played a very important role with that. Like I said, we had over 50 people, and all of the commission papers had some member of the consortium on them. We had 7 or 8 of our folks on panels or as keynotes. The summit came during the same time that President Obama is talking about the need for prevention and lifestyle change as part of the basis of good health care in this country, and on what health reform might look like. This group really brought a tremendous amount of experience and practicality to the table, and I think we’ll, hopefully, have a major influence to bring more focus on integrative medicine into the health care reform scenario now. JB: I really want to support and second your acknowledgement as to what a watershed meeting it was. You know, I’m kind of a consummate meeting-goer for many, many years, and I think it was one of the best organized and also visionary meetings that really developed collaboration among people of disparate fields in ways that I hadn’t seen in other meetings. I think what will come out of that in the monograph should be very remarkable. Simultaneously, as you know, there were the Senate hearings on integrative health care for a healthier America. Senator Harkin, who spoke at the IOM meeting on Friday was, I think, one of the most visionary…you know, kind of “integrative thinking” in his own presentation. He was one of the principals in the Senate hearing. I found it interesting and I’m sure you have as well, Vic, this point-counterpoint that we have in society, which I think is good because it kind of distills some of the debates down into a central theme. What we see is, on the other side of the house, people saying that nothing has really ever happened that is good out of NCCAM other than to prove that alternative and complementary therapies don’t work and that Harkin has been a handmaiden for unscientific medicine, and that these things are really all just taking us in the wrong direction; we should stay where we really know what we are doing and not wander off into voodoo medicine. You’ve probably seen the websites that are now propounding that this week. Do you have any thoughts about that point-counterpoint, or do you think that’s just all part of the healthy argument? Senate Support for Integrative Medicine VS: You bet. First of all, I’m enormously impressed with Senator Harkin’s vision. Just a couple of simple examples of things that he has done, besides starting the Office of Alternative Medicine: he started a program (he is from Iowa, as you), and he looked at Iowa and a few surrounding states and looked at underprivileged schools, and put together a free fruits and vegetables program for 100 schools. He had a little hassle doing that. People thought the kids would throw apple cores at each other, which, of course, I never did when I was a kid. It was so successful. Many of these children had never eaten a fresh orange or apple; it was always other kinds of food. He was able to improve the attitudes and the nutrition of those kids, and now he has expanded that program to a billion dollar program across the country to get fresh nutrition into these schools. He has also taken on the vending machine companies that are in schools selling junk food, and has been able to replace high-fructose-corn-syrup-based drinks, which fuel childhood obesity, and all these high-carbohydrate sugar snacks. So the man…he’s the third-ranking member of the Senate’s Health Affairs Committee, and he has a vision and a passion for this work like no other. The other thing that I believe that Senator Harkin really gets, and this kind of replays a conversation I’ve had several times in the last week with the media and at the IOM, is that moving around how we reimburse health care right now is like moving deck chairs on the Titanic. Unless we do some fundamental change in the way that medical care is delivered, we are simply feeding an ever-increasing beast that is unsustainable in terms of cost and indefensible in terms of patient outcomes. The problems that we have are based primarily on our avoidance of basic lifestyle changes that are necessary to support good health and prevent disease with the kind of Pollyanna-ish expectation that when we get our heart attack there will be a technological cure for it, and when we get cancer we’ll be able to fix that. So we end up disproportionately rewarding specialty care. Over 60{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of physicians in this country are specialists; less that 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} are primary care; less than 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of students now (medical students) are going into primary care because it is not adequately reimbursed, and the lifestyle of the primary care doctor is very strenuous, trying to manage in the face of the fact that you can council a patient for 30 minutes on their diabetes and maybe make a $100, but if the hospital cuts the person’s foot off for diabetic gangrene, they make $10,000. It is just a disproportionate share going into secondary tertiary care that could have been prevented. So I think Harkin really gets it. Unless we change our workforce and our policies of reimbursement, no matter how we rearrange how we are paying things at the top, it is going to be unsustainable. That’s a piece where this counterpoint, I think, needs to come out and people need to understand that you have to change the paradigm. I think patients understand that now. It is not just those of us in medicine and academia that realize that the model is not working. JB: That leads, obviously, to maybe a final question on this path that we’re on (not to say that the journey’s over, it is still continuing), but operating system. How do we encode all of these things into a system that respects and really has reverence for the body/mind connection and the environment and still recognizes the biology, physiology, and some of those things? I know you have been evaluating looking at the functional medicine model. Do you have any thoughts as to whether that’s a part of a bridge that builds the structure among these different things? VS: I think it is essential and I addressed it in my keynote vision statement when I was at the IOM. In a sense, it is part of the solution to the primary care quandary. If we broaden the base of primary care practitioners to nurse practitioners, physician’s assistants, complementary practitioners (naturopaths, chiropractors, etc.), and physicians who have a different level of training then end up addressing more complex problems. This ends up often being this poly-factorial systems biology approach that functional medicine does so well. I had a patient this morning, Jeff, who came in. She was a 40-ish year-old lady from Germany and South Africa (both places), had three kids, and just had a diffuse number of symptoms that were disposed of by her preceding doctors by a recommendation that she take an antidepressant. She had fatigue, brain fog, emotional lability, constipation, easily cold, decreased libido, some depression, poor sleep, and everything seemed to start 10 years ago, when she had some change in her hormonal therapy. We took a careful dietary and lifestyle history. This was a great opportunity for my student to learn a systems approach to biology. I talked to this lady for probably 90 minutes (fortunately I had that today), but was able to kind of create a story for her that she understood that her problem wasn’t a single thing; it wasn’t her hormones, and it wasn’t mood, and it wasn’t her structural problems with her back surgery, but it was a combination of things. I think that is where she could have gone to 10 different specialists. She could have gone back to orthopedic clinic and the pain clinic, and the endocrine and the gynecologist. We are generalists, by disposition, to step back and look at it from the high altitude of instead of 8 different organ systems we have 8 potential windows into the body’s function or dysfunction. And you can keep people like that from overusing healthcare resources, having adverse events from too much testing or too much medication, so that’s where this systems biology is the cutting edge that links that high-touch with high-tech medicine. JB: That’s beautiful. I’d like to close with one last question (I could go on, I know). This is an open-ended-probably colloquial-question, but maybe you could give me a sound bite. You alluded to the patient’s story. I’d like to go down to the reason for being for medicine, which is the patient, ultimately. Not for the doctor, not for the technology, not for the reimbursement company. We go to the primacy of the patient at the center of their own healing opportunity and then we talk about the therapeutic encounter. How does all of this-from your experience, Vic-really translate down into that seminal moment of healing? How does the patient relate differently from your experience to that which would be more related to disease diagnosis and treatment of traditional kind of approach? VS: You bet. Just let me follow-up with this example that I was just talking about. This lady looked at me and she said, “I’ve been to so many doctors and they don’t hear me. I tell them things and they don’t listen to what I’m saying.” So I looked her in the eye, and I said, “Okay, you tell me what it is that you feel these other doctors are not hearing you say.” Then she kind of went down her list of things. You could visibly see she was relieved. So I take the next step, and I say, “What do you think is wrong and what will it take for you to heal?” So that involves the patient at the sensor-the nexus-of the healing event. It is not something that is done to them, it is something that is done in collaboration with a trusted advisor who can be a primary care doctor, or a specialist doctor, or a non-physician that has other healing tradition. JB: We are really talking about collaboration versus judgment, I guess. Or it is some kind of a different nature of the relationship from which the context of healing can occur. I guess that’s really applicable to almost any center. It could be in surgery as well as an outpatient clinic, it seems. VS: You bet. But one of the things I’ve learned from the functional medicine training is that that patient’s story is nodal. Sir William Osler said it takes at least 30 minutes for the patient to really tell their story, and that was over 100 years ago. I don’t think it is anything less than that now, and probably is later and if you get on their side of the table and listen to their story, they’ll tell you their diagnosis. JB: Dr, Sierpina, I want to thank you. What an insight; I can see that your patients love you. You bring that quality that everyone looks for when they define a good doctor. And your constant quest, and willingness to continue to learn, and push at the edge, and refine, interpretively, the model…it’s a model for all of us. Thanks for all of your work. Thanks for your leadership. And thanks for your friendship. VS: Jeff, thank you for everything you’ve done over the years to bring this whole idea of systems biology into health and healing that helps bridge the sciences of biochemistry, molecular biology, genetics, genomics into a cutting edge of really helping people manage chronic disease and complex disease that otherwise people throw that hands up at and just otherwise shop from one doc to the next in an ever decreasing spiral of happiness (or unhappiness). JB: Thanks a million and we’ll be checking in with you, and the best of luck in everything you are doing. VS: Thanks, Jeff. Be well. I’m sure that you have the same thought after hearing Dr. Sierpina as I, and that is this field that we call integrative functional medicine draws from some of the most remarkable minds. These are people who have had experience in the field and continue to question and answer the problem of why people get sick and what to do about it and are willing to have a non-judgmental view of that which works. They keep their minds open, and-I would call it-have neuronal plasticity, or the willingness to accept new information, and look at actually what does work-not what is presumed to work, but actually what does work. It is really extraordinarily heart-warming to hear someone like Dr. Sierpina talk about his experiences as a family physician, working through his experience with patients, learning from his patients, and ultimately seeing how this system of healing fits together, and that the context of healing is more than just the absence of disease. And it is more than just treating the diagnosis. It is setting up the healing environment. I think that is a unifying theme that seems to tie together so many of the leaders in this field. We recently heard from Dr. Berman about his work at the integrative medical program at the University of Maryland School of Medicine, and now Dr. Sierpina. We’ve had the opportunity to hear from Dr. Wayne Jonas, past director of the National Center for Complementary and Alternative Medicine and now the director of the Samueli Institute. The characteristics that tie these individuals together seem to be kind of common threads in the field of looking at the context of healing, the context of disease, the context of ill health and finding the appropriate ecology for the patient, personalized to their need that draws together diet, lifestyle, environment, past histories, antecedents. This is the underpinning, really, of the functional medicine model. As much as we can take away specifics, I think we can take away the more general theme that seems to embody and characterize this field of good medicine. We thank Dr. Sierpina for once again guiding us in that direction.  

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Bibliography

1 Institute for Functional Medicine. Textbook of Functional Medicine. 1st ed. Gig Harbor, WA: Institute for Functional Medicine, 2005. 2 Fries J. Aging, natural death and the compression of morbidity. N Engl J Med. 1980;303:130-5. 3 http://nihroadmap.nih.gov/buildingblocks/ 4 Holman H. Chronic disease-the need for a new clinical education. JAMA. 2004;292:1057-1059. 5 Osler W. Masters in medicine: nurse and patient. RI Med J. 1971;54:33-36. 6 Olshansky SJ, Passaro DJ, Hershow RC, Hayflick L, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005;352:1138-1145. 7 http://www.iom.edu/CMS/28312/52555.aspx 8 Thomas L. The Medusa and the Snail. More Notes of a Biology Watcher. New York: Penguin Books, 1995. 9 Thomas L. The Youngest Science: Notes of a Medicine Watcher. New York: Penguin Books, 1983. 10 http://help.senate.gov/Hearings/2009_02_26/EMKstatement.pdf 11 Ivanov A, Nash-Barboza S, Hinkis S, Caudill MA. Genetic variants in phosphatidylethanolamine N-methylenetetrahydrofolate dehydrogenase influence biomarkers of choline metabolism when folate intake is restricted. J Am Dietetic Assn. 2009;109(2):313-318. 12 Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin in Rheum. 2008;20:648-655. 13 Schaars CF, Stalenhoef AFH. Effects of ubiquinone (coenzyme Q10) on myopathy in statin users. Curr Opin in Lipid. 2008;19:553-557. 14 Molyneux SL, Young JM, Florkowski CM, Lever M, George PM. Coenzyme Q10: is there a clinical role and a case for management? Clin Biochem Rev. 2008;29:71-82. 15 Chatzizisis YS. What is the connection between statins and coenzyme Q10? Harvard Heart Letter. September 2008. 16 Gast GCM, de Roos NM, Sluijs I, Bots ML, Beulens JWJ, et al. A high menaquinone reduces the incidence of coronary heart disease in women. Nutr Metab Cardiovasc Dis. Feb 2008 [Epub ahead of print] 17 Sierpina V, et al. Integration of the biopsychosocial model: perpectives of medical students and residents. Acad Med. 2008;83(1):20-27. 18 Sierpina V, Schneeweiss R, Frenkel M, Bulik R, Maypole J. Barriers, strategies, and lessons learned from complementary and alternative medicine curricular initiatives. Acad Med. 2007;82(10):946-950.

Welcome to Functional Medicine Update for May of 2009. As you know, this is a year of tremendous change in healthcare policy and planning, and in looking forward as to what our healthcare system will look like over the next years to come. As we are going through this dynamic process of contemplation, consideration, and reflection, data comes up that might be quite important as we start looking at the options for where the healthcare system might go. These data relate to disease prevalence, morbidity patterns and loss of work years, lowered quality of life, and trying to define the origin of conditions and then map them against certain physiological processes that relate to their etiology. As I have said this, I have tied together quite a few disciplines of healthcare evaluation, including epidemiology, biostatistical evaluation and population-based studies (demographics), and even tissue pathology and cellular physiology. All of these are related, in part, to a drift-a warp and weft-of a change in function of people. This is a change in function in an individual as it relates to the impact the environment is having over time and how it translates through the physiological process into what we see as general health or disease patterns. I think this is an interesting concept and it reminds me a little bit of tributaries coming together to form a major river that then flows to the oceans. With the gene pool, these considerations of uniqueness that we each have are locked into our genome and get bathed by and exposed to our environment (and our environment may be shared among all sorts of different genotypes), which then gives rise to-as we are heading down towards the sea-a confluence of those gene-unique interactions with the environment to produce patterns that we call diseases that appear in populations. Ultimately those tributaries collect into smaller rivers and into, finally, a major river, where we start shaping those major patterns that relate to healthcare expenditures With this metaphor that I am describing of traveling to the sea, we can see some remarkable changes that have been occurring in disease patterns over the last 15 years, specifically with the rising prevalence of type 2 diabetes. As a student back in the 1960s, I recall that we were told that the incidence of diabetes had remained relatively constant in the population (somewhere between 2 and 3 percent of the population), giving us this view of it being determined and fixed somehow in our genes. Yet in the 21st century, we are witnessing a dramatic increase in the area of what used to be called adult-onset diabetes and is now called type 2 diabetes, which relates to not the changing of our genes, but the changing of epigenetic signals (the environmental interaction with our genes) to give rise to expression across many different genotypes of what we ultimately name as a disease (as if everyone who had that disease shared the same common background and etiology). In my metaphor, the disease is the river, and the river comes from the individual tributaries. One of the contributors to this increasing prevalence of type 2 diabetes is the insulin resistance/hyperinsulinemia situation that we are seeing, is the change in how the message of insulin is and transmitted/transferred/transduced. The beta cells of the endocrine pancreas are still producing insulin, and maybe even working harder to produce extra amounts of insulin, but the message from that insulin is not being appropriately transmitted into cellular function. This is what we call syndrome X (from Gerald Reaven’s nomenclature) or insulin resistance/hyperinsulinemia/metabolic syndrome. Insulin is a Pleiotropic Hormone The core signaling and intercellular signal transduction process that comes from interruption of insulin’s responsiveness gives rise not just to an alteration in blood sugar, but it is now recognized that insulin is a very important pleiotropic hormone that influences many other aspects of gene expression; it overlaps with the cell physiological response that we associate with other diseases. In medical parlance, we call these co-morbidities, and included would be things like inflammatory diseases, osteoporosis, dementia, various kinds of cancer (like that of cancer of the colon, breast, and prostate), or cardiovascular diseases of certain types (small vessel disease). These co-morbidities really share common etiologies in this river of confluence that I am describing, as it pertains to the interaction of an altered environment with multiple genotypes to create an expression of outcome that we measure in a biomarker called blood sugar, from which is ultimately defined a disease called diabetes. The functional changes that occurred well before the onset of that diagnosis, however, are profound. Because insulin, in its high level, is insensitive at the cellular membrane in altering intercellular signal transduction, then affects many functions other than just the translocation of the GLUT4 receptor to the cell membrane, and glucose transport across the cell membrane into the cell. We recognize that people with metabolic syndrome/hyperinsulinemia present with biomarkers that are indicative of other changes, like hypertriglyceridemia or low levels of what is called the protective apolipoprotein that makes up HDL (so low HDL and a low apo A-I). Graded Effect of Insulin Response was Not Recognized 30 Years Ago There are obviously many other things that are going on other than just poor uptake of sugar across the cell membrane as one moves along the trajectory of this increasing degree of insulin resistance. I said something in that sentence that I think is quite important clinically. Nearly 30 years ago, I had the opportunity to speak at a conference on reactive hypoglycemia at the University of Washington School of Medicine in Seattle. At that conference, the then head of the endocrinology department-a world-renowned expert on diabetes-made the statement that there was no evidence (at that time) of a graded effect of insulin response (from optimal insulin sensitivity to the lack of insulin response that we call diabetes), and therefore one could not use a gradient effect logic to describe differing degrees of expression of insulin problems. In the 30 years that have passed since that conference, this field has certainly changed considerably. If he were living today, I think Dr. Bierman, who was a fantastic contributor to our understanding of diabetes and actually authored the textbook that I had originally studied out of on diabetes, would probably say it is quite interesting how our understanding of insulin signaling has changed dramatically. We have started to now see that these gradient effects of degrees of insulin resistance are true and it is not “all patients are the same.” Not every tributary that makes its way to the river of what we call type 2 diabetes is the same. Within that body of water that travels to the sea called type 2 diabetes, are different subgroups of individuals who really have different variations on a theme as it relates to how each presents with insulin resistance. That, then, is a very important clinical takeaway, because if we are looking for “the” type 2 diabetic, and we want to put everybody into a single kind of diagnostic criteria using univariant types of logic (which means looking for aberrant blood sugar on a fasting blood sugar level or elevated insulin on a fasting blood insulin level), we are probably going to miss many, many people who show different variations on this theme, who are still at risk as they travel down this river of life to various disorders that we associate with hyperinsulinemia/insulin resistance. You might be saying I am going into this in greater detail than probably you really need because you are already aware of this, but sometimes I want to come back and revisit old things in new ways. We are starting to recognize that this interrelationship of insulin signaling to inflammatory signaling, to cell regulatory factors that relate to cell replication, to factors that relate to cell apoptosis and mitochondrial phosphorylation and bioenegetics-that all of those new kind of discoveries at the cellular level are about how insulin plays roles in each of these processes and ultimately even influences cellular redox (the reduction oxidation levels of cells) and how that relates to oxidative stress, and free radical pathology, and genomic damage and instability, which we learned about from Michael Fenech in a 2008 issue. All of the issues that I’ve just described could be put under the umbrella of insulin resistance or type 2 diabetes, but you can see-just by the way I stated it-that there may be different ways that individuals express each of those based upon their own specific interrelationship between their environment and their genes There has been a longstanding question as to whether this insulin resistance/hyperinsulinemia/metabolic syndrome does or does not, in fact, correlate with increasing statistical risk of cardiovascular disease. I think it is important to point out that the term “cardiovascular disease” almost implies that it is a single condition, but as we know, it is really cardiovascular diseases. There are many different manifestations of disorders of the vascular system. To give a gross type of differentiation, we could talk about large vessel disease and small vessel disease. In general, we would say that individuals with hyperinsulinemia/insulin resistance are individuals who have an increased risk for vascular endothelial dysfunction that ties together with small vessel disease. If we look at metabolic syndrome and its effect on predicting cardiovascular events in individuals who have normal fasting glucose, what happens if we go back and do a 15-year retrospective study of them? I want to emphasize again-these are people who present with normal fasting blood sugar, but who have elevated fasting triglycerides and low HDLs. We would say they have the underlying early stage of insulin resistance. They are pre-diabetic. They are metabolic syndrome patients. And they might easily be missed in a traditional assessment because they don’t look like they are diseased; they look like they are metabolically dysfunctional. Results of a 15-Year Follow-Up Study What happens if we go back and evaluate them 15 years earlier? This was the question of a study that was actually done and published in the journal Atherosclerosis in 2008.1 As I said, these were the results of a 15-year follow-up. These researchers found metabolic syndrome to be predictive of cardiovascular events regardless of the presence of impaired fasting glucose or type 2 diabetes. I’m trying to get us to recognize that looking at early warning precursor markers for later stage pathology is where we need to start focusing our attention in the new healthcare reform movement. By the time we get to overt pathology, the requirement for much more interventional drugs, surgery, and hospitalization becomes the principal tool we use to manage those conditions at their tertiary stage of pathology. I think the view that is emerging is that biomarkers-the right biomarkers, validated biomarkers-that look at functional disturbances early on that demonstrate a trajectory towards a later stage pathology (in this case, looking at derangements in insulin signaling) are very valuable as an inclusion criteria for the new medicine to create an appropriate mosaic of where that person’s genes and environment interact to give rise to their function. Again, I want to emphasize this study looking at patients with normal fasting glucose, without type 2 diabetes, and following them for 15 years-and these are people who had elevated triglyceride/low HDL levels, meaning metabolic syndrome, with an increased waist-to-hip ratio-it was found that there was a very strong correlation, in the absence of impaired fasting glucose, of this condition with later stage cardiovascular disease. Far-Ranging Questions and Opinions about Biomarkers The biomarker questions that we are talking about can be far-ranging. We are going to hear about this issue from an expert in the area of lifestyle medicine and biomarker analysis as it relates to establishing risk to some of these metabolic dysfunctions, Ralph La Forge, and I think you are going to love his comments-very, very eloquent comments-from his work at Duke University Medical Center. But before we get to the discussion with Ralph La Forge, I would just like to review a few of the biomarkers that we often now employ for evaluating relative risk to these metabolic disturbances that we say are related to insulin signaling dysfunctions. LDL-to-HDL Cholesterol Ratio The first is the obvious LDL-to-HDL cholesterol ratio. I am reminded of a wonderful investigator from the department of nutritional sciences at the University of Connecticut, Dr. Maria Luz Fernandez. In some of her recent publications, Dr. Fernandez has talked about the importance of the LDL-to-HDL cholesterol ratio being a more reliable clinical tool than LDL cholesterol (itself) to evaluate cardiovascular disease risk, including HDL and LDL in the same analyte determinant.2 What you end up doing is looking at the risk to both large vessel disease and small vessel disease, because the HDL particles appear to be more related to aspects of insulin signaling, and the LDL particle seems to be more related to aspects of lipid dynamics. There is an interrelationship between those-I don’t want to say they are totally independent variables-but HDL is a more sensitive mark of insulin signaling, and there LDL is a more sensitive mark of lipid biosynthesis and metabolism with LDL. So controversy exists, as you know, regarding what the best method is for identifying those individuals who are at increased risk for coronary heart disease. We have recently seen from the JUPITER trial (the Paul Ridker trial that we talked about in a previous issue of Functional Medicine Update) that hsCRP (an inflammatory biomarker) has been suggested as another important indicator of the relative risk to cardiovascular disease. You’ll hear Ralph La Forge talk about his view on hsCRP a little later, but for now we need to go back to these lipid biomarkers, and that leads us into recognizing that the National Cholesterol Education Adult Treatment Panel III (ATP III), guidelines have suggested that there should be specific targets for LDL cholesterol. People have now talked about cholesterol LDL levels below 70 milligrams per deciliter. For many people this target results in them being prescribed a statin, because to get their LDL to that level they often have to be on a statin. Maybe the more important thing is to look at the relative relationship between the LDL level and the HDL level. If we say the LDL level should be 120 or less and the HDL level should be 60 or more, then we would say that an LDL-to-HDL ratio should be 2-to-1 or less and the lower the LDL-to-HDL ratio, the lower the risk to both vascular disease of large vessels and small vessels. Apolipoprotein B and Apolipoprotein A-I In that ratio scheme, we have combined a little bit of the aspects of insulin signaling, inflammatory response and the lipid dynamic biosynthesis, and the so-called HMG-CoA-reductase pathway that leads to cholesterol biosynthesis. As you probably know, for the LDL particle, the protein carrying factor for that particle is apolipoprotein B. There is now evidence (as you will hear about-again-in greater detail later in this issue of Functional Medicine Update) that apolipoprotein B may be a more sensitive marker than LDL itself in picking up relative dyslipidemias associated with altered lipid biosynthesis metabolism and insulin signaling. In fact, there are now people who are saying the best risk factor might be to use the apolipo B particle and compare it to the apolipo A-I because apolipoprotein A-I is the principal apolipoprotein found in the HDL particle that relates to cholesterol efflux, meaning pulling cholesterol out of the artery wall, and it is very significantly associated with things like inflammatory mediation and insulin signaling. So as you have dysinsulinism and insulin resistance, apolipoprotein A-I goes down and apolipoprotein B goes up. Maybe the apo B-to-A-I ratio is even better than the LDL-to-HDL ratio. There is some controversy about that presently, I would have to say. At the Functional Medicine Research Center, we have worked with metabolic syndrome patients and published and article in Nutrition and Metabolism 2008.3 Our work indicated that insulin resistance was most reflective in the biomarker of the apo B-to-A-I ratio, and when that ratio became 0.7 to 1 or greater, that person had an increasing relative risk to vascular disease. It was seemingly a precursor to that of elevation of LDL itself, or the altered LDL-HDL ratio. In panels of biomarkers that are trying to couple together insulin sensitivity, inflammatory markers, and lipid biosynthesis and metabolism, one might consider that the apo B-to-apo A-I ratio could be a very useful tool. In fact, Dr. Fernandez speaks about this in a number of her recent publications that are related to work that is going on now at the National Lipid Association in looking at the ratios of the two. We also recognize that the HDL particle, which exists in a number of different isoforms, is very complex because it is made up 44 different proteins. It is the most complex of the apolipoproteins. As we learned from Dr. Roger Newton in a previous issue of Functional Medicine Update, we should see HDL as a functional lipoprotein because it serves to transport things and be involved with metabolism. It has paraoxonase 1 as one component. That is an enzyme that is involved in detox; it has antioxidant potential-it is an antioxidant soaking up free radicals itself. It has myeloperoxidase as part of its particle composition. It has cholesterol ester transport protein, which is involved in how cholesterol is moving in and out of the artery wall. So it is a very complex lipoprotein that also has to do with the prevention of lipid peroxidation. When we are measuring things like the apolipo A-I, which is a surrogate marker for HDL function, and apolipo B, which is a surrogate marker for LDL function, we are getting a little bit more detail on evaluating the functional aspects of how these lipid particles operate within the vasculature. LDL Oxidation Let’s just look at a quick snapshot of the work that Jay Heinecke and his colleagues are doing on HDL at the University of Washington Medical School in Seattle.4 We know that genetic, clinical, and pharmacological studies implicate elevated levels of LDL in the pathogenesis of atherosclerosis. Paradoxically, as Dr. Heinecke points out, native LDL fails to exert potentially atherogenic effects in vitro, suggesting that it must be modified to promote vascular disease. Indeed, many lines of evidence now support that. This is the Daniel Steinberg hypothesis, as presented at the University of California, San Diego, by Dr. Steinberg many years ago, suggesting that oxidative damage to LDL is one important mechanism for rendering lipoproteins atherogenic. So LDL in its native state may not be atherogenic until it gets oxidized. Then the question is: what oxidizes LDL and what prevents LDL from being oxidized? That leads to the HDL part of the story. In contrast to LDL, HDL (the beneficial form of blood cholesterol) protects the artery wall from atherosclerosis. Even in individuals whose LDL levels are low, HDL remains a strong, independent predictor of coronary artery disease, meaning you could have low LDL and a low HDL, and still have an elevated risk to heart disease. The strong relationship between low levels of HDL and the risk of atherosclerosis and coronary disease has been attributed to many different mechanisms, and I think these mechanisms have been emerging over the last 30 years of discovery about HDL physiology. We now recognize that HDL transfers cholesterol from peripheral tissues to the liver, where the metabolites of the sterol cholesterol are then excreted into the bile, so we say HDL is involved with cholesterol efflux from the artery wall. That may then lead to its cardioprotective effects. Animal and human studies have the raised the possibility that HDL also slows vascular disease by blocking the inflammation (serving as an anti-inflammatory). For example, hypercholesterolemic mice deficient in apo A-I are known to develop systemic inflammation and recombinant HDL blocks vascular inflammation in atherosclerosis-prone rabbits. One potential mechanism involves the detoxification of lipid hydroperoxides, which are potentially atherogenic. And as I mentioned earlier, enzymes within the HDL particle, including paraoxonase 1, cholesterol HDL transferase, and lipoprotein-associated phospholipase A-2, have been proposed to degrade lipid oxidation products and actually help to protect LDL from being oxidized. As I said, oxidized LDL is apparently the atherogenic form of LDL. Lipid hydroperoxides are the initial products when lipids are damaged by this oxidative process-the so-called free radical oxidation. HDL is the major carrier of these antioxidant properties and several factors might account for the fact that HDL contains more lipid hydroperoxides than LDL, including the greater susceptibility of HDL lipids to oxidation in vivo, the preferential accumulation of lipid hydroperoxides in HDL, and the apparent ability of HDL to degrade lipid oxidation products. So lipid oxidation can also generate advanced products of oxidation such as alkanes, aldehydes, and isoprostanes, and these can all participate, then, in the active promotion of free radical oxidative injury to other cells and tissues and biomolecules. When put together, these observations, I think you can see, suggest that HDL plays a major role in the transport and metabolism of lipid hydroperoxides in vivo, and these processes contribute to the cardioprotective effects of HDL. I think we are seeing that HDL is a major lipoprotein carrier of things like isoprostanes, and aldehydes, and other oxidation products that tends to take them to the liver, where they can be degraded before they can have activity on other cell types, or other lipoprotein types. In some ways it is sacrificing itself for the game, right? The HDL is putting itself out there to be the preferential particle that soaks up these oxidants and then takes the peroxide products and transports them for their metabolism. Lipoprotein-Associated Phospholipase A2 I think it is very important to look at HDL with a different eye than that with which we would look at LDL, and say, “As a biomarker for dyslipidemia, dysinsulinism, and free radical oxidative stress, we would put HDL in a pretty important category for evaluation.” Now you probably recognize that this lipoprotein-associated phospholipase A2 (which I have referred to as the PLAC test)-that enzyme (protein/enzyme) is associated with HDL, and it has also developed its own ability to be seen as a surrogate biomarker for atherosclerotic risk, particularly unstable plaque. A recent study looking at the association of lipoprotein-associated phospholipase A2 (or Lp-PLA2) mass and activity with coronary and aortic atherosclerosis was published in Clinical Chemistry.5 The investigators found that Lp-PLA2 (or PLAC test) was strongly associated with coronary atherosclerosis in those who had unstable plaque. So it may be a surrogate marker for plaque instability as associated with inflammatory response, more so than just looking at atherogenesis itself. If you put the PLAC test together with an HDL evaluation and an apo A-I evaluation, you start to develop kind of a mosaic of understanding about things such as cholesterol efflux from the artery wall, the accumulation of lipid peroxides for processing, the protection against LDL oxidation, and the relative amount of inflammatory process that is going on in the artery wall that relates to unstable plaque. Why Test for Nontraditional Biomarkers? I think these are extended markers beyond the traditional biomarkers for evaluating relative risk to cardiovascular disease. They help us to differentiate the tributaries of this river that we call type 2 diabetes or cardiovascular disease. Now you might say, “Well, some of these sound like specialized tests (the PLAC test, or the apo A-I test, or the apo B test)-these are not traditional, standard, risk factor analytes.” And that’s true. So you might then say, “What good can I get from the things that are found in my standard blood chemistries, like the fasting triglyceride-to-HDL lipoprotein ratio (the TG-to-HDL ratio)?” Well, that’s a pretty good first start, and certainly if you are not going to do specialized biomarker evaluation, it would be good to look at the triglyceride-to-HDL ratio. There are many, many different papers that have been published on the relationship of elevated triglyceride-to-HDL ratio and the association with insulin resistance and metabolic syndrome that show that it’s a powerful predictor of all-cause mortality and cardiovascular events. In fact, one of the more recent studies in this area was published in the American Heart Journal in 2009.6 This was a study actually done with postmenopausal women, looking at their relative risk to cardiovascular events, knowing that heart disease is the number one killer in postmenopausal women. In this study it was found that the elevation of the triglyceride-to-HDL ratio predicted all-cause mortality in these women as they went on to have all kinds of different conditions, including that of myocardial infarction itself. We would certainly say the TG-to-HDL-C ratio (HDL cholesterol ratio) is a very, very important independent predictor of all-cause and cardiovascular events that relates to more than just dyslipidemia; it also relates to dysinsulinism. You might say, “What level of ratio increase are we talking about that is a strong predictor?” In this particular study looking at the TG-HDL ratios, they found that when you got above 4, you got into the higher risk category, and that, as it went up monotonically from 4 up to as high as 18, there was increasing relative risk at a very dramatic statistical increase. Above 4-to-1 with your triglyceride-to-HDL ratio appears to be moving into an increasing relative risk category. The Omega-3 Index There is one other biomarker that I wanted to add to this list that may appear to some of you to be esoteric and not usual and customary, but I think it has a very potentially important additional value for assessing aspects that are modifiable pertaining to risk to dysinsulinism, so it is another way of evaluating and looking at the different tributaries of the river that we call type 2 diabetes. This biomarker is what Dr. William Harris calls the Omega-3 Index. The Omega-3 Index is evaluating the relative levels of omega-3 fatty acids found in red blood cell membranes in comparison to omega-6 fatty acids. For those of us who have been in this field for some time this doesn’t sound remarkable. In fact, we can go all the way back to David Horrobin, back in the 1970s, who talked extensively about omega-3 fatty acids and their relationship to cardiovascular incidence. What has emerged recently is recognition that in our Western population, eating a standard Western diet, that we have seen a significant shift in the fatty acid profile of red cell membrane lipids (phospholipids), moving this Omega-3 Index more and more towards a low ratio of omega-3 to omega-6 fatty acids. Dr. Harris, who is at the Lipid and Diabetes Research Center at the American Heart Institute at St. Luke’s Hospital and the University of Missouri in Kansas City, has been looking at this extensively over many years. His recent paper in Preventive Medicine I think really does a nice job of describing the Omega-3 Index as a new and cholesterol-independent risk factor for cardiovascular disease, and also for type 2 diabetes.7 In this study, the researchers looked at a number of individuals with a wide range of different functional characteristics and performed red cell membrane fatty acid analysis. They then looked at a content of EPA plus DHA in the red blood cell membranes (expressed as a percent of total fatty acids), which is what they call the “Omega-3 Index.” They graded these individuals based upon that number (the fatty acid index, which is the combination of EPA-DHA divided by the total fatty acids, so looking at percentage). When they did this they found something very, very interesting: the individuals in the high-risk category had a very low Omega-3 Index, meaning their percent of DHA and EPA as a total percent of fatty acids in their red cell membranes was generally below 4{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} (somewhere in the range of 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} and below were in a reasonably high-risk group). There was a fairly significant correlation between the Omega-3 Index and this relative risk to cardiovascular disease, with low index being associated with increasing risk (so an inverse relationship). In individuals who had very low relative risk to vascular disease, they found that their cardiovascular Omega-3 Index was more in the range of 10 {56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} or higher (10-12{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the total fatty acids in the red cell membrane were that of DHA plus EPA). Here is, I think, another very interesting assessment that is cholesterol-independent that helps us to understand something about dynamics that relate to prostanoids and eicosanoids and the relative effects that these have on inflammatory processes, membrane construction, and intercellular signal transduction. What happens if you supplement with EPA and DHA? What happens to the levels of these fatty acids in the red cell membrane? That was discussed in this particular paper. They gave graded doses of fatty acid supplements at a half-gram a day of EPA/DHA, at one gram a day, and at two grams a day. I want to emphasize for those of you that are deciding how much a patient needs to get to these levels, you need to look at the percentage of the total fatty acids in the supplement to determine what its relative percentage is of EPA/DHA. So the levels I gave you of 0.5 grams, one gram, and two grams is of the combination of EPA/DHA. If you had a supplement that was only 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} omega-3 fatty acids, you’d have to double these doses to get to these levels I’m describing. When they did the graded dose study, what they found is that the omega-3 went up kind of monotonically with the increasing intake of DHA and EPA as a supplement. So you can, over a period of about 12 weeks, demonstrably indicate (or find) that there is a significant increase in the omega-3 fatty acid index in the red cell membranes of people who have been supplemented. If you then correlate all of this data that I’m describing with the outcome in populations relative to their prevalence of cardiovascular disease (and this could be the GISSI study, the DART study, the Public Health Service Physicians’ Study, the Seattle Heart Study), what you find (and this was described very nicely in Dr. Harris’ article) is that those individuals in these large population-based studies who had the highest omega-3 index had the lowest incidence of vascular disease, both small- and large-vessel disease. I think the Omega-3 Index is another biomarker that can be used for tracking something that is modifiable. A laboratory that does this testing has to be very capable of evaluating (accurately, sensitively, and reproducibly) the levels of fatty acids found in the red cell membrane. I’m not talking about plasma-free fatty acids; I’m talking about plasma-bound phospholipid materials that are found in the cellular membranes of red cells, so this is looking at red cell membrane phospholipid fatty acids, another indication. (By the way, we would probably like to get our omega-3 index up at 8 or above in individuals who are having this test done, so it is a way of marking where they start and following where they finish.) We’ve talked about apo B and apo A-I. We’ve added the fatty acid index, and we’ve talked about HDL-C and LDL. All of these are relatively important markers for looking at how we differentiate patients who are in these tributaries that ultimately flow down into diseases that we call either cardiovascular disease or diabetes. The last thing I want to mention has to do with this metabolic syndrome and how it is influenced by central body fat, or visceral adipose tissue. We now recognize that metabolic syndrome is a constellation of inter-related metabolic risk factors, as I mentioned, that appear to directly promote the development of both diabetes and cardiovascular disease. We now start looking at the confusion between the syndrome and obesity. Does metabolic syndrome get caused by obesity, or is obesity a manifestation of metabolic changes associated with some alteration in insulin signaling? What seems to be emerging now (and I’m taking from a review that just appeared in Hypertension Research in 2008 that I think is very well-written) is that we now would characterize metabolic syndrome as a condition associated with altered adipose tissue physiology, and obesity is really probably a result of (rather than the cause of) the condition.8 If we look in the fat mass itself–the central fat mass (the central adipose tissue)–it is characterized (on doing biopsy) by the association of activated macrophages and monocytes with activated adipocytes. They are sharing this imflammatory profile, and you actually start getting the death of adipocytes and macrophages that produce kind of a necrotic process in the fat that further amplifies and stimulates inflammatory processes, systemically. You see in the blood of people, then, elevated hsCRP levels and elevated TNF-alpha inflammatory cytokines, so we would say that there is an underlying process of inflammation as it pertains to this inter-relationship between the immune system and the fat mass adipocytes that is further a part of the complex etiology of this metabolic disturbance we call metabolic syndrome. To review, there is the hsCRP elevation, there is the increase in inflammatory markers, there is ultimately the increase in PLAC test values, and there is the oxidation of HDL. I want to emphasize that the emerging thought is that obesity, in and of itself, is not the cause of-but rather is the result of-metabolic disturbances that create these outcomes. I hope this has given you some news to use in how you assess patients and actually start to use this understanding of the tributary that leads to the river that ultimately leads to the terms type 2 diabetes or heart disease. I think you are going to enjoy hearing more from our clinician of the month.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Ralph La Forge, MSc Managing Director, Duke Lipid Disorder Physician Education Program Duke University Medical Center Division of Endocrinology, Metabolism, & Nutrition DUMC 3510 Durham, NC 27710 We are at that very interesting point in Functional Medicine Update, where, really, the tire meets the road and we look at the clinical applications of some of these recent investigations and published studies. Right now, as we are talking about changes in healthcare planning, policy, and delivery over the years to come, there is probably no more important area than that which we will discuss with our clinician of this month , Ralph La Forge. Ralph is an expert in what we will call therapeutic lifestyle changes. His work at Duke University Medical Center in the Division of Endocrinology, Metabolism, and Nutrition is, I think, really at the forefront of what’s going on. Ralph has his Bachelor’s in Zoology from the University of Texas, and his Master’s of Science from the University of Wisconsin, La Crosse. He has been at the Duke University Medical Center, Division of Endocrinology, Metabolism, and Nutrition for a number of years, really looking at the role that therapeutic lifestyle change (and specifically diet, exercise, and stress management) has on health outcomes. His background, obviously, is very strong in the area of exercise physiology and exercise prescription, but he has extended considerably into the area of diet and lifestyle and how it pertains to modulation of risk factors for major chronic diseases. Ralph, it is really a pleasure to have you on Functional Medicine Update. I think the first question I would like to jump on is about cholesterol-the nature of the risk and this whole dyslipidemia issue. As a public health issue, once people knew their number (their cholesterol number) that they could get from a health fair, suddenly their interest in cardiac disease prevention changed from that of being somebody else’s problem to being their own problem. What have you seen in the field as it relates to dyslipidemia being kind of the stepping stone into peoples’ understanding of their relative risk? The Role of Lifestyle Management in Reduction of Cardiovascular Disease Risk RL: Well, after about 900 to 1000 clinical trials over the last two-and-a-half decades, I think we have hit the nail on the head multiple times: especially high LDL cholesterol (that’s the bad cholesterol) is definitely correlated quite strongly with vascular disease (both cerebral vascular disease and cardiovascular disease). Of the other lipids (those other than cholesterol and LDL cholesterol), one that has really been getting a lot of attention in last couple of years is triglycerides, which are very much related to obesity and what we call the metabolic syndrome. Lifestyle management (diet or physical activity or both) probably has a better focus (at least in the short term) on reducing triglycerides and perhaps increasing HDL a bit. After weight is lost, of course, LDL is reduced. There is no question that the large number of 100-million-dollar-plus clinical trials (mostly statin trials, drug trials) have shown us that even modest reductions in cholesterol, particularly LDL cholesterol, reduces risk of your first heart attack if you are a primary prevention-type patient. If you have had coronary disease already, or have already had a previous heart attack, certainly aggressive cholesterol therapy can reduce a recurrent event. My big bone all along has been that lifestyle changes (even modest), if they are adhered to, clearly reduce risk of diabetes, but also cardiovascular disease, through mechanisms other than just lipids and cholesterol reduction. As a general rule, it takes quite an ardent following of lifestyle behaviors to reduce LDL cholesterol. Generally, diet and exercise don’t hold the same power at reducing (especially in the speed of reducing) LDL cholesterol compared to some of the drugs; I don’t think anybody will argue that. But I have always said diet and exercise have other benefits that have been, in some cases, even more attendant to the mechanisms of risk reduction than just myopically looking at LDL cholesterol. JB: One of your recent articles that I think was very well-written is titled “Therapeutic Lifestyle Changes: Lost Horizons?” and talks about the pleiotropic benefits-the multiple benefits-of a therapeutic lifestyle change. You say, “One of the longest standing statin promotional advertisements reads, ‘When diet and exercise fail, meet another candidate for lipid-lowering therapy.’”9 You go on to say it is almost subliminal that we are assumed to fail before we start, which then presupposes that a person needs to be on the cholesterol-lowering drug before they even give serious attention to therapeutic lifestyle changes. That really begs a question that relates to someone we interviewed last year in 2008, Dr. James Wright from the University of British Columbia School of Medicine. You probably know Dr. Wright authored (or actually co-authored) a very controversial paper in Lancet in which he and his colleague from Harvard did a retrospective analysis of the published primary prevention trials on statins and they came to the conclusion that the benefit to individuals on primary prevention of taking statins alone was probably far less than that which we recognize based on number-to-treat.10 They came to the view (based on the published intervention trials) that the NTT for statins in primary therapy (primary prevention) is probably greater than 60, which they said is, from a pharmacological model, kind of a crapshoot. When you talk about pleiotropic effects of a therapeutic lifestyle change program, it sounds to me like it may be much more efficacious than an NTT of 60 plus for individuals on statins. Number-Needed-to-Treat Data is Open to Interpretation RL: You know, the NTT (the number needed to treat) is dependent on the baseline risk to begin with. The higher your risk (the more risk factors you have) and the older you are affects the number needed to treat, and it can drop substantially down to as low as 6 or 7, as we saw with the Diabetes Prevention Program (again, they were not addressing first heart attack, they were addressing new onset diabetes). In other words, the higher the total cholesterol at baseline and the higher total global risk of the patient (including cholesterol, blood pressure, and all the other Framingham Risk Factors), the more efficacious and cost-effective statins are. I don’t see anybody arguing that statement. The option that I have always promoted is that within the lowest risk subsets (the majority of us are in the high-end of low-to-moderate risk level), many are taking prophylactic statins and other drugs to perhaps defer risk. That is where there is some question about the cost-effectiveness. For that group of people (including myself), sufficient energy expenditure per week/per day and the right choice of dietary behaviors (I’m not talking about a diet, per se, I’m just talking about the right choice of foodstuffs over the course of a day, a week, a month, or a year) would certainly be cost beneficial, especially from a cardiometabolic risk perspective. What I mean by that is that both the immediate risk of diabetes and metabolic disease and the later risk (usually it comes a little later) of cardiovascular disease are addressed. The number needed to treat is certainly very high in some patient subsets, especially in primary prevention. We just saw in the JUPITER trial (one of the largest statin trials ever) with rosuvastatin in 18,000 older men and women that had absolutely normal total LDL the NNT averaged about 108. The only risk factor the participants really had other than their age being around 66 years on average, was a high C-reactive protein (at around 4 or 4.1). The investigators stopped the main intervention at two years (it was supposed to be a five-year trial) and saw that there was unimpeachable statistical significant reduction in first event risk or around 44 to 45{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. If you looked at the number to treat needed to treat that many patients with that level of statin therapy (which happened to be 20 milligrams of rosuvastatin), the number needed to treat was around 100. But if you took the trial all the way out to five years and projected it, the number needed to treat was 25. So there is a lot of manipulation of the numbers. I try not to get too caught up in it other than what is… You know, we have sort have lost our horizon, especially against some of the pharmacotherapies for people that are fairly average risk and not super-high risk. We have lost the horizon on the efficacy of modest but consistent lifestyle changes. For instance, just adding 1000 calories of exercise a week, and just making a couple of substitutions in diet would be equivalent to the risk reduction that we saw in the Diabetes Prevention Program, where the number needed to treat to prevent diabetes was 5 (5 to 7, depending on how long you take the trial out). JB: You’ve raised some very, very important questions there, clinically. We went from the biomarker of LDL cholesterol and total cholesterol, then to hsCRP-are there other biomarkers that one would throw a net over that give us a better snapshot of relative risk? Perspective on Biomarkers RL: There are 47 biomarkers on my list. Biomarkers that independently score risk above the traditional risk factors are very few. Everybody says there are some, but nobody can provide sufficient data with multi-ethnic groups across all ages that stand out as an independent, added measure of risk. One that is forthcoming that is probably (I’m going to take a guess, here) going to get some consensus with the next NIH guidelines on dyslipidemia, which will be out about a year from now (called ATP4), will be apoprotein B, which is very close to the same thing, but not identical, to what we call non-HDL. There is an apo B particle on every triglyceride-rich lipoprotein. In other words, on every lipid particle in the blood, (except HDL), there is an apo B particle on it. So if you’re measuring apo B, or if you simply take your lipid profile that you get from the doctor’s office and subtract HDL (the smaller number-HDL cholesterol) from the total cholesterol, you get non-HDL. Non-HDL and apo B are very close to the same thing. That measure (either non-HDL or, perhaps a little more specifically, apo B) will be looking at both cholesterol-rich and triglyceride-rich particles. With apo B, you are talking about a measure that is going to be more reflective of lifestyle risk in more of an immediate fashion. For example, if you just stop drinking pop today (if you are someone drinking 3 or 4 Coca Colas each day), one thing that will be reflected in your blood test in the next 48 to 72 hours will be apo B or non-HDL, whereas LDL and total cholesterol HDL (if it’s affected at all) may take some time. It is quite undisputable (just from the last two years of research and clinical trials) that apoprotein B and non-HDL may be as important, and in some cases, especially in diabetic patients and patients with metabolic syndrome, it is actually a better target of therapy for reducing cardiovascular risk than LDL cholesterol. We are not forgetting about LDL by any means, but we’ve now got a new measure that may supersede LDL by a small measure if the clinical trials continue to show that it is a great target for therapy. I would have to say, C-reactive protein can also be an independent measure of risk-it has been shown in numerous studies-but when you add it to a traditional Framingham risk scoring tool, the consensus is divided that it is that much benefit-that it adds anything to it-with one exception: if you are in the moderate risk range (that means if your 10-year probability of having an acute, coronary event is 10 to 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}), high C-reactive protein can actually bump you up to the high risk classification, but it doesn’t help much in predictive modeling if you are in the low risk or the high risk subset. The final analysis for CRP is not completely in yet, but the big question for the payers is, “Okay, don’t tell me there are more biomarkers; tell me there is a biomarker that is better than what we have now and we’ll identify more people over a 10-year period or longer that are going to infarct or have diabetes or whatever else.” That’s really what they are looking for and is of substantial importance to them. JB: That really leads me to a very interesting collateral question that is related to the subtitle of your paper, “Therapeutic Lifestyle Changes: Pleiotropic Benefits.” As you have already mentioned, the pleiotropic effects of a therapeutic lifestyle change might then have an effect on metabolism (such as to normalize a variety of metabolic disturbances that are associated with distorted physiology), and therefore what we need to look at is a pattern of biomarkers, not just put our eggs in a basket related to the biomarker of the month. Do you think we are getting into a pattern recognition kind of portfolio effect? Biomarkers and Test-Retest Reliabilities RL: Yes, that’s a good question. I don’t know what to make of all the biomarkers. I mean, all of them are, to some degree, more or less transduced by every thought you think, every minute of the day. What does that mean, is the big question? Beyond weight loss and beyond total or LDL cholesterol reduction, all of the biomarkers are important, especially the inflammatory markers (the inflammatory cytokines, like interleukin-6 and CRP and others). But they have test-retest reliabilities that are very wide. You can do a biomarker litany test on an individual, split the sample and have one sample analyzed at one time of the day and then in the next aliquot have the next sample, and the lab bias can be anywhere-and this is true for LDL cholesterol-from 8 to 15 to 20 percent. It is very hard to grasp some of the biomarkers as standards that are stable enough to get our hands around so we won’t get pre- and post-test changes due to lifestyle measures. Probably the most noteworthy pleiotropic effect I can think of is AMP kinase activation. AMP kinase is an enzyme that is very much involved in energy production with every muscular contraction; it has to do with exercise, of course (even very low levels of exercise). AMP kinase activation is one of the principal foci of many of the anti-diabetic drugs, especially a wonderful drug-it is probably the drug in diabetes-and that is metformin, otherwise known as Glucophage. Glucophage and intentional types of exercise (I’m talking about walking for health, or that type of exercise) almost are duplicative of one another in their mechanisms in the muscle cell and in the liver. They almost have exactly the same responses. In fact, I’ve gone so far as to say that every step you take is an AMP kinase activator-you’ve taken small milligrams of metformin with every step you walk. But you are going to have to walk, and you are going to have to walk quite a bit. It is very close to the same effect, if not almost identical. Does that mean we need to measure AMP kinase as a separate act? Absolutely not. It is so variable from minute to minute that you couldn’t. If we look at apolipoprotein B, as I said earlier, that’s a little bit more stable. It does need to be fasting, and depending on the assay you use (and they are narrowing down the assay to just one, so everybody is on the same page). We’re going to get a test-retest reliability that is plus or minus about a little under 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, which will be very good, whereas if you just measure triglycerides as a biomarker, triglycerides reflect a lot of lifestyle. In fact, it is probably the best single lifestyle marker you have that is on a traditional lipid profile in the doctor’s office. It has a test reliability or variability co-efficient plus or minus about 35{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. It is like glucose; it goes up and down a lot. Personally, I can’t justify taking a whole litany of biomarkers (a collection of them) all at once, and then advising based on the average outcome to the assays, in terms of what someone should be doing by increasing their energy expenditure or eating more fish or whatever. But what I could do, perhaps, is take tier one of those biomarkers, which might be the most evidence-based ones, and do that-perhaps baseline and then every 8 to 12 weeks for the first year until we get the patient to where they think they should be. One of those targets would be lipids (apolipoprotein B, LDL cholesterol). Another target would be, perhaps, waist circumference. Of course, there is blood pressure-it’s not a biomarker, but if it’s measured correctly that would be another indicator. (I’m saying a lot there because I think sphygomometers often are not used correctly in physicians’ offices-you’ve seen how people pump up the manometer in about 2 seconds and they drop it in about 1 second until you have 149 over 77.) And I would also use, perhaps, C-reactive protein. CRP is affected by weight loss and smoking cessation. It has also been shown in a number of studies recently that the fitter you are the lower your CRP (it doesn’t mean it completely normalizes, but it does tend to come down with weight loss, and of course, improving your fitness). Another measure that has gotten a lot of attention over the last five years is LDL particle number (not to be confused with the regular LDL cholesterol). LDL particle number is a great measure of modest lifestyle changes, especially moderate levels of exercise. LDL cholesterol that you’d have measured in your physician’s office is not a very good marker (visit to visit) of how much exercise you are doing (it will be, ultimately, as you lose weight). LDL particle number is measured through nuclear magnetic resonance imaging (NMR). When you measure LDL particle number, it will drop in real time as you become more engaged in exercise, versus waiting for 6 to 12 months (if at all) to watch your LDL change. And LDL particle number probably is more meaningful than LDL cholesterol milligrams per deciliter. That’s my take on some of the more important markers that are pretty responsive to lifestyle changes, even modest levels of lifestyle changes. JB: That was a fantastic review. I compliment you. That covered a huge body of literature very, very succinctly. You said something that I thought was quite interesting that I want to come back to pick up on, and that is the question concerning body mass index or central adiposity. There is a big question that continues to be controversial: how much weight does a person have to lose? Do they have get down to their ideal body height-to-weight ratio based on the Metropolitan Insurance Table Data? What is a realistic target/objective for a person with elevated BMI? RL: We don’t use BMI as a central measure for the metabolic syndrome. You use it in the clinic, of course, to measure someone’s baseline, but it is not a targeted therapy, per se, for a pre-diabetic, or someone with the metabolic syndrome, which has, of course, consensus standards of risk factors that have cut points. For instance, one cut point for a male’s waist circumference would be 40 inches or greater (this would qualify for the metabolic syndrome), if you are measuring waist circumference correctly (which then takes some skill). In a woman, the measurement might be 35 inches or greater. Waist circumference and BMI are very closely correlated, but central adiposity is a little easier to rationalize as a pre-diabetes equivalent, or a pre-diabetes risk factor, or a metabolic syndrome risk factor. Although in the last two years there have been several papers on large populations that said there wasn’t that much discrimination of significance between measuring BMI and waist circumference. It’s hard for me to hang my hat totally on one or the other, but one thing I will say: waist circumference or BMI don’t give you a lot of real time feedback from doctor’s visit to doctor’s visit (that means every 6 to 8 weeks). I mean, they will change, but some of the biomarkers change a little bit faster and may be more responsive to modest lifestyle changes than weight. I still put adiposity or anthropometric changes in sort of a tier two class. They are in a tier one class in terms of predicting risk, no question; they are very, very important. But in terms of follow-up, I would rather measure behavioral follow-up than biomarker follow-up or anthropometric follow-up. Is not what we are trying to do from visit to visit measure the step count, the food choices, the stress and disease, someone’s perception of their quality of life? Is that not the bottom line and does that not correlate as much (if not in some cases more) with heart vascular events or metabolic disease than the biomarkers do? You need both, is what I’m saying, but I think we need to put (as a biomarker) weekly step count on a reliable, well-engineered clinical pedometer as high as we would (if not more) than a lipid profile, for instance. JB: That’s very, very helpful. That’s really clinical news to use. Could you give us some thoughts as to whether these concepts of therapeutic lifestyle change have been put to the test of trials, and if so, have the results looked favorable? People often ask about, “Show me. Give me the proof.” RL: Oh yes. It’s funny because there is not as much consensus standard on how to walk and how to eat as there is how to measure lipids and waist circumference. It’s coming of age, though. Let me just talk about one clinical trial that is going on now that had its first data published a little over a year ago called the Look AHEAD Trial. The Look AHEAD Trial is a very large trial of a little over 5000 diabetic patients. The Look AHEAD Trial is using absolutely the same lifestyle intervention as the big, head-turning, New England Journal of Medicine-published diabetes prevention trial that was published six years ago. A modest level of lifestyle changes in that diabetes prevention study delayed the onset of diabetes almost 60{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} compared to metformin, and metformin actually reduced new-onset diabetes itself.11 The Look AHEAD Trial is doing exactly the same study, except it is not using pre-diabetic or metabolic syndrome patients; it is using diabetic patients. The only difference is that rather than 150 minutes per week of exercise, they are doing 175 minutes per week of exercise, or what they are essentially doing is adding about 20,000 step counts per week to the patients’ existing habits (over time; they don’t do it all at once). It is one of the first trials that is actually measuring more judiciously and systematically the lifestyle changes (both diet and especially exercise). I don’t have it right in front of me-but at the one-year mark they already lost just at 9{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of body weight. There are naysayers, including some of my own colleagues (not necessarily here at Duke, but just around the country and world) that say diabetics cannot lose weight (there’s a huge mythology out there that diabetics have some mitochondrial dysfunction where they can’t oxidize fatty acids sufficiently to lose weight); we’ve never subscribed to that, at least I haven’t. The Look AHEAD Trial, at one year, showed just right at 9{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} versus the control group that lost little or none. It also showed about a 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction in many of the diabetes meds that participants were on at one year. I like to point at that one because that is a huge sponsored trial with adequate subject number with good statistical power. There are many much, much smaller lifestyle trials that have done the same thing, but they don’t have the statistical power that you can argue with a little bit. JB: Oh boy. I’ll tell you, when we hear you speaking we wonder why this hasn’t gotten more traction in medicine today. It is so overwhelming. Do Clinical Studies Overlook Physical Activity? RL: Dr. Bland, look at any package insert or any drug. Believe me, I’m hoping I’m not being too negative for drug therapy because we absolutely we have to have anti-lipemic drug therapy in my line of work, especially for people that already have disease. Clearly. First and foremost. Half of my work is with the National Lipid Association-with lifestyle changes there-but I certainly subscribe to the appropriate use of drug therapy for lipid disorders when it is necessary. But if you look at every anti-lipidemic, anti-cholesterol, or anti-triglyceride drug, in the package insert they will always have a lifestyle washout. It will show the list of clinical trials that were used to rationalize the efficacy of the drug to the FDA for approval. Of course, they always have 8, to 12, to 16 weeks of dietary intervention first. Nobody ever talks about physical activity. It is not in the vocabulary. It is always dietary intervention washout after so many weeks of diet, which, you know, actually has some efficacy, as they will show. But they leave it at that, with very modest dietary changes, and what is never, ever, posted in there is a behavior that probably has more far-reaching metabolic benefits in real time, and that is physical activity. And I’m not just talking about exercise, which is more systematic physical activity, I’m just talking about any physical activity. In the article you read, Dr. Telford from Australia did a wonderful review: is it the physical activity or the weight loss that reduces risk?12 He says that 74 papers he reviews never quantify the effects of exercise. They always ruled in or ruled out dietary changes, and never calculated energy expenditure as a possible intervention or a possible contaminant to the outcomes of the study. It is virtually lost. That is just like these package inserts. They don’t give credit for what would otherwise be a significant risk-reducer (not necessarily a significant LDL reducer, for instance, in statin therapy, but a significant risk reduction). Is not what we’re trying to do reduce risk? Of course through reducing lipids, but isn’t the bigger picture reducing risk? And if that is the case, why do we give such little accounting of physical activity in any of these studies, especially in the early phases of these drug trials? JB: Yes, that’s beautifully stated. Let me, if I can, just switch slightly over to the question of diet, nutrition, and food plans. We have a lot of controversy, obviously, floating around in discussion and in the literature about the most appropriate diet for inducing metabolic restoration. I think you made some very nice comments in your paper about studies that have been published-Esposito’s work and others-as it pertains to a diet of variety and moderation. Could you tell us a little bit about your view on diet right now? RL: I’m not a dietitian, but I’ve reviewed a lot of dietary trials and been involved in a number of them. If you rank order all the labeled diets-the more popular diets-over the last 15 years, without question Mediterranean types of diets have, by far, the most evidence base in terms of cardiometabolic risk reduction, mostly on the vascular end (that is, reducing the risk of cardiovascular disease and maybe, to a little less extent, on metabolic disease like diabetes). I have to say the elements of a Mediterranean-type diet look like absolutely the best mix of nutrients from the fish, the nuts, the grains, and even the very, very modest/low consumption of alcohol. It looks like the most doable. Of course, there is no one Mediterranean diet, per se. It is more of a concept that involves a variety of nutrients. A handful of investigators have spent their lives (and there are about 100 papers-published papers in refereed journals) on the biomarker responsivness to such dietary intervention. Clearly, if you look at the LYON Study from 15 years ago (one of the most important studies ever looking at Mediterranean-type diets reducing sudden death from coronary disease) and reflect back on that study and other studies like it, on the mechanisms of how such a balanced diet of fish, nuts, fruits and vegetables, whole grains could do such a thing, we clearly know that that type of diet is anti-inflammatory, tends to increase the threshold for ventricular arrhythmias (it doesn’t mean that if you have extra heartbeats they all go away, but you have fewer of them), decreased synthesis of some of the cytokines, and clearly improved arterial wall motion (or what we call endothelial function). Also, it is anti-thrombotic. In other words, it is a little bit, if you will, like an aspirin effect. I shouldn’t call it aspirin, but a little bit of an anti-platelet effect. Other diets have this too, but if you had to add and balance all of the nutrients of the Mediterranean concept, you’d probably have everything you need. There is enough flexibility in it to satisfy most peoples’ craving for one nutrient over another. JB: I noticed that you had been a co-author/collaborator in a very interesting paper I read that appeared in the journal Atherosclerosis in 2006 looking at diet and exercise versus pioglitazone in managing diabetogenic risk in patients with obesity and how that influences atherogenicity, lipoprotein particle size, and the like.13 Can you kind of review your conclusions? RL: That was an original paper by the Mayo Clinic (some of our colleagues at the Mayo Clinic). I didn’t have anything to do with the original paper in Diabetes Care some years ago, but I saw it and I called the investigators and I said, “Geez, can I get some of the bloodwork from that? You didn’t mention much about the exercise and the lipid response. All you basically said is pioglitazone is a good drug.” And it was a good drug; it increased sensitivity and it had a positive effect on the metabolic syndrome, although it did tend to increase fat stores a little bit like glitazones do, but they didn’t do much analysis of the exercise. So I actually got the data from this study, along with Dr. Shadid, who was the lead author, and said, “Can I get the bloodwork? I want to do NMR, which will take a much harder look at all the lipoproteins and LDL particle numbers and all that.” Well sure enough, when you looked at pioglitazone, at least 30 milligrams a day, versus the diet and exercise (and it was very modest), the exercise was adding about 1200 calories of exercise per week to these people (it was only about 40 people). Twelve hundred calories of exercise a week is about 10 miles of walking a week, so originally is was a very modest amount. And they decreased the total caloric intake by around 400-500 calories a day. What we found is that compared to pioglitazone, this modest dietary/exercise intervention in these patients with the metabolic syndrome, essentially in every category except for insulin sensitization, was remarkably more beneficial. And pioglitazone (otherwise known as Actos) was beneficial, definitely. It’s a good drug-a great drug; it really is. But when you matched it against modest but systematic approach to consistent lifestyle changes… This did not come out in the original paper (it didn’t even come out in my paper because I wasn’t the lead author-it was a piogliatzone-focused paper). But in fairness to my co-authors, they did say that diet and exercise (the modest lifestyle change) was at least as good as the pioglitazone, and one thing it did (over an above the pioglitazone course) is it prevented any further weight gain. In fact, participants actually lost weight rather than gained weight like you do on the glitazone meds. It had the same efficacy on increasing insulin sensitivity. The other thing diet and exercise did was it had a much more beneficial effect on the VLDL and reducing triglycerides. So it was a small study just saying that in many cases, for diabetes patients, if you can get the patients to walk more, lifestyle is a definite beneficial option to the medicine, or at least to be used in combination therapy with the medicine. JB: I really want to compliment you. What you’ve covered in this last 40 minutes is just a spectacular landscape of clinical medicine taken down into the place where it really makes a difference and that’s in patient management. I think your work is fundamentally important at this time when we are really contemplating cost-effective ways of improving the health of the world and certainly of the United States, specifically. I want to really encourage you in continuing this extraordinarily important work, and hopefully your voice will be heard in those decision-making quarters that are really going to decide how dollars are going to be spent on the way our healthcare system will look in the years to come. Mr. La Forge, thank you so much. It has been fascinating. RL: Thank you so much, Dr. Bland. JB: We’ll be following your work very closely. RL: Thank you.

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Bibliography

1 Noto D, Barabagallo CM, Cefalu AB, Falletta A, Sapienza M. The metabolic syndrome predicts cardiovascular events in subjects with normal fasting glucose: results of a 15 years follow-up in a Mediterranean population. Atherosclerosis. 2008;197(1):147-153. 2 Fernandez ML, Webb D. The LDL to HDL cholesterol ratio as a valuable tool to evaluate coronary heart disease risk. J Am Coll Nutr. 2008;27(1):1-5. Review. 3 Lerman RH, Minich DM, Darland G, Lanb JJ, Schiltz B, et al. Enhancement of a modified Mediterranean-style, low glycemic load diet with specific phytochemicals improves cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia in a randomized trial. Nutr Metab (Lond). 2008;5:29. 4 Shao B, Heinecke JW. HDL, lipid peroxidation, and atherosclerosis. J Lipid Res. 2009;50(4):599-601. 5 Brilakis E, Khera A, Saeed B, Banerjee S, McGuire DK. Association of lipoprotein-associated phospholipase A2 mass and activity with coronary and aortic atherosclerosis: findings from the Dallas heart study. Clin Chem. 2008;54(12):1975-1981. 6 Bittner V, Johnson BD, Zineh I, Rogers WJ, Vido D, et al. The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: a report from the women’s ischemia syndrome evaluation (WISE). Am Heart J. 2009;157(3):548-555. 7 Harris WH, von Schacky C. The omega-3 index: a new risk factor for death from coronary heart disease? Prev Med. 2004;39(1):212-220. 8 Oda E. The metabolic syndrome as a concept of adipose tissue disease. Hypertens Res. 2008;31(7):1283-1291. 9 La Forge R. Therapeutic lifestyle changes: lost horizons-TLC’s pleitropic benefits. Lipid Spin (National Lipid Association). 2008;6(4). 10 Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet. 2007;369(9557):168-169. 11 Pi-Sunyer X, Blackburn G, Brancati FL, Bray GA, Bright R, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care. 2007;30(6):1374-1383. 12 Telford RD. Low physical activity and obesity: causes of chronic disease or simply predictors? Med Sci Sports Exerc. 2007;39(8):1233-1240. 13 Shadid S, La Forge R, Otvos JD, Jensen MD. Treatment of obesity with diet/exercise versus pioglitazone has distinct effects on lipoprotein particle size. Atherosclerosis. 2006;188(2):370-376

Welcome to the June 2009 issue of Functional Medicine Update. You are going to really enjoy this issue, I can tell you. This will be the first time in the history of Functional Medicine Update that we will have a two-part series on a topic. Why will we donate that much time in June and July to one topic? It is because of the importance of understanding gluten and gluten sensitivity. The clinicians of the month that you are going to hear from are two of the leading proponents and experts in the area of gluten and celiac disease. This month we’ll set the clinical stage for what, in next month’s issue (the July 2009 issue), will be a very new look (at a mechanistic level) at the physiology and pathophysiology of gluten and its relationship to not only regional gastrointestinal problems, but also to systemic relationships. This will really be a very interesting two-part series, I think, to look at the functional medicine nature of gluten as a problem family of molecules related to a triggering of immunological inflammatory response. As we get into this topic, which will be immunologically focused over the next two months, I thought it might be worthwhile to go back and look at few of the issues that have been recurring themes in functional medicine over the years. I think these issues are important in setting the stage for the discussions in June and July. The first thing I would like to talk about relates to omega-3 fatty acids and their relationship to immune function. There are certain kinds of (what we call) fundamental nutritional products that have entered the domain of practitioners across a wide range of backgrounds, degrees, and certifications. In the early 1980s, I had the privilege of working with the original group that was bringing softgel omega-3 fatty acid capsules from England to the United States. The original work on omega-3 fatty acids was done by Dr. Hugh Sinclair, as well as by Bang and Dyerberg in Denmark, who had discovered that in the Greenland Eskimos, consumption of very high omega-3-containing diets led to a very significant reduction of incidence of cardiovascular disease. That flew in the face of traditional logic at that time, which said that fat was bad and we should cut fat out of the diet. We were into the anti-fat movement back then and did not differentiate the types of fat. In Greenland, people were consuming in excess of 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of their calories as fat and yet they had a very low incidence of cardiovascular disease. Researchers originally thought, “Well, they must be genetically protected against this high-fat diet, these Greenland Eskimos.” But yet, when they looked at it epidemiologically, it was found that when Eskimos moved from Greenland to Northeast Canada, where they were eating a lower-fat diet (but now in more the Canadian form of fat diet which is the North American fat), that their cardiovascular disease suddenly went up and became like that of other residents in Canada. Then it was said, “Well hold on, it can’t be genetic protection because they’ve just lowered their fat, yet their cardiovascular incidence has gone up, so there must be more to this.” The work of Bang, Dyerberg, and Sinclair is an extraordinary detective story. They eventually elucidated the active principle within the oil that the Eskimos were consuming through local water mammals in Greenland, which was the omega-3 fatty acids, and in particular, rich eicosapentaenoic acid, the 20 carbon atom fatty acid omega-3 (meaning the last degree of unsaturation and the fatty acid side chain was 3 carbons in from the methyl end of the chain). As an eicosapenta it is 5 degrees of unsaturation and is an oil that is metabolized differently than arachidonic acid, which is a 4 unsaturated fatty acid up to 20 carbon in length, in which the last double-bond is 6 carbons in from the methyl end. The arachidonic acid family has a very different downstream elaboration into prostaglandins (the 2 series prostaglandins), which are proinflammatory, pro-platelet adhesive, and pro-cell proliferative versus the omega-3 fatty acids, which move downstream into a different series of eicosanoids that are anti-inflammatory in nature and balance the activity of the arachidonic acid-derived prostanoids. Then: Only Forward-Thinkers Seemed to Understand the Role of Omega-3 Fatty Acids in Cardiovascular, Mental, and Immunological Health In the 1970s, a group in New York state and New England-the Ames group-included forward-looking practitioners (medical doctors) that met with people like Donald Rudin and David Horrobin, who, early on, were talking about omega-3 fatty acids and health in the United States. At that time, David Horrobin was based in Canada (in Montreal) as a medical school professor working on psychiatric health. Don Rudin was a psychiatrist in the northeastern United States. They both did a brilliant job in communicating with the medical community in the Ames group about the role omega-3 fatty acids play across a wide range of physiological functions–not just cardiovascular health, but mental health and immunological health. The first supplements that came to the United States that contained omega-3 fatty acids were called MaxEPA, produced by the RP Shearer Company in England. I was fortunate to be one of the spokespeople for this new omega-3 fatty acid preparation, and was actually able to get funding (as a university professor) for studies on MaxEPA incorporation into red cell membrane lipids in human student volunteers (medical student volunteers). I published some papers back in the early 1980s on this topic, and was one of the first investigators looking at the role of MaxEPA and incorporation with supplemented diets of people living in the states. Validation Comes in a New England Journal of Medicine Article Later, in the middle to late 1980s, Elias Corey and a group of collaborators at Harvard University published what I think is a landmark paper in The New England Journal of Medicine describing the effects that omega-3 MaxEPA supplementation had in human volunteers on monocyte adhesion, chemoattraction, and ultimately leukotriene secretion as it relates to pro-inflammatory mediation in people supplemented with omega-3 fatty acids.1Once it was in The New England Journal of Medicine it was on the big board; many people hadn’t understood why oils would have any effect on the immune system when this paper was published. For those individuals who were already in the flow of understanding, it was a very big breakthrough to have a paper published showing that human volunteers supplemented with six grams a day of a mixture of different omega-3 fatty acids and omega-6 polyunsaturated fatty acids (MaxEPA) had a marked clinical effect on their stimulated production of leukotrienes as it relates to downregulation of 5-hypoxygenase enzyme activity. This article was a big “wow,” and it indicated that there might be something to the story that omega-3 fatty acids can have an anti-inflammatory or an inflammation-modulating effect. Now: Many Papers Looking at Mechanisms and Clinical Activity From that period on (from the publication of The New England Journal of Medicine paper until now, 2009), we have seen literally thousands of papers published in many, many journals looking at mechanisms and clinical activity. I am specifically thinking of the work of Joel Kremer at Albany Medical College in New York showing that in patients with rheumatoid arthritis, supplementation versus a placebo led to improved joint mobility, lowered pain, lower involuntary use of pain medication; this was work that was published in the late 1980s and early 1990s.2,3 As this concept has rolled forward, I have heard of studies showing that people with inflammatory bowel disease taking an enterically coated EPA formula had lowered inflammation and better recovery from inflammatory bowel disease. We’ve seen many, many different modifications and extensions since the early observations of Bang, Dyerberg, and Hugh Sinclair in Greenland with the Eskimos. In an issue of Functional Medicine Update several years ago, I was very fortunate to have the opportunity to interview Dr. Dyerberg, who gave a brilliant historical record of these discoveries and his work in Greenland and how those observations advanced this whole field. What Sources of Omega-3 Supplements Are Available Today? With that in mind then, what are the various sources of omega-3 fatty acid supplements that are now available today? The story has gotten a little bit more complex. We know that the first member of the omega-3 fatty acid family is a substance called gamma linolenic acid, which is an 18-carbon atom fatty acid that is omega-3 with 3 degrees of unsaturation. Through a series of elongase and desaturase enzymes, gamma linolenic acid becomes eicosapentaenoic acid (or EPA) (that’s a 20-carbon fatty acid with 5 degrees of unsaturation). Ultimately that goes into another chain elongation/desaturation to become docosahexaenoic acid (or DHA). So we have this kind of metabolic tree, so to speak, of the omega-3 fatty acids that most people in this field have memorized and recite on demand; it’s kind of a right of passage to know this fatty acid biosynthetic pathway. The sources of omega-3 fatty acids that are available now include both vegetable sources and animal sources, and there is some confusion in the marketplace as to what are the most efficacious and clinically beneficial forms of omega-3 supplements. Let’s just review this very quickly. As a reminder, the omega-3 metabolic biosynthetic pathway starts upstream with an 18-carbon fatty acid called alpha linolenic acid (or ALA). This is a triply unsaturated omega-3 fatty acid that is then desaturated and elongated by enzymes into the 20-carbon atom fatty acid with 5 double bonds omega-3 called EPA (eicosapentaenoic acid), which is then further converted by elongation/desaturation into the 22 carbon atom fatty acid with 6 double bonds called docosahexaenoic acid (or DHA). It has been thought that one could derive the benefit by going upstream and utilizing the vegetable origin of the downstream animal DHA and EPA by using ALA, which is derived from things like cold water vegetable oils such as borage oil or flax seed oil. It has been recognized that there is benefit from supplementation with these ALA-containing oils One can use data from studies like the Lyon Heart Study, which showed that individuals who consumed diets that were higher in calorie percent of the omega-3 vegetable oil ALAs had a lowered incidence of cardiovascular disease. This was one of the most remarkable clinical intervention trials in nutrition that has ever been published. In fact, the results were so dramatically different between the group that took the omega-3 oils in their diet (polyunsaturated oils) versus those that ate longer-chain saturated fatty acids, that they had to call off the study because there was such a significant increased risk in incidence of cardiovascular in those individuals who consumed the longer-chain saturated fatty acids. There seems to be something very cardioprotective about the polyunsaturated omega-3 oils. We recognize that these fatty acids are very labile to cooking and to oxygen (to high temperature and oxygen), and also to light. These need to be freshly prepared and kept cold, and ideally kept under an inert atmosphere if they are going to be stored for any period of time. Some EPA is found in some vegetable sources but at a very small level. We would normally think of EPA as being more animal-derived origin (fish, in this case). Fish don’t make EPA from scratch; they basically eat the precursors from the krill and the krill gets it from the phytoplankton, so it comes up through the food chain in a biosynthetic pathway. So the ALA gets converted to the EPA, which the fish eat and then there is some conversion into DHA. We might say, “Well, let’s go back to the source-to the vegetable source,” and certainly there is some advantage in consuming the omega-3 vegetable oils, however the conversion in humans (the enzymes that are required to do the elongation and desaturation of ALA into EPA) is very slow in process and it is difficult to elevate EPA levels by giving ALA supplementation. If you really wanted to have a marked effect on EPA levels within membrane phospholipids, it is better to give EPA directly. The other vegetable source is DHA because there are algal forms of DHA. DHA has now become a major supplement that is fortified within infant formula. An algal-derived DHA product that can ultimately increase the omega-3 content of infant formula has been identified in clinical trials to be very effective in improving retinal function and potentially brain function as well (two percent of the phospholipids of the brain are occupied by omega-3 DHA). It has a very important functional characteristic, and it is kind of a conditionally essential nutrient. As such, it must be obtained through the diet. For infants and pregnant women, proper omega-3 fatty acid intake is very important, including DHA directly. One can get an algal or vegetable-based omega-3 chain elongated desaturated product directly from vegetable-based products. If you want EPA in high concentration, however, you really have to go to an animal-derived product (at this point, fish) to really create the highest concentration (to get up in the 60{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} range). It really depends on what the clinician is trying to do. In general nutrition intake (for salad oils and so forth), the ALA flax seed oil or sesame oil can be very desirable, but for cooking at high temperature one probably wouldn’t want to use the very labile omega-3-rich vegetable oils because they are very easily damaged by heat and oxygen. You probably want to stay with the monounsaturated linoleic acid (olive oil) for those purposes. If you are trying to improve neuronal composition and retinal composition, the DHA-rich oils and even vegetable-based DHA can be very primary and therapeutic in that area. And if you are looking for the anti-inflammatory effects then you’re probably going to be looking at the EPA-rich oils that come from animal products (from fish). Again, the therapeutic dose of these oils for anti-inflammation or immune modulation is somewhere between, say, one and three grams per day of omega-3 EPA. So if you have a product that is something like 60{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} EPA/DHA, then you are going to have to have three one-gram pills a day to get to your threshold of around a gram of EPA (just to give you kind of a sense as to magnitude). That would be about three grams of the mixture of EPA/DHA high potency formula. I hope that helps to make some sense of this interesting immune modulation question related to the omega-3 oils. The other companion topic that I think will help lead into our discussion this month with the clinicians has to do with insulin resistance/hyperinsulinemia/inflammation, and the relationship that has to immunological balance and how that relates to things like omega-3 oils and other immune-modulating nutrients. In the functional medicine model, our approach is to look at the antecedents that are related to events that trigger the release of various mediators that modulate function and ultimately produce the signs and symptoms of different duration, frequency, and intensity in the individual. It is a different model of evaluating the patient than focusing on a differential diagnosis. It doesn’t mean that the diagnosis of a disease is irrelevant, but what we are looking for is the underlying kind of ecology of what we later call a disease by looking at antecedents, triggers, and mediators giving rise to signs and symptoms. This information is then focused through the lens that we call the functional medicine matrix, which gives rise to an understanding (hopefully) of the systems biology consequences of disturbances that give rise to signs and symptoms With that in mind, let me talk about some very interesting work that is emerging about cognitive performance-related issues (dementia) and various types of antibodies that are formed as a consequence to response to inflammatory mediators.4 One of the major triggering devices for these inflammatory mediators appears to be that of events that lead to the production of advanced glycosylation end products (or AGEs-AGE proteins). These proteins upregulate the activity of what are called the receptors of advanced glycosylated end products (the so-called RAGE receptors) on the surface of white cells. Basically, when a person is insulin resistant and having inflammatory mediation they are “enRAGEd” (to use kind of a play on words). If it occurs in the microglia of the brain, this can have effects on neuronal function leading to neuronal apoptosis and cell death, and ultimately to decline in neuronal reserve, which we later call cognitive dysfunction. This dementia/cognitive performance connection is very, very strong. In the next discussion we’re going to be talking about what could trigger these RAGE receptor activations and immunoglobulins that relate against brain function (myelin as well as neuronal function). Are there other agents (like sporing proteins) that may trigger this in immunologically susceptible individuals? Of course the answer is yes. Gluten is going to be the agent we’ll be discussing. Let’s turn to our wonderful discussion with our two clinicians of the month this month. The first interview is going to be with Alice Bast. I want to make sure to say that the opinions Alice will be sharing with you are her own personal opinions, not necessarily that of every member of her scientific advisory group for her foundation, or the foundation itself. She is an individual who has extensive personal experience with this gluten-related story.

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INTERVIEW TRANSCRIPT

Christine Doherty, ND Balance Point Natural Medicine 354 Nashua Street Milford, NH 03055 www.pointnatural.com www.glutenfreevitamins.com Of all the people I have met, Dr. Christine Doherty has certainly focused her practice very effectively on intervention with patients who have complex immunological problems that are associated with gluten and alpha gliadin sensitivity. Let me quickly introduce Dr. Doherty’s background. I am very proud to say she is a graduate of Bastyr University, and received her degree from the naturopathic doctorate program in 1998. She has been in private practice in New Hampshire since 1999 and has worked with thousands of patients, all ages, with different forms of chronic illness. In 1999, Dr. Doherty was appointed by Governor Shaheen of New Hampshire to a three-year term on the New Hampshire Osteoporosis Council. She was Vice President of the New Hampshire Association of Naturopathic Doctors from 2002-2005. She attended the National Institutes of Health Consensus Conference on Celiac Disease in 2004 and has been a medical advisor and speaker for the Southern New Hampshire Gluten Intolerance Association since 2004. Recently (in 2008), Governor Lynch appointed Dr. Doherty to the New Hampshire Board of Naturopathic Examiners for a five-year term. She has a very esteemed background and a clinical series of experiences. Dr. Doherty, welcome to Functional Medicine Update, and it is really a privilege to have you as a representative of the naturopathic community. CD: Thank you so much, Dr. Bland. I feel truly privileged to be with you today. JB: Let me start with a question that I like to use to initiate these conversations: Can you tell us a little bit about how you made the decision to become a naturopathic doctor? I know that you traveled through your undergraduate education at Concordia University in Montreal, Quebec, so you probably have some French in your background. Maybe you can tell us how you got to Bastyr. Personal Experience with Celiac Disease Leads to Medical Degree CD: It was really through my own illness, I think. My undergraduate degree was actually in fine art; I majored in painting and art history, and the last thing on my mind was that I would ever go into medicine. But I was really interested in alternative medicine, and I spent a summer working at an art gallery in Santa Fe, where I met an 80-year-old chiropractor, Jay Shearer, and he really sort of revolutionized my way of looking at my health. He told me I had to go off dairy and he modified my diet more. I’d been working to modify my diet since I was probably about 13 because I had been sick most of my life (since childhood), and I had a sense that something food-related was the problem. I’d gone through being macrobiotic, I’d gone through being vegetarian, vegan, you name it. He really helped me feel better, and that really opened my eyes to the concept of actually having a career in natural medicine. At that same point in time, a friend of mine had started dating a first-year student at Bastyr in the naturopathic medicine program (from Montreal). I had never heard of naturopathic medicine, and we sat down for lunch and by the end of that lunch I thought, “This is what I am going to do with my life.” I went back to school and I got a pre-med degree (because, obviously, the fine art degree wasn’t going to cut it), and I never really looked back. As I said, I had been sick for a long time and I’d been to a lot of different doctors over the years and no one could ever make sense of my seemingly unrelated symptoms and my chronic anemia. I’m blue-eyed and blonde. I used to bruise really easily. I actually had one doctor diagnose me as a blue-eyed blonde and that that was the cause of all my problems, which I knew was just a ridiculous answer. My illness was part of what drove me to get my doctorate in medicine. The MDs, at that point, didn’t have the answer I was seeking, so that’s where naturopathic medicine made sense to me. JB: You’ve done such a magnificent job of taking that experience and translating it into help for literally thousands of patients. I think the interesting part of all of our journeys is what we collect as experiences (either our own personal experiences, or that with loved ones, or family, or friends, or in the world at large), and we then become our stories, basically, and our stories become our life and they kind of guide us toward our trajectory. Can you share a little bit about this path? It sounds like you had some very extraordinary epiphanies that kind of guided you, probably, as to how to better help your patients. CD: Yes. I made it all the way through naturopathic school and I still didn’t really know what was wrong with me. I still didn’t feel like I had the answer I was seeking. To give you more background on my medical history, when I was young, even as a child I remember having joint pain, bone pain, abdominal pain, irritable bowel syndrome. It got to the point where I just stopped telling doctors about what symptoms I was having because I knew they couldn’t really make sense of it. As I got to my teen years, I started getting really heavy periods and weight gain. The bone pain got even worse, and I remember telling my dentist that whenever I drank beer my gums would bleed uncontrollably. He said, “There is absolutely no connection between beer drinking and gum bleeding. You just need to floss your teeth.” I remember thinking, “If I floss my teeth I’m going to bleed to death.” It was definitely a connection in my mind. When I was about 13, I developed a really itchy, vesicular rash on my lower back, which would travel around over the next 25 years. I spent one summer in France, living on baguettes, and by the end of that summer I had this rash all over me. When I got back to Canada and went back to my regular diet, the rash went back down to one or two spots. In retrospect, I now know it was the dermatitis herpetaformis. As I mentioned, I experimented with a lot of different dietary pathways. By the time I got to Bastyr, I started getting even sicker. My liver became inflamed (my liver enzymes were elevated). I was always anemic; my iron levels (my ferritins) would be around 6 or 7 on average. I had a lot of infections. I was definitely irritable, moody, and fatigued a lot. It all started getting much more serious after I got married. I married an acupuncturist right after we graduated and we started trying to get pregnant. Two years later I still wasn’t pregnant, so that was when we started to think, “Okay, I’m definitely medically infertile at this point.” My husband and I undertook a really intensive program. We took gluten out of our diet (we both did it). We did yoga everyday. Lo’ and behold, I got pregnant the first month. In retrospect, that was the major piece of the puzzle. I wish I had known that gluten was really the cornerstone of everything, because I went right back to eating gluten as soon as I was pregnant. I had a very complicated pregnancy. It was unbelievable, really. I developed hypertension. I got gestational diabetes. Something bizarre happened to my thyroid; it was both hyper and hypo. I even wound up at an endocrinologist’s office and they couldn’t make heads or tails of it. I went into premature labor at 27 weeks. With the acupuncture everyday I managed to keep the baby to term (I went on bed rest). The delivery was complicated. I developed septicemia, so I was very ill. I had the baby and that all went fine, thank goodness. About four days later I developed severe abdominal pain; I mean, just mind-boggling pain. I wound up going back to the doctor and he said, “Oh well, you’ve just got a urinary tract infection.” I had done an abdominal exam on myself and I found a huge abdominal mass. It turns out it was a fibroid (a necrotic fibroid), but they thought it was a sarcoma, which basically-I knew-would have meant that I probably only had a year to live. Initially they thought it was a hematoma, so they watched it. Eight weeks later (bear in mind I have a newborn through all of this), I had a radical cancer surgery, and they basically took out half of my small intestine, ten lymph nodes, two-thirds of my large intestine, and it was quite a rough recovery. And then I basically went into immune failure for the next two years. I got the Norwalk virus. I got trigeminal neuritis. I got four bouts of bacterial pneumonia. Eighteen months later, I was back in for more surgery from obstructions from adhesions and they removed my gall bladder. I definitely felt like I was dying. I knew there was something wrong with me, and I just couldn’t figure out what it was. No matter how much iron I took my iron levels wouldn’t come up. I was getting pretty desperate to find the answer. A low point was when I developed severe nystagmus. I was vomiting uncontrollably at a play date at the local park and had to be carried out by ambulance. I had severe bouts of vertigo for about another year-and-a-half after that happened, so I was definitely having neurological problems. I haven’t even emphasized the gut piece, but I was having constant gut pain. One day I was sitting in my clinic waiting room and I was reading the magazines on the coffee table. I think Eat Well was the magazine, and it had a headline that said “Could Wheat Be the Problem?” (or gluten-I can’t remember the exact title). “Do have constant anemia? Do you have infertility?” It kind of listed through a lot of my symptoms, and it was the epiphany that I had been waiting for. I tested myself, and sure enough it came up positive. I went gluten-free, and I was really lucky that I responded. The rash went away (finally!). All my gut symptoms healed up. My immune system is much, much better. I occasionally get a cold-once a year, maybe (my doctors had told me they had surgically immune-compromised me because they had removed so much of my gut). I have no doubt the gluten-free diet saved my life. I feel really blessed, and I guess evangelical, since it was my past that led me to this point. That is kind of the synopsis. JB: First of all, thank you very much for sharing that. I know that’s a very, very personal story and it probably brings back all sorts of memories. For people listening, it certainly, without any question, is a resume of qualification of your expertise in this area, that’s for sure… CD: Come by the hard way…! JB: No kidding! I have been fortunate to hear this story before because you and I spoke and I was deeply moved and very touched by not only your vigilance as to how you walked through this personally, but by the maintenance of your positive attitude, which undoubtedly was a factor in your recovery because not everybody has that resilience, emotionally. I’m reminded of the book, which I have cited in past issues of Functional Medicine Update, called How Doctor’s Think, by Jerome Groopman from Harvard.5 He starts that book by going through a case history–a medical detective story that goes on for many pages–about this poor woman who has all these symptoms, and all these problems, and multiple surgeries, and the conclusion of the story is the same as your conclusion. Length of Time to Diagnosis Can Lead to Trauma CD: Oh yes. I’m not alone. I have met a lot of other patients with fairly similar histories. The average length to diagnosis is 9 years, and there are a lot of people out there for whom it is 25 years. You accumulate a lot of trauma (medical issues) in that 25 years. JB: Could tell us a little bit about some of your clinical high points since you’ve had this extraordinary learning experience yourself? I think for most people they still think that food has to be a friend, and that wheat within our food is considered a good food group. How can we suddenly be saying there is something bad about it? Maybe you can tell us a little bit about, in your clinical work, how you present this to patients and some of the things you have seen in patients as they have made their own changes and transformations. Celiac Disease Can Lead to Long-Term Nutritional Deficiencies CD: I totally see what you are saying about how we think it is a health food. I remember when I was first diagnosed, I’d think, “What do you mean I can’t have a piece of Ezekial bread but I can drink a Coke?” It turned my whole concept of what was good and what was bad on ear. Obviously a Coke would not be good, but suddenly that was something that wouldn’t kill me, whereas a piece of bread would, and that was just a really bizarre paradigm shift. In terms of the clinical approach to patients, it’s going to sound almost embarrassingly simple. What I have found, over the years, is that you have to start with the nutrition. When I was at the NIH Consensus Conference there was a moment that was another epiphany for me and has really guided my work. A woman, Cynthia Cooper, who is the head of the Gluten Intolerance Group of North America, said the statistic that 10 years after diagnosis 50 percent of celiacs still have multiple nutritional deficiencies. I have definitely seen that in practice. People have been gluten-free for years, but they are still not feeling well. They are tired, they are irritable, they are depressed, they are not sleeping well, they have brain fog, and they may still have gut symptoms. This is where I really see starting with the basics of nutritional supplementation. I often see patients who have been to other doctors (including holistic doctors) and they have been given more specific things ( for the liver, for example), but often nobody has just looked at the basics, like whether they have an essential fatty acid deficiency. They often have issues with fat soluble vitamin absorption, so it is a really good idea to give them the active forms of all of them, and I give them the fat soluble versions of vitamin A, not just beta carotene, because I find they don’t convert the beta carotene very well. The other sneaky thing about this population is they have been suffering a long time. Just as I got to the point where I didn’t bother mentioning so many of my symptoms, I find you have to ask specific questions about things like night vision and how are they sleeping. They’ll try to boil it down, but if you start asking about things like chronic canker sores (which is another symptom I definitely had for years), that is when they start seeing they’ve got all these symptoms of deficiencies, but they’re not putting it together with their celiac (and neither are their doctors, in many cases). A lot of those are just symptoms of deficiency. Getting the B vitamins in there, the calcium, the magnesium, all the minerals, the essential fatty acids will often do wonders. Beyond that, you sometimes have to look for other food intolerances, enzymes, and food allergies. One theory that I’m working on right now and seeing kind of develop in practice is that I think a lot of patients aren’t true celiacs in the sense that they have the IgA-antibodies and the villous atrophy, but they have all the same symptoms and they definitely respond to the gluten-free diet. I think a lot of them actually have an IgE-wheat allergy. When I have brought that up with some of the celiac specialists they have said, “Oh, there’s no good test for that.” There is so much more to the picture than we really understand about gluten, and I don’t want to boil it down to just celiac. There are so many things that respond, clinically, to the gluten-free diet. But I think the important thing is to rule out celiac first, because once they go gluten-free it is much more difficult to test them and the serology is negative fairly quickly. JB: That leads into, I think, a very important question for those who may be less familiar than you in assessing patients. First of all I want to ask a simple question: did you ever have a mucosal biopsy yourself throughout this whole history? Did you have villous atrophy? CD: Strangely I don’t think ever went to a gastroenterologist even though I had so many symptoms. I had a biopsy set up, and at that point it was about a four-month waiting list. I was getting sick about every three weeks, so I knew I would have another bout of pneumonia and probably another couple of nasty infections before I would get there, so I just didn’t have the patience. In retrospect I realize there is a lot to be said for getting the biopsy. I obviously never wanted to go back and challenge it because it had such a huge clinical impact on me. For patients, I do emphasize that they will be asked over and over if they have ever had the biopsy. For communication, it’s the only way to practically know how much damage is happening internally. So yes, I think there’s definitely a place for the biopsy, but I wound up skipping it just for timing reasons (and probably out of desperation, frankly). JB: How about when you work up a patient? What are the assessments, or testing, or diagnostic methods that you have found useful? Clinical Methods for Assessing and Testing Patients for Celiac Disease CD: I usually start with the celiac panel. That would be a tissue transglutaminase IgA, anti-endometrial IgA, total IgA (because about 4{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of patients are IgA-deficient), and then the anti-gliadin IgG and IgA, and sometimes (especially if they have a family member) I’ll do the genetic screening as well (because theoretically if they don’t have the gene, they likely won’t ever develop celiac). That’s what I start with, and then if they come back positive then I would refer them on to a gastroenterologist. Some people absolutely refuse to do the biopsy, in which case I tell them that as long as they make peace with it and understand that it is a definite part of the diagnosis then fine, but I respect their choices. Typically I explain to them why they probably would want it (I find that a lot of people are super excited to have an answer that finally ties together all of their symptoms). They go gluten-free and then they start feeling better, and then they start saying, “Well, I never had the biopsy. Maybe I really don’t have to be on this diet for the rest of my life.” They swear to me up and down that will never happen, but I’ve seen it happen time and time again). That is an interesting thing I have learned from experience. JB: After you’ve got all this data in on a person and let’s say it looks equivocal, which often is the case, what do you do at that point? Do you have to have iron-clad information, or how do you read the shades of gray? Celiac Testing Data Can Be Clear as Mud CD: You’re so right. I’m sure any clinician who is reading these tests is seeing the shades of gray. Often I’m brought in to try and interpret. I call it “clear as mud.” There are a lot of different tests and one can come up positive and not another. But the other really important piece to remember about the diagnosis is the third part, which is the response to the diet. I try to get as much information as I can. I make sure they go to a gastroenterologist who is familiar with the interepithelial lymphocyte screening, so they don’t just look for total villous atrophy; they know to do the stains (because that can show early celiac). Once we have all of the information or we see if they have a family history or if they’ve got the genes, then I’ll do a trial of the gluten-free diet. I have started testing with the immunocap IgE test for wheat, or I will also do an IgE anti-gliadin and wheat profile, and a lot of times they come up on that. To the best of my knowledge, it doesn’t necessarily mean they’ll progress to celiac. Again, I often like to have the genes to know how at risk they are for going down that road. Basically, the reason patients come to see me is they want to feel better. They don’t care so much about the testing, it’s the doctors that get all caught up in it. They just want to feel better and that’s where the gluten-free diet comes in because you don’t know until you try. Another really important thing that I’ve learned over the years that is hard to get your head around as a doctor is that when it comes to the testing, there is almost no correlation between how positive the tests are and how clinically ill the patient is. I have seen people with tissue transglutaminase (let’s say normal is over 3) of 500, positive biopsy, and their only symptom is a little acid reflux occasionally. And I have seen other people who are at a 4 tissue transglutaminase, and they are literally dying from multiple autoimmune diseases and they are completely collapsing and in and out of the hospital. JB: Very, very interesting. Again, we don’t want to treat the numbers, we want to treat the patients. CD: You can’t with this disease because the numbers are deceptive. You really don’t know, and then with the neurological patients, often they’ll respond with the anti-gliadin antibodies and not so much with the tissue transglutaminase. The bottom line is I try to explain all this to patients, which can be a challenge, and then we do a trial of the gluten-free diet. Often they’ll see huge response with that, especially in conjunction with, (as I said) basic nutrition. A lot of times their adrenal glands are extremely taxed because they have been through hell and they have been really sick for a long time. Their moods are often an issue. The number one symptom in children is irritability. I have seen a couple of kids now who had been diagnosed as bipolar, and they were celiac. We get them off the gluten and on a multi, some fish oil, and some probiotics. Within two or three months they are completely different personalities. JB: That is so interesting. I have a quick anecdote for you. In 1978, I was on sabbatical and teaching at the Evergreen State College in Olympia, WA. My class was a very interesting group of students that followed me through the whole year because of the way the curriculum was set up that college. One of them was an older-age student who was the wife of a math professor at the university. She had a son who was nine and had all sorts of neurocognitive problems and behavioral problems. He had been seen by the school psychologist and was going to be in Special Ed, and they were very worried about him; he seemed like a very troubled young boy. Not knowing nearly what you know-this is back in ’78-I kind of naively said (based on what I had read), “Maybe he ought to be taken off gluten-containing foods and dairy for a short period of time as kind of an elimination diet just to see how he does.” I had been to a previous seminar with the founder of the American Academy of Environmental Medicine, who was a world-expert in food allergy testing by elimination, and so I thought maybe it would help. In three months, that boy-as you are describing-completely turned around. The dark circles under his eyes went away. He gained weight. He gained energy. He was a top student in his class. They had thought he was retarded; he was not retarded. For me, that was a real experience. CD: It’s miraculous, isn’t it, when you see that kind of incredible transformation, just by taking one protein out of the diet? There is this wonderful pediatric gastroenterologist at UCLA, and at one of her lectures she said that all of the animals who are adapted to eat gluten have four stomachs and chew their cud. I thought, “You know, our little human digestive tract…” This is part of where I think gluten intolerance comes in, too. If there is any level of compromise, I think gluten is one of the first things to go. It is a spiral molecule, first of all, and so I think our enzymes just have a hard time getting in there and breaking it down, but I often think of the four-stomachs and chewing cud. This stuff is really hard to digest. JB: Let me ask you about treatment because I know there is a very big discussion on this point as to how rigorous exclusion of gluten needs to be to get clinical improvement. Maybe there are different variations on a theme, relative to presentation (some people can tolerate more than others). What is your view, clinically, on how rigorous the diet needs to be? Compliance with a Gluten-Free Diet CD: In the patients I see (and a lot of people come to see me because they haven’t gotten better from the first-line diets alone), it becomes about contamination and environmental issues. I wind up doing a fair amount of troubleshooting, for example, “You can’t handle your dog food and then pick up a piece of your gluten-free toast. You are going to get sick.” The way I kind of describe it to patients is, “When you got the flu, did you ever see the flu get into your system? That is what our immune system is designed to deal with: things that we never even see. So the molecular amounts of gluten (or, let’s say, a crumb of something) is plenty for our immune system to have a full-blown reaction to.” You are absolutely right. Some people are more sensitive than others. The problem with celiac is that you can’t rely on the symptoms, so that person may be able to have a burger every once in a while, or not be particularly careful about their soy sauce. They could be marching down the road to cancer, but not necessarily have symptoms. They can truly be asymptomatic. It’s weird that you can’t monitor how dangerous the disease is and how strict they need to be just based on symptoms, so I tend to err on the side of caution and recommend everybody be as strict as they can. Have the separate toasters. Don’t use the wooden chopping blocks where people cut the bread in the family. Don’t use sponges that then spread the gluten all over the counter and then you put down your piece of bread or your spoon. I see a lot of patients get better once they get that rigorous about it. It really comes down to the molecular level, I think. JB: And how about compliance? Often people will express good intentions, but when it comes to the rigors of daily living, stuff is lost in translation. CD: I’m sure that happens all the time. Where you can really see it is the recommendation that if one person in the family is diagnosed with celiac, every other member should be tested. (Every first-degree relative is supposed to be screened, symptomatic or not.) With all of the patients I have worked with, I have seen maybe one family where they all agreed to get tested. Usually they say, “I see how you’re living and I don’t want to do that. I don’t want to know.” There are a whole lot of people out there who literally have celiac and absolutely refuse to be tested because they don’t want to comply with the diet in any way, shape, or form, so yes, it is a spectrum. I think a lot of the people who see me are pretty motivated because they are fairly sick. I find my patients (as far as I know, anyway-they don’t always tell me) are pretty compliant, mostly because they feel better. With any disease (and I know you certainly know this), it isn’t just about the diet. People have to be exercising, they have to be sleeping, they’ve got to be well-hydrated, and they’ve got to be happy. They have to have beneficial emotional pieces in their life. I work on it beyond just the diet; you really have to look at the whole thing. JB: I think that comes across so strongly, just hearing your tone of voice, your affect, and the way that you approach this. I think, again, it comes down to the art of health care that has to do with the patient/practitioner interaction-that very privileged moment in the exam room when you are talking with them and you are presenting something that is different. I get the feeling I’d love to be on the diet with you as my counselor. CD: Thank you! JB: Let me close with one last question. As you have had this ever-increasing experience of watching patients get better through this approach, what do you see the future looking like? How do you see the trajectory taking us into the future? CD: I’d like to think that all the undiagnosed celiacs are finally going to get discovered (minus the ones who refuse to be tested, of course). I read a statistic yesterday that said more people in America have celiac disease than ulcerative colitis, Crohn’s disease, and cystic fibrosis combined.6 I thought that kind of drove the point home. What I’m hoping-and I think everybody who is advocating for celiac is hoping-is that really the big thing is to get people diagnosed. There’s a ton of great dietary resources out there. There are a ton of restaurants that now have gluten-free menus, lots of national chains. It’s a huge, exploding market in terms of the options; it has never been as easy to be gluten-free as it is now and I’m sure it’s just going to get easier. I’m optimistic. I’ve seen a huge change just in the five years that I’ve been gluten-free. When I lecture to doctors, it’s still about, “Here are the celiacs; recognize them, screen them, and then get them on the road to wellness.” But once they are gluten-free and their deficiencies are fixed, they are just like everybody else. Their mortality rate is just like everybody else. We can be fine. JB: You are an incredible model for that-your spirit, your energy, your advocacy, you are going to be a guide for many, many thousands of people, both those that are in your practice and those that are touched by the people that have been in your practice. Thank you very, very much. This has been extraordinarily insightful. Anyone who may have come in to listening to this that didn’t have some sense as to the depth of this issue certainly couldn’t go away without now seeing the impact of it and the importance of it. Dr. Doherty, thank you so much. Our very best to you and keep doing what you are doing so well. CD: Thank you and same to you. I hope you got as much out of that extraordinary two-part interview with Alice Bast and Dr. Christine Doherty as I did. That was a tremendous amount of news-to-use and dense both in personal experience as well as general information on the whole gluten effect. Of course, we’re going to be hearing much more about this, mechanistically with our discussion next month in the July issue. A New Book Called The Gluten Effect I did want to give you some information about a good book that you can send your patients to. It is a contemporary book on the gluten story that is called The Gluten Effect.7 The authors are two dear friends and colleagues-the Petersens (Dr. Vikki and Rick Petersen). This book is now available in most bookstores, or from Amazon, or any of the book sellers-The Gluten Effect. It is written for the patient, to bring them up to speed as to the implications of the story beyond that which they might have heard of frank celiac disease. The book is another resource that you might keep in mind for your patients-The Gluten Effect.

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Bibliography

1 Lee TH, Hoover RL, Williams JD, Sperling RI, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med. 1985;312(19):1217-1224. 2 Kremer JM, Jubiz W, Michalek A, Rynes RI, Bartholomew LE, et al. Fish-oil fatty acid supplementation in active rheumatoid arthritis. A double-blinded, controlled, crossover study. Ann Intern Med. 1987;106(4):497-503. 3 Kremer JM, Lawrence DA, Jubiz W, DiGiacomo R, Rynes R, et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunological effects. Arthritis Rheum. 1990;33(6):810-820. 4 Wilson JS, Mruthinti S, Buccafusco JJ, Schade RF, Mitchell MB, et al. Anti-RAGE and A&beta; immunoglobulin levels are related to dementia level and cognitive performance. J Gerontol A Biol Sci Med Sci. 2009;64A(2):264-271. 5 Groopman, Jerome. How Doctors Think. Boston: Houghton-Mifflin Company, 2007. 6 http://celiac-disease.com/facts-statistics-about-celiac-disease/ 7 Petersen, Vikki, and Richard Petersen. The Gluten Effect. True Health Publishing, 2009.

Welcome to Functional Medicine Update for July 2009. We were very fortunate last month to start a two-part series on gluten and its relationship to immunological function. We had amazing interviews with Alice Bast and Dr. Doherty. That was a wonderful introduction to this important topic, but there are many questions still unanswered and we are going to pick up the topic again in this month’s issue. I don’t want to overpromise and under-deliver; there will still be unanswered questions at the end of this issue. This is an evolving story that is opening up at a very dramatically rapid rate and it would be presumptuous of me to suggest that we’ll be able to bring all the ends together and close this into a tidy, fully understood conclusion by the end of this issue. But I think we will make some extraordinary advances forward in our understanding of this issue, particularly because of the remarkable research that you are going to hear much more about from our researcher of the month, Dr. Kristina Harris, who works in the group of Alessio Fasano at the University of Maryland School of Medicine in the Department of Pathology. I think you are going to be absolutely amazed at what you are going to hear from Dr. Harris and her recent published work. What you will be hearing first is Dr. Harris’ interview about her work and the implications it may have beyond just celiac sprue. Then I will continue the discussion after the interview, and I will look at some of the other clinical implications, particularly things like neurological-related issues, such as autistic spectrum disorder. Without further ado, let’s get right to the heart of the matter with Dr. Harris.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Kristina Harris, PhD University of Maryland School of Medicine 10 S. Pine Street MSTF Bldg Room 8-56 Baltimore, MD 21201 This is the place in Functional Medicine Update where our energy rises because we have a chance to hear from a leading clinician or researcher of the month. We are going to be doing two-part series on a topic that is extraordinarily important. This interview will be one of the components in this two-part series on gluten/alpha-gliadin and its relationship to autoimmunity and celiac disease. The reason this topic really requires two parts is because this field is rapidly exploding with new information, both clinical and at the basic research level. To help guide this discussion, we are very fortunate to have with us Dr. Kristina Michelle Harris, post-doctoral fellow at the University of Maryland School of Medicine. I think Dr. Harris has an extraordinarily interesting background. She did undergraduate work at Southern Illinois University Hospital where she did a lot of work in histology, which gives you good eyes to the world because you are looking at how cells perform and trying to understand, from the morphology of cells and their architecture, their function. From there she went to the University of Maryland School of Medicine in pathology and recently finished her PhD there. I call her a young investigator because with each passing year it is amazing how many people now are young relative to my age (so I guess it’s a compliment to Dr. Harris). She has done some extraordinary work. I think the title of her thesis tells you why this is such an important topic for us to be discussing. The title of her thesis was “Investigation of IL-23 Response to Wheat Gliadin, the Primary Etiological Agent in Celiac Disease.”1 Many of you may already be tapped in to the connection, but if you do not understand the Interleukin-23 component, you are going to learn much more about it today. Dr. Harris has recently authored a number of important contributions to the literature. One of these articles appeared in the Journal of Immunology in 2008 and was titled “Cutting Edge: IL-1 Controls the IL-23 Response Induced by Gliadin, the Etiologic Agent in Celiac Disease.”2 Dr. Harris, we welcome you to Functional Medicine Update. How did your journey in life go from your work in histology into the work that you are doing now? KH: Well, that’s a very interesting question. As with most things, they just kind of tend to happen. I was doing histology at SIU because that was one of the only laboratories that I was able to get into immediately after finishing my Bachelor studies and I wanted laboratory experience, period. We had a great histology director there. I was doing that work for the spring semester. To get a full-time job I had applied to various positions out here on the east coast. Dr. Mann brought me in and he had a really interesting project dealing with vaccine adjuvants for cancer, which is work described in one of the first papers that I published.3 So I actually came to Maryland looking at cancer immunotherapy and Dr. Mann brought me in as a lab tech to do that kind of project. I did that for about a year. Another investigator here at the university is big in celiac disease research, and that is Dr. Fasano. He was looking for somebody to collaborate with in the field of immunology. At the time I was thinking about going back to school to do my doctoral studies, so we thought it would be a great collaboration to get together and let me kind of take over the immunology aspect of the celiac studies. I was particularly interested in the innate immune response because of the discovery of IL-23 and the IL-17 pathway in tissue-specific autoimmunity. JB: That’s a wonderful introduction. I like to think of myself as a student of science and a reader of the journals. Occasionally when we are reading science we hit on an article that just lights us up and it is an “a-ha” experience. I really want to compliment you because I think this cutting edge article in the Journal of Immunology that I described earlier (co-authored with Dr. Fasano and Dr. Mann) is really one of those “stand up in the crowd”-type articles. To me there are so many things not too far below the surface in this article that are extraordinarily important. It’s very rich and really good work. I think you are to be complimented on the quality of this work. Let’s get into it. KH: Thank you so much. Reviewing the Major Players in the Immune System JB: Thank you. For those who are not as familiar with the whole immunological cascade as you are, let’s kind of review the players in the immune system that relate to environmental responses in the gastrointestinal-associated lymphoid tissue (or the GALT). Maybe you could tell us a little about the dendritic cells and the peripheral blood mononuclear cells and how they get activated to produce pro-inflammatory cytokines, and the CD16 cells, and the Th-17. Maybe you could take us through the players so we understand the cast of characters. KH: With the gastrointestinal immune system, the epithelial layer really provides the first barrier to the environment. This is really a unique lymphoid organ because it is exposed to a vast array of exogenous antigens from food and commensals that line the intestinal tract. It is really important that the epithelial cells and these intestinal dendritic cells (which also can kind of extend their dendrites out into the lumen) have cross-talk and kind of maintain a nice homeostatic level of inflammation and a healthy gut. Upon insult by either an invading pathogen or tissue damage, these dendritic cells, or monocytes that come in from the peripheral blood, actually can sense various pattern molecules. When they detect these danger signals (as we like to call them), they will then become activated and secrete numerous types of chemicals that we like to call cytokines and chemokines, that then direct the downstream events (i.e. the adaptive immune response). JB: How does that relate to things we have often heard about: the thymus-dependent 1 and the thymus-dependent 2 (or Th1 and Th2) type of responses? We recognize that that is kind of a simplified view; there is really much more orchestration. KH: Depending on the combination of cytokines that these dendritic cells (or other types of antigen-presenting cells) secrete, that will ultimately direct which type of T-cell response you get (if it is Th1, Th2, or now the Th17). We also have regulatory T cells that are involved in all of this. It is really a complicated process with a lot of different entities interacting/controlling these responses. The Role of Toll-Like Receptors in the Signaling Cascade JB: Sitting on the surface of all of these immune cells are different receptors that pick up these messages (these exogenous messages), one of which is the family we have heard a lot about recently: the TLRs, or the toll-like receptors. Can you tell us a little bit how the toll-like receptors fit into this signaling cascade? KH: The toll-like receptors are considered a pattern-recognition receptor. They will recognize certain sugar structures/ lipid structures that are conserved on bacteria or fungus. Upon sensing them, they induce a cascade of activating signals within the dendritic cell that then leads to transcription of the pro-inflammatory mediators that I was describing. JB: Good. Now we are getting to the next level of complexity. Could you tell us a little bit about Th17? What is its personality relative to these thymus-dependent lymphocytes? KH: Sure. For many, many years autoimmune disease was ascribed to the IL-12/Th1 paradigm. I’m not necessarily saying that should be completely discarded because I think that’s still a really important part of the process. But now we have this other player involved-the Th17 cell-and it’s primarily thought to be a pathogenic memory-type CD4 T cell. In response to IL-23, IL-1beta, and perhaps IL-6 and TGFbeta, these cells will secrete pro-inflammatory cytokines that then recruit neutrophils and other types of cells that directly destroy the surrounding tissue. JB: Good. Now you have introduced IL-23, a new cytokine that has to do, somehow, with the antigen-presenting cell physiology. Where does that come from? Interleukin-23 (IL-23): A New Cytokine and Its Role in Cell Physiology KH: IL-23 is primarily produced by antigen-presenting cells, so dendritic cells, macrophages, monocytes. No one has ever provided any evidence of that any lymphocyte population can make this potent pro-inflammatory cytokine. JB: Is there a strong connection, then, between secretion of IL-23 and various autoimmune diseases, and if so does it cut across multiple autoimmune diseases or is it specific for a certain diagnosis? KH: Yes. There is a very tight correlation with increased levels of IL-23 in various different types of tissue-specific autoimmune diseases, so rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn’s disease-all of these autoimmune diseases have been associated with increased IL-23 production at the lesion. JB: I don’t want to lead you into saying something you don’t feel, but let me just tell you quickly about the functional medicine concept and see what you think of it. The functional medicine concept is less focused on differential diagnosis and more focused on what we call patient-centered assessment, which relates to antecedents, triggers, and mediators producing signs and symptoms of different duration, frequency, and intensity in the patient. So rather than what we call it, it’s where it came from that is the focus in the functional medicine model. To look at the antecedents, which in the model could be things like HLA-DQ2, for instance, and then we’d say a trigger could be gluten, and then a mediator could be IL-23, and it would span out into a variety of different clinical presentations depending upon the patient’s own individual characteristics. It is less what we call it; it is more the mechanism by how it got there. Does this, at all, ring into this model that you are describing with some resonance? A Focus on the Production of IL-23 Rather than Downstream Effects KH: Yes, exactly. That’s actually why I was so excited about this project and why I think it is so important, because upon discovering IL-23 and the Th17 pathway, it seemed like everybody was focused on the downstream effects of IL-23 (the specific effects within each different type of disease). But nobody was really paying attention or focusing on what was initiating the production of IL-23 and that’s why we decided to go that angle, because it seemed like if you block that then you could potentially have therapy for multiple chronic inflammatory diseases versus just one. JB: I’m having fun. I hope you are… KH: I am. Absolutely. JB: You are teaching me a lot. Now let’s move from that to celiac disease. In my past nomenclature, using the kind of differential diagnosis etiology model, celiac disease is considered a Th1-dominant disease. But now it would suggest, from what you are saying in your work, which you are going to go into, that this IL-23/Th17 pathway may open up different ways of thinking about celiac disease beyond just a Th1-dominant disease with no other confounders. Is that reasonable to say? KH: Sure. Yes. Absolutely. JB: Tell us a little bit about how you came to that understanding. Research Opens Up Different Ways of Thinking about Celiac Disease KH: We wanted to compare the innate immune response, looking at IL-23 and IL-1beta and the other innate-type cytokines in people that have celiac disease, and compare those responses to individuals that have the HLA type but are perfectly healthy and never developed the disease. We thought this might point us in the right direction of what is different between these individuals. What is so confusing about celiac disease is that about 30 &ndash; 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the normal healthy population share the DR3-DQ2 haplotype and are exposed to these dietary glutens regularly but they never develop the disease. We think that might be because they have different genetic polymorphisms in the genes that encode the innate-type proteins. We took peripheral blood cells from either celiac patients or the HLA-DQ2-positive healthy individuals, and we just exposed them, in vitro, to the gluten-derived antigen, gliadin. And then we harvested the cell culture supernatants and measured the levels of IL-23 and IL-1 and the other cytokines. What we found was that the peripheral blood cells from the celiac patients produced significantly higher levels of IL-23 and the related pro-inflammatory mediators in response to gliadin than did the healthy donors, indicating the IL-23 pathway may be part of the pathogenesis of celiac disease. JB: I don’t want to interrupt, but there is a question that was burning in my mind as I read your work and I may have missed this…I’ll ask the question and see if I missed it. In your healthy population, did that include any of the genotyped HLA-DQ2 or DR3 people that didn’t have symptoms? KH: Yes. In the paper that we published in JI, all of those healthy donors were DR3 and DQ2 positive and did not have disease. Study Focuses on People with the Genotype Who Do Not Express the Inflammatory Condition JB: I want to make sure our listeners understand that because I think this is a very critically important thing. There is 95{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} penetrance, if I’m not mistaken, in celiac disease, with HLA-DQ2, and DR3 positives, and so I think clinicians might think that that is a one-to-one correlation. But what we are saying here is that there are people with those genotypes who do not express the inflammatory condition, so it is only an antecedent, and it is not an expression pattern yet. KH: Right. I would say the majority of individuals that are DR3 and DQ2 do not develop celiac disease. Only like 1{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. JB: For the other 99{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of people with those HLA haplotypes, do they go on to get other autoimmune diseases or can we say that they are just like the run-of-the-mill people? They don’t have any increased prevalence of any autoimmune disease? KH: I think we can say that about 35{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of healthy individuals have that haplotype and remain healthy. But I would say-and I think it’s important for people, if you are looking for a possible diagnosis of celiac disease-if they have relatives that have other class II-associated autoimmune diseases, like type 1 diabetes or rheumatoid arthritis, etc., that those individuals are about 8 to 15 times more likely to develop celiac disease than someone that doesn’t have autoimmune diseases in the family. JB: I think that is such a clinically important observation you just made because in our functional medicine model (to restate what I’ve already said), what we call it is not as important as the soil in which it was embedded. If there is a family susceptibility to immunological disturbance, then it may present in one as MS, another in type 1 diabetes, and a third… KH: Right. JB: Exactly. Rather than the diagnosis being a kind monozygotic penetrance into the disease, basically. KH: Right. It seems like depending on the combination of what you inherit you may or may not develop one of these diseases. Gluten-Derived Gliadin Peptides and Innate Response JB: Let’s move to the next part of your incredible work. Tell us a little bit about what you think is unique about gluten-derived gliadin peptides and the response (the so-called PTGs-the pepsin-trypsin digest of gliadin), which I always find interesting because the pepsin-trypsin digest produce proteoids, or these peptides, that may have different immunogenicity or haptenic effects than that of the intact protein itself. Tell us a little bit about that. KH: When we do the pepsin-trypsin digestion we get a very heterogeneous product, which consists of basically at least over 50 different proteins. This makes it very difficult to narrow down what exactly is inducing the innate response (for me, anyway-I’ve actually been trying to do this for about the last four months now and I still haven’t been able to pinpoint exactly which fractions, or which epitopes, are inducing this inflammatory response in my dendritic cells). But we do know for the T-cell response, that the pepsin-trypsin gliadin contains epitopes that are particularly well-suited for the DQ2 and DQ8 binding pockets, so this has helped explain the DQ association and the adaptive immune response. But as far as the properties of gliadin that are inducing the innate immune response, I think it has to do with glycosylation, and I think that certain fractions of the wheat gliadin are probably involved because only certain fractions are thought to by glycosylated, whereas the others are not. But I have not been able to pin this down, so I can’t say that with any definition. JB: Again, I think where we are going here-where you are taking us, not where we are going, you are taking us-is extraordinarily important new territory. Even without having the answers, the questions themselves are very clinically important. For the sake of the clinicians who are not necessarily immunologists, let me make sure that they are following along. Dr. Bland Summarizes the Research You have observed that these pepsin-trypsin digests of gluten, which have this composite of different weight molecular peptides, some of which are glycosylated and some of which may not be as glycosylated, can trigger monocyte release of IL-23, and there then could be immune-dominant epitopes present within that mixture-you’re just not yet sure which they are when you do a fractionation-but some of them do have preferential binding for the pockets of HLA-DQ2 and DQ8 or DR3. Am I summarizing what you just said correctly? KH: Yes. Excellent. JB: Now the question that we might have is: Given that this pepsin-trypsin digest that we do in a test tube is at least similar to what goes on in the human…? KH: Right. We do this because this is supposed to be most representative of what happens in the digestive tract. JB: So now we have different digestive functions among different people. KH: Exactly. JB: So could that account for differing populations of these immuno-dominant epitopes from gluten? KH: Perhaps. JB: Part of your work, I think, will be taking us through something related to looking at how things need to be broken down maybe to lower their immunological memory. KH: Exactly. Different Results with Synthetic Peptides JB: So now let’s ask a question that I know you have studied because I’ve seen it in the paper. What happens if you make synthetic derivatives of the alpha gliadin-type peptide sequence? I know you are studying incubated p31-43 alpha-gliadin peptides, or 25 overlapping synthetic peptides spanning the entire sequence of alpha-gliadin. What did you learn from that, with these synthetic peptides? KH: These synthetic peptides did absolutely nothing as far as inducing the pro-inflammatory response that I get with the whole pepsin-trypsin digest. They are missing something. They are not the proper structure, and they don’t have any of the post-translational modifications. It is just peptide. I really do think that ultimately it is going to come down to some carbohydrate structures on there that are important for the innate immune response. Beta Glucan Also Showed Positive Response JB: That ties to something that for a lot of the clinicians listening may be kind of an “a-ha” for them (it was an “a-ha” for me). I think I knew it, but you really drove it home with your article much more strongly for me. Tell us a little about beta glucan, because beta glucan also showed positive response in IL-23 as I read your paper, but we don’t think of beta glucan as being a gluten-related molecule. KH: Right. We used beta glucan because other immunologists had used that. Mainly they’ll pick beta glucan from yeast or something to induce the IL-23 immune response. We opted to go for beta glucan from barley because barley is one of the triggering agents in celiac disease. With beta glucan you just have glucose molecules; I think it is over a thousand glucose molecules that make up beta glucan. What we found is that if we just add beta glucan alone, that we could induce IL-23 from the monocytes and the DC subsets. What was interesting is that it took way higher concentrations of the beta glucan compared to the pepsin-trypsin digest of gliadin. On the one hand it looks like we are getting a similar response, but I don’t know that they are initiating it the same way. It seems more likely that the pepsin-trypsin gliadin might be using a 2-receptor signal because there is protein and carbohydrate and multiple epitopes in there, whereas the beta glucan is just a bunch of glucoses. JB: I think it is important, again, for clinicians who are listening, to make sure they understand this concept of structure/function. Yes, beta glucan is just a polymer of glucose, but it has a specific branched configuration of the way glucoses are put together into the polymer that is different than starch, amylose, or dextrins. I believe this construct that shape of molecules triggers immunological response is a very important part of the story for people to understand because I think there is a simplistic view in the minds of many that somehow gluten is just a foreign protein no matter what we call it, when really gluten is just a descriptor for a whole complex array of molecules that are both in the gluten fraction and can get further broken down into other peptic digests that then have different personalities, so we have to be conscious about what we call things, I believe. KH: Right. Absolutely. In fact, I really don’t like that gliadin is called gliadin because it seems singular. Whenever anyone ask me, “What is it?” they expect me to say, “It’s an octopeptide,” or something, but it is a huge array of proteins. You are absolutely right. JB: In your paper you made an interesting comment. I’d have to say it is pushing at my edge of understanding, so maybe you can help us. You said (as I recall) that the response from this work with the synthetic peptides and the p31-43 alpha-gliadin peptides suggests that the response had to be derived from beta, gamma, or omega gliadin, not necessarily alpha. Could you help me understand what that means? Innate Immune Response May Be Tied to Omega Gliadins: More Research is Needed KH: Sure. Within gluten there are the two main protein fractions: gliadin and glutinen, which are also thought to be antigenic in celiac disease. But then gliadin can be broken down further into four other fractions: omega-5, omega-1,2, alpha beta, and then gamma gliadins, depending on their amino acid structure, their glutamine content, and their molecular weight. The synthetic peptides that we used were based off the alpha-gliadin structure. We didn’t look at any of the other (the omegas or the gamma gliadins). Actually the omega gliadins are the ones that have been shown to be glycosylated. I really think that these are going to be the ones that are important for inducing the innate immune response, but I haven’t proven that yet. Could Different Cultivars Be Related to the Increasing Frequency of Gluten-Related Problems? JB: I’ve had this question asked of me: “Doesn’t it seem, Jeff, interesting to you that this frequency of gluten-related problems seems to be increasing at a fairly dramatic rate in our population?” If you look at the literature it went from 1 in several thousand to 1 in (depending on what literature you want to look at) 300 or something like that. Could this be because we have different cultivars of wheat now, or grains, that have differing epitopic presentations, or is it that our immune systems (as humans) are all confused? Could it be the fact that what we think is gluten isn’t the same gluten that we ate when we ate the original cultivars in Italy, or something? KH: I think the different cultivars could be part of it. I also think a lot of that increase in frequency has to do with detection methods, because a lot of cases went undetected for awhile. As far as immune response, there is still the issue of molecular mimicry. If you have more virus or vaccines that might be triggering immune response it might, accidentally, cross react with gluten peptides. All of these things could contribute to the increased incidence. Could Gluten Sensitivity and Autistic Spectrum Disorder Share Common Factors Related to Immunological Alteration? JB: That’s very interesting because one of the questions that I’ve had asked of me is, “Do you think there is a correlation between the rising frequency of what we call autistic spectrum disorders, which is immunologically related dysfunction, and that of gluten sensitivity?” It doesn’t necessarily mean one causes the other, but maybe they share common factors related to immunological alteration. It’s an interesting hypothesis. KH: It’s very interesting. This has caught my attention on several occasions. Recently it seems like there is a lot of autism awareness out there. And rotavirus-that one really perks my ear because there are antibodies in celiac patients that cross react with rotavirus. There does seem to be a connection, here. It is definitely something we need to think about. JB: Again, I’m trying to be cautious not to lead you into things that you feel uncomfortable saying, but it seems to me in reading your papers that the HLA-DQ2 genotype in symptom-positive people may not have a severe presentation of symptoms unless there are other underlying factors like the things that stimulate IL-1beta production, because it seemed like IL-1beta aggravated the production of IL-23 and maybe made the condition more amplified. Am I on the right track, here? KH: You are, yes. That was one of the surprising things we found, that IL-1beta, alone, could induce secretion of IL-23. So if you have a situation where you have overproduction of IL-1beta, which is a pro-inflammatory cytokine, versus its natural inhibitor, the IL-1 receptor antagonist, then ultimately you would be driving an IL-23 response. This is an imbalance that has been noted in multiple different types of chronic inflammation. It goes back to that functional medicine [concept]. JB: The basic concept of kind of a network biology approach to looking at the immune system… KH: Right. JB: So if you had an underlying inflammation that was associated with higher levels of IL-1beta and lower levels of IL-1 receptor antagonist and then you laid on top that a DQ2 and a gluten diet, now you might be loading the dice, is what we are saying. KH: Right. JB: You can see-I’m tracing with you my thinking as I walk through your paper-why it was so profound for me. It then suggests that there are other inflamed tissues beyond the mucosa of the small intestine that could be influenced because it might be produced locally but act globally, and so we start talking about IL-1beta inducing IL-23 p19 mRNA in human synoviocytes and myofibroblasts, which suggests to me that maybe things happen systemically from what we thought of as a regional GI problem. Is there something to that? KH: Well I definitely think that the gut is connected to just about everything else. I don’t know if you are aware of the skin condition of celiac disease (the dermatitis herpetiformis), where people actually develop skin lesions and if they go on a gluten-free diet then it is completely remedied. And then there is also gluten ataxia, which affects the nervous system. So I think this immune response that may initially start in the gut can definitely affect extra-intestinal sites. JB: That would talk, clinically, to things like the reports talking about MS-like symptoms in patients with neuritic plaques that, when put on a gluten-free diet, the plaques remain but the symptoms go into remission. KH: Yes. JB: There may be something about neuritic inflammation, here, beyond just a plaque formation. KH: Yes, or the autistic children that go on a gluten-free casein diet and seem to do much better with that. JB: This leads us to ask how we take all of this extraordinarily interesting and complex information and take it from the research lab to the clinic. Are there certain tests that we should be doing? What about genetic testing for celiac predisposition? What kinds of things lead us to the right questions, as a clinician? KH: I think the first thing is heredity. Does the family have a history of other autoimmune-type diseases? And then the test for detecting celiac disease is relatively easy-you just do the antibody for tissue transglutaminase from the peripheral blood (at least for the screening). So that would be an easy way, I think, to screen for celiac disease. JB: And if a person was found on a genotypic test to be DRQ2-positive, meaning at-risk to gluten-related sensitivity, but they didn’t present with clinical symptoms, would they go on a gluten-free diet, do you think, or do you think they would look for the antibodies, or they would look for mucosal biopsy? KH: Do the mucosal biopsy. I don’t want to complicate matters, but there is also gluten sensitivity that isn’t celiac disease. And only half of those people have the DR3-DQ2 haplotype. This is yet another facet of what dietary gluten can do. JB: How can that be? Tell us a little bit about that. How can you have this immunological thing going on without having digestive…. Multiple Factors May Be Involved in Innate Immune Response KH: Well they don’t develop the autoimmunity, so it appears that it gets initiated. With what I am doing perhaps maybe the gluten is inducing the innate immune response, but then at some point it gets regulated. But these people are uncomfortable; they don’t feel well, but their intestinal epithelium is still intact. But they do have an infiltration of lymphocytes within the epithelium, and if they go on a gluten-free diet then it remedies. This is new information to me and I’m still trying to process it. It’s very interesting that only half of them are the DQ2. I think that perhaps the combination of genes that may be involved in the innate immune response may be the same in these individuals and those with celiac disease, but yet there are other genes or environmental insults that are then adding the push toward to the autoimmune disease and celiac disease, but that doesn’t occur in these individuals. JB: Wow. KH: And it is not an IgE allergy, either. We’re not exactly sure what it is yet, but I’m just putting it out there. Could Probiotics Favorably Influence the Antigenicity of Gluten in People with Gluten Sensitivity? JB: That’s fascinating. I could continue this discussion ad infinitum, but I’ll restrain myself and ask just one last question. I have seen some reports recently (preliminary reports) suggesting that there are enteric bacteria, or what might even be called probiotics, that could favorably influence the antigenicity or the epitopic sensitization of gluten in people that have gluten sensitivity.4,5 Have you seen any of these reports and if so is there any plausible mechanism that you can think of from your work that would explain that? KH: I haven’t read those reports yet, but as soon as I get off the phone with you I’m going to because I had actually thought of this, too, with regards to the IL-1 receptor antagonists and the IL-1beta story. I had thought that if you could introduce a probiotic or something that would upregulate the anti-inflammatory mediators, such as IL-1RA, that that might be protective for patients with celiac disease. That would be a possible mechanism-that these probiotics are inducing immunoregulatory mediators that are keeping the immune system at bay. JB: I can’t tell you how much I appreciate this. You should see my face-I’ve got a big smile. This conversation really lights up every neuron of cognitive interest that I’ve got because I think you are really bridging many different disciplines. This is truly integrative, translational research. I think it is opening up a whole new door. I think it is courageous research because it is not so siloed; it has many different implications. I applaud what you are doing, and if you stay on this track we are going to be hearing your name all sorts of places because this is very important work. I hope you are getting support from your associates and from the funding agencies to continue this work. KH: Thank you so much for having me. This is really quite an honor to get to do this. I really appreciate it. JB: I just want to say in close that this is, as I said, is the first time in 27 years that we have had a new investigator who is in the first phase of her clinical and basic science research talk to the community. I say this sets a very good precedent. Thank you very much for charting new territory for us. KH: Thank you. I hope that you were as excited and stimulated by the discussion that we just had with Dr. Harris as I was. This is one of the landmark, threshold-types of discoveries, I think, in terms of helping us to understand and pull together information about gluten and its effect on the immune system. Why are we seeing more prevalence today? Is there a difference in the composition of gluten? What about our grains and our agricultural methods and our seeds? And how about the body’s immune function? Are there other covariables that work together to trigger immunological dysfunction and make a person’s reaction to gluten more prevalent? All of these are very, very interesting questions. And then what does the gut have to do with this? Is the gut ecology of some importance as it relates to gluten sensitivity? That question will be further advanced as we move into the August 2009 issue. We are going to be discussing with Dr. Delzenne and Dr. Cani (from Université catholique de Louvain in Belgium) some extraordinary work they are doing on the gut microecology/the microbiome and its relationship to immunological function. Dr. Bland’s Interview Takeaways Let me go back and pick up a couple of the very important points laid out by Dr. Harris in her interview (to review a couple of the clinical takeaways). First of all, we recognize celiac disease is categorized as a member of the autoimmune disease family related to auto-antibodies of the small intestine that then lead to localized and regional inflammatory response and ultimately can produce histopathology of the small intestine. We recognize that there are certain genetic lineages or linkages to this condition through the HLA-DQ2, and to some smaller extent the HLA-DQ8, polymorphisms, which then code for increasing susceptibility to adverse or immunological response to gluten. This appears to have some relationship to the composition and structure of individual members within the gluten family. Gluten is a Term that Applies to a Family of Different Proteins Recall, if you would, that gluten is a term that applies to a family of different proteins that have similar electrophoretic mobility and similar kinds of personalities as it relates to their primary amino acid sequence. But there may be differences in specific composition within the members of the family as it pertains to post-translational glycosylation reactions, and so they may have different degrees of glycosylated residues that change their epitopic personalities slightly, one member to another. So we might say “gluten” as the general generic family, but we really should be talking about the specific members within the gluten family that are the antigenic determinants that really create these autoimmune-type responses in genetically susceptible individuals. I believe Dr. Harris said that the HLA association only accounts for about 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the genetic requirement for Crohn’s disease, celiac disease, and its relationship to gluten. It’s not just kind of a hard-wired genetic effect; there are many people that are carriers of the HLA-DQ2 polymorphism that never experience celiac disease, even when consuming gluten in their diet. Why? Why are some individuals experiencing the condition and others not? I think that is the environmental functional variable that is the interesting component of Dr. Harris’ presentation. The Relevance of Dr. Harris’ Research What did the Harris and Fasano group really help us to understand? They helped us understand that although many individuals that carry the DQ2 and the DQ8 polymorphisms who consume gluten never experience the disease, there are other variables that relate to the specific personality of these antigenic determinants and autoimmune disease in these individuals that modify the expression of these characteristics. Their group recently provided the first evidence that this IL-23 immune response pathway may be involved in the cascade of events that manifest themselves ultimately as celiac disease. This new connection to IL-23 and its connection back upstream to the release of IL-1 and TNFalpha by the gut-associated immune system may then help us to understand covariables that set the stage for the DQ2 and the DQ8 polymorphisms to be more susceptible to expressing themselves as celiac disease. So we are talking about covariables, or modifiers (other factors within the web that set the stage for the person, then, to express these characteristics more overtly as celiac disease). So this IL-23 immune response pathway is involved in the cascade of events that manifest as celiac disease. IL-23, as Dr. Harris pointed out, is a potent cytokine that is related to innate immunity. It has been implicated in the pathogenesis of other tissue-specific autoimmune diseases, particularly those that influence the endocrine system, like thyroiditis. When we go into this discussion a little bit more deeply, we’re talking about systemic autoimmune susceptibilities, as well as regional effects on the gastrointestinal system. I think this is where the topic gets much more broadly implicated for looking at immune-related dysfunctions of a wide variety of different diagnostic codes, including, possibly, even those of the nervous system (having to do an anti-myelin antibodies/anti-phospholipid antibodies) with cardiovascular disease), and spreading this into other areas where we have this immunological activation that occurs systemically through these pathways. The downstream effects of IL-23 have been the primary focus of autoimmune research recently. The agents that initiate the production in the context of autoimmunity are still being developed or understood. By looking at IL-23 response induced by gliadin, Dr. Harris’ and Dr. Fasano’s group was able to actually demonstrate that this (for the first time) looks like a primary etiologic agent in the expression of celiac disease. And what they went on to show, just to remind you, was that the CD-16 monocytes were identified as the primary source of IL-1beta, and ultimately trigger the production and expression of IL-23 as related to the ingestion of gluten. It was found to be significantly overexpressed in the peripheral blood mononuclear cells from Crohn’s disease patients, suggesting a role for this activated pathway in the pathophysiology of Crohn’s disease. Neither monocyte-derived immature dendritic cells, nor monocytes that were colony-stimulating-factor-derived macrophages recapitulated the response, however (as was discussed by Dr. Harris), incubation with interferon gamma generated a population of these dendritic cells that ultimately secreted IL-23, IL-6, and tumor necrosis factor alpha upon exposure to gliadin. There has to be the priming of the cells by some kind of low-grade inflammation, it appears, before these cells become reactive to gluten and then release IL-23 and start this cascade of events that seems to be associated with the pathophysiology of Crohn’s disease. These are obviously novel findings. They are pretty remarkable new findings that suggest a functional role for a number of candidate genes other than just HLA-DQ2 and HLA-DQ8 that are associated with altered innate immune response and activation of certain pathways associated with inflammatory conditions, and even suggests that there has to be a presaging, low-inflammatory potential going on at the gut to amplify the relative expression of cells that secrete IL-23 and start the cascade of events that we ultimately diagnose as Crohn’s disease. As you heard from Dr. Harris, one of the other interesting features of this work was the recognition that you could initiate some of the same response by agents other than gluten that are found in specific foods. Admittedly, these agents had to be at higher levels in order to initiate this reaction, but it didn’t appear as if it was necessarily gluten-specific; there were other reactive molecules that were glycosylated glycoprotein-type molecules that could initiate these IL-23 responses as well. One of the most remarkable features of this discussion with Dr. Harris-and I’m sure you took this away-was that the patterns of glycosylation of specific gluten proteins appeared to be directly related to the effects they would have on triggering (through a specific cell type) the release of IL-23 and initiation of this condition. That would suggest that if you had gluten without certain glycosylation patterns of those proteins it might still be gluten in terms of its definition by electrophoretic profiling on a protein map, but it may not be an antigenic determinant/epitopic determinant for this immune-type response that produces inflammation. This may explain-I want to speculate on this for a moment-why people have been able to travel in certain places in the world that have other cultivars of grains and consume wheat-like products, and have more tolerance of those wheat-like products than they have had by eating grains in the United States. Could our glycosylation patterns of gluten proteins have been modified through genetic hybridization in such a way that we actually are starting to witness altered epitopic determinants that then trigger this cascade of events that leads to IL-23 release and so forth? That’s a question that I don’t think has been fully resolved nor answered, but I think it is a very interesting operational question that deserves more explanation and exploration. This may also help us to understand why there have been reports that have demonstrated that various types of enzyme preparations, when orally consumed, may help patients who were previously gluten sensitive tolerate gluten-containing grains. The increased digestion resulting from breaking down glycosyl residues on gluten proteins and reducing antigenic polypeptides down to leuko-antigenic digestive products may then result in lowering the memory of antigenicity and making them more neutral to the immune system. We are starting to witness examples of possible therapeutic agents that can be orally administered to try to make these grains more tolerant to people that have some degree of sensitivity (immunological sensitivity) by reducing their immunological recognition to the inflammatory cascade, presumably by their influence on gut-immune function and ability (possibly) to secrete enzymes that help break down glycosyl residues and alter the antigenic determinants within these gluten-containing molecules. What we are starting to see is the gastrointestinal milieu or the gut microbiome may play roles also in increasing or decreasing the relative sensitivity to gluten. This opens some very interesting and important potential therapeutic doors. For most patients, when you tell them they have to be on a total gluten-restricted diet (gluten-elimination diet), it’s a very, very complicated thing to live in the “normal” world because gluten, in very small amounts, is found in so many different products and even at trace amounts may contribute to this sensitivity. If one could make it more easy for a patient to actually modify their gluten intake by still being able to live in the normal world, this would improve compliance, adherence, and certainly improve clinical outcome. It may be that new digestive preparations-enzyme preparations and different strains of probiotic organisms–can help to improve gut ecology and gut function in such a way as to lower the immune reaction to certain levels of gluten-containing materials. I want to emphasize there are those people who are exquisitely sensitive to these molecules. It is like a peanut allergy: sometimes peanut oils being cooked at a restaurant can produce enough antigens in the vapor to trigger anaphylactic response in a person who has a peanut allergy. I don’t want to underestimate the seriousness of gluten reaction and immunological sensitivity. I think it is important to demonstrate or to at least understand the range of reactions that people can have (from very acute immune response to more mild response). I’m speaking about modifying those that are more on the mild end of gluten response, and making their regime and diet a little bit more easily complied with. For those people that have the extreme gluten response, I think elimination (rigorous elimination) is the sine qua non for their management. There is a clinical art in this; it can’t strictly be determined by antibody testing. I think the proof of the pudding is the clinical outcome in the patient with elimination/provocation. People that can’t even stand 20 parts per million of gluten in their food are those individuals who are obviously on the side of very high sensitivity and have a large immunological reaction. But, as has been pointed out, one of the variables that can lower sensitivity to gluten (based upon the work of Dr. Harris and Dr. Fasano) is to lower the general immune response and inflammation vigilance of the gut-associated lymphoid tissue by resetting the gut function. There are many people that have chronically activated gut-immune system inflammatory response just by the nature of eating a high fat/high sugar diet; they put the immune system of their gut on notice continuously. Do you know the old Pasteur saying “Chance favors the prepared mind”? If the immune system of the gut is already activated then it is more readily sensitized to other triggers, like these antigenic determinants/epitotic determinants in gluten, which can put the straw on the camel’s back and push this over into an acute inflammatory response. I think gut ecology becomes a very important part of the therapeutic approach towards patients with gluten sensitivity. Even for those patients (as Alice Bast pointed out in the June issue) that have been put on a rigorous gluten-free diet, often years of activation of their gut function results in inflammatory, low-grade, chronic problems of their gut-immune function, which needs to be normalized to restore really good health and to get them feeling good again and to absorb nutrients more effectively and restore their gut mucosal absorptive surface. I think the 4R Program, which we’ve discussed so many times over the years inFunctional Medicine Update becomes, again, such an important clinical tool: Remove, Replace, Reinoculate, Repair. I think this is almost like a mantra if you have listened to Functional Medicine Update over the years. “Remove” means to get rid of the organisms that may be parasitic or those organisms that could produce toxic byproducts. Get rid of the food allergens, get rid of the environmental chemicals that might activate immune-gut dysfunction. That is the Remove “R.” The next one is “Replace.” That is to assist by improving digestion and bile acid secretion. If necessary, this can include exocrine pancreatic replacement therapy using digestive aids to acidify the chyme in individuals that have aplastic anemia type-B with parietal cell loss and low stomach acid secretion and have an under acid chyme that then produces a lowered stimulation of bile release and pancreatic enzyme release. Again, there is a clinical art in this to balance the patient properly, to improve their digestive function through the second “R,” the Replace phase. The third “R” is Reinoculate. This is where we add back the friendly probiotic organisms, the symbiotic bacteria, and has to do with the use of both prebiotics and probiotics in combination. We’re going to talk about this in much more detail with our clinicians/researchers of the month in the August 2009 issue, Professor Delzenne and Dr. Cani. The last “R” is the Repair phase of the 4R program, which is adding back those nutrients in adequate quantities that help to restore proper gut mucosal activity, knowing that the gut mucosa turns over every week or so and it is replaced. The gut is a constantly regenerating cell line and so we want to give it back the nutrients necessary (L-glutamine, L-arginine, pantothenic acid, zinc in a non-irritating form, vitamin E), a variety of agents that help to restore proper gut-immune function. It may even have to do with the addition of certain phytochemicals that help to balance the gut-immune-inflammatory response, like curcumin from turmeric, or ECGC from green tea, or iso-alpha acids from hops, all of which have been demonstrated to have favorable effects on gut-immune-inflammatory response. These are, I think, very interesting approaches that can be employed clinically. People have often asked me over the years, “In functional medicine, if you were to develop one tool from the tool kit of the functional medicine process, what would you go to first? What would be the most important singular tool to develop expertise with?” I would have to say it is the 4R program. Once a clinician becomes comfortable and skilled in the art of applying the 4R program, they will be amazed at how many patients with a wide variety of complaints–from dermatological to neurological, gastrointestinal to cardiovascular, insulin to even things like metabolic syndrome–improve. This gut-immune connection to so many functions of the body is one of those very important cornerstones in the functional medicine matrix. I know I have said this probably ad nauseum, but the 4R program is really more than just an acronym to recite on demand. It really becomes a series of very important clinical steps in designing a program personalized to that patient’s need to use their gut-immune system as a friend rather than a foe and to allow them to be more tolerant to this complex environment (nutritional, internal, and outside environment) that we are exposed to. Going back again to Dr. Harris’ comments, I think it is very important for us all to recognize that the personalized response an individual has (notwithstanding their HLA determinants that give them some relative risk–the HLA-DQ2 and HLA-DQ8) to gluten is going to depend upon things that relate to the gastrointestinal milieu and the underlying sensitivity that the GI immune system (the gastrointestinal-associated lymphoid tissue and the mucosal-associated lymphoid tissue, or the MALT) have to the local environment. Balancing the immune system of the gut, using appropriate prebiotics and digestive aids, and of course using either a rotation or an elimination-type diet become the sine qua non for better clinical approaches towards this problem. This also relates, obviously, to other kinds of inflammation modulating nutrients. In last month’s Functional Medicine Update, we talked about omega-3 fatty acids and the favorable role they have on immune modulation. We have also talked about such things as stabilizing insulin using a low glycemic load type of diet because high insulin levels can be contributing to proinflammation and activation in the gut of various types of cell proliferative processes and inflammatory immune response. Again, we use a systemic, network-thinking-type of approach to this problem. It is not just solely elimination of gluten in the absence of looking at all these other covariables that may be modulators of both the susceptibility and the severity of response to the triggering molecules (the glycosylated versions of gluten). Exploring a Connection Between Gluten Sensitivity and Central Nervous System Disorders, Including Autistic Spectrum Disorders (ASD) With that in mind, then, let’s finish up this discussion by taking one more step forward by talking about the connection between gluten and central nervous system-type problems. The one that has been in the news most significantly of late is autistic spectrum disorders, or ASD. I know this is a very controversial topic and I don’t want to make a very complex topic overly simplistic and be misleading, but I do believe that there is increasing evidence to support the fact that ASD, as it expresses, is not just a sole response to a monozygotic genetic linkage. It is a lot like this gluten connection to autoimmune diseases. There may be genetic linkages that increase the relative susceptibility, but it is not just a gene that produces this condition called ASD in absentia to other covariables. There are many covariables that can modulate the immune system in such a way as to result in activation of brain neuronal pathways that ultimately present themselves as this definition of autism or autistic spectrum disorders. I am reminded of this from my experiences at the Institute for the Achievement of Human Potential in Philadelphia, PA, where they have worked with what they call mid-brain-injured children, who are really those that are often diagnosed as autistic. By utilizing their approach, which is a multi-phasic and multi-parameter approach using physical training and nutrition and stimulation, patterning, many of these children (who have very significant difficulties) have achieved significant improvement over the course of therapy, with their parents providing the therapeutic approach at home. The approach involves dietary modification, including taking antigens out of their diet and encouraging improved nutrient quality. This requires getting these children on higher protein diets and lower sugars and simple carbohydrates-the things that most of us would think are important for overall health. Getting these children into proper programs of structured physical and neurological training-all of this is part of the approach. I think it is very interesting that they have recognized the importance of gut ecology in these children as well-I guess you would call it gut hygiene. Getting these children to have regular bowel movements and applying the 4R Program in ways that can conveniently be done at home by the use of probiotic and prebiotic organisms and so forth. We recognize that this complex etiology that we call autism has many different variables, but one of the interesting variables appears to be oxidative stress (what we call oxidative neuronal stress). Where does oxidative neuronal stress emerge? What is the triggering agent? I don’t think it is “the” triggering agent, I think there are many triggering agents for neuronal oxidative stress in specific regions of the brain. Certainly one of these can be hypoxia. Overview of the Biochemistry of Oxidative Stress We recognize that one of the most paradoxical situations is that oxidative stress occurs in the states of low oxygen tension within tissues, which seems almost counterintuitive. How could a low oxygen tension produce a high oxidative potential within tissues? The reason for it, simply (not to go into the very complex biochemistry), is that lowering oxygen tension in an oxygen-requiring environment alters mitochondrial redox potential (the reduction/oxidation potential), and shifts that redox into a state where you get incomplete oxidative chemistry and you get more intermediate free radicals being formed (these are both oxygen and nitrogen free radicals) that can be involved with what we call oxidative stress or free radical pathology. Ischemic events are associated with a whole array of different neurodegenerative conditions, some of which are related to autism itself. Study on the Effects of Hyperbaric Oxygen Treatment in Children with Autism There is this very nice clinical trial that has recently been published in BMC Pediatrics in 2009.6 This is a collaborative group of investigators working with autistic children and their families across multiple centers that have been looking at the effects of hyperbaric oxygen treatment with children with autism. This is a multi-centered, randomized, double-blind, controlled trial that includes the International Child Development Resource Center, the Center for Autism Research and Education, the True Health Medical Center in Naperville, IL, the Princess Anne Medical Associates in Virginia Beach, Therapeutic Pathways in East Troy, WI, Biognosys in Nanuet, NY, and the Rimland Center in Lynchburg, VA. These centers looked at 62 children from ages 2 to 7 with a mean age of about 5 years, randomly assigned to 40 hourly treatments of either hyperbaric treatment at 1.3 atmospheres and 24{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} oxygen, or slightly pressurize room air, and looking at the Clinical Global Impression outcome, the Aberrant Behavior Checklist, and the Autism Treatment Evaluation Checklist response. They found very significant improvement in the treatment group that got the hyperbaric treatment versus those children that did not. How does it work and why does it work? Why do these kids’ brains not seem to be getting enough oxygen? Is it a respiratory problem? Is it a transport problem? Does it have anything to do with anemia? Does it have something to do with mitochondrial oxidative phosphorylation (you have to force the furnace of the cells to work harder)? There are many, many variables, obviously, that regulate oxygen delivery to the brain. I find this a very interesting study because it was 50 some years ago that the Institutes for Human Potential (the Domans being the principals there) started talking about childhood neurological problems being associated with a deficiency of the most important nutrient in the brain, oxygen. They really framed their whole program around ways of helping that child to deliver better oxygenation to the brain through physical training, mental training, and nutritional intervention. There is a convergence, I think, between this work of hyperbaric treatment for children and ASD and the work being done for 50 some years to improve oxygenation. At The Institutes for the Achievement for Human Potential, they have even developed a therapy called inhalation therapy, using rebreathing (bagging the children) to improve the CO2 and get the bore effect to drive more oxygen into their cells, and showing significant improvement in many of these kids (the technique is also called masking). There certainly seems to be something about oxygenation of the brain and these children with these “mid-brain” or autistic-related changes. How does that relates to things like immune function, perfusion, and endothelial function? Think back, if you would, about delivering oxygen. It has to do with vascularization. It has to do transport of oxygen. It is not just necessarily passively diffusing; it has to be transported and delivered to the site where it is used. The reducing agent and the oxidizing agents that are present in the mitochondria control the energy efficiency of the body, so you need to have an oxidizing agent and you need to have a reducing agent. The reducing agent comes from nutrients and the oxidizing agent comes from oxygen, so you get this ability to have the oxidizing agent reduced into water (molecular oxygen, or diatomic oxygen). I think we are starting to witness kind of a theme emerging that takes an observation (hyperbaric oxygen treatment improving clinical outcomes in autistic children), and ties it back to a complex mechanism of understanding of why oxygen could be a limiting nutrient in those children and what factors we can use other than hyperbarics to improve oxygenation, oxidative chemistry, redox potential, mitochondrial oxidative phosphorylation, and neuronal energy production. This ties into the interview we had with Jill James on autism a year ago in which she talked about the work she is doing in glutathione as a centrally important substance and as an intercellular redox agent (cellular antioxidants that couple between glutathione and oxidized glutathione disulfide). How does the glutathione connection have anything to do with the hyperbaric connection that has anything to do with the gluten connection that has anything to do with what we know as nodular ileal hyperplasia and its relationship to immunization and that of autism? All of these things are interrelated, one to the other through a process of distortion of the web of the immune system and function and its influence on vascular function and inflammation. I think that an emerging theme-a conceptual framework: to look at autism with a broader lens from a functional approach. There may be genes that ultimately determine relative susceptibility in certain children, just as there are genes that determine susceptibility to gluten-induced celiac disease (as we have mentioned, the HLA-DQ2 and DQ8). But those genes in and of themselves are not the sine qua non determinants of the expression into the disease. It is other environmental modifiers that regulate promoter regions of genes and may have epigenetic influence on how genes can ultimately be expressed that then become the modifiable factors that relate to the expression of that condition. Delivering oxygen through hyperbarics may treat an oxygen deprivation condition in the region of the brain. This begs the question: why did that person have that oxygen deprivation? What led to the poor relative perfusion of certain regions of the brain that power up mitochondria? Could it have been an immunological problem that leads to a vascular constriction, or endothelial dysfunction, or to toxic burden on mitochondrial that then downregulates the activity of the electron transport chain and requires more oxygen to drive this process through? All of these are questions that I think are very important as we start to look at the environmental links to this rising tide of autistic spectrum disorder that is seen in our society. I believe that what Dr. Harris has shared with us as it relates to her (or their) emerging understanding of the mechanism, has a spreading effect into a variety of companion relationships that connect the gut to the immune system to the nervous system to bioenergetics to redox potential, and ultimately even into these observations of the beneficial effects of hyperbaric oxygen in treating children with autistic spectrum disorder. This, to me, is the language and logic that underlies the functional medicine model, versus that which is singular in its drive to a diagnosis and then once a diagnosis has been determined, finding the drug that modifies the endpoint that correlates with that diagnosis. Obviously the functional medicine model, as I am describing it, has some degree of confusion. It is not as comfortable because it doesn’t have the clear edges that the diagnostic model has in which you have a comfort zone, and can say, “I now have a diagnosis and I now have a drug or a series of drugs that I can use for the treatment of that condition that matches that diagnosis.” In the case of what we have been describing over the last two issues ofFunctional Medicine Update as it relates to this gluten story, we can see that there are many variables that intersect to give rise to increasing relative susceptibility and severity of response to a trigger, which in the case of gluten, could be celiac disease as the endpoint. What we have said is that you not only need to deal with the immediate obvious trigger, but you need to also be considerate of the environment in which that trigger is operating, because only 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the people with the genetic susceptibility ultimately have the trigger lead to the mediators that are associated with celiac disease. We also then said this relationship of an environmental agent (in this case, the dietary agent gluten), in the form in which it has epitopic relationship with the immune system (so specific glycosylated forms of the gluten molecules) then triggers, in effect, not only regionally but systemically, and so that correlates with things like autoimmune thyroiditis. It correlates with things like anti-phospholipid syndrome that now is associated with vascular disease risk. It correlates with dementia and neurodegenerative diseases. You can only understand those “comorbidities” if you understand the potential mechanisms by which this immunological shift can occur in the patient and the variables that augment or modify its expression. That is, I think, the discomfort or insecurity of the functional medicine model, because it doesn’t have those clean edges that the diagnostic model has. With functional medicine, there are other questions. Why are these conditions being seen in this patient? What are the other variables that relate to the triggering (their antecedents, their genetic past, their medical past, their environmental past, their ecology) the outcome that we see as that dysfunction? Withthis model of gluten and celiac disease there is a very tight correlation of an environmental factor to an autoimmune disease then gets confused (to some degree) when focused through the functional medicine lens, because now we say, “Hold it. Not everybody with those genes that are susceptible end up with a disease when they are exposed to that environmental agent, gluten. And not every gluten produces the same response.” So there are many modifiers and variables that need to be evaluated if we are really going to improve patient outcome and not just use the one-size-fits-all-type mentality and then lose people on the edges. The functional medicine model allows us to ask (and actually even demands of us to ask) the right questions. I think the work of Dr. Harris and Dr. Fasano that was described in this issue helps us to understand the evolving science that supports asking these questions, because there is more below the waterline than meets the eye in every one of these stories. As we start to explore it you see that we start to broaden our understanding of how other covariables influence the expression of those conditions into the disease that ultimately results. I’m very emboldened and encouraged by the last two issues (the June and July issues) of Functional Medicine Update, which have really helped us to pinpoint the importance of gluten as it relates to a triggering factor for a variety of systemic and regional inflammatory conditions. This may be an operational model to support the difference between a drive toward a sine qua non of diagnosis versus a functional medicine model, which is to drive towards a sine qua non of mechanism and understanding the variables that influence, in that patient, the expression of those signs and symptoms. I hope I have given you some tools to use and through the wonderful experience and knowledge of our clinicians and researchers of the month that you have taken some big steps forward in better understanding this gluten story. We’re going to explore the next step in August when we talk with Professor Delzenne and Dr. Cani. Thanks for being with us.  

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Bibliography

1 Harris KM. (2008) Investigation of the IL-23 Response to Wheat Gliadin, the Primary Etiologic Agent in Celiac Disease. PhD thesis. University of Maryland Graduate School. 2 Harris KM, Fasano A, Mann DL. Cutting edge: IL-1 controls the IL-23 response induced by gliadin, the eetiologic agent in celiac disease. J Immunol. 2008;181(7):4457-4460. 3 Mann DL, Celluzzi CM, Hankey KG, Harris KM, Ida Y, et al. Combining conventional therapies with intra-tumoral injection of autologous dendritic cells and activated T cells to treat patients with advanced cancers. NYAS Annals (submitted March 12, 2009). 4 Lindfors K, Blomqvist T, Juuti-Uusitalo K, Stenman S, Venalainen J, et al. Live probiotic Bifidobacterium lactis bacteria inhibit the toxic effects induced by wheat gliadin in epithelial cell culture. Clin Exp Immunol. 2008;152(3):552-558. 5 Wichers H. Immunomodulation by food: promising concept for mitigating allergic disease? Anal Bioanal Chem. 2009 May 20. [Epub ahead of print] 6 Rossignol DA, Rossignol LW, Smith S, Schneider C, Logerquist S, et al. Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trial. BMC Pediatrics. 2009;9:21.

Welcome to August 2009 Functional Medicine Update. If you have been listening the last two months, you know we’ve been exploring a topic that really is evolving very rapidly and has significant clinical implications. Certainly all the questions aren’t yet resolved, but we are starting to see the landscape of this concept of a food that is considered “good” to now become-in the minds of some (and in their physiologies)-a “poison.” The food of one is the poison for some. I’m talking about gluten and its relationship to grain-based protein products. You might ask the question: What’s really going on with gluten? Why is something that has been in our diets for some period of time (since the rise of the agricultural revolution in the golden triangle of the world-in civilization-some 40,000 years ago) now emerging, ultimately, to be a contributor to chronic-related illnesses? This is about far more than just celiac disease. As you have listened to the last two issues of Functional Medicine Update, you certainly have heard our extraordinary clinicians and resource experts talk about the rising tide of chronic age-related diseases that are associated with the activation of the immune system by the exposure to what would be considered a natural part of grain-based proteins, the gluten family of molecules. Last month, in our July issue, we took another step forward in understanding that maybe there are things occurring as a consequence of genetic hybridization (or epigenomic modulation) through altered environmental situations that impact the regulation of protein synthesis within grains that are post-translationally modifying the gluten molecules to make them more epitopically reactive, to make them more immunologically seen as a foreigner. This concept of post-translational modification, or epigenetic modification, which has been a major theme for functional medicine in the last year (including two webinars that we have done on nutritional epigenomics), is truly a revolutionary concept that is emerging at the frontier of knowledge in the area of functional and nutritional medicine. I would say it is helping us to better understand not only the rising tide of certain types of chronic age-related diseases, but also how they may have heritable impacts on future generations in ways that we previously never fully understood. This concept may help us understand how things like autism are increasing in prevalence at a much faster rate than we would expect by normal, Darwinian, natural-selection-types of processes. There may be factors that tie to certain environmental alterations that have epigenetically tagged the genome in such a way as to create an outcome that we call autistic spectrum disorders. This theme is much broader than just celiac disease. Certainly celiac disease is part of the story, but it isn’t the whole story. The environment is connected to the individual through the digestive system (through the gut recognition system–the mucosal-associated lymphoid tissue and the gastrointestinal-associated lymphoid tissue, or the MALT and the GALT), and that communicates information to the immunological recognition system of the body through the Kupffer cells of the liver to the circulating white cells, and ultimately even into the neurological system through the microglia (or the brain’s immune system). This interconnectedness that I’m describing can alter the functional state of the organism to express itself as disorders of immunological alarm across many diagnostic categories, not just that of a digestive disorder with inflammatory bowel disease (Crohn’s disease or celiac disease). These disorders can connect to type 1 diabetes, rheumatoid arthritis, multiple sclerosis, or maybe even pre-senile dementia. These more complicated connections are now starting to be seen through the lens of this web of physiological immune-neuroendocrine interaction. So the broad theme becomes this term that connects together multiple organs: neuro-immuno-endocrinology (depending on how you put the order of the words together). This term means something that connects the nervous system to the immune system to the endocrine system that ultimately leads to the translation of outside messages to inside alarm reactions within the body. The Microbiota Community: Symbionts, Commensals, and Parasitic Bacteria Part of this story involves the translation between the outside environment (let’s say our food) and the inside communication system (our immune, nervous, and endocrine systems) through an intermediary. That intermediary is our gut enteric flora. I think we often neglect being mindful of the fact that in our intestinal tract we have a very vast community of microbiota, which can participate in our function at three different levels. One level is that which we call symbionts, which help us to function. Symbionts can digest things way down in this plumbing called our digestive tract and produce secondary trophic factors that are immunologically sensitizing and help balance our immune system and make our immune system more capable of properly regulating function. They can synthesize vitamins. They can transform certain things like lignans in food into various bioactive materials like equol, which then can augment endocrine function and immune function. Symbionts can have a variety of very favorable effects on modulating function of the body. The second class of microbiota that live in our intestinal tract are called commensals. The commensals take up space and create their own personalities in our digestive tract, but they don’t seem to really produce many substances that are necessarily beneficial for the host, nor do they produce substances that are detrimental to the host. They just kind of reside in the gut and take up some space and are friendly neighbors, but they don’t necessarily do a lot to build new cities, so to speak. We would call these commensals. The third family most often gets our concern. These are organisms that produce secondary byproducts from their metabolism that may be potentially harmful to the host. They may be nitrogen-based molecules or derivatives of these compounds that become toxic, both directly to the gastrointestinal mucosa (in other words, they may be in situ carcinogens that are being produced), or they may be absorbed through enteropathic circulation and ultimately influence, at a distance, function by sending out putative messages of neurotransmission, or by being molecular mimicry substances that modulate the way that our body is signaling to itself. These organisms play a role in causing our immune system and our nervous system to be on guard and ready to do battle. We call this the parasitic family of gut enteric bacteria. The Gut Microbiota Are Constantly Dynamic It turns out that these class distinctions that I’ve just made among symbionts, commensals, and parasites are somewhat arbitrary because under certain conditions, in the immune system of our gut, what was once a friendly bacterium can come to be seen as a not-so-friendly bacterium. We could have something that was a commensal , that under a different immunological distress of our gut now suddenly becomes parasitic and releases into circulation cell wall debris from that bacterium that are called lipopolysaccharides (or LPS). In a leaky gut or a permeable gut situation, LPS can induce systemic inflammatory response and be a contributor, therefore, to overall systemic immune activation. I think we need to be a little cautious when differentiating symbionts from commensals from parasites, and make sure we recognize that they are in constant equilibrium balance and dynamic interaction with the environment of the gastrointestinal tract. They can change their personalities to some degree, based upon the state of the environment. However, with that said, I would say that there are certain bacteria (Clostridia and rotaviruses and things) that are more likely to be known as gut parasites (or gut-offending bacteria, or viruses) that create dysfunction rather than create function. By doing cultures, we would be able to determine a prevalence of those particular species that are more likely to be associated with an alarm reaction of the body rather than a quieting or a balancing of the immune system. Generally we use things like stool cultures or erectile swabs to try to identify organisms that have toxic/parasitic-related functions. The Relationship Between the Bacterial Flora and the Foods We Eat With all of that in mind, here is the logical question I think you would ask: Is there a connection between the species and the activity of this bacterial flora that resides in our gut and the way that we respond to certain food-related information molecules? When we eat, we are not just eating calories, or bulk, or vitamins and minerals and essential fatty acids and essential amino acids. We are also eating information molecules, and those information molecules can elicit a response by binding to receptors that trigger certain kinds of ligand receptor interactions that then alters intercellular signal transduction processes, and ultimately signals, at a distance, certain information content to the body. It could be friendly information or it could be information about a foreigner onboard (or, “we need to call out the guard and do battle”). Is there a correlation between the way the information molecules eaten in the diet are received and translated into transmissible information in the body based upon the gut microbiota or gut flora? That is the question I am raising. It’s a very interesting question. We could then go right back and look at something like gluten, and say, “Do different gut flora have different impacts upon the way a person would respond to gluten in their diet, or is it gluten is gluten is gluten, regardless of what is present in the digestive system or in the gut microbiota?” That question connects the last two months of Functional Medicine Update on gluten and its relationship to neuro-endocrine-immune alteration and function to that of this month’s issue. We are going to have the privilege of talking to two of the most remarkable researchers in the field of gut flora and the relationship it has to function. I think the connection between the June and July issues of Functional Medicine Update and this month is exemplified by an interesting paper that was published recently in the British Journal of Nutrition called “Effects of a Gluten-Free Diet on Gut Microbiota and Immune Function in Healthy Adult Human Subjects.”1 Here is where we connect the concept of gluten together with gut microflora, and how those together, then, impact immune function. The authors of this paper point out that it is well known that diet influences the composition of gut microbiota, and therefore has an impact on host health. It is kind of a new emerging understanding for us that when we are talking about the relationship of food to health, we have to interpose our discussion with the topic of the gut flora because the food response may be different in an individual depending upon the status of their gut community/ecology. This is particularly seen in patients suffering from food-related dysfunctions, where they have what they call adverse reactions to food. In this discussion, I want to differentiate between strict food allergy and atypical reactions to specific foods because, as we know, there may be things like histamine reactions or response to phenylethylamine or other kinds of constituents within food that produce a toxic-like reaction that resembles a food allergy but is not actually a true allergy; you would not pick this up as an IgE- or an IgG-mediated response. In the last two months we have talked a lot about celiac disease as a permanent intolerance to cereal gluten proteins. The therapy of choice in patients with celiac disease and gluten intolerance is to adhere to this lifelong gluten-free diet, which becomes the standard of identity for that person. The Effects of a Gluten-Free Diet on the Gut Microbiota This study in the British Journal of Nutrition contrasts with ideas about a gluten-free diet that we have been developing over the last two months in Functional Medicine Update. This study, examined the effects of a gluten-free diet on the composition and immune function of the gut microbiota in healthy human subjects over one month, and the fecal microbiota was found to modify itself significantly on a gluten-free diet. When the authors of the study looked at the Bifidobacteria, Clostridium, and other types of fecal microflora, they found very interesting differences after being on the gluten-free diet (and this is in people without gluten intolerance, I might add-these are “normal” individuals). “Normal” really is in the eye of the beholder. I think that term tends to be one that we overuse in medicine. I think “people who didn’t have demonstrable gluten sensitivity” would probably be a better way of saying it. In this study, alteration in various gut microflora was quite significant when individuals were put on the gluten-free diet. The study authors looked at things like various cytokines, such as TNF alpha, interferon gamma, interleukin-10, and interleukin-8 production by blood mononuclear cells. They found there was a very significant difference in immune reaction in these healthy individuals after they were put on the gluten-free diet and their gut microflora changed. The results suggested that the gluten-free diet constitutes an environmental variable that influences gut health, even in individuals without gluten sensitivity, by modulating gut microbiota and the influence they have (secondary effects they have) on gut-immune function and ultimately on systemic immune function. This is a complex web of interaction. We can’t just say it is only a consequence of looking at a reactive molecule (gluten) that then hits a target receptor in the gut to initiate, in genetically susceptible individuals, an immune activation that we call celiac disease. There are many different levels, or shades, of this in different individuals that have to do with the complex shifting of the microbiological community that is in our gut, how that influences or interacts with the gut-immune system of that individual, how that diet then plays a role in modulating that function, and ultimately altering or affecting immune function activity. That leads us to the question: Can you modulate the immune system through food? That is a very interesting question that looks beyond just gluten sensitivity. Many papers have now been published that would tend to support the idea that it appears as if food can be used as a systemic immune-modulating component, both for the betterment of the immune resiliency and plasticity, and also because some foods can activate the immune system and put that person in a constant state of vigilance (their immune system in a constant state of alarm). One of the things that would certainly initiate increased vigilance (and you are going to hear more about from our wonderful researchers this month), is a high-fat/high-sugar diet, which, when consumed on a repetitive basis, is known to constantly keep the immune system of the gut in a hyper-vigilant state, and it can modify gut enteric bacteria. You have a different species-a different community-of gut flora when you eat a high-fat/high-sugar diet than you would on a diet that is lower in saturated animal fat and lower in simple carbohydrate in the form of sugars. That, then, has influence not just regionally on gut-immune function, but systemically on overall immune vigilance. I’m quoting from a 2009 article that characterizes the kind of theme that I’m discussing, titled “Immunomodulation by Food: A Promising Concept for Mitigating Allergic Disease?”2 In this particular paper the author advanced the thought that if you have a person that has a problem with food sensitivities and allergies, you ought to go back and re-evaluate the whole of the diet, not just for the allergic-producing substances in that diet, but for how the diet, as a whole that they have been consuming, may contribute to alteration of gut enteric flora and ultimately to activation of the immune system in the absence of a true food allergy. There may be diets that would be considered inflammatory-prone diets that initiate gut inflammatory processes that create systemic immune activation, rather than just regional conditions that we see as Crohn’s disease, or colitis, or inflammatory bowel disease. I think these are very interesting topics that are starting to develop that have deep clinical implications because we often don’t think of the diet at large as being a variable that could be very important clinically for modifying a patient’s overall neuro-endocrine-immune function in the absence of allergic response. Clinically we do things like make sure we screen various foods for their allergic potential in that individual by IgE or IgG testing.If a person comes up negative on a screen then we often make the assumption that their diet must not be a major contributor to their immune dysfunction because we didn’t pick up a lot of food-related allergies. But lower than that (or below that) is the question of how their diet, notwithstanding the allergic component, may be influencing gut enteric flora and gastrointestinal-associated immune function that then has a spreading effect to the whole of the body with regard to neuro-endocrine-immune function and/or dysfunction. I think it raises the bar higher. It spreads the clinical importance for doing the appropriate evaluation, and there are certain diets that even in the absence of allergens can induce immunological dysregulation of activation. As I’ve said (and as you will hear more about today), diets that are very high in saturated fat and sugars have a greater possibility of doing this. What about diets that contain all sorts of funny molecules, like trans fatty acids from partial hydrogenation? Or what about diets that contain a rich array of chemicals like preservatives, emulsifiers, texturants, or synthetic antioxidants? Are we sure this complex chemical soup that we have been feeding individuals doesn’t have some immunological effect upon gut flora and ultimately gut-immune function that is unique to that individual? That a “clean” diet (a diet that is minimally processed, organic, and rich in things that are close to the soil) doesn’t have a salutary effect on immune function, regardless of whether there is an allergy or a non-allergy component that is part of the process? I think these are really important emerging parts of the story, and certainly this immunomodulation-by- food concept that appeared in Analytical Chemistry and Bioanalytical Chemistry is a very interesting part. The author states, “The importance of a properly functioning and well-balanced immune system for maintaining health has become strikingly evident. Roughly, since World War II, there has been an apparent decrease in the prevalence of ‘traditional’ infectious diseases, with a concomitant increase in immune-related disorders.” Certainly part of this is the increasing presence of allergies. A relationship with changes in lifestyle factors such as the increasing use of various types of antibiotics seems a part of changing this whole gut flora-immune relationship, but also (as the author points out), diet can affect the functioning of immune parameters, and maybe we ought to apply this concept of diet and its relationship to immune function at the gut level in attempts to prevent or mitigate allergic reactions, versus the development of targeted diets and targeted food products that really are immune modulating using the gut receptor system as a way of signaling friendly balanced immune function to the rest of the body. The article goes on to talk about the fact that there may be both pro- and prebiotics that influence this in a favorable way, and that these types of materials then may help to balance the Th1/Th2 types of immunological balance that we have spoken so much about in previous issues of Functional Medicine Update, and ultimately lead to immunoregulation or immunomodulation We are really talking about interposing the gut microbiome between diet and immune function in our clinical thought process. The microbiome is emerging to be a very important part of expressing its personality in terms of how the immune function operates. There was a very nice paper recently published in the Journal of Gastroenterology. It’s a review paper titled “Targeting the Gut Microbiome with Probiotics and Prebiotics,” and the subtitle is “Gastroenterology enters the Metagenomics era,” which I think this is a very interesting concept.3 What the authors of this article talk about is that the “metagenomics” (meaning not the genome of the host, but the genome of species that are interrelated and living with the host– the gut microbiome) can influence the function of the individual. It is this kind of metagenomic connection to the human microbiome that expands our knowledge of the composition of microbial communities and how they influence human function. This article really does a nice job of helping to increase understanding of how microbial variation and differences in the genes of bugs in our gut can then alter the information that is translated to our gut-associated immune system that then remodels (or tailors) our human-associated gut-immune function. Physiological features such as the development of innate and adaptive immunity, relative susceptibilities to infection, immune tolerance, bioavailability of nutrients, and (obviously) also intestinal barrier function or gut mucosal integrity are all modified by changing the composition of these microbial communities, or the gut microbiome. As the field of gastroenterology is evolving, it is starting to recognize that GI system function is profoundly affected by the gastrointestinal microbiota. Now that that is understood, ways to rationally modify the actual gut environment to then improve functional status of the immune system is becoming “a new frontier” of gastroenterology. The article authors talk about first kind of sterilizing the bowel of unfriendly organisms using antibiotics (this sounds a little bit like our 4R Program of Remove, Replace, Reinoculate, Repair). The first step is remove the unwanted critters that are actually inducing immunological dysfunction, and then add back (as we suggest in our 4R Program with the replace, reinoculate, and repair phases) the appropriate environmental agents, which would be done by giving prebiotics and probiotics and nutrients such as pantothenic acids, glutamine, and arginine that help to stabilize gut mucosal integrity. The prebiotic/probiotic supplementation can enhance a proliferation of beneficial microbes that then stabilize immune system function. The human microbiome then can be manipulated by smart strategies to prevent and treat not only localized gastrointestinal disorders, such as acute gastroenteritis, antibiotic-associated diarrhea, colitis, inflammatory bowel disease, irritable bowel syndrome, and necrotizing enterocolitis, but also a variety of other systemic disorders, including even far-reaching disorders we have talked about in previous issues of Functional Medicine Update, such as cardiovascular disease risk as it pertains to endothelial dysfunction that is associated with immunological dysregulation that may have started in the gut with a permeable mucosa. There is a web of interacting variables that we would call a functional medicine connection: the connection of gut-immune function to endothelial function in the vasculature in cardiovascular disease. I think this Gastroenterology article/review paper from 2009 really does a nice job of laying out the concept (the landscape) of how diet can specifically be tailored to deliver functional characteristics that improve the gut microbiota, which then ultimately modulates immune function, which then has systemic implications. These implications, clinically, are quite far reaching. Let me give you some thoughts about this in preparation for the discussion we are going to have with our researchers/clinicians on this topic. What about using probiotics to improve outcomes after gastric bariatric surgery (the Roux-en-Y gastric bypass surgery)? A very nice paper was published in the Journal of Gastrointestinal Surgery in 2009 looking at improved outcome in patients at six months who had been supplemented with probiotics after completing Roux-en-Y gastric bypass surgery for morbid obesity.4 It’s a very interesting study showing that probiotic administration not only reduced bacterial overgrowth of the resident intestine, but it also improved vitamin B12 bioavailability, which is one of the concerns that you often have post-surgery because by reducing the intestinal mucosal surface area for absorption, often these patients end up with nutrient malabsorption syndrome. So it improved vitamin B12 bioavailability and weight loss and reduced inflammation post-surgery, providing evidence that the GI microbiota is very, very important for maintaining proper immune function, but also in helping to stimulate greater weight loss when the bacterial microbiota have the right speciation and number. According to these findings, the success after Roux-en-Y surgery is in part related to re-establishing proper gut microflora because GI microbiota-if they are of the right families-can help influence appropriate weight loss, post-surgical intervention. The concept that somehow friendly bacteria can influence weight loss may apply beyond that of just the bariatric surgery patient. Could it be that our obesity epidemic is in part related to a diet which is altering our gut microflora in such a way as to reduce its favorable effect on signaling that is associated with proper insulin and hormone balance and ultimately fat metabolism, or fat deposition in adipocytes? In other words, can altered gut flora cause obesity? That’s an interesting question, and one that you are going to hear more about from the principal investigators belonging to one of the first groups to discover this relationship Is there a connection that is emerging to between altered gut flora and systemic toxicity or inflammation? The answer is yes. Papers are now being published virtually every month on this rapidly advancing field of understanding I am going to cite one that appeared recently in Cancer Research titled “Intestinal Mucosal Inflammation Leads to Systemic Genotoxicity in Mice.”5 In this particular paper, the authors were looking to ask whether a condition with altered gut mucosal integrity with inflammation and its relationship to altered gut flora could have an influence systemically on altered oxidative stress and free radical injury ultimately measured by changes in patency of DNA in circulating white cells in the animal. In other words, is genomic instability induced by a localized gut inflammatory response and altered gut flora? In 2008 we had an extraordinary discussion with Dr. Michael Fenech, a principal research investigator at the CSIRO in Adelaide, Australia. He told us that one of the best biomarkers for the effect that diet has on oxidative-related dysfunction and injury at the cellular level is to look at genomic instability using the micronucleus assay, which looks for damage to DNA and the genome as a consequence of oxidative stress. This is very reproducible technology that could be used for assessing relative injury to the “book of life,” the most precious thing that we own and want to protect within not only our germ cells, but our somatic cells. This study from Cancer Research in 2009 that I am describing showed that regional inflammatory responses in the gut, through activation of the gut-associated immune system and altered gut flora that contribute to that, produces a systemic oxidative load (or reactive oxygen species) that then induces systemic genotoxicity as seen by altered genomic stability (reduced genomic stability) through increased micronucleus formation. Here, again, is a very important kind of closing-the-loop concept that ties together what is going on in the gut with its immune system, to what is happening systemically and how that translates over to a precipitating trigger to inflammatory response (in this case, circulating immune cells in which the DNA in those cells are actually seen by micronucleus assay to be injured in their nucleosome integrity and their genomic stability to be adversely influenced). These topics that we have been describing within Functional Medicine Update for the last couple of years on epigenetics and genomic stability, environmental influences on the epigenome and on gut function and gluten sensitivity, and now on gut enteric flora-all are interconnected and may be part of our better understanding of the prevalence of various types of diseases that we are seeing that range from obesity through atherosclerosis, neurological dysfunctions and diseases, and ultimately into even chronic fatigue syndrome and fibromyalgia. These are very complex immunological disorders associated with immune disturbances. What about pain syndrome? Certainly the gut flora also has a very interesting influence on pain, both regional pain and systemic pain. I cited a paper a few years ago that appeared in Nature Medicine that kind of addresses our thinking in this area; it was titled ” Lactobacillus acidolpholus Modulates Intestinal Pain and Induces Opioid and Cannabinoid Receptors.”6This was a very interesting study that looked at the influence that various probiotic organisms have (these are favorable symbionts) when supplemented, and how they influence the receptor activation of pain receptors in the gut, not only reducing the activation of pain receptors in individuals that may have gut pain, but also transmission of that pain through gut mechanisms (the systemic pain-related dysfunction). I want to emphasize that this particular study I’m citing was a study done under control conditions with rodents, but it was able to demonstrate (under controlled conditions) that there is a very significant advantage to favorable symbiotic organisms modulating intestinal pain and through modulation of the opioid and cannabinoid receptor activities that have to do with pain transmission and activation. By the way, this work was done by Professor Desreumaux and his colleagues in Belgium. This month we will be actually talking to investigators that are in the same field, at the same university, in the same country. There is a lot of activity going on in Belgium and in France pertaining to the probiotic connection to immune function and inflammatory function. I think this Nature Medicine paper is another very important part of our advancing understanding as to how proper gut flora may influence pain reception and pain transmission (starting from the gut, but having systemic influences). Lastly, I want to talk about this whole concept of does metabolism really change? Does whole-organism metabolism change as a consequence of the differing types of enteric microflora or microbiota that are present? There are many papers that are now being published in this area. I mentioned one about the Roux-en-Y gastric bypass surgery and the influence that probiotics have on weight loss, suggesting that there is a systemic effect from gut flora on thermogenesis and storage of calories. We are starting to see ever increasing reports of the metabolic activity of gut microbiota contributing to the pathogenesis of obesity and also hepatic steatosis, which we call nonalcoholic fatty liver disease, or we call nonalcoholic steatohepatits in the more extreme cases. In past issues of Functional Medicine Update we’ve correlated these liver conditions with metabolic syndrome and hyperinsulinemia, and in this issue, we are correlating metabolic syndrome and hyperinsulinemia with alterations in enteric microbiota. In other words, change in the microbiome. I’m now quoting from a paper that just appeared in the American Journal ofClinical Nutrition that showed that by changing gut enteric microbiota we can actually influence fatty acid composition within the liver in animal studies (this is both in rodents and in pigs) and change adipose tissue deposition (in other words, cause weight loss).7 This is an extraordinary new emerging concept–that this interposition of gut microflora (the microbiome) between our environment, our gut, and our immune system may be a modulator of function that signals distantly to the body through various types of neuro-endocrine-immune-modulating systems to alter function. I hope I’ve set the stage and teed you up for what I believe to be one of the most exciting interviews you’ll hear. We are going to be talking with fundamental researchers that are making these discoveries every day in their laboratories.

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INTERVIEW TRANSCRIPT

Nathalie Delzenne, PhD Associate Professor Patrice Cani, PhD Postdoctoral Researcher Université catholique de Louvain School of Pharmacy Division of Biochemical Toxicology SFAR 7360 Avenue Mounier 73 B-1200 Brussels Belgium Here we are once again at that section of Functional Medicine Update that is really, I think, the heart of our issue every month. This month we are very fortunate to have a double-hitter (a homerun, so to speak) because we not only have a clinician and a researcher, but we have two very, very well-respected scientific celebrities in the field. You are going to learn more about some things that are presently in the news-things that I think are at the forefront of functional and nutritional medicine. Let me introduce our two guests today. Dr. Nathalie Delzenne is a Professor at the Université catholique de Louvain in Belgium. You are aware of her work whether you are familiar with her name or not. She has been at the forefront of research into prebiotics, probiotics, and symbiotics for some period of time and is very actively involved (with her research group) in this whole relationship between the microbiome (gut enteric bacteria) and its relationship to general metabolism. I think you are going to learn some extraordinary things from Dr. Delzenne. Dr. Delzenne graduated in pharmacy in 1986 and obtained her PhD in 1991 from the School of Pharmacy at Université catholique de Louvain. She followed human nutrition and did studies at Université de Lausanne in Switzerland. She has been a NATO grant recipient, and she spent years in France at INSERM, where she was involved in studies on nutritional modulation of gene expression. She is a member of the European Academy of Nutritional Science and is a member of the staff at the Division of Biochemical Toxicology at the Université catholique de Louvain. Professor Delzenne’s colleague is Patrice Cani. Dr. Cani is a doctoral fellow who also graduated from the Université catholique de Louvain, and is now working as a research associate in collaboration with Dr. Delzenne. Their productivity and creativity-innovation-in this area is really remarkable. The number of publications that have come out of their group over the last few years is truly impressive. Professor Delzenne and Dr. Cani, welcome to Functional Medicine Update. Tell us a little bit about the concept of prebiotics, probiotics, and symbiotics, just so we can establish the context of how they relate to the metabolism of enteric flora and systemic immune function. Belgium Has Been an Active Site for Research on Probiotics and Prebiotics ND: Thanks very much and thank you also for the kind introduction. I think we are lucky to be in Belgium because this concept of probiotics was born in the lab where we are now, but with another person-maybe you know his name-Marcel Roberfroid. In our lab, we have been working for years on the concept of the nutritional modulation of the gut microbiota. This concept is not so new. It has been known for a long time that some bacteria could have beneficial effects on physiology in human bodies. These bacteria tend to be given orally and they are considered probiotics. They remain viable within the gastrointestinal tract and can exert beneficial effect on the host. This concept of probiotics (in the diet or given as a supplement) having beneficial effect has been known for a long time. What has been known for a less significant period of time (since 1995, to be precise) is the concept of prebiotics. Prebiotics are compounds which are not digested in the upper part of the gastrointestinal tract. They are fermented by specific types of bacteria in the gut, and therefore, they modulate the endogenous population of the gut microbiota and exert (also) interesting effects on the physiology of the body. Both concepts are similar but different; when you have a probiotic you give a bacteria, and when you have a prebiotic you give a substrate for endogenous bacteria. The rationale is that when you do that you improve some functions of the body. For the symbiotics concept it means that you have a mix of probiotics and prebiotics given together to exert interesting functions. I should say the concept of prebiotics was born with the help of Glenn Gibson in the UK, and John Cummings, and Marcel Roberfroid here in Belgium. Maybe we are the sons and daughters of Marcel in that concept. JB: I think you are very good daughters and sons. I have had the pleasure of knowing Professor Roberfroid for the last few years. I would say he is kind of the founding father of this field. You are coming from a very good lineage and you are keeping the spirit alive and well. Your work is stunning. Let me take this concept to the next level. One of the things that has so intrigued the world scientific community about your work is the recognition that these enteric flora not only influence regionally gastrointestinal immune function through the gastrointestinal-associated lymphoid tissue, but also seem to have influence on systemic immune function and systemic metabolic function. I’m thinking of one of your papers that appeared in the journal Diabetes in 2007 that talks about metabolic endotoxemia, obesity, and insulin resistance, which seems like a very interesting combination of topics.8 How does toxemia result? What does the gut enteric bacteria have to do with this and how does that influence obesity and insulin resistance? These are very interesting concepts that maybe people would have never put together. Can you tell us a little bit about that? Metabolic Endotoxemia: An Explanation of the Term and the Research ND: I propose that I give you the first rationale of this idea that we could have modulation of systemic inflammation due to probiotics intake, and after that I will give the phone to Patrice Cani, so you have his view of these new results related to metabolic endotoxemia and the modulation of that by the gut microbiota. We were working for years on the fact that when you give some prebiotics you may have systemic effects. For example, you may modulate the liver metabolism, thereby decreasing lipogenesis and triglycerides. With research, we have discovered that some immune cells which were present in the liver tissue, namely the Kupffer cells, may be activated through the intake of prebiotics and it may be protective, at least in animals (because these were experimental studies). It may protect the animals against endotoxemia due to really high dose of lipopolysaccharides. So we had in hand, a few years ago, the fact that (for reasons we didn’t know yet) we could modulate the systemic function (immune function) of the body, thereby improving health in animals after an acute infection. I will give the phone now to Patrice Cani. He went further with this story, looking at not only acute endotoxemia, but more metabolic endotoxemia and how the modulation of the gut microbiota may play a role in this field. PC: Hello. JB: Hello, Dr. Cani. It’s very nice to hear your voice and thank you for being a participant with us. PC: Thank you. Thank you for the invitation. I will give you some information concerning metabolic endotoxemia. Several years ago, we knew that obesity was related to low-grade inflammation and type 2 diabetes, as well as insulin resistance. The mechanisms linking the development of obesity, insulin resistance, and inflammation were poorly understood. While looking in the literature for some proinflammatory compounds, we found that LPS is a very important proinflammatory molecule. In looking at the context of a high-fat diet feeding, we always found that the high-fat diet feeding induced obesity, insulin resistance, and inflammation only when the gut microbiota was present. Germ-free mice resist the high-fat-diet-induced obesity and metabolic disorders. Following these two concepts, we measured the LPS in the plasma in mice fed high-fat diets throughout the day, and we found that plasma LPS was first detectable in the plasma, but also always remained higher in the high-fat-diet-fed mice as compared to the normal-chow fed mice. When we looked at the gut microbiota composition, we were first concerned by the fact that the Gram-negative bacteria (the one giving the LPS) were it is not modulated by the high-fat diet. The Gram-positive bacteria were decreased, and more specifically Bifidobacteria were decreased, following the high-fat-diet feeding. At this point, we were able to hypothesize that LPS was involved in the development of insulin resistance and metabolic endotoxemia. We used LPS at low dose in mice by using osmotic minipumps to mimic the metabolic endotoxemia we observed following the high-fat-diet feeding. We observed that by giving a normal-chow diet and giving low-dose LPS, we were able to increase visceral adipose tissue and mice developed some metabolic disorders related to insulin resistance (hepatic insulin resistance and inflammation). Finally, we decided to restore the Bifidobacteria content in high-fat-diet-fed mice by using prebiotics. We found that by feeding mice prebiotics we completely restored the metabolic disorders. High-fat mice fed with prebiotics resist the development of inflammation induced by the high-fat diet. At that time, we found a nice correlation between prebiotics and blood endotoxin levels. After, we found that since LPS could be increased by the elimination of gut microbiota and that gut permeability could be one of the major points involved in the development of higher endotoxemia in our model, we studied metabolic gut permeability following high-fat-diet feeding and found that high-fat-diet feeding, per se, increases gut permeability in mice fed the high-fat diet, and gut permeability was also increased in genetically obese mice (ob/ob mice). JB: This work that you are describing to me is absolutely revolutionary. It really reflects what we have been talking about now for 20 years in functional medicine because you can only understand this relationship (as you’ve described it) if you look at physiology in an ecological perspective (look at it as a systems-wide situation). You can’t understand this if you look at it in a compartmentalized, organ-specific perspective. I’m just really amazed at the innovation and the design of your experiments-how you have been able to start unraveling this very complex web of interaction. I applaud you both (or your whole group) for this. If I can just kind of make sure that our listeners understand the significance of what you have said-because I think it’s really one of those “threshold” new concepts. You related to us the fact that this observation that gnobiotic mice (or mice that have sterilized digestive tracts-they don’t have bacteria when they are fed a high-fat diet) don’t get this insulin resistance and metabolic syndrome, which normal mice with gut enteric bacteria get when fed the same diet. And then what you found is that the bacteria that seemed to be most associated with this response to a high-fat diet that led to what we call insulin resistance or metabolic syndrome appeared to be those of specific families (when you broke them down into Gram-negative or Gram-positive bacteria) associated with a deficiency of the Gram-positive Bifidobacteria that made these animals more responsive, in terms of hyperinsulinemia, to the diet. Have I summarized what you’ve said correctly or are there modifications to what I have said? PC: Exactly. It is exactly that. ND: Maybe I can add something. We always look at what we already know. In the context of the gut microbiota it is true that the modulation of the Bifidobacteria plays a role in view of what we have shown, but I’m pretty sure that there are also a lot of other strains of bacteria that could play a role and that could be modulated by the prebiotics, probiotics, and whatever approach touches the gut microbiota. I really think we are just at the beginning of the discovery of some types of bacteria or some types of bacterial metabolic activity that could be implicated in this process. In the view of today, we work on Bifidobacteria because we know them, but there are (I am pretty sure) a lot of bacteria prone to have positive effects on gut biofunction, gut immunity, and systemic immunity. JB: Very, very interesting. A term that you have used is kind of new to gastroenterology, and that is “metabolic endotoxemia.” For most students in the medical sciences, when they hear “endotoxemia” they think of sepsis; they think of acute infection as it relates to a very significant (or maybe even catastrophic) breakdown of gut mucosal defense and a very high load (systemically) of bacteria, and the person ends up with septicemia. I think is very important to differentiate metabolic endotoxemia. It can occur in people who are “apparently healthy,” meaning they are not acutely ill, but they have a stress on their immune system as it relates to this kind of chronic leakage of bacterial LPS and the effect that it has on their immune system. Am I describing this term correctly, “metabolic endotoxemia?” ND: I can say that this term, metabolic endotoxemia, is used by some scientists and not by others. Some people also talk about low-tone inflammation or low-tone endotoxemia, in order to make a clear difference between the two concepts of high endotoxemia and low endotoxemia levels. I can give the phone to Patrice, who participated in the studies with humans. PC: The term “metabolic endotoxemia” was used, as you described, to differentiate from the high levels of LPS known in sepsis. Metabolic endotoxemia means that we can observe LPS (or plasma endotoxemia) levels of variation in healthy subjects, as well as in obese patients. We know LPS can be modulated in healthy subjects by simply feeding a high-fat diet; it has been demonstrated that a fat meal increases LPS levels. This increase is really low compared to sepsis (an increase of 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}–a two-fold increase–following the diet). It is really important to make the difference between the terms “LPS” and “proinflammatory properties of LPS.” In healthy subjects, we found and observed this LPS variation, so the term “metabolic endotoxemia,” as Nathalie explained before, could sometimes be confusing for people and should perhaps be defined as “low endotoxemia levels,” or should be revised because “metabolic” is sometimes a term which cannot be used in all conditions. In our research, “metabolic endotoxemia,” was used to describe high-fat-diet-fed mice in an obese context, but we can also observe the very small variation of endotoxemia in healthy subjects following a normal high-fat meal. JB: That’s very helpful. In the United States there is a nonscientific term that has been coined to describe what you are saying much more scientifically. This term is “leaky gut syndrome,” which describes this partial breakdown of gut mucosal barrier function as a consequence of regional immune activation in the gut-associated lymphoid tissue, which then allows for the leakage of middle molecular weight molecules across the GI barrier. This leakage then has access to systemic circulation, influencing downstream (as you said earlier) the Kupffer cells in the liver, and the circulating white cells, and maybe even the immune system of the brain-the microglia-so that you get this more systemic relationship to the load of inflammatory activating substances. We’ve coined this term “leaky gut syndrome.” Do you think that is a little bit too loose in the language or do you think that kind of describes what we are talking about? Difference Between Metabolic Endotoxemia and Leaky Gut ND: We can say that sometimes a leaky gut is observed in the pathological situations we are talking about. For example, the high-fat diet may also induce some leaky gut, but we are not aware of all the mechanisms that create systemic inflammation from the gut. It is true that leaky gut may be one way to proceed, but also some physiological functions may be related (for example, the absorption of the lipopolysaccharides to the normal lipid absorption may play a role, and maybe other mechanisms could start in the gut). In gut inflammation certain cytokines may drive some immune response outside the gut and into the systemic circulation and systemic organs. I don’t think we can say there is one first event (leaky gut) leading to all other events. I think there are several mechanisms by which you can have a translation of inflammation coming from the gut into the systemic body. We are far away from having one sole mechanism and one sole result. Leaky gut is only part of the story. JB: Thank you. That is very helpful. We have been speaking about a number of your papers. One that I was very impressed with appeared in Diabetologia in 2007 on the effect of Bifidobacteria in response to high-fat meals and its relationship to endotoxemia.9 You have another very interesting paper that appeared in Current Opinion in Clinical Nutrition and Metabolic Care that talks about the metabolic contribution and the energy homeostasis contribution that gut flora have.10 Could you tell us a little bit about it? I think often people forget about the fact that we have over a kilogram of living organisms in our intestinal tract and these have their own personalities and energy metabolism, which has an influence on metabolism in general. Maybe you can comment on your understanding and help us to see how these relationships between bacteria and systemic metabolism can relate? ND: There are a lot of teams working on this in the world. I think the team of Jeff Gordon was one of the first to show that gut bacteria provide energy because they are able (sometimes) to use energy that escaped our own digestion process. But it is rather a simplistic view just only to say that the gut bacteria are able to use the substrate that escaped our digestion, therefore providing energy by the production of the fatty acids, for example. It is one way to have energy, but in view of our diet, we may say that this process of sparing energy through fermentation is not big enough to explain changes in the whole body. I think the team of Jeff Gordon has really shown that beside the fact that you may have some energy sparing coming from the gut fermentation, you may also have the modulation of some metabolic processes that can help the body to spare energy, for example, lipoprotein lipase activity and adipose tissue function and so on. What is very strange is that when studies are done it is mostly to say the whole gut microbiota have a role in sparing energy in different ways. But what we can say in view of our results and others, is that specific qualitative modulation of the gut microbiota may lead to the inverse process. Just because you have a lot of bacteria, it doesn’t mean you are able to spare energy. No. The composition-the qualitative composition of the gut microbiota-may modulate this process and sometimes (as we have observed in rats but it has not been shown in humans) it can decrease the energy harvest as compared to a diet that does not improve this gut microbiota. Once again it is a complex story. I It is completely true that the gut microbiota play a role in energy harvesting. But sometimes qualitative modulation of the gut microbiota may lead to changes in the physiological function that may lead to a decrease in fat mass development or a decrease in food intake and so on. So it depends, really, on what is observed and how it works. JB: That’s beautifully said. You and Dr. Cani have a very nice paper that has just been published in the journal Gut in 2009 describing changes in gut microbiota and their influence on mucosal permeability and signaling through GLP-2.11 Could you tell us a little bit about that? That is a very interesting part of the story-that there may be these receptors on the GI mucosa that signal systemically through incretins or other messaging molecules. I think this another fascinating part of your discovery. Influence of Gut Microbiota on Mucosal Permeability and Signaling PC: We had previously demonstrated that the proglucagon-related peptides (I mean glucagon-like peptide 1 [GLP-1] and GLP-2) were modulated by the gut microbiota. We had previously demonstrated that changing gut microbiota by using prebiotics improved insulin resistance, glucose tolerance, and deceases energy intake. We had observed that this phenomenon was always associated with an increase in GLP-1 production. GLP-1 is a peptide involved in insulin secretion and insulin sensitivity (it increases insulin secretion and insulin sensitivity), and it increases satiety also. But GLP-1 is produced by a proglucagon, and a proglucagon is also able to produce (at the same time) glucagon-like peptide 2 (GLP-2). GLP-2 has been demonstrated to be involved in intestinal homeostasis. It increases epithelial cell proliferation and it is now used in clinical drug trials in Phase 2 and Phase 3 to improve gut permeability and nutrient absorption in short bowel syndrome, for instance. Knowing that prebiotics were involved in changes in GLP-2 and knowing that in ob/ob mice obesity is associated with an increase in gut permeability, we decided to change the gut microbiota by using the prebiotics to see if we were able to change gut permeability in that context. When we changed gut microbiota by using the prebiotics, we improved gut permeability in obese mice and we observed that the GLP-2 prediction was also increased, as well as the GLP-1. We found nice correlation between the plasma GLP-2 levels and endotoxemia levels (in both plasma and endotoxemia levels). We hypothesized that GLP-2 could be involved in the increase in gut barrier function. To demonstrate that GLP-2 was involved in this effect, we treated obese mice concomitantly with prebiotics. We changed the gut microbiota by using prebiotics and we blocked the activation of the receptor by GLP-2 antagonists. Using this protocol, we demonstrated that blocking the GLP-2 receptor while we changed gut microbiotacompletely blocked the positive impact of the gut microbiota. Blocking the GLP-2 receptor and at the same time changing gut microbiota cannot change gut permeability; gut permeability remains higher in the prebiotics-treated mice even if the gut microbiota was changed. This phenomenon would maybe have an impact in a feasible condition. I mean that GLP-2 could be involved in the maintenance of the gut barrier function. This hypothesis remains to be demonstrated now in healthy conditions, but this experiment put forward one of the new mechanisms by which changes in gut microbiota can change gut permeability and help demonstrate the new molecular mechanism by which gut microbiota improved the gut barrier function. JB: That is just stunning work. Again, I want to compliment you both and your group. This is very pioneering and important work that really relates to this whole signaling revolution that we are seeing emerge today in a systems biology approach to medicine, which is really the foundation of what we have been calling functional medicine for 20 years. Thank you both. In the short few minutes remaining, let me get to the bottom line, which I’m sure a lot of the clinicians that are listening are wondering about. Given all of these extraordinary benefits that pre- and probiotics have (or the symbiotics have) in modulating gut immune function and systemic immune function, how does a clinician start to apply this information? We have talked about Bifidobacteria and we’ve talked about specific prebiotics that may serve as selective substrates for these symbiotic bacteria. Can you give us some thoughts as to how you see this translating over into clinical management? Clinical Implications of Research on the Gut Microbiota ND: What I can say is that fortunately there are now more and more clinical intervention studies that appear concerning the influence of probiotics and probiotics in new context, I should say, (so context that shares obesity and so on). There are not so many papers at the moment, Clinicians now starting to be convinced about a method of modulation of the gut microbiota performed by a non-drug approach. It is not clearly a pharmacological approach, but it touches functions that are related to the normal physiology and improvement of physiology in humans. Obesity has not been considered a disease for very long, and there has been a place for compounds like prebiotics or probiotics to improve the functions associated with the fat mass development. But now obesity basically has become a disease because of the severity of the associated disorders it may lead to. Therefore, it is now also in the heads of the clinicians to think about compounds that could be given in the context of the pathophysiological relevance in obesity now. They have, really, in my view, a good future. They are just at the frontier between nutrition and drugs, but I think that they are more than that. We will also have, maybe, a more common view with people who are commercializing some compounds related to the improvement of physiological function, and the people who are working in nutrition, purely. We know those compounds (at least the prebiotics, for example) are present in the normal diet, which may be helpful in convincing clinicians that those products may be helpful for people. You don’t have to necessary to kill bacteria with a drug to obtain efficient effect in some contexts. We can work with a more physiological approach, and I am pretty sure that now the physicians will be convinced of the relevance of this effect. JB: That’s really important information. I was reminded of a paper that appeared in the March issue of the Journal of Gastroenterological Surgery in which they were talking about patients that have morbid obesity and undergo gastric bypass surgery (the Roux-en-Y gastric bypass procedure) and they find that when patients are supplemented with pre- and probiotics post-surgery they have a much better outcome. They have better nutritional status. They have better vitamin B12 status. They don’t gain weight back as quickly. And their overall health and immune function is improved. I think the story that you are talking about, Professor Delzenne, relates to so many applications of this concept in clinical practice is really starting to be seen. I want to thank you both. We really appreciate you being available to share with the listeners of this series. We have been doing this for 27 years and I have had the fortune of interviewing some remarkable contributors to the emergence of the new medicine. I’d have to say this discussion/interview about your work would stand head-to-shoulders with the most interesting and clinically relevant of those topics that we have had the pleasure of discussing. Thank you for making yourself available, and thank you for all of us in the medical community on your pioneering work and the diligence you are bringing to your research. ND: Thanks very much. We really hope this will help us have a lot of contacts in the future with many people in America. We are really proud of the way that you presented us, also. Good luck, also. JB: Thank you so much. Dr. Cani, thank you as well. We will be in touch and following your work very closely. I hope you came away from listening to that interview with the kind of goosebump-experience that I had. That was an extraordinary journey we took with Professor Delzenne and Dr. Cani, unfolding the story of the important role that the gut microbiome plays in modulating function throughout the whole of the body-the systemic signaling. Let me remind you of a few of the papers this group of investigators has been responsible for publishing that I think demonstrates the rapid change in this field. These are all 2008 &ndash; 2009 contributions to the literature. The first one is titled “Gut Microflora as a Target for Energy and Metabolic Homestasis.” This topic is exactly in the sweet spot of looking at how friendly bacteria (or the proper gut microbiome) can favorably influence homeostasis of energetics( in other words, maintenance of proper body composition). When the immune system is responding to what it considers to be a foreign gut microflora, dysfunction can induce inflammation processes that are associated with altered adipocyte function, insulin signaling, and the relationship to energy storage. You might say, “Why is does the body do this? Why does it store energy under alarm?” Maybe this is a very longstanding evolutionary benefit. If you think of the most significant stresses to human survival throughout time, it would be things like starvation and infection. It may be that the body evolved a particular protective mechanism to store energy for a continued battle against what might be considered deprivation and insult, and to shut down functions it doesn’t need as importantly as it needs to defend itself against the apparent insult. It might be that this regulation against inflammation of energy storage is part of this protective system of maintenance of energy to mount immune response, and cell repair, and so forth. This paper that appeared in Current Opinion in Clinical Nutrition and Metabolic Care, authored by Dr. Cani and Dr. Delzenne, I think is a very important contribution to our understanding of how gut microflora can be an important part of our therapeutic target for improving energy metabolism and weight management. Another paper that appeared during the last year is titled “A Place for Dietary Fibre in the Management of the Metabolic Syndrome, “12 In this paper they are talking about dietary fiber, and not just in terms of slowing the release of glucose across the GI tract, which is the traditional way we have thought of it (as being an influence on digestion and assimilation of simple carbohydrate, which then lowers the load on the insulin regulating mechanisms). They are also talking about certain types of dietary fiber being fermented in the gut by friendly bacteria (or symbionts) to induce not only regional protection upon GI mucosal integrity, but on functional aspects of the GI immune system, which then has favorable effects on systemic immunity, lowering inflammation and having a trophic effect on immune balance. Again, this was another paper that appeared in Current Opinion in Clinical Nutrition and Metabolic Care, showing that things like large arabinogalactans, beta glucans, and other types of what we call prebiotics have a favorable effect in stimulating the metabolic relay and allowing specific agents to regulate things like appetite, and inflammation, and even bioenergetics. A more recent paper appeared in the journal Gut, which I think is a very important journal. This significant article is titled “Changes in Gut Microbiota Control Inflammation in Obese Mice Through a Mechanism Involving GLP-2-Driven Improvement of gut permeability.” In previous issues of Functional Medicine Update over the last several years we have discussed the glucagon-like peptide-1 and the glucagon-peptide-2 (or GLP-1 and GLP-2)-related neuroendocrine functions that then alter things like insulin signaling and immune function, systemically. What this paper that appeared in the journal Gut talks about is that by modulating gut microflora, inflammatory processes in the gut are altered, which then changes this glucagon-like, peptide-driven, neurochemical message and improves gut mucosal integrity and lowers systemic inflammation. This work has also has indicated (and Dr. Delzenne and Dr. Cani have published papers) showing that appropriate bacteria (enteric bacteria-part of the microbiome) will lower gut inflammation and improve GLP-1 signaling through the adipocyte, which then regulates insulin through these incretin types of signaling mechanisms. Those of you who are familiar with diabetic drugs know that Byetta is a drug that is a GLP-1 agonist. It blocks the enzyme that breaks down glucagon-like peptide and enhances insulin activity as an agonist of incretin activity. Here’s a case where you are getting increased activity of GLP-1 directly at the gut mucosal level by friendly bacteria (gut mucosal activity). The connection of gut to insulin signaling through gut microflora (the microbiota) is another very, very interesting emerging topic that this group is advancing. Lastly, the research coming from this group has shown that selective increases in friendly bacteria (like Bifidobacteria in the gut microbiome) improves the tolerance people have to high-fat-induced diabetes, which reduces mucosal integrity, lowers inflammation of the gut, and reduces the concern of absorption of bacterial LPS and activation, systemically, of inflammation (i.e. this would be called reduction of the risk to chronic endotoxemia). That is another paper that they published in their series. This work was published in Diabetologica, and demonstrates (once again) that appropriate probiotic and prebiotic supplementation can modulate the risk to endotoxemia. I hope you are starting to see that this theme that we are developing-connecting food as a signaling mechanism to the gut microbiome, and to the gut immune system, and to systemic response–is an extraordinary new chapter that is emerging in functional medicine. Thanks for being with us. We’ll look forward to sharing more in September.

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Bibliography

1 De Palma G, Nadal I, Collado MC, Sanz Y. Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. Br J Nutr. 2009 May 18:1-7. [Epub ahead of print] 2 Wichers H. Immunomodulation by food: promising concept for mitigating allergic disease? Anal Bioanal Chem. 2009 May 20. [Epub ahead of print] 3 Preidis GA, Versalovic J. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era. Gastroenterology. 2009;136:2025-2031. 4 Woodard GA, Encarnacion B, Downey JR, Peraza J, Chong K, et al. Probiotics improve outcomes after Roux-en-Y gastric bypass surgery: a prospective randomized trial. J Gastrointest Surg. 2009;13(7):1198-1204. 5 Westbrook AM, Wei B, Braun J, Schiestl RH. Intestinal mucosal inflammation leads to systemic genotoxicity in mice. Cancer Res. 2009;69(11):4828-4834. 6 Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, et at. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nature Med. 2007;13(1):35-37. 7 Wall R, Ross RP, Shanahan F, O’Mahony L, O’Mahony C, et al. Metabolic activity of the enteric microbiota influences the fatty acid composition of murine and porcine liver and adipose tissues. Am J Clin Nutr. 2009;89:1393-1401. 8 Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761-1772. 9 Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, et al. Selective increases of bifidobacteria in gut microflora improves high-fat diet-induced diabetes through a mechanism associated with endotoxemia. Diabetologia. 2007;50(11):2374-2383. 10 Cani PD, Delzenne NM. Gut microflora as a target for energy and metabolic homeostasis. Curr Opin Clin Nutr Metab Care. 2007;10:729-734. 11 Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58(8):1091-1103. 12 Delzenne NM, Cani PD. A place for dietary fibre in the management of metabolic syndrome. Curr Opin Clin Nutr Metab Care. 2005;8:636-640.

Welcome to the September 2009 issue of Functional Medicine Update . Those of you who have been listening over the last several months know there is a theme for 2009, and that theme is really connecting environmental factors that modulate and influence the neuroendocrine immune system and ultimately signal to the body either immunological stability or immunological vigilance and activation. We started off in June and July with some extraordinary discussion concerning gluten as one family of molecules that modulate immune function and ultimately inflammatory signaling. We used that as an example to demonstrate that food and its constituents contain information responded to by the body in a very unique way (a personalized way) based upon the unique sensitivities locked into that person’s signaling processes connected to their genes and their epigenome in ways that make their environmental response different than that of others. From there, we went into the August issue and an extraordinary discussion with Professor Delzenne and Dr. Cani related to the modulating effects of the gut microbiome and how it influences the translation of the signals from the environment into intercellular signal transduction processes that can have far-reaching, distant effects upon function, including that of neurologic function and cardiovascular function. Even things related to obesity can be tied to alterations in the gut microbiome, as was mentioned in that issue. In this issue-September-we have the privilege of speaking with another remarkable clinician, in this case a periodontist from Singapore who is of high repute and background (academic and clinical). She will be talking to us about another locus in the body for immunological dysregulation, and that is infection in the oral cavity and the relationship that has to systemic health. As a clinician, when you are starting to really evaluate, from a functional medicine perspective, the antecedents, triggers, and mediators that give rise to the signs and symptoms of disease, you start looking where the triggers may reside. We’ve talked about dietary triggers, environmental triggers, gut microbial triggers, and now we are going to talk about infection in the oral cavity and in the sinuses-other resident places in the body where a smoldering activation of the immune system can occur that alters the functional status of the neuroendocrine immune system that then spreads itself through unique susceptibilities or sensitivities into differing diseases in differing individuals. I’d like to state that this is a unique model to functional medicine, but, as you probably know, it is not. It’s a model from Hans Selye, who adapted a term from physics into physiology (stress), and that appropriated term talked about agents that would modulate immune function and endocrine function in such a way as to have diverse effects on the appearance of diseases that cut across many different diagnostic codes (or ICD-9 codes) and different subspecialties of medicine. A stress factor could be seen in one individual as peptic ulcers, and in another it could be seen as a heart attack, and in a third it could be seen as osteoporosis, and in a fourth it could be seen as diabetes. This construct that a factor in the environment could spread itself through different susceptibilities or sensitivities into different expressed diseases in differing individuals is a very different model than that of, for instance, bacterially induced disease, where we say a specific bacterium, such as a pneumococcus bacterium, produces a specific disease called pneumonia, for which a specific molecule is there to treat it (that would be, say, an antibiotic like penicillin). That model, which is a very simple linear reductionistic model for the origin of disease certainly has merit and value, but it is only one of multiple etiologies that are associated with the origin of disease. In chronic disease, it would appear as if the “bug” (in the previous example, the bacteria), is related to its environment, which is related to the susceptibilities or sensitivities of the individual, and ultimately, then, it spreads itself into a myriad of potential diseases, not just one disease. That is certainly going to be the theme that you’ll hear about in this month’s Functional Medicine Update To peak your interest, let me give you an interesting quote that just recently was published by the American Academy of Periodontology. This was from their most recent contribution to the American College of Cardiology. It may seem that these are strange bedfellows and that we have cut across wide swaths of differing disciplines within the health and medical sciences, going from dentistry and periodontology to looking at cardiology and heart-related dysfunction. How does this all work? To me this is a classic example of what we have been trying to develop over the last 20 years as we’ve defined functional medicine. It is not just psychosomatic medicine, and not just geriatric disability medicine, but medicine that is related to a web of interaction, a hologram of physiology, a matrix of interacting variables. What does this press release say? This is a summer 2009 press release and it states, “Cardiovascular disease, the leading killer of men and women in the United States, is a major public health issue contributing to 2400 deaths each day. Periodontal disease, a chronic inflammatory disease that destroys bone and gum tissues that support teeth affects nearly 75 percent of Americans and is the major cause of adult tooth loss. And while the prevalence rates of these disease states seems grim, research suggests that managing one disease may reduce the risk for the other.”1 Does this sound at all familiar to the theme that we have been describing in functional medicine for two decades, plus? The press release goes on to say, “A consensus paper on the relationship between heart disease and gum disease was recently published concurrently in two leading publications, the American Journal of Cardiology (AJC), a publication circulated to 30,000 cardiologists, and the Journal of Periodontology (JOP), the official publication of the American Academy of Periodontology (AAP). Developed in concert by cardiologists, the physicians specialized in treating diseases of the heart, and periodontists, the dentists with advanced training in the treatment and prevention of periodontal disease, the paper contains clinical recommendations for both medical and dental professionals to use in managing patients living with, or who are at risk for, either disease. As a result of the paper, cardiologists may now examine a patient’s mouth, and periodontists may begin asking questions about heart health and family history of heart disease.” The line is blurry. The disciplines look a little bit more fuzzy. Going on, the press release says, “The clinical recommendations were developed at a meeting held earlier this year of top opinion-leaders in both cardiology and periodontology. In addition to the clinical recommendations, the consensus paper summarizes the scientific evidence that links periodontal disease and cardiovascular disease and explains the underlying biologic and inflammatory mechanisms that may be the basis for this connection.” “According to Dr. Kenneth Kornman…Editor of the Journal of Periodontology [and an expert, I might add, in inflammatory disorders]…the cooperation between the cardiology and periodontology communities is an important first step in helping patients reduce the risk of these associated diseases.” Dr. Kornman is quoted as saying, “Inflammation is a major risk factor for heart disease, and periodontal disease may increase the inflammation level throughout the body. Since several studies have shown that patients with periodontal disease have increased risk [of] cardiovascular disease, we felt it was important to develop clinical recommendations for our respective specialties. Therefore, you will now see cardiologists and periodontists joining forces to help [their] patients.” “For patients this may mean receiving some unconventional advice from their periodontist or cardiologist. The clinical recommendations outlined in the consensus paper advise that periodontists not only inform their patients of the increased risk of cardiovascular disease associated with periodontal disease, but also assess their risk for future cardiovascular disease and guide them to be evaluated for the major risk factors. The paper also recommends that physicians managing patients with cardiovascular disease evaluate the mouth for the basic signs of periodontal disease [including such signs] as significant tooth loss, visual signs of oral inflammation, and receding gums.” “While additional research will help identify the precise relationships [among] periodontal disease and cardiovascular disease, recent emphasis has been placed on the role of inflammation-the body’s reaction to fight off infection….” “Both periodontal disease and cardiovascular disease are inflammatory diseases, and inflammation is the common mechanism that connects them,” says Dr. David Cochran, President of the American Association of Periodontology and the Chair of Periodontics at the University of Texas Health Science Center at San Antonio. “The clinical recommendations included in the consensus paper will help periodontists and cardiologists control the inflammatory burden in the body as a result of gum disease or heart disease, thereby helping to reduce further disease progression, and ultimately improve our patients’ overall health.” I think you can kind of get the drift, can’t you? It is a time of change. Disciplinary boundaries are being broken down. The walls are coming down, to use a metaphor. The age of interconnectedness has started to emerge. We don’t just call these comorbidities-periodontal disease and cardiovascular disease. What we would rather call them are disorders coming from a single inflammatory burden-a single trigger that triggers mediators that are shared among different tissues that give rise to diseases of different name. It clearly indicates that clinicians need to be very mindful of looking for sites of focal inflammation in the body–places where resident bacteria and viruses continue to elicit an immune response that causes an inflamed response. What are the most significant singular advances that have occurred through medical technology that have improved health outcome in large populations? At the head of that list has to be something that medicine had probably very little (directly) to do with, but had remarkable impacts upon reducing the burden of infectious disease and the attendant effects it has on inflammatory response. I’m speaking about hygiene, sanitation, and nutrition. These principal factors (which are taught very little in traditional primary therapies and may be relegated to the sidebar of public health) represent extraordinarily important contributions to the overall reduction and burden of disease in populations over the last 150 years. Revisiting the Writings of Ivan Illich Ivan Illich wrote a book that I consider absolutely to be a classic read for everyone in the field; the book was called Medical Nemesis. That book really describes, very factually, how important the introduction of sanitation, hygiene, and nutrition was coming into the 19th and early 20th centuries on improving life expectancy and reducing disease, morbidities, and premature mortalities. There is a nice article that was published that goes back, retrospectively, and looks at the important contribution that Medical Nemesis, as a book, and even Ivan Illich, as an author, made to our understanding of medicine.2 The article appeared in the journal Medicine, Health Care, and Philosophy in 2003. Ivan Illich has subsequently passed away. Medical Nemesis, which I used back in my professorial years in the 70s as one of my textbooks for required reading for students, is now kind of a forgotten book, but I think it has a very powerful implication even today. Ivan Illich was known as a philosopher, historian, priest, and social commentator. He died in Bremen, Germany in December of 2002. He was noted originally for his critique of the church, education, and medicine, but his concepts really dealt with very fundamental issues. These issues related to the relationship of humans to their environment and how their ideas about this relationship shaped their outcome, both as individuals and as populations, and what this all means in terms of medicine, and in particular the role of health care in contemporary society. If you ever get a chance to get hold of a copy of Medical Nemesis at your library I urge you to pick it up and read it. It is a fairly short read, but it is a profoundly dense book, relative to ideas, because it helps us to recognize the important role that certain things that we take for granted (proper sanitation, hygiene, and nutrition) have on overall burden of disease, and that those things make pale, in comparison, all other medical therapies that have been developed since, even antibiotics. These three things are the principal drivers for the improvement in human life expectancy over the past 150 years, and yet often we relegate these to second tier importance because we now take them for granted. This concept of “Is it the bugs or the environment that produced the disease?” is still as much a debate today as it was back in the day of Pasteur at the end of the 19th century/beginning of the 20th century. We know that the “la terraine,” the environment in which the bugs live, is very important for determining their pathogenesis, but we also know the presence of the bug can be important as well. It is a combination of both factors. If you have immunologically compromised patients you have more potential for the growth of organisms, and the growth of more organisms produces more toxic byproducts that activate and alter the immune system function. Which does what? Dysregulate the body’s defense system and allow for more bugs to grow. Now we are in a tight cycle of self-replication-a positive feedback cycle, so to speak. You have to break the link. How do you break the link? You can kill the bugs, but as we know, you also have to change the terrain. You have to improve the functional status of the organism so that they can resist the growth of these bugs (these opportunistic organisms that may always be out there). That has been the longstanding challenge, hasn’t it? To balance, in medical therapy, those two factors: reduction of the appearance of the bug that is the offending agent (for which we have done a culture or a swab and we recognize that we have a certain sensitivity to a certain medication for that bug), and then to enhance the integrity of the soil of that individual (meaning their environment, so as to result in an environment that is less likely to support the growth and the survival of those opportunistic, infectious organisms). In periodontal disease, oral hygiene, proper sanitation, and proper nutrition are important. The bugs will always be there because the mouth is a very fertile ground for growing bugs. You have to combine together the Illich-like concepts of sanitation, hygiene, and nutrition in order to manage, preventively, the potential for triggering immunological activation and inflammation. You don’t want a person to be on antibiotics their whole life; what you want is their body to modulate their function (la terraine). These concepts are very interesting because they contract right back to the cellular level. Now we are developing cellular cytology and ways of looking, individually, within the macromolecules of cells and seeing how environmental factors like chronic inflammation that comes with infection can actually alter cellular function and imprint the genes of those cells with epigenomic tags that may set that cell into a certain phenotype of alarm and perpetuate this alarm over time. We recognize that these processes that are associated with constant exposure to inflammatory response from an activated immune system also ultimately erode the actual book of life by contributing to the shortening of the ends of our chromosomes (the telomeres), which can influence the stability of our genome (we talked about this in a previous issue with Dr. Michael Fenech). Genomic instability comes with inflammation and oxidative stress, and ultimately reduces the patency of the message in our book of life that gets translated into the integrity of our cellular function. All of this maybe sounds a little bit theoretical, broad brush, and not clinically relevant to when you are sitting in the exam room with that patient. You may say, “That’s really great on a theoretical level-I like the story-but it really doesn’t relate much to what I’m seeing in my patients.” I want to cite a new paper that may help you to understand how it does relate to your patients. How Telomere Length Relates to Your Patients How do you improve the quality of the immune system through nutrition? That is a topic that we have been discussing for the last several months in Functional Medicine Update. We might say it another way: Does the proper intake of simple things like multivitamins have any influence on the signaling that ultimately regulates telomere length and genomic stability? That is an interesting question. An answer partially emerged when, in a recent issue of the American Journal of Clinical Nutrition, a paper titled “Multivitamin Use and Telomere Length in Women” was published.3 The authors of this paper are from the National Institutes for Environmental Health Sciences in the National Institutes of Health Research Triangle in North Carolina, as well as the University of Utah, Department of Human Genetics. They evaluated (in women) the influence that a multivitamin supplement had on telomere length. These were women 35&ndash;74 years, who took a multivitamin and had their diets evaluated through a nutrient intake questionnaire (a 146-item food questionnaire). White blood cell (leukocyte) DNA was analyzed to look at telomere length. This is similar to one study I described in an earlier issue of Functional Medicine Update that was done at the University of California, San Francisco, in men with prostate cancer who were put on a lifestyle therapy (this was in collaboration with Dr. Dean Ornish), in which researchers showed (and reported in The Lancet magazine in 2008) that the lifestyle therapy with diet, stress reduction, and exercise resulted in improved telomerase activity in the men that placed on lifestyle therapy versus controls.4 Telomeres are the TTAGGG tandem repeat sequence at the end of chromosomes that relate to the prevention of detrimental recombination and degradation of our book of life (our chromosomes). In somatic cells, the length of telomeres decreases with each cell division, and this is related to the Hayflick Number (which I also discussed in a previous issue). Leonard Hayflick, who was a cell biologist at Stanford many years ago, found that cells could (in culture) go about 50 cell doublings before they could no longer replicate, and this had something to do with the continued loss of the length of their telomeres, until they eventually were unable to maintain proper genomic stability and the message of their book of life was unable to be adequately translated into the next generation of cells. As a result of this research, telomere length has been proposed as a marker for biological aging. Consistent with this hypothesis, preliminary epidemiological studies have related shorter telomeres to higher mortality and higher risk of certain age-related chronic diseases, including heart disease and cancer. Experimental evidence suggests that oxidative stress and chronic inflammation contribute to the attrition of telomeres and their loss of cellular replication. Now there is increasing evidence to at least suggest that several micronutrients (including antioxidants, vitamins, and minerals) can help modulate states of oxidative stress in chronic inflammation. We could postulate, therefore, that these micronutrients could affect the rate of degradation or attrition of telomeres. Based on articles Dr. Bruce Ames and others have published over the years, multivitamin supplements (in an orthomolecular manner) can influence the relative protection against oxidative injury and the processes that may relate to the loss of these telomeres. Going back to the study on women published in the American Journal of Clinical Nutrition, the investigators recruited these women and put them on a vitamin supplement (versus those who were not supplemented). This was a fairly, what we would consider to be “run-of-the-mill”-type nutritional supplement. These were not megavitamin doses nor extraordinary formulations, but just kind of your standard vitamin/mineral protection supplements. The researchers then looked, over time, at the average telomere length in these women. This study differed from the Ornish study that looked at telomerase activity and showed an increase in activity of the telomere repair enzyme (telomerase). In this study, the actual lengths of telomeres (in white cells) were evaluated, and it was found that there was a statistically significant increase in average telomere length in those individuals taking the vitamin supplement. High-Potency Antioxidants Appear to Have Greater Influence on Protecting Telomeres Nutrient formulations that had high potency antioxidants appeared to have greater influence on protecting telomeres. Those supplements that were what you might consider to be just B vitamins alone didn’t have nearly the effect of those that were multi-nutrient with high antioxidant formulations that were taken at least 4 to 6 days a week. In those particular examples there was much higher uptake and there appeared to be a dose-response relationship: the more frequently the person took it corresponded to the highest response in improving the length of their telomeres. Data from this study certainly suggests strongly that enhanced vitamin/mineral intake and increasing antioxidant level intake has a positive impact on maintenance of telomere length. If you believe (as the basis of science, now, is seeming to believe) that maintenance of telomere length is one of the principles associated with reduced biological aging and age-related chronic disease risk, then we would say this cell marker would track to a positive health outcome in these individuals who are taking the higher doses of vitamins containing antioxidants. There is a very interesting editorial that follows this paper that appeared in the American Journal of Clinical Nutrition, and the editorial goes on to say some very interesting things.5The author of the editorial says that leukocyte telomere length (LTL) is associated with age-related disorders (as was measured in this particular study), particularly atherosclerotic risk. Conflicting results have been published on whether the leukocyte telomere length forecasts survival in the elderly, but recent research using a same-sex twin model clearly showed that co-twins with a shorter leukocyte telomere length were more likely to die first. These observations support the hypothesis (or the proposition) that leukocyte telomere length is a biomarker of human aging. Telomeres are known as the “mitotic clock” in cultured human somatic cells, and it appears, in this issue, that this telomere length is generally used as a marker, therefore biological aging based upon this biological clock mechanism. I think that if you look at the influence that we are talking about, it looks as if the increase in telomere length with multinutrient supplementation tracks back to protection of functional characteristics that are very important for the maintenance of high-functioning life, in this case in humans (not in rodents and not in single cells, but in humans). How does that track back to the other side of the equation, which are those things that would increase inflammatory burden, oxidative injury, and the relative pressure on enhancing the rate of loss of telomeres? That answer has to do with things like focal infection and its relationship to proinflammatory initiation. In past issues of Functional Medicine Update, we’ve talked about the gut as being a site of potential focal inflammation, and in this issue we are going to move into talking about the oral cavity. One could think of the sinuses or other sites in the body where focal infection is associated with proinflammatory initiation, increased oxidative injury, shortening of telomeres, and lowered biological function. You could say, “Well, there must be a variety of antioxidants that influence these processes. What would we put at the head of the list?” I don’t think we can put anything at the “head” of the list because they all work together in a cooperative manner to create an envelope of function to help to protect against oxidative injury and inflammatory excesses. We should really think of this as a team rather than as the “antioxidant-of-the-month”-type of club. Coenzyme Q10 Supplementation Used in a Study Involving Infertile Men There are, however, cases of selective supplementation with individual antioxidants have been demonstrated to have clinical benefit. A recent report that I think is very interesting appears in the Journal of Urology that talks about the efficacy of a single antioxidant supplement at high dose, and this would be coenzyme Q10, or ubiquinone.6 Coenzyme Q10, in this case, was administered to a total of 212 infertile men with idiopathic difficulties and low sperm count. These were randomly assigned to receive either 300 milligrams of coenzyme Q10 daily, or a similar placebo regime. They were placed on a treatment phase. Semen analyses were then done to look at anti-sperm antibodies and various hormonal levels in these men and the motility and vitality of sperm. By the way, you might ask, “Why would they choose to use coenzyme Q10 in this particular condition?” As you probably know, sperm are really just an inclusion body with a huge amount of mitochondria. Sperm have to have a lot of energy in order to swim, and their tail is powered by mitochondria (oxidative phosphorylation), and when the tail falls off, so fall off the mitochondria. The sperm are driven by this biochemical reactor called the mitochondria (the energy powerhouse of that cell), and therefore defects in mitochondrial oxidative phosphorylation have been identified to be associated with sperm-related problems and infertility. That is one of the reasons they chose coenzyme Q10 for this study-because it is one of the antioxidants that has been clearly identified to be very important in the electron transport chain for protecting mitochondrial bioenergetics. What were the results of this study that was published in the Journal of Urology in 2009? What the researchers found was a very significant, statistically important improvement in semen parameters in the 300 mg coenzyme Q10 daily supplementation group versus the placebo group. They suggest that further studies are needed to draw a final conclusion, but the results do seem to implicate coenzyme Q10 supplementation as being very valuable in improving sperm quality; now what is needed is a more prolonged study to look at pregnancy (in situations where men were infertile and attempting to impregnate their partner and lead to term birth). I think this is a very interesting and encouraging story that talks about the role that a single antioxidant can have on a functional characteristic (in this case, coenzyme Q10 on sperm function in males). What we are really talking about is modulating various gene-response influences. If inappropriately modulated, these end up being translated or becoming a disease that we eventually can put a name on. Going back to Dr. Dean Ornish’s work that he did in prostate cancer, I think it is very interesting to hear what happened in males with prostate cancer following two years of lifestyle intervention. There is a very nice paper that was published in the journal Urology in 2008 authored by Dr. Ornish and his colleagues from the University of San Francisco School of Medicine.7 As a result of this study, what they report is that patients with early-stage prostate cancer choosing active surveillance might be able to avoid or delay conventional treatment at least two years (the study length of this study) by changing their lifestyle diet components. In this case not only did telomerase activities increase, but the progression of cancer (as measured by PSA and other examinations) was retarded as well versus a group that didn’t engage in lifestyle intervention, which involved using a minimally processed fundamental diet along with stress reduction and exercise. So lifestyle intervention in prostate cancer patients was demonstrated to have a very significant influence on improving status at two years. This is a clinical example, not just a cell example. Management of Inflammatory Signaling Can Have an Influence on Cognition What about things like neurodegenerative diseases? Probably at the head of this list is Alzheimer’s disease. There is a very powerful body of literature that is now emerging around Alzheimer’s disease prevention and even early management through metabolic management of inflammatory signaling through diet and lifestyle intervention. I found an article that appeared recently in 2009 titled “The Alzheimer’s Disease&ndash;Diabetes Angle: Inevitable Fate of Aging or Metabolic Imbalances Limiting Successful Aging” to be a very important paper.8 This article appeared in the Journal of Alzheimer’s Disease in 2009. In this short article, the authors suggest that Alzheimer’s disease is not an inevitable consequence of aging, but rather it is an inevitable consequence of aging processes associated with altered signaling and increased inflammation connected to dietary signals that enhance immune activation and inflammatory response through hyperinsulinemia and uncoupling mitochondrial oxidative phosphorylation and free radical oxidative stress. Diet and lifestyle intervention in this condition can modulate, epigenetically, the phenotype (in other words, the expression of what we later call Alzheimer’s disease). There is also a magnificent review article on this topic that appeared in Behavioural BrainResearch in 2008 titled “Epigenetic Codes in Cognition and Behaviour.”9 This is such a dramatically powerful article because it really gets us away from the feeling that these neurological diseases are genetically hardwired and are inevitable. Rather there are many modifying factors that relate to diet and lifestyle that signal (through these kinase signaling processes) either a friendly response to our environment, or an alarm state that puts the neurological system at war with itself by altering epigenetic tags, changing histone acetylation/deacetylation/methylation patterns in promoter regions of genes, upregulating expression of proinflammatory genes, and inducing what later becomes known as neurofibrillary tangles, or oxidative injury in the nigrostriatal regions of the brain that we associate with Parkinson’s disease. I think these epigenetic codes in cognition and behavior and environmental influences on it are extraordinarily important. How much of this equation is related to nutrition? Are nutrients major players in this or are they just minor bit players? There is a marvelous review paper on this subject titled “Brain Foods: The Effects of Nutrients on Brain Function.”10 This article appeared in the July 2008 issue of Nature Reviews Neuroscience and the author talks about how epigenetic regulation through diet and exercise and reduction of environmental exposure to toxins can modulate, epigenetically, the expression of factors that ultimately might initiate problems in cognition and problems in neurochemical function that, at later stage, we diagnose as a disease such as Parkinson’s or Alzheimer’s. This regulation includes things like omega-3 fatty acids, but also things like phytochemicals that come from garlic, and grapes and peanut skins, and cruciferous vegetables. This complex diet-with an array of these phytochemicals-plays a role in modulating insulin signaling, oxidative stress, telomerase shortening, and epigenetic signaling. Even vitamin D may play a very important role in cognitive performance in middle age and older individuals. And if you don’t understand this, the Journal of Neurology, Neurosurgery, and Psychiatry published a very powerful paper in 2009 that demonstrated that people with low 25-hydroxyvitamin D levels had declined cognitive performance in middle age versus those that had higher 25-hydroxyvitamin D levels.11 All of this is part of how our environment signals to our cells and creates an outcome called our phenotype. With that in mind, let’s move to our extraordinary discussion with our clinician/researcher of the month, who is going to tell us a little bit about the periodontal connection to inflammatory signaling and diseases beyond that of diseases of the oral cavity.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Gan Siok Ngoh, BDS, MSc Orchard Scotts Dental 501 Orchard Road #05-08 Wheeelock Place Singapore 23 8880 One of the great privileges of the life that I have been fortunate enough to lead over the years is travel and meeting some extraordinary people, internationally, who are doing really pace-setting work. In this issue you are going to have the benefit of traveling internationally with me (at least telephonically) to visit with Dr. Gan Siok Ngoh, who is in periodontology, and who I had the privilege of meeting at an international conference in Singapore a couple of years ago. I am absolutely impressed by the scholarship and the clinical acumen that she has brought to her work that relates to the oral-systemic link to health and disease. After hearing her talk, I asked her whether she would be willing to share the information she had provided to the audience with listeners of Functional Medicine Update and she said yes. Now we have been able to finally arrange the time. Let me tell you a little bit about her. Dr. Gan has a degree in dental surgery from Singapore and was in government dental practice for two years, then went into private general practice. She moved from that into a hospital-based general dental practice. In 1991, through the UK, she attained her Masters in Science in periodontology. Dr. Gan obviously has a very interesting research base as well as a clinical base. She has been in solo practice, in a hospital-based dental practice with a focus on periodontology and full-mouth dentistry, and from 1992&ndash;2008 had also been looking at the relationship to chronic degenerative and immune-compromised diseases. During that time she also became very skilled in a variety of complementary (and what we might call functional) medicine integrated strategies and techniques that she now brings into her practice. So she has a very wide-ranging background, from very solid dentistry into the science and research model, and then into the integrative model as well. We couldn’t find a more well-schooled nor more clinically experienced person to cover this important topic than Dr. Gan. Let me welcome you, Dr. Gan, to Functional Medicine Update. It is a very great privilege and honor to be able to talk with you today. GSN: Thank you very much for the invitation. I am more than happy to share with you my experiences and my knowledge. JB: Let me ask the question that probably everyone would want to know first: How did you come to extend your traditional periodontal practice and background into these other areas that we’ll be discussing as it relates to systemic health? There must have been some things that you observed or something that affected you to want to broaden your perspective. GSN: When I started working in a hospital-based practice, I was seeing a lot of immuno-compromised patients-patients with chronic degenerative diseases. And I was very upset that with all the formal knowledge we had, we were not able to actually help the patients fully. That got me into searching, and searching, and searching, and that led me to Switzerland, to Canada, to Austria, to Germany, Hungary…to find out about other therapies that could help augment the healing processes of an individual. I began to notice, also, from my studies in traditional Chinese medicine, Ayurvedic medicine, and hormone toxicology, that the mouth and oral tissues are able to express certain other symptoms if we look closely enough. And because my interest is periodontology (the science of the gums), that led me into understanding the tissues and how they behave and what they are telling us. JB: That’s a fantastic segue into my next question. A lot of the clinicians that are listening are not experts in the oral health area. Maybe it would be helpful for you to give us some primer information on plaque, gingivitis, the periodontium, and the microbiology of the mouth to set the context so we are all understanding the language. The Microbiology of the Mouth GSN: When you stop brushing your teeth, bacteria in the mouth adhere to the oral sulcus with highly specific mechanisms. After the attachment, the aggregate organize themselves around teeth structures to produce dental plaque or what you call dental biofilm. This is a sticky, gelatinous polysacchariade mass that harbors physically structured microbial communities. Over time or upon removal, it can harbor pathogenic disease-causing species in large numbers. This is demonstrated and it causes inflammation or gingivitis. Gum disease is the most common disease, even for the health conscious. This local inflammation tries to protect the body against the onslaught of the bacterial infection resulting in the vessels being more permeable, bleeding, and activation of complement clotting and kinin systems. Without removal of these bacteria, you have invasion of these bacteria into the tissues, causing a lot of systemic effects. Unknown to many people, we actually have immune cells (our polymorphonuclear neutrophils) coming out from the gingival sulcus to fight against the bacteria every day in normal individuals. This is something that most physicians-and most people-don’t realize. The neutrophils are actually attracted there by the bacteria and the antigens. They would go there to phagocyte hosts that digest and clear away the bacteria. However, if they are not able to clear away the bacteria, the inflammation becomes even more enlarged. The proinflammatory cytokines produced in the tissues by the fibroblasts, which are the predominant cells of the gums, would elaborate prostaglandins, interleukin-1beta, interleukin-6, interleukin-8, tumor necrosis factor alpha, and interferon gamma, which are mediators that modulate inflammation, both locally and systemically. The systemic endocrine effect evidence is supported by the findings of increased hepatic production of C-reactive proteins and fibrinogen among patients with periodontal disease. In fact, we also see it in production of specific antibodies to the oral organisms in the peripheral blood. This is the systemic relationship and we can give you evidence the periodontitis, although it can be a local inflammation, has a big systemic link. JB: This is absolutely remarkable. When we are talking about chronic inflammation, I think many of us forget the importance of the oral cavity as a reservoir or as an incubator for inflammatory triggers. This reminds me slightly of the work of Barry Marshall with H. pylori and peptic ulcer disease. Dr. Marshall, who subsequently won the Nobel Prize in medicine and physiology for his discovery, tried to get people to understand that the infection of the organism mobilized the body’s immune defense and produced this tissue destruction that was really a result of the body’s own response the stealth organism (the H. pylori). It sounds like organisms in the mouth may be producing a similar type of effect to that which he observed in the H. pylori. So it sounds like there is some similarity here about the relationship between environment, organisms, and systemic inflammation. GSN: Definitely. And the presence of these oral organisms in the host tissue (the gingival tissue) can cause it to become ulcerated when it is diseased. When you are eating or chewing or talking, you are actually pushing all of these bacteria and their products into the sub-epithelial components to exert systemic inflammatory response. That would activate, also, the monocyte/macrophage access and upregulate catabolic cytokines and inflammatory mediators. We know that with the upregulation of all these proinflammatory mediators and cytokines there is also a change in the serum lipid metabolism, causing a lot of changes, like the upregulation of C-reactive protein and the fibrinogen, and that induces atherosclerosis through the ICAM-1 expression and clot formation. That brings us to the co-relationship with heart disease. JB: Before we take that step, can I just stop [you there]? For some of our individuals who are not dental practitioners, they may forget or not be mindful of some of the early clinical science–things like shrinkage of gums, or bleeding gums upon brushing, or some of the things that maybe they haven’t correlated in their minds as being really markers of soft and hard tissue inflammatory processes. Can you help us understand, from your expertise, what the mouth looks like when we start to see these processes occurring? What kind of warning signs does the patient present with? Warning Signs to Look For in the Mouth GSN: In the very initial stage, you will have reddening of the gums and there will be bleeding, and the patient might complain of pain or discomfort. If it is looked at more closely and probed, then you would be able to elicit some bleeding in the gums, or when you use a brush to get into the gingival sulcus and that draws blood, that is really an indication that there is already inflammation going on at the base of gingival sulci. JB: Does shrinkage of the gums (which a lot of patients complain about-that their gums seem to be receding), is that related to this process? GSN: Yes. Definitely. When there is a shrinkage of the gums, which can occur in younger patients, older patients, or at any age, it is also a result of the disease that has already destroyed the periodontal tissues causing loss of the gingival tissues, because healing would oscillate between destruction and tissue regeneration and repair. As the destruction of the gums carries on during the inflammation, the tissues will be lost and then the tissues will shrink, and so the patients will present with longer teeth. Sometimes patients who present with increased tooth mobility or who tell the dentist that their teeth have changed may have recurrent gum infections. Those are telltale signs that they actually have a deeper chronic inflammatory disease going on. JB: I have heard it said that the principal risk factor for periodontal disease is poor oral hygiene (lack of proper oral hygiene-brushing and flossing), but it seems, from the way you are describing it, there may be also some systemic risk factors beyond that of the regional bacterial factor. So it may be a combination-is that what I am hearing? There may be extended risk factors to periodontal disease beyond that just of oral hygiene issues? GSN: Definitely it is more than just oral hygiene, although the bacteria is the etiological factor in the process of this periodontal disease. It is the host response that is very much affected, so as we said earlier, the polymorphonuclear neutrophils are the first line of defense. If there are any defects in the PMN leukocytes, then there would be also a defect in the host response resulting in more structural destruction, as is seen in patients who are diabetics and patients who have autoimmune diseases like rheumatoid arthritis. Systemic conditions are also a very important part. JB: It sounds like what you are describing is that the oral cavity is a laboratory (or an early-warning place) in the body that we should really pay attention to because it allows us to see, visually, aspects of the body’s immune system, nutritional status, and local host effects that may be not easily as seen if it is occurring inside the body, like in the vasculature. This is like a telltale, almost, for us, it appears. Clues About Systemic Health Can Be Found in the Mouth GSN: Exactly right, and that is why, as a periodontist, I find a lot of interesting things going on inside the oral cavity and how the tissues present themselves. The type of bleeding, even, can tell me that the liver is in a very distressed state. The way the tissues are keratinized and the way the tissues behave when the patient brushes, and the way the tongue…the accumulations of the bacteria/plaque on the tongue…give me an indication of the gastrointestinal dysfunction as well, and this is where I use nutritional products (nutrigenomics) to help modulate the host response. I feel this is a very innovative way of treating periodontitis–a very nutritional and environmental/lifestyle way of helping the patient to get their health back by boosting up their immunity because 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of our immune cells come from the gut. JB: I think what you just said is extraordinarily important for those who are listening because what you are really emphasizing is that the oral cavity is a biomarker for the functional status of the immune, neurologic, and endocrine systems and that what we are really looking at, therefore, is this network of physiological function, of which the oral cavity is one of the important barometers. So this is very consistent with the functional medicine model and needs to be brought much more into the examination and evaluation of the patient, it would seem, from what you just said. GSN: Exactly right. Over the years I have learned more about functional medicine and I have incorporated it into my practice. I am able to see more results-better results-without having to use drugs and antibiotics in the treatment of periodontitis/gingivitis, and I am helping patients to get back to that balance of health. Of course, lifestyle factors like smoking, inadequate sleep, and chronic stress (the three most important lifestyle factors affecting the progression of periodonditis) have to be addressed, and this is something that I would also have to address with patients during periodontitis treatment. JB: With that in mind, let’s now shift back to where you were going: let’s look at the systemic diseases that are linked with periodontal infections. Maybe you can help us to understand the breadth of those conditions, which have been demonstrated in the literature to have a connection. Systemic Conditions Research Shows to be Associated with Periodontal Disease GSN: Cardiovascular disease, preterm/low-birth-weight babies, diabetes, rheumatoid arthritis, and adrenal and respiratory diseases have been linked with periodontal infections and there are many papers and research that have been supporting these findings. Recently some of these papers indicate that periodontal disease causes changes in the systemic physiology. A recent paper in The Lancet suggested that there is a close association with a predisposition for certain kinds of cancers, like pancreatic and kidney cancers.12 To understand the cellular molecular mechanisms responsible for the cyclical association, I think one must identify the common physiological changes that produce the synergy when periodontal disease and systemic conditions coexist. Let’s look at the cardiovascular system. In the infection theories, the dental infections are risk factors for atherosclerotic disease because the streptococcus protein is associated with platelet aggregation. Porphymonas gingivalis activate and have been known to multiply in endothelial cells and contribute to acute thromboembolic events. A distant injury by the circulating oral microbiotoxins promotes cardiovascular pathologies, like the Gram-negative polysaccharides, which would induce the adipose production of interleukin-6 and that would upregulate the C-reactive proteins. So this distant inflammation from the locally produced cytokines would exert systemic effects, causing changes in the serum lipid levels and increasing the serum C-reactive proteins. You know that with an increase in C-reactive proteins of rapid origin, there is an induction of the ICAM-1 expression and the clot formation, and contribution to atherogenesis. JB: So when we look at this extraordinary mechanism that correlates or connects periodontitis to systemic disease, I think one of the questions I’ve heard people ask (who are not nearly as familiar with this topic as you) is, “Do we think periodontitis causes this, or is it just an associative risk factor?” In other words, is it an effect or is it a cause that really relates to the linkage to cardiovascular disease or type 2 diabetes? An analogy would be cholesterol: we know that cholesterol is very highly correlated (when it is elevated) with the increasing risk to heart disease, but the question is, does it cause it or is it just an associative factor? What is your opinion? Do you believe that the infection in the periodontium in the oral cavity is the causative agent or is it the effect of other things that are leading to this immunological disturbance? GSN: I think there are cyclical events surrounding when these two conditions coexist, such that one would augment the other. And there is also a possibility that oral inflammation, with an increase of the serum proinflammatory cytokines and the change in the immune response (where the antibodies to the bacteria are not effective against the microorganisms in the biofilm), forms immune complexes and cross reacts with the host tissues, further causing damage. A constant bacteremia is induced when the person eats and chews (you are actually pushing bacteria into your circulation system). That, in itself, upregulates and sets the stage and can even predispose the patient to the onset of diabetes and coronary heart disease because of the upregulation of the inflammatory markers, the bacteremia, and the change in the immune response (the upregulation of the proinflammatory cytokines and probably a reduction of the cofactors). It is a cyclical association. JB: Yes. That’s a wonderful explanation, and that fits so nicely into the functional medicine matrix network model. In your presentation I recall you cited a very interesting study on carotid intimal medial thickness, which I think was Desvarieaux’s work from 2005, correlating periodontal bacterial burden with CIMT.13 Can you remind our listeners of that study? That sounds very, very interesting. GSN: In this study, which was an epidemiological study of 1000 patients where they had no history of myocardial infarct or stroke, using DNA techniques and B-mode ultrasound, they were able to find that the intima medial thickness was closely related with antibody levels, and stroke and coronary heart disease were more influenced by the periodontal microorganisms than the antibody titer levels that were high. The elevated antibodies appeared to be associated with periodontal disease and chronic systemic conditions (that is, the coronary heart disease and diabetes). That is why dentists and physicians both have to be on the alert for this. I show in my presentation that I picked up, through orthopantomography (OPG), a thickening (or rather a calcification) of a carotid erythema. I quickly referred the patient to the cardiologist for intervention and possibly saved him (I hope) from myocardial infarct or a stroke. I have had patients who have also reported that prior to their stroke they had actually recurring dental infections (oral infections) and they felt that that contributed to the onset of their stroke. This is a real-life scenario that we have to be paying attention to as well, before the evidence comes out, to show the direct correlation. JB: This is one of those kinds of “goosebump” discussions for me that is so interesting and has so many implications. Last month we had the privilege of interviewing Professor Delzenne and Dr. Cani from Louvain Catholic University, who are working on the obesity/enteric bacteria connection. They have demonstrated that obesity in animals is related to the kinds of bacteria that live in their gut, and they can actually cause obesity to be treated by just changing bacterial flora in the gut. Now we are talking about the oral cavity with bacterial burden of different potential pathogens and inflammatory response. I wonder if there is any connection among obesity, periodontal disease, and, say, diabetes or heart disease. Is a connection starting to be seen there? Obesity and Periodontal Disease GSN: Yes, definitely. The recent data is that obesity is considered as one of the risk factors for periodontal disease because obesity, itself, alters the metabolic and endocrine function of the adipose tissue, resulting in increased production of fatty acids, hormones, cytokines, and acute phase reactants. So the obesity constitutes the low-grade chronic inflammatory state. Increase in the body mass index is associated with increase in number and size of adipose sites, which are highly active metabolically, producing large amounts of TNF alpha and interleukin-6; one-third of circulating interleukin-6 is produced in adipose tissue. TNF alpha also produces insulin resistance at the receptor level. So similarly, periodontal disease is associated with increased cytokine levels of tumor necrosis factor alpha, interleukin-6, predisposing the patient to insulin resistance. It is also clinically experienced that patients who are obese also have a more inflamed state of their periodontia. JB: How about the connection to metabolic syndrome or insulin resistance/hyperinsulinemia (which is often one of the risk factors-increased waist-to-hip ratio and central adiposity)? Do you see any connection in insulin resistance with that of periodontal disease or has that not been demonstrated? GSN: There is a model where insulin resistance, which is induced by the TNF alpha production, and which is exacerbated by obesity, would cause (also) an increase in hyperinsulinemia and hyperglycemia (worsening the glycemic index), priming the patient for worsening of the diabetes and priming that patient for periodontal disease. In periodontal disease patients we also find that they have an increase of serum lipid level changes, like the LDP cholesterol and triglycerides, and this also upregulates the C-reactive proteins in the liver and primes the patient also for heart disease. Definitely there is an inter-relationship of diabetes and cardiovascular disease with periodontal disease. JB: That is really fascinating (the way you are describing it). Again, it sounds like it is almost like what we would call a dog chasing its tail: the infection can increase inflammation, inflammation can then blunt insulin sensitivity, blunted insulin sensitivity results in hyperinsulinemia, which then adversely affects the immune system to increase more inflammation. So it sounds like what we are talking about is a cycle of amplified potential pathology, as you get a patient into that situation where they have the periodontal infection, and then away they go with inflammation and insulin resistance. One makes the other worse, it sounds like to me. GSN: Yes, exactly right. In fact, you can have infections (non-periodontal infections) and that could also produce worsening of the insulin resistance and aggravate a glycemic control. Once the infection is controlled, the insulin resistance can persist for weeks or months after the clinical recovery from the infection. Although periodontal treatment can reduce the Gram-negative infections and inflammation and restore the insulin sensitivity over time, it can still result in improved metabolic control. JB: That is a nice segue or transition into probably what a lot of our listeners are thinking now, and that is, “What are the therapeutic options, then, for patients that have periodontal disease in these systemic inflammatory conditions? How do you approach this?” Maybe you could tell us a little bit about (from a dental practitioner’s perspective and from a systemic integrative practitioner’s perspective) how one approaches this? Therapeutic Options for Periodontal Disease GSN: The key role is played by the presence of bacteria, so of course for a dentist, our main focus and target would be the removal of these bacteria as a requirement for periodontal disease treatment. That would include professional methods of removal with repeated scaling and good cleaning, whether surgically or non-surgically; the use of antibiotics, systemically and locally; and administered, where needed, the use of antiseptics. One new approach is actually reduction of the serum lipid levels, which seems promising, and the introduction, also, of omega-3 fatty acids to help with the resolution of the healing phase of the inflammation after the periodontal treatment, because it has been found that the omega-3 fatty acids are able to promote the resolution of the inflammation. And, of course, teeth brushing on a regular basis is very important because microbiofilm is a tenacious physical barrier. It protects the bacterial colonies from the effects of antibiotics, antiseptics, and host defense mechanisms. I feel that the most effective is still tooth brushing. It is a very humbling experience, but it is actually preventing the growth of the bacteria into very complex microbiofilms, where we need very strong germicides or biocides to kill these biofilms and cause a lot of other damage along the way. They even disrupt the bacteria within the gut. My main tool is actually the toothbrush and teaching the patient how to brush. It goes back to basics: brushing with water is good enough, and brushing correctly and precisely and at regular intervals. JB: That is really important information. That is the “news-to-use” that is very powerful. I think your concept of destroying biofilms systemically by giving drugs versus regionally by doing it mechanically, that is a very important point for everybody to keep in mind-that these biofilms can be very tough to get rid of, and when you try to treat them systemically you are treating a lot of things that you probably don’t want to have an effect on, so the regional mechanical disruption using brushing sounds really wise. Because more and more people are moving away from hand brushing to mechanized brushing using various types of devices that are electrically driven, do you find the same benefit from the kinds of electromechanical brushing devices that you do with a hand brush? Brushing: Is Low Tech Best? GSN: Manual tooth brushing allows you to feel things very closely and it lets you experience it correctly. If you have a motorized brush it can be too fast for you to feel. I think that we have a lot of sensation in our gums, and it is there for a purpose-for us to feel it and to know whether we are brushing correctly. The design of the brush, where you have fine bristle ends to get into the healthy gingival sulcus, is very important to prevent further build up of the biofilm in the gingival sulci. Whether you use mechanical or whether you use manual is really up to you, but the method and precision of doing it on a regular basis is very important. I fully embrace technology where you can use it to help you and take out the tedium of tooth brushing. Of course, some people are oral enthusiasts and they brush away their gums. It has to be closely monitored and supervised. Each person has to be taught exactly how to brush their teeth because the gingival biotype and the gingival morphology around all of the teeth are different. I believe that this can be done by everybody. If you are not so dexterous you may need a motorized toothbrush to help you, but I have taught brushing to blind patients and they can be very good at it. It is a very kinesthetic kind of technique and I think many people-once they get it and they feel it and they experience it-are able to take it home. This would even help them to prevent any cardiovascular events, even. Website Recommended for More Information JB: Very, very powerful information. I want you to say a few words in close, if you would, about the magnificent website: www.thesystemiclink.com. Can you tell us a little bit about that? I think it is really very important. GSN: They did a lot of studies in oral hygiene and how oral hygiene strategies can be instituted to prevent cardiovascular events. Of course this web link can be shared with everybody. JB: For anybody that wants kind of the bibliography, they can really find tremendous referential support for what you’ve been talking about. You are an amazing person. You are not only obviously a very attentive dentist and one who is bringing the skill of your craft to your patients, but you are also expanding this sphere of influence to people around the world. What an important topic as we move into this age of more and more opportunistic infection and its relationship to chronic disease. GSN: I feel that periodontal disease, with dental care, is highly preventable, and it can be very simple. It starts with just a toothbrush and water and awareness. You can prevent a lot of other systemic problems that can result from the build-up of biofilm, so why not make it freely available information to people and make it part of a routine in life and normalcy? People should not be afraid of brushing their teeth-of feeling their mouth-because that feeling/feedback that they get is a big indication to them as to how their immune system is doing and how the inflammation state is through the presence of bacteria and pathogens in the mouth. If people can really grasp this, they can really help themselves a lot and prevent diseases. I think everybody wants to go into old age happily and healthily without having to incur more hospital visits and hospital costs. I think if oral care can be instituted as simply as possible (without fear), we would be helping patients a lot, eventually physicians as well. JB: Dr. Gan, I want to thank you so much. This has been a very illuminating visit with you. It is not only that you have contextualized this in a wonderfully supportive way, but you have given us some real news-to-use to take away from this. Oftentimes people might come away from these discussions saying, “That was very interesting, but I’m not sure what I should really do.” In this case it is very clear, from your directive, what should be done. I think coming to the website, www.thesystemiclink.com, can provide them with the next step. Thank you and we wish you the very, very best in your continued work and look forward to sharing with you at another time. GSN: Thank you very much again. I’m not sure if this issue of Functional Medicine Update has hit you as it has hit me, but this has been a very kind of profound “a-ha” issue for me. The story that we have been telling for (now) 27 (going on 28) years in Functional Medicine Update is really starting to become rich, deep, mature, and powerful. It is incorporating discoveries across many, many disciplines, and it is demonstrating the convergence of those discoveries around a theme: that the way we have been approaching medicine over the previous 100 years, to look for the cause of a disease and treat it with a drug or a specific surgery, is only part of the story. That if we really want to understand “the” story of the rising tide of the burden of chronic disease, we have to broaden the lens of understanding into these areas of contributing factors that modulate genomic and epigenomic expression patterns and ultimately regulate how cells, tissues, organs, organ systems and whole bodies respond to the world in which they find themselves. The Sacred Law of Salads I came across a recent paper, whose title I think probably sounds very esoteric, but it is a really interesting paper that really ties much of this together. The title is “Giacomo’s Castelvetro’s Salads. Anti-HER2 Oncogene Nutraceuticals Since the 17th Century?”14 Now, does that get your interest at all? What does that all mean “Giacomo Castelvetro’s Salads, Anti-HER2 Oncogene Nutraceuticals Since the 17th Century”? It goes something like this (just to show you why this issue of Functional Medicine Update has been so profound for me): “We are accumulating evidence to suggest that 17th century Renaissance foodways–largely based on old “Mediterranean dietary traditions”– may provide new nutraceutical management strategies against HER2-positive breast cancer disease in the 21st century. Epidemiological and experimental studies begin to support the notion that “The Sacred Law of Salads” (i.e., raw vegetables, plenty of generous olive oil)–originally proposed in 1614 by Giacomo Castelvetro in his book The Fruit, Herbs & Vegetables of Italy–might be considered the first ( unintended) example of customized diets for the management of chronic disease, including breast cancer prevention, based upon individual genetic make-up… First, the so-called salad vegetable dietary patterns (i.e., a high consumption of raw vegetables and olive oil) appears to exert a protective effect confined to the HER2-positive breast cancer subtype with no significant influence on the occurrence of HER2-negative breast cancers. Second, all the main olive oil constituents (i.e., the omega-9 monounsaturated fatty acid and polyphenolic compounds such as the secoiridoid glycoside oleuropein or the lignin acetoxypinoresinol dramatically reduce HER2 expression and specifically induce apoptotic cell death in cultured HER-2-positive breast cancer cells, with marginal effects against HER2-negative cells. Third, an olive oil-rich diet negatively influences experimental mammary tumorigenesis in rats, likewise decreasing HER2 expression.” If early 1600s Castelvetro’s salads can be used as dietary protocols capable of protecting women against biologically aggressive HER2 &ndash;positive breast cancer subtypes, then what else might we see-what spreading effect might this have-on reduction of the burden of chronic disease? Who are those that are most susceptible to positive influence and how can you reduce the triggers that ultimately weave their way into the phenotype of complex disease? That is the theme I think that we are taking away from the last several months of Functional Medicine Update. I would say it is the dawn of “back to the future”-reappropriating old knowledge in new ways. Thanks for being with us.

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Bibliography

1 http://www.perio.org/consumer/perio_cardio.htm 2 Barnet RJ. Ivan Illich and the Nemesis of Medicine. Med Health Care Philos. 2003;6(3):273-286. 3 Xu Q, Parks CG, DeRoo LA, Cawthon RM, Sandler DP, Chen H. Multivitamin use and telomere length in women. Am J Clin Nutr. 2009;89:1857-1863. 4 Ornish D, Lin J, Daubenmier J, Weidner G, Epel E, et al. Increased telomerase activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol. 2008;9(11):1048-1057. 5 Aviv A. Leukocyte telomere length: the telomere tale continues. Am J Clin Nutr. 2009;89:1721-1722. 6 Safarinejad MR. Efficacy of coenzyme Q10 on semen parameters, sperm function and reproductive hormones in infertile men. J Urol. 2009;182(1):237-248. 7 Frattaroli J, Weldner G, Dnistrian AM, Kemp C, Daubenmier JJ, et al. Clinical events in prostate cancer lifestyle trial: results from two years of follow-up. Urology. 2008;72(6):1319-1323. 8 Bierhaus A, Nawroth PP. The Alzheimer’s disease-diabetes angle: inevitable fate of aging or metabolic imbalance limiting successful aging.J Alzheimers Dis. 2009;16(4):673-675. 9 Graff J, Mansuy IM. Epigenetic codes in cognition and behavior. Behav Brain Res. 2008;192(1):70-87. 10 Gomez-Pinilla F. Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci. 2008;9(7):568-578. 11 Lee DM, Tajar A, Ulubaev A, Pendleton N, O’Neill TW, et al. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. J Neurol Neurosurg Psychiatry. 2009;80(7):722-729. 12 Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K. Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol. 2008;9(6):550-558. 13 Desvarieux M, Demmer RT, Rundek T, Boden-Albala B, Jacobs DR Jr, et al. Periodontal microbiota and carotid intima-media thickness: the Oral Infections and Vascular Disease Epidemiological Study (INVEST). Circulation. 2005;111(5):576-582. 14 Colomer R, Lupu R, Papadimitropoulou A, Vellón L, Vázquez-Martín A, et al. Giacomo Castelvetro’s salads. Anti-HER2 oncogene nutraceuticaals since the 17th century? Clin Transl Oncol. 2008;10:30-34.

Welcome to Functional Medicine Update for October 2009. If you have been listening and following along with our intellectual content over the last several months, you’ll recognize that we have been developing this concept of signaling to intercellular communication that occurs by outside environmental agents, like gluten, allergens, toxins, or inflammatory proactivating agents, and how that signaling ultimately influences the phenotype of cells or the expression of what we call later the clinical presentation of the patient. This follows very nicely within the context of the functional medicine assessment concept: looking at antecedents, followed by triggers that trigger the release of various mediators from specific cell types. These mediators go on to regulate function downstream in multiple cell lines to ultimately produce what we see in the clinic as signs and symptoms with different duration, frequency, and intensity. This is a very different model than the traditional differential diagnosis model. Rather, what we are doing in this particular process is understanding the origin of the disorder and how it spreads out into multiple different presentations, knowing that we have comorbidities, which refers to multiple organ systems being influenced in different ways by shared processes or shared mechanisms. That is the functional concept that underlies the functional medicine model as we have been describing it for many years. We have really had a wonderful journey with a number of clinicians and investigators over this 2009 year, who have been helping us to understand genomic uniqueness and the influence of expression signaling from outside agents, including things like gluten (which we spent quite a bit of time on) and more recently gut enteric bacteria (how they influence signaling systemically). I hope these interviews have opened up a richer and more robust view of the origin of chronic disease and new opportunities for both its prevention and management based upon this strategy Just as we are developing this theme, what do you think appears in Scientific Americanmagazine in their August 2009 issue? It is an incredibly rich article-beautifully written-and (as always with Scientific American) wonderfully illustrated, titled “Surprises From Celiac Disease,” authored by none other than Dr. Alessio Fasano, now at the University of Maryland, and the person who was the principal investigator in discovering many of the mechanisms at which gluten can initiate, at the brush border cell and at the mucosal barrier, alteration in gut mucosal integrity that he has termed (and we have used this term for many years) “leaky gut.”1 As a gastroenterologist, Dr. Fasano has started to put this term “leaky gut” and gut permeability on the map related to localized gut inflammatory response, as it pertains to the gut as an immune organ. I think you will find this a very interesting article. I urge you to go to the Scientific Americanwebsite and look at this mechanistic discussion of gluten and gut permeability. Included is a beautiful diagram/illustration that looks like we a functional medicine teaching diagram. The brush border cells have proper intercellular junctions that get disturbed by various proinflammatory signaling processes from outside molecules (like gluten) in genetically susceptible individuals, leading to breakdown of gut permeability and opening of the portals of entry to larger molecular weight molecules that can initiate a generalized immune response. I think this article is a very nice confirmation that this field is growing in greater recognition and visibility. We are really talking about the changing of metabolism as a space in time that relates to altering the web of physiology. As you know, one of the fundamental tenets of functional medicine is this web-like interaction, and that concept is really gaining traction now in the field of general science and certainly in systems biology. A recent paper that was published that helps us to understand this better appeared in the Journal ofProteome Research in the October issue of 2009, in which they talked about individual human phenotypes actually reflecting the influence of the environment .2 If you look at identical twins, which they did in this particular study, and do pattern recognition of their metabolites by complex dendritic analysis (this is very complex pattern analysis-it is kind of almost artificial intelligence of the data set [multiple analytes]), they found that a pair of identical twins in different environments, particularly different nutritional environments, showed a difference in how their metabolites clustered. There is a genetic underpinning (your basic map) that is common between the two identical twins, but then there is this environmental factor laid on top that modifies or distorts their web, making them less the same than they were prior to being in different environments, and diet is a major modifier of that . The gut connection to enteric bacteria and its spreading effect through the whole systemic circulation through information signaling molecules is a whole new paradigm that is opening up in medicine, and that is the topic we will be discussing and focusing on in this issue of Functional MedicineUpdate

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INTERVIEW TRANSCRIPT

Researcher of the Month Trevor Marshall, PhD Adjunct Professor School of Biological Sciences and Biotechnology Murdoch University Western Australia Director Autoimmunity Research Foundation Thousand Oaks, CA www.trevormarshall.com www.autoimmunityresearch.org www.marshallprotocol.com Here we are once again at that portion of Functional Medicine Update that I know you, like I, look forward to each month with anticipation and that is our Functional Medicine Update Clinician/Researcher of the Month area, where you hear the “news-to-use” from the people who are really making the new medicine happen. You are not going to be disappointed this month, I can assure you, because we have one of the clearest, fresh, and innovative thinkers that I think I have had the privilege to interview, Dr. Trevor Marshall. Let me tell you a little bit about Dr. Marshall. If we want to talk about a Renaissance man, this gentleman has diverse interests, ranging from biotechnology and medicine, into things like digital information sciences and digital media and the way that one assembles complex information into systems and cross-disciplinary thinking. You’ll see it woven beautifully into the work that he is going to share with us today, which has to do with the burden of autoimmune disease, which cuts across many different diagnostic categories and affects every subspecialty of medicine when we talk about dysregulation or altered regulation of the immune system that often gets put under the rubric of autoimmune disease. Dr. Marshall is an adjunct professor at the School of Biological Sciences and Biotechnology at Murdoch University in Western Australia. He is also the past Chair of the Engineering in Medicine and Biology Society, and he is currently Director of the Autoimmunity Research Foundation in California, which you will be learning more about as we go through this interview. Dr. Marshall, it is really a great privilege and pleasure to have you here to share your diverse background and talents and discoveries with us. Given that I’ve already presaged that this interview is going to involve discussions about the immune system (the immune system kind of gone into overdrive), could you help us review the concept of innate immune response and its relationship to bacteria, and viruses, and things like antimicrobial peptides? Your work is founded upon this whole emerging concept of the innate immune system. Can help us understand a little bit about the background? The Difference Between the Adaptive Immune System and the Innate Immune System TM: It’s great to be here. The focus of research, particularly on the autoimmune diseases for the last four or five decades, has been on what we call the adaptive immune system. That is where the antibodies are generated and are recognized by the lymphocyte clones and then become memory cells. Should a pathogen attack again at a later point, the body has the ability to recognize them with antibodies generated in the past. This is what is called the adaptive immune system. The innate immune system is like the final line of defense that the body has. Once the pathogens manage to get within the cells of the immune system itself (within the cells that generate those antibodies and generally protect the body), the innate immune system kicks in to try and protect the cells from the pathogens. There are a number of obligate cytoplasmic pathogens (that means pathogens that get within the actual phagocytic cells-the cells of the innate immune system that are supposed to gobble up these bacteria; the known ones include mycobacterium, of course, and some others as well). Typically, the methods by which those pathogens invade the innate immune system vary. What we have found is that there is a persistence-what I call a metagenomic microbiota. Metagenomic means there are many genomes involved, many more than one species accumulate during the lifetime. And microbiota is a community of microbes; you might think of it as a biofilm-protected community because there is usually a biofilm central area of these inclusions and then a cytoskeleton (an exoskeleton) around the outside. Think of it as a vacuole in a phagocyte…a vacuole which is full of living and persisting bugs rather than being filled with dead pieces of bugs. That is really what we are dealing with these chronic diseases. JB: To me, this sounds like an extraordinary step forward in understanding this connection between…what would you call it?…I guess the genome that is not a eukaryotic genome…It would be this diverse microbiome genome and that of our own cells in the immune system. It sounds to me like what we are saying is that we are starting to get information from a non-relative genomic that then has an effect both internally in our innate immune system and systemically. Genomes of Bacteria Have Now Been Sequenced TM: Clinical medicine has retained the concept that the human body is a sterile compartment. Basically, that there are no pathogens within the human body except for the normal, acute-phase pathogens that cause sickness. And those acute-phase pathogens, by and large, are capable of being cultivated in the laboratory and observed with the tools that medicine has had available to it prior to the explosion of the genome in this 21st century (in the last decade). There are now over 2400 bacteria whose genomes have been fully sequenced (essentially fully sequenced), in addition to the human genome. Typically the bacterial genomes are smaller, but they are still producing a large number of proteins, enzymes, lipids, etc., and we can actually study these bacteria in some detail now by looking at their genomes and comparing the genomes with that of Homo sapiens itself, looking for things like molecular mimicry, and also with other known pathogens, looking for things like the way that the bacteria evade the immune system, for example. JB: How does the body regulate this burden? It obviously must have built in systems that can get to these biofilms or this microbiota burden. What are the mechanisms by which the immune system has some protection against this? TM: The body has this innate immune system I spoke about, which consists of a number of factors. The key defense are the so-called antimicrobial peptides, which are relatively small molecule proteins (there are larger molecules-actually the molecules transcribe from the genome as larger molecules and then they break down to the smaller peptides), which target specific known pathogens, against which Homo sapiens has managed to survive in the past. There is one very important antimicrobial, which is called cathelicidin. Cathelicidin is the main antimicrobial that allows the phagocytes to protect themselves from intraphagocytic invaders (or invaders that actually get through the outer layer of the phagocyte and try and persist in the cytoplasm). But there are also others; there are the beta defensins and alpha defensins, which are pretty active in the gut and in other areas of the body as well. Totally, there are about 24 families of antimicrobial peptides that have been identified at this point in time (or antimicrobial genes–let me put it that way) that translate into peptides and proteins that have been identified at this particular point in time. There are a number of ways that these transcribe from the genome, but many of them are transcribed by what we know as the type 1 nuclear receptors). JB: That leads us into a really interesting cross fertilization in this field. Our field of science often tends to be compartmentalized and different disciplines don’t talk to one another, but I think you have done a very good job of helping us to recognize that the body doesn’t subscribe to any specific professional society; it works as a community. We are going to transition now to one of those nuclear receptors, which you have really brought to the forefront of our attention. That is the vitamin D receptor and how that plays a role in this whole process. Can you help us understand that? Defining the Vitamin D Nuclear Receptor (VDR) TM: The vitamin D receptor is one of the nuclear receptors. Let me call it a sister receptor because it is part of a complementary team with the progesterone receptor, with the androgen receptor, with the alpha and beta thyroid receptors, with the glucocorticoid receptors, with the mineralocorticoid receptor, and the PPAR alpha and gamma. They are the main ones. They form a set, which we call the type 1 nuclear receptors, and they work together as a set, transcribing genes or expressing genes from the genome into the proteins and later the enzymes and other metabolites that the body needs in order to function correctly. There is one nuclear receptor called the VDR (the vitamin D receptor), which is responsible for transcribing or expressing about 3{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of all the genes in the human body. It is fairly important. There is quite a lot of redundancy in the human genome; it is remarkable resilient and able to deal with challenge. So there is quite a bit of redundancy, but the VDR is responsible for transcribing over 900 genes that have been confirmed at this point, which is about 3{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the total human genome. This particular receptor transcribes genes ranging all the way from the metastasis suppressor type 1 all the way through to many, many genes associated with the development of the human fetus. It is a very, very important transcription factor. A transcription factor is something that will transcribe the genes that are on the genome into proteins that the body needs in order to work. JB: You are helping us take an important step, and that is to start off with understanding a little bit about the innate immune system and the complex relationship it has with microorganisms and the complex microbiome. We have said that part of the regulation of the innate system and its expression of genes (over 900 genes) is regulated by the VDR (the vitamin D receptor), which plays a very important role in concert with other orphan nuclear receptors in regulating genomic transcription. Going upstream from there, the question is: What are the various types of activators or suppressors or modulators of the vitamin D receptor? One of them must be vitamin D. Let’s talk a little bit about that? Confusion about Vitamin D Dates Back to Early Research TM: Right. The vitamin D receptor became known as the vitamin D receptor because of the substance (or a metabolite of the substance) that was called vitamin D back in about 1903 through about the 1920s when the vitamin was being studied. A substance was identified back then-a secosteroid-and that means a steroid which is a little bit more flexible than the other steroids. This secosteroid was called vitamin D. In its activated form, it is the substance in a healthy human body that allows the VDR to transcribe all of these genes. The whole confusion about vitamin D and the VDR and whether it helps people fight off cancer or whether it prevents cancer or whether it makes cancers worse…all of the dissension at the moment in the clinical world around what vitamin D actually does is based on the mistaken notion that it is a nutrient. It is not a nutrient. The body produces all of the vitamin D it needs. It can get excess vitamin D from, for example, exposure of the skin to sunshine, and from the diet (for example, eating large quantities of fish will increase the level of vitamin D in the bloodstream), but the vitamin D that is needed in order to transcribe the genome is produced inside each of the cells where the VDR is present. All the exogenous, or externally supplied, vitamin D can do is to try and disturb the homeostasis that is set up within the cell itself. JB: I want to make sure that our listeners are following because this is a fairly complex area. The secosteroid, which would be that which converted in the body from 7-dehydrocholesterol into cholecalciferol then gets further converted, as you say, into a vitamin D receptor modulator, which is 1,25-dihydroxyvitamin D3 (what you now are really talking about as a hormone modulator), so that goes through several control points… TM: Yes, it’s a nuclear hormone, though. It’s not an endocrine hormone. It is not a signaling hormone. It leaks from the cell into the bloodstream and it can be measured in very low quantities in the bloodstream, but it doesn’t have a signaling mechanism an endocrine hormone); it’s a nuclear hormone. Assessment of Vitamin D Status JB: I know in our field the clinicians are measuring, as a status evaluator for (or biomarker for) vitamin D status, the 25-hydroxy precursor to the 1,25. It would sound, from what you are saying, that we ought to have some information about 1,25 levels as well as 25. Can you tell us a little bit about assessment? TM: These pathogens, including mycobacteria, Borrelia, and Epstein-Barr virus are known to downregulate the VDR. They actually stop the VDR from doing its job properly. Whether you look at those or you look at the pathogens (the metagenomic microbiota) that accumulate to ultimately cause chronic disease, they do this by knocking out the VDR. As we said earlier, the VDR is responsible for a significant proportion of the body’s own antimicrobials. If a pathogen is going to survive and persist, it clearly has to knock that receptor out, and it does, in fact knock that receptor out. When the receptor is knocked out, you usually detect a lowered level in the bloodstream of this metabolite called 25-hydroxyvitamin D, which is the normal one that is measured to assess vitamin D status. The 1,25-dihydroxy (the active hormone), which is much, much harder to measure usually rises when the VDR becomes dysfunctional in chronic disease, but the one that is easier to measure (the one that we measure for vitamin D status) drops. I’m sure you would have seen all of the studies over the last decade that show that just about every chronic disease is associated with a drop in the blood level of 25-D. The reason for that is the body’s own homeostasis (the control systems that control the generation of metabolites within the cells); it is the body’s own homeostasis trying to force the 25-D to a level where the VDR can do its job properly. It fails to do its job when pathogens manage to overcome the innate immune defense system. My colleagues just published a paper in Autoimmunity Reviews pointing out that although the low levels of vitamin D are associated with the chronic diseases, you cannot correct or reverse the chronic diseases by increasing the level of vitamin D.3 Vitamin D is not a nutrient, it is a marker. JB: I think this is a very important point for clinicians because we have been led to believe that the assessment of 25-hydroxy D is measuring a vitamin deficiency and that by repleting the vitamin you manage the deficiency, which then treats the downstream deficiency signs and symptoms. This model that you are presenting, based upon this background, is certainly a different model. Vitamin D Supplementation is More Complex than Just Treating a Deficiency TM: Yes. Our paper documents a number of studies that have showed conflicting results. In fact, just last week the Institute of Medicine of the National Academies held a hearing where two of my colleagues spoke.4 They have done a complete report of all of the literature (a summary of all the literature) on vitamin D (whether it is beneficial or not beneficial). Their official study came back with the conclusion that there is just too much variance. There is no distinct thread that can be pulled out of all the studies that have gone on in the past. The reason for this is actually fairly simple. I said that the VDR is responsible for transcribing about 3{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the total human genome. When you construct an experiment to change the way that the body transcribes that 3{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the total human genome, a lot of things change (at least 900 metabolites, plus all of the downstream affects that those have). A clinical study-especially the clinical studies that have been based on the concept that vitamin D is a nutrient-are not capable of measuring that many variables. If you have a typical cohort of a few hundred patients, for example, you would be lucky to be able to deal with 4 or 5 variables, and typically you try and constrain yourself to look at just one endpoint. The problem with the VDR and its ligand, activated vitamin D, is that when you change the homeostasis around the VDR, you are changing about 3{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the total genome, and lots and lots of things change. It’s just not possible to measure all of the changes that occur and understand how they fit into the scheme of things unless you study it at the level of the biology, and not just at the level of the evidence base. JB: That’s a really important point. Let me parrot back something to make sure that I’m following correctly. What I have heard you say (and I’m going to sound bite this to hopefully make it simple) is that the effect of the burden of the microbiome on our innate immune system then has implications on the secosteroid metabolism through the VDR effects so that the 1,25-dihydroxy and the 25-hydroxy levels reflect more as an assessment of the burden of the microbiota on our immune system than a pure vitamin D-deficiency relationship. Therefore, ipso facto, if you just give more vitamin D to treat what you thought was an apparent vitamin D deficiency (based upon a 25-hydroxy serum level), you may be actually going the wrong way. TM: Right. You are trying to force the body to increase the metabolite that the body itself has decided needs to be lower in order for the cells to continue to function correctly. 25-D is regulated down by the cells in the chronic disease processes (those processes which are based on microbiota which overcomes the VDR in order to survive). You’ll recall the reason that overcoming the VDR is an important survival mechanism is because many of the antimicrobials are produced by the VDR. There is one step we took that I didn’t explain in any real detail. We started talking about microbiome. Since we’ve been able to identify the genomes of the bacteria that coexist with Homo sapiens, we have found, for example, that the saliva contains over 100 species of bacteria, and that ranges from Yercinia, Neisseria, obviously strep and staph, and all the way through; about 100 species are in normal saliva from healthy individuals. In hip joints you will find a whole range of bacteria, many of which have never been seen as being human pathogens or actually capable of being internalized in the human body (Methylobacter, Lysobacter), and even the Eubacteria, which were previously only found in hydrothermal vents at the bottom of the ocean (hydrothermal vent Eubacteria). These can now be found because their genomes can be found and identified with DNA sequencing. JB: I think you’ve actually said it in your publications that more than 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the genomes in the human are not eukaryotic. TM: Yes. That’s a number that came from the National Institutes of Health (NIH) Microbiome Project, which seeks to more closely define how many pathogens and species we are dealing with and where they are located in the human body.5 That’s an ongoing project. Some of the early results are in. I mentioned the salivary microbiome, for example. There will be a lot more studies coming in over the next few years that will enable us to really understand the way in which Homo sapiens lives in harmony with the bacteria flora that (on this planet, at least) are far more numerous than Homo sapiens, itself. JB: That begs one interesting question related to polymorphisms or genetic variations that could have influence on the regulatory components of the innate immune system, for instance, polymorphisms of VDR. Have certain SNPs been identified that are more sensitive to dysregulation or altered regulation in this process? TM: This is a very difficult and technical area. One can make the argument that the concept of a polymorphism and a SNP is based on the concept of a single genome for Homo sapiens and not on a mix of genomes in the samples being measured and analyzed. When the bacteria living in symbiosis with Homo sapiens interfere with (or affect) the transcription and repair mechanisms of Homo sapiens itself, then there is clearly the opportunity for genetic variation to occur as a result of the pathogens. But honestly, there just is too little known at this point about precisely how the human genome protects itself and precisely how the pathogens integrate their DNA with the human DNA. Once again, over the next few years that will become a lot clearer. I’m not an expert in that area because I frankly think at this point it’s a waste of time to be looking at genetic variations in one genome when there actually are hundreds of genomes present in the body. You get a measurement error potential, and you certainly get interpretation error potential. JB: Thank you. Let me just go back to one point that we talked about earlier. If we can, I want to see if we can get clarity for the clinicians. Based on what you have said, is it or is it not, in your opinion, important to measure (if you are doing an assessment of this whole immune interrelationship with vitamin D) both 1,25-hydroxy and 25-hydroxy or is that still not going to give you the information you are looking for? Vitamin D Status as a Marker for Chronic Disease TM: Well it actually is a fairly good marker of chronic disease. One of my colleagues, Dr. Greg Blaney, from British Columbia, just published in Frontiers of Autoimmunity, which is put out by the Annals of theNew York Academy of Sciences, a paper that explains (with his particular patients) how the best indicator of chronic disease has been an elevated 1,25-dihydroxyvitamin D, frequently associated with a depressed vitamin D status (or 25-hydroxyvitamin D).6 That is a paper, showing that it is one of the best markers of chronic disease, in fact. By chronic disease, I mean the chronic disease where the pathogens have overcome the VDR in order to persist in the human body. JB: That’s very helpful. Thank you. The big next step in the journey that we are taking with you is to talk about how this understanding of the emerging view of the innate immune system and its regulation by endogenous and exogenous factors could influence the clinical approach to various autoimmune diseases. Principally, the way we have been treating them recently is just to knock down the immune system and try to treat the symptoms rather than the cause. Can you tell us a little bit about how this model is helping us maybe moving toward clinical approaches?7 TM: Yes. You are correct. It is typical that in all of the rheumatic, autoimmune, and many other chronic diseases, including asthma, for example, that corticosteroids are used in order to suppress the inflammation based upon the concept that it is the inflammation that is causing the problem and the disease symptoms. But, when you are looking at inflammation, that is driven by bacteria (by pathogens), then the inflammation is actually beneficial because it is the body’s own response trying to knock down the pathogenic load and generating inflammation from the cytokine storm that it produces as part of doing that. And, indeed, applying corticosteroids to reduce the inflammation and reduce the body’s ability to deal with the pathogens, is in the long run going to bring relapse. That has been documented in some of the more serious chronic diseases. For example, if you take sarcoidosis, which is a really end-stage chronic disease because in sarcoidosis the phagocytes, monocytes, and macrophages actually exist in clumps or granuloma, which don’t consist of any other tissue-related cells specifically, but where more than 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the cells in the granuloma are these innate immune primary defense cells (the monocytes and the macrophages). In that particular end-stage disease,the vitamin D dysfunction has actually been known for some time. And with that disease, it becomes clear to see that when you use corticosteroids to make the patient feel better and suppress the symptoms in the short run, that there is almost invariable relapse. I can remember a paper which came out in the 90s (quite a decent study by Gottlieb, et al) which showed that something like a 78{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} relapse rate following withdrawal of corticosteroid in sarcoidosis. We would expect the same pattern in the other chronic diseases and autoimmune diseases as well. JB: I know that in your papers you’ve suggested (maybe at a lower level of risk, I’m not sure, than corticosteroids) that excessive use of vitamin D in these cases might lead to kind of temporary immune suppression but later-stage rebound effect like you are describing. That is kind of a highlight that you have cautioned us about, I believe. TM: The body is designed to be able to deal with vitamin D from external sources (vitamin D from sunshine, for example, on the skin). When vitamin D falls on the skin, the skin reacts to protect itself from, for example, carcinogens that are produced as a result of UV light falling on the skin. The skin acts to protect itself, and in doing so, in healthy people, it produces some 25-D, which accumulates in the bloodstream and then in the tissues of the patients. Also when patients have food which contains a significant amount of vitamin D, such as, for example, fish or mushrooms (especially irradiated mushrooms), then that also accumulates in the bloodstream. This doesn’t do any harm until it gets to a level at which it starts to interfere with the processes within the cell. There is an attenuation between the bloodstream and inside the cell, which is about 20 to 1 (10&ndash;20 to 1), so at concentrations around 20 nanograms per mil (around 20&ndash;25 nanograms per mil) 25-D, the vitamin D in the bloodstream starts to become immunosuppressive; it starts to interfere with the way that the VDR is activated within the cells. JB: This very complex regulatory process that you have been describing takes us beyond the simple concept of measuring a number and then giving an agent to treat the number. That is, I think, what we are taking away from your discussion. TM: Right. We’ve known for a long time that if you give vitamin D to a group of people, that every one of them will behave differently, that every one of them will end up with a different value for the blood metabolite. It is not a linear “vitamin D in, goodness out”-type of paradigm, which is what you would expect from a nutrient, incidentally (toxicity issues aside). A nutrient you would expect to be a first-order mass action-type of system, but what you actually find with the vitamin D metabolites is a very complex control system, more of an eighth-order, involving two other transcription factors (PXR and CBP), which produce the enzymes. It is quite a complex diagram. I published it in Figure 1 of my bioessay in 2008 if anybody is inclined to actually go into all of the various things that affect the operation of the innate immune system, affect the operation of the VDR itself.8 JB: Let’s move into an example of an autoimmune disease that certain receives a tremendous amount of attention and one that you have helped us understand more about. That is fibromyalgia, which is an interesting kind of “wastepaper basket” diagnosis for many people because it doesn’t seem like it has a clear etiology, and therefore, often, the treatments are kind of shotgun. We have a new drug approved in the states, Lyrica, which is a gabapentin analog that basically treats (maybe) the pain without treating the cause; there are a lot of questions about that. It seems that there hasn’t been a treatment that is focused on the cause because no one knew the cause. People say, “Well, it is a disorder of the HPA system (the hypothalamus/pituitary/adrenal axis).” What does that mean? Where is did the origin of that come from? Your model-and your concept-really lends itself to a better explanation of an etiology. Can you tell us a little bit about that? TM: Fibromyalgia was one of the pleasant surprises that we got once we started to focus on the disease sarcoidosis. We found that fibromyalgia and another disease (another diagnosis), chronic fatigue syndrome, both responded well to the VDR agonist. We use a VDR agonist, which is a small molecule. In this case, it is a sartan that was developed primarily to target the angiotensin 2 receptor, but it also targets the VDR quite well when the dosing is changed. When we used the VDR agonist to switch the VDR back on again, there are a number of reasons why vitamin D, itself, can’t switch the VDR back on again, but to understand them I’ve really got to go in to the structure of the proteins and things and that’s pretty heavy stuff. When somebody gets sick, then vitamin D can no longer activate the VDR; it has to be activated with a different drug. We were fortunate enough to be able to find a drug that would do that, which is in the US formulary and it is regarded as a very safe drug; that drug is called Olmesartan medoxomil. When that is dosed in the correct way, then the VDR is reactivated again, and the innate immune system is incrementally activated and it allows the body to start to recognize the pathogens and also make sure that it keeps transcribing the 913 genes, and particularly the anti-cancer genes that are amongst that set. Once we started to do that, we found that there were a whole range of diagnoses that were responding that we hadn’t really expected to respond. As I said, chronic fatigue syndrome, fibromyalgia, and some of the other neurological conditions as well: obsessive compulsive disorder and bipolar were some things that were fairly common in our cohorts. The symptoms tended to resolve at the same time as the underlying inflammatory diagnosis resolved. JB: Did you find that this was a class effect in the angiotensin receptor blocker drugs or was it specific? TM: No. It is unique to Olmesartan medoxomil. Only Olmesartan medoxomil is the correct shape to get into the VDR and activate it. JB: And the doses that are required are generally…? TM: Just a little bit above the levels that are used for hypertension. But it has to be taken fairly frequently, and it has to be the slightly higher concentration because the affinity of the drug for the VDR is less than the affinity of the drug for the angiotensin type 2 receptor. VDR Research Links to Obesity and the Gut JB: You know, it would sound to me, as you are unweaving this story for us, and then talking about what has been called the Marshall Protocol, that you are really discovering an interesting generalized mechanism that relates to the etiology of many chronic-related illnesses. I know you have also done some collaborative work on the obesity epidemic, which might seem far away from what we are talking about, but by this mechanism, it actually interconnects. Can you tell us how those all kind of fit together? TM: Well, when I wrote the bioessay in 2008, I can remember one of the peer reviewers came back and objected to me referring to obesity as a disease. We got into a discussion. I pointed out that there had been a number of studies on closed communities. There were studies on native Indian communities, for example, in the United States, where the entire way of life of school children was changed in these small tight communities in order to try and curb the incidence of obesity, and it totally failed. The normal connection that we accept–that obesity is a result of lifestyle–has never been able to be confirmed in trials. In fact, quite the opposite has been shown-that obesity appears to be a disease-related process. And since we find it surging in the American population at the same rate as we see other conditions surging (the other conditions that we know are VDR-related in our population), obesity is likely to end up considered a disease of the same nature, where the pathogens are overcoming the VDR in order to survive and persist. JB: It’s very interesting. We just had the privilege of interviewing Professor Delzenne and Dr. Cani at Louvain University (Catholic University) in Belgium, who have been doing quite a bit of work on the gut enteric microflora and its relationship to obesity in which they have been able to show (at least in the animal model) that by altering gut flora they can alter the energy economy of the animal and actually treat obesity. It would seem that what you are describing has some correlation with their work. Would that seem reasonable? TM: Oh, yes. There is also work being done at Washington University in St. Louis (I’m not sure if that was what you were citing as well as the Belgian work), but there is quite a lot of research being done on trying to understand gut flora. Much of the flora in the body is in the gut, of course, because it accumulates there. It comes in through food and water and things that we ingest, and it accumulates there. Many of these pathogens have learned how to persist. For example, Helicobacter pylori persists for year after year after year in some patients; it is very, very difficult to eliminate. I’m sure your listeners would understand that many bacteria species are competitive, for example, strep always tries to kill off staph that are in the vicinity, and staph does the favor in return, trying to kill off any strep in the vicinity. In fact, some of the antibiotics that are most effective against staph were isolated from strep bacteria forms in the past. So there is a competitive environment set up, and as we fully understand that competitive environment we will probably be able to figure out interventions that will allow us to more effectively deal with diseases like obesity. The Autoimmunity Research Foundation JB: This all interestingly connects with your activity as a Director of the Autoimmunity Research Foundation, which is centered in California. Can you tell us a little bit about that? It sounds like a very interesting organization. TM: The Autoimmunity Research Foundation is a 501(c)3 nonprofit organization. All of our staff are volunteers at this particular point, although we are transitioning right now. It was set up back in 2004 primarily to handle the clinical study (the phase II clinical study) that was running from 2002 to early 2008. It was a fairly loose organization with myself and some colleagues, just to give us a focus for coordinating the corporate structure and the things that one needs in a corporate structure. Now we are starting to collaborate with others. For example, we have signed a deal with West China Hospital, which is in Szechuan Province in China. West China Hospital is the largest clinical center in the world, with 4600 beds and 2.5 million outpatients a year. We just signed an agreement with them to commence a number of studies (collaborative studies) to implement this new science in a Chinese environment (make the fruits of these discoveries available in China), and also at the same time, of course, produce good evidence-based double-blinded studies that can help persuade people in the west that science is changing medicine. JB: Tell us a little bit, if you would, about this 2002&ndash;2008 open-label clinical study. That sounds very interesting. Dr. Marshall’s Background in Engineering TM: I’m not an MD. In fact, I have a PhD, and my PhD was on mathematical modeling of insulin and glucose homeostasis in diabetic and healthy individuals and dated back to the late 1970s/early 1980s. My primary focus, throughout my career as an academic, has been on teaching science subjects, but not medical science subjects. I started to transition to an interest in biomedicine back then in the 80s. But what happened towards the end of the 20th century, with the push towards the genome and sequencing the genome and then understanding the genome, is that translational people (people who could not only understand the biology involved, but could also understand the computer systems involved and the computer programs which are needed to analyze the genome and analyze how proteins move and exist in the environment) were starting to become available. I started to get back into biomedicine with a vengeance back around the turn of the century (around 1999/2000), and used the experience that I built up over my lifetime both from the computing side of things with the biology. We had done some work in the 90s. For example, I designed the big array computer, which we used in the early PET scans (Positron Emission Tomography scanners) from Hamamatsu Photonics in Japan. Basically, what really opened up the fields of discovery was the availability of these tools (these computing tools) that could enable us to analyze exactly how the human body worked to a much greater degree of accuracy and detail than we had been able to do to that date. JB: And with all of this extraordinary visionary science (really translational science), it seems very interesting that you have made this connection between the genomes of various species, regulatory signaling, ultimate changes of phenotypes, and how that translates or maps against the appearance of what are fairly new disease prevalences in the chronic disease area in our society. It begs a question: Are we just burdened now by more “funny bugs,” or is it because we are living longer that we are seeing more of this, or is has it always been there and we just didn’t see the elephant in the corner? New Studies to Be Done in China TM: It’s all of the above. First, we are burdened by more bugs. For example, I was talking to one of my colleagues in China who went to London for her postdoc, and about 3 months into her postdoc she came down with really bad rheumatoid arthritis, which she has been obviously unable to shake and which will probably significantly impair her as she goes through life. That’s an MD/PhD person who I’m sure was being very careful and not doing anything silly. These pathogens that are present in the various environments, in the various countries, in the various food chains, in the various populations differ. There is quite a lot of work (research) being done at the Imperial College in London on what is called the metabolome. What they are doing is they are measuring (in urine) proteins which cannot be produced from the human genome, but can only be produced from various bacterial species. And they are using this to gain some insight into the diversity of how the human body operates in symbiosis with different species in the different areas. You get totally different sets of proteins from Japanese residents, for example, than you get from Chinese residents, and that you get from USA residents. They are carrying a totally different flora, and we are talking about urine, so we are not talking just about gut flora, here, but rather we are talking about overall flora in the body. But the fascinating thing is that when Japanese move to the USA, suddenly the metabolites they start to produce become more assimilated with those that are in the USA. In other words, they are picking up the species that are found in the USA and vice versa, and you can see that in some of the data. My final slide, when I gave the keynote at the World Gene Congress last December, in fact is a slide of that data.9 As travel has allowed us to move around more freely, we have all become more exposed to these things, plus there is the global food chain. Our food now is sourced from all over the world, and the food is most definitely not sterile (not when we are talking about these intracellular pathogens). So food is a factor. Travel is a factor. The use of inappropriate antibiotics is a factor. The antibiotics that we use most commonly (penicillins and cyclosporins, the beta lactams) in fact get rid of the acute infection, but they make a latent-phase infection even worse. There are a number of factors. And then, of course, there is the overriding factor that sometime during the 20th century we decided that vitamin D was a vitamin and that sunbathing was good for you. The population is going to take some time to recover from the combined effects of all of those problems. JB: Thank you. This is extraordinarily interesting. Just one last question. If I didn’t ask it I know it would be in the minds of some of our listeners. This hangs together so wonderfully-the way that you have developed your concepts, your published studies over the years with your collaborators-so it begs a question about why this concept has not been generally accepted. What do you think is necessary to get it generally accepted? TM: Time. Because of my background in computing, I was able to very quickly ask the right questions of the molecular programs (the molecular simulations that I am doing of the genomes I am looking at) and make the discoveries ahead of mainstream. My colleagues gave presentations last week at the Institute of Medicine (National Academies), and one of the members of the IOM committee came up to a colleague after the presentation and said, “Look, you can’t do what you guys are trying to do with proteins. You just can’t do this. I am a chemist. I know. You can’t do this. You can’t use molecular forces and interatomic forces to analyze how these proteins interact.” It is going to take awhile for acceptance and understanding of all of these new tools. I just happen to have been able to do it quickly and efficiently because of my background, that’s all. JB: That’s very, very exciting. Just another note: I found very interesting, Dr. Marshall, as I had a chance to learn more about you and your background, this kind of Renaissance thinking that you have has cut all the way across into the entertainment industry and you did some work on electronic music synthesizers as well and some of the media that has come out of that technology. TM: Oh, goodness. I was running a company while I was putting myself through engineering school, providing sound equipment for rock music groups and some of the people I worked with (for example, Bon Scott, who went on to head AC/DC, and some of the others…Doc Neeson also) became fairly famous in the intervening years. It was interesting, but it was really a job. As soon as I graduated I took an academic position in Papua New Guinea and left the music behind. But I did enjoy that period of my career; it was fun. JB: You are a very interesting man and we will keep in touch because clearly you have got your finger on the pulse of some possible explanations of things that have been enigmas for a long time. We thank you so much for spending this time with us and wish you the best in your continued work. TM: Thank you very much, indeed. JB: It has been our pleasure. We really thank Dr. Marshall for being a provocateur par excellence for our Functional Medicine Update series. This all derives out of his group and his own recent publications: “Autoimmune Disease in the Era of the Metagenome” and “Vitamin D, An Alternate Hypothesis.”, These are very nice publications that have come from his research and collaboration with colleagues at Georgetown University and Weill Cornell Medical College (Amy Proal and Paul Albert), that appeared in Autoimmunity Reviews in 2009. We are starting to see some very interesting provocation of new concepts that tie together some observations from epidemiological animal studies, some human observational trials, historical information, and the emerging science of molecular genetics and systems biology, all of which are pointing us toward new thoughts, new questions, and new hypotheses that may help us to resolve some of the complexity of managing a patient with complex chronic disease. A press release came out recently that particularly focused on the vitamin D and autoimmune disease question. This was a press release that was generating a lot of visibility because the title was “Vitamin D May Exacerbate Autoimmune Disease.”10 This was a press release that followed the Autoimmunity Reviews paper and was released by Paul Albert, who is one of the collaborators working with Dr. Marshall. Paul Albert is at the Weill Medical College associated with Cornell University. In this press release, which appeared in the April 2009 media, he states, “Deficiency in vitamin D has been widely regarded as contributing to autoimmune disease, but a review appearing in Autoimmunity Reviews explains that low levels of vitamin D in patients with autoimmune disease may be a result rather than a cause of disease and that supplementing with vitamin D may actually exacerbate autoimmune disease.” The press release goes on to talk about the paper that you heard Dr. Marshall review in his presentation, looking at the insights on molecular biology, showing that 25-hydroxy D inactivates (rather than activates) its native receptor. As you heard Dr. Marshall talk about, his team explains that by deactivating the vitamin D receptor, and subsequently the immune response, 25-hydroxy D lowers the inflammation caused by many of the bacteria that are insulting the immune system and allows them to spread more easily in the long run if we do short-term kind anti-inflammatory modulation but we don’t arrest the growth of the bacteria. It is kind of a good story on the front end and maybe a bad story on the longer term outcome; this is the position that is being taken. Other Researchers Are Also Studying the VDR There is a very nice paper that appeared recently in the Annals of the New York Academy of Sciences titled “Dysregulation of the Vitamin D Nuclear Receptor Contributing to the Higher Prevalence of Some Autoimmune Diseases in Women” that describes more of this relationship that Dr. Marshall is talking about.11 There are many groups around the world that are actively involved in this whole area, so I don’t want to give the impression that it is just Dr. Marshall and his colleagues. There is also a very nice review that appeared in Trends in Molecular Medicine in 2008 titled “Therapeutic Implications of the Toll-like Receptor and Vitamin D Receptor Partnership,” showing that the allergens (or proinflammatory agents) that activate the toll-like receptor that triggers inflammation couples itself together with cross communication with the vitamin D receptor.12 This article describes (just as Dr. Marshall was leading us to understand) how the innate immune system provides the host with an immediate and rapid defense against invading microbes, and how detection of foreign invaders is mediated by this class of receptors that are known as the pattern recognition receptors, which are a family of toll-like receptors (TLRs). There are ten functional toll-like receptors that have been identified, and they respond to pathogen-associated molecular patterns that are associated with bacteria, mycoplasma, fungi, and even viruses. The activation of these toll-like receptors leads to direct antimicrobial activity, even against things like biofilms (discussed by Dr. Marshall). This activity induces an antiviral gene program. It was reported in this paper that the toll-like receptor 2 activation, for instance, leads to the use of vitamin D as a mechanism to combat mycobacterium tuberculosis. Now investigators are focusing on findings that can relate the toll-like receptor-induced antimicrobial mechanisms in humans and the therapeutic implications of these findings and the interconnection between this vitamin D receptor communication pathway, gene expression, and activation of TLRs. Toll-like receptors are attractive therapeutic agents and they interface, in their activity, with vitamin D metabolism of 25-hydroxy D (the secosteroid, the pro hormone) into its 1,25-dihydroxy form. This research is emerging from many different avenues. Another paper that was very interesting appeared in the Journal of Clinical Investigation. This article was from 2007, and investigators looked at induction of toll-like receptor-2 activation and the release of antimicrobial peptides by immune cells through a vitamin D-dependent mechanism.13 This is work out of the University of California, San Diego, and the department of dermatology at the David Geffen UCLA School of Medicine. It is really interesting that many investigators are using systems biology thinking to pull together observations from different fields to look at how antimicrobial influences are expressed by genes in specific cell lines, activated through certain receptor site pathways, and how they relate to these class I nuclear orphan receptor activations, of which the vitamin D receptor is a partner. Vitamin D is more than just the sunshine vitamin. I think that is what we are taking away from this. There is a lot more to the story that relates to activation, repression, and regulation of over 900 genes that are tied together with this vitamin D receptor. In fact, we also know that altered vitamin D receptor coactivator interactions can lead to over-activated receptor as well as under-activated. A little is good, but a whole lot more might not be better. This concept was described the Journal of Steroid Biochemistry and Molecular Biology some years ago.14 Dr. Marshall related to us that there are ligands that can modulate the vitamin D receptor and this process of signaling. One of those is the class of drugs called angiotensin-receptor blockers that can have effects on the immune system versus the VDR and class I nuclear orphan receptors. In fact, Dr. Marshall and his colleagues were involved with theoretical modeling of the relationship of the combination of these molecules, specifically with the active site of the VDR. This was some beautiful work published in Biomed Central in 2006 that really shows how these two things fit together and might influence the activity of the vitamin D receptor by modulating its function.15 This research is one of the reasons Dr. Marshall was talking about The Marshall Protocol for the management of fibromyalgia and use of higher levels of intervention with a specific member of the angiotensin receptor blocker family of drugs. Th is particular angiotensin receptor blocker seems to fit in best in that active site and downregulate the overly active VDR signaling and therefore allow proper antimicrobial activity of the body with the antimicrobial peptides to be produced so that the body has its own natural antibiotics, basically, being produced and not being suppressed. Lastly, of course, is the topic of the enteric bacteria in the gut. We have a kilogram and a half (in most human GI tracts) of living critters (many different species). Do they influence, through their signaling processes, aspects that have to do with activity of cellular metabolism and things like insulin sensitivity and energy storage or energy utilization in mitochondrial oxidative phosphoylation? The answer is apparently yes. We heard this from Professor Delzenne and Dr. Cani recently. We also alluded to it in this interview with Dr. Marshall. And there are more and more papers coming out from other groups, one of which is a recent paper titled “The Microbiome and Obesity: Is Obesity Linked to Our Gut Flora?”16 This was from Frank Tsai and Walter Coyle at the Department of Gastroenterology and Hepatology at Scripps. They have been looking at the human gut as a lush microbial ecosystem with about one hundred trillion microorganisms, whose collective genome (called the “microbiome”) contains a hundred fold more genes than the entire human genome. The symbiosis of our extended genome plays a role in host homeostasis and energy extraction from the diet, and so there are now many studies that have advanced our understanding of how the microbiome has effects on metabolism, obesity, and health. The so-called “metagenomic” studies that Dr. Marshall was alluding to demonstrate that certain mixes of gut bacteria may protect or predispose the host to obesity and may have signaling processes that regulate activities of the toll-like receptors and then signal through the VDR and have influence on gene expression across multiple cell lines. This is a new biology, isn’t it? This is a new era that we are moving into in understanding, at a much deeper level, both the complexity, and the beauty, and the opportunity for modulating chronic disease in a different way, rather than just treating the effects. It is about actually getting down to the root causes of how specific uniqueness in a person may be translated into their own disease process by exposure to specific agents. I want to be very cautious here that we don’t throw the baby out with the bathwater and we recognize that vitamin D is still a very important vitamin, and there are people that are insufficient relative to the precursor, which is the cholecalciferol molecule, and therefore this doesn’t mean [we should] stop concerning ourselves with vitamin D, or that nobody should be supplementing it. This discussion just puts in balance, once again, this premise that we have learned time and time over the years: if a little is good, a whole lot more is not necessarily better. We want to find the right dose for the right person to produce the right outcome; that is the basic watchword.

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1 Fasano A. Surprises from celiac disease. Sci Am. 2009;301(2):54-61. 2 Bernini P, Bertini I, Luchinat C, Nepi S, Saccenti E, et al. Individual human phenotypes in metabolic space and time. J Proteome Res. 2009;8(9):4264-4271. 3 Albert PJ, Proal AD, Marshall TG. Vitamin D: the alternative hypothesis. Autoimmun Rev. 2009;8(8):639-644. 4 http://www.iom.edu/CMS/3788/61170/68400.aspx 5 Proal A, Albert PJ, Marshall TG. Autoimmune disease in the era of the metagenome. Autoimmun Rev. 2009;8(8):677-681. 6 Blaney GP, Albert PJ, Proal AD. Vitamin D metabolites as clinical markers in autoimmune and chronic disease. AnnN Y Acad Sci. 2009;1173:384-390. 7 Gottlieb JE, Israel HL, Steiner RM, Triolo J, Patrick H. Outcome in sarcoidosis. The relationship of relapse to corticosteroid therapy. Chest. 1997;111(3):623-631. 8 Marshall TG. Vitamin D discovery outpaces FDA decision-making. Bioessays. 2008;30(2):173-182. 9 http://www.vimeo.com/2585394 10 http://www.bio-medicine.org/biology-news-1/Vitamin-D-may-exacerbate-autoimmune-disease-7924-1/ 11 Proal AD, Albert PJ, Marshall TG. Dysregulation of the vitamin D nuclear receptor may contribute to the higher prevalence of some autoimmune diseases in women. Ann N Y Acad Sci. 2009;1173:252-259. 12 Liu PT, Krutzik SR, Modlin RL. Therapeutic implications of the TLR and VDR partnership. Trends Mol Med. 2007;13(3):117-124. 13 Schauber J, Dorschner RA, Coda AB, Büchau AS, Liu PT, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest 2007;117(3):803-811. 14 Eelen G, Verlinden L, Van Camp M, Claessens F, De Clerq P, et al. Altered vitamin D receptor-coactivator interactions reflect superagonism of vitamin D analogs. J Steroid Biochem Mol Biol. 2005;97(1-2):65-68. 15 Marshall TG, Lee RE, Marshall FE. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theor Biol Med Model. 2006;3:1. 16 Tsai F, Coyle WJ. The microbiome and obesity: is obesity linked to our gut flora? Curr Gastroenterol Rep. 2009;11(4):307-313. 17 Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134(6):1129-1140. 18 Cannell JJ, Zasloff M, Garland CF, Scragg R, Giovannucci E. On the epidemiology of influenza. Virol J. 2008;5:29. Review.

Welcome to Functional Medicine Update for November 2009. What a year it has been so far in Functional Medicine Update. I hope you have enjoyed the last few months as much as I have. I think you’ll agree that we have been traveling on a journey together that has been quite remarkable as it relates to the emergence of this systems biology approach-the functional medicine approach-to medicine. Certainly this journey is going to continue this month in our November issue, in which you will hear an extraordinary interview with Dr. Alejandro Junger from New York City, who will be speaking about his experiences with the functional medicine model in what we call a “tire-meets-the-road”-type of conversation about how the model really applies in clinical practice and how one can make this concept actually work in patient management. Nationally (and even internationally), we are in the throes of one of the most remarkable debates about health care that I have experienced. What will the healthcare system look like as we move forward in the 21st century? Everybody has their view of the answer to that question (obviously with much room for debate, controversy, and discussion) about the scenario that will define the healthcare system of the future. My colleague, Jay Johnson, found an insightful view that summarizes the present state healthcare reform, and I thought it would be fitting (with a degree of levity) to start off our November issue. If you will bear with me, I’ll share this little humorous thought about the healthcare system:

“Apparently the American Medical Association has weighed in on the new economic stimulus package and how it interrelates to the healthcare reform… The Allergists voted to scratch it, but the Dermatologists advised not to make any rash moves. The Gastroenterologists had sort of a gut feeling about it, but the Neurologists thought the Administration had a lot of nerve. The Obstetricians felt that they were laboring under a misconception. The Ophthalmologists considered the idea shortsighted. Pathologists yelled, ‘Over my dead body!’ While the Pediatricians said, ‘Oh, grow up!’ The Psychiatrists thought the whole idea was madness, while the Radiologists could see right through it. Surgeons decided to wash their hands of the whole thing. The Internists thought it was a bitter pill to swallow, and the Plastic Surgeons said, ‘This puts a whole new face on the matter.’ The Podiatrists thought it was a step forward, but the Urologists were pretty pissed off about the whole idea. The Anesthesiologists thought the whole idea was a gas, and the Cardiologists didn’t have the heart to say no… In the end, the Proctologists won out, leaving the entire decision about what to do with health reform, up to the ‘rear-end’ people in Washington, DC.”

A very interesting little insightful thought about the present healthcare debate and reform. But with seriousness, now, let’s move back to the real business at hand, which is how to make this system that has been a disease-care system balanced with a healthcare component. That has been the focus of Functional Medicine Update, and the efforts made on behalf of functional medicine through the Institute for Functional Medicine since its inception. To give you a little bit of an update as to what has happened over the last several months related to the topics we have been discussing, I’m now going to do kind of a “potpourri” discussion with you on a variety of topics. I think each one stands alone as a little weigh point on the overall view of the functional medicine matrix and might be considered a “node” in our understanding of how everything connects together to form the web of clinical practice that we called the systems biology in medicine functional medicine model. Let’s talk about toxicity first and review what’s gone on over the last few months in this area. In each one of these little vignettes, I’m going to take you back to past discussions we’ve had in Functional Medicine Update and just kind of bring you up to speed. In the past, we talked about the extraordinary emerging idea that there seems to be a correlation between marginally elevated gamma glutamyl transpeptidase levels (GGTP levels) in serology (this would be in the upper quintile of even the normal range of this liver enzyme), and the association with overall chronic disease. And also how that connects together with body burden as it relates to various environmental lipid-soluble toxins, particularly things like polynuclear aromatic hydrocarbons (PAH) and other toxic substances. In previous issues of Functional Medicine Update, we reviewed how this connection between chronic illness and marginally elevated (within the normal range) of GGTP also connects together with type 2 diabetes as a specific disease entity that is associated with this connection of what are called “POPs” (Persistent Organic Pollutants) that can be measured in the blood, and upper elevated levels of GGTP and serology.1, 2 There was another part of this story that was quite fascinating that I think had some pretty important clinical implications. In evaluating the Health and Nutrition Examination Survey III data (the largest database that connects together health indices and nutrition status of the population), it was found that there was no direct correlation-I want to emphasize, NO direct correlation-between type 2 diabetes and obesity in the absence of elevated normal levels of GGTP in the serology. That’s a fairly interesting observation because most of us have assumed that obesity, in and of itself, causes insulin resistance and leads to type 2 diabetes. But yet, this particular epidemiological statistical evaluation does not show a strong correlation between obesity and the onset of type 2 diabetes in the absence of elevated GGTP levels.3 We normally assume that GGTP is a measure of alcohol and drug-related abuse problems. In fact, it has been used as a way of actually following compliance with substance abuse programs. But now the evidence is suggesting that gamma glutamyl transpeptidase may be related more to an overall burden that the body has as it pertains to potential toxic exposure, as evidenced by a very strong correlation of serum levels of persistent organic pollutants and increased levels of GGTP, and then the subsequent connection to that of type 2 diabetes. As I mentioned, in the absence of this connection between GGTP and the level of persistent organic pollutants in the blood there was not a significant association with obesity and diabetes. It is only in those people who have increased body mass index and who also have increased levels of GGTP where there is a very strong correlation with type 2 diabetes. What Does Gamma Glutamyl Transpeptidase Do? What does this enzyme that is present in the blood-gamma glutamyl transpeptidase-really do? Why is it there? I think we have often assumed that it is similar to that of ALT and AST, the two principle liver function test enzymes that we use to measure liver pathology. Those enzymes, which are amino transferase enzymes, are found in hepatocytes in high levels because they are involved with amino acid metabolism and they are released into the blood when these cells die. It is recognized that there is a very strong correlation between liver cell death caused by cirrhosis and hepatitis and elevated ALT and AST levels, so that is part of our liver function test evaluation in serology for liver pathology. The Three Personalities of Glutathione I think we’ve also assumed that GGTP is elevated by the same route (the death of liver cells), but actually that is not totally true. Gamma glutamyl transpeptidase is an enzyme whose function in the body is involved glutathione recycling. As contrasted to your normal alpha amino acids, like alpha glutamic acid, the gamma glutamyl residue, gamma glutamic acid, is a unique amino acid that is found within the tripeptide that we call glutathione. Gamma glutamyl transpeptidase is actually used for recycling and reforming the glutathione molecule and it is upregulated in its activity when the body has greater turnover of glutathione. When would that be? That would be times when the body is under either oxidative stress or under xenobiotic load. Recall, if you would, that glutathione is a very important biomolecule that kind of has three personalities, one of which is the important role it plays in the glutathione recycling system pertaining to antioxidation through glutathione and glutathione disulfide. You remember the enzymes: glutathione reductase, which requires a flavin adenine dinucleotide for its activation (which is vitamin B2-derived cofactor), and the other is glutathione peroxidase, which you know as a selenium-requiring enzyme. So there are some nutritional relationships (through trace minerals and vitamins) for the proper support of glutathione activity through the glutathione peroxidase/glutathione reductase system. The other part of this is glutathione’s recycling/resynthesis. The gamma glutamyl residues get broken off and resynthesized through the GGTP activity in part, so when there is increased turnover of glutathione, you have increased activity of GGTP. If one activity is related to oxidation, the other activity of glutathione is related to detoxification. It conjugates as a phase II conjugating nutrient with specific biotransformed intermediates in the detoxification process, which then conjugates with the specific biotransformed intermediates to form mercapturates (this makes it water soluble and then it can be excreted in the urine or transition to the bile to be excreted in the feces). So the second role of glutathione is that of detoxification. If you have a higher body burden of toxins and your body tries to upregulate its detoxification functions specific to those factors of phase II glutathione conjugation, then GGTP activity also rises to meet that need. And the third role of glutathione is it is used in the formation of various forms of what are called the leukotrienes (the proinflammatory mediators derived from arachidonic acid). So there are multiple roles (three roles) for the glutathione molecule, and the one that I have been speaking to here that I think has a direct and interesting relationship to this story about toxicity, serum levels of persistent organic pollutants, increased serum levels of GGTP, and the association with chronic disease (particularly type 2 diabetes) has to do with the role that glutathione plays in detoxifying foreign chemicals or xenobiotics. With the elevation of GGTP, we are really talking about the nature of how the body might have a resident body burden of toxins, which means exposure to substances can correlate themselves with the relative risk to various chronic-related illnesses. Bisphenol A and Dose Response Toxicity One molecule that has received a considerable amount of attention is a plasticizer called bisphenol A (BPA). There is a wide body of literature supporting concern about bisphenol A as a toxicological material at a very low concentration. The concept of dose response toxicity, which often toxicologists think about, is at a slightly different level of story when we get to these very low levels of exposure because it is not a direct dose response; it has almost a xenohormetic effect. (Xenohormetic means having a much larger effect than we would anticipate based on the low level of that chemical, but if the chemical hits the right receptor, it has the right communication with the gene expression patterns, and it modulates function in a way that can amplify its effects across cell types.) With a xenohormetic effect, you might have a broader physiological outcome in terms of immunotoxicology or neurotoxicology than you would have anticipated just looking at the concentrations of material alone. One should not be misled into thinking that just because something is in the part-per-million level (or sub-part-per-million level) that it is necessarily safe and benign. And all of this ties together with the emerging recognition that toxins and toxicity can play a role as one of the triggering factors for modifying the web of physiology and inducing a transition in gene expression that is associated with alarm reactions and ultimately chronic illness. Results from a New Animal Study on Low-Level Atrazine Exposure With that as a backdrop, let me bring you up to speed on a number of the other papers that have been published recently in this area. One that is very consistent with this view that I have been describing is another nice paper from Dr. Pak and Dr. Lee’s group, two of the investigators that really started looking at the connection between POPs and type 2 diabetes. This article was recently published in PLoS free access biomedical journal, and titled “Chronic Exposure to the Herbicide Atrazine and its Relationship to Mitochondrial Dysfunction and Insulin Resistance.”4 I think this a very important paper because, as the authors state, there is an overlap between areas in the United States where the herbicide Atrazine is heavily used and obesity-prevalent chronic illness. This is consistent with this model that I have been describing that ties together body burden of various toxins with altered function and how that ultimately translates into chronic illness. In this particular study, they used an animal model in which the dose response could be controlled. They used at Sprague-Dawley rats, which they treated with exposure to low levels (less than 30 part-per-billion) of Atrazine per day in their drinking water for five months. . The researchers then fed one group of rats a high-fat diet and the other a regular diet. Parameters of insulin resistance were measured, and then later morphological and functional activities of mitochondria were evaluated in tissues of both groups of Atrazine-exposed animals. What the researchers found was that chronic administration of this low level of pesticide, Atrazine, decreased basal metabolic rate and was found to increase body weight, intra-abdominal fat, and insulin resistance without changing food intake or physical activity level. Let me say it again. The exposure to this specific environmental agent (this xenobiotic) at low levels of exposure with a high-fat diet resulted in blunting of the insulin signaling, increased body mass index (with intra-abdominal fat deposition), and decreased metabolic rate (meaning it had an adverse effect on mitochondrial function), without changing either food intake or physical activity. I think we have been led to believe that the obesity epidemic is solely the manifestation of eating luxurious, calorie-rich, fast food diets. But could it be that the diets that we are eating, and the environment to which we are exposed, also contain other information (like this Atrazine or bisphenol A) that are blunting our physiology in such a way as to induce energy storage rather than energy utilization, and result in a contribution to the obesity/insulin resistance and type 2 diabetes epidemics? That is what this study appears to suggest, at least. In this study, did they see any changes in mitochondrial oxidative phosphorylation (energy powerhouse activity) in these animals that were exposed at this very low level to this herbicide Atrazine? In looking at the mitochondria in skeletal muscle and liver, they found that the mitochondria had disrupted cristae. It was found to block the levels of oxidative phosphorylation complexes 1 and 2 in the electron transport chain, resulting in decreased oxygen consumption. This suggests, through this combination of information, that this low level of exposure to Atrazine suppressed the insulin-mediated phosphorylation and had an adverse effect on kinase signaling, the very important signaling process (intercellular signal transduction) that translates messages of insulin from the outside of the cells to the inside of the genes to result in appropriate glucose transport and bioenergetics of the cell. The results suggest that long-term exposure to the herbicide Atrazine might contribute to the development of insulin resistance, and then later result in obesity as a secondary (not a primary) effect, particularly exacerbated when a high fat diet is present. I think mitochondrial oxidative phosphorylation is a very important part of this emerging story. What’s the clinical outcome? I guess we’d call it metabolic detoxification. It is finding the way to lower the body burden in patients by improving their detoxification and excretory routes to eliminate these mitochondrial toxins, and to enhance, then, mitochondrial function, oxygen utilization, and ultimately induce more appropriate insulin signaling, kinase signaling, and glucoregulation. That’s my first little vignette. Let me now go to the second vignette. We had an extraordinary interview with a periodontist who told us about the amazing connection that is emerging between oral health and systemic health. This discussion focused on periodontitis and its relationship to atherosclerotic cardiovascular disease risk. I want to come back and revisit this just briefly. There was an amazing and well-written editorial that appeared in the July 2009 issue of the Journal of Periodontology that discusses (and provides an extraordinary bibliography) this relationship between cardiology and periodontology.5 In fact, this was a joint article written collaboratively by the editors of the American Journal of Cardiology and the Journal ofPeriodontology. Who would have believed there would be dentists co-collaborating with cardiologists to write an article about the connection between the oral health and the cardiovascular system? This is a very interesting example of the web in which disease names become less important than the soil in which these situations arose. This is the whole basis of our functional medicine thinking. In this particular paper, which I think is beautifully written, there are some wonderful color illustrations showing the relationship between oral health and the appearance of cardiovascular disease. The article describes mechanistic proposals based upon the levels of proinflammatory cytokines found in individuals, and talks about the fact that these are non-cholesterol-related risk factors that are more inflammatory and associated with cardiovascular disease. By increasing oral hygiene, inflammatory burden is reduced from chronic infection and inflammation that results from periodontitis. That, then, lowers systemic inflammatory biomarkers–things like intercellular adhesion molecule 1, vascular adhesion molecule, and the things that relate to monocyte stickiness to the arterial endothelium and initiating the atherogenic process. The Oral Cavity Can Be a Site of Focal Chronic Infection I think this is emerging to be a well-understood connection. Specific recommendations came out of this article about how to manage patients and to preventively engage in proper oral health, and what treatment to use in those people who have periodontitis. Periodontitis is more than just a regional oral health problem; it has a systemic connection. When thinking about triggering factors that relate to altering or distorting metabolic webs that lead towards chronic disease, don’t forget the sites of focal chronic infection: the oral cavity, sinus cavities, and the gastrointestinal tract. These are important areas within the body where low-grade, simmering infection can induce chronic inflammatory response, and there is at least a statistical relationship to increasing risk of various chronic diseases that have an inflammatory etiology. We should probably also recognize, once again, that these situations are not uniform in their impact on all genotypes. There are specific genotypes that have higher levels of sensitivity, such as in people with specific IL-1 beta gene sensitivities (receptor site sensitivities) or specific TNFalpha (tumor necrosis factor) genotypic susceptibilities. What I’m saying is that people with certain SNPs (single nucleotide polymorphisms) may be at higher risk than others relative to a proinflammatory insult. We can’t say all people are at risk to the same degree, but what we can say is that there is an increasing relative risk as you have increasing localized inflammatory processes going on (as to how that can spread to systemic disease etiology). Let me move to the next factoid I want to discuss, which relates to the emerging therapeutic potential for functional medicine and disease management and prevention. That relates to the extraordinary discussion we had recently with Professor Delzenne and Dr. Cani at Catholic University of Louvain. They were helping us to understand more about the microbiome and the complexity of the population of enteric flora that creates a very important community in our gastrointestinal tract and can either be friend or foe depending upon the species of bacteria, their relative population number, and their activity. We talked with Professor Delzenne and Dr. Cani about the role of probiotics and prebiotics in reestablishing appropriate gut enteric health and the influence this has on a healthy microbiome. A New Study on Probiotic Use in Children Since that discussion, a very interesting paper has been subsequently published, which I think bears on this whole story. This article was in Pediatrics in 2009 and titled “Probiotic Effects on Cold and Influenza-like Symptom Incidents and Duration in Children.”6 Let me give you the specifics of this study because I think it is a very interesting study with provocative, if not important, implications. What was this study? The objective was to try to see if probiotic administration in healthy children could influence the appearance of cold and flu during the winter season. This was a double-blind placebo-controlled study in 326 eligible children, 3 &ndash; 5 years of age. They were assigned randomly to receive either a placebo or a supplement of Lactobacillus acidolphilus NCFM, or a combination of Lactobacillus acidophilus strain NCFM along with Bifidobacterium animalis (this is the Bi-07 strain). The children were treated twice daily for six months with either the placebo or one of the two arms of the treatment. After the six months, the intervention with probiotics in these children 3 &ndash; 5 years of age was found to be very safe. There were no apparent ADRs (adverse reactions) that occurred in these children. It was also found to be very effective at statistically significant levels It was a cause-and-effect observation that the supplementation for six months was effective in reducing fever, rhinorrhea, coughing incidence, the duration of symptoms, and even the need for antibiotic prescriptions during the course of the cold and flu season with children 3 &ndash; 5 years of age. What did they measure to come to this conclusion? The fever incidence was reduced by 53{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in the acidolphilus alone, and almost 73{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in the group that got the acidolphilus plus the bifido bacterium. Coughing incidence was reduced by 41{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in the acidophilus alone and 62{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in the combination of two strains of bacteria. Rhinorrhea, 28{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in acidophilus alone (NCFM strain) and 58.8{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in the combination of acidophilus NCFM plus the bifido bacterium lactus 07. There is a story here: you get added clinical improvement by giving the combination of the Lactobacillus acidophilus NCFM along with the bifido bacterium. It seemed like in all clinical indicators, there was an improvement by the combination of the two strains. When you look at antibiotic use incidence, it was reduced relative to placebo by 68{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} with the single strain, and 84{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} with the combination strains. In terms of reductions in days absent from group childcare, there was about a 32{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction in absenteeism (about a third less absenteeism days due to cold or flu-like symptoms when measured against the placebo). I think this is a very compelling study that helps to validate that enteric bacteria and the microbiome have a role that is not just regional in terms of the GI function. It has a systemic effect. It has a functional effect on the whole of the body by modulating immune function. And this occurs throughout the gastrointestinal-associated lymphoid tissue (where more than 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the body’s immune system resides) and the signaling to the rest of the body through the liver, the circulating immune cells, and the lymph tissue, and ultimately having an effect on overall systemic immunity. I think this is a very compelling story in support of this model that the gut is the center of the immune function. What we send as information to the gut, be it bad food, or toxins, or chronic infection, can have effects systemically on our overall immune integrity and function.

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INTERVIEW TRANSCRIPT

Clinician of the Month Alejandro Junger, MD Eleven Eleven Wellness Center 32 W. 22nd Street #5 New York, NY 10010 www.cleanrevolution.tv Well, here we are once again at our clinician and/or researcher of the month component of the Functional Medicine Update. You’re in for an extraordinary treat. This month I am speaking with a clinician who will describe his experiences and his interests to you in ways that I think makes functional medicine stand up and be real. Sometimes I have been criticized (and I think justifiably so) for being a little bit in the blue sky, airy-fairy, idealistic, intellectual, and immersed in the world of theory, rather than taking things down to the ground level of where the tires meet the road, where the mechanics can deliver improved outcome and quality of care to patients. That role is going to be certainly fulfilled in my discussion in with this month’s clinician of the month, Dr. Alejandro Junger. You may already have some identification with his name if you are familiar with his book, Clean: The Revolutionary Program to Restore the Body’s Natural Ability to Heal Itself.11 There is so much more within this book than just a program. There is also the person behind the program and its philosophy, and how he has brought functional medicine into an interface with consumer and patient need through this remove-, restore-, rejuvenation-type of approach. Dr. Junger, it is really a great privilege to have you as a guest for Functional Medicine Update, and also to have you in the studio today. Thanks for being with us. AJ: Thank you. It’s an honor to be here talking to you. JB: I always start with this question: With the many journeys that a person could be on in their life, the many different trails they could take-different pathways-you’ve selected a path that meets your particular background, interests, and needs. Your journey has led you to the broad matrix that we call functional medicine. Tell us a little bit what your path was and how your journey took you here. Change in Lifestyle Leads to Change in Health AJ: I went to medical school in Uruguay in South America. When I graduated, I traveled to New York to do my internship/residency in internal medicine, which I did at NYU Downtown Hospital in Manhattan. Then I moved to Lenox Hill Hospital (also NYU-affiliated at that time) to do my cardiology fellowship. The change in lifestyle from Uruguay to New York put me in a state-a physical, and mental, and emotional state-that was diseased. In looking for help I consulted a gastroenterologist for digestive problems that were diagnosed as irritable bowel syndrome. I saw an allergist due to my severe allergies, which at times required prednisone. And then I saw a psychiatrist for what was diagnosed as depression. All in all, within three consultations, I was left with seven prescription medications, which did not make sense to me. I had a shock at that time, not only because I saw myself with a future of depending on drugs, but also because I realized this was the type of medicine that I was practicing. The shock was double. At that point I decided to stop everything and look for a different solution to my problems. JB: I think this is a point that differentiates, to me, individuals who finally get to functional medicine from those who have maybe similar thoughts but never get there. There is a point of action, and some people are afraid to pull the trigger, or take the step, or make the commitment. And people like you make a commitment. Your action took you where? AJ: Some people say, “How courageous of you.” But the truth is, I had no option. I really, literally, was just looking to ease my disease. One of the first things that I noticed was that my mind was constantly producing thoughts. I say, “My mind was producing thoughts,” as opposed to saying, “I was thinking,” because that’s when I realized that there was nobody there initiating those thoughts. In fact, if I had a choice, I wouldn’t have been thinking 95{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the thoughts that were appearing in my mind. My burning desire was to answer, “Where are these thoughts coming from? Who is deciding about these thoughts? Why do I wake up in the morning and I think about the check I have to pay, and I remember this and that, and if I’m thinking of things in the future I become anxious, and if I’m thinking of things in the past I become sad? These thoughts that are just appearing in my mind are playing my emotions like a symphony with a life of its own.” So that was my burning desire, to answer those questions: Where are these thoughts coming from? Who is producing them? And how can I get rid of them? I started studying everything I could about where thoughts come from. I used to go to libraries (the psychiatry and psychology sections). I read and I underlined anything that made sense and resonated with me. The references that I was finding were from the New Age section. I was shifting from the psychology and psychiatry section to the New Age section, then to the Eastern Philosophy section, and finally found a book on meditation, which said, basically, that meditation was the way to slow down and even stop the thinking process. I said, “This is what I need.” I found a meditation teacher and ended up in a monastery in India, trying to, basically, shut my mind. JB: So tell us a little bit about that. It must have been quite an interesting transformation from New York. From New York City to an Ashram in India AJ: That was an incredible experience. I ended up directing a group of healthcare practitioners from different modalities who came from all over the world. I always say that without even ever hearing the term “integrative medicine,” I was directing a team of practitioners from different philosophies and modalities from all over the world. This was my experience of integrative medicine. JB: In that capacity, I think you were serving as a teacher and as a student simultaneously. Did you actually have, through that kind of involvement, some relationship to patient care, or was this more just talking about where one should go? AJ: Oh no, no, no. We were actually running a clinic in the ashram, in the monastery. We were seeing up to 2000 people at any given time, who were living there, from all over the world. We were running the first aid station (the clinic). We would get a patient and we would sit him in the middle, with all of us around asking questions-Ayurvedic medicine, Chinese medicine, the chiropractor, the hands-on healer. And then we would discuss how each one could contribute to the treatment of this patient with the best tools that we had without conflicting with each other. At times, the Ayurvedic doctor prescribed a diet, and at times I had to take patients to the hospital in Bombay, which was four hours away. For example, there was a patient that was having severe bleeding. The Ayurvedic doctor wanted to start him on a certain diet and I said, “This is for later. Let’s take this patient, let’s cauterize that artery or vein that is bleeding, and then we’ll start on a diet.” JB: As you did this, this must have been very interesting from a pedagogical or learning system basis. What you were almost realizing is a different educational system from the kind of top-down, lecture-series-type of approach (a didactic system) of Western medicine to a participatory collaborative system. It probably spoke to your mind and the thoughts you were having in a very different way, I would imagine. Learning About Different Approaches to Heath Care AJ: More than speaking to my mind, it cracked my mind open. One of the things that I base my life on is that you cannot argue with success. When you see that meditation is successful in treating a certain state, there is no argument there. I learned from Chinese medicine some things that were very effective: I learned how needles and certain herbs work very powerfully. I learned how Ayurvedic doctors divide the dosages according to the constitution and how diet influences them powerfully. I learned how meditation has a place in achieving a state of well being. I couldn’t deny it. This was imprinted in me so powerfully that I still carry it around with me today. From India Back to New York City JB: We’re going to jump forward for a second and then come back and fill in the gap. The jump forward is now I want the listener to be thinking, “Okay, we’re now in an ashram in India. Dr. Junger is overseeing and collaborating with this group of integrative practitioners.” Now we are going to segue really quickly, time-feed forward, to this very successful medical clinic that you and Dr. Lipman share in Manhattan, one of the most busy, energy-intensive, time-compressed centers in the universe (or at least in the known universe, as it relates to the world). In between those two places resides your life. As they say, life is what happens in between our plans. Tell us a little bit about how you got to this extraordinarily thriving practice from the ashram. AJ: My family is Jewish and from South America. Actually, my parents are both Holocaust survivors. When I told them that I was going to an ashram-their golden boy, just graduated from cardiology training, now going to fulfill their dreams of achieving something in the world and suddenly I’m dropping out and leaving–they were desperate. My father made me promise him that a year later I would meet him in New York and we would recap. Once I was in New York, I realized that I needed to make some money to live. I applied for work, and I found a job in a very busy cardiology practice in Palm Springs. I went back to practicing medicine. I said, “I’m going to bring everything that I learned in the ashram into my practice,” which was an impossible thing to do. I realized that in order for me to be in competition and to be considered profitable as a partner in this practice, I had to see a certain quota of patients, which left me with about 7 to 10 minutes per patient. Two years into this, I was literally hating medicine again. Not only that, I was back to eating foods from a hospital cafeteria, and back to being depressed, allergic, and having irritable bowels. At that time, just by chance, a friend of mine had gone to a detox cleansing center and had an incredible experience. I had seen him ten days before he went. In ten days, he dropped about 15 pounds, he looked younger, and it was such a transformation. I said, “I have to learn what this guy did that put him in this state.” This was what I wanted to be able to do for people when I went to medical school. I went to the center, which was called the We Care Center in Desert Hot Springs, near Palm Springs. I saw what other people were going through. I immediately signed up for the program, and in 14 days, basically, my allergies, my depression, and my irritable bowel syndrome completely disappeared. I was so blown away that I started going to the center regularly, and sending my friends, my family, and then my patients. The owner of the center asked me to start lecturing there, or at least sharing with the clients there what I was finding that could explain, from a medical point of view, the results that we were seeing. But it wasn’t until I did my first AFMCP that I understood-that I was able to translate, physiologically and biochemically-what I was seeing that was kind of miraculous, in a way, because I didn’t have the scientific language to explain it. Finding Functional Medicine JB: I know when a lot of doctors go through the course, Applying Functional Medicine in Clinical Practice, they have kind of an “a-ha” or an epiphany experience, and it kinds of hits them at a level of saying, “Well, this is actually why I went to medical school. This is what I thought I was going to be doing when I got out into practice.” And then the translation of that (and incorporation of it) into their lives becomes the real challenge. It’s like having a feel-good experience and you then have to return back to the real world. What happened after AFMCP for you? AJ: For me, it was different. For me, the high moment of “This is what I wanted to do when I went to medical school” came before, but the intellectual understanding of what was happening to people was not there. That was the “a-ha” moment for me. Functional medicine and AFMCP gave me the language, and the intellectual tools to understand the physiology behind what I was witnessing, which was kind of magical to me. Functional medicine gave me the translation. It gave me the explanation of something. You know when a magician explains the trick it seems so easy, but when you see it for the first time, you are just blown away? This is what functional medicine did for me. JB: From there, you and Dr. Lipman have developed an incredible repartee-a partnership-which is not always easy with very creative people who have a lot of sense as to what the universe should look like. Partnership can be the best of all worlds, and it can be challenging as well. But your clinic has just started to radiate goodness to patients of all types and dispositions and backgrounds. Tell us a little bit about what goes on for you in Manhattan. AJ: I actually moved to New York from Palm Springs, where I was practicing. I left my practice, basically. I left three months before becoming a partner in a very busy practice with a very big promise of monetary remuneration. I actually went to We Care, and became the medical director, which was basically nothing more than sitting under a tree with people and talking about (what I didn’t know) was functional medicine at that time (what I was trying to understand): how to integrate fasting, cleansing, and detoxification into a wellness plan, and how to think of it in terms of not contradicting what their doctors were telling them. I moved to Los Angeles, kept working at We Care, and met a Chinese medicine practitioner there, Dr. Drew Francis, who introduced me to functional medicine. That was when the “a-ha” moment happened. I worked with Dr. Francis for awhile, and then was invited by Donna Karan to speak at her Urban Zen Initiative. She is trying to change medicine in the United States after a very bad experience with her late husband, who had lung cancer. She wanted to give him other aspects of care that Western medicine was not providing in the hospital, and she was denied. Even with all her power and all her contacts, she was not able to give her husband access to acupuncture and other modalities that would have made his demise easier. She is on a crusade to change medicine. She created this movement called the Urban Zen movement. She invited me, through a patient that I have, to speak at this conference where Frank Lipman was one of the speakers. After we heard each other speak, we became curious about each other. Frank came to me and basically asked me, “What’s your name?” “Alejandro.” He said, “You know, I’ve been looking for a partner for ten years, and I think it’s you. I know you live in Los Angeles, but you’ve got to come and work with me.” So I did. I sometimes compare this to a rookie playing basketball and Michael Jordan comes and says, “Come play with me.” You’re not going to say no. That’s what I felt like when Frank invited me to work with him. What has happened is we work in offices next to each other, and we just basically run from room to room. When he has a patient he comes and he says, “Alex, listen, come,” and he puts me in the room and the patient has two opinions in one. And I do the same thing: I pull him into my room. That’s how we work in a very simple and interactive way that patients really like. That’s a big part of the success that we have been seeing in the clinic. Not that Frank hasn’t seen it before, because Frank was a very established practitioner before he met me, but these are some of the things that are happening now with both of us in the clinic. JB: I think it is interesting how circles work within circles. Things come 360 and remorph themselves. This Lenox Hospital experience you had that was your residency in cardiology…it kind of remorphed in your life, it seems, now that you are back in practice. Tell us a little bit about Lenox Hospital. Cooperative Work with Lenox Hill Hospital AJ: I did my fellowship in cardiology at Lenox Hill Hospital. One of the attending physicians, who was one of my dearest professors/teachers there, was a doctor called Dr. Rony Shimony. He is the cardiologist with the biggest heart that I known. Even though he practices Western medicine in a very extreme way-he really uses interventional cardiology a lot, angioplasties and angiograms-he gets results above the statistics of Western medicine because of his open heart, because he loves his patients, and because he’s such a good man. I had established a close friendship with him, and when I came back to New York 15 years later, we established contact. Through our interaction, he actually invited me to help him at the office one day a week, and basically was exposed to everything I am doing with Frank. That led him to be willing to start an integrative service at the cardiology department at Lenox Hill Hospital. That’s what we are working on right now. We are working on, basically, in my mind, bringing functional medicine into Lenox Hill Hospital. JB: There is a thread that ties all of this together that should be fairly obvious to the listener, and that thread is that you are man of passion, you are a man of principle, you are a person that is directed by experience, and you are guided by a series of deep objectives as to where you want your life to go, but you are not necessarily a guy that runs his life off a set of plans out of the “seven ways to be successful” or the “motivational seminar series of the month” club. Tell us a little bit about how that has worked for you. AJ: Well, when I was doing my fellowship and I was depressed and had irritable bowel syndrome I wish I could have gone to a course and within five days resolve everything and make a plan for my life, but I had to actually do it the hard way. I was desperately looking for a solution for my problems, and that led me to find functional medicine. And because it helped me so much, first my friends and then my family, and then my patients started to ask for it, I had no choice. This is what organically happened to my practice, and I’m happy that it did. JB: I know for a lot of people who come into this field, they are very enthusiastic about it. They know that it resonates correctly with their sense of what they want to do, but often they don’t know exactly how to structurally pound it into the model to make it a success financially or procedurally and from a tactical point of view. Do you have any guidance as to how that-not that there is a master design but just from your experience–kind of led you into what appears to be escalating success? AJ: The only thing that I can say is that if you focus on results, if you focus on giving to your patients what is going to bring them to a better state, that’s really the formula that I use. Word of mouth spreads. People are looking for results. When you have good results with patients, everything else happens on its own. JB: I’ve been criticized over the years, and I’ll share this criticism with you (I’d like to offload some of it off my shoulders). The criticism is: “Jeff you have spoken for years and years,” (in my case, now over 30 years), “about this functional medicine concept, but you have been a little irresponsible in doing this because you don’t have any long-term outcome studies to demonstrate that patients really will live longer, or they are really better off than if they would have just stayed the course, stayed with the prescription and done a traditional standard of care. Don’t you think, Jeff, you are misleading people into thinking this is the Holy Grail or they are going to get something that they wouldn’t have gotten by just following what everybody else (by board certification) feels is the right path?” What would be your response to a person who criticizes me for that? AJ: My response to that person would be, “You should really take a look at those double-blind, clinical, placebo-controlled studies-how they are done, why they are done, who are they done with, how the meta-analysis is made.” There is this idea that science and Western medicine have the answer for everything and is the gold standard to compare things to. And if you really understand how those numbers are gotten, and the many things that are omitted from these studies, then you actually lean on to something like functional medicine to guide yourself. JB: Now tell us a little bit about what you’ve seen in the patients you’ve been applying this construct of Clean and the functional medicine kind of personalization. Give us kind of a Rorschach test as to how this looks to a patient who has gone through your program. Patient Success Stories from the Clean Program AJ: I have so many stories, but I can think of a few that are really remarkable. For example, I had this 28-year-old lady. She is an architect. She came to me with a cough that was persistent for like three years. She had gone through several courses of antibiotics. She had even had a bronchoscopy with a biopsy taken. She went to every extreme and came to me as a final resource to deal with her problem. I put her on a detox program (on the Clean program), and within three weeks her cough had completely disappeared. But then she called me and she said, “Doctor, something really strange happened.” I said, “What happened?” She said, “Well, I started really getting blurred vision, and I didn’t really understand what was happening, so I went to my ophthalmologist.” Basically, what ended up happening is she had worn glasses for the last five years, and she didn’t need her glasses anymore. Her blurred vision was because her glasses were not needed anymore. So that was an incredible result. And there is another one. This lady recently-a 38-year-old who was sent by one of my celebrity clients-said, “Doctor, I come to you. I don’t believe in what you do, but Western medicine, which is what I believe in, wants to give me chemotherapy.” I said, “What’s the problem?” “I have something called ankylosing spondylitis, which is an autoimmune disease, and it is characterized by the finding of anti-Ro antibody.” One of the things that I now understand is that the confusion of the immune system in attacking yourself many times is originating in your gut, with the leaky gut syndrome, which is not recognized by Western medicine. Basically I put this lady through the process (through the program). She did really, really well, and then later on we found that she had very, very high levels of mercury. I started treating her with oral chelation. To make a long story short, not only did she avoid chemotherapy, but her anti-Ro basically turned negative. Her rheumatologist, who was one of the top rheumatologists in the United States (and I’m not going to name any names), basically sent her an email saying that she was committing suicide and that the doctor that was doing this to her should be put in jail and his license should be taken away. So we are going to frame the anti-Ro negative, and we are going to send it to him. And she actually, clinically, looks incredible, much better. Her pains from the ankylosing spondylitis-her hip pains-have completely disappeared, and she is a new person. JB: It’s really fascinating, isn’t it? It’s hard for any of us to know what we don’t know. We’re told what we should know, but we’re not told what we don’t know. I was very intrigued in the August issue of 2009 of Scientific American, which I would consider a fairly conservative, science-for-the-average-person-type journal, had a wonderful article on gluten authored by Alessio Fasano, who is in pathology now at Maryland (he was at gastroenterology at the University of North Carolina School of Medicine and now he’s in GI and pathology at Maryland). He is, I think, considered one of the top experts in the world on celiac disease. In that article there is a fascinating diagram, as only Scientific American can do with beautiful medical illustrations (color) of a leaky gut. And he’s talking about the fact that once you have opened the portals of entry with a gluten sensitivity, that many other middle molecular weight molecules can swim across the gut into the blood and have access to the immune system and can initiate systemic effects. This thing that was so vehemently rejected for years as not factually correct is now starting to get traction because we don’t know what we don’t know until we start to know it. AJ: Not only that, we often find what we look for, but we only look for what we know. Right? JB: That’s very well said. AJ: So that’s one of the big problems that we have-that Western medicine only looks at a certain spectrum of problems and has a way of detecting them, but they only look for what they know. That is where the confusion comes. JB: In the few moments we have remaining, I’d like to ask just one last question that I think could be very helpful for some of our listeners: As a person who is watching this field unfold, watching the national healthcare debates be raging, recognizing that we are in a demographic transition with aging baby boomers, knowing that we’re in a global economic kind of meltdown, and re-annealing with a new alloy probably coming out of this time into the 21st century, what’s your view of medicine for your colleagues? What’s your view of getting up every morning, putting your shoes and socks on and doing your work, and is there anything that you would pass on from your path that might be helpful for some of us who are still on our path. AJ: Yes. People ask me, “Do you like your work?” I don’t really consider my work and my life different. I wouldn’t be doing anything else. When I’m not working, when I’m not in the office, I’m doing the same thing. In a way, to find what you really, really like to do–to find what you really want to do–is one of the most important things. And this is important because what I see is all my colleagues that are still trapped in the Western system-in the modern, Western medical system-actually hate their jobs. Many, many times they went into medicine with these ideas, with these principles, and then find this system that is, in a way, prostituted by competition and the politics inside the hospital. It degenerates the whole thing so much that they end up looking at their work as a job. They can’t wait to get out of the hospital, and they can’t wait to sign off their beepers and get the hell out of there. I don’t see that in my life anymore. I consider myself so fortunate because from the time I wake up until I go to sleep, for me life and work is the same thing. This is, I think, one of the most important things that one should look for: What is it that you really, really want to do? What is it that you really like to do? And then everything happens on its own. JB: Do you worry at all about losing touch with “medicine”? In other words, losing touch with all the skills that you developed-the bioscience, the hours that you spent developing certain types of understanding and knowledge? AJ: The thing is, if you get the Textbook of Functional Medicine, you see that actually you will be much more versed in those things than if you were in medical school. Another aspect of that question is the whole aspect of how hospitals work and how these technologies can be used. The thing is this: Of the 100 percent of diseases that exist today, 10 percent are actually very, very well treated with Western medicine. If I am having a heart attack, I’m not going to take any anti-inflammatory herbs or going to meditate. I’m going to the first cath lab that can open my artery and save my myocardium. Now, afterwards, then I’m going to meditate and I’m going to do the nutrigenomic aspect of switching my genes, but that 10 percent of acute problems are actually very well treated by Western medicine. There is nothing comparable to it. The 90 other percent of diseases, which are the chronic diseases that we are trying to force the Western medicine tools into solving-that’s what we have to change. That is where functional medicine has a place and a role that is very, very important for us to bring in. JB: And how about the voices that were there that started you down this path, that kind of became the master of your change? Have they changed? AJ: Again, you can’t argue with success. When people see results, they start looking at you with more respect and with more interest. Actually, whenever you touch them in their personal life, and you resolve any problem that they have or their family members have, then you have a convert. That’s what I’m doing. I’m just spreading the word and trying to help as many people as possible. JB: I can’t tell you how much I, personally-and I think every listener-appreciates this inspirational sharing. I mean you went well below (or well above, actually) the normal kind of reductionistic discussion that often pertains to bioscience and 21st century medicine. It’s really the connections. It’s really the sense of the principle, the purpose: What is healing all about? Where does it come from? It comes from an intentionality that radiates from everything you talk about. AJ: And for me to be sitting here with you is really an honor, and coming full circle because you gave me the possibility of expressing myself and of understanding what I was witnessing as miraculous, as weird, and understand that this is actually very, very well explained. JB: Thank you, Dr. Junger. We look forward to seeing Clean continue to do its job of cleaning and hearing of your success, and of course, what a great partnership with Dr. Lipman. I can see the two of you really would be a force to reckon with. AJ: Thank you. JB: Thank you so much. The best to you. Once again we really thank Dr. Junger for an extraordinary contribution to understanding how this functional medicine model can be applied successfully in managing patients and developing a very exciting and rewarding practice. In Closing: High-Level Supplementation of Essential Fatty Acids Let me talk a little bit about one of the aspects that has been on our radar screen for some time-probably the most well-understood, well-researched, and widely accepted nutritional intervention product within the armamentarium of our tools–and that is essential fatty acids. I’m reminded of the Ames group in the New England area that was meeting with Dr. Donald Rudin and Dr. David Horrobin early on-this would have been probably the late 70s-to talk about the role that omega-3 fatty acid insufficiency had on increasing the relative risk to all sorts of health issues, including psychiatric disturbances, neurological disturbances, and cardiovascular, immunological, inflammatory disturbances. This was back in the late 70s. How long does it take for medicine to change a lightbulb? In this case, we are thirty years downstream and it’s now become an “a-ha” for many people as they start to understand the role that omega-3 fatty acids play. But as with anything, a little is good and a whole lot more might not be better. In fact, a whole lot more might be not as good. This is the Tolman’s Law of Pharmacology that says everything is toxic at some level. With regard to omega-3 fatty acids, we have alpha-linolenic acid as the first member of the omega-3s, and then we have docosahexaenoic eicosopentaenoic acid (so that’s DHA and EPA, respectively). Which of these are the best, and what roles do they play? What’s the best dose response and are there any adverse side effects? There are a lot of questions, certainly, when we start supplementing or using therapeutic doses of these various substances that we need to properly address and answer. One of the things that has been stated is that supplementation with DHA results in increased levels of LDL cholesterol. I’ve heard that being expressed in a number of places. DHA, as you know, is found in very high levels in various marine algae. In fact, EPA and DHA are not really manufactured primarily by fish. They come as a consequence of the fish consuming things within the food chain where the omega-3 fatty acids are already manufactured for them, and they get concentrated within the fish tissues as a consequence of them consuming foods that have it. Certain forms of marine algae have high levels of DHA. You can start looking at the algal vegetarian supplementation of humans with high levels of DHA (when I talk about high levels, I’m talking about something on the order of, say, one-and-a-half to two grams per day of DHA-that’s a very high level of DHA, specifically), and you can ask: what is the effect that that has on serum lipids? A paper was published in the Journal of Nutrition in which that intervention trial was done.12 In this study what they found is that the consumption of DHA capsules did increase DHA serum levels and phospholipid levels by 246 percent, so it had a very remarkable effect in increasing DHA. It actually lowered the LDL-to-HDL ratio, and it also lowered serum triglyceride concentrations. This concept that DHA supplementation increases LDL…there may be those individuals who have a variant response, but at least in the case of use of algal form of DHA supplementation in humans, this study didn’t find an elevation; they saw a reduction in LDL and an improved LDL-to-HDL ratio. This was further confirmed in another interesting paper published in the American College of NutritionJournal, looking at intervention in individuals who consumed up to 2.5 grams a day of DHA for six weeks, where it was found, once again, that triglycerides were significantly reduced, and HDL was increased.13 I think that we can say that there is generally a favorable trend towards cholesterol HDL ratios and LDL/HDL ratios, as well as a lowered triglyceride level in people that are supplemented with fairly high doses of DHA, and also its companion, EPA. I hope that’s some help in kind of making sense of this information with regard to fatty acid supplementation. I look forward to being with you next month.

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1 Lee DH, Lee IK, Song K, Steffes M, Toscano W, et al. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999-2002. Diabetes Care. 2006;29(11):2567. 2 Lee DK, Lee IK, Jin SH, Steffes M, Jacobs DR Jr. Association between serum concentrations of persistent organic pollutants and insulin resistance among nondiabetic adults: results from the National Health and Nutrition Examination Survey 1999-2002. Diabetes Care. 2007;30(3):622-628. 3 Lim JS, Lee DH, Park JY, Jin SH, Jacobs DR Jr. A strong interaction between serum gamma-glutamyltransferase and obesity on the risk of prevalent type 2 diabetes: results from the Third National Health and Nutrition Examination Survey. Clin Chem. 2007;53(6):1092-1098. 4 Lim S, Ahn SY, Song IC, Chung MH, Jang HC, et al. Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance. PLoS One. 2009;4(4):e5186. 5 Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, et al. The American Journal of Cardiology and Journal of Periodontology editors’ consensus: periodontitis and atherosclerotic cardiovascular disease. J Periodontol. 2009;80(7):1021-1032. 6 Leyer GJ, Li S, Mubasher ME, Reifer C, Ouwehand AC. Probiotic effects on cold and influenza-like symptom incidence and duration in children. Pediatrics. 2009;124(2):e172-179. 7 Fasano A. Surprises from celiac disease. Sci Am. 2009;301(2):54-61. 8 Konic-Ristic A, Dodig D, Krstic R, Jelic S, Stankovic I, et al. Different levels of humoral immunoreactivity to different wheat cultivars gliadin are present in patients with celiac disease and in patients with multiple myeloma. BMC Immunol. 2009;10:32. 9 Djoussé L, Driver JA, Gaziano JM. Relation between modifiable lifestyle factors and lifetime risk of heart failure. JAMA. 2009;302(4):394-400. 10 Unterberger A, Szyf M, Nathanielsz PW, Cox LA. Organ and gestational age effects of maternal nutrient restriction on global methylation in fetal baboons. J Med Primatol. 2009;38:219-227. 11 Junger A. Clean: the revolutionary program to restore the body’s natural ability to heal itself. New York: HarperOne, 2009. 12 Conquer JA, Holub BJ. Supplementation with an algae source of docosahexaenoic acid increases (n-3) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects. J Nutr. 1996;126(12):3032-3039. 13 Davidson MH, Maki KC, Kalkowski J, Schaefer EJ, Torri SA, et al. Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr. 1997;16(3):236-243.

Welcome to the December 2009 issue of Functional Medicine Update. This is an issue to remember for all of us. Never in the history of functional medicine have we had-on the same issue-two of the founding fathers of molecular medicine and functional medicine. In this issue, you are going to be privileged to hear from two people, both unfortunately now deceased, who made extraordinary contributions to the birthing of our field: Dr. Linus Pauling, two-time Nobel Prize-winning laureate (in fact, still, even today, the only person to have won two independent Nobel Prizes in two different fields-one in chemistry and the other in peace), and secondly, Dr. Abram Hoffer, MD, PhD, father of orthomolecular psychiatry and one of the extraordinary contributors to the whole paradigm of functional nutrition and its relationship to neurological activity. With that as an introduction, let me presage the comments that you are going hear from Dr. Pauling. This is an interview that I had the privilege of doing with him back in the early 1980s, when I was a research associate at the Linus Pauling Institute of Science and Medicine on sabbatical from my teaching position at the university. This is a historical interview and I think you’ll find it quite interesting to get Dr. Pauling’s take, in the early 1980s, on what the status of affairs was as it pertained to vitamin C and orthomolecular medicine then, and his forecast of what it would be in the future. We’ll wait for his own comments to see how good a forecaster he was. I think you’ll find it an extraordinarily prescient discussion. The True Pioneers of Chemistry and Medicine Before we get into Dr. Pauling’s interview, I thought it might set the tone if we go back and review the history that led up to this extraordinary 1982 interview, as well as my later interview with Dr. AbramHoffer in 2008. The theme derives out of the intellectual soil that existed at the end of the 19th century. In terms of science and medicine, the 19th century was a period of time featuring people like Rudolf Virchow, the father of modern pathology, who explored the origin of disease as a pathological-based condition, and codified, in a systematic way, tissue pathology to define diseases as entities related to these pathologies. This was tied together with the development of the concept of human genetics as Gregor Mendel’s discoveries (which had lain dormant for a hundred years because of the church) were resurrected and better understood. It was also a major theme in the work of Gregory Bateson at the end of the 19th beginning of the 20th century, in the connection with inherited traits and how that interrelated with Charles Darwin (the understanding of the nature of evolution and natural selection) during this same period. All of this early work comes together in the 20th century in what we consider to be the modern concept of the origin of disease. This period was also the time of origin of systematic organic chemistry Emil Fischer, the extraordinary German chemist, was starting to help us understand that there wasn’t some vitalism in natural molecules-that they were interrelated with molecules that could be seen in a test tube. There was also the work of Wöhler on the conversion of cyanate into urea, and ultimately the recognition that the inorganic and organic world are connected through chemistry. The concept of vitalism was put aside as the concept of a reductionistic understanding of the milieu of life started to emerge. The origin of the age of vitamins started to emerge right at the turn of the 20th century with the discovery of the anti-beriberi factors (the Eichman work on thiamine as an agent that could prevent and treat beriberi). The “vit amine” meant the substances that were derived vital amines from food. We then tie that together with Elie Metchnikoff, who was working at the Pasteur Institute and won a Nobel Prize in medicine for his discoveries about the origin of the immune system. Later, he developed his prolongation of life concept, which relates to the colon as a site of origin of many diseases through the alteration of the immune system. All of this was happening during the latter portion of the 19th century. It was an epic period for setting new paradigms in place. The start of the 21st century has been a similar epic period as we start to look at systems biology, molecular medicine, and start the influence of various agents in the environment on genomic expression (nutrigenomics, nutriproteomics, and nutrimetabolimics-what we call the “trilogy of ‘omics”). A new way of looking at the origin of dysfunction, metabolic disturbance, and ultimately chronic disease is being established. The Contributions of Dr. Archibald Garrod At the turn of the 20th century, an extraordinary person by the name of Dr. Archibald Garrod was also doing research. He was a third-generation medical doctor whose father was really the person given creditfor discovering the first autoimmune disease (gout). On a thread put in a gout patient’s urine, his father crystallized the first crystals of uric acid thanks to the birthing of organic chemistry. rom that was born the molecular connection to the first autoimmune disease. Dr. Archibald Garrod (the son) then took these concepts and actually wrote the first textbook on autoimmune disease that was set in the English literature back in the late 1800s and early 1900s. He then took this concept even farther by looking at colored compounds in urine. This started the age of spectroscopy and the understanding of chromophores and how light-abstracting compounds that gave rise to color could be used to identify chemical constituents. Colored urine was a very interesting part of the application of this concept of spectroscopy in the late 19th century/early 20th century. Dr. Garrod was able to start looking at some of the porphyrias and at things that were related to colored compounds in urine. He identified the first genetic metabolism diseases of infancy, alkaptonuria. His article was published originally in The Lancet in 1902 and titled “The Incidence of Alkaptonuria: A Study in Chemical Individuality,” and it really represented the birthing of the whole field of molecular uniqueness, biochemical individuality, and later what we called molecular medicine, which was a term coined by Dr. Linus Pauling.1 I think if you went back and read the 1902 article by Dr. Garrod, you would find that many of things it describes are as modern today as they were at the turn of the last century. I find it absolutely fascinating that when he looks at the concept of a genetic metabolism disease through the lens of that period of time and his own connection between the chemical world and the physiological and medical world, that from that emerges a platform for understanding the origin of many diseases that were previously not understood at all. This is what Thomas Kuhn called a “paradigm shift,” a major shift in thinking. I quote from a part of Dr. Garrod’s landmark paper. He says, “There are good reasons for thinking that alkaptonuria is not the manifestation of a disease but is rather of the nature of an alternative course of metabolism, harmless and usually congenital and lifelong. Witness is borne to its harmlessness by those who have manifested the peculiarity without any apparent detriment to health from infancy on into adult and even into advanced life.” We can see that those individuals who excrete excess levels of homogentisic acid have a unique metabolism that is controlled by aspects of their family history. I suggest that he is talking very beautifully about the nature of biochemical individuality, and how it can express itself into the phenotype over the course of living. In terms of genetic uniquenesses, some things are seen in infancy, and other things are seen later in life. What we might consider to be a genetic defect might actually be defined as a genetic uniqueness, requiring a specific environment in order to minimize the potential adverse effects of that uniqueness, or to optimize the positive nature of that genetic uniqueness. I want you to recall when this was written in 1902 this was fairly early on. Bateson’s argument was that we needed to look at genes and genetic lineages, and look at these dominant/recessive characteristics that were originally described in peas through the work of the great monk working in his garden, Gregor Mendel. From that extraordinary soil (to use the gardening metaphor) of Dr. Garrod, came the germination of this concept of molecular uniqueness and biochemical individuality. The Contributions of Dr. James Neel Let’s roll the hourglass forward into the middle 1900s. Now I’m in the 20th century (1949), and an extraordinary series of papers appeared in Science magazine. The first is by a gentleman by the name of James Neel, who was the chairman/director of the heredity clinic/laboratory, department of biology, at the University of Michigan. This is a paper that appeared in the July 15, 1949 issue of Science magazine, in which he wrote about the inheritance of a genetic metabolism-related disorder, sickle cell anemia.2 I want you to recall the timeline: We are 50 years downstream now from where Dr. Garrod was talking about the porphyrias, and alkaptonuria, and other genetic metabolism disorders that could be seen, clinically, as altered color of urine (with these colored compounds being excreted in the urine as a consequence of different metabolism). Some of these urine compounds, by the way, didn’t develop as colored compounds until the urine was exposed to light because they undergo photochemical reactions with these metabolites to produce conjugated compounds that are colored, so this is a whole interesting chapter of evolution of the chemistry connection to medicine and to genetics. In 1949, James Neel writes about what happens in a drop of blood from a member of a family who has sickle cell anemia. You get this bizarre clumping of the cells in this sickle, or holly leaf, shape. The ability of these erythrocytes to sickle is a phenomena that appears to be attended by no pathological consequences in the majority of these individuals until-and I want to emphasize this-they are thrust into some kind of unusual environment. This could be stress, sleep deprivation, dehydration, physical trauma, or infection. At that point of stress, this characteristic (this genetic tendency) for these blood cells to pack in these unusual ways-these sickling configurations-can result in a pathological outcome that can have multi-organ involvement: it can affect the heart, the circulatory system, the musculature, the liver, and the kidneys. You get a multiple-organ influence from a biochemical uniqueness that is encoded in the genes of these individuals, who are triggered into this pathological state by environmental factors. Here is the genes/environment connection demonstrated through the concept of sickle cell anemia. We recognize these are inherited susceptibility factors. It doesn’t mean that a person who has these genes for sickling situations will necessarily be in crisis. What it means is they have an increased susceptibility to certain environmental factors. The Contributions of Dr. Linus Pauling and Dr. Harvey Itano The companion paper that followed Dr. Neel’s article in 1949 is, to me, one of the most dramatic “a-ha” papers that has appeared in the literature. It came from the pen of Dr. Linus Pauling, working with his post-doctoral student, Dr. Harvey Itano. This article is titled, “Sickle Cell Anemia, a Molecular Disease.”3 This is the first time (as far as I know) that the term “molecular disease” was used in the English-speaking literature, ollowing on from Archibald Garrod’s work really that had been done way back when at the turn of the 20th century. Dr. Pauling, then a professor at the California Institute of Technology (CalTech), developed an extraordinary way of looking at these sickling cells. Being a chemist, he looked at the uniqueness of these red cells and said, “What do they have in them that other cells don’t have?” And of course all of us know that they have hemoglobin, and hemoglobin is an iron porphyrin molecule, and iron is a ferromagnetic element (it has effects in magnetic fields). He was able to demonstrate that there were different spin states in the iron and hemoglobin in the sickle cells versus normal red cells. By utilizing a very interesting way of evaluating the effect of the cell’s biomagnetic field, he was able to start differentiating cells that would be sickled versus those not sickled, and start looking at the actual chemistry of how this whole process of altered hemoglobin was formed in the sickle cell individual. Eventually, because he was also a protein chemist and very interested in structure/function, he was able to isolate and analyze the protein structure (the beta globulin molecule of hemoglobin) and found that there was a single cell deletion (or substitution/mutation). As a consequence of this mutation of one amino acid for another, that single change in this large chain of amino acids was at a critical point of the structure of that protein, causing that globular protein (as part of the hemoglobin molecule) to then change the whole structure of hemoglobin, to make it more able to be packed into this configuration that led to sickling, and ultimately distorting the shape of the whole red cell: it looks like a sickle and it cuts its way through the vasculature, causing pathology when it starts packing together. This concept that a single amino acid change caused by a single gene alteration could lead to a very serious series of crises and diseases that cut across multiple organs (the reason he called this a molecular disease) was a major paradigm shift in thinking about the origin of disease. Recall, if you would, the major theme about the origin of disease to that point was infectious disease. That was a major (obviously) breakthrough in understanding the origin of disease at the turn of the last century, with Louis Pasteur and others who had really helped us to understand that certain bugs can cause disease through this process of infection and the interrelationship with the immune system and so forth. From that, then, was later then born this additional concept of the origin of disease-this genetic metabolism disease-where genes and environment interrelate to give rise to the expression of an outcome in the phenotype called the disease (in this case, a sickling crisis). The Contributions of Dr. Roger Williams This follows on nicely-this intellectual lineage-from the soil that was first prepared by Archibald Garrod. Just to show you how there is consanguineous concepts of discovery that occur in great epic periods, in that same time period (1949) another well-known figure-someone we would consider one of the founding fathers of functional medicine-was doing his work, and this is Dr. Roger Williams. At the time, he was working as a faculty member at the Clayton Foundation for Research, in the chemistry department at the University of Texas, where he later was department chairman, in Austin, Texas. He was an esteemed biochemist who was actually credited with discovering pantothenic acid. Dr. Williams had been the president of the American Chemical Society, the largest professional society for chemists in the United States. During the same period of time that Dr. Pauling was writing his paper on sickle cell anemia as a molecular disease with Dr. Itano on sickle cell anemia as a molecular disease (this whole concept of genetic uniquenesses giving rise to single changes in proteins that give rise to the expression, under certain environmental conditions, of disease), Dr. Williams was developing his concept of genetotrophic disease. Genetotrophic disease was an extraordinary concept for that time, and I believe, was published in 1950 for the first time in The Lancet. 4 This was February 11 of 1950-a classic article. In this article, Dr. Williams wrote about this theme of disease occurring as a consequence of a genetic uniqueness and certain nutritional insufficiencies as another part of this paradigm shifting discovery. I quote, “Based essentially upon recent findings in genetics and biochemistry which have not yet been incorporated into medical thought, the concept of genetotrophic disease may, we believe, lead to an understanding of many diseases whose etiology is, at present, obscure.” What is this concept of genetotrophic disease? This is the concept that we each have genetic uniqueness for many things, one of which is the need for specific nutrients to promote proper functional physiology. And if, in fact, those needs that we each individually have, based on our genetics, are not met, then the result could be dysfunctional metabolism, which over time can lead to disease. This is very interesting if you think about it for a moment, because it almost goes back to HP Himsworth and his work. He was the person who was credited, as the head of the endocrinology department at the University of London School of Medicine (very highly esteemed director of medical research in England at the time), with discovering metabolic syndrome and insulin resistance. He was quoted as saying, “The history of modern knowledge is concerned in no small degree with man’s attempt to escape from his previous concepts.” He was talking about insulin resistance and hyperinsulinemia as a different form of diabetes than that of just frank insulin deficiency (what we now know to be called type 1 diabetes). He also said, “The history of modern knowledge is concerned in no small way with man’s attempt to escape from his previous concepts,” because he had a hard time getting his colleagues to understand there could be a second type of diabetes that was associated not with a deficiency of insulin, but an insufficiency of insulin promoting proper signaling or proper function. Williams quotes Himsworth when he talks about the paradigm shifting concept of a genetotrophic disease in this fantastic article that appeared in The Lancet. In this article, he writes about etiology of diseases, like heart disease, diabetes, and arthritis, and other conditions such as alcoholism having their root origin in genetic uniqueness and nutritional insufficiency based upon the individual’s own uniqueness that is not being met by their nutritional intake. Dr. Williams also writes about mental disease and various types of things like schizophrenia maybe being the result of inadequacy of specific nutrients to the genetic need of that individual. He says, “There is a prodigious amount of data to indicate combined genetic and nutritional influences in many forms of mental disease that an entire volume might be written on this topic alone.” For many years it has been seen that there are forms of dementia and other nutritional-associated symptoms of mental illness that could be tracked back to genetics not being adequately supported by proper nutrition. Now, in the 21st century, I think we are witnessing a revisiting-a rediscovery-of these paradigms that were developed from the work of people like Archibald Garrod, and later Dr. Pauling and Dr. Williams. Dr. Williams took this concept of genetotrophic disease into an even more descriptive level in a wonderful review article he authored in Nutrition Reviews.5 This was in September of 1950, early on in the first publications of Nutrition Reviews. He writes about the extraordinary research that was in the literature that he believed supported the concept of genetic uniqueness and what he later called biochemical individuality. This now takes us to 1968, and 1968 was an epic landmark period in the history of our field of functional medicine. That was the year that Dr. Linus Pauling authored what I consider to be one of the great papers-a paper that was probably not understood as well as it should have been in terms of its impact on the future trajectory of medicine. This paper appeared in Science magazine (April 19, 1968), and was titled “Orthomolecular Psychiatry: Varying the Concentrations of Substances Normally Present in the Human Body My Control Mental Disease.”6 In this paper, Dr. Pauling really builds upon what Dr. Williams discussed “Genetotrophic Disease.” Dr Pauling writes about optimizing molecular concentrations of what he called “orthomolecular substances,” which are substances that are native to the human body, and how that then influences enzyme function, and how that enzyme function controls and regulates cellular activity in the phenotype of the individual. Also, how individuals with unique genetics might have enzymes that are slightly different in their structure and function from that of other individuals, and therefore their need for coenzymes to promote proper enzyme function may be slightly higher. This leads to the orthomolecular supplementation concept: It is not that individuals are getting superordinate amounts of supplements, but rather they are getting the level of nutrients necessary under their unique genes to promote proper enzyme function. This is the application of Le Chatelier’s Principle.Le Chatelier was the French chemist who lived at the height of the French Revolution, and whose concept was that you apply stress to an equilibrium, and the equilibrium moves in the direction to minimize the stress. (That’s kind of a metaphor, isn’t it, to the French Revolution?) The chemistry outcome of that is you add more of your substrate and you push that, then, through the equilibrium dynamics onto more product. In this case, increasing the activity and amount of a cofactor (or a coenzyme) can promote more of the apo enzyme becoming the halo enzyme (the active enzyme) that then catalyzes that specific reaction. This is the basis for things like the use of more B12 at hundreds of times the RDI for megaloblastic anemia, or for the use of oral B6 and folate for people with homocysteinemia. This is the specific applications of the conceptual framework that Dr. Pauling was speaking to: You can’t change the genes, but you can change the environment that would then promote proper enzyme function. The Contributions of Dr. Bruce Ames This concept that is described in “Orthomolecular Psychiatry,” this landmark paper, leads us into a period of nearly 40 years of debate and controversy, and up-and-down, and “What does this really mean?” This debate and controversy led usto a moment in time that I think is one of those “a-ha” moments, which I think was the publication in 2002 of a review paper by Bruce Ames, and Ilan Elson-Schwab, and Eli Silver. It appeared in the American Journal of Clinical Nutrition in 2002, and the title of this paper was “High Dose Vitamin Therapy: Stimulating Variant Enzymes With Decreased Coenzyme Binding Affinity: Relevance to Genetic Disease and Polymorphisms.”7 It was necessary that a paper such as this be written by a scholar such as Dr. Ames, an icon in the field, to help to support the lineage of the development of this theme–Archibald Garrod to Roger Williamsto Linus Pauling. In this review paper, which has 377 references, Dr. Ames and his co-authors did a brilliant job of really supporting this concept of genetotrophic disease, orthomolecular medicine, and molecular medicine, as it pertains to the role that nutritional supplements can have in specific cases for promoting proper function. In this paper he writes, “As many as one-third of mutations in a gene result in the corresponding enzyme having an increased Michaelis constant [this means decreased binding affinity] for [its respective] coenzyme,” which is generally vitamin-derived. This results in a lower rate of reaction. “About 50 human genetic diseases due to defective enzymes can be remediated or ameliorated by the administration [he says] of high doses of vitamin component of the corresponding coenzyme, which at least partially restores enzymatic activity.” He then writes about single-nucleotide polymorphisms, in which the variant amino acid “reduces coenzyme binding and thus enzymatic activity” and these can be remediable by raising cellular concentrations of the cofactor. This is the very concept that Linus Pauling discussed in 1968 in his Science article. Dr. Ames gives many examples and applications of this, clinically, that have been proven in the literature. And with 377 references, anyone that says there is no science needs to do their homework. That leads us, now, into the 21st century, with the development of nutrigenomics and nutriproteomics and nutrimetabolomics, and how this relates to individual need for nutrients to promote individual function. It ties to the vitamin C controversy. It ties to all the things that we have seen debated, including the niacin and schizophrenia controversy, and the B6 and folate controversy (the homocysteinemia)-all the things that are still being debated today. With that, let’s go to the father of this whole concept, Dr. Linus Pauling, and hear what he had to say in 1982.

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INTERVIEW TRANSCRIPT

Clinicians/Researchers of the Month Linus Pauling, PhD 1901-1994 Recipient of the Nobel Prize in Chemistry, 1954 Recipient of the Nobel Peace Prize, 1962 Interview recorded at the Linus Pauling Institute of Science and Medicine, 1982 JB: Hello. I’m Dr. Jeff Bland. I’m a Senior Research Fellow at the Linus Pauling Institute of Science and Medicine. It’s a great pleasure today to be with Dr. Linus Pauling, the Chairman of the Board and the chief visionary influence on the Linus Pauling Institute’s activities. I’m here today to really engage in a fireside chat with Dr. Pauling to discuss some of the areas of his interest and some of his research progress that he’s making and, really, hopefully acquaint you with some of things that are not only going on here at the Institute, but in the field science and health care in general. Without further ado, let me thank Dr. Pauling very much for being with us today and for sharing this moment of his precious time. Nice to have you with us, Dr. Pauling. LP: Well, thank you! I’m glad to be here. JB: I’m going to start, if I could, just for the sake of the listeners, asking you if you might review for us some of your recent activities. I know you have been traveling all around, and you have been speaking to many groups. I’m sure we’d all like to hear some of the things that have occupied your time. Projects at the Linus Pauling Institute, 1982 LP: Well, you know, I divide my time, it turns out, into thirds. One-third of the time I work on basic problems of science, which I have been interested in for a long time (since 1922 when I carried out my first research). So I still make quantum mechanical calculations about molecular structures and crystal structure, the nature of metals, and the structure of nuclei. Then, one-third of my time is devoted to collaborating with other people here in the Linus Pauling Institute in our attack on medical problems. Right now, we are just finishing up a big study of the effectiveness of vitamin C in controlling cancer in mice. It has turned out, I’m glad to say, that the vitamin C has great value. It slows down, greatly, the development of spontaneous breast cancer in a strain of mice that develop these cancers. I collaborate with many people in the Institute in their research, in considerable part by talking with them about what they are doing and giving them advice, perhaps, or making suggestions on the basis of my years of experience. The job of answering letters from people who write in for advice is a considerable one that takes up a good bit of my time. Then, the other third of my time, I travel. I travel to give talks, largely about vitamins and health, or about health in general, especially in relation to nutrition. Some of them about world peace, because why should I be working on improving the health of people if the world is going to be destroyed in a great nuclear war? We need to have a future, to believe that we are going to have a future, that the human race will have a future in order to justify our trying to control cancer, and heart disease, and other diseases. And of course, some of the talks that I give on these trips that I take are about science. JB: I’d like, if I could, to sort of switch the topic and ask you…you alluded to this exciting study here at the Institute that has been ongoing for a couple of years as it relates to vitamin C’s impact upon spontaneous mammary cancer in mice. That’s but one of a number of exciting types of work that are going on in the Institute. I’m sure that our listeners would like to hear a little bit more about some of the other things happening at the Institute. Could you say a few words about that? In His Own Words: Dr. Pauling’s Views on Vitamin C LP: Some of the investigators in the Institute are working on the question of, “Just what is cancer?” How does cancer originate in the human body? During recent years (the last 20 years), it has been possible to get information about genetic influences. About the role of genes, which are polynucleotide DNA (strings of DNA molecules) in causing cancer and in achieving almost everything else that goes on in the human body. Our investigators have been involved in the recent work on oncogenes. Oncogenes are genes that are involved in cancer. They are closely related to genes that are present in every human being or in every animal of the species under study. When one of these pro-oncogenes (a gene that might become an oncogene) undergoes a genetic mutation, it becomes an oncogene, a gene that changes the nature of the organism in such a way that a cancer develops. There may be some second effects that also must occur (more than one change is usually involved in the production of cancer). So this very modern technique of studying the DNA molecules that determine the nature of an individual human being, including the cancers that he might produce, is being used by workers/investigators in our Institute. A different attack is being made by Dr. Constance Tsao and her associates. This is to study certain chemical substances that are produced by oxidation of vitamin C. It was discovered 10 or 15 years ago by Dr. Omura-well, in fact, by his teacher, who then retired, but Dr. Omura has continued-that oxidation products of vitamin C, which are found in the human body after vitamin C is ingested, have greater anti-cancer activity in animals than vitamin C itself has.8 This hasn’t been followed up by anyone. There are a number of these oxidation products, different substances that you get by reaction of vitamin C and oxygen. We don’t know whether all of them have greater anti-cancer activity than vitamin C or only one or two of them, and we don’t understand at all how they work in controlling cancer. It may turn out that much of the anti-cancer activity of vitamin C results from its oxidation in the human body to these oxidation products. So I have hope that this will turn out to be a really significant effort that will lead to an advance in our ability to control cancer. Vitamin C, itself, of course, works in other ways than just through the oxidation products. It is required for the efficient operation of the immune system. We know that when the immune system is functioning well, the probability of dying from cancer is less than when the immune system is not functioning well. After an operation for removal of a cancer, in almost every patient, there are, in the blood stream, millions of malignant cells. And yet, only some of these patients then later develop metastatic cancer. Others do not. Why? It is believed-and I think quite rightly-that if your immune system is working well, then that system can detect the malignant cells, prepare them for destruction, and then carry out their destruction. And so in the people who have a well-working immune system, the malignant cells are destroyed and metastases do not occur. Vitamin C is known to potentiate the immune system in various ways. An English investigator named Vallance showed that more antibodies that can identify the malignant cells are farmed with a high intake of vitamin C than with a low intake.9 More molecules of complement are farmed as a result of additional vitamin C. Molecules of complement have to attach themselves to the complex of a malignant cell, or a group of malignant cells, and antibodies, in order that these malignant cells be destroyed. With a high intake of vitamin C, you produce more of the T-lymphocytes that can destroy these marked malignant cells (the complex of the antibodies complement and the malignant cells). And it has been known for 40 years (more than 40 years-nearly 50 years) that vitamin C is required in these T-lymphocytes and phagocytes and white cells, generally, in the order that they be able to destroy infected cells and malignant cells. Vitamin C is intimately involved in the process of protecting the human body against infections and against malignancies because the only way the human body has of destroying these infected cells and malignant cells is with use of vitamin C. So vitamin C is important to cancer in many ways. Now we are just embarking on a new project that I am especially interested in. This is vitamin C in relation to heart disease. Evidence has been turning up during recent years about the involvement of vitamin C in heart disease. There is a good correlation between incidence of heart disease and the amount of cholesterol in the body, and also the amount of low-density lipoprotein. This low-density lipoprotein is the protein that consists of molecules that can carry cholesterol molecules out to cells in the body where they are required for proper functioning of the cells. Cholesterol is a very important substance. Sometimes, however, the amount of cholesterol is too great and it gets involved in laying down plaques in the blood vessels. There is another protein (a lipoprotein) whose molecules have a function of picking up cholesterol and carrying it back to the organs where it is destroyed in the liver, converted into bile acids that are then eliminated from the body. Well, vitamin C has been shown to speed up the rate of conversion of cholesterol to bile acids, and that means you are bleeding off the cholesterol, so that level in the body goes down. It has also been shown to cause the production of more high-density lipoprotein. That means you have more of the protein that removes cholesterol from the blood vessels and carries it to the liver to be destroyed. Also, it cuts down (slows down) the rate of production of low-density lipoprotein so that you have a smaller number of the molecules that carried the cholesterol out to the blood vessels where the plaques can be formed. It also cuts down the amount of triglycerides in the blood, and there is a correlation between triglycerides and heart attack. So with all of these correlations, we can see cutting down the total cholesterol, the low-density lipoprotein, and the triglycerides, and increasing the high-density lipoprotein and speeding up the rate of destruction of the cholesterol (converting it to bile acids), we can see that vitamin C might well be correlated in a very striking way with heart disease. A high intake of vitamin C may turn out to be the best way of protecting yourself against heart disease. Our epidemiological associate, Dr. James Enstrom, has published a paper describing a study that he made of several hundred people who had been ingesting larger amounts of vitamin C than the population as a whole (on the average about a gram and a half of 1500 milligrams of vitamin C).10 They had only about half the probability of dying of heart disease at each age as the control population (similar sub-populations in California), who were on an ordinary diet with an ordinary intake of vitamin C. There are other differences between the two populations that he compared, but it seems likely that this high intake of vitamin C is largely responsible for their having only half as much mortality from heart disease (age standardized, age corrected mortality). Well, they had only half as much mortality from cancer, too, and from other diseases. Vitamin C is not a specific remedy-a wonder drug-against cancer , or against the common cold, or against the flu, or hepatitis, or viral pneumonia, or herpes infections, or heart disease. It is not a specific wonder drug. What it does is to build up the human body to the state of health that all human beings ought to be in. When I read what the Food and Nutrition Board says, that 60 milligrams of vitamin C a day is enough for all persons in ordinary good health, I think they should say, “All persons in ordinary poor health.” If you want to be in what ought to be ordinary good health, you have to take additional vitamin C. Of course, I believe that the arguments that support this conclusion are really thoroughly convincing. They are the sort of arguments that appeal to me as a scientist. I am accustomed to looking at the facts and trying to draw some logical conclusions from them. Other people, perhaps, are not so accustomed to doing that. I would say that the evidence that high intake (many times the usually recommended amount-RDA-of vitamin C) is needed for good health. That conclusion is thoroughly justified by the evidence. JB: I’d like to respond and say that this relationship between vitamin C and heart disease is a very interesting controversy recently in the literature that I believe falls right in line with what you are talking about-that some people interpret data differently. There was a report in the American Journal of Clinical Nutrition by some supposed responsible investigators saying that vitamin C did not increase high-density lipoprotein cholesterol and did not lower total cholesterol.11 However, in examining the protocol of the study, it was found that the average starting cholesterol of this group was about three-quarters the value of the standard average American cholesterol level, meaning it was about 175 where the normal value is about 220 for the average person. And it had already been pointed out in 1976, through another series of investigations, that vitamin C is most effective in lowering cholesterol and raising HDL when a person has an elevated blood cholesterol level, meaning that the study population selected in this study was already almost guaranteed to show a negative result, which I found to be something that was either naiveté on the part of the investigators, or more likely that they were trying to make a certain political statement through the misuse of science.12,13 LP: Yes. It is true that if you want to find out what some investigators have observed, you have to go back and read their entire paper, not just read a statement that someone has made, even the investigators themselves have made, about what results they have obtained. People are often misled by statements that some investigator showed that this substance did not have any value, when, in fact, he had observed some value, but not so great as he had expected to observe, or when the number of subjects was so small that he was not able to show, with statistical significance, that there was a positive effect. Very often the mistake is made that when an investigator has used a certain number of subjects, which might be rather small, and has failed to show benefit from the treatment at what is considered a statistically significant level, the results are described as his having shown that there was no effect, when, in fact, he hadn’t that there was no effect, he had just not succeeded in showing that there was an effect. The statistical treatment that you give if you are trying to answer these two questions is quite different. Response to View that Vitamin C Has Toxic Effects JB: One of the most common questions, Dr. Pauling, that the average person asks about vitamin C therapy, particularly today, in light of a lot of the published information in the wire service and in magazines and newspapers, is surrounding vitamin C’s supposed toxic effects. I think that there are several notable reports that have occurred in the literature lately. I know you responded very eloquently to a paper that appeared in Seminars on Oncology lately by a Dr. Mary Sestili, who has commented that vitamin C has toxic effects, potentially, when used in cancer therapy.14 And you have also previously responded to Dr. Victor Herbert, hematologist, who says that vitamin C supplementation may destroy vitamin B12.15 We also hear that vitamin C supplementation supposedly causes kidney stones through its metabolism to oxalate. And recently there has been the report by Professor Cerklewski at Oregon State University that somehow vitamin C supplements cause an antagonism of copper metabolism in the body and leads to copper deficiency anemia.16 I think it would be very useful for our listeners to sort of put this into perspective. Could you comment on vitamin C’s toxicity for us? LP: Human beings differ from one another. There may well be a few human beings who should not take very large doses of vitamin C. But they are so rare, in my opinion, that it is justified for me to say that vitamin C is essentially completely non-toxic. Some of the arguments that have been presented are based on a misunderstanding. We know that the common sort of kidney stone has a greater tendency to form in alkaline urine than in acidic urine. But uncommon forms have a greater tendency to form in acidic urine. When my book Vitamin C and the Common Cold came out it was immediately attacked in a publication mainly for doctors.17 The statement was made that vitamin C, in the form of ascorbic acid, keeps the urine acidic, and so increases the tendency to form certain kinds of kidney stones (the less common kinds). That is true, but it isn’t an effect of vitamin C. Vitamin C is the ascorbate ion. You can’t take pure vitamin C because you can’t get hold of a large aggregate of negatively charged ion; there always is a positive ion along with them. And that can be either hydrogen ion, or sodium ion, or calcium ion, or some other ion. Ordinary vitamin C tablets contain ascorbic acid, which is vitamin C with hydrogen ion. They make the urine acidic. It isn’t the vitamin C, then, that increases the tendency to form these uncommon stones. It is the hydrogen ion that you are taking along with the ascorbate ion. But, to keep the urine acidic decreases the tendency to form the common stones. Not many people form stones, anyway. And fewer still know what kind they might have a tendency to form. If you happen to know that you have a tendency to form common kidney stones, then you would be wise to take ascorbic acid (vitamin C in the form of ascorbic acid-the common way in which it is available), or to take some other acidifying agent. But the ascorbic acid is the best thing to take to cut down the chance of forming the common kidney stones. If you know that you have formed one of the uncommon kind, then the doctor may well advise you to keep the urine alkaline. You could take baking soda as an alkalinizing agent, or you can take sodium ascorbate. And when take sodium ascorbate you are not only protecting yourself to some extent against forming additional kidney stones of that uncommon kind, but you are also benefitting from the vitamin C. With the oxalate stones, there may be one person described in the medical literature as having an oxalate stone formed because of a large volume amount of vitamin C that he took. That is possibly a real effect for that person of a special genotype. The number of these cases is so small that I don’t think that that is a reason not to take vitamin C. For some of these other statements, Dr. Victor Herbert saying that vitamin C destroys vitamin B12 and you may get pernicious anemia was based on an error that he and his associate made when they analyzed their foods for vitamin B12. They just didn’t use the standard procedure for making the analysis for vitamin B12. And when other investigators repeated their work, when they used Dr. Herbert’s method they got the same results he had gotten, but when they used the standard method they found that practically none of the vitamin B12 had been destroyed. Only a small amount of loosely bound vitamin B12 had been destroyed. So the statement that vitamin C can cause pernicious anemia, or B12 deficient anemia, is just not in accordance with the facts; it was based on an error. With the investigator at Oregon State University, Dr. Cerklewski, who reported that the copper level in the blood went down when the subjects were given large doses of vitamin C, the situation has been exacerbated by a writer in one of the popular newspapers who misrepresented Dr. Cerklewski’s work. First he said that Dr. Cerklewski took the subjects off the vitamin C after 60 days (or whatever period) in order to protect them from dying of anemia. Dr. Cerklewski says this just isn’t true. He said that in his paper he mentioned the possibility that this lower copper level would lead to an iron deficiency (anemia-failure to incorporate iron in the red blood cells and the hemoglobin for the red blood cells). But he didn’t think that it would occur; he just mentioned that as a possibility (a rather distant possibility). The scare statements that you will get anemia (die of anemia) if you take large doses of vitamin C are not justified by the statements of the investigator himself. Vitamin C improves the workings of the human body so much, that it may well be that people will produce as much hemoglobin as they need, even though their copper levels are somewhat less than in other people when they are on a smaller intake of vitamin C. So there is no evidence, really, to support that conclusion about vitamin C and anemia. The same thing is true for many other statements that are made about possible dangers of vitamin C, one of which is that if you take large doses of vitamin C and then stop you will develop scurvy. Or if a mother-a pregnant woman-takes large doses the child is apt to have special needs for vitamin C such that that child will be ascorbutic on the ordinary intake of vitamin C that would not permit scurvy to develop. There just is no evidence to support this. There is a rebound effect, which, in fact, was discovered ten years ago by my associates. It is a rebound effect that occurs after you have been taking large doses of vitamin C and stop suddenly, the level in the blood goes below that corresponding to the ordinary low intake, and it stays low for a few days. I recommend that people taper off if they want to stop a large dose instead of stopping. Dr. Anderson, in Toronto, carried out a study in which he checked whether people have an increased probability of developing the common cold (respiratory illness) during this period after they have stopped a large intake, than they have ordinarily on the ordinary low intake. He found he couldn’t detect any increased incidence of respiratory illness during this period when the level in the blood is lower than usual.18 So, there is an effect. It’s not an important effect. Nevertheless, I suggest that people should taper off over a period of a week or two if they have been taking large doses. And then I say, “But better still, don’t stop the large doses.” If a patient goes to the hospital (a person who has been supplementary vitamins), the doctor is apt to stop the supplementary vitamins. This is wrong. The doctors should be giving larger amounts of vitamin C and other vitamins to patients in hospitals. You know, we are troubled about the fact that the cost of medical care in the United States is very high. We are spending hundreds of billions of dollars on medical care, hospital care: six-, seven-, eight-hundred dollars a day for patients in the hospital. It has been known for forty years that you can cut down the length of stay in the hospital by two or three or four days (or by thirty or forty or fifty percent for a longer stay) if the patient receives large amounts of vitamin C. After a surgical operation, the wounds heal faster with vitamin C. It has been known for about fifty years that vitamin C is required for wound healing. You can’t manufacture collagen, connective tissue, scar tissue. You just can’t heal wounds if you don’t have vitamin C. When a person not getting vitamin C begins to die of scurvy, if he has an old scar, it is apt to break open again because he is not manufacturing collagen. In fact, his joints fall apart, his blood vessels burst, because he is not making the collagen which is required for the strength of these organs and tissues. And vitamin C is needed-absolutely needed-to make collagen. So your body is stronger when you take vitamin C. Now, about what my associates are doing. Dr. Cameron, when he first gave large doses of vitamin C to terminal cancer patients in Scotland (and he deserves the credit for having discovered, by his clinical observations, that vitamin C really has value for cancer patients), one of the things that Dr. Cameron noticed was that the patients said, “Doctor, I feel so strong!” They not only didn’t feel sick (have this cachexia, just feeling miserable that is characteristic of cancer), and not only developed good appetites instead of being anorexic (not able to eat because the food didn’t taste good), but they also got strong. Dr. Cameron wondered, “What can vitamin C be doing that makes the patient say that they feel strong?” And they were strong. He mentions that one of his patients, who, in Scotland, liked to play golf, was able to lower his golf score after he got out of the hospital. And another (a retired man) took on the job of chopping wood (not as a job, but just because he liked doing it-he felt strong and he brought chopped wood around to Dr. Cameron and other people). Also, Cameron noticed that in the accounts of scurvy, when sailors used to die on ships with scurvy, the first sign of the scurvy was lassitude and lack of muscular strength, and then the body began falling apart, later. The gums ulcerated and the teeth fell out, and the joints, and so on, and the person died. What about this lack of muscular strength and regaining strength in Cameron’s patients? There is a simple chemical substance named carnitine, which is present in muscle juice to the extent of about one percent. (If you squeeze meat, the juice that you get out contains carnitine.) Carnitine is required for muscular activity. You know, you burn fuel in the body to provide the energy for muscular work. This is burned in the cells in the muscle. The fuel that you burn is fat (at least, one of the fuels). Carnitine is required to carry molecules of fat into these cells where they can be burned to provide muscular energy. Just a couple of years ago, a biochemist showed that carnitine can be made from lysine, an amino acid present in the body (present in meat, too). Lysine, by chemical reactions that take place in the human body, catalyzed by certain enzymes, two of which are hydroxylation reactions that require vitamin C. You can’t make carnitine from lysine without vitamin C. The fact that people sometimes say, “I have to eat red meat to be strong,” it may be that they are getting carnitine from the meat and that helps them to be strong, or also getting lysine, which is present in larger amounts in meat protein than in vegetable protein. And if they have enough vitamin C, they can convert the lysine to carnitine and thus have even greater muscular strength. One of the investigations that we are carrying out as a result of the various observations by Dr. Cameron and by others is to study human beings. How much carnitine is in their bodies? How much is floating around in the blood? And if you give a person extra lysine and extra vitamin C, does he then produce more carnitine and become stronger, too? Vitamin C and Selenium JB: Dr. Pauling, one of the other very commonly asked questions surrounding vitamin C’s use in supplemental doses has to do with another antioxidant (knowing that vitamin C is considered a biological antioxidant that works in the water soluble portion of cells). This other antioxidant is the trace element selenium, which is receiving quite a bit of attention recently because it is supposedly a cancer-preventive nutrient. It has suggested by Dr. Walter Mertz at the USDA that high-dose vitamin C therapy antagonizes selenium status, or at least prevents selenium absorption from the diet. Do you have any comments on that relationship? LP: I’m not sure that my comments are as significant as those that you would make. I would think that selenate or selenite might well be reduced to elementary selenium by ascorbate. That selenium…an organic molecule such as selenium methionine or some other organic compound would probably not be affected by the ascorbate. But I’d be interested to know your opinion on this point. JB: I concur with your comment. In fact, a paper in which the oxidation reduction relationships between inorganic selenium and selenite, selenate, and selenious acid in vitamin C and the organics (organoselenium, selenium methionine, selenium cysteine) confirmed exactly what you just pointed out and that is that there was not a reduction in the organic forms of selenium to selenium metal, where there was in the inorganic selenite, selenate forms. So it would seem to me that if you were supplementing with a sodium selenite preparation and taking high-dose vitamin C that you may render some of the selenium unabsorbable, but if you were taking the organically bound form it would be a very small probability reaction. LP: Yes, and of course, the organically bound form probably is selenium minus one, already as far reduced as possible so that ascorbate couldn’t reduce it any further. JB: Exactly right. One of the other things, quickly, that you might want to comment on is the suggestion that you can utilize a fat soluble form of ascorbate called ascorbyl palmitate, where the ascorbic acid molecule is a esterified palmitic acid, and that this is supposedly a very useful antioxidant in the fat soluble milieu of cells. That you should be taking a supplement of ascorbyl palmitate. Do you have any comment on that? LP: I would need to be convinced that we need that fat soluble form of ascorbate if we are taking enough of the fat soluble antioxidant vitamin E. My recommendation would be to spend your money on vitamin E and save money by buying the cheap form of vitamin C, rather than to buy a more expensive form of vitamin C. Moreover, I don’t think anyone should rely entirely on this fat soluble form. It might be taken as an adjunct to an amount of ascorbate, itself (ascorbic acid or sodium ascorbate or calcium ascorbate, itself). JB: What dosage level would be considered for the average consumer who is reasonably well (let’s say not sick)? What dosage level of vitamin C would be considered at a range they would have concern about excessive intake? Is there some range that we might say, for the average person, would be the desirable range? LP: Vitamin C isn’t very expensive. What I buy costs about a cent-and-a-half a gram (the ascorbic acids crystals) and one-gram tablets you can get for around three cents a tablet (three cents a gram). So it isn’t very expensive. My twelve grams a day comes to about eighteen cents a day. Nevertheless, people may not want to spend too much money on vitamins. I say a little extra vitamin C does a lot of good. To take even 250 or 500 milligrams does a lot of good. To take 1000 milligrams a day does more good. To take 5000, 10,000 milligrams still more good. But in general, I don’t complain about a person telling me that he takes 1000 milligrams a day, or 2000 milligrams a day. As people get older I think it would be wise for them to increase the intake. I’ve already mentioned, I think, that I think that the twelve grams (12,000 milligrams) that I take is probably the right physiological amount. You can get along pretty well with a somewhat smaller amount. I think that’s the right one. Now, a person can find his own upper limit from the gastrointestinal response that was observed ten years ago by Dr. Cameron and more recently by Dr. Cathcart.19 Dr. Cameron observed that a sick person can take much larger amounts of vitamin C by mouth without it acting as a laxative or having too much of a laxative effect (producing looseness of the bowels) than the same person when he gets well. Consequently, it might be good for a person to find out what his gastrointestinal limit is, and if it’s unusually high it may well mean that he has a special need for vitamin C, that he really is not in the best of health. I can take only about twelve grams a day (well, I could take more if I split it up into a succession of small doses, but not much more). Some people can take twenty or thirty grams a day before they get this response, even though they consider that they are in good health. A really sick person, Dr. Cathcart reported, might have to take as much as 200 grams in a day to get this response, but he can’t do that day after day. In a few days he is well if he has mononucleosis or hepatitis or some such disease and has had to cut down his intake. This man who comes to see me every few months (the chemist down in San Jose) still has metastatic cancer. It’s clear that he is not well, both because you can see the metastases when he has CAT scans made and also because he can take his 130 grams a day without having far too much looseness of the bowels. So he is not well. He is able to work, to stay alive, for eight years, but he hasn’t been able to get rid of the cancer and get back into good health. Some people do, apparently, succeed in that. JB: I know that the listeners would probably like this to go on indefinitely, but we certainly have to recognize that you have many, many other responsibilities today and we appreciate your time. I would like, however, to leave with one last question being put to you before we have a chance to get together to do this in the future. That is: I think a lot of people see the rate of change of information occurring and how quickly science is evolving and developing and we all probably feel a little bit of a state of overwhelm. As a visionary, as a person who has been a major contributor to the field of science and health care and had your finger on the pulse of what’s been happening for 70+ years, what is your vision as to what is occurring right now and the kind of future that you see for health care? Dr. Pauling’s Thoughts (in 1982) about the Future of Medicine LP: I think that it will be recognized before long that the greatest contribution to medicine made in the last quarter of the 20th century is the recognition that nutrition, including nutritional supplements, can be used in a far more effective way to improve health, prevent disease, and even in the treatment of disease, usually as an adjunct to a conventional therapy, than had been possible than it had been used in the past. In particular, I think vitamin C, which is unique among the vitamins in two or three respects, will be found to have very great value. The estimate that I have made about the value of nutritional supplements, vitamin C, and some other health practices has been increasing. That is, the value of these (my estimate of their value) has been getting greater year after year. In an article that I wrote recently, I made the estimate that in this way it should be possible to increase the length of the period of well-being and the length of life by 35 years, which would mean around 110 years as a life expectancy rather than 75 years.20 And this, I feel, is desirable. There are periods in life when you are miserable. When you were young you were miserable-at least I was miserable before I found the proper relationship to the world as a whole, to the opposite sex, and so on. I was not happy as a child and as a teenager; I was miserable. I expect that there may well be a period of misery associated with the decline in health that culminates in death. It may be that this could be shortened (this second period of misery). The first, I think, has got worse in the last twenty years with the relaxation of the social pressures on young people to behave that kept them from getting involved with problems so intimately as they are now involved. I believe that we can then increase the length of the period of well-being with respect to the period of less well-being, that is, we’ll win out in this way by being happier over a greater fraction of our lives than at the present time. So now going from this extraordinary discussion with Dr. Linus Pauling concerning his view of orthomolecular medicine, vitamin C, and the future of this molecular medicine concept, let’s move to the next important founding father of this concept in the 20th century, and that is Dr. Abram Hoffer, who, as you know, as a psychiatrist and a PhD in chemistry, birthed the concept of orthomolecular psychiatry. And also, he was in practice, seeing patients up to the end of his life. An incredible contributor to our field, who I had the great fortune of being able to interview just very shortly before his transition and moving on. With that, let’s talk in the 21st century, with Dr. Abram Hoffer and his view of this whole field.

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Clinicians/Researchers of the Month Abram Hoffer, MD, PhD 1917-2009 Interviewed in his office in British Columbia, Canada, December 2008 JB: This is a great privilege for me. I’m representing the Institute for Functional Medicine. We’ve been very fortunate, at the Institute for Functional Medicine, for the past 14 years, to, every year, honor someone who we feel has provided meritorious distinction in the field of functional medicine. We’ve named this award for a person who is really one of the founding fathers of functional medicine and that is Dr. Linus Pauling. There is probably no recipient that would be more deserving for this Linus Pauling Award than the person I’m so privileged to be able to honor today, and that is Dr. Abram Hoffer. Dr. Hoffer, this is the 14th Linus Pauling Functional Medicine Award. We wanted to save it for when it got rich enough to be really worth something. We think that you-as one of the founding fathers of the whole paradigm upon which functional medicine is built-really represents the core of what we are trying to teach doctors in the future. The plaque says, “For a lifetime of pioneering work that has elucidated the important role of biochemical uniqueness and orthomolecular therapies in a wide variety of chronic mental health conditions, the Institute recognizes Dr. Abram Hoffer’s significant contribution to the evolution of functional medicine’s knowledge and intellectual architecture for the prevention and treatment of complex mental health disorders.” We want to thank you for your many decades of extraordinary leadership in developing this field. AH: Dr. Bland, thank you very much. This is one of the highest honors I never expected to receive. Linus was a fantastic person, a major fantastic person-my mentor-and I think he not only changed medicine, he certainly changed my life as well. Thank you very much. JB: Thank you very much. Well deserved and, as I said, there would be no functional medicine if not for Abram Hoffer, Linus Pauling, and Roger Williams. AH: Thank you. JB: This is a really special opportunity, Dr. Hoffer, for me. As you probably know I’ve valued (as have, literally, tens of thousands of practitioners) from your work and your insight. To sit down in your office, here, in Victoria, British Columbia and know that you are still practicing psychiatry at the level of wisdom that you can bring to this discipline is absolutely amazing. It’s something that we all aspire to do in our own professional lives. Not many of us will be as successful in creating a whole new concept as you have created, but certainly your model of “stick-to-it-ness,” and discipline, and dedication to your patients is a model for all of us. I’d like to just start-we can go all the way back, obviously, to before 1957, but 1957 is kind of, for me, where I started my understanding of you by reading your first paper published on niacin and schizophrenia. How would a psychiatrist even be interested in niacin? Dr. Hoffer’s Unique Background and His Collaboration with Dr. Osmond AH: Well, I would say, luckily for me, Jeff, I got my first degree as a PhD, and later on I got my MD. Now, there is a different set up, as you know. You learn to do things differently. A PhD is taught how to think and a doctor is taught how to remember. And having taken my PhD first was a great thing for me to have done it that way. After I was made director of psychiatric research for the province of Saskatchewan in 1950, I had the following qualification: I knew absolutely nothing about psychiatry. Which I think (looking back on it) was superb, because I hadn’t been taught all the things that you could not do. So it was my job to do something about these poor schizophrenic patients. Half of them at our mental hospitals would never get up; none of them would get up. We had no treatment. It was absolutely awful what happened to them. Luckily, at this time, Dr. Humphry Osmond was brought out from England. We were desperately short of doctors to man our mental hospitals in Saskatchewan, and Dr. Osmond came out. I didn’t know he was coming, nor did he know that I was interested in research. When he arrived in the fall of 1951-a very hot, dusty Saskatchewan day-I met him at Dr. McKericker’s offices in Regina, and it turned out he brought with him a very important paper. He and his friend, John Smythies-John Smythies is still alive and living in California-they had done some work with mescaline, the active principal of peyote.21 And they had concluded that the experience induced by mescaline was in many ways similar to the one induced by schizophrenia. Now, this was an interesting observation. It had been made before by another doctor-Dr. Taylor Stocking-some years before, but what he and John Smythies did was even more unique after that. They then looked up the chemical structures of mescaline, which in many ways is similar to adrenaline (it’s what you might call a catecholamine). They concluded that the question with the question: was it possible that in the body of the schizophrenic patient there might be a compound with the properties of mescaline and some similarity in structure to adrenaline? He brought that paper with him. Now he had first presented that idea in England, but they thought it was so absolutely awful that he was told they rejected it. He was so unhappy at this that he told his wife that he would have to get out of England as far as he could. And when he saw in The London Times an ad asking for psychiatrists to come to Saskatchewan, he said to his wife, “That’s far enough. I think I can go there.” So he came there hoping that he could do some research. We met. And after we learned how to understand each other (because he spoke with an English accent and I spoke with a prairie accent), so after we learned to communicate we became very close friends. I looked at the idea very carefully and it made sense. It made so much sense. And so I began (since I was in charge of the research and had time to do the reading and the study and collecting money-all the other stuff you have to do)…so I looked up formulas for all of the known (at that time) hallucinogens, and they all had-and I remember just thinking, one day I’m sitting at my kitchen table and my wife was doing the dishes and I’m sitting at the table, all covered with papers, and I’m drawing down formula, and I said, “Oh my God. There it is.” They were indoles. They were indoles, and you know what that meant. Because there is a law in chemistry that compounds with similar structures tend to have similar properties. I said, “Oh God. There it is.” So we said, “We now have a new formula. The hypothesis will be: look in the body for something which has the properties of mescaline and is similar in structure to adrenaline. It’s got to be an indole.” Now, indoles in the cells (there are many of them found in the body-as you know, they are made in the gut, and not all of them would be that important). We had to narrow it down to indoles that might be derived from adrenaline. And in those days there were only two that we knew about: one was called adrenochrome (which later on we discovered could be converted into adrenolutin), and the other one was (by theory) noradrenochrome. So that gave us the hypothesis. It’s kind of long-winded, but I will speed it up a bit. We didn’t really care about the hypothesis. We wanted a treatment. We didn’t care about the hypothesis. I knew then that most hypotheses turn out to be dead wrong. That’s the way it goes in medicine. We wanted a treatment, and since I had taken my PhD in Minnesota, and my PhD thesis had been on B complex vitamins and wheat, I was familiar with the vitamins and I knew all about pellagra and the diseases it causes. We said to ourselves, “Well, let’s try niacin.” Maybe if we get niacin we can protect the body against the impact of this hallucinogen that we thought was present, but we didn’t know its structure. We didn’t know yet about that. So that’s how we hit upon niacin. And I recall (it’s still vivid), that there was a very middle-aged woman. She was the head stenographer of a large company in Regina and she became paranoid. Right after the war they used to have Christmas parties (maybe they still do). One day after the party this very moral, good woman got the idea that her boss was in love with her. They had never had a relationship. She became so depressed because she thought it was going to break up her marriage. She went into a deep depression and was admitted to our hospital (under someone else). There, she had shock treatment and she was better for six months. Then she went to another Christmas party. Same thing, again. Went into a depression. Came back to the hospital again. Had shock another time. Nothing happened. And then she came under my care. So I said, “Okay. She’s going to be number one. I’m not going to give her anymore shock treatments; she already had three series. She hadn’t responded.” We had no drugs (no tranquilizers). We had barbiturates and we had the narcotics; that’s all we had. And so I started her on niacin. She didn’t like to take it (most people didn’t like to take it-the flushing kind-that’s all we had). But anyway, she took it and she gradually got better. And after about two or three months in hospital, she was okay. Discharge her. A couple of years later, her sister brings her back again. She is getting paranoid one more. What happened? She had stopped taking her niacin. So I called her into the office, and I’m very rough and I yell at her and tell her I’ll do all sorts of terrible things to her, including shock, if she doesn’t go right back onto the vitamins again. She went back onto the niacin. She gets well. And after two years she stops taking it. Another relapse. Same thing: put her back on niacin and she gets well. So now she stays on it and after about five or six years of niacin, she says, “Dr. Hoffer, I’ve been doing so well for four or five years, do you think it is okay for me to go off?” I said, “Okay, let’s try.” And she went off her niacin and she remained well thereafter. She went back to her senior job, looking after thirty stenographers in this stenographic pool. Jeff, when you see one person like that get well, there’s no doubt anymore. I mean, there was some doubt, but there was no evidence for scientific doubt because if one person can do it, surely there are going to be more who respond the same way. And that led us to our first controlled studies that we did (the first double-blind, controlled studies in the history of psychiatry and the first in the United States). In England they had done double-blinds on arthritis, but they had never done any in any other fields, so we were the first. And our double-blind experiments showed that we could double the two-year recovery rate of patients when we gave them niacin or niacinamide compared to placebo controls. So that was basically how we got started, and we published that paper, and we were lucky that we got that published because the editor was a close friend of mine (otherwise he wouldn’t have taken it).22 JB: When I look back and I listen to your story, I’m reminded of so many interesting things. We could call them fortuitous or serendipitous or directed. Here is a person, in your case, that gets a PhD in a chemical field and understands about pellagra and niacin, as it relates to an entirely different field and discipline from that of psychiatry. Then goes to medicine and focuses on psychiatry. And then, because of a creative mind, makes the connection. As I recall, in your paper, you were maybe the first group to talk about the similarity between pellagrous dementia being schizophreniform with schizophrenia. AH: Correct. JB: So that connection is a brilliant leap of abstraction for most people, but for you it was clearly obvious. Early Work Results in Criticism from Colleagues AH: It was so clearly obvious that I didn’t think people ever would object. I thought I would be looked upon as a hero. I said, “Oh my God. The psychiatrists are going to love me now.” By that time I was very popular, anyway, because I was doing a lot of nonsense research that didn’t mean anything. And as long as I published papers that had no meaning-you know what I’m talking about-I was popular. But after we published that first paper that you read, guess what? They said, “Oh my God. That guy’s a heretic!” And at that time, of course, as you know, the tranquilizers came in (in ’55, ’56, ’57), and they were financially so rewarding to the big drug companies that they overwhelmed the whole field. And today psychiatry is owned by the Big Pharma; that’s what has happened to psychiatry today. JB: As you made this discovery, I find it extraordinarily interesting, from an intellectual development perspective, that you took the pre-pellagrous dementia connection to schizophrenia, and then you asked questions about what other genetic metabolism disorders associated with nutrition can we think about that could have central nervous system effects (like hyperhomocysteinemia). And then you talked about B6 and B12 and folate, so your model got extended and seemed to be able to be mapped against many of these conditions. Establishing the American Schizophrenia Association AH: That’s true, and that wasn’t just by my doing. We were able to assemble…we organized the American Schizophrenia Association many years ago, and we were able to enlist the interest of a bunch of very good American psychiatrists (Dr. Ted Robie from New Jersey, Alan Koch from New York), a whole bunch of very brilliant psychiatrists. And we were wide open at that time. Since I was the Director of Research I had lots of time. I made myself everything-I was Chairman, I was this, I was that. We would meet twice a year as a committee on research of the American Schizophrenia Association. We were wide open. Alan Koch would say, “Hey guys, I had a patient that wasn’t talking. He was mute.” And he says, “I put him on vitamin B6 and it was an amazing change.” So we all said, “Hey, isn’t that amazing?” instead of saying, “Forget that nonsense. You can’t do that.” We said, “Isn’t that interesting?” So at the next meeting we would someone would come [and say], “I tried out what Koch said, and hey guys, it works.” We had these informal meetings and this was a fantastic amount of information, and that’s when we brought Linus Pauling in. I remember we had our meeting in Vancouver at the home of Dr. Ross McLean. There I am Chairman of the meeting, and as the Chairman you’re not supposed to do anything (you are supposed to just sit there and be quiet and make sure things are running properly). So I’m listening to all my colleagues (there were 10 of us) reading their fantastic papers. They are talking about folic acid, they are talking about B6, talking about zinc. Carl Pfeiffer-everyone-they are all giving us some amazing information. So I said to myself, “Isn’t it fantastic? Here is this very important information and no one hears about it. We have to publish it.” So David Hawkins is sitting on my right, and he’s a good friend of mine. “David,” I said (to the group), “we have to publish a book.” So they stop and since I’m the chairman they have to listen to me (that’s the power of the chair). I said, “David, you are going to be the editor.” And he gulped. He said, “What?!” I said, “Don’t worry, we’ll help you. Each one of us will submit a chapter.” So eventually David said, “Okay, he thought he would do it.” So after awhile we were starting to organize this book. It occurred to one of us (I don’t know who it was-it might have been David) that maybe we could ask Linus Pauling to become an editor. I am talking about the book Orthomolecular Psychiatry.23 So David-not I-I think David wrote to Pauling and asked him. And Pauling said yes, he would, on one condition. The condition was that he would have to approve of every paper that appeared in it. So we, of course, said, “Fantastic!” And that’s how that book came out. Because we had that spirit of cooperation, we were able to examine new ideas so quickly we didn’t have to wait for these terribly slow university-sponsored….If you have an idea today in psychiatry forget it. By the time you’re ready to go forward two years later you will have lost interest in it. We didn’t have those handicaps in those days towards doing research because we knew the basic rule of medicine: First, do no harm. And you cannot harm your patients by giving them vitamins. It was fantastic. Collaborating with Dr. Linus Pauling JB: Now you have talked an epic chapter that I think propelled this whole model that you birthed forward, and that was the 1968 publication in Science magazine authored by Pauling of the article “Orthomolecular Psychiatry.” That seemed to put the discipline up on the big board. Did that change the visibility for you or what you had been doing? AH: Yes, it did. It gave it prestige. It also gave us a lot of work. I remember what happened. I had not met Linus Pauling before then. Apparently he had been getting letters from a large number of Americans who had heard about the vitamin approach and were putting themselves on it and were getting some response. So he was getting more interested. And it fitted in with his own basic concept of molecular medicine. I think this had been gestating in his mind for some time. So one day I get a letter from Linus Pauling. “Dear Dr. Hoffer,” he said, “I am enclosing a manuscript which I propose to send to Science. Would you please go over it to make sure you are properly quoted?” Now isn’t that amazing? JB: Fantastic. AH: Can you think of any other scientist that would do that? He was so honest. And so I read it, and of course Linus Pauling never made any mistakes. I read it carefully. He quoted us. He was very fair and very honest (what he wrote about this). I wrote back and said, “It’s absolutely great.” Then he came along with the word. At that time, we had been playing with the word “Megavitamin Therapy,” which I didn’t really like that much because there is no such thing as a megavitamin; it just doesn’t exist. When he published this paper I said, “That’s the answer. This term of Linus Pauling’s covers almost everything that we are going to do.” Since then I haven’t thought of anything better than the term “orthomolecular.” But even amongst my colleagues they became very upset because they were getting used to the term “megavitamin therapy.” We had our own conservatives, as well as liberals, in our own group. So I took on a major role. I said, “I am going to defend the word ‘orthomolecular’ until it kills me. It is going to become ‘the’ word.” And since, again, I was Chairman and I had some prestige, I was able to gradually force the word in. Even with the journal, Orthomolecular Medicine, for many years people wanted me to change the word because “orthomolecular” is very unpopular. I said, “So what? Of course it is unpopular, but we are going to change that.” And thank God, Jeff, we are actually changing. The word is becoming well-known, popular in Europe, in Brazil, many other places. And recently (in the past few weeks) we have had people here from Portugal, people here from all over the place who are, in fact, so determined to go back home and start up with this word. Now it’s a temporary word. It’s a temporary word I think because one day when all of medicine is orthomolecular we won’t need the term. We will drop the term “orthomolecular” and we’ll say this is what modern medicine is and anyone who doesn’t practice it will be subject to malpractice suits. JB: You mentioned this book, and it strikes-for me-such an important chapter in my life, because as a young assistant professor in 1970 I was searching for models and mentors outside my own department and trying to carve out my identity as a young, new, emerging academic researcher, I happened on to that book in…I think it was probably ’71 or ’72 (in that early 1970s period) and it just was like finding the Rosetta Stone for me. When I opened that book, it was so powerful. Each chapter was like a treasure. You had assembled such a remarkable group of authors and thinkers. AH: But don’t forget, we also had the master read each paper, and he was so kind. I remember, in one paper I sent to him-a manuscript…I like to write content. I think a paper (its content) is important. I’m a bit more sloppy when it comes it comes to punctuation and style. I just don’t have enough energy to do that. In one of my papers I think I left out a comma. And Linus is too polite to tell me, “You forgot to put that comma in,” so he sent me a letter and he said, “Dear Abram,” he said, “I think your secretary forgot to put a common in (in this particular slot).” Isn’t that amazing? JB: That’s so Dr. Pauling. The two of you share something very common that I think great people have, and that’s humility and grace. I think you both have that. AH: He had that. He was like a racehorse that never lost a race. And I knew that when Linus joined us, I said to all my friends, “The battle is over. We won.” The world may not know it for a long time, but we knew we had won the battle because his theories, even today, are so sound. I’m sure you know. And the sad thing is that if the drug companies had accepted his view, they wouldn’t have wasted billions and billions of dollars finding toxic drugs that do more harm than good. It has been a terrible waste. The drug industry has been a terrible waste. I was proud to be a psychiatrist. Very proud. I started as a standard psychiatrist; I got my specialty in psychiatry. I became well-known in that field. I was one of the five top directors of psychiatric research in the United States and Canada. We were the first to bring Haldol in; I remember I was one of that first study group to do Haldol. I knew drugs. I knew drugs. I was an MD. And I was proud of it. Now, guess what? Now, I have turned against it. I now have concluded (and since I am no longer practicing as a doctor I can talk freely because they can’t take away my license if I don’t practice anymore), if every psychiatrist were to go to Mars, they would be worse off and we would be better off. That’s my opinion. JB: When we look at the development of this whole wonderful rich model, the concept that Dr. Pauling proposes in that paper on orthomolecular psychiatry in Science magazine was a concept that was fairly sophisticated for the average doctor because it talks about mass action and kinetic rate constants, and it talked about enzyme binding to coenzymes. These are things that the average doc doesn’t think that much about, but some (now) 30 years later, Dr. Bruce Ames at Berkeley comes back with this marvelous paper that kind of says, “Guys, relook at this. This is all right.” AH: That’s right. In his last paper he maintains that most of the conditions, in fact, are a result of some metabolic fault of this type. Now, Harry Foster and I wrote that book, and I stole Linus Pauling’s title (I hope he forgives me for a bit of plagiarism, but I thought it was such a nice title I would honor him by using it). In this book we maintain, as a result of very careful studies, that half the population of North America would benefit by taking B3, either niacin or niacinamide.24 It is a very, very important nutrient. They are all important, but this one is of particular import. Linus Pauling suggested that we lost the ability to convert sugar into vitamin C-what is it…25 or 50 billion years ago-that this was advantageous as long as our diet contained enough vitamin C. I think the same thing is happening with B3 and tryptophan. There was a major change in 1800. The first description clinically of schizophrenia was around 1800. Before then it was rare. Around 1800 it was a major change in that the millers learned how to make white flour. On my PhD I was a flour chemist; I did analyses on flour. So they learned how to make white flour, which had lost all of its B vitamins, and I think it was after that that we gradually began to see an increase in the incidence of schizophrenia. It keeps on going up. David Horrobin, a good friend of mine, in his book Adam and Eve (or something), maintains that the genes for schizophrenia (I think there is more than one-I think there are a whole bunch of them) are gradually sweeping into the population.25 And my prediction is that if we all are still here a million years from today, we will all have the genes and no one will be sick. Because if we are intelligent enough we will make sure that every human gets the right quantities of B vitamins (not just niacin-all the B vitamins). My prediction is that almost half of all the human illnesses will vanish; they will vanish within 10 years. JB: This sounds very consistent, also, with Dr. Roger Williams’ concept of genetotrophic disease. AH: Absolutely. JB: You were all birthed in the same period of time-you, Dr. Pauling, and Dr.Williams-in the 40s and coming into the 50s was when this concept really emerged beautifully. AH: Yes. I knew Roger Williams. He was a great guy. Unfortunately he was deaf and blind (almost) at the end of his life, but he was great. I loved his work. In fact, I refer to his concept frequently. I have a friend who was the world’s greatest pianist, Anton Kuerti. He is a Canadian. Beautiful pianist. You remember Roger Williams made the comparison of an orchestra. In other words, each member of the orchestra plays a vital role, otherwise you don’t have a symphony if you don’t have everyone playing from the same book with the same conductor and the same music-you have a cacophony, you don’t have a symphony. I tell this story, which is true. In Boston, a few months ago, Anton Kuerti, who is the world’s greatest pianist, was at a concert where his son was the conductor. That evening they were having a show and the pianist who was supposed to perform couldn’t make it. So without any notice he called upon his dad to come forward and play and they had a fantastic concert. So this was reported in The Economist. I thought that was absolutely great. I talk about this and I say that according to Linus Pauling, no nutrient can be substituted by any xenobiotic-if you need niacin, no drug is going to replace it; you have to give that. So I say it is like suppose in a concert the first violinist dies (or faints, or something) and the conductor decides the show much go on so he invites the drummer to play in his place. I think you aren’t going to have a symphony. Unfortunately every nutrient is like Anton Kuerti: every nutrient has to play its own role and you cannot replace it. And that is my major complaint about the drug: they are trying hard-because they can’t patent vitamins-to find a drug that will replace niacin. My friends and I discovered it lowered cholesterol levels in 1954. You can’t patent niacin. If I could have taken a patent on it I’d be a billionaire today, because drug companies have spent billions trying to find a compound that has the same good beneficial properties of niacin without any of the terrible side effects that the statins have. It’s not available. It is the combination of Roger Williams and Linus Pauling that I think were two of the main contributors to this whole field, and I have depended upon them really hugely. JB: What you are teaching all of us, as we are hearing your story, is that all great new paradigms start with observation. AH: Absolutely. JB: And that being a good observer and being not afraid of your observation, and saying, “This is something really remarkable that I need to follow-up on.” Not just discounting it as an aberration. Strong Opinions about Double-Blind Trials AH: Jeff, you’re totally right. I absolutely agree with you. The only honest scientists are good observers and thinkers. The double-blinds don’t tell you anything. Double-blinds are a fraud. I think they should be totally made illegal. They shouldn’t permit them at all. You have to have good, honest (I should have said honest) [people] who don’t have any conflict of interest with the drug companies. Because once you are working for a drug company, honesty flies out the window. That’s harsh, but I am absolutely convinced that it is true. And so does the literature. JB: Let’s start back at the turn of the last century for a moment, because I would like to trace the impact of your intellectual development on medicine from talking, first, about Sir Archibald Garrod, who was credited as the founding person for the field of genetic metabolism diseases of infancy. AH: Great work. Fantastic work. JB: That, then, was kind of leading people to the belief that we had these inborn errors of metabolism that created Wilson’s, Gaucher’s, Fabry’s, this whole constellation…methylmalonic acidurias and Hartnup’s disease, and so forth. And then along comes Abram Hoffer and Humphry Osmond and for the first time a model of biological psychiatry is born, which takes these constructs that there are these molecular processes going on in the body that have genetic relationships that are one-size-not-fitting all. That there is a differentiation. AH: That’s right. JB: What you birthed, it seems to me, is the biological psychiatric revolution from the observations you made. But then it appears to me (and this is my question) that biological psychiatry, as you birthed it, got perverted into becoming a new form of pharmacology with new-to-nature molecules. AH: That’s right. JB: How did that happen? How did a good idea get transmuted? AH: The idea that Sir Archibald Garrod developed…that was a fantastic idea. And the early pioneers in the use of vitamins were of that type. In fact, almost all the papers dealing with vitamins published until 1950 were positive. It is amazing the amount of literature that describes the many virtues of these vitamins. But they were tied down to what I call the “vitamins-as-prevention” paradigm, which meant that you only needed vitamins for a very few classical deficiency diseases like scurvy and pellagra and so on. And they couldn’t break this concept into saying, “Maybe we should try higher dosages.” The early pioneers-the early pellagrologists-who did such great classical work in the United States, they were using all sorts of doses of vitamins and tried getting good results. So this was the beginning of breaking down the concept of the old paradigm. I’ve known some of my friends who lost their license to practice because they gave their patients vitamin C. It sounds unbelievable. It is laughable. It has happened. So we try to move into the new paradigm, which says, “Look upon vitamins as treatment potential, they way you would a drug. If a patient has a severe type of pneumonia, you’re not going to give him 10,000 units of penicillin a day when he needs 10 million.” What’s happening today in the literature is that all these negative papers, if you read them carefully, they’ll make a claim that no one ever made before: they’ll claim, “Vitamin E prevents heart disease.” Well, whoever claimed that? I don’t know of any who have said that. What they have said is that if you do have heart disease you can get a lot of help by taking enough vitamin E. So having made a spurious claim, they then go ahead and do a study, giving their patients 50 units of vitamin E a day. They spend millions on this stupid study, and then they come up with the right conclusion: “We were right. It doesn’t help.” This is what has been happening in the whole field of nutrition. The whole nutritional literature is unbelievable. There is a very famous Greek professor of philosophy and mathematics, and he is very blunt, like I am, and he says 80 percent of the stuff published in medical journals is wrong. Eighty percent of the stuff in medical journals is wrong. I think he’s underestimating it. I think the most interesting parts of today’s medical journals are the ads because they have beautiful pictures and they are well written and they are full of lies…You know, the medical ads are superb for fooling the public. The content-not that interesting because it is written by the drug companies, mostly. JB: So we have talked now about extraordinary successes and contributions and things you are very proud of. Are there things that you look back and you say, “These are things I wish I would have done differently?” AH: I wish they would have believed me. They main thing I wondered is, “Why didn’t they believe me? Why didn’t they?” JB: Why do you think they didn’t? AH: Oh, I know now why. You have just gone through a very exciting, interesting election campaign in the United States. You have a president elect who, for the first time, is black. He spent 600 million dollars (at least) on the campaign. He apparently had one of the most promising campaigns ever run in the United States. And all he had to do is to persuade a few people that they could elect him if he was black. Now if it takes that much money to change the attitude, you can imagine how much money it is going to take to change the medical attitude of those who are already firmly convinced they have the answers. The answer the medical profession has is more drugs, more drugs. They are still looking for the Holy Grail that they will never, ever find. That’s the answer. The only way we can deal with that is to do what you are doing: education, education, and education. We have to demand more and more. Teach the doctors. If you can teach 30,000 doctors, and if 10 percent of them are convinced, you have made a major contribution. And it is happening. JB: That’s a very optimistic note. Now, with your very senior perspective and seeing how things travel through time and space in the evolution of the profession, what’s your view of medicine as we look forward to the future? Dr. Hoffer, Age 90, Discusses the Future of Medicine AH: I don’t complain about all of medicine. I think surgery is superb. If I were in a car accident I would want to go to a modern surgeon; they do a beautiful job. I think that neurology is just about the same as psychiatry. The worst branches of medicine are neurology, internal medicine, pediatrics, and some of the others. I think that the surgeons are the ones who are really the tops in the field. Maybe that’s because they get paid the most, I don’t know. I’m hopeful that this will change. Also, we have to widen the people who are allowed to treat. We have to bring in the naturopaths. We have to bring in all sorts of therapists. We have to allow psychologists to practice orthomolecular. And also we have to give patients freedom. We don’t have enough freedom-you in the states and we in Canada. We don’t have enough freedom to select our doctors. For example, in Canada I had a young schizophrenic male, who was both on drugs, which he got free from the government, and he was on niacin that he would have to buy himself. He was doing well. And then he came to me and he said, “Dr. Hoffer, I can’t afford to buy the niacin.” It was five dollars a month. Can’t afford it. He smoked. I said, “Why don’t you quit smoking?” “No. I couldn’t quit smoking.” He could afford that. Because the government wouldn’t pay for the five dollars a month, he had to stop taking the niacin, and he remained sick forever. That’s what is happening to our reasoning. JB: I believe that what you are speaking to is more than a medical paradigm. It is a thought process as to how we, as individuals, take responsibility, understand something about our bodies, and then elect to do something as advocates for our own health, and taking charge of that. And medicine is there to help educate and support patients, but in the end, there has to be some responsibility, doesn’t there, with the patient taking charge? AH: I’m absolutely convinced of that. I think that the Americans made a major mistake when they changed the FDA Act under Jack Kennedy. You may remember that before that, the only policy was to check on the toxicity, and if they could prove that the drug was non-toxic they said, “That’s your problem hereafter.” I think that wasn’t a bad policy. But when they gave the FDA the role of ruling on the efficacy of drugs, it developed an enormous problem. Imagine yourself: you are the head of the FDA and a drug company and says, “We have this application” and they’ll send you a boxcar full of data that you have to go over. And you have to decide, “Shall I release it or not?” And if you release it and three years later it turns out you have killed 100,000 people, you are not going to be very happy about that. So they developed a system which took away all guilt. They began to use the double-blind controlled study as the arbiter of whether anything is good or not, and if the p value is at .05, “Okay, well it’s not our fault. That’s what the P value said.” There is a drug that is now used and it’s very common for Alzheimer’s. I understand that the company that produced that, the first 11 or 12 studies they submitted to the FDA were all negative. The 13th or 14th were positive, and according to FDA rules, if you get one positive out of ten, they’ll still approve it. So here we have this drug, which I know well doesn’t do anything, except make the drug companies rich. We have too much of that. I don’t know how we can do that. We have to change the patent system. If we had allowed vitamins to be patented, different situation. JB: We are at a very interesting juncture, I think, in human history. There are these epic points in human history-inflection points. We have kind of assumed that cultural history grows kind of linearly, but it doesn’t. It grows in fits and starts and we’re now in one of those really interesting exponential change periods. As we see this change occur, the leverage of wisdom that comes from the past will become very important for determining our future. If a doctor was starting out today and you were to meet with them, what guidance would you give them? AH: Before I would accept them into medicine, I would want them to take a course in the history of medicine. The history of medicine and the history of conflict. Most doctors don’t know that. For example, anesthesia was opposed because the male doctors knew that women had to suffer pain. God said that when you had to have a baby you had to suffer pain. So therefore, you could not use it to relieve suffering. Except for Queen Victoria, who thought she was probably God in her own right, so she accepted ether, and that broke the log jam. Once she used ether for having one of her babies, pretty soon doctors were clamoring to claim they had discovered it first. She broke the log jam. Did you know that the stethoscope was opposed for a long time? You knew about that. And the reason was that it was indecent to listen to a female chest. You were not allowed to put your ear up against a female chest. Why not? Male doctors weren’t allowed to do that, so they used rolled up paper. And then they started the stethoscope and that took a long time to bring in. So the history of medicine tells us that it takes anywhere between 40 and 60 years for a new paradigm to get established. So I would want them all to take a course in the history of medicine-a really good course in the history of medicine. I would want them to take a course in the doctor-patient relationship-how important it is that you be a human dealing with a human of equal value. You are not talking down to a servant or to a slave. In the medical profession, they think they are gods and sitting in front of them are their poor slaves. The slave says, “Doc, I have a headache.” “Great. Take this pill. Out you go. Don’t bother me anymore.” How are we going to change that? I would insist they take courses in sexuality, which they don’t do now. Most doctors know nothing about sex except that of their own experiences. We’d have to prepare them by actually spending a year or two in preparation for what they would take as medicine. And then I would like to see two streams into medicine. Medicine, after all, is a technology. It is not a science; it is a technology. We need it. We need superb technologists. That’s why the surgeons are so great. Surgeons aren’t scientists, but they are excellent technologists. They know exactly what to do and how fast to do it. They know what to do. So we need to have two streams: one stream goes into a technical school, which gives you an MD but you don’t do any basic research (or if you do, you switch), then we would have the second one where you would go on to a university to take a PhD in medicine, which would then teach you the elements of honest research and train you to look into new ideas whenever they develop. We have to completely change the whole system of medicine. We have to take from the drug companies any influence they have. We have to prevent them from giving any money to the universities (that’s going to be a problem). We have to force the governments to become more responsible and to take over the burden that they really should be caring (because they’ll save so much money if they do it properly). These are the things I think we’d have to do. We have to reorganize the whole system of medical education. Won’t happen in my time. JB: It is fascinating. In the United States, now, less than ten percent of the incoming students are interesting in doing any what is traditionally called family practice. They are all being pulled into specialty medicine because that’s where the money is to be made. AH: That’s right. JB: And so we’re losing a lot of the things that you’re talking about: the skill of listening to patients, the skill of being there (present) to understand a patient’s complex etiology of their condition. Some of the things that are the most profound in medicine, you’re saying, are the simplest things if they are properly applied. AH: That’s right. I can’t stop talking about the things I’ve seen. I remember one patient that I had to admit to hospital. She was on 5 or 6 or 12 medications. I said, “Hey, nothing. Withdraw everything. Take her off everything.” A week later she’s feeling great. I had a woman come here with a printout list of 28 drugs she was taking. She’s 75. She’s on 28 different drugs, and she says to me (seriously), “Doctor Hoffer, I have to take every one of them.” It puts me in a terrible position. She’s already taking 28, are you going to add 3 or 4 more to this big list? We are overmedicating. We are killing. Take it from me, Jeff, this is a prediction. We are heading for a major catastrophe. Imagine all of the hundreds of thousands of schizophrenic patients who have been on drugs 10, 15, 20 years. It’s the same as the HIV virus (they’ve been on these retroviral drugs). Everyone claims, “Isn’t that fantastic? They don’t die.” Well, they don’t die as fast. Many wish they would. They are not healthy. They are very, very sick people. They cannot perform, they are mostly sick, they have to take huge amounts of drugs. They get all sorts of illnesses, like tuberculosis, lesions, cancer, everything. We are heading into a very sick century. If China really wants to beat the Americans, they should forbid any Chinese from taking any American drugs. They will remain as healthy or sick as they are now, which Linus Pauling called “a moderate state of ill health,” and the Americans and Canadians…we’ll go downhill. Down, down, down. We’re going to run out of people who can work because there will be too many sick. Our major industry is going to be nursing and doctors. We are creating a society where we need more doctors, more nurses, more caretakers, more this, more that. We will spend all of our money just simply looking after ourselves. Who is going to build our highways? Who is going to make our equipment? Maybe that’s why we’re sending everything offshore, because we don’t have enough people left behind to do these things. We are creating a very sick society. In Closing: Dr. Bland’s Tribute to Dr. Pauling and Dr. Hoffer and his Thoughts on the Future I hope that you were as moved as I was to hear Dr. Hoffer, and also to put it into the context of a 20-year previous interview with Dr. Linus Pauling. Just to have those voices resonating in our ears and influencing our nervous systems and patterning our thinking is like putting a virus of hope and goodness into our system of learning. What an amazing two contributors they are to the paradigm of what we have been talking about. You know, I reminded myself as I listened to these interviews that I was very fortunate, also, to interview Dr. Roger Williams. I think it is really fascinating to think through how these three individuals, who were all living at the same time, gave birth to not only an industry, but to a field of medicine that will gain traction as we move into the 21 st century further and becomes a systems biology functional approach towards health care. Really epic kinds of landmark discussions. Let me, if I can, say a few things about Dr. Hoffer’s contributions, for those of you who might want a little additional information. Dr. Hoffer has two sons, one of whom is a research professor of medicine at McGill University, at the Lady Davis Institute for Medical Research and the Jewish General Hospital in Montreal, Quebec, Canada. He is also an MD, PhD; this is Leonard John Hoffer. I was very intrigued to learn, showing coincidence in life, that Dr. John Hoffer was a doctoral student at the same time that our own Dr. Bob Lerman was getting his PhD in nutrition at MIT and so they shared the same department and the same research professor as medical doctors going through their PhD programs in nutrition. Dr. Lerman is one of our chief investigators and our clinical directors in our functional medicine clinical research center. It is kind of, again, showing the consanguinity of knowledge and interaction in kind of how ideas spread from individuals who share intellectual domains and sometimes even physical domains and how these contacts can create spreading effects in terms of the stickiness of new ideas. Dr. Hoffer, who obviously grew up in the environment with his father (you can only imagine what was talked about around the dinner table), ultimately moved on to become a psychiatrist on his own and also a PhD in sciences. He has been studying many, many things from a basic and clinical science perspective, one of which is to revisit these vitamin therapy and schizophrenia discoveries that his father had made. In a recent review paper that he authored in the Journal of Psychiatry and Related Sciences (this is in 2008), he talks about the fact that “it is dismaying that well into the 21st century, schizophrenia remains a highly prevalent, devastating, and poorly understood disease for which the only accepted therapy is non-specific antipsychotic and antiseizure medication.”26 He goes on to say that, “Fresh approaches, even unconventional ones, should be welcomed for study by the psychiatric community if they are biologically plausible and non-toxic.” In a review article-this article in 2008-he summarizes the evidence that certain vitamin insufficiencies can worsen the symptoms of schizophrenia, and the evidence that at doses of certain vitamins could improve the core metabolic abnormalities that predispose some people to develop it. It rounds the history, in this article, of the controversial vitamin-based therapy that his father and Humphry Osmond discovered for schizophrenia, called orthomolecular psychiatry, and the collaborative work with Dr. Linus Pauling that you heard Dr. Abram Hoffer talk about in his interview. He ultimately concludes, in this review article, advocating a process for discovering promising new schizophrenia therapies that involve small, carefully conducted clinical trials of nutrient combinations in appropriately selected patients. This is, again, part of the evolving frontier of this paradigm that we have been describing to look at nutrient insufficiencies from an orthomolecular genetotrophic disease perspective, and to modulate them in the individual needs (personalized nutrition or personalized medicine, in this case) to improve their function. It is currently popular to regard schizophrenia as a multiple hit, neurodevelopmental disorder, but equally plausible is the older hypothesis of a toxic psychosis triggered by an abnormal endogenous metabolite. Organic brain disorders, including indistinguishable forms of schizophrenia, may be induced by certain drugs and by neurological, metabolic, and inflammatory and infectious diseases. Such disorders account for approximately five percent of cases initially diagnosed as first episode schizophrenia by expert psychiatrists. We start thinking that maybe not all forms of schizophrenia come from nutrient insufficiencies because it is a heterogeneous diagnosis, but if we could pick out those that are responsive to nutrient insufficiencies we might be able to get very marked clinical improvement in some percentage. Who knows if that percentage is 5, 10, or 20 percent or whatever it might be based upon a more personalized approach that is dependent upon proper assessment, so this has to go back to proper biochemical assessment: asking the right questions to get the right answers. If you don’t ask the right questions, you never get the answers. What kind of assessment do we do for looking at general nutritional status and biochemical individual needs and this whole genetotrophic origin in the soil that Archibald Garrod talked about at the turn of the 19th to the 20th century? With that in mind, it leads us into this concept that, as Dr. Abram Hoffer pointed out, the signs of schizophrenia look very similar in presentation to part of the triad of presenting symptoms of pellagra: dermatitis, diarrhea, and dementia. These dementia-like affects resemble very closely some of the things that are associated with schizophreniform presentations. As we get into this whole metabolite question and we start looking at genetic metabolism diseases associated with nutrient need, like cystemia or pellagrous dementia or things that are related to beriberi, or things that are related to issues of various megaloblastic anemias, we see that they all have kind of the schizophreniform affects that are presented in the individuals, suggesting metabolite toxicity, to use a term loosely, that has been seen as a consequence of insufficiency of specific nutrients needed by the genetic uniqueness of that individual. So we not only have niacin (vitamin B3), but pyridoxine (B6), and evidence on folic acid, and evidence on ascorbic acid. There’s good data on all of these having influences on metabolic function in genetically unique individuals that can lower the load of secondary toxic metabolites. So I think we are starting to witness maybe a revisiting of this now 50-year-old model that was presented by Dr. Hoffer. He talked about it in his interview, and I find it very, very interesting, because if you look at Dr. Hoffer’s original papers, what you will find that these papers that appeared in The Lancet really discussed this metabolite hypothesis in a very, very, what I would consider precise way, given the knowledge we had about physiological chemistry in the middle 20th century. We have kind of dismissed these out of hand for reasons that are not easily understandable, and we’ve kind of from that, then, just said, “Well, we need to find drugs to block the function or to arrest a certain outcome and to treat a symptom without looking deeper at where the cause of these conditions that we call schizophrenia might originate.” I think this paper that appeared in The Lancet, again, in the same period of time (in the early 50s and 1960s)-this actually was titled “Massive Niacin Treatment in Schizophrenia: Review of a 9-Year Study.”27 This was Abram Hoffer and Humphry Osmond in The Lancet, 1962. It’s a classic. They go on to say (as Dr. Hoffer in his interview pointed out), their interest in niacin began at the end of 1951 when exploring ideas developed with Dr. John Smythies. By the way, that’s the same John Smythies that you probably know is credited with having the observation that neural tube defects are found in babies born by mothers who are suffering from folic acid insufficiency. It took some 50 years from the discovery of Smythies of this association between B vitamin deficiencies and encephalopathy and neural tube defects (the most common birth defects) before that was generally accepted. In these discussions among Humphry Osmond, Abram Hoffer, and John Smythies was born this niacin concept. He goes on to say, “We thought that schizophrenia might be caused by a disorder of adrenaline metabolism in which the body produced a substance with metabolic toxicity that induced psychological effects that were similar to that of, say, some of the psychotrophic drugs, like mescaline or D-lysergic acid diethylamide (LSD). These ideas have since been called the adrenaline or adrenochrome metabolite theory of schizophrenia and it is a special example of that particular theory. I think that these conceptual frameworks, which maybe were dismissed early on when they were first presented and published are now being revisited in the age of metabolic medicine and the age of network and systems biology. That takes us to a further reflection on Dr. Pauling’s work because what we really said is that maybe there is something about general function that is related to immune defense, and to cell repair, and cell replication that has to do with individual nutritional status. This has its roots in the concept of orthomolecular medicine. I found a very interesting kind of example of this that appeared in the journal Neurology in 2008 in which the investigators-this is a group from the VA Medical Center in Oklahoma City-reported that intervening, post-stroke, in patients with an intensive nutritional supplement program significantly improved their outcomes.28 They wrote that intensive nutritional supplementation using readily available commercial preparations was found to improve motor recovery in previously undernourished patients receiving intensive in-patient rehabilitation after stroke, and therefore an induced effect (in this case, a stroke event) may enhance the level of need of specific nutrients for improving outcome in a post-stroke situation. Again, it’s a whole series of variables: genetic uniqueness coupled with environmental factors give rise to the individual need for specific nutrients, and one size doesn’t fit all, and it’s not just on the back of a cereal box that you learn about what the level of nutrients are for optimal function of that individual. I think that’s a very interesting kind conceptual framework as it pertains to this emerging theme that both Dr. Pauling and Dr. Hoffer talked about. The vitamin C and cancer story was a fully engaged discussion when I was at the Pauling Institute as a Research Scientist back in the early 1980s (at the time I interviewed Dr. Pauling). There was very strong criticism of the concept of vitamin C and cancer (the Ewan Cameron and Linus Pauling concept). In fact, Dr. Moertel, who was one of the principals in oncology at the Mayo Clinic, made a very big story about debunking (supposedly) the vitamin C/cancer connection, but now we come to the more recent period of the 21stcentury and we see this magnificent bit of work and paper that was authored by Dr. Baltz Frye and Steve Lawson, from the Linus Pauling Institute at Oregon State University that appeared in the Proceedings of the National Academy of Sciences in 2008.29 In this paper they write about vitamin C and cancer being revisited in light of the more recent work that has been published on vitamin C and cancer by Chen, et al, titled “Pharmacological Doses of Ascorbate Act as a Pro-oxidant and Decrease Growth of Aggressive Tumor Xenographs in Animals.”30 This was another Proceedings of the National Academies of Science paper from 2008. There is also some extraordinary work that’s been done at the NIH looking at the graded doses of vitamin C in humans as it pertains to individual needs, showing the diversity of need using in situ kinetics. This is Mark Levine’s work. He is an endocrinologist at NIH who has found that the level of need of vitamin C from person to person is far greater than we thought. And then we get into therapeutic doses of vitamin C, where we are actually using vitamin C intravenously as a potential selective pro-oxidant to induce, in cells that have been transformed that have poor antioxidant defense mechanism, selective alteration in their reactive oxygen species production, causing internal cell suicide to occur (apoptosis). What we are starting to see is that millimolar concentrations of extracellular vitamin C kill cancer cells in these xenographed animals but not normal cells, once again reopening what Dr. Pauling had talked about with Dr. Cameron back in the 1970s and 1980s. Today, new methods for understanding of the role that particular augmented levels of certain nutrients (in this case, vitamin C) might have as therapeutic agents-safe, non-toxic therapeutic agents-are being explored. I think the story is not over. It is continuing to be revisited, and what Dr. Pauling talked about in this interview in 1982 is still emerging to be seen today. A very nice paper authored by Dr. Leonard John Hoffer and Dr. Mark Levine-this was a Phase I clinical trial of IV ascorbic acid in advanced malignancy (a human intervention trial)-was published in the Annals of Oncology in 2008.31 This group of investigators reported that high doses of intravenous vitamin C was well tolerated. They were unable to demonstrate, in this phase I study, anti-cancer activity when administered to patients with previously treated advanced malignancies, however what they say is that there might be benefit synergistic administration of vitamin C, intravenously, with other cytoxic or redox-active molecules to enhance the cytotoxicity in a selective way. Work is still ongoing. We are still learning more about this story. We are still learning about the different nutritional needs of the individual as determined by their genetics and therapeutic nutrition-what we call nutritional pharmacology (enhanced levels of specific nutrients beyond that that you would use for normal maintenance for therapeutic application in disease states or environmentally altered physiology). We still have a lot of confusion in the epidemiological literature about how important some of these antioxidant vitamins are in helping to protect function and enhance health over the long term and reduce the risk of disease. We have papers like one that appeared in the Journal of the American Medical Association in 2008 titled “Vitamin E and C in the Prevention of Cardiovascular Disease in Men.”32 In this large, long-term trial of male physicians, it was reported that neither vitamin E or C supplementation reduced the risk of major cardiovascular events and the data do provide not support for the use of these supplements for the prevention of cardiovascular disease. However, again, we have to kind of ask the question: Is there data lost in the mass? Should we be stratifying the data? Should we be looking at those cohorts that are most genetically unique and susceptible? Should we be screening for biomarkers that are more likely to be responsive so we don’t lose them in the mass of the non-responders because we didn’t tease out those that are most uniquely at risk? The same thing can hold true for sodium restriction and hypertension, or cholesterol/dietary restrictions and hypercholesterolemia. There are a myriad of examples of individuals who have specifically higher risk to certain things as a consequence of their environmental choices versus the body politic. One can even use gluten as an example. Not everybody has gluten sensitivity, but for those individuals who do have gluten intolerance, the food which may be good for one becomes the poison for another. They may be lost in the mass of a large study, but this is very real for those people who end up with celiac sprue and who may be, statistically, an aberration in a large study. For them, eating wheat is very dangerous. By the same token, we might say that concept could be applied to things like the roles various vitamin supplements and nutrient supplements have on modulation of relative risk in individuals with unique susceptibility. Their data points get lost in the mass of those that are non-responders because not everybody needs the same thing, and we make decisions from the law of averages. Dr. Roger Williams said something very powerful about this. He said, “Nutrition is for real people. Statistical humans are of little interest.” Yet as we look at the history of the way we learn about therapeutic applications of various agents, we recognize that we often apply them to 70 kilogram mythical humans (the statistical average). We regress to the mean. Sometimes you can regress to the mean and lose all your value of specificity. I believe that in this age of personalization and genomics, what we are going to recognize is that we lost a lot of very important data by just throwing them out as the law of the averages, losing them in the noise. This might even be true for autism and the relationship of autistic disorders to MMR vaccination. It may be that in the gross level of children there is very low penetrance of the susceptibility to MMR being the etiological trigger for autism, but in a small percentage of individual children, this may be a real trigger for immunological activation, and as a consequence for them, they end up with a neurological risk that is lost in the average of means. I suggest that we are moving from this “massification” concept of medicine to a personalization concept of medicine. The individual has primacy. The statistical human is of lower interest. It’s much easier to do statistical studies and to group everybody together. That makes it fairly simple. It is much more complicated when you start stratifying and looking at differential effects, and individualization, and biochemical individuality, and orthomolecular and systems biology. That’s certainly a more complicated situation. If we have squeezed out all of the value-the low-hanging fruit, so to speak-of the single agent against single outcome, maybe it is time (if we are really going to rectangularize the survival curve for compressed morbidity and increase the health span) that we start to look at this new model-this systems biology model, this differential biochemically stratified model-looking at individuality that is really born out of the discoveries of Archibald Garrod and geneticists of the transition of the 19th to the 20th century and moving in to the transition of genomics, as a paradigm, in the 21st century. This is ultimately leading into systems biology, which is the future of where functional medicine and functional nutrition is going. I hope that you appreciate that what you have just witnessed (by listening to the interviews with Dr. Pauling and Dr. Hoffer) is really the birthing of what has taken more than a hundred years to evolve and to mature. This is a paradigm shift in thinking-a frame shift in the way we see the origin of disease, this new lens of filtering information through. It’s not just an individual therapy that we’re talking about, it’s a conceptual shift in the framework of how we understand and manage chronic age-related diseases at the individual level, at the patient-specific level, at that moment that we are in the exam room with that patient at that senescent, humanistic level of discourse about how to manifest the appropriate program for them. It is not the program for the average, but the program for that individual patient as they present with their antecedents and triggers, exposing them to their mediators, which ultimately creates their signs and symptoms. This is the functional medicine model. This is what we have been talking about for more than 20 years. I believe that it is starting to gain traction, gain an understanding, gain fundamental science that supports the paradigm, and now the challenge is finding ways to really apply this effectively in the clinic. I hope what you have learned from the discussions with Dr. Pauling and Dr. Hoffer is that we are on this journey together. It is one step at a time. It is an evolving paradigm. But truth is its own victory. It wills out in the end, and there is a fundamental truth to this model that is emerging that will ultimately deliver a more effective patient-centered medicine that results in better patient outcome and ultimately achieves what Dr. Pauling and his wife, Ava Helen, talked about with me years ago when I asked them why the Pauling Institute of Science and Medicine was born, and he said, very simply, “It was to find ways to reduce human suffering.” I think this model that we are describing can deliver that outcome in a humanistic, cost-effective way. Thanks so much for listening to this epic version of Functional Medicine Update. I think this will stand, timeless, when we go back and re-listen, in years to come, to Dr. Pauling and Dr. Hoffer and their prescient view of the future of medicine.

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Bibliography

1 Garrod AE. The incidence of alkaptonuria: a study in chemical individuality. Yale J Biol Med. 2002;75(4):221-231. (Originally published in The Lancet, pp. 1616-1620, 1902.) 2 Neel JV. The inheritance of sickle cell anemia. Science. 1949;110:64-66. 3 Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science. 1949;110:543-548. 4 Williams RJ, Beerstecher E, Berry LJ. The concept of genetotrophic disease. Lancet. 1950(6599):287-289. 5 Williams RJ. Concept of genetotrophic disease. Nutr Rev. 1950;8(9):257-260. 6 Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(825)265-271. 7Ames BA, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms. Am J Clin Nutr. 002;75:616-658. 8 Yamafuji K, Nakamura Y, Omura H, Soeda T, Gyotoku K. Antitumor potency of ascorbic, dehydroascorbic, or 2,3-diketogulonic acid and their action on deoxyribonucleic acid. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol. 1971;76(1):1-7. 9 Vallance S. Leucocyte ascorbic acid and the leucocyte count. Br J Nutr. 1979;41(3):409-411. 10 Enstrom JE, Pauling L. Mortality among health-conscious elderly Californians. Proc Natl Acad Sci USA. 1982;79(19):6023-6027. 11 Johnson GE, Obenshain SS. Nonresponsiveness of serum high-density lipoprotein-cholesterol to high dose ascorbic acid administration in normal men. Am J Clin Nutr. 1981;34:2088-2091. 12 Ginter E. Ascorbic acid in cholesterol and bile acid metabolism.Ann N Y Acad Sci. 1975;258:410-421. 13 Hornig D, Weiser H. Ascorbic acid and cholesterol: effect of graded oral intakes on cholesterol conversion to bile acids in guinea-pigs. Experientia. 1976;32(6):687-689. 14 Sestili MA. Possible adverse health effects of vitamin C and ascorbic acid. Semin Oncol. 1983;10(3):299-304 15 Herbert V, Jacob E, Wong KT. Destruction of vitamin B12 by vitamin C. Am J Clin Nutr. 1977;30(3):297-299. 16 Finley EB, Cerklewski FL. Influence of ascorbic acid supplementation on copper status in young adult men. Am J Clin Nutr. 1983;37(4):553-556. 17 Pauling L. Vitamin C and the Common Cold. WH Freeman & Company. San Francisco: 1970. 18 Anderson TW. Large scale studies with vitamin C. Acta Vitaminol Enzymol. 1977;31(1-5):43-50. 19 Cathcart RF. Vitamin C, titrating to bowel tolerance, anascorbemia, and acute induced scurvy. Med Hypotheses. 1981;7(11):1359-1376. 20 Pauling L. Vitamin C and longevity. Agressologie. 1983;24(7):317-319. 21 Osmond H, Smythies J. Schizophrenia: a new approach. J Mental Sci. 1952;98:309-315. 22 Hoffer A, Osmond H, Callbeck MJ, Kahan I. Treatment of schizophrenia with nicotinic acid and nicotinamide. J Clin Exp Psychopathol. 1957;18(2):131-158. 23 Hawkins DR and Linus Pauling.Orthomolecular Psychiatry. WH Freeman & Co. San Francisco: 1973. 24 Hoffer A and Harry Foster. Feel Better, Live Longer with Vitamin B-3: Nutrient Deficiency and Dependency. CCNM Press. Toronto: 2007. 25 Horrobin DF. The Madness of Adam and Eve: How Schizophrenia Shaped Humanity. Bantam Press. New York: 2002. 26 Hoffer LJ. Vitamin therapy in schizophrenia. Isr J Psychiatry Relat Sci. 2008;45(1):3-10. 27 Osmond H, Hoffer A. Massive niacin treatment in schizophrenia. Lancet. 1962;1(7724):316-319. 28 Rabadi MH, Coar PL, Lukin M, Lesser M, Blass JP. Intensive nutritional supplements can improve outcomes in stroke rehabilitation. Neurology. 2008;71(23):1856-1861. 29 Frei B, Lawson S. Vitamin C and cancer revisited. Proc Natl Acad Sci USA. 2008;105(32):11037-11038. 30 Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenographs in mice. Proc Natl Acad Sci USA. 2008;105(32):11105-11109. 31 Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. 2008;19:1969-1974. 32 Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C. Vitamins E and C in the prevention of cardiovascular disease in men. The physicians’ health study II randomized controlled trial. JAMA. 2008;300(18):2123-2133.

Welcome to Functional Medicine Update for January 2008. Yes, we are starting a new year, and what a year it is going to be. With many things on the horizon, I think this field of functional medicine is going to continue to wake up and move into its young adulthood in 2008. The Women’s Health Initiative (WHI): Five Years Later In this issue I want to focus on what has been one of the more controversial areas within medicine over the past several years: hormone replacement therapy and the Women’s Health Initiative. The reason I have chosen this topic is because I think it is a model for the controversy that exists about how you prove things in medicine. What are safe and effective therapeutic agents, are we asking the right questions, and is the formalism by which we go about diagnosing and treating conditions really consistent with the emerging understanding of biology and human physiology? We have come a long way in understanding more about systems biology approaches towards the function of the organism rather than just looking at pathology as a single entity that we call a disease. I’d like to take us back to July 2002, when the National Heart, Lung, and Blood Institute of the NIH initiated a firestorm in women’s health by announcing the termination of the estrogen and progestin arm of the Women’s Health Initiative (WHI). The announcement was followed by a number of publications in the Journal of the American Medical Association. One paper was titled “Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results from the WHI Randomized Control Trial” in which it was suggested that overall health risk exceeded benefits from use of combined estrogen plus progestin for an average of 5.2 year follow-up among healthy, postmenopausal, US women.1 All-cause mortality was not affected during the trial. “The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen of hormone replacement therapy should not be initiated or continued for primary prevention of coronary heart disease,” according to this JAMA article that really started this firestorm. An Expert Criticizes the WHI and Calls for Transparency Within the field of obstetrics and gynecology, the question was raised: How did we jump on the bandwagon and supplement women with estrogen and progestins if the follow-up work demonstrated they weren’t able to deliver the proposed clinical outcome (reduce the risk of the major cause of death in postmenopausal women– cardiovascular disease)? A very interesting article appeared recently in the journal Menopause Management, in September/October 2007, authored by Dr. Wulf Utian.2 Some of you know that name. He is the Executive Director of the National Association of Menopausal Management and a consultant in women’s health at the Cleveland Clinic, and he is pulled out often as a resident expert in this area of hormone replacement therapy. He authored this editorial about the WHI that was quite scathing-its format, structure, the way the data was released, the conclusions drawn, and the integrity of the investigators. The editorial was a pretty broad-brush indictment of the way the whole study was done and the results publicized. In reading this piece, you come away with the opinion (I think) that there was collusion, and there was a political agenda of the WHI that was anti-hormone replacement therapy and that is why the results were reported the way that they were. In fact, at the conclusion of his article, Dr. Utian says-and I’ll quote-“For these [data] to be accepted with confidence, it is well time for the NIH to bring all their WHI investigators together to develop a transparent and comprehensive summary of their results. It is also time for the WHI investigators to cease their stubborn defense and misrepresentation of their 2002 data, and to return to scientific integrity. Do they owe a mea culpa? In my opinion, ‘yes.’ But there are important and relevant data in the WHI study that need to be clearly and honestly placed in perspective…” The reason I’m going into this in such great detail is that by cohort analysis of this data, you’ll find that some women were at much higher risk to problems with regard to cardiovascular outcome than others, and it appeared as if those women who took ERT in the perimenopausal period (at younger age) didn’t have the risk that women who took it postmenopausally did. The question is taking the right compounds at the right time. Of course, that wasn’t really what was told to be either safe or effective to a generation or two of obstetricians and gynecologists. It was said that HRT was highly studied and safe and effective for ranges of intervention for prevention of bone loss, menopausal symptoms of sweating, vaginal dryness, and dysphoria, and also for reducing the risk of cardiovascular disease (a major risk in postmenopause). I think we can always use 20/20 hindsight, but the bottom line is that there were a couple of generations of women who got estrogen replacement therapy since it was heavily promoted by Robert Wood Wilson in his book, Feminine Forever, back in the 1960s. Since then, we have had this general thought that the research was secure, that there was a strong body of literature that ERT was both safe and effective, and that we wouldn’t do anything in medicine other than scientific medicine. Now that there are some doubts cast on this, we are doing post hoc kind of microanalysis, placing the blame on the WHI investigators rather than on assumptions made for almost 40 years about what is safe and effective without really having data from which we can prove it. This is kind of turning around the tables and going from being the accused to being the accuser, which I find a very fascinating chapter in the way that we deal with new information. Rather than accept that it is important to recognize that maybe we didn’t have all the answers and were making inappropriate conclusions, what we do is shift the blame over to somebody else; it’s like Pin-the-Tail-on-the-Donkey. Decision-Making in Medicine: Cautionary Tales from Epidemiology There is a very interesting editorial that was written by Gary Taubes and published in The New York Times that I thought was an eloquent review of this controversy, without a lot of value judgment built in.3 It is kind an overview of the whole process of decision making in medicine, using the WHI and hormone replacement therapy as a specific example (a case in point). Mr. Taubes says that originally women took estrogen only to relieve hot flashes, sweating, and vaginal dryness thanks to the best-seller I have already mentioned, Feminine Forever. In the mid-1990s, the American Heart Association, the American College of Physicians, and the American College of Obstetricians and Gynecologists had all conducted what they considered reasonable review of the literature, and they concluded that the beneficial effects of HRT were sufficiently well established and it could be recommended to older women as a means of warding off both heart disease and osteoporosis. By 2001, 15 million women were filling HRT prescriptions annually. Of these, perhaps 5 million were older women taking the drug solely with the expectation that it would allow them to lead a longer and healthier life by preventing heart disease and osteoporosis. A year later, the tide turned. In the summer of 2002, estrogen therapy was exposed. Dr. Jerry Avorn, a Harvard epidemiologist, has called it the “estrogen debacle” and a “case study waiting to written” on the elusive search for truth in medicine. Many explanations have been offered to make sense of this here-today-gone-tomorrow nature of medical wisdom that we were advised with confidence one year that becomes reversed the next. It calls into question the whole nature of whether we are truly practicing “scientific medicine” or medicine of lore. The simplest explanation, according to Mr. Taubes, is that the natural rhythm of science has ebbs and flows. An observation leads to hypothesis, the hypothesis is tested, and if it fails this year’s test, which is always the most likely outcome in any scientific endeavor, then we change our opinion. This concept of locking in stone an idea without really understanding what you are talking about without qualification, to me, is emerging to be problematic and it is certainly a case in point with HRT. With most issues of diet, lifestyle, and disease, hypotheses begin to transform into the public health recommendations only after receiving the requisite support from a field of research known as epidemiology. This science evolved over the last 250 years to make sense of epidemics (hence the name “epidemiology” and its relationship to infectious disease). Since the 1950s, epidemiology has been used to identify (or at least to try to identify) the causes of common chronic diseases that befall us, particularly heart disease and cancer. In this process, the perception of what epidemiological research can legitimately accomplish, at least by the public and the press, is maybe actually far in excess of what is reality. The case of hormone replacement therapy for postmenopausal women is just one of the cautionary tales in the annals of epidemiology. Until there are case-intervention, controlled studies, much is unknown. Many of the conclusions that we derive about benefit are built around a presumption from epidemiology, which is a statistical analysis that has many confounding variables for which you really can’t control, even if you try to use proper statistical methods. I think what we have learned through this whole process of HRT and the WHI is to be very sober about drawing conclusions from short-term studies or from epidemiological research and moving into long-term decision making, particularly for things that people may be taking for years or maybe even decades. Unfortunately, this flip-flop rhythm of science has historically been seen in many areas, not just in the area of HRT, and we have had reverse decision making later on-better information that came through longer-term intervention trials. The difficulty is that a lot medical decision-making today is built on short-term intervention studies and epidemiological research, which doesn’t necessarily then lead us into an understanding of long-term intervention outcome, both from a benefit and a risk relationship. Natural versus Synthetic Molecules I think that this particular discussion has a lot of below-the-water-line implication. It doesn’t even really address a more critical issue: using compounds in hormone replacement therapy that are not natural to human physiology because they have “super” hormone characteristics built on certain biological endpoints that are measured in absence of looking at the full effect on the interconnectedness of our physiology. I’m talking about progestins, which have a very strong effect on reproductive biology, but have a different effect on neurochemistry and immunology than natural-source progesterone. We might say we are looking at trying to examine an elephant with a microscope-we’re not looking at the whole organism; we’re not looking at the interaction of all of these things in the system called the “human being.” You might ask why we aren’t doing studies of long-term intervention, comparing synthetic molecules to that of the natural-source molecules or bioidentical hormones to see if, in fact, there is different outcome, safety, and benefit from the substitution of one family of molecules for another. I think you all know the reasons. First of all, the cost of long-term intervention trials is astronomical. Second, there is really not a lot of motivation for intervening with bioidentical hormones in a controlled trial over a long period of time because the assumption has been made that the synthetically manipulated molecules have a higher biological activity and therefore are “better” than the bioidentical hormones. This notion is built around the presumption that comes from looking at a few variables that we call the biological indicators of the overall function of these hormones. Now we know that these hormones have pleotrophic effects across many organ systems and we have been isolating the effects of the hormones on just a few of their pleotrophic influences. There is a little bit of similarity here to the situation with vitamin E. I know this may appear a very oblique analogy, but let me give it to you. How is the recommended dietary allowance for vitamin E established? It is a difficult standard to establish because there is no deficiency disease associated with vitamin E loss in the diet (it doesn’t produce conditions like scurvy, beri beri, or pellagra); its influences on function are much more subtle and take place over a longer time. How would individuals establish an appropriate amount that was required for function, or a biological potency? It was decided that an animal model would be used, because in the rodent (e.g., the rat) vitamin E is required during pregnancy to lead to patency of the pregnancy. In the absence of proper vitamin E, what happens is you get fetal resorption, and that’s a measurable outcome (to look at resorption in the absence of proper vitamin E in the diet). The question was: How much vitamin E does it take in the diet to prevent rat fetal resorption? By quantifying this through animal studies, investigators were able to find a certain level of activity of vitamin E that was requisite for prevention of rat fetal resorption, and they called that the International Unit Scale, or an IU. What about the synthetic forms of vitamin E that came out after the IU was determined, such as the racemic DL–tocopherols, which were less expensive? When studied in these bioassays for rat fetal resorption, they actually had higher potency (1.39 IUs per milligram versus 1 unit per milligram for the naturally-source vitamin E). People started saying that the synthetic vitamin E looked like it may be as active or very active and would be preferable because it was less expensive. Recall, though, that the way that vitamin E was assessed in its potency was to look at its ability to prevent rat fetal resorption, which is not the reason that most people are concerned about vitamin E in their own diet. Are there other roles that vitamin E has? Does it have pleotrophic effects on human physiology other than what is seen in a rat in terms of its reproductive biology? Of course the answer is yes. The more vitamin E is studied, the more influence it is found to have on cellular function. One would ask, then, is the way that we asses its biological potency (of the synthetic vitamin E) really adequate to be realistic about how to compare it to the natural-source vitamin E in humans? This is a similar example (or at least an analogy to) the situation with estrogenic and progestrogenic hormones. If we measure biological potency based on one biomarker of a family of pleotrophic effects and we establish that as being higher potency (meaning “better”), then in our minds we say these other effects must be unimportant and therefore the best products to use are standardized, potentized derivatives of natural source estrogens and progestins that we call these synthetic molecules. I think that is another reason why there hasn’t been an inclination or enthusiasm about doing long-term intervention trials with bioidentical hormones. I haven’t even mentioned the patent issue or return on investment to companies that sell these products. Bioidentical Hormones: The State of the Science What is the state of science of the bioidentical hormones in supplementation or in replacement therapy? That is an interesting and controversial topic that has lots of heat on both sides. We need to really go down to ground zero and start looking at the state of science in order to get some type of intelligent answer to that question about the comparison between a bioidentical hormone replacement (that would be natural estrogens and progesterone) versus synthetic estrogen derivatives and progestins. On this subject, the literature is a little confusing because there is a limited amount of comparative data doing head-to-head intervention trials of medroxyprogesterone acetate versus, say, bioidentical progesterone, or estradiol versus some of the estrogen derivatives. But that research that has been published to date-and I want to emphasize “seems to indicate” because we don’t have the long-term, large-study-subject trials that we’d like to make definitive answers-suggests that there is a difference in biological activity of the bioidentical versus the synthetic estrogens and progestins. I believe this is a result of the fact that these bioidentical hormones have pleotrophic effects across many different organs because we find receptor sites for these hormones on so many different tissues and organs that then are beyond that of reproductive biology and influence, then, the neuro-endocrine-immune system in very complex ways beyond that of maybe what these synthetic molecules were engineered to be optimal to do, which was just a few of the myriad effects that the bioidentical hormones have. When we talk bioidentical, we are really talking about a term that describes specific hormones that are identical in molecular structure to hormones made in the human body. With estrogens, we are talking about things like estradiol, estrone, and estriol. Are conjugated equine estrogens bioidentical? The answer is no because pregnant mares produce a different series of estrogen derivatives. They are natural to the horse, but they are not natural to the woman. These are things like equaline and equalinin; these are the so-called B-ring unsaturated estrogens, which are different than the bioidentical estrogens that a woman’s body produces. B-ring unsaturated estrogens have different metabolisms, different cell receptor activities, and different functional outcomes than human-nature-identical estrogens. I think the chemistry becomes a little complicated here because we often don’t think about trace constituents in equine conjugated estrogens, but these-even in small amount-could have significant influence on modulating effects. They may even be metabolized in different ways and they are more likely to be converted into the 4-hydroxy estrogen derivatives, which may have some problematic risk related to breast and other types of reproductive cancers. The story is always greater than it might seem. That is what we learn in life in general, but certainly in medicine also. We can take things at a superficial level or we can start deeper drilling, and the more deeply we drill the more we learn about differences that we were unaware of. Going beyond estrogens, we can move into the androgens and progesterone. These are also relevant to this bioidentical category because nature-identical, or bioidentical, progesterone is different than the progestins or the progestegens (the synthetic derivatives) which have been found to have very high biological activity. As I mentioned, that biological activity has really been focused on its effects on reproductive biology, not on many of the other effects that progesterone has in the nervous system and the immune system at receptor sites outside of the reproductive system. It would be wonderful if we could sit down and we could absolutely define unequivocally the differences between bioidentical hormones and synthetic hormones and resolve this discussion once and for all, but it is not likely that that is going to ever occur. I don’t think the studies that would be required to give us complete comfort with this discussion will ever be funded or accomplished. We have to use information that is suggested (that is inferential) and follows what I call “rules of reasonableness.” Within the context of experts in the field, there are rules of reasonableness-things that make some biological sense, that have a history of greater potential for safety and effectiveness. How does this relate to the WHI trial and the recent disillusionment that maybe cardiovascular protection was not afforded by giving conjugated equine estrogens and synthetic progestins? It is very possible that rather than throwing the baby out with the bathwater and just saying hormone replacement therapy doesn’t work, we might try defining the right partners and the right players and those that have the right communication across multiple organ systems. That leads us, obviously, into a very interesting question: Do we really have to engage in hormone replacement therapy in order to get these beneficial effects? A woman who is suffering from very severe dysphoria as a consequence of excurgencies in her hormone levels during perimenopause, or has night sweats and is suffering from insomnia, and her days are very blue, and she has hot flushes…these are very complicated symptoms. As many women would point out, this period of their lives may be associated with a kind of “living hell,” and that’s what Robert Wood Wilson talked about in his book Feminine Forever. This is a transient period, but it may seem that it goes on forever for the woman who is suffering, so she is looking for relief of symptoms. Of course, some dysphoric symptoms have been modified by using various types of antidepressant medication in lower dose to try to modulate the depressive effects, and also to influence thermal regulation and lower sweating (to some degree) and hot flushing. There are some alternative medications that have been used in place of hormone replacement therapy, but then there is also the diet and lifestyle intervention component and how that relates not only to severe menopause symptoms that a woman is having, but also to the health outcomes (postmenopausally) for cardiovascular disease, osteoporosis, and even cancer. What are the strategic approaches that may provide alternatives to hormone replacement therapy, be it either bioidentical hormone replacement therapy or synthetic hormones? Diet, Exercise, and Lifestyle Intervention during Perimenopause When I think of this question, I am always reminded of the extraordinary work that has been developed that doesn’t get much shrift in these discussions. This is work focused on diet, lifestyle, and exercise intervention for women who have these complicated highs and lows associated with altering hormones during the perimenopausal period, as well as how the benefits of those diet and lifestyle and exercise interventions stay with a woman throughout the postmenopausal period and as long as she continues to maintain those lifestyle commitments. These interventions can greatly lower a woman’s relative risk to all of the major postmenopausal diseases. Literature-many different studies-has been published on this with no evidence of toxicity or adverse effects. I wonder why we never see much discussion about diet, exercise, and lifestyle interventions. The discussion is always, seemingly, about bioidentical hormones versus synthetic hormones. Maybe the voice should be louder about not taking hormones as a first choice at all, but rather looking at how we modulate stress, activity patterns, and diet in women who are going through the dramatic changes in hormone levels in perimenopause, and how these choices could be used to hopefully modulate these excurgencies of hormones and affect positively mood serum lipids, and neuroendocrine function associated with hot flushing and night sweats. Are there trials that have been done and published that illustrate the positive benefit of diet, and lifestyle, and exercise modulation during perimenopause and menopause? The answer is absolutely yes-even studies throughout the postmenopausal period. Some interesting work appeared even before the 1977 paper in The New England Journal of Medicine by Dr. George Mann called “Diet-Heart: End of and Era.”4 He actually discussed the work of Ansel Keys back in the 1950s on the management of heart disease risk by dietary intervention. This was basically to modulate dietary fat intake and to improve the P-to-S ratio (the polyunsaturated-to-saturated fat ratio) as a primary intervention for the control of heart disease risk factors. We can go back to the work of E.H. Ahrens, Jr. in 1969, or back to the 50s with Ansel Keys’ work, to examine this dominant theme about how to prevent heart disease by dietary fat modulation. The difficulty with this intervention, when it was employed within the food industry, was it really meant doing partially hydrogenated vegetable oils, and it meant getting people on high linolenic-acid containing diets from corn oil. As a consequence of this we started to see a declining intake of omega-3 fatty acids, and we started to recognize in the last 10 years that these omega-3 fatty acids are very important for neuro-endocrine-immune function. Omega-3 fatty acids help to establish mood. They help to establish immune function. And they even help to establish insulin sensitivity and lipid levels in the serum (lowering triglycerides and having a salutary effect upon lipoproteinemias). When we started to introduce a concept of lowering fat and increasing the P-to-S ratio in the diet, and then modulating this by increasing animal protein, we now recognize that we may have started to shift people over (specifically women) into more and more endocrinological imbalances (neuro-endocrine-immune imbalances). That is really part of what Dr. Mann was speaking to back in his 1977 article. His advocacy was that we need to take a better snapshot of which diets are important for lowering cardiovascular disease risk, modifying cholesterol biosynthesis, and improving cholesterol conversion to cholic acid (one of the bile acids) to help in proper digestive process, increase hormonal metabolism, and excrete hormones by binding with bile acids and eliminating these hormones that had been metabolized in the feces so they wouldn’t have long residence in the body. It all fits together with a different model. Do vegetarian women who consume more omega-3 fatty acids as a natural consequence of their diet and have lower animal protein and higher fiber (and also, by the way, higher phytochemicals as part of their vegetarian diet) have altered estrogen metabolism, estrogen levels, sex-hormone-binding globulin levels, different insulin sensitivity, different lipoproteins in their blood, and different serum lipids? The answer is yes to all of those questions. By just changing the diet to a more vegetable-based diet with higher fiber, higher phytochemicals, lower animal fats, and lower partially hydrogenated vegetable oils, you end up with a different endocrinological response that modulates many of these hormones that we see in excurgency during perimenopause. I think this is an interesting context to use in looking at this debate between hormone replacement therapy and always assuming that the debate is only between synthetic hormones and bioidentical hormones. Let me give you another part of the story that I think is quite fascinating. This has to do with the composition of the lipoproteins that are associated with atherogenic risk and how they really reflect a more dramatic change in endocrinology and immunology than just that of the serum lipids that we measure. Recall that fats that are transported around your blood (be it cholesterol or triglycerides) have to ride on the back of a carrier because fats don’t dissolve well in blood. They have to be carried around by a detergent-like molecule that has an ability to look both like water (which is principally what the blood is made of) and like fat. These are called the apolipoproteins and they have the names A, B, C, D, and E. We talked at length with Dr. Roger Newton in a 2007 edition of Functional Medicine Update, about one of those apolipoproteins-apolipoprotein E-and also about one of the packages of apolipoproteins with lipid to form what are called serum lipoproteins (that was the HDL lipoprotein). To quickly summarize Dr. Newton’s beautiful discussion with us, the HDL particles really break down into different sub-families of HDLs that have different physiological effects, and the different sub-particles are a consequence of the fact that there are different proteins found within the HDL particle. These proteins (these apolipoproteins) are manufactured in the liver as a consequence of messages that the liver gets from the outside environment. These messages could be stress messages. They could be hormone messages. They could be nutritional messages, phytochemical messages, toxins, or allergens-all of these things influence the endocrine and immune system in such a way to then send signals to the liver to modulate the gene expression and change the pattern of lipoprotein synthesis. That, then, binds fats in different packages, which we see in our blood as a simple elevated blood fat level (or an altered blood fat level) with different HDL levels or different HDL type. If you look at a patient who, for instance, has insulin resistance/metabolic syndrome and they are on their way to getting type 2 diabetes, you’ll find that their blood fats change composition. Triglycerides tend to go up and HDL tends to go down, so the triglyceride-to-HDL ratio tends to be elevated. This is one of the surrogate markers for metabolic syndrome. As you get above 4-to-1 (ratio of fasting triglycerides to HDL), it indicates increasing relative risk to metabolic syndrome and its severity moving on into type 2 diabetes. Why is that? It is because the signaling that occurs in a hyperinsulinemic state induces a whole series of changes relative to lipoprotein synthesis and lipid biosynthesis (hepatic biolipid synthesis), so what we get is an alteration in the type and family of lipoproteins that are floating around in our blood. The LDLs, intermediate LDLs, and HDLs change in their composition and magnitude. If we were to really start asking questions about how would we properly modulate the hormones of postmenopausal or perimenopausal women through diet and lifestyle intervention, we might start looking not just at the hormones themselves, but also at the outcome that these hormones have on things like lipoproteins as a surrogate marker because we know that changes in hormone levels alter inflammatory markers, alter insulin signaling, and have pleotrophic effects on gene expression, some of which are reflected in altering levels of HDL, LDL, and ultimately the apolipoproteins themselves. A paper was just published describing what happens to individuals as they drift into atherogenesis (to the apolipoproteins that are found in HDL as part of the HDL particle). This article was published in the Journal of Clinical Investigation in 2007, and what the authors did is examine the proteins that make up the HDL particle and how these proteins can change in composition under conditions of inflammation or hormonal modulation.5 Surprisingly (to some of us maybe), they found that the HDL particle is actually made up of more than 20 different proteins, and those proteins that bind the fat to make up HDL can change in composition based upon the state of the individual. For example, if the person is in an inflammatory situation, there is a different composition of the HDL protein particles than there is in a person without inflammation. The point I am trying to bring attention to is that when we look at diet, lifestyle, and exercise intervention and estrogen modulation, we see a whole series of physiological variables, including serum lipids, apolipoprotein levels, or apolipoprotein B or A-1 ratios. Things like oxidative stress and inflammatory markers can be used to identify a trajectory towards problems not solely related just to estrogen or progesterone levels. How the signaling occurs in the context of that web of that individual woman’s physiology is important. We are going to talk more with our researcher of the month in a moment about estrogen metabolism and its effects on the body. We know that estrogen metabolism, (producing these hydroxylated estrogens) can influence inflammatory markers and oxidative stress, and that ties together with potential bone loss risk. By lowering inflammation and improving estrogen metabolism, you can also lower bone loss risk in the face of the same estrogen levels; it is not just simply estradiol, estrone, and estriol. I’m now quoting from a recent paper that appeared in the Proceedings of the National Academy of Science in 2007 looking at oxidative stress and its relationship to bone loss in estrogen-deficient animals and how this relates to dendritic cell activation and ultimately resorption of bone.6 This story is much more complex than we have given credit for. We know that other hormones like thyroid hormone play a role. As estrogen levels change, the thyroid hormone receptivity changes, and so women on thyroid hormone replacement therapy may have different effects on their estrogen levels. These women may have to balance their thyroid hormone if they are taking estrogen or they may have to balance their estrogen if they are taking thyroid. This was published in the journal Thyroid in 2004.7 The Role of Diet in Modulating Estrogen Metabolism We also know that diet plays a role in modulating estrogen metabolism. Soy isoflavones with soy protein has an effect on upregulating estrogen metabolism into the 2-hydroxy estrogens. It is also known believed soy isoflavones do not have a significant effect on suppressing iodine, nor thyroid function. This is-I think-in contrast to what some people are saying recently: that soy supplements suppress thyroid. An article in the Journal of Medicinal Foodthat appeared in 2003 showed that isoflavone supplements from soy do not affect thyroid function in iodine-replete postmenopausal women.8 In fact, in a nice review of soy protein and soy bean isoflavones on thyroid function in healthy adults, it was found that only in the hypothyroid person and those with iodine deficiency that soy isoflavones have an adverse effect on thyroid function. I’m quoting from Thyroid, volume 16, page 249 in 2006.9 Another interesting review paper appeared in the American Journal of Clinical Nutrition in 2002 that is a collaborative study among a number of investigators looking at the effect of soy protein on endogenous hormones in postmenopausal women and finding that soy protein had a salutary and beneficial effect on estrogen and progesterone hormones without an adverse effect on thyroid hormone except (again) in those women who were iodine deficient and had suppressed thyroid function.10 Again, my point is that before we jump to the conclusion that we need to replace hormones (be it either bioidentical or synthetic, and get engaged in this whole question of what is better and what is safer, knowing that the bioidentical certainly speaks more to the evolutionary history) we ought to look at lifestyle intervention. Diet plays a very important role. Cruciferous vegetables, soy proteins, complex carbohydrates (unrefined, rich in fibers), a more vegetarian shift, staying away from partially hydrogenated vegetable oils, saturated fats, and even too much of linoleic acid-rich corn oils. Moving back into a centric position relative to diet, lifestyle, and exercise may be the principal way of modulating both the symptoms of perimenopause and even later-stage postmenopausal disease risk. I hope this has been helpful as a context we have set for our discussion with our researcher of the month.

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INTERVIEW TRANSCRIPT Clinician/Researcher of the Month Eleanor Rogan, PhD Eppley Institute for Research in Cancer University of Nebraska 8210 Bowie Drive Omaha, NE 68114 Once again we are at that place in Functional Medicine Update that I know you all look forward to. I say that every issue because I do look forward to it so much, and that is our discussion with someone who is making news on the frontier of medicine. We are very fortunate to come back and revisit one of our researchers of the month from 2006. I said we would come back for a second chance to talk to with her because the ongoing work in her laboratory is absolutely fascinating and is opening up a whole new era as it relates to cancer prevention and possibly even cancer management. In a recent personal communication she commented to me (and I’m quoting), “An estimated 1,444,920 men and women will be diagnosed with cancer in 2007, and of those, it is estimated that 559,650 will die from the disease.”11 The goal of the work of she and her colleagues is to reduce this incidence of cancer, both the initiation and obviously mortality. They think they have identified the initiating step in the induction of breast and other human cancers and know how to prevent its occurrence. That’s a very strong statement. The research that you will be hearing about introduces a new approach to cancer prevention that could be adopted widely, and new diagnostic technology could be available to determine risk of developing cancer long before a tumor is detectable, which is really at the functional biochemical or cell level. These outcomes could result in advancements in reducing the incidence of cancer across the population within the next decade. Our discussion this month is with Dr. Eleanor Rogan. Just to remind you all of Dr. Rogan’s extraordinary background: she is a professor at the Eppley Institute for Research in Cancer and Department Pharmaceutical Sciences from 1990 to the present in biochemistry and molecular biology. She also became the Chair of the Department of Environmental Agriculture and Occupational Health at the College of Public Health in 2007, so congratulations, Dr. Rogan, for that nice advancement and promotion. She has 200-plus publications in very highly esteemed journals. In April of 2006, she was a researcher of the month in Functional Medicine Update, and also was awarded (in May 2006) what I consider a very prestigious award, the Institute for Functional Medicine Linus Pauling Award. With all of that fanfare, Dr. Rogan, we welcome you once again to Functional Medicine Update. We are sitting on the edge of our seats with excited anticipation of the discussion about how things have gone in your laboratories and your work over the last year. ER: Thank you. JB: Let me start, if I can, for those people who may not have had the privilege of hearing you previously talk, with the discovery of the catechol estrogens and DNA adducts and how that interrelates with the potential initiation of cancer. Maybe you could give a brief summary as to how you made these discoveries initially and got into what really is some exquisite and difficult chemistry to evolve this field that most people would say you and your group have created? Background Research on Polycyclic Hydrocarbons and DNA Adducts ER: My long-time collaborator and I spent a lot of years studying chemical carcinogenesis by a different group of compounds called polycyclic hydrocarbons that are present in smoke whenever you burn anything organic. We studied those because we had the technology to do so, but also because we recognized early on that they shared some chemical properties with estrogens, and we were really interested in the estrogens. This approach enabled us (when we finally had the technical ability to work with estrogens) to make rapid progress because we could apply the knowledge we had learned from working with the polycyclic hydrocarbons. Our approach all along has been that estrogens, in addition to the whole variety of processes that they mediate through estrogen receptors, also can be metabolized incorrectly and form metabolites that are reactive and, in fact, react with DNA. One part of our hypothesis was that it could be the endogenous estrogens (the ones that all of us-both men and women-have in our bodies) that could be metabolized to forms that react with DNA. We started out, naturally, studying in test tube reactions, and then in laboratory animals, and then finally we got to cultured cells, studying these reactions and finding that indeed the estrogens are metabolized. Normally estrogens are metabolized to another form called catechol estrogens. These are important and they have functions in the body and they are okay, but then they can occasionally be further metabolized to something called catechol estrogen quinones, and these are the forms that actually react with DNA. The problem is that when they react with DNA, they overwhelmingly (more than 99.9{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}) form what is called a DNA adduct, where the estrogen has actually attached itself to a DNA base. When they do that (form these adducts), the bond is broken between the DNA base (the adenine or the guanine) and the deoxyribo sugar that makes up the backbone of DNA. So the estrogen (let’s say, adenine) adduct is released from the DNA and that leaves a little gap known as apurinic site, and these can be mutagenic. Our lab has also developed a lot of evidence on that, and we think it is the mutations coming from these lost adducts that can (if they are in the critical genes) end up starting the process that leads to cancer. The last time I talked on this program, we had developed a lot of evidence that showed that, both in test tube and in laboratory animals, and now we have gone on from there. JB: Before we jump into that exciting new work I just want to go back and make sure that some of our clinicians who are not biochemists understand the real significance of what you just said. I’d like to review this concept of estrogen metabolism because I think there is still an idea in the minds of many clinicians that estrogen really is estradiol, estrone, and estriol, and perhaps they are not so aware of these estrogen metabolites that come by way of cytochrome P450 oxidation of the estrogens that are common and into these secondary metabolites-the 2-hydroxylated, 16-hydroxylated, and 4-hydroxylated estrogens. I think just for the sake of review you might want to let people know that there is a lot of activity of these metabolites that has come from your research, and that environmental factors influence the metabolism of estrogen into these active metabolites. So I’d like you to kind of focus on that for a second. ER: Okay. Absolutely, agents in the environment certainly affect how estrogens are metabolized. There are environmental compounds that, in particular, induce forms of cytochrome P450 (CYP), specifically there is one called cytochrome P450 1B1 (CYP1B1) that gets induced by a lot of environmental contaminants. When the P450s are induced, that leads to higher levels of the catechol estrogens (the 4-catechol estrogens and the 2-catechol estrogens). This can set up a dangerous situation because these catechol estrogens then can be further oxidized either by other cytochrome P450s or peroxidase enzymes to the catechol estrogen quinones that are reactive. JB: Great. There’s a little bit of chemistry here that I want people to understand: the difference between the adducts that might derive from the 2-hydroxy estrogens or the 2,3 catechol quinones versus those that derive from the 3,4 catechol estrogens, which are the 4-hydroxy compounds. You talked about these apurinic adducts. For a lot of people, when they think of injuries to DNA, they think there are repair enzymes. Aren’t there ligases that cut out the damaged DNA nucleotides and insert new ones? I’d like you to tell us a little bit about the difference between those adducts that are more easily repaired versus those that are not. ER: Okay. The apurinic sites that are left in the DNA-these little gaps because the adduct left-they are typically repaired by a process called base excision repair. For many years everyone thought that this process of DNA repair was error-free; it never made a mistake. More recently, our lab demonstrated, and now other labs have started concurring, that this process does make mistakes and you can get so-called “error-prone” repair. We think this happens when a cell gets overwhelmed because it’s got too many apurinic sites to repair, and so it ends up making mistakes because there is such pressure on the system. These mistakes, then, get fixed in the DNA and then inherited by all the daughter cells when the cell divides. This is how you end up with errors-these mutations-that can begin the process leading to cancer. JB: Is there a difference if the woman or man were to metabolize their estrogens in such a way that they predominantly produce the 2-hydroxylated estrogens versus those that produce the 4-hydroxylated estrogens in terms of their carcinogenicity? ER: Yes. There clearly is a difference. For a long time the 2-catechol estrogens were considered not to be carcinogenic while the 4-catechol estrogens did induce tumors in laboratory experiments (in animals). More recently it was found that the 2-catechol estrogens are very slightly carcinogenic, but the 4-catechol estrogens are more carcinogenic. Interestingly, we have found that when the 2-catechol estrogens and 4-catechol estrogens…if you mix them together and you oxidize them to the quinones and have them react with DNA, the 2-catechol estrogens compete very poorly. In fact, if you want to get as many adducts that have 2-catechol estrogens in them as 4-catechol estrogens in them, you have to have a ratio of 95{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} 2-catechol estrogen there and only 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} 4-catechol estrogen. Otherwise, the 2-catechol estrogen just doesn’t seem to be able to compete to make any adducts. We think this is probably why the 4-catechol estrogens are so much stronger carcinogens than the 2-catechol estrogens. JB: That’s fascinating. I just read a recent paper from an investigator by the name of Devra Davis-you are probably familiar with her work-and she was talking about xenoestrogens and how they have a higher carcinogenicity. She was actually quoting your work, saying that the xenoestrogens (like some of these plasticizer molecules) induce more 4-hydroxylated estrogens and more of the 3,4 catechol quinones. Is that what you have found or is that similar to what you understand?12 ER: We have not directly studied the xenoestrogens, but I know that others have and indeed that is exactly what we think the xenoestrogens and some other environmental contaminants are doing-that they induce the enzymes, particularly this cytochrome P450 1B1, so that you get higher levels of the catechol estrogen quinones that make the adducts that lead to the mutations. JB: Great. I think you have done a superb job of giving us all the background, so now we are going to go on to the point that you were leading into-the more recent work. I have been to a number of OB/GYN meetings over the last couple of years and it is very interesting when you talk to that community. I raise your extraordinary work to some of these individuals and say, “What do you think of this work? It really sounds groundbreaking and it opens up all sorts of new doors towards chemoprevention and even maybe management of the disease?” I often hear the response, “Well, it is very interesting intellectually, but there is no real clinical relevance that has been proven for this.” How would you respond because I’m sure you’ve had that point brought to you? New Methodology for Examining DNA Adducts in Urine has been Developed ER: I’m happy to say that that is now an incorrect statement because we now have one very small study published, and another one in press, and we are writing up a third study, and finishing a fourth study. I should really backtrack and say that in 2003 we published a study looking at breast tissues from either women who didn’t have breast cancer or women who did have breast cancer (but we didn’t look at the tumor tissue, we looked what we’ll call “normal” tissue from the same breast).13 What we found was that the biochemistry had changed. In the women with breast tumors we saw higher levels of the 4-catechol estrogens and also some conjugates from them (at that time we couldn’t measure DNA adducts but we could do it with the conjugates), so it was clear that these quinones were forming in greater amount in women who had breast cancer; that is the first study that we did. Now we have developed the methodology to look at urine samples (and that’s what we have published and I’ll just say, parenthetically, we can do the same thing in serum) where we’ve taken urine samples, in one case, from three different groups of women. One group was the control group of women who were healthy and had a low normal risk of breast cancer. A second group was women identified by oncologists, due to a variety of characteristics, as having high risk of breast cancer. And then there was a third group of women who had breast cancer. We are now able to look at their urine samples and look at 40 different estrogen metabolites, conjugates, and, most importantly, the DNA adducts that I have described as coming from the catechol estrogens. What we find is that the level of the DNA adducts indicating that their DNA has been damaged by the catechol estrogen quinones are significantly higher in women at high risk of breast cancer and women with breast cancer compared to the normal women of low breast cancer risk. This is highly significantly different between these populations. What this suggests or tells us is really two things. One is that it appears the estrogen DNA adducts are biomarkers for risk of developing breast cancer, and it makes it clear for the first time that these adduct levels are high; that the DNA damage has already happened in women who don’t have breast cancer yet, but they are at high risk of it. I think that is the groundbreaking, really paradigm-shifting research that has now been accepted for publication. JB: Congratulations to you and your colleagues. That is a very big step forward and hopefully people who have had blinders on will get a little neuronal plasticity and be able to look at this work and its significance with a clean slate. One of the things that has been so extraordinary, I believe, for the field is the discovery that you have made that this not only applies to women, but now has application to men. I thought the recent publication from your group in Journal of the Prostate in 2006 on the potential biomarkers for early risk assessment of prostate cancer following the same model was groundbreaking.14 I think there are still many, many, many people in the medical profession treating patients (males) who have prostate cancer who don’t understand this estrogen connection at all. Maybe you could help us to understand this a little bit better. Relationship to Prostate Cancer ER: Okay. Actually I have to give credit to another scientist named Martin Bosland, who, in the middle 90s, developed a model for prostate cancer in rats. He developed the hypothesis and found that if these rats were treated once with estradiol and then he implanted them with testosterone, all of his rats developed prostate cancer. He developed this idea that estradiol initiates prostate cancer and then testosterone promotes the tumors. That is really the fundamental hypothesis of the role that we think estrogens play in the development (the induction) of prostate cancer. Following up on that idea, we had a small group of samples of men with prostate cancer or control men who were not diagnosed with prostate cancer. In that first paper we only measured one type of DNA adducts-the ones that are formed with adenine bases-but, indeed, in that (which we did with a colleague at Kansas State) we used three different independent analytical methods and saw exactly the same thing, which is that the men with prostate cancer had high levels of these adducts in their urine samples while the control men had background levels that were right at the level of our ability to detect anything by any of these methods. The study was a little funny (humorous) in our lab because we had gone to great lengths to try to improve the sensitivity of our analytical method and then when we actually measured the samples from the men with prostate cancer we had to go back and scale everything differently because the levels were so high. We published that, as you said, in 2006. We have now repeated that in a second set-a larger set-of men, with and without prostate cancer. This time we have done it the same way we have done with the women in which we analyze the 40 estrogen metabolites, conjugates, and DNA adducts, but we got the same result: a highly significant difference in that the men with prostate cancer had much higher levels of estrogen DNA adducts in their urine compared to the control men who don’t have prostate cancer. How I think we can relate this to prostate cancer is by thinking about the estrogens men have in lower levels than women but that can (if metabolized wrong) start the process that ends up leading to prostate cancer. I’d like to make a little point here that relates to this because men, obviously, have much lower levels of estrogens than women do. In our experience, our hypothesis, and our findings it is not the level of the estrogens, it is how their metabolism is balanced. There are two or three enzymes that we think of as activating enzymes (for example, cytochrome P450 1B1) that push the estrogens toward making these reactive forms, but then there are two or three enzymes that we consider protective enzymes and they tend to push this whole process back toward the catechol estrogens that are not reactive. We think that for each person there is a balance of this process (the activating against the protective, or deactivating enzyme activities), and hopefully a person is kind of in a homeostatic balance where you don’t get large amounts of the adducts formed. We think this relates to genetic factors (the balance of enzyme activities), but also is influenced by diet and lifestyle and environment–those kinds of other issues. JB: I am very fascinated. As you describe the more recent work in men with prostate cancer and DNA adduct formation–I’m going from memory here so I may be wrong–it sounds very reminiscent of the kind of results that you got under controlled conditions a number of years ago with animals where you actually treated male animals (as I recall) with 5DHT and with the estrogen metabolites. I think in the animal model you showed some very similar results, didn’t you? ER: We did. We do have a paper on that (we collaborated with Martin Bosland on that).15 JB: Yes, I thought so. So this all holds together-it sounds to me-very, very consistently. ER: It does. One of the very satisfying things for us now is we are doing a lot of work in a cell culture system that has human breast epithelial cells and they have been immortalized so they continue to grow, but they are not transformed, and when we treat them with the estrogens (with estradiol, for example), we not only see the DNA adducts form, but we also can get the cells to transform to malignant cells. We can affect this process by modulating the levels of these different enzyme activities. JB: So, now I am going to ask you what I think is a complicated question so I’ll try to make it as clear as possible. I have heard in conversations with some people in the scientific community that this association that you’ve discovered with your colleagues is very good science and well done and irrefutable, but it doesn’t necessarily demonstrate that the formation of the catechol estrogens is the limiting step in this process; it could be other factors that regulate adduct formation that are beyond the 3,4, the 2,3 catechol estrogen formation. What would be your response to that? ER: My response would be that in a sense it is always hard to prove a negative. You know, to prove that there is nothing else involved. I think the fact that we can now see that by changing these enzyme activities and getting more adducts formed or fewer adducts formed and then seeing that in concert with that the human breast epithelial cells either transform to malignancy or they don’t, that that is very strong evidence that this is what is playing the key role in transformation. To our disappointment, we haven’t been able to demonstrate this in animals because there isn’t really a good animal model for this. There is this male prostate cancer model, but it is pretty complicated and it hasn’t lent itself to really definitive studies, and there is no good animal model for this for breast cancer. So that is disappointing. I have to acknowledge that we could never say that at this point this is carved in stone, but I think there is a lot more evidence for this than there is for anything else. JB: That leads us to how these things are modulated, both in a positive and a negative way. Let me first start with probably one of the more controversial areas-that is the WHI and the HRT studies. Do we know anything about HRT, at this point, in adduct formation, or is that still an area of research? ER: No, we don’t know anything about that. We actually had hoped to be able to do some analyses on samples from the Women’s Health Initiative, which could have given us information on that, but it turned out that their sample sizes are too small (the size of the samples-the volume) for our level of technology at this point. So that hasn’t worked out, and we have not yet secured funds to look at HRT. JB: So let’s move from there. You already alluded to some of the xenoestrogens and environmental polyaromatic nuclear hydrocarbons and other kinds of compounds. How about the nutrition area? Are there nutritional agents that both encourage and discourage the formation of the catechol estrogens? ER: There are nutritional supplements that do discourage the formation of the adducts. I’d say one of the most widely used ones is N-Acetyl-Cysteine (NAC). There are a number of antioxidants. I haven’t tested this, but I’m certain that sulfurophane, which you find in broccoli, would inhibit adduct formation because I know that it induces an enzyme called quinone reductase and that would take the catechol estrogen quinones back to catechols and they wouldn’t be reactive then. JB: And how about glutathione s-transferase and glutathione reductase? Are those enzymes involved with that process? ER: Well, you know what has surprised us as we have looked at the samples (particularly in women because we have done more but also in men) is we expected that the level of glutathione conjugates in the urine would be a lot greater than the level of DNA adducts, and that hasn’t turned out to be true. They are really pretty comparable. To our surprise, it doesn’t look like glutathione is a big scavenger here-as big a protective agent in the cell-as we thought it probably would be. I would not look to the glutathione s-transferases as being tremendously helpful here. That is a tentative finding that surprised us. JB: That’s very interesting. It kind of points more towards other phytochemicals that might have influence on some of these detoxifying enzymes. That leads to a question. You have been at the University of Nebraska now, I think, since the middle 1970s (somewhere around 1976)? That’s coming up over 30 years and you have been very diligent and really have done some very hard work in terms of this chemistry, which is not easy; these are very difficult metabolites and compounds to measure and to develop the procedures for. How has the University of Nebraska looked at your work, and do you feel like sometimes you have to be away from home with slides in order to really be seen as a leader? Are you starting to be acknowledged within your own place of 30 years? ER: To some extent. I would say that probably very typically a lot of the effort here in the cancer center is aimed at therapeutics and a lot of people focused on curing cancer and making therapies better. Prevention is not so much on the radar screen for a lot of people. However, among the physicians on campus (some of the physicians), there is a great deal of interest in this, and we have always had really great collaboration with various physicians here. In fact, my colleague gave us a translational research seminar about three weeks ago and we had a new clinician come up and make an appointment to come see us because he said he wants to try this out and he wants to give us urine samples from his patients and see what we see with them. In that regard, I think people are very much taking notice and beginning to think about what this could contribute in the future to developing something for the patient population. JB: That’s very exciting. I guess part of driving this will be the ability to assess biomarkers in patients. Often we don’t think about that which we can’t see. Where are we in the future, do you think, in developing a method for evaluating, clinically, these adduct biomarkers? Anticipated Clinical Applications ER: What we are doing now in the laboratory in analyzing these compounds could actually be done as special chemistry in a clinical lab. We know the guy in charge of that here and he’s got a mass spectrometer that’s basically just like ours. It would be fairly cumbersome, though. One of our goals in the near future is to probably work with a company that makes mass specs in order to develop this so it could be more routine for a clinical lab. The assay is there; it just would be a matter of how to make this so any hospital lab could do it and they get a good result. We also have a colleague-an analytical person-who has been working for several years now to try and make a chip-based assay. We have monoclonal antibodies to the DNA adducts, and to use that approach. So we are working in both of those directions. JB: On behalf of all of our listeners I want to thank you. The diligence that you have put into this work and how it is evolving and your most recent, really exciting results in women with breast cancer and with prostate cancer in males is extraordinary and I think it just once again demonstrates (for all of us) the importance of committing ourselves to an idea and working through the barriers and the challenges and watching things evolve, knowing that the work is not always easy. I think you’re really making an extraordinary contribution and I believe-you used the word “translational” science-we are going to see your work actually open doors for all sorts of translational science. It will, in fact, result in what you talked about in your introduction, that is, the reduction of risk and incidence of cancer. I want to thank you so much for making this information available to all of us. ER: You’re welcome and I have enjoyed discussing it with you. JB: We’ll check in again soon. Connections: Nutritional Hormesis, Xenohormesis, and Neurohormesis Dr. Rogan talked about translational science and I think it is a really interesting case in point to look at what translational science means in terms of her eloquent presentation and the extraordinary work that she and her group have done in this DNA adduct and breast and prostate cancer area. That takes us back to where we were in the December 2007 issue of Functional Medicine Update, talking about nutritional hormesis and xenohormesis and how these interrelate to cellular function and protective effects of low-level stress compounds on inducing gene expression that encourages anti-stress response of the cell. Is there a segue or a connection between what we heard in December 2007 and what you are learning from Dr. Rogan in her most recent work in January 2008? As an example of the connector between these two issues, I would like to cite a recent paper that appeared inTrends in Neuroscience that came out of the Laboratory of Neurosciences National Institute on Aging, the intramural research program in Baltimore, Maryland.16 This is the work of Dr. Mark Mattson and his colleagues that I think is very insightful because it speaks into this whole topic that we were just discussing, which is the question of how you prevent these untoward events that lead to these DNA adducts that might initiate cancer of the breast or prostate or other tissues. As Dr. Rogan pointed out, some of this relates to altering things like detoxification pathways through gene response elements like nuclear regulatory factor 2 (or NRF2), which is a regulatory factor that is very important for turning on and turning off the genes that are associated with detoxification. And that associates with the antioxidant response element genes that are associated with protection against oxidative stress and these are all woven together and they have loci on the genome that are in proximity to one another, and, in fact, they have similar regulators. Their regulatory elements (their response elements) share homology. Is this coincidental? Very little in nature, probably, is coincidental. These are interrelated patterns of metabolism and the relationship it has to antioxidant response element and to detoxification enzyme production as a consequence of upregulation of things like NRF2. How does that relate to hormesis and various phytochemicals that can help to improve redox potential in cells, shift to greater levels of detoxification, and lower the levels of the secondary metabolites that are associated with carcinogenesis? That is what this article by Mattson talks about: low-level substances that induce adaptive stress responses (these hormetic phytochemicals). I think we have been talking about this at some length, but this is just another example of where this might apply. Plant cells contain many different chemicals that exert biological effects on organisms that ingest them, and considerations from evolution suggest that many of these phytochemicals with biologic activities are beneficial for mammals. They evolved as toxins that protect the plant from insects and other damaging organisms and actually serve as anti-stress compounds by the humans that eat them. They have effects upon regulatory pathways associated with reducing chemical and various environmental stress factors. As you probably know, there are thousands of such compounds that have been found within plants. These are secondary metabolites in plants we call phytochemicals and include such things as flavanoids, and terpenoids, and alkaloids, indole-related compounds like indole-3-carbinol, which we know upregulates the formation of the 2-hydroxy estrogens. Things like the monoterpenes, eugenol, the essential oils, for instance, have these properties of affecting the detox response elements, as well as the antioxidant response elements. The question is, when you eat a diet that is rich in these compounds, how do they influence, then, the metabolism of carcinogens and/or the effects on cellular redox potential (the reduction oxidation potential) by lowering oxidative stress? We call those simply antioxidants in the parlance of commonality, but they are really not antioxidants; they are more regulators of gene expression that then control cellular metabolism, oxidoreductive capacity, mitochondrial function, and ultimately the expression of various enzymes that are mono-oxygenases (like the cytochrome P450s) that are involved with detoxification phase I and phase II conjugases. This concept of eating certain dietary factors, for instance, from grapes, we now know about and have talked about with people like Christoph Westphal from Sirtris (about the resveratrol effect upon specific gene induction through SIRT1 genes). We know from previous discussions with Dr, Johanna Lampe from the Fred Hutchinson Cancer Research Institute about the role that sulfurophane plays and other various types of glucosinolates in cruciferous vegetables (the broccoli, cauliflower, cabbage, Brussels sprout family). Two years ago on Functional Medicine Update we talked with an investigator who was looking at the anti-inflammatory effects in rheumatoid arthritis of tumeric’s active ingredient (at least, one of them) called curcumin and how that influences the NRF (nuclear regulatory factors) and the redox elements in inflammation. We know about St. John’s Wort and hypericin, which has effects upon these same regulatory factors. We know about allicin in garlic that affects these regulatory factors, and we know that catechins that are found in tea (both black and green tea) have these influences. These are dietary agents that all influence the processes that Dr. Rogan was talking about, that modulate, through enzymatic activity, the flux of these catechol estrogens into or out of the potential adduct formation. So there is an extraordinary opportunity here to connect together the work that is going on in phytochemistry, in cellular physiology, and in detoxification and oxidative stress research and antioxidants with the relationship that we are talking about with metabolism of compounds like estrogen that can go into these secondary metabolites that can be potentially carcinogenic. I just wanted to make sure that you recognized that when Dr. Rogan was talking about agents in the diet that may defend against the formation of these potential carcinogenic adducts that we are talking about the same types of molecules that are chemoprotective, which we have discussed in many previous issues of Functional Medicine Update. I hope that that leads you into some clinical thoughts about diet modulation and selected formation of pharmacological activities from some of these bioactive compounds from food. Thank you very much for being with us and we’ll look forward to our February 2008 issue.

Welcome to Functional Medicine Update for February 2008. I’m going to state the obvious: we all know that plants make vitamins. What I mean by that is plants have the capability of biosynthesizing what we call vital amines, or vitamins (for example, thiamine, riboflavin, and pyridoxine). Plants have this capability of producing the complex array of substances that are necessary to support mammalian metabolism and serve as co-factors and/or antioxidants. They make tocopherols (vitamin E), and they make ascorbic acid (vitamin C). This edition of Functional Medicine Update is going to be an update not only on the role of plant-derived vitamins on physiology, but also the thousands (literally) additional secondary metabolites plants make called phytochemicals and the role they play on physiology. Secondary metabolites make this lexicon of bioactive components from plant foods much, much broader than we previously recognized when we thought that plants only made vitamins. We now recognize the therapeutic potential of substances that come out of the plant kingdom is extraordinary. And I’m not just thinking of anti-cancer substances or anti-depressive substances, but I am talking about a whole array of hormetic substances (nutritional hormesis is a topic that has been identified and defined in previous editions of Functional Medicine Update). The Mechanism of Secondary Metabolites Secondary metabolites are small molecules found in foods that modulate signal transduction processes in a cell in a tissue-specific way to induce altered phenotype through altered effects on the epigenome. Through genetic expression, proteomics, and metabolomics, this complex process weaves its way and ultimately gives rise to the outcome of health of each individual (their function). It is the interface between functional medicine and nutrition (this transduction process) that is modulated, in part, through nutritionally hormetic substances. This is going to be the topic of this month’s Functional Medicine Update. Let’s start, if we can, with a little back-to-the-future discussion. I want to take us back, in my experience, to the early 1980s when I had the privilege of working (on my sabbatical year) at the Linus Pauling Institute of Science and Medicine. As you know, Dr. Linus Pauling was a two-time Nobel Prize-winning laureate. As far as I know, even today he is still the only person to have won, solo, two Nobel Prizes in two different fields (one in chemistry and one in peace). The Evolution of Pauling’s Interest in Vitamin C In the later years of his career, vitamin C (ascorbic acid) obviously became a major part of Dr. Pauling’s focus, both for its nutritional and pharmacological effects. He was a proponent of vitamin C for the common cold and flu, and his best-selling nutrition books changed the whole complexion of nutrition science and the nutritional supplement industry, and even medicine, to some great extent. Even those who railed against the concept that vitamin C taken in supplemental doses could have any positive health benefit still were challenged to the task of thinking about their discipline in a different way-looking at nutrition from a different perspective. We might consider that time as the dawn of the new era of nutrition, and now we are starting to witness it unfold in the 21st century. Pioneers like Roger Williams and Dr. Linus Pauling really helped guide us into this new era. I was talking with Dr. Pauling in 1982 about vitamin C and asked him a question I’m sure he had been asked tens of thousands of times: How did he come to this vitamin C connection and his interest in it? He said there were two reasons that his interest peaked around ascorbic acid. One reason was his meeting of Dr. Irwin Stone. Some of you who have been in this field for many years will certainly remember him. Dr. Stone was a PhD who had looked at the evolutionary changes in biosynthetic capability for vitamin C in different animals and found a mutation in the human genome that resulted in a loss of the enzyme L-gluconolactone oxidase a few million years ago, which then resulted in the inability of humans to biosynthesize vitamin C from glucose. Vitamin C biosynthesis is able to be done in virtually all other animal species except the fruit bat, the guinea pig, and the human, who have lost the ability to manufacture ascorbic acid from the biosynthetic pathway coming out from glucose. There are people who still maintain some resident ability in their own genome to biosynthesize vitamin C, which is a fascinating part of the story (it is kind of a legacy from the past). They still have a little bit of that L-gluconolactone oxidase activity, which is activated under stress. As Irwin Stone talked about in his early works, and then later Dr. Pauling talked about, animals like the goat synthesize 100 or so milligrams of vitamin C a day under low stress conditions. When they are put under high stress, biosynthesis of vitamin C will be activated some ten-fold and produce thousands of milligrams of vitamin C. The goat has about the same body mass as a human, so why is it we don’t feel that we need more vitamin C under stress? We can’t make it, like a goat does. We can’t turn on our liver to manufacture more ascorbic acid from glucose, so maybe it becomes a conditionally essential nutrient at higher doses for us under physiologic or environmental stress. That was a very interesting part of Dr. Stone’s anthropological arguments and also Dr. Pauling’s. That was one feature that got Dr. Pauling very interested in the vitamin C/ascorbic acid story. The second was a personal experience (one of which many of you may not be aware of). The Linus Pauling Institute archives are now on the worldwide web. Much of his correspondence and early letters are now digitized, so those of you that are “Paulingophiles” can go back and find out a lot about the conversations and communications that Dr. Pauling was having with scientists, politicians, policy makers, and thought leaders around the world over this dynamic period in the 30s, 40s, 50s, 60s, and 70s. I find it personally very interesting that so many of the letters, if you go back into his archives and you look at the letters that were written in the 50s, were actually typed on the same typewriter he was still using when I was at the Institute in the 80s. Each typewriter has its own unique kind of thumbprint, and you can actually see this in the letters that were written (in terms of the print style, the same compositional uniqueness was maintained into the 1980s). The 1950s was an interesting period relative to Dr. Pauling’s understanding of vitamin C. At that time, you’ll recall, he was at the California Institute of Technology in Pasadena. Around 1950 or 1951, he and his wife Ava Helen were attending a scientific congress on the east coast. Back in the 1950s, airplane travel between coasts was not common; therefore, to return from this meeting in New York to California they were on the train. He developed a very severe back problem during this trip, and later it became known to him that it really wasn’t a back problem; it was a kidney problem. By the time he arrived in California at the end of this trip, he had very severe kidney-related inflammation. He went to one of the most renowned nephrologists at Stanford University School of Medicine, who basically said, “You need to go on the Addis Program.” The Addis Program (developed by Dr. Thomas Addis), was a protein-modified diet coupled with (very interestingly) supplemental vitamin C at high dose, which at that time was a very new substance that you could get in purified crystalline form. The diagnosis at this time for Dr. Pauling was Bright’s disease, which is what chronic glomerular nephritis was called back in this period (all kinds of kidney inflammatory disorders were lumped under one title called Bright’s disease, named after the gentleman who discovered the origin of this condition). Dr. Pauling was placed on this specific intervention, which was extraordinarily successful for him. He became a real believer that this glomerial nephritis/Bright’s disease treatment with the dietary intervention developed by Thomas Addis at Stanford University using supplemental vitamin C had some unique characteristic that deserved his attention. It was a combination, I think, of Irwin Stone and his own experience with Bright’s disease and vitamin C that resulted in-for the rest of his life-interest intellectually, clinically, and scientifically in the role of vitamin C in human health and disease. What I find interesting is that it is often said that supplemental vitamin C causes kidney stones and so people are very worried about vitamin C and kidney disease when taken at supplemental doses above 6 grams a day. But if you actually go to the literature and do a fairly significant and complete survey, you’ll find there are virtually only a couple of clinical observational case reports on kidney stones being produced by vitamin C at high doses in people that were marginally undernourished, so you already wonder about the confounding variables. There are a number of other reports indicating that supplemental vitamin C taken by people with urogenital infections or who have kidney inflammation actually had positive clinical outcome and effects on their situation. I think Dr. Pauling’s own case experience was a very interesting kind of point on the curve related to, starting back in 1951, his journey down the vitamin C path. This journey ultimately led into all sorts of things, one of which was collaborative work with Ewen Cameron, a Scottish surgeon, on vitamin C and cancer. When I was at the Institute in the early 80s, this debate was heated because there was extraordinary work being done under the oversight of Dr. Moertel at Mayo, who found that vitamin C didn’t have a positive impact on cancer outcome. The impact of vitamin C on cancer was debated among Moertel and Pauling and Cameron at some length. Coming now into the 21st century, we start to see retrospective studies being published that demonstrate that intravenous vitamin C does appear to have a positive benefit on patients with various forms of cancer, particularly noted in their energy and quality of life, and possibly even their survival (although that probably is still open to some level of controversy). There was a nice review published in Integrative Cancer Therapies in 2005 titled “Orthomolecular Oncology Review: Ascorbic Acid and Cancer 25 Years Later.”1 Some very nice work done by Dr. Mark Levine at the National Institutes of Health has also recently been published. Dr. Levine is an endocrinologist who has been studying, the effect vitamin C has on human physiology using in situ kinetics under rigorous conditions. He has been able to identify (once again) that there is (at least from a fundamental mechanistic understanding) a rationale for the use of higher-dose, supplemental vitamin C therapy during certain kinds of oncological events.2 Although Dr. Pauling was discounted early on by many of his colleagues when he came to the concept of supplemental vitamin C as being beneficial, as we learn more over time, we recognize the multiple effects that these interesting small molecules derived from plants have on physiology, I think some of his conceptualizations look a lot more reasonable today in light of these new discoveries than they looked to some back in the 50s, 60s, 70s, and even 80s. I think we should keep the jury out on this, but certainly the vitamin C story is a lot more than just the prevention of scurvy. I think we can say that with absolute assurance.” Antioxidant” is too Simple a Term When we question the role phytochemicals have on function, they are often relegated to a simple term, which is antioxidation. I think that is essentially an oversimplification because what we are starting to learn is that “antioxidant” is a very general term that doesn’t relate specifically to how that molecule or collection of molecules interface with different cells, different tissues, or different organs with specificity to induce different cellular or functional outcome. I think what we are starting to recognize is that these “antioxidant effects” really surround bioenergetic effects that these nutrients have by regulating cellular physiology in a very specific way, through signal transduction processes. We shouldn’t generalize, I think, to just say “antioxidants.” We ought to be talking about the specific role that families of molecules derived from plant foods have on specific cellular functions. With that in mind, let’s talk a little bit about what happens when you get dysfunctional bioenergetics. Other than the person is tired, worn out, can’t think straight, has muscle mass loss, and their immune system has kind of gone awry (the kind of gross effects of low bioenergetics), at the cellular level what we see is oxidative stress often occurring with free radical pathology. It could be from oxygen radicals or nitrogen radicals, but we have lost the ability to regulate these intermediary molecules that are high energy, promiscuous molecules called free radicals that can damage macromolecules like proteins, nucleic acids, or lipids and cause cellular injury. The concept of keeping the mitochondrial bioenergetics intact is a very fundamentally important part of any positive intervention program in nutritional therapy. The reason I threw the term “mitochondria” in there is that the mitochondrion is the site of bioenergetics in the mammalian cell. In the plant, the chloroplast is where a lot of the energy is transduced from the capturing of photons of light from the sun. The comparable site of reaction for that function in mammalian cells, or eukaryotic cells, is in the mitochondrion, the energy powerhouse where oxygen is utilized, water is produced, and substrates such as glucose, fatty acids, and amino acids are burned as fuel in the process of respiration to give rise to an ultimate building of reducing power in the cell through ATP and NADPH and other high energy co-factors that help to maintain structure and function to the cell, and that are powered by this furnace, or energy powerhouse, called the mitochondrion. As the cell becomes dysfunctional as a consequence of breakdown in the integrity of the cellular processes, it then translates into altered mitochondrial function increased release of these secondary oxidants that we call free radicals, that then injure the cell and cause, ultimately, cellular death or suicide that we associate with apoptotic changes, leading to programmed cell death or to induced cellular death and pathology. So maintenance of mitochondrial function, as we have all learned, is extraordinarily important for the prevention of oxidative stress and the role that “antioxidants” are presumed to have in some way influencing bioenergetics and mitochondrial function and preventing oxidative injury. What is the effect of a sublethal mitochondrial stress on physiological function? That was the discussion in a Medical Hypotheses article in 2006 in which the authors talked about a term called “mitohormesis.”3 Mitohormesis takes the term “hormesis” (small substances having larger physiological effects) and applies it to the mitochondrion. In this particular article, the authors are looking specifically at the role that dietary phytonutrients (or phytochemicals) have serving as mitohormetic agents-agents that stimulate proper mitochondrial function. So rather than talking about these phytochemicals as antioxidants, we are (in this case) giving them a more specific role: they influence the signal transduction process (what translates the outside world to the inside function of the mitochondria) and then regulate mitochondrial function to prevent it uncoupling and producing oxidants and engaging in oxidative stress. The Impact of Uncoupling Reactions Under conditions where the mitochondria has lost its functional integrity and you start to have phase transitions in mitochondrial oxidative phosphorylation and the production of more oxidants (the so-called uncoupling reactions), what we can then have (even in mild mitochondrial uncoupling) is impact on myocyte function (on muscle cell function), and that induces sarcomeric changes, which then causes metabolic sarcopenia (the loss of flesh). You start to see injury to muscle, muscle apoptosis, and lowering of muscle mass, and this may be a contributor to the process that we see of lowered strength and vitality with aging (as we start getting this increased oxidative stress effect). I’m now quoting, actually, from a nice paper that ties together this mild mitochondrial uncoupling and its effect upon muscle cell integrity in vivo and how that relates to cellular aging. This was in the Proceedings of theNational Academy of Sciences, volume 104 in 2007.4 I think this is some very nice work using magnetic resonance spectroscopy studies and looking at phosphocreatine and ATP levels in muscle, which is an indirect measurement in the whole organism of mitochondrial function and muscle cell activity. The results showed that even mild uncoupling of mitochondrial function led to decreased muscle cell bioenergics and increased oxidative injury in muscle cells. This is work actually out of the University of Washington, Department of Physiology and Biophysics, using NMR technologies to evaluate, in whole, exercising muscle in intact human beings (their bioenergetics). This is not just an esoteric topic. As I connect this to other work, I believe we can actually observe it, even in fairly mild cases of mitochondrial uncoupling. These are not constitutive mitochondropathies, where we are talking about people who have inborn errors of mitochondrial genetics. Here we are talking about induced mild mitochondrial uncoupling that is a result of environmental factors-things like insulin resistance, metabolic syndrome, hyperinsulinemia, high uric acid levels, high inflammatory cytokines as a consequence of inflammation. I think this study is important because all of these induce alterations in myocyte mitochondrial function and cause mitochondrial uncoupling and oxidative stress. It is a little bit like a dog chasing its tail: once you get this started, it tends to run around on itself as a self-perpetuating cycle, so you have to break the cycle. You have to break the cycle and put back the integrity of the energy powerhouse of the cell, which is the role of the mitochondria. Mitochondrial Dysfunction Can Affect Cognition The mitochondria is the center for signal transduction as well as bioenergetics. It plays a very important role in regulating intracellular signals that modify organelle function within the cell and signal to the nucleus in the genome messages that help regulate gene expression and ultimately proteomic effects within the cell. There was a very nice paper published in Free Radical Biology and Medicine in 2004 talking about mitochondrial dysfunction and how it relates to oxidative stress.5 It can ultimately lead to things that impact cardiovascular function and neurological function, and is particularly seen in things like epilepsy, central nervous system problems, or seizure disorders, where the brain and heart are very dependent upon mitochondrial integrity for their function. We recognize that even modest interruption-or let’s call it mutation-of mitochondrial DNA as a consequence of oxidative stress can have an adverse effect upon cognition. This has been shown in animal studies where inducing mitochondrial oxidative injuries to mitochondrial DNA leads to poor performance in mazes by animals and an increase in what you would call biological age with reduced cognitive and memory effects in the animal. By the way, this was found in Nature Genetics, volume 35, page 65.6 Mitochondrial Dysfunction and Insulin Resistance An interesting paper published in the New England Journal of Medicine a number of years ago-this was in 2004-showed that impaired mitochondrial activity, as a result of type 2 diabetes and insulin resistance, has adverse effects upon muscle cell function and on neurologic function, and may contribute to the impairment and the progression of degeneration seen in type 2 diabetes.7 In fact, mitochondrial dysfunction is associated very early on with insulin resistance. They are very closely tied together, the metabolic syndrome and mitochondrial dysfunction. Again, I want to emphasize I am not talking about constitutive inborn errors of mitochondrial function. I am talking about induced effects that occur as a consequence of altered environment and altered physiologic status, in this case hyperinsulinemia/insulin resistance being associated with mitochondrial dysfunction. This was published in Science magazine.8 I think we can say there is a very close correlation between chronic disease-neurologic, cardiovascular, metabolic disease-and the relationship to altered mitochondrial bioenergetics, oxidative stress, and how that may relate to the need for specific phytochemicals that modulate intercellular signal transduction and can put these functions back on the rails, so to speak. Phytochemicals can help to regulate altered control points that are set points associated with bioenergetic dysfunctions. Metformin has a Positive Effect on Mitochondrial Metabolism Looking at type 2 diabetes as an example, if you intervene with a drug like Glucophage (or metformin), what you find is that metformin has a positive impact on mitochondrial metabolism.9 It reduces mitochondrial oxidative stress, which is one of the benefits it imparts in the management of type 2 diabetes and subsequently has an effect on improved insulin signaling. These are pleotrophic effects that these drugs (or these agents) have, similar to what we see with some of the phytochemicals (they don’t just affect one function, they have effect across the broad array of function). That is why I think the term “antioxidant” that we apply to these plant-derived materials like vitamin C (we certainly could talk about a whole array of other phytochemicals) is too simplistic a term. We know that once insulin has been normalized, it helps improve biochemical function and bioenergetics and lowering of oxidative stress within the mitochondria. It is kind of a push-pull argument. You could say that improving biochemical bioenergetics at the mitochondrial level will improve insulin signaling, or you could say improving insulin signaling improves bioenergetics and reduces mitochondrial oxidative stress. In some senses, I guess you would say that those therapies that improve insulin sensitivity are antioxidant by nature because they improve mitochondrial bioenergetics, as contrasted to those interventions that enhance mitochondrial dysfunction and are associated with increased insulin resistance. High Sucrose Diet and Mitochondrial Bioenergetics Let’s have an example. Let’s give a very high-sucrose diet to animals and look at what effect it has on mitochondrial bioenergetics, skeletal muscle, and liver function. What we find in these studies is that a very high-sucrose/high-sugar diet induces mitochondrial dysfunction, oxidative stress, and is associated with altered skeletal muscle and liver function and increased apoptosis (cellular death) in those tissues.10 I want to emphasize that these are animal studies in which the sugar percentage calories have been greatly exaggerated to try to make a point, but I think what we are seeing (at least from the implied work of these studies) is that there can be an affect mitigated by environmental choices on mitochondrial bioenergetics. If you eat a diet that is devoid of phytochemicals, or you eat a diet that is very high in fat and sugar, you are pushing mitochondrial bioenergetics and intracellular signal transduction towards the state of oxidative injury and towards an altered state of inflammation. We know this dysfunction occurs in the mitochondria of type 2 diabetics. We now have some sense as to the molecular mechanisms that may show how this occurs in the cell (the mitochondrial dysfunction) and its relationship to insulin signaling. And we know that insulin regulation of mitochondrial proteins adversely affects, or has an effect upon, oxidative phosphorylation in human muscle. This story has certainly expanded in its depth and density over the last 5 to 10 years such that I think we can say that the environment does, in fact, influence mitochondrial bioenergetics. That we don’t have to use the story of mitochondrial dysfunction as only an inborn error of metabolism story, and that we can now look at an induced effect caused by altered lifestyle, environmental factors, exposure to chemicals, exposure to radiation, or exposure to stress-all of these, then, can have impact upon bioenergetics. If we then take away the signal transduction normalizing substances, which are the phytochemicals in the diet that were part of our human history, that then further tips the balance towards increased dysfunctional signaling and altered bioenergetics Clinically, what does this map against? I’ve talked about cardiac disorders. I’ve talked about neurological disorders. I’ve talked about dysinsulinism associated with cardiometabolic syndrome or with type 2 diabetes. What about things like the disorders of the 21st century? Chronic fatigue syndrome, fibromyalgia syndrome, multiple chemical sensitivity syndrome, Gulf War syndrome? As you probably know from previous editions of Functional Medicine Update, we have talked at length with experts in the field on this very topic. Dr. Paul Cheney was one of our extraordinary contributors in our clinician-of-the-month discussion about oxygen being a potential antioxidant when given in the right concentrations, and low oxygen tension (ischemia) being a pro-oxidant. We have talked with Dr. Martin Pall twice as our Functional Medicine Updateclinician/researcher of the month column about the work of nitric oxide, its relationship to peroxynitrite, how that relates to oxidative mitochondrial uncoupling through the activation of the immune system and inflammatory response, and how chronic fatigue syndrome and fibromyalgia may be considered conditions associated with mitochondrial dysfunction and with this whole concept of inflammatory disorders and altered cellular signaling at the cell pathology level. Erythrocyte Damage in CFS Patients Recently it has been reported that if you look in the red blood cells of chronic fatigue syndrome patients, you will find very significant evidence of erythrocyte oxidative damage. This was published in the Archives of Medical Research in 2007.11 This study implies there is a strong likelihood that this increase in erythrocyte oxidation seen in CFS is a manifestation of what occurs as a consequence of systemic increased inflammatory and oxidative response to the condition. So the identity of the triggering agent is still open for discussion, but the pathophysiology of chronic fatigue syndrome and fibromyalgia seems to have a relationship to the same story of activation of oxidative injury. If you look in the literature for correlations between oxidative injury and multiple chemical sensitivity, or oxidative injury and fibromyalgia, you’ll see a number of published papers that provide strong support for this model. In the Federation Proceedings Journal (the FASEBjournal), a paper authored by Dr. Pall showing that N-Methyl-D-Aspartate (NMDA) sensitization and stimulation by peroxynitrate/nitric oxide, as well as organic solvents, may be a mechanism to explain chemical sensitivity and it ties together with mitochondrial uncoupling and oxidative stress.12 Another paper that was published in Environmental Health Perspectives in 2003 discusses elevated nitric oxide/peroxynitrite as it relates not only multiple chemical sensitivity, but also to neurological disorders and ties together multiple chemical sensitivity to, again, mitochondrial uncoupling.13 I think we are starting to witness a very interesting evolution of our understanding of the etiology of some of these complex disorders that associate themselves with muscle pain, cognitive dysfunction, immunological dysfunctions or lymphadenopathy, generalized bone weariness, and inability to think clearly (“foggy brain” syndrome). All of these may be early manifestations of these conditions of oxidative stress/mitochondrial uncoupling. And that begs the question, of course: what role does altered diet (if any) play in both progression of these conditions, and maybe their remediation, by changing the diet to enhance the level of intake of specific cellular signaling substances (i.e., phytochemicals) that can modulate these processes? Dr. Bruce Ames, a world-renown investigator in this field (Professor Emeritus at the University of California, Berkley, Department of Biochemistry, and recently now working extensively at the Children’s Hospital Oakland Research Institute), has authored a series of papers offering up some of the therapeutic potential that derives out of this model, one of which is an article titled “A Role for Nutritional Supplements in Optimizing Health,” what he calls “The Metabolic Tune-up.” This article appeared in Archives of Biochemistry in Biophysics in 2004.14 Dr. Bruce Ames on Genomic Instability I was very fortunate to be present at a recent Bruce Ames Symposium that was held in his honor at the University of California at Davis on nutrigenomics and the effect of nutrients on the epigenome, and to have a conversation with Dr. Ames. Dr. Ames and I were talking about the role that micronutrients can play-vitamins and minerals and various phytochemicals-on cellular function, mitochondrial oxidative phosphorylation, energetics, and promotion of healthy aging. He said that if we take a gross view of the role these complex families of nutrients, we see that they help to stabilize genome. They prevent genomic instability. Genomic instability is a consequence of all sorts of adverse physiological functions or processes going on, one of which is related to oxidative injury that causes genome instability. Genome instability associates itself with cancer. It associates itself with increased cellular death. It associates itself with cardiopathies and with dysfunctional insulin signaling. His concept is that if we feed the right nutrients in the right doses, we can provide the cofactors and signaling substances necessary to promote proper oxidative phosphorylation, bioenergetics, and mitochondrial energy production. In his article, he talks about the things we all know, but often forget about because they are so simple: vitamin B12, folic acid, vitamin B6, vitamins C, E, minerals such as iron and zinc, which he says appears to mimic the ability to prevent radiation damage in cells and help to stabilize the genome against environmental enzyme difficulties. Preventing Upcoupling with Co-enzyme Q10 Supplementation We also know that there are other cofactors that play roles in these processes, and one of these is co-enzyme Q10 (ubiquinone). There are a series of papers that have been published demonstrating the role of therapeutic intake vitamin Q, or Co-enzyme Q10, has on these processes, one of which was titled “Nutritional Cofactor Treatment in Mitochondrial Disorders.” This appeared in the Journal of the American Dietetic Association in 2003, and is research showing the important role Co-enzyme Q10 has in the oxidative phosphorylation profile, helping to prevent uncoupling of factor 4 and establish appropriate bioenergetics in individuals who have a functional Co-Q10 deficiency.15 These may be people, for instance, on statin drugs. Or it may be people under higher oxidative stress as a consequence of chemical exposure, psychological, or environmental stresses. Co-enzyme Q10, which is not considered a vitamin, as such, becomes a functionally conditional nutrient. For individuals with specific need, doses between 50 and 100 milligrams a day of Co-enzyme Q10 become valuable. We know Co-enzyme Q10 supplements will improve mitochondrial function and tissue levels, not only of CoQ10, but also vitamin E, which helps to maintain proper tocopherol levels in tissues. This was demonstrated in a study published in the Journal of Nutrition in 2003.16 Co-enzyme Q10 works along with another interesting mitochondrially active nutrient (conditionally essential nutrient): L-carnitine. There are a number of papers that have been published over the years on the efficacy of supplementation with L-carnitine for individuals who have compromised nutritional status, increased mitochondrial oxidative stress, and fatigue as a presenting symptom. An interesting paper was published in the journal Nutritionin 2006 on the use of L-carnitine therapy, giving 6000 milligrams a day to patients who had fatigue and were undergoing anti-cancer therapies; the findings showed improvement in mitochondrial function by lowering oxidative stress.17 I think what we are starting to witness is a very interesting relationship between modified nutritional environment and promotion of proper intercellular signaling and bioenergetics, which ultimately regulates the integrity of cellular function. There is a program that has been put out there for treating chronic fatigue syndrome that a number of clinicians are using called The Marshall Protocol. It is built around trying to use some of these cofactor materials like NADH, in supplemental levels, to try to activate bioenergetics and reducing factor.18,19,20,21,22 I think the takeaway that we have had over the years from the papers we have published in this area indicate there is not a silver bullet of any one specific intervention. It is lowering the environmental stress that induces mitochondrial uncoupling and oxidative injury. It is improving intercellular signaling by putting a person back on a diet that is rich and complex with regard to phytochemicals; getting them away from sugar, fat, alcohol, and caffeine in excessive doses; and then properly supplementing specific nutrients, like those that Dr. Ames talks about in his “metabolic tune-up” and the rich array of phytochemicals that regulate bioenergetics. With that as a conceptual framework, let’s move to our researcher of the month, and I think we’ll take this discussion to the next level of your understanding and open up all sorts of new potential doors for both therapeutics and prevention. I would like to introduce Dr. Mary Ann Lila.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Mary Ann Lila, PhD University of Illinois 1021 Plant Sciences Laboratory, MC-634 1201 South Dorner Drive Urbana, IL 61801 We are at that portion of our monthly Functional Medicine Update that I know you and I both look forward to with great anticipation and that is our researcher or clinician of the month section. This month, I feel very privileged to have an individual who is a very well-respected professional in the area of phytochemistry. She is a professor at the University of Illinois, and doing work as the head of the College of Agriculture, Consumer, and Environmental Sciences program, the Global Connect portion of what is called ACES (Agriculture, Consumer, and Environmental Sciences). Beyond that, she has done extraordinary work in understanding the phytochemistry of bioactive components of plants. What got me interested in finding an opportunity to speak with her was a wonderful paper that she authored in the Journal of Science of Food and Agriculture in 2006. It was a perspective paper titled “The Nature-versus-Nurture Debate on Bioactive Phytochemicals: The Genome versus Terroir.”23 Dr. Mary Ann Lila, we welcome you to Functional Medicine Update and want to thank you for giving us some of your valuable time. Let me start with this question first: What got you, personally, into the whole area of bioactives from food and the role that phytochemicals have in nutrition? MAL: It’s interesting because I have been working in nutritional sciences here for the last 15 years, but my actual training-my PhD research-was in plant sciences. So it is kind of a strange, but very useful blend of expertise because most of my colleagues that I interact with in nutritional sciences are very good at doing bioassays on compounds, looking for their mechanisms of action in the human body, but really have very little understanding of how a plant makes these compounds and why a plant is enticed to make certain compounds. Plants are not doing it for altruism; they are doing it for their own survival. It has been a real good blend of talents to be able to use what I know about plants in order to control or to enhance what a plant can do for human health. JB: Let’s talk, just briefly, about the point you just made because for many of our listeners they may not be familiar with this concept about secondary metabolites from plants or even primary metabolites that we call phytochemicals. Why do plants make them? It seems like it takes a lot of their metabolic energy to do that work, and some of these molecules are very sophisticated in structure. Tell us a little bit about why phytochemicals are in plants, from kind of a teleological perspective. Why Do Plants Make Phytochemicals? MAL: That is really, really a good question. It costs the plant quite a bit, in terms of energy, to produce a secondary compound. They are called secondary compounds because they are not essential for the plant to grow and develop. So a plant that is growing under ideal conditions of sunlight and fertility will put all of its energy into simply growing and photosynthesizing. But when it has some kind of stress or insult in the environment, it will cease or slow down the growth process and start putting some of its resources instead into producing secondary compounds that will protect it, perhaps against an herbivore, an insect predator, maybe protect it against intense UV light, salt stress-all these kinds of things that can otherwise damage plant tissues, the secondary metabolites can inhibit those stressors in the environment. A plant, being a sisal organism, really has no choice; it has to chemically protect itself, and it uses a diversity of different mechanisms, not just one magic bullet to do each task. It uses a lot of redundancy-a lot of overlapping chemicals or similar chemicals that all together will protect it. So there are a lot of interactions going on when a plant puts its chemical cocktail together to protect itself. And interestingly, these same compounds that a plant uses to protect itself will interact with human therapeutic targets and help to prevent or provide therapy against human disease, or just enhance the human metabolism, so it is really a huge benefit to the consumer of these plants. JB: Just to give our listeners kind of a quick thumbnail as to the broad range of experiences you’ve had from your research-I’m looking at some of your recent publications that have titles like “Identification of Isoflavone Glycosized from Pueraria lobata…,” “A Comparative Evaluation of Anticancer Properties of European and American Elderberry Fruits,” “Beyerane Diterpenoids from the Heartwood…” and effects that they have, “Serum Testosterone Reduction Following Short-term Phytofluene, Lycopene, or Tomato Powder Consumption in F344 Rats,” “Comparative Phytochemical Characterization of Rhodiola Species,” and so forth.24,25,26,27,28 Obviously, you’ve had a very broad range of experiences looking at these secondary metabolites in plants. Have you found differences in, say, individual cultivars in how they produce the phytochemicals and then, beyond the cultivars, are there differences in how the environment influences gene expression and secondary metabolite biosynthesis in an individual cultivar? That gets into this question of nature versus nurture and how it reflects in the plant (their output). Genotype Differences Affect Secondary Metabolite Production MAL: There are absolutely huge genotype differences in how a single species of plant will produce a secondary metabolite. The reason I have that diversity of looking at all kinds of different phytochemicals that you have just listed is because I’m part of a botanical center for age-related diseases, which is actually based in Purdue, looking specifically at metabolites from plants that will help bone health, or dementia, or other age-related diseases. And then I’m also part of an international cooperative biodiversity group, which is working in Central Asia, looking at plants that have bioactive properties that have been-because they are former Soviet Union-totally hidden from Western medicine for all these years (the whole Soviet regime). Now that these countries (Uzbekistan, Kyrgyzstan, Kazakhstan, and Tajikistan) are independent countries and rather impoverished, they are looking for opportunities to really validate some of their natural medicines that have been hidden from the west and really have some tremendous properties. Now the reason that I have been working specifically in Central Asia is that these are some of the most inland countries in the world. This gets to the whole point of why a plant produces secondary metabolites and what makes different plants produce different metabolites. They are inland countries. That means they are not buffered by the ocean at all. That means they have very hot summers and very cold winters. That means the plants that manage to survive in these environments are extremely stressed, and, as a result, will be extremely jam-packed with secondary metabolites. They may not be beautiful, but they definitely are full of metabolites that have benefit for human health. You mentioned different cultivars, and one of the problems we have is that with conventional breeding-this is not on purpose, but just because we have been selecting plants for beauty, for keeping quality, shipping ability, sweetness-we have been breeding out secondary metabolites in many of our wild species and producing a commodity for the supermarket that has good shelf life and is attractive. One thing that I have looked at quite a bit is going back to the wild, going back to plants that are enduring stress in the wild, that aren’t pampered in the field, and seeing what we can learn about their secondary metabolites what we can do to maybe get some of these back into conventional mainstream vegetables and fruits for the American public. I have also looked at some commodities that maybe haven’t been available (or are underappreciated) in the American marketplace, but maybe are known locally in different countries for their value as foods and medicines. JB: Wow, you have said so much in that… MAL: And I completely forget the original question… JB: No, you didn’t. It just kind of leads me to an exploding series of thoughts. We recently interviewed, on Functional Medicine Update, Dr. Christoph Westphal, who is the CEO of Sirtris Pharma, who has made these discoveries about the SIRT1 and 2 genes and their relationship to certain effects on the epigenome. He spoke about resveratrol, in particular, but he also identified there are many other compounds that they are working on as well. The concept was born out of a discovery and a term that was coined by Dr. David Sinclair at Harvard that I know you are familiar with called “xenohormesis” (that there are small levels of substances that can initiate, through signal transduction processes, larger effects on physiology than we might have expected based upon the small amount that might have actually gotten in the body). So you get this amplification effect of the right molecule at the right place, or the right combination of molecules. You’ve just been speaking to what (probably) Sinclair and Christoph would call a xenohormesis concept, and you have also spoken, I think, to possibly the difference between a product produced by organic agriculture versus that which is produced by a less stressed, nonorganic environment. Is there any validity to that concept (that this might help explain the difference in composition between organic and nonorganic)? Organic versus Nonorganic Composition of Plants MAL: It may well. I have to say that there have been very few scientific, replicated trials to really validate this point. Logically, it makes sense, based on what we know about wild versus cultivated. Organic, being a very low-input crop (low pesticides, natural fertility, a lot more stresses), it makes good sense that organic crop would have higher content of natural phytochemicals, and therefore more health benefit. There really haven’t been a whole lot of replicated trials. I’m not quite sure why that is because it is a real good argument and it needs to be done. JB: Let’s also talk a little bit about another theme that you described for us, and that is the difference between, say, single molecules versus mixtures of molecules. The plant produces, as you said, these families of molecules. In fact, in one of your review papers-I can’t remember if it was the recent Annals of New York Academy of Sciences paper “From Beans to Berries and Beyond: Teamwork between Plant Chemicals for Protection of Optimal Human Health” or if it was in “The Nature versus Nurture Debate on Bioactive Phytochemicals,” but you made the point that plants may produce a different repertoire, or different portfolio, of phytochemicals based upon different environmental circumstances.29 They have the gene potential to produce different families and they select (based on certain growing conditions) which family they will produce. That leads us to believe, then, that there must be some benefit in the “anti-stress” compounds for specific types of stressors as mixture, not as single molecules. MAL: Absolutely the case. I think that is why America has been so slow compared to a lot of other countries in really embracing the concept of foods as medicine because we are kind of a pharmacy-oriented, “big pharma” country. The pharma industry will look at compounds that are of value using high-throughput screens that will look at the effect on one enzyme (multiple samples looking at one enzyme) and that is the bioassay that they use. A plant is very, very different (a plant extract) because it is maybe hitting multiple targets at once, and maybe at lower levels than a single synthetic compound, so big pharma has not been ready to embrace plants as a source of medicine for that reason. Plants change their own metabolism and their own output of secondaries very much in response to the environment. Research on Berries in Alaska I’ll give you one example. We are looking at berries that are growing in Alaska. This is an extremely stressful environment. This is an EPA-funded project because we are looking at this tribal resource (it is native Alaskans who use berries for health, specifically diabetes) and what is happening to these berries in the face of global warming. We are looking at three different locations in Alaska: one that is very, very far north (a whaling village way up on the northern coast of Alaska); one that is halfway out on the Aleutian Islands; and one that is in southern Alaska. We are looking at how the same species of berry will differ in phytochemical composition given its location, and how climate change is actually impacting on not just the survival of these plants, but the compositions of the bioactive compounds in them. In some cases it is not all bad in terms of bioactivity. It is just dependent on how the climate is changing-if it is drought conditions, if it is flood. Warming, in itself, is something that is very much shifting the high antioxidant potential of these berries; it is changing because of global warming. JB: As it changes have you seen different, I guess, ORAC value, or however we would measure (in a gross sense) antioxidant capability of the global warming grown berries? Does it increase the ORAC or does it decrease, or does it change certain characteristics of oxygen radical absorbing capacity? MAL: That’s a long-term study-to actually look at the impact of global warming because it is a slow process-but what we are doing is looking at different environmental locations right now in the state of Alaska (which is a huge state) which have natural changes in their climatic conditions, and measuring differences in the same species based on what is naturally there now and what is shifting, so we can predict how global warming will be changing some of the these. The ORAC values tend…they are extremely high now in Alaska just because sometimes there is 23 hours day length during the growing season, so there is intense UV light. The prediction is that the ORAC may be decreased-that the antioxidant value should be decreased-if they are less stressed (if they have less cold temperature), but this remains to be seen. We need to really be able to look at this over a period of time. JB: One of the questions I have had asked of me, and I think it is a good question that I think you would be much more likely (as an expert) to help us understand is: When a plant is stressed and it produces these anti-stress families of secondary metabolites (be it either to cold stress, UV stress, insect stress, whatever it might be-a different portfolio, maybe for different types of stresses), does it also run the risk, in human consumption, of raising the production of potentially toxic metabolites for the human? I am thinking of an example I learned about with celery several years ago. Celery, when grown under stress conditions, can produce a higher level of compounds that can induce allergy in some people. I guess it begs the question: Does this always produce a beneficial effect for a human who might consume the food? MAL: No, you are quite right. There is not always a beneficial effect, but I would say that the incidence of actually finding a toxic effect is very rare in these cases (under the stressed plants). We always tend to look (in our research) at plants that have a long history of human use. Maybe not known to the American market, but a long history of human use in whatever country we are visiting, so, you know, we aren’t going for something that is going to be a natural toxin. Plants, of course, are wonderful chemists and they have some of the most deadly poisons that are out there, but we are always looking at those things that have a long traditional use. The Bioavailability Question JB: Now another area that I noticed you have been involved with from your publications related to your research is the concept of bioavailability and I think this is another big area of, seemingly, controversy in the field because people have said, “Well, a lot of these bioactive compounds from plants which seem active in a test tube and in vitro experiment and cell culture, when given to animals they are highly bio-unavailable and therefore they really don’t have any effect on the organism. But, of course, that assumes that there is some kind of a direct dose-response kind of relationship and they don’t go through some xenohormetic mechanism. Tell us a little bit about your understanding of this bioavailability question. MAL: It is quite true that when we consume foods and we know a certain compound in the food is bioactive (for example, resveratrol in red wine), sometimes we cannot see the dose response effect that we are used to looking at with synthetic pharmacological compounds. This is, in part, because it is just beyond the limits of the sensitivity of our instruments, and in part because the real way that plants are working is this mixture of compounds, not one single compound that should be increasing in its dose response. Those are complications that have hurt the research, or hurt the acceptance of plants as a source of medicines in the medical community. What we are finding is that the medical industry (for example, the medical practitioners) were unwilling to accept the whole concept of red wine being heart-protective because they didn’t see the bioavailability. Very little of it actually seemed to get into the bloodstream. Now, with more sophisticated methods of measuring metabolites in the bloodstream, we are seeing that what we eat-what we actually consume-is immediately being metabolized into something that we weren’t expecting. In the blood, which has a rather neutral pH, the cyanin, for example, that is in red wine is going to be metabolized into other molecules like chalcones, which are not recognizable as the original compound that was eaten. There may be things we are not measuring because they become something else. One thing we are doing in our lab, which is a little bit groundbreaking but it has been a lot of fun, pertains to some of these plants that produce bioactive compounds, like tomatoes that produce lycopene and all of the lycopene precursors that are beneficial for prostate cancer. We have been looking at grapes and resveratrol and flavonoids in the grapes that are beneficial for cardiovascular and anti-cancer effects and other things as well. And we have been looking at other sources of isoflavones, like kudzu, for example, which is a noxious weed in the south of the United States but it is a wonderful ingredient for isoflavones in Chinese herbal medicine. We have been looking at all of these things and growing them in plant cell culture, or in organ culture (like rapidly growing roots of kudzu in test tubes). When we feed these plants in tissue culture a radioactive source of sugar (radiolabeled source of sugar), the metabolites become radiolabeled. Then we are able to isolate radiolabeled isoflavones, for example, feed them to rodent models, and absolutely see where that label goes. Is it isolated in the liver? Does it pass the blood-brain barrier? How long is it in the bloodstream and how quickly is it excreted? We have been able to see where some of these metabolites, which by our conventional measurements we really didn’t think were getting in there, or we didn’t think that measureable levels were getting into the bloodstream, we are able to see that something is getting in there. Some kind of metabolite from the original labeled compound is definitely passing through the animal and localizing in certain organs. For the first time, last summer, we were able to show, through collaboration with our colleagues at Purdue and the Center for Age-Related Diseases, that flavonoids from grape, when eaten (when ingested by rats), were able to pass through the blood-brain barrier and be localized in regions of the brain, which kind of works for why you have some anti-Alzheimer’s and anti-Parkinson’s disease effects from these metabolites, even though we weren’t able to measure them getting into the brain because we didn’t know what we were looking for once they are metabolized. So this radiolabeling has been a real key to show where these things are going and how they are actually working. JB: That is really fascinating. In essence, it sounds a little like what you are doing is ADME work with natural phytochemicals (Absorption, Distribution, Metabolism, Excretion), which is like a Phase I-type of IND except here we are dealing with nature’s laboratory of phytochemicals. Once you have determined the metabolites and their localization and excretion, then I guess the next question is what is their bioactivity? Could they be more bioactive than the original materials that were put in the mouth? Then you get into ex vivo analyses. You are probably looking at some studies along that line as well, I would imagine? MAL: We are just now, yes. Plant Extracts as Adaptogens JB: That is very exciting. So that raises-for me-a very interesting, provocative question. There are so many interesting questions that are provoked by your work and your comments, but there is one that strikes me specifically. You have described the mixtures of molecules that are produced in response to environmental factors working on the genome of the plant and its unique, specific book of life, and that produces these secondary phytochemicals which then have an influence on the physiology of the plant. Then we consume that plant (possibly-let’s say it is an edible plant for humans), and those anti-stress compounds in the plant then are absorbed at some level and have some impact, either directly or through metabolism as you have just described, and get localized in certain organs or tissues. And then there has been this long-standing question as to whether these mixtures of molecules serve as some adaptogens. That is a term that has floated around in the botanical medicine literature for a long period of time. It is kind of one of those words that doesn’t seem to have a specific definition, but it says that low levels of something help the body to adapt to stress. I am wondering about these compounds that are in these mixtures. Undoubtedly if we did a traditional pharmacological evaluation they would probably have very high IC50s (meaning they would be considered fairly low potency molecules in comparison to a new-to-nature molecule that had come out of drug discovery), but the mixture of these molecules, as you have described them, even though their individual potencies may be low, may influence physiology in such a way as to produce this normalization effect, which is called adaptogenic. Am I at all moving…? MAL: You are exactly right. An adaptogen would be something that increases the nonspecific resistance of an organism. That’s a definition that we use, and actually that is one of the main foci of our work in Central Asia, in the stands, because the Soviet regime was very interested in plant extracts that would (as an adaptogen) help reduce fatigue, increase endurance, reduce hypoxia for soldiers climbing over the mountains, things like that that would enhance human metabolism. Many of the root crops that we have been working with there definitely have these adaptogenic effects. That is exactly one of our areas of research. JB: So this would be like your Rhodiola rosea? MAL: That is one of them and Ajuga is another one (Adjuga turkestanica), which is something that is actually used. In some countries, Ajuga leaves are used in salads, just like Arugula (they are very similar, actually). It is something we haven’t embraced in the United States because we don’t know about it, but in other countries it is used (different kinds of Ajuga). With these kinds of things, what they have is a compound called a phytoecdysteroid. It is a steroid-like compound; it has the same shape as a steroid without the bad effects of a metabolic steroid, so it is a natural, steroid-like compound that increases resistance. Some of these Ajugas have very high levels in their leaves. Spinach is another mainstream vegetable that has low levels of phytoecdysteroids. Maybe back when the Popeye cartoon was on-you know, before a lot of things were bred out of spinach-Popeye wasn’t kidding when he ate his spinach and had the good muscle mass because those phytoecdysteroids really do help in endurance and muscle mass. JB: I’m now going to ask the very provocative, kind of philosophical question. What you have just described obviously is a whole different way of looking at pharmaceutical science. It is a different way of looking at medicinal chemistry. It is a different way of looking at even therapeutic (let’s call it preventive) and chronic disease management than the traditional method that we have taught health providers to practice their medicine from. How long will it take, do you think, to filter this message that you are describing into a place where it can actually make a difference in clinical practice? MAL: You know, we are just at that point now because finally-just in the last few years-we have come up with screening methods that are high content, that we can look at the effect of multiple genes at once (putting a plant extract on a cancer cell line, for example, and look at the effect on multiple genes at once, or doing verse transcriptase PCR to look at multiple targets at one), so finally we have the tools to look at an extract not like a pharmaceutical compound, but has multiple targets and we can get to the bottom of what is working. We have always been very good breeders in this country (well, throughout the world). We can get traits into plants that we want. But we haven’t known what to look for until now. We are just at the breakthrough point where we are figuring out what compounds and what mixtures of compounds are important, and with the correct tools, which we now have at our fingertips, we are able to either put new health-enhancing properties into mainstream fruits and vegetables, or introduce fruits and vegetables from other parts of the world that are underappreciated and under-recognized in the United States and get them into our marketplace so that we have wonderful, health-protective sources so people can responsibly select foods for their own diet and the diet of their families with health in mind, not just calories and nutrition, but health-protective properties. JB: That’s really very, very exciting. My last question is, given that you are an expert in this field, what plant foods do you consider, at this point, most interesting from a health perspective based on these phytochemical arrays and why? The Phenomenal Wild Blueberry MAL: The most exciting one for me has been the wild blueberry. This is a particular species of blueberry (Vaccinium angustafolium). It grows only-only, only-in maritime provinces of Canada and coastal Maine. The reason this is so exciting to me is this berry has such a variety of health-protective effects. We found anti-cancer effects, and not just anti-cancer in that one enzyme is knocked out. We have effects against the promotion, initiation, and proliferation stages of cancer from berry extracts, and different compounds in the berry are giving protection at all these different stages of carcinogenesis. There are cardioprotective effects with wild blueberry, anti-diabetic effects, anti-infection, dental health effects. One of my colleagues at Tufts University is doing cognitive and motor function with age-related diseases and how berries can actually help give relief to an aging patient who has memory loss; it can bring back memory. It is amazing to me that this little berry has such a variety of different benefits for human health. Now, all blueberries are great. All blueberries are in a class by themselves, but the wild blueberry, in particular, has been just phenomenal. JB: That is a really great little insight for us. You make a wonderful comment-well, you make a number of wonderful comments, but one that stands out in the close here is the comment that it is very interesting that some of these phytochemical mixtures derive from plants have effect on physiological processes across a wide range of diseases. It is not like one plant for one disease. It is more of a mechanism, which I think is a very interesting concept. MAL: It is absolutely true. The co-evolution of animals and plants probably contributed to that. It is on a timescale that is beyond my comprehension, but we find plants as sources of biologically active molecules and mixtures that we just simply don’t find in any other source (any synthetic source). JB: If there anything that you would want to leave if you were talking to several thousand health practitioners who are going out to give recommendations to their patients? Is there anything that you would want them to think about as they go into those exam rooms with their patients given all of this extraordinary new information? MAL: Just stay tuned because I really think we are at the point of huge breakthroughs for fruits and vegetables, in particular. People now who want to be proactive about their health are so willing to go into health food stores and buy Echinacea extract and Gingko extract, and not that these things are bad, but they’ll buy these little tablets with exotic things in them, but we have really some specifically health-protective phytochemicals in mainstream fruits and vegetables, and we can enhance those in mainstream fruits and vegetables and bring them to the diet, to the American table. So really, just stay tuned because these things are going to be coming out more and more now that the research is just flourishing. JB: Well, Dr. Mary Ann Lila, I want to thank you so much, both for the extraordinary work you’ve done and for the eloquent way you present it. It gets us all pretty excited about what the future may be for both prevention and maybe even therapeutic medicine where these concepts get integrated more into the exam and treatment room. Thank you very, very much for the time that you spent with us. MAL: Sure enough.   Natural Foods as the “New” Pharmacology We want to thank Dr. Lila, once again, for that extraordinarily insightful and provocative series of comments and discussion about her own work and that of the field. Can you see the future of medicine and where it is going to integrate this “new pharmacology” which I find to be almost an ironic term (“new”). This is historic pharmacology. This is the way we ate in times before standing agriculture, when the foods kind of had evolved through time with us in the largest laboratory experiment that has ever been done: that of evolution and natural selection where the interaction of our food supply with human physiology and its genetic structure was that which had been evolved over millennia. We have obviously intervened and modified this relationship somewhat with standing agriculture and new cultivars, the way that we grow food products by taking the stress off the plants with herbicides and various biocides and fertilizers and sun protection and all of these things change the family of these secondary metabolites that then modulate human function in different ways, so it is a very fascinating chapter in nutritional medicine that we are starting to see opened up. This is providing support to a lot of what has been discussed within the natural foods field for some tens of years. In fact, going back into the 18th century, we saw the origins of these concepts of natural, minimally processed foods having a different effect on physiology than processed foods. It is a very, very interesting chapter in the evolution of our understanding. There are all sorts of extraordinary papers coming from many highly competent research labs around the world that are adding depth and dimensions to this story. In the Journal of Cancer Research, an article titled “Grape Seed Extract is an Aromatase Inhibitor and a Suppressor of Aromatase Expression” was published showing, again, the wide, pleotrophic effects that many of these secondary metabolites have on physiological function in mammals.30 Aromatase is the enzyme that converts androgens to estrogens and it is expressed at higher levels in breast tissues, and (particularly more in cancerous breast tissue than normal breast tissue). There have been many synthetic compounds that have been studied, and some approved (Aromadex being one) for the blocking of the aromatase enzyme to result in lowered estrogen levels in situ in localized tissues. But the question has been raised for some time, were there natural substances in a complex, minimally processed diet that could influence this A-ring aromatization of the steroid nucleus from androgens to estrogens and therefore have estrogen modulating effects? One that has been discovered and described in this particular paper is grape seed extract, containing high levels of procyanidin dimers that have been shown to be reasonably potent inhibitors of aromatase. This-again I want to emphasize-was a combination of in vitro studies and also animal study, looking in vitro at the MCF7 breast cancer cells (these are cells that are immortalized as a consequence of having undergone transition to cancer cells). It has been shown that grape seed extract has a very beneficial effect on preventing the production, locally, by these cells of estrogens from androgen precursors and also in animal interventions was shown to lower the production of estrogens in specific tissues (in this case, breast tissue). It seems to be that these procyanidins have an aromatase inhibition effect, or let’s call it modulating effect, and suppress, then, localized production of estrogen. So that’s just another of the myriad pleotrophic examples that demonstrate the wide range of physiological functions these secondary metabolites can have. Another of those that was described in this session with Dr. Lila was Pueraria lobata (or kudzu) isoflavones, and they have unique estrogen modulating effects as well, which are different than the soy isoflavones — genistein and diadzein. A paper that was published in Plant Medica talks about isoflavones that are unique to the Pueraria lobata/Pueraria mirificafamily and how they influence estrogen receptor activities alpha and beta (without having the estrogen drive for mitosis that you see with 17beta-estradiol) and can modulate estrogen functional status at the receptor site.31 Again, many different influences that these plant phytochemicals have (as we use this kind of complementary concept that agents in plants evolved as anti-stress compounds) then have physiological, normalizing, or anti-stress effects in the human. Of course, that raises the broad question about what kind of diet delivers the highest level of these phytochemicals and that is a diet that is minimally processed, rich in vegetable foods, fruits and vegetables, and whole grains. So is there any difference we can ascribe to a vegetarian diet and health outcomes in the human? Although this has been a reasonably controversial topic in some bodies of literature, I think the data, over years, has come to pass to say that a well-balanced vegetarian diet providing adequate levels of protein, vitamins, and minerals, in fact, delivers, in population-based epidemiological studies good health outcome, looking at Seventh Day Adventists, looking at groups of people who elected to be on vegan diets-the health outcomes look very favorable. In fact, blood pressure regulation and vegetarian diets was the topic of a review paper in Nutrition Reviews authored by Susan Berkow and Neil Barnard.32 This was in the January 2005 issue and focused on high blood pressure and its management with vegetable-based diets. It translates into the DASH-type diet (Dietary Approaches toward Stopping Hypertension). There are many papers-if you do a meta-analysis-of roles that vegetable-based diets have on blood pressure. With a search you are going to find over 20 papers that have all shown positive benefit as a consequence of the nutrient composition of vegetable diets, not only the mineral content of potassium and magnesium with low sodium, but also the high level of phytochemicals that serve as vascular-active substances that help to improve endothelial function. We even know that diets that are very high in these phytochemicals have been ascribed as anti-cancer diets and have preventive effects. There is a very nice paper that appeared in the Journal of Clinical Oncology in 2007 titled “Greater Survival After Breast Cancer in Physically Active Women with High Vegetable/Fruit Intake Regardless of Obesity.”33 This paper again showed that there must be something of interest related to the portfolio or the profile of these phytochemicals and how they influence outcome in a secondary prevention trial in women who have had breast cancer. I think that we are starting to see the convergence of various lines of observation and intervention research, ranging from epidemiological human work, to animal studies, to in vitrowork, to cell culture work, to–even now–some intervention trials. There is a wonderful prospective study of the relationship between fruit and vegetable intake and the risk of prostate cancer that was recently published. This was in the Journal of the National Cancer Institute in 2007.34 This study showed a very positive correlation between high intake of cruciferous vegetables (including broccoli and cauliflower) and a reduction in the relative risk of aggressive prostate cancer, particularly extra prostatic disease. What we are starting to witness is a kind of a convergence of our observational-and almost intuitional-thoughts that high vegetable and fruit and whole grain diets play a positive role in health, and now the mechanistic underpinning of that and the fact that different cultivars grown in different conditions can have differing levels of these beneficial phytochemicals. So it is an exciting story and we thank Dr. Lila very much for adding another chapter to our evolving understanding. We’ll look forward to seeing you next month in Functional Medicine Update.

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Bibliography

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Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures. Free Radic Biol Med. 2004;37(12):1951-1962. 6 Roubertoux PL, Sluyter F, Carlier M, Marcet B, Maarouf-Veray F. Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet. 2003;35(1):65-69. 7 Falk Peterson K, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350(7):664-671. 8 Falk Peterson K, Befroy D, Dufour S, Dziura J, Ariyan C, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003;300:1140-1142. Leverve XM, Guigas B, Detaille D, Batandier C, Koceir EA, et al. Mitochondrial metabolism and type-2 diabetes: a specific target of metformin. Diabetes Metab. 2003;29:6S88-6S94. 10 Lambert K, Py G, Robert E, Mercier J. Does high-sucrose diet alter skeletal muscle and liver mitochondrial respiration? Horm Metab Res. 2003;35:546-550. 11 Richards RS, Wang L, Jelinek H. Erythrocyte oxidative damage in chronic fatigue syndrome. Arch Med Res. 2007;38(1):94-98. 12 Pall ML. NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity. FASEB. 2002;16:1407-1417. 13 Pall ML. Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity:central role of N-methyl-D-aspartate receptors in the sensitivity mechanism. Environ Health Perspect. 2003;111(12):1461-1464. 14 Ames BN. A role for supplements in optimizing health: the metabolic tune-up. Arch Biochem Biophys. 2004; 423(1):227-234. 15 Marriage B, Clandinin MT, Glerum M. Nutritional cofactor treatment in mitochondrial disorders. J Am Diet Assoc. 2003;103(8):1029-1038. 16 Kamzalov S, Sumien N, Forster MJ, Sohal RS. Coenzyme Q intake elevates the mitochondrial and tissue levels of coenzyme Q and alpha-tocopherol in young mice. J Nutr. 2003;133(10):3175-3180. 17 Gramignano G, Lusso MR, Madeddu C, Massa E, Serpe R, et al. Efficacy of L-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition. 2006;22(12):136-145. 18 http://www.immunesupport.com/library/showarticle.cfm/id/5784 19 http://members.aol.com/SynergyHN/MPI8.html 20 http://www.lassesen.com/cfids/MarshallProtocolRisks.htm 21 http://www.mecfscanberra.org.au/docs/deed_marshall.htm 22 http://www.marshallprotocol.com/forum2/366.html 23 Lila MA. The nature-versus-nurture debate on bioactive phytochemicals: the genome versus terroir. J Sci Food Agric. 2006;86:2510-2515. 24 Prasain J, Reppert A, Jones K, Moore II, DR, Barnes S, Lila MA. Identification of isoflavone glycosides from Pueraria lobata in vitro culture by tandem mass spectrometry. Phytochem Anal. 2007;18(1):50-59. 25 Thole JM, Kraft TFB, Sueiro LA, Kang YH, Gills JJ, et al. A comparative evaluation of the anticancer properties of European and American elderberry fruits. J Med Food. 2006;9:498-504. 26 Grace MH, Faraldos JA, Lila MA, Coates RM. Ent-beyerane diterpenoids from the heartwood of Excoecaria parvifolia. Phytochemistry. 2007;68:546-553. 27 Campbell J, Lila MA, Nakamura M, Erdman Jr. JW. Serum testosterone reduction following short-term phytofluene, lycopene, or tomato powder consumption in F344 rats. J Nutr. 2006;136:2813-2819. 28 Yousef G, Grace M, Cheng D, Belolipov IV, Raskin I, Lila MA. Comparative phytochemical characterization of three Rhodiola species. Phytochemistry. 2006;67:2380-2391. 29 Lila MA. From beans to berries and beyond: teamwork between plant chemicals for protection of optimal human health. Ann N Y Acad Sci. 2007;1114:372-380. 30 Kijima I, Phung S, Hur G, Kwok SL, Chen S. Grape seed extract is an aromatase inhibitor and a suppressor of aromatase expression. Cancer Res. 2006;66(11)5960-5967. 31 Chansakaow S, Ishikawa T, Sekine K, Okada M, Higuchi Y, et al. Isoflavonoids from Pueraria mirifica and their estrogenic activity. Plant Med. 2000;66:572-575. 32 Berkow SE, Barnard ND. Blood pressure regulation and vegetarian diets. Nutr Rev. 2005;63(1):1-8. 33 Pierce JP, Stefanick ML, Flatt SW, Natatajan L, Sternfeld B, et al. Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol. 2007;25(17):2345-2351. 34 Kirsh VA, Peters U, Mayne ST, Subar AF, Chatterjee N, et al. Prospective study of fruit and vegetable intake and risk of prostate cancer. J Natl Cancer Inst. 2007;99(15):1200-1209.

Welcome to Functional Medicine Update for March 2008. I have a real treat in store for you this month in that we are going to have the opportunity to speak about the dermatological implications of functional medicine with an expert functional medicine practitioner, Dr. Valori Treloar, who is a board-certified dermatologist and a functional medicine practitioner. Dr. Treloar will talk about the relationships of functional matrix-related assessment for dermatological conditions. I think you are going to find this fascinating because we know the skin is important in an overall assessment of physiological health status. Certainly in nutrition we learn, early on, how to use the skin for assessing certain things: peteccia formation with hemorrhagic problems, chilosis (looking at the nose as an indication for B vitamin sufficiency), or looking at skin lesions that have to do with dermatitis (such as gluten sensitivity). The skin is a valuable tool for doing kind of a systemic run-through of factors of the immune system and nutritional status. You are going to hear much more about that as this evolves beautifully with Dr. Treloar and her concepts. Before we get to the interview, however, let me talk once again about how signals are established in the body that ultimately weave themselves into physiologic function. I think we recognize that we often use, in medicine, surrogate markers for evaluating what we consider the flame or the fire that is going on at the physiologic level. We look at the smoke (which is my analogy for the surrogate markers), and define what the flame looks like (i.e. the pathology). There are many, many different markers that we use in medicine for evaluation to at least gain some insight into what is going on. Some of these markers, such as lipid functions and lipid analyses, become early-warning assessment tools for cardiovascular disease risk and other functional problems related to alterations in the web of physiology. Let me focus on lipoproteins for now. The understanding of lipoproteins has been a major breakthrough in functional cardiology, and it now turns out that it relates to many other endocrine, inflammatory, and immunological factors. Other than just being owned by cardiology, itself, we now see lipoproteins as surrogate markers for many different distortions in physiologic function. Let’s talk about the HDL/LDL/VLDL/IDL-type of nomenclature, which has to do with density of various lipoproteins. When they were first identified by ultracentrifugation, you could see various bands that were related to certain densities of material. We know that fats don’t dissolve in blood well because fats and water don’t dissolve. Fats have to be transported in the body by detergent-like molecules that we call apolipoproteins, and these apolipoproteins have names like A, B, C, D, and E. These apolipoproteins are synthesized in the liver, generally, by signals that occur from outside the body and inside the body that stimulate upregulation of the genes that express the formation of these proteins (or at least the messenger RNA that later become these proteins, which then encode the names of apo A, B, C, D, and E). There are subcategories under each one of those big families of apolipoproteins. Each one of those apolipoproteins, when synthesized in the liver, transports different lipids. This could be different distributions of long-chain, medium-chain, and short-chain fatty acids, triglyceride remnants, or particles and other fat soluble molecules. These are all bound together in lipoprotein particles that have different densities, therefore they are given names such as IDL, HDL, or VLDL. Over the years, what we have found is that certain of these particles are associated with increasing risk to disease, and others appear to be associated with decreasing risk to disease. These associations are why the “good cholesterol/bad cholesterol” nomenclature emerged. LDL is the low-density lipoprotein associated with particles that appear to have greater atherogenicity (or at least be associated with the atherogenic process). Those lipoproteins associated with HDL appear to be antiatherogenic and are involved with cholesterol efflux (meaning cholesterol moving out of the artery wall). We had a wonderful discussion of the different associations in a past Functional Medicine Update clinician/researcher of the month interview with Dr. Roger Newton. Dr. Newton told us a great deal about the HDL particle. We have started to see an increasing focus on HDL lipoproteins and their association with a reduction of cardiovascular risk. These particles (be it HDL, LDL, or VDL) don’t just occur spontaneously in the blood. They are synthesized in the liver as a result of signals that can be endocrine-, immune-, or inflammatory-related. These particles reflect a state of function of the whole body. Changes in Physiological Function Can Lead to Changes in Lipoproteins As a person’s state of physiological function changes, their lipoproteins can change. With women who undergo the menopause, it is a rule of reasonableness that often their blood lipids change (their cholesterol goes up). This change in cholesterol is not because a woman started eating a higher cholesterol and fat diet, but because the synthesis of her apolipoproteins changed upon reduction of ovarian estrogen secretion and altered androgen/estrogen levels, which then triggers the liver to manufacture different apolipoproteins and transports lipids like cholesterol in different ways out of the liver into the systemic circulation. To put a woman solely on a fat-restricted diet will not be effective. To modify her atherogenic dyslipidemia, it is necessary to regulate the signals that associate themselves with the proper construction of these transport molecules, as well as cholesterol biosynthesis and triglyceride biosynthesis. This is an issue that is much more complex than just fat restriction; we are talking about endocrine-related signaling that regulates the production of these lipoproteins that take fats out of the liver into the blood. We know that stress hormones also affect the production of apolipoproteins. You often see people under stress have differing lipoprotein levels in their blood and different serum lipids. You can have a person who has experienced a high immediate stress and his or her triglycerides might go up even though a high-fat meal was not eaten. My recollection is that this was shown in a study in the early 70s with Le Mans race car drivers. As I recall, during the course of the 24-hour race, the drivers’ serum triglyceride levels went up even though they weren’t eating and it took several weeks after the race for them to come back down into normal range because they were actually under stress hormone modulation, producing different transport molecules to bring lipids out of the liver into the blood. You might say, why does the body do that? There could be some evolutionary benefit (to try to feed cells with energy in response to stress). In this case, the energy is the lipid–these fat molecules like triglycerides that can, in fact, be used as a source of metabolic fuel. When we are examining these markers in the blood that we call lipoproteins, we are examining very complex factors related to an endocrine, immune, and/or inflammatory, environmental response. Even xenobiotic exposures can alter serum lipid levels and can induce hepatic changes in lipid biosynthesis. With regard to the HDL particle, an understanding of the metabolism and biological actions of HDL is really starting to emerge very beautifully. Roger Newton published a wonderful paper in Atherosclerosis Supplementsback in 2002 related to HDL therapy for acute treatment of atherosclerosis and the understanding of the metabolism and biological actions of HDL that I think helped point us in the right direction as to how important this lipoprotein is in signaling antioxidation and proper lipid transport.1 HDL is the Most Sophisticated Lipoprotein Particle From the work of Jay Heinecke and his colleagues at the University of Washington School of Medicine, we know that the HDL particle is the most sophisticated of the lipoprotein particles in that it contains some 42 different proteins, and these proteins are involved with lipid metabolism.2,3 Some of these proteins are protein ACE inhibitors, some are acute-phase response proteins, and others have complement regulation. They all, then, have a functional component. HDL is more than just a particle that transports fat and helps keep cholesterol and triglycerides from building up in the artery wall. It has a very dramatic influence on signaling processes by docking to receptor sites for the HDL on the surface of cells and signaling through the composition of these protein-specific types of activity. Within the HDL lipoprotein you have apo E, for instance. You can have apo E-2, 3, or 4, and we know that depending upon the genetics of the apo E configuration you might have differing relative risk. Apo E-4 double alleles we associate with increasing risk to cardiovascular disease and Alzheimer’s dementia, whereas apo-2,3 variations are lower risk categories. People who have the conferred benefit a double apo E-2 haplotype are those who seem to have longevity genes. This is because the apo E has an effect on cellular antioxidation, so an HDL particle is actually seen as an antioxidant particle in some instances. It also has enzymes like myeloperoxidase within the composition of the HDL particle and that has its effects, then, on serving as part of the body’s immune defense system and part of the redox pathway of the body. What I am trying to get you to understand is that these lipoproteins are more than just transport for fat. They have functional characteristics that are regulating–at peripheral cellular sites–many different functions that influence gene expression patterns in those cells. And based on the composition of the apolipoproteins (which is, in fact, related to the stimulation of gene expression for their synthesis through the endocrine, nervous, and immune systems), you can alter not just the transport of fat from the liver to the blood, but also the effect that those apolipoproteins have on peripheral cellular sites serving as functional characteristics. This is a genes-and-environment situation. If you are conferred with the genetic luck of the draw and you get the Milano protein apo A-1 configuration, you have a very low HDL, but you have a very low incidence of cardiovascular disease because these Milano A protein mutations confer a reduced risk of oxidative injury and inflammatory-induced atherogenesis. Apo A-1 is part of the HDL particle that helps to pull lipids out of the artery wall, so you want your apo A-1 levels to be high, and you want your apolipoprotein B levels to be low because apolipoprotein B is the principle apolipoprotein associated with LDL atherogenic particles and the delivery of fat into the artery wall (cholesterol and triglyceride). You want your apo B to be low and your A-1 high, which leads us to recognize that the apo B-to-A-1 ratio is a very important risk factor determinant for atherogenicity and cardiometabolic syndrome. You can have the laboratory measure apo B to A-1. If that number-that quotient-is greater than 0.6 to 1 when apo B is divided by A-1 levels, then it is associated with increasing relative risk. When you get up to 0.8, relative risk to cardiovascular disease is almost double. You want your apo B to A-1 ratio to be below 0.6 to 1. Diet and lifestyle intervention plays a very big role in lowering the apo B to A-1 ratio. In fact, Dr. Katherine Esposito, in a recent issue of Arteriosclerosis, Thrombosis, and Vascular Biology, describes her work on optimal treatments for metabolic syndrome and cardiometabolic syndrome and she points out that the Mediterranean Diet has a very desirable influence on altering the apo B to A-1 ratio (lowering the apo B to A-1 ratio).4 It also increases the activity of paraoxonase (PON1, as it is abbreviated), which is an antioxidant enzyme within the HDL particle. Through intervention with Mediterranean Diet, you get increased antioxidant activity, which lowers the apo B and increases the apo A-1 component, and you get reduction of myeloperoxidase-induced oxidation, another positive benefit. What is my takeaway? My takeaway is that diet (as altered cellular signaling) has a much more profound influence than just delivering lipid, protein, or carbohydrate. In a complex diet like the Mediterranean Diet that is rich in fruits, nuts, berries, and vegetables that have differing phytochemical compositions that influence gene expression, the information molecules influence intercellular signal transduction in such a way as to induce or encourage proper lipoprotein composition to transport the right fats to the right place, and also serve functionally as antioxidants and cellular restorative agents. I hope this gives you a different perspective about the physiologic function of apolipoproteins than that which you might have had in the past (where you just thought of them as lipid transport agents). The apolipoproteins have become important markers and managers of cardiovascular risk. This was actually described in a Quarterly Journal of Medicine paper back in 2006.5 The ratio of apolipoprotein B to apolipoprotein A-1 has become not only an important risk factor for cardiometabolic syndrome, but also an important therapeutic target for how diet, lifestyle, and exercise can improve outcome in patients who have dyslipidemia. I am now quoting from the Journal of Internal Medicine 2006.6 In metabolic syndrome, the ratio of apolipoprotein B to apolipoprotein A-1 becomes a very important risk factor identifier for cardiometabolic risk. This is some wonderful work by Dr. Walldius and his colleagues in which this ratio of less than 0.6 to 1 of apo B to A-1 is a desirable target for intervention and can be used for following the success of therapy as we try to lower apo B and increase apo A-1 as indicators of cardiometabolic risk associated with intervention.7 This is one kind of surrogate marker/risk factor/analyte that you can use when you are establishing your intervention program and you want to follow it in the patient to determine how they are proceeding.. What other analyte has emerged to be very valuable for assessing relative risk of cardiometabolic syndrome and insulin dysregulation? The one that I have seen with increasing frequency in publications in top-flight journals is lipoprotein-associated phospholipase A2 (sometimes this is called the PLAC test). This is a measurement (indirectly) of atherogenic inflammatory lesions. I am now quoting from a paper in Circulationfrom 2005 looking at the Rotterdam Heart Study and examining the value of measuring lipoprotein-associated phospholipase A2 activity and finding that it was very strongly associated with risk of coronary heart disease and ischemic stroke.8 The study clearly demonstrated that elevated levels of Lp-PLA2 activity was an independent predictor of coronary heart disease and ischemic stroke in the general population, and might be a very good extended risk factor for vascular disease, particularly for those individuals with inflammatory underlying etiology because it is measuring inflammatory markers associated with arterial plaque. This is just one of many papers that have identified PLA2 as being a very important independent risk factor. Another paper that you might be familiar with comes from the West Scotland Coronary Prevention Study Group work published in the New England Journal of Medicine.9 This group found that lipoprotein-associated phospholipase A2 was an independent predictor of coronary heart disease beyond that of just cholesterol HDL or LDL itself, again because it provides a strong risk factor assessment for inflammatory arterial endothelial dysfunction. Comparison to hs-CRP How does this compare to hs-CRP, the Dr. Robert Ridker-extended risk factor for inflammatory connections to atherosclerosis? I think the PLAC test, or the PLA2 test, along with the apo B to A-1 ratio, the atherogenic particle number, and hs-CRP frames a new, extended panel for cardiovascular risk factors that evaluates cholesterol dynamics, lipoprotein physiology, and inflammation simultaneously and can give us a much better trajectory towards cardiovascular function that is modified by hyperinsulinemia. I would say that the lipoprotein-associated phospholipase A2 should be added together with hs-CRP, and the apo B to apo A-1 ratio analysis. I think we can say-in fact, I am actually quoting from a paper in the Journal of Endocrinology and Metabolism-that lipoprotein lipase A2 has benefits beyond that of the other traditional risk factors for picking up people who have this underlying inflammatory component.10 I am often asked a question: How do you evaluate, more specifically, inflammatory potential associated with atherogenic risk and ischemic stroke risk? I would suggest the lipoprotein phospholipase A2 in plasma as a useful tool for evaluating high risk. More and more papers are being published on this important area. A paper in a 2006 issue of the Arteriosclerosis, Thrombosis, and Vascular Biology journal again showed that this marker predicts future cardiovascular risk in patients.11 I think we can say that we are witnessing the emergence of a profound new extended risk factor that allows better assessment of vascular inflammatory potential. How does this all translate clinically? What we are really saying is that when we analyze a patient’s plasma or serum for various analytes, and we look at markers such as cholesterol (LDL cholesterol, HDL cholesterol, or triglycerides), that we are really measuring a functional status of how those lipids are being transported around the body–out of various sites where they are biosynthesized, to delivery into other cells at a distance (or tissues at a distance like the artery wall)–and that this transport occurs on the backbone of molecules that have the personality and responsibility for making fat soluble in the blood, which is water, and are called apolipoproteins. This synthesis of the various apolipoproteins (these transport molecules) is reflective of the overall function of individuals, both how their genes make these apolipoproteins (that means their genetic history) and how the stimulation of the genes by environmental signals trigger the genes to produce these transport molecules. Again, it is genes and environment. If a family has a familial hypercholesterolemia, they have the genes that both synthesized cholesterol (or triglycerides) at higher levels, and they may also have genes that increase the production of these transport apolipoproteins. That is a genetic situation. Beyond that, then, are the environmental factors that influence the synthesis of these transport agents and the lipids. For most people who have elevated blood cholesterol and triglyceride levels, it is not the specific genes that control this (like “hard-wired”), it is the environmental factors that modulate gene expression that induce, then, the hyperlipidemias. What are the environmental factors? What is modifiable? How do we think, functionally, of a systems biology approach towards this? We look at things that increase inflammatory potential, things that increase immunological dysregulation-this could be allergies, toxins, infectious agents, microbiological agents-that induce altered immune function, and then lastly, obviously, we would look at things like environmental agents (toxic chemicals that might alter various redox processes within the liver that cause alterations in the syntheses of these apolipoproteins and then transport lipids differently to arterial cell walls. If we put all of this together, I think we recognize that it is not simple and we cannot just say, “Oh, the number is high. Let’s just deliver an agent to lower that number.” What we should really be doing is looking at the environment (the context of that patient). We should be looking at the signals they are receiving at the genetic level that are modulating lipoprotein synthesis and lipid synthesis and creating what we see as elevations or reductions in certain lipoproteins. Insulin is one of those surrogate markers, or signaling molecules, that influences the synthesis of these lipoproteins. If you have hyperinsulinemia (meaning a higher circulating level of insulin than normally required to cause uptake of glucose and glucose transport), one of the effects is activity of gene expression that regulates and alters your apolipoprotein levels. We have said metabolic syndrome/hyperinsulinemia is associated with altered levels of apo B to A-1 (increasing apo B, decreasing apolipoprotein A-1). That becomes a marker that can be used as a tool for evaluating related insulin signaling function. Is this analysis something that every person should routinely have done? It is an expensive analyte; if you don’t have to do it, why should you do it? Why should you put apo B and A-1 in your panel? I would say that for general, garden-variety assessment, it is probably not cost-effective to include the apo B to A-1 ratio. But for patients who have evidence of insulin resistance, with an elevated triglyceride/low HDL, then I think that inclusion of the apo B to A-1 ratio is valuable because it tracks so closely with relative risk to cardiometabolic dysfunction. As you probably know, cardiac disease associated with insulin resistance is one of the major risk factors, so I think the apo B to A-1 ratio becomes effective and important there The companion to this is what we call the atherogenic particle size and particle number. There are a number of laboratories that do this now as another cardiovascular risk factor determinant, when you look at both the atherogenic-dense particles and their size and number. This could be done by NMR or by other technologies whereby you get a particle number and atherogenic index. That can be coupled together with your apo B to A-1 ratio to better define relative physiological function that can be seen later as associated with focal inflammation of the artery wall (so you get a higher calcium score, and you get higher atherogenic risk). We are going back in time, aren’t we, looking at an earlier progression of signs before we get to acute pathology and a defined disease state. We are looking at ways to intervene and track successful intervention early. By going earlier, it requires less hard-hitting intervention This implies that we would get more benefit if we were (early on) doing diet and lifestyle intervention. Early warning, milder intervention, improved function. That’s the strategy as opposed to waiting much later in the sequence of events where pathology starts to develop-we get an atheromatous plaque, it is fibrous, it’s got a fibrous cap on it, and now we have a whole different thing about stable versus unstable plaque, which is a different concern than if we were to catch this earlier and have a much less aggressive need for intervention (meaning stenting or bypass or more aggressive pharmacotherapy). I think the use of such things as the apo B to A-1 ratio, the lipid particle size and number, things like hs-CRP and the PLA2 (or PLAC) test become all very important parts of our understanding of defining relative risk and then tracking a patient on intervention to see how these parameters improve over time. “Over time” means 6 to 12 weeks; generally that is how long it takes, by diet and lifestyle intervention, to start seeing demonstrable improvements in these analytes. So a 6 to 12 week intervention using a Mediterranean-style diet, regular exercise program, stress management, and obviously smoking cessation. Now we start to provide alternatives: phytochemical-rich diets that modulate these intercellular signaling processes that are associated with inflammation and oxidative free-radical pathology. This all becomes the standard for a functional medicine early warning intervention. I hope I have put this into some context for you. Often we are confronted in this field with the question: What tests are cost effective? Obviously if we were to put the whole kitchen sink behind analysis, the bill for evaluation could run in the tens of thousands of dollars, so you have to ask what are the most cost-effective, evaluative tools for a functional assessment and how do you layer these on. You want to start with the least expensive profile, and then as additional questions become more of concern, you start adding more tests to get more specificity. My suggestion is to start with a standard lipid profile, do an anthropometric evaluation of waist-to-hip ratio, look at the traditional metabolic syndrome risk factors — blood pressure, elevated triglyceride/HDL ratio — and look at elevated uric acid levels in the blood. If all of these things demonstrate a trajectory towards metabolic syndrome (triglyceride/HDL ratio is above 4 to 1, you have marginally elevated triglyceride levels, you’ve got GGTP levels that are in the upper level of normal [that is gamma glutamyl transpeptidase levels], you’ve got some marginal elevation of ALT or AST suggesting nonalcoholic fatty liver disorder, you’ve got increased central adiposity, and increased marginal systolic and diastolic blood pressure increases), now you say, “Well this patient really has all of these risk factors for metabolic syndrome. I want to track the success of intervention by utilizing something that is sensitive to the major concern, which is cardiac risk.” So now you might, then, layer on the apo B to A-1 ratio test and also the atherogenic dyslipidemia-type of inflammatory test using plaques, and the carotid IMT test, and the peripheral vasal occlusion test that I have talked about (the use of brachial artery occlusive test). All of these become, then, different layers of functional assessment that one can employ to both design personalized intervention and to follow the success of therapy. When we put this all together, it obviously, then, suggests that there is a systemic influence from hyperinsulinemia and dyslipidemia; it is not just a localized effect on the vasculature. The systemic effect is because these signaling molecules, like insulin, affect gene expression in multiple tissue types, not just solely on that related to diabetes or cardiovascular disease. That is why looking at a whole-body assessment and taking the functional medicine assessment (which is antecedents, triggers, and mediators resulting in signs and symptoms) becomes a different strategy for patient work-up than just looking for the differential diagnosis. We want to start by looking at a variety of different signs and symptoms from a detailed personal health history, a good physical examination, a good family history, so that we start piecing together this puzzle of antecedents, triggers, and mediators resulting in the signs and the symptoms the patient presents with. The signs and the symptoms are related to the multi-organ types of observationals that come from a very good physical and history. It comes back to not relying on laboratory, but relying on the art of being a good observer-of using the brain as a device to develop patterns. Our brain is more capable of doing that than the best of supercomputers. We are taking in multiple data, collecting it, analyzing it, processing it through our skilled observer status, and then coming from that to an understanding of where that patient appears to lie on this trajectory of risk associated with things like dysfunctional insulin signaling or hyperinsulinemia. That is why this interview that we are going to move to next is so important. Because a web of interconnectedness becomes our basis for doing a physical and health history and assessment, it takes us into areas that are outside our normal disciplinary myopia. Organs aren’t just cut off at the boundaries of that organ; they are interconnected through signaling molecules to all other organs. This is why our discussion with our clinician of the month, Dr. Valori Treloar, is so important. As a dermatologist, her lens that she sees the world through has to do with the skin (its integrity and function). The skin is going to be influenced very heavily by the same signaling molecules that affect other organs of the body: the inflammatory mediators like TNF alpha, IL-6, interferon gamma. These influence replication and inflammation processes that pop up on the cutaneous portion of our body and may be reflective of what is going on systemically. Insulin and hyperlipidemias all relate, as you know, to alterations in skin integrity (xanthomas, for instance, are associated with familiar hypercholesterolemia). That is an extreme example, but well before that we see many different cutaneous examples of dysfunctional signaling, inflammation, and hyperinsulinemia. With that in mind, it is a good time to move to our clinician of the month, Dr. Valori Treloar.

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INTERVIEW TRANSCRIPT

Valori Treloar, MD Integrative Dermatology 1172 Beacon Street, Suite 402 Newton, MA 02461 We are at the very “looked-forward-to portion” of Functional Medicine Update, our clinician of the month. I am really excited this month to speak with a board-certified dermatologist who is really a functional dermatologist. Her clinic is Integrative Dermatology-its own title gives the definition-and this is Dr. Valori Treloar. I’d like to-in introducing her-talk a little bit about her background through the eyes and words of a colleague, Dr. Bill Danby, who is in the Section of Dermatology, Department of Medicine at Dartmouth University. Dr. Danby has recently written the forward to Dr. Treloar’s book (which I think is mandatory reading) called The Clear Skin Diet.18 I think this-if I can be so bold as to kind of abstract from his forward-will give you a sense as to how remarkable Dr. Treloar is in this whole field of integrative dermatology. An Introduction by Dr. Bill Danby Dr. Danby says it is a very high compliment to be asked to write a forward. As he has gone down his path of discovery, he has gotten more and more interested about the concept of diet and how it interrelates with dermatological function (I’m kind of paraphrasing). “All this,” he says, “led me eventually to approach, with considerable trepidation, the high priest of nutritional epidemiological studies [who we have interviewed on FMU in the past], Dr. Walter Willett, the Frederick John Stare Professor of Epidemiology and Nutrition at the Department of Nutrition, Harvard School of Public Health. I think I detected some incredulity during our initial meeting, but for reasons we’ve never discussed, he must have wondered if there was something to it because he assigned Clement Adebamowo, a postdoctoral fellow, to the work. After a lot of heavy lifting, Clement had his Doctor of Science, I had a 30-year-old question answered, and the association between milk and acne was proven. The word ‘association’ is important because we are still puzzling over the molecular mechanisms involved, but the original work has led further, and following my presentation on the subject to the Massachusetts Academy of Dermatology a few years ago, Dr. Val Treloar quietly presented herself and we got talking, and talking, and talking. I found that Val, partly because of her additional training but more out of a deep and abiding interest, has an encyclopedic knowledge of the relationship of foods to our most important hormonal and inflammatory processes. This extends far and away beyond my grasp, and, as she points out, far beyond what is taught to (or learned by) today’s (and yesterday’s) medical students.” I think that is a very wonderful introduction of Dr. Treloar and what she brings to us today on Functional Medicine Update. Valori, welcome to Functional Medicine Update and I guess the first question is, how does a dermatologist end up becoming an integrative dermatologist, and having gone through the Applying Functional Medicine in Clinical Practice training program, and being a leader in functional medicine in this field? That is kind of an interesting path. VT: I owe it all to you, Jeff. I am sure my story is the same one that you hear over and over again. After 10 years in clinical practice I was really getting kind of frustrated with the limitations of my conventional dermatology toolbox for my patients with chronic disease. I started sort of gently looking outside of the box and was handed The 20-Day Rejuvenation Diet. What doctor in their right mind would read a book with such a title? I was really astonished by what I read in that book, and then I went and signed up to take the AFMCP (Applying Functional Medicine in Clinical Practice–it was the last one that was offered over long weekends in two consecutive months). I made the transcontinental trip twice (October and November of the year 2000), and became more and more convinced and amazed as I went through AFMCP. I really came to an epiphany: I had a whole new toolbox to offer my patients. Then, of course, I had to go and study a little bit. I bought a few nutrition text books. My kids were away at camp that summer and I would get up early before my workday and spend a few hours plowing through the textbooks. I sat for the certifying exam of the American College of Nutrition, and I really turned into a PubMed nerd because I was delighted to discover that there was this whole parallel universe of science and nutrition applied to cutaneous disease. Granted, much of it is biochemical and animal models and cell culture–there is not a large volume of human, double-blinded, placebo-controlled, randomized trials-but I really did feel that in discussion with my patients, when I told them about the biochemistry, the physiology made a lot of sense and that I really thought that we were taking very little risk by improving diets and adding prudent nutrient supplements and that we might get a real benefit. My patients (many of them) were wide open to this approach; they were as frustrated as I was with having been through the whole mill of conventional treatments with not much response. I have really had that wonderful experience that a lot of us have of being exhilarated by the new ways that we can help people, and some life changes that we can really help people go through. JB: When I look at your background, it reminds me of “the road less traveled,” as I guess they say. It is a more difficult path, obviously, for people to have done what you have done: a Bachelor of Science from the University of Michigan and your Medical Doctor degree from Boston University, then your residency at the VA in Boston and Tufts University, and a research fellowship with Syntex Dermatology Research Center, and then all of your years of clinical experience as a staff dermatologist at Harvard University Health Service, at the Marino Center for Progressive Medicine, and in private practice in Wellesley and now Newton, Massachusetts. That is a lot of years. One might say that could really put you in stead to be an excellent traditional dermatologist. But then you add on top of that all these other things that you are talking about that have to come from this internal drive to be a seeker, at some personal sacrifice, obviously, both in time and I would probably say maybe even in money, in the end-an aspiration to seek out and do better. What drives a person like you to this? What’s the motivation? VT: I think it is this whole idea of dreading certain patients darkening your door because you really are scrambling at the bottom of your toolbox and you are kind of running out of things, and then suddenly to have that now overflowing with new tools. And there is a lot of creativity, I think, to it. We, as clinicians, really recognize all that biochemical individuality is so real, that our patients are unique, and the art of medicine is exploring variations in treatment options to find the find the right match for the right patient. You have often spoken about the “mythical” average 70 kilogram man not being really representative of the vast majority of our patient population. It really does come from recognizing that people are different and you need to explore variations on treatment options to deal with that biochemical individuality. JB: You know, there are three fields of healthcare that always struck me as being very interesting first-level understandings of functional medicine from what we see in the patient, as contrasted to things that might be buried deep within the anatomy, like internal medicine. Those fields are ophthalmology, dentistry, and obviously dermatology. As you talk to the traditional people in those professions-the ophthalmologist or the dentist or the traditional dermatologist-they may not see what they are dealing with everyday as being connected to the rest of the body. They may not think of the eyes as being kind of a window into the overall physiological status of the patient, or what is going on in the hard and soft tissue of the mouth as being related to other systemic factors, or, in the case of dermatology, the skin being an organ of vital barrier influence that has relationships to all these other functions. When you talk to your colleagues, how do you get them to see this broader functional aspect of dermatology? VT: I think that a lot of my colleagues really enjoy being reminded about the basic science and biochemistry behind the diseases that we deal with in dermatology, in particular because we are so good at describing what we see and it has been a descriptive field for so long. We all recognize (those of use who are clinicians, anyway) that when we give a patient a name to their disease, much of the time we are not telling them anything. One of my favorite conditions to discuss with my patients is a rash called periorificial dermatitis. I say to them, “Oh yeah, you have periorificial dermatitis.” It is pink, scaly, little bumps around the mouth, the nose, and around the eyes. And they say, “Oh, what is that?” And I say, “It’s a rash around the eyes, nose, and mouth.” So we have given it a great name. Do we have any idea why it happens? We have some approaches that, basically, have been empirically tried over the years that seem to be helpful, but I don’t know why it happens. My colleagues…we all share that frustration of “Yeah, I can give it a name but don’t ask me what that means because I’m not really sure why it is happening to you now.” What is fun about functional medicine is that you have the whole matrix to start exploring. What has changed in the patient’s life that may have been relevant to causing this and to suddenly, at this point, become a problem? The nice thing about being a board-certified dermatologist is that I can certainly offer them the conventional therapy that seems to be helpful in suppressing those symptoms and knocking them down, but at the same time, we can explore what seems to turn the processes on so that they will be less reliant on the medications. My colleagues-a lot of them-are open to the question. They really understand that we don’t know what is going on for a lot of the diseases that we are very good at describing. It is an interesting puzzle and I think a lot of us go into dermatology because we like puzzles. There is a lot of contact dermatitis that you get to explore. What is happening in the environment to bring that on? I think that a lot of people find it intriguing. JB: That is a wonderful segue into the first thing that the reader of your book, The Clear Skin Diet, a Nutritional Plan that Works, is exposed to and that is the quote you have offered, which is: “This book is dedicated to the medical professionals and scientists who continue to think outside the box. Thanks for demonstrating that the only myth concerning acne and diet is that which states there is no connection between the two.” That is a very provocative introduction. Tell us a little bit, if you would, about how you have kind of teased apart and understand this connection between diet and acne? Two Disciplines, One Philosophy VT: I have to give credit to my co-author, Alan Logan, who truly did the bulk of the writing and is certainly the one who came up with that, as you say, “provocative” comment. He actually had a few more comments that I think would have been taken by my colleagues as somewhat insulting. One of the things that he and I did together as we rewrote the book was calm down the rhetoric a little bit and that was done, in part, because I want my colleagues to see this as a resource. When Alan and I started looking at this material, we found that we had come to the same position, starting from very different places (he is a naturopathic physician; I’m a board-certified dermatologist with an interest in nutrition), and we had found all of the same papers. We had found all the same references. When we sat down and started talking we realized that we really had a kernel of truth in here. We are really excited about providing the information not only to patients, for whom I think it is really useful (hopefully), but also as a place for our colleagues to go to really sort of begin to understand why the biochemistry and physiology of nutrition truly has an impact on the pathophysiology of acne. It is quite heavily referenced. I find that a lot of us have a tendency to do this in functional medicine when we try to write for the public. We reference a little more heavily than is comfortable for most of our readers who are patients, hoping that they will show it to their doctors, and their doctors will look and see that there is some compelling evidence to support the approach. JB: I noticed that you have done a really nice job in the book, as I read it, in taking the complex concept of the functional medicine matrix, or the web, and breaking it down into component parts that can be kind of bitten off and absorbed one at a time. The thesis that you developed, which I think is very convincing (very compelling), is that if you look at a former clear skin nation, and you use Japan as an example, and look at what has happened to their skin as their diet has changed, you see very strong epidemiological and kind of statistical changes. Tell us a little about what this Japanese precedent suggests. Former “Clear Skin” Nations and Peoples: Japan, the Inuit, Peru, and More VT: I find that to be a fascinating story, and that is one that Alan is particularly good at describing (that is his chapter; he is married to a Japanese woman and spends a lot of time living in Japan-is very connected with the culture there) and I think that the story of the Okinawans, which is pretty well described, is representative of a number of different cultures. It is not just Japan where we have seen that the encroachment culture (largely a Western diet, rich in refined carbohydrates and hydrogenated vegetable oils and other vegetable oils) is associated with an increase in inflammatory disease. It turns out that Schaefer really made a clear observation of the Inuit when he was up there in the 60s and the 70s as Western influence really started coming into that area. The Inuit were renowned for their gorgeous, clear complexions and complete lack of acne. It became very clear that as the kids started eating candy and the sodas and a much more Westernized diet started replacing their omega-3 fatty acid/protein-rich diet that the kids started getting acne. It was a very profound, very obvious change to the people who were there during those decades. A similar change could be described in Portugal and was also described in Peru. And there is the wonderful story that was published in the Archives of Dermatology in the year 2002 with Loren Cordain as the lead author (and no dermatologists as authors, by the way).19 It is a most amazing story, looking at the Ache and Kitavan people who are still living essentially Stone Age lives with that diet rich in fiber-wild game, small amounts of gathered vegetables, and fish (very omega-3-rich, fiber-rich, plant polyphenol-rich diet). These cultures had no acne. He went on to speculate about how their stable insulin levels, which had been documented, compared and contrasted sharply to the spiking insulin levels that we see with a typical American diet that results from several carbohydrate-rich meals and snacks throughout the day, and that the area under the curve is much higher for insulin, and then speculated about how insulin could perhaps be having an effect on testosterone levels because of a decrease in hepatic production of sex hormone binding globulin. It was a wonderful article, just sort of bringing together some of these observations-very rare observations-over the years about how Western culture seemed to have an influence on acne (or the Western diet seemed to have an influence on acne), sort of beginning the process of pulling it together and trying to figure out what the mechanisms were. JB: It is very interesting. We had the privilege of interviewing Dr. Cordain on Functional Medicine Update on this whole Paleolithic Diet concept a number of years ago. He had just, at that point, completed and I think had accepted for publication the article you are referring to, and he was making, as you mentioned, as a non-dermatologist, some observations. But taking that from the observational level and moving it into the clinic obviously is the proof in the pudding, so to speak. What you are doing and how you have described it in your book is you are taking the concept of metabolic syndrome/dysinsulinemia and describing how that interrelates with hormones. We often say that in adolescence the reason that boys and girls get acne is because they are starting (if they are a girl) into their menstruating years, and if they are a boy they are starting to develop their testosterone levels, and these are just the natural consequences of their developmental process. But you have seen, clinically, obviously, a very different implication of that. It is not just necessarily the natural process of going through that first stage of development in becoming an adult. Could you tell us a little bit about your clinical experience in what some people say is just a natural association of hormones with acne versus the environment/genes association with acne? An Integrative Approach to Teenage Acne VT: We point out to the kids at the very beginning that there are people at all ends of the spectrum. There are kids who no matter what they eat are going to have gorgeous, clear skin. And there are kids who are going to do everything we tell them to do and they are still going to have acne, and that is (again) this biochemical individuality (a genetic variability among the kids). But the vast majority of kids are somewhere in the middle, where diet really does make a huge difference. Because of the name of my practice and the nature of my practice I get to see a lot of kids who get it-teenagers who really do take some responsibility for their health. Everybody says teenagers aren’t willing to change their diet, but a lot of these kids really are. They are smart. They get it. We find ways for them to snack that are healthier. When I have a kid, I sit down with them and we talk: What is your typical breakfast, lunch, and dinner?; What do you usually snack on?; How well are you sleeping?; How many times a night do you wake up?; On a scale of 1 to 10 what number do you give the stresses that you are experiencing in your life?; What kind of exercises are you performing now-are you playing on a sports team?; What other exercises are you doing? We work our way through that, which is one of the worksheets in the back of the book, and the kids and I sit down together and say, “Here are places where maybe changes would make a difference.” Sometimes kids are a little resistant. I say, “Look, you can take all this information and do with it whatever you want, but if I told you that if you are one of these lucky people who eliminates dairy from your diet and your acne goes away is it worth it for you?” Most of these kids are saying, “Yeah, that would be worth it for me.” And the other point we make-and Loren Cordain makes this point in a lot of his books-is if you cheat once a week you are still 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} compliant and you are probably still going to have excellent benefit. A lot of these kids will have a threshold. This is all pure speculation on my part, but we explore it individually. There are kids who can have a few dairy products. They can have cheese once or twice a week. They can have ice cream once a week mixed in with their otherwise really healthy diet and they tolerate it, and that is variable from kid to kid. It really is surprising how quickly you can go through this material with somebody and come up with a few places where they can instigate a few little changes and explore it on their own. Again, because I have the luxury of being able to prescribe, I will also give them some retin-A, and if they are really inflammatory nodular scarring, I will put them on an antibiotic to quiet that process down and minimize their scarring while they are incorporating their lifestyle changes. We almost always are able, then, to withdraw the antibiotics, continue them on their probiotics to help keep their gut in a healthier state, and find that they (because of the lifestyle changes they have made) no longer require the antibiotics to maintain control over their acne. It is a wonderful position to be in to say, “Okay, we are going to use these powerful tools. They have side effects so we will want you to not rely on them, so we are going to work on the lifestyle changes which take longer to give you a benefit, but we will be able to then withdraw the pharmaceutical medications and their risks, and leave you with better control of your health.” JB: I’m so impressed with the way that you have contextualized this. The two of you, in the book, I think have found that very-difficult-to-find balance between your clinical experience and your observations and the vast years of observations that you have made coupled with what the literature is saying and the trajectory. I notice there are over 300 references that you provide at the back of your book that really document all of these associations from a mechanistic level. It is like the Magna Carta of functional medicine dermatology. It is really very, very well done. When you talk about kind of using the matrix, or what we call the functional medicine web, it appears to me that you’ve really found the way that this applies very nicely to dermatology. I love the chapter on gut function as it relates to dermatological problems with the skin, kind of as a reflection of immune dysfunction — and the use of pre- and probiotics. Has that been a difficult thing for you to describe to patients-how the gut might connect to the skin? VT: I don’t think so. You know, people know their bodies. I think people pay attention more than we think. A lot of people will say, “Well, of course,” when you suggest there is a connection, and, “Yeah, that does make sense.” A lot of people come to me saying, “Oh my God, it is so nice to find a dermatologist who gets it; who confirms my impression-validates my impression-that when I eat this way I get better, when I eat that way I get worse.” As I always say to them, “I don’t argue with success.” JB: That’s the proof of the pudding, no question. So this takes us, obviously, to a very pragmatic place. That is, integrative dermatology is a unique title that might raise the eyebrows of those who have some presumption as to what either integrative medicine or functional medicine is, and it also maybe makes it more complicated in terms of how you define fee-for-service and spend the time with your patients. How have you worked all these kind of real-world mechanistic issues out in your practice? VT: I have to say I really have a lot of enthusiasm for what I do. A passion about it, really. My colleagues will comment, “You are so passionate about this,” and they listen and I take a page out of your book. I always stand up in meetings (we have meetings at our local hospital; we have them in town here in Boston; there are a number of academic monthly meetings; there are regional meetings for the New England Dermatologic Society). I make a point of standing up. I try to stand up at all of these meetings. I cite references supporting some kind of nutritional intervention for one of the diseases that we are discussing. I get, for the most part, blank stares. Every once in a while I see people scribbling notes. At every meeting, someone comes up to me and asks for a little more information. And there are people who now recognize me and will come up to me and start asking me questions about their own personal nutrition or some patients in whom they have started exploring (fish oil is a real favorite these days and a lot of people are kind of exploring it). So, I figure if I have one person scribbling notes from making a statement (which I try to have well-supported with literature) I am getting someplace. A lot of my colleagues will say now that they have patients who come to them and say, “Well, Doc, isn’t there something I can do other than take these medicines?” and they will say, “I have just the dermatologist for you.” And they will send these patients over to me. Those patients and I are a great fit. One of my colleagues says, “I am very happy to have someone who shares their mindset, who I know is well-trained and is not just flying by the seat of their pants, who is using really good science to try to make these decisions.” So, it is happening slowly-that people are hearing the message and at least beginning to open their minds a little bit. They are not quite ready to try to incorporate this into their own practice, but they are recognizing that they have value. It has been since 2000 (8 years) that I have been slowly working on them. JB: I would like to acknowledge actually four things that seem to characterize what I have heard you say as to why you are a success and will continue to be a growing success, whereas others in our field may still be aspiring to find this level of success by implementing these concepts in their practice and are finding it awkward. It seems like there are four things that stand out to me. I am sure there are more than four, but these are the four that kind of stand high on the marquee. Number one is you are really hard-working and diligent in your self education. You have not taken this lightly, you have taken it like going back to school and saying, “I’m going to really become a master to the level that I can of this new body of information and it is going to require some work and dedication,” and cooperation in your family support because time is still 24 hours a day. That hard work/diligence component is one thing that really defines you and, I think, your success. The second obviously kind of drives out of that and that is that you have used that hard work to get into the primary literature, to some extent, and ferret out a lot of the science that gives you the supporting documentation beyond your own experience that you can use on your side, both for patient education and for colleague education, and maybe even third-party reimbursement education, if necessary, about why you do what you do. It is pretty hard to argue 300 citations that are all from tier-one, peer-reviewed literature. I think the foundation in good science and, hopefully, functional medicine and AFMCP provided some part of that in your education. And then three, obviously, is attitude. Anyone who listens to you sees the advocacy and the balance-what I would call your positive affirmation that there are things we can do. You are open-minded, you’re a seeker, you’re an explorer, you are working cooperatively with your patients, and you are very excited about the advocacy that you can bring to that patient’s problems. You know, the best sales job is positive attitude and excitement about what you are doing. You certainly bring that. And then lastly, fourth, is all of this is contextualized in balance, I think. You are not way out there on the limb of extremism. You are using the best tool, which is the basic concept, I think, of functional medicine-the right tool at the right place, getting away from the old maxim of “if all you have is a hammer, everything is a nail.” It is using the right tool or tools at the right time, and that concept of balance really makes your outcome, I think, even more successful. Maybe there are some takeaways for all sorts of other listeners beyond that of the field of dermatology just as to how you are approaching this in your own field so successfully. As they would say in Australia, “Good on ya.” It sounds like you are really doing a magnificent job. VT: You have been very kind, Jeff, and I want to thank you for giving me this whole new way of looking at my work. JB: Thank you and I would really recommend your book to our listeners because dermatology is part of what people carry around all the time on their outside and it reflects their inside function. I think The Clear Skin Diet, this book that I think you co-authored so beautifully with Alan Logan, in itself is a very unique combination of a naturopath and a board-certified dermatologist working together collaboratively. I think you brought the best of both worlds into this book. I want to thank you so much for spending the time with us. I know you’ve got to get to patients, but you have really given a lot of us some pearls to use, so thank you. VT: Thanks so much. I certainly hope that you had the same feeling that I had in listening to Dr. Treloar speak about her practice and her journey as a dermatologist. It was just so enriching. It reminds me of why the Institute for Functional Medicine and the whole functional medicine concept was really developed over the last 17 years and why it has evolved-because it is made up of people like Dr. Treloar who bring this exuberant commitment (as Dr. David Jones talks about, “a re-enchantment with medicine”) to just continue to strive to do better every day and to bring the full weight of their skills and their thoughts and experience into the practice of healthcare delivery. You can really feel it, can’t you, when you hear her speaking and talking about her experience? One of the topics that Dr. Treloar addressed in the book The Clear Skin Diet in some greater detail has to do with the gut-skin connection and this whole concept of pre- and probiotics. Isn’t it interesting to watch the evolution of this field? It was probably 26 years ago, as I recall, that we first talked about probiotics and gastrointestinal-associated lymphoid tissue function (the gut-immune system, in other words) and how that influences systemic inflammatory markers. I didn’t think at the time we were so far ahead of the pack, but I guess, really, when you look back a quarter of a century, we were pretty much an early adopter of this concept of looking at the gut from a different perspective (from a functional perspective) as part of the immune system, and how that influences the brain, the liver, the systemic circulating white cells, and ultimately every cell in the body. Cochrane Collaboration Publishes Review of the Effects of Probiotics I’m very pleased to see that recently the Cochrane Collaboration, which you probably know is this wonderful group of individuals who have collected together their expertise to evaluate the evidence-based medicine surrounding different types of medical therapies, some of which have to do with what has been traditionally called integrative medical therapies or complementary alternative medical therapies, or maybe even functional medicine therapies. Within that domain are some of the Cochrane Collaboration reviews of the effects of probiotics on gastrointestinal function and gastrointestinal disease. We might have thought 25 years ago, when we first talked about this on Functional Medicine Update, that this was not within the prevue of traditional medicine. It is starting to actually be able to fulfill the criteria of support from groups like the Cochrane Collaboration. I’d like to just quickly review what they recently wrote about: probiotics for maintaining the remission of inflammatory bowel disease and Crohn’s disease. You can find this, actually, in the 2007 publication of the Cochrane Collaboration.20 This review is part of what you can find on www.thecochranelibrary.com, under the concept of Crohn’s disease and probiotics. As we review this kind of meta-analysis, we are coming to recognize this systematic review has taken us into a different level of support for this gut-immune connection to gut flora and how that influences, then, local and systemic immunological factors. I think it is a very, very interesting examination of this emerging view for how probiotics and prebiotics might influence gastrointestinal function and systemic inflammation. They talk aboutSaccharomyces boulardii, which has received more and more attention as a potential therapeutic probiotic for the management of inflammatory bowel disease. The authors go on to say, however, that if you looked at all the studies that have been published in the peer-reviewed literature, you are not led to recognize that there is an overwhelming support of probiotics in isolation as being therapeutically successful. In fact, they go on to say there is no evidence to suggest that probiotics are beneficial for the maintenance or remission of Crohn’s disease unless there have been other things done, and so these are more complementary types of interventions, and that is, of course, the functional medicine model-it is not magic bullets, it is not one thing, it is changing diet, it is intervening with the appropriate therapeutic support agents, and it is the best medicine, so to speak, and that is what Dr. Treloar was obviously talking about. Often I think we tend to think of some of these interventions as being green medicines or silver bullets: “Just do this instead of that.” So we give probiotics instead of antibiotics, or probiotics instead of sulfasalazine. What we really should be looking at, as Dr. Treloar so beautifully stated in her presentation, is the use of these agents in combination as a consequence of the way we have evaluated that patient through the functional medicine matrix and personalized their therapy. They may be on antibiotics. They may be on immunoreactive compounds. They are also going to have to eat and so we are tailoring the diet correctly: we are giving them adjunctive nutrients where possible, we are reinoculating the bowel using the 4R program, and the objective is to use as little medicine as possible for the shortest duration as possible while trying to improve, obviously, the rate of recovery and the prevention of recidivism or relapse. I think that the studies that are often done, unfortunately, use agents just one at a time as kind of single agents against these diseases, and then we go back and we say, “The research doesn’t support the use of probiotics in inflammatory bowel disease,” or “The research doesn’t support the use of probiotics for managing insulin resistance,” or “The research doesn’t indicate that probiotics are good for hepatocellular injury in inflammatory liver disease.” That is because some of this research was done isolated, one agent at a time, rather than looking at the complex of that agent (in this case, pre- and probiotics) in the combination of personalized therapy for the patient. Obviously the reason that we don’t have the data is it is very difficult to design these studies to look at combination therapies and do it in stratified ways that are individualized to the patient. So you start saying, “We can’t even find a methodology to prove our hypothesis.” You have to use inferential information, you have to use case studies, you have to use animal studies, you have to use epidemiological work, and you have to use intervention trials that have cohort analysis that have demonstrated success. In other words, it is the combination of information together that paints a picture towards support of improved patient outcome, rather than kind of a one agent against one outcome variable. The Cochrane Collaboration evaluation, to me, shows there is definitely benefit to probiotics, but we can’t unequivocally state that it is the magic bullet for Crohn’s disease or inflammatory bowel disease as a single agent intervention against placebo. Once again, that calls for (in my mind) the kind of approach Dr. Treloar was describing, which is a functional medicine approach that uses a combination of variables for managing the patient’s topography of their dysfunction or their disease, the architecture of their disease, which is more than just one agent influencing physiological function, and it requires more than one agent, then, to normalize their function. I believe this is a kind of nice specific example of a more general theme that you heard from her presentation about how to look at a whole organism as it pertains to a dermatological condition and say that the dermatological condition is a reflection of an imbalance in the whole organism, now let’s look within the functional medicine matrix at where those balances may reside in that patient, be it insulin or stress hormones or food allergies or gut dysbiosis or imbalanced dietary intake of various agents or omega-6/omega-3 fatty acid imbalances-you start looking at that full mosaic to design the program that is individualized to the patient. From that, then, comes the treatment of choice, and ultimately the best medicine for that patient. Thank you very much for your attention and we really, once again, thank Dr. Treloar for her very high skills in communicating how functional medicine works in a dermatological practice. We’ll look forward to sharing with you next month.

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Bibliography

1 Newton RS, Krause BR. HDL therapy for the acute treatment of atherosclerosis. Atheroscler Suppl. 2002;3(4):31-38. 2 Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, et al. Shotgun proteomic implicates protease inhibition and complement activation in the anti-inflammatory properties of HDL. J Clin Invest. 2007;117(3):746-756. 3 Bergt C, Pennathur S, Fu X, Byun J, O’Brien J, et al. The myeloperoxidase product hypochlorus acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Proc Nat Acad Sci. 2004;101(35):13032-13037. 4 Giugliano D, Esposito K. Optimal treatments for the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2006;26;30. http://atvb.ahajournals.org/cgi/content/full/26/4/e30 5 Chan DC, Watts GF. Apolipoproteins as markers and managers of coronary risk. QJ Med. 2006;99:277-287. 6 Charlton-Menys V, Durrington P. Apolipoproteins AI and B as therapeutic targets. J Intern Med. 2006;259(5):462-472. 7 Walldius G, Junger I. Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-modifying therapy. J Intern Med. 2004;255:188-205. 8 Oei HH, van der Meer IM, Hofman A, Koudstaal PJ, Stijnen T, et al. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke. Circulation. 2005;111(5):570-575. 9 Packard CJ, O’Reilly D, Caslake MJ, McMahon AD, Ford I. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. New Engl J Med. 2000;343(16):1148-1155. 10 Sudhir K. Lipoprotein-associated phospholipase A2, a novel inflammatory biomarker and independent risk predictor for cardiovascular disease. J Clin Endocrin Metab. 2005;90(5):3100-3105. 11 Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arterioscler Thromb Vasc Biol. 2006;26(7):1586-1593. 12 Corretti M. Brachial artery reactivity:clinical tool or research toy? J Am Soc Echocardiogr. 2004;17(6):693-696. 13 Houston MC, Cooil B, Olafsson BJ, Raggi P. Juice powder concentrate and systemic blood pressure, progression of coronary artery calcium and antioxidant status in hypertensive subjects: a pilot study. eCAM 2007 4(4):455-462;doi:10.1093/ecam/ne1108. (http://ecam.oxfordjournals.org) 14 Engler MB, Engler MM, Chen CY, Malloy MJ, Browne A, et al. Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J Am Coll Nutr. 2004;23(3):197-204. 15 Cortes B, Nunez I, Cofan M, Gilabert R, Perez-Heras A, et al. Acute effects of high-fat meals enriched with walnuts or olive oil on postprandial function. J Am Coll Cardiol. 2006;48(8):1666-1671. 16 Tang WJ, Hu CP, Chen MF, Deng PY, Li YJ. Epigallocatechin gallate preserves endothelial function by reducing the endogenous nitric oxide synthase inhibitor level. Can J Physiol Pharmacol. 2006;84:163-171. 17 Wang TD, Chen WJ, Cheng WC, Lin JW, Chen MF, Lee YT. Relation of improvement in endothelium-dependent flow-mediated vasodilation after rosiglitazone to changes in asymmetric dimethylarginine, endothelin-1, and C-reactive protein in nondiabetic patients with the metabolic syndrome. Am J Cardiol. 2006;98(8):1057-1062. 18 Logan AC, Treloar V. The Clear Skin Diet. Cumberland House Publishing. 2007 19 Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris: a disease of Western civilization. Arch Dermatol. 2002;138(12):1584-1590. 20 Rolfe VE, Fortun PJ, Hawkey CJ, Bath-Hextall F. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews. 2006;4 (Art. No.: CD004826 DOI: 10.1002/14651858.CD004826.pub2).

Welcome to Functional Medicine Update for April 2008. Occasionally we have something happen in biosciences and medicine that is so profound it rocks our world. Such is the case for this edition of Functional Medicine Update. This was unexpected and unplanned, but this particular issue is so important. I hope you can clear some space in your thinking because the information contained within it is quite profound. The source of this information is Dr. James Wright, a professor of medicine at the Department of Anesthesiology, Pharmacology, and Therapeutics at the Medical School, University of British Columbia, and his colleague, Jay Abramson, at Harvard Medical School Dr. Wright and Dr. Abramson came to my attention through the paper they wrote in The Lancet in 2007.1 This article was titled “Are Lipid-Lowering Guidelines Evidence-Based?” In this article, it is stated that between 13 and 36 million Americans are now in candidate status for statin use as a preventive agent for coronary heart disease. Guidelines for the use of statins have come out of seven randomized clinical trials. And yet, says Dr. Wright, none of the studies actually provides evidence that statins should be used as they are in medicine today. Should Statins be Used in Primary Prevention? For adults aged between 30 and 80 years old who already have occlusive vascular disease, statins can confer a benefit in total cardiovascular mortality. The controversy doesn’t involve secondary prevention, but rather primary prevention (that is, people without occlusive vascular disease). Should people without occlusive vascular disease receive statins? With about three quarters of those who presently take statins in the category of primary prevention in the United States, the answer has huge economic and health implications. In formulating recommendations for primary prevention, why do authors of guidelines not rely on the data that already exists from the primary prevention trials? asks Dr. Wright. Dr. Wright and Dr. Abramson pooled data from all eight randomized trials that compared statins with placebo in primary prevention populations at increased risk. The analysis isn’t perfect because these trials were not solely primary prevention, with 8.5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of patients having occlusive vascular disease at baseline in these trials. They use two outcomes to estimate overall benefit (benefit minus harm): total mortality and total serious adverse events. Total mortality was not reduced by statins in these primary prevention trials. In the two trials that reported total significant adverse events, such events were not reduced by statins. The frequency of cardiovascular events, a less encompassing outcome, has been reduced by statins, however the absolute risk reduction of 1.5 percent is small and means that 67 people have to be treated for five years to one such cardiovascular event, so the NTT is above 50, which Dr. Wright says is basically a “crapshoot” (meaning it is not a very good drug). Statins did not reduce total coronary heart disease events in 10,990 women in these primary prevention trials. Similarly, in 3239 men and women older than 69 years, statins did not reduce total cardiovascular events. The analysis of Dr. Wright and Dr. Abramson, therefore, suggests that lipid-lowering statins should not be prescribed for true primary prevention in women of any age, or for men older than 69 years. High-risk men (30 to 69 years) should be advised about the fact that it takes more than 50 patients, treated for five years, to prevent one event, and there is such a very high level of adverse events from statins. Dr. Wright and Dr. Abramson say that if you start looking at adverse effects, you will find that statins aren’t even used in athletes because of the very serious myopathy that can occur. In fact, there is now evidence to suggest that myopathic events are much more prevalent than would be seen from the previous clinical trials when they are applied in clinical practice. In another article Dr. Wright wrote for The Lancet, he goes on to say that the hypothesis that statin benefits might be disappointing because people stop taking them due to myopathy deserves more testing.2 We now recognize that in individuals who use statins, often the more they exercise the more myopathy they get, which then reduces their incentive to exercise and increases sedentary lifestyle and relative risk (an unbeknownst potential adverse side effect of statins). With that as the context for this issue of Functional Medicine Update, let’s hear from Dr. Wright himself about his view of this extraordinary analysis.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month JM Wright, MD, PhD Professor, Departments of Medicine & Anesthesiology, Pharmacology & Therapeutics University of British Columbia 2176 Health Sciences Mall Vancouver, BC V6T 1Z3 CANADA I’m very fortunate today to be able to introduce you to Dr. JM Wright, MD, PhD, Professor at the Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia Health Sciences and Medical School in Vancouver, British Columbia-a local Northwesterner, and we are always very pleased when we have the chance talk with a luminary from our Pacific Northwest. Dr. Wright’s work has a direct relationship to the whole of functional medicine and the primary prevention of chronic, age-related diseases. Dr. Wright has authored some remarkable papers about the field of primary prevention. One article that I was quite interested in appeared in the Canadian Medical Association Journal in 2005 and was titled “Are the Benefits of Statins a Class Effect?”3 The place where we have most recently had a chance to hear about Dr. Wright’s thinking was in BusinessWeek magazine in, January 2008.4 This article features a wonderful discussion about Dr. Wright as both a Professor at the University of British Columbia and also as a clinician in practice, one of his patients (Mr. Winn, who had been on Lipitor as part of his therapeutic for lowering cholesterol), and Dr. Wright’s evaluation of the success of the class of statin drugs (which represents about 28 billion dollars in annual sales in America). I would like to welcome you, Dr. Wright, to Functional Medicine Update. Could tell us a little bit about the history of your interest in doing this kind of evaluation (looking at outcome-related studies and the difference between primary and secondary prevention)? I think it will help us to understand the context of your work a little bit better. Taking a Closer Look at the Data JMW: Thank you. It is a pleasure to be here. The real issue is that statins originally came on the stage when they were found to have some effectiveness in secondary prevention, so the big trials were in people who had already had a heart attack. In that setting, I would say that statins have some modest effectiveness. I don’t think it is as striking as a lot of people think, but we accept that there is some effectiveness and we recommend statins be offered to people who have had a heart attack. What I also realized was that most of the people who were being offered the drug and who were taking the drug were actually people who had never had a heart attack, or a stroke, or had peripheral vascular disease. They were basically healthy people, and they were deemed to be at risk because they had had their cholesterol measured (or other things) and then were being told that they should be taking statins. We got involved in really looking at the evidence of the effectiveness of statins in that setting. When we really got into the data, we were quite surprised at how trivial the benefit is and that in most of those kinds of populations there really isn’t any overall benefit. When you look at all serious adverse events and all hospitalizations, there is really no reduction in the people taking statins. That was initially quite surprising to us, but it convinced us that for most of the people who are basically healthy, there is no net health benefit. Accuracy of Pharmaceutical Advertising JB: Obviously this is considered by many to be quite a remarkable observation because we have been told-in fact, even as recently as picking up the Journal of the American Medical Association just last week and looking at the advertisements for Lipitor with the graphic of a heart with a sentence that says “I love second chances” and it talks, in bold, about 41{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} risk reduction-and I think people have this view that we have these large-scale, multi-center, clinical trials that have demonstrated unequivocally very dramatic effects in primary prevention, something like a 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}-plus reduction in the relative risk to heart attack. It begs the question: How can these advertisements and how can this information be distributed so widely to people who are making decisions with their patients? JMW: They have to be accurate to some degree. What it means (when they talk about relative risk reduction and primary prevention populations) is that they are only looking at cardiovascular serious adverse events, and they are talking about a reduction in those events of from 3{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} to 2{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, which is approximately a one-third reduction. But in reality, that is only a 1{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction in absolute terms, and that means that you have to treat a hundred patients for five years to prevent one cardiovascular serious adverse event. Our analyses show that when you look at total serious adverse events (or total hospitalizations), they are not reduced. The data also suggest that there is some harm occurring and that the net benefit isn’t even 1{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. Do you follow that? Number to Treat Data JB: Yes, I certainly do. That leads to this concept (which for most of us we probably don’t think about) of the number to treat to get a successful outcome. The number you just gave is 100 to treat to get one successful reduction of a heart attack (or a vascular event) in a primary prevention trial. In the article in which you are quoted in BusinessWeek, it says anything with a number to treat above 50 is not a really great drug (I think the term that was used was “crapshoot,” which is a pretty strong vernacular). If 100 is the number, and 50 and above is not so good, it suggests that we are spending a lot of money on a crapshoot. JMW: That’s right. I would say that for most primary prevention situations, that’s what you are looking at-you are looking a number needed to treat somewhere between 50 and 100. Some of my patients say, “Well, I really think I should take this,” and they are quite anxious and they are willing to potentially take it-then I present that information to them in those terms and I take some time to make sure that they understand what that means. In my experience, most people (when they really do understand how small the benefit is) change their minds and say, “Well maybe it is not such a good idea.” JB: In your experience, in patients using statins in primary prevention (and I know I’m talking here across a wide variety of different products in that class), are side effects (things like neuromuscular issues or myopathies occurring? What percent would be considered a reasonable percent of adverse side effects? Statins and Adverse Side Effects JMW: That’s the other big issue with the statins. We know of some adverse effects, but the number is growing as we are learning more. Initially it was said that the only serious side effect is muscle damage and that it is a very rare event. That is true-in the randomized trials it was a rare event-but we do know that it occurs. I think most doctors know people who have had severe muscle damage with the statins, so it is not as rare as it might seem. But there are other adverse events that we are starting to recognize and one of them is peripheral neuropathy. That is occurring in a fairly small percentage of people (it is hard to know how many). It has also been shown now that interstitial pneumonitis is clearly an adverse effect of statins. One of the recent trials called the SPARKLE trial has demonstrated that in the statin group there was an increase in hemorrhagic strokes and that appears to be caused by the statins. And then there are these rare people who are having these unusual cognitive effects, which I think is quite concerning because it is not easy to appreciate how that might be happening, but it is certainly something that could be subtle and could be occurring in more people than we think. JB: I have also heard, clinically, of reports in males about changes in libido, which may have something to do with altering androgen levels. Is that something you have observed clinically? JMW: Not personally, but I have certainly heard of that as well. That is another potential adverse effect. JB: If one was to sum all of this up, are we talking about relative percentage in normal dose of 1{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}–what would you estimate? JMW: When you add them all up, I think it is in the range of 1{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} to 2{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} over five years, and that is really what the benefit is as well. That’s where I think that the harms are equal to the benefit. I think it is possible that that is the case. That’s really, I think, what we need to be doing more trials on and really looking more carefully at. For people who are healthy and in this primary prevention setting who are being considered for statins basically because they have risk factors, I think it makes much more sense for them to look at their risk factors and see how those could be modified by changing their lifestyle, changing their diet, increasing their amount of exercise, etc. That makes much more sense than hoping that taking the drug will resolve the problem for them when the potential benefit is so small and there are potential risks (some of which are unknown) , I think. JB: I was recently at a conference on vascular medicine where Dr. James Liao was the principal presenter from the vascular medicine research unit at the Brigham and Women’s Hospital and Harvard Medical School. He was going over the kind of intervention trials with statins that had been done and supposedly demonstrate positive outcome, like the Scandinavian Simvastatin Survival Study and the Cholesterol and Recurrent Events (or CURE) Study, and the Long-Term Intervention with Prevastatin in Ischemic Disease (or the LIPID) Study, or the West Scotland Coronary Prevention Study, or the Air Force Texas Coronary Atherosclerosis Prevention Study, or the Heart Protection Study-and when he reviewed all of these in combination (there was a big graph of these-a spreadsheet in which he was showing the data), he was saying that they all demonstrate (as a cumulative–several thousands of patients) positive outcome and very marked reduction of cardiovascular risk. And so it is those kinds of seminars that are presented to medical personnel who are making decisions for their patients that leads them to believe that these must be the most highly studied, efficacious medications that have ever come to pass. Clearly, the reputations of the presenters are good, coming from reputable institutions. How do we get into this situation where these issues that you are raising haven’t been considered fully? JMW: I think that it is a flaw in the way that it is presented. What you have described there is, I think, exactly the situation. All of those trials that you described there, except the West Scotland trial and the Air Force trial, are secondary prevention trials. When you combine the secondary prevention trials with the primary prevention trials, the number of events occurring in the secondary prevention trials is so much greater than in the primary prevention trials that it swamps the data from the primary prevention trials and you can’t see it. I think it is just wrong. As clinicians, we can easily recognize in our patients the ones who have had an event versus the ones who haven’t had an event and that’s really the clinically important distinction. That’s why we have been pushing forward and saying we really need to look at the primary prevention data separately and present that information to patients in that setting. When you do that, that is when you are surprised at how small the potential benefit is and the fact that there is really no proven reduction in mortality. When you look at total serious adverse events they are not reduced, so that certainly suggests that there is no overall health benefit for those people. JB: I think that is a really remarkable discovery/observation for all of us. That begs an interesting question because we do know that a patient who has hypercholesterolemia and goes onto statins for primary prevention will see a reduction (normally) of between 15 and 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in their cholesterol and their supposed atherogenic LDL cholesterol. Does this beg a question about the validity of the cholesterol hypothesis of atherogenesis as being the dominant or principal or only biomarker for the condition? JMW: I think, yes, there are some major questions about that as well. A lot of the statin trial data suggests that the reduction in the LDL isn’t the reason that the statins are beneficial. There is quite a bit of evidence suggesting that it isn’t as simple as just the cholesterol and the LDL cholesterol. When the person is taking the drug and their measures are better that doesn’t necessarily mean that they should be feeling “Oh well, I’m good now and I don’t have anything to be concerned about.” We don’t know for sure that that is the complete answer. There is this recent study… are you familiar with this ENHANCE study? JB: Oh, yes. Please tell us… JMW: That study showed that if you take a statin plus ezetimibe (I’ve forgotten the trade name right now… ), you get a significant reduction in LDL cholesterol. But that study also shows that you get no reduction in the measure that they were looking at (a measure of atherosclerosis in the vessels). There was no reduction, and in fact there was increase in that associated with the reduction in the bad cholesterol. So that is certainly is part of the evidence against this whole cholesterol hypothesis. JB: I think the trade name is Vytorin? JMW: Yes, that is right. That is the combination pill with simvastatin, I think. JB: When you look at all of this, it seems very persuasive–or at least highly suggestive–that the only documented, real positive outcome data we have on primary prevention goes back to what you were saying earlier: diet, lifestyle, and exercise intervention. It looks like the data there is stronger than that which we have been led to believe about statins. JMW: Yes. The trials are maybe not quite as big or as good as some of the statin trials, but the magnitude of the benefit of diet and exercise appears to be more, and I don’t think you have to be too concerned about a downside to improving your diet and getting some regular exercise. It certainly makes much more sense (and stopping smoking… all the things that we do know have a benefit). Risk Factors versus Pathonemonic Factors JB: It begs one last question, which I think is–from the clinical/medical perspective-an interesting point, and that has to do with the differentiation between a risk factor and a pathonemonic factor. I think for most clinicians, they probably associate a risk factor with an actual contributor to the mechanism of the etiology of that disease. One could have a surrogate risk factor (in this case it may be cholesterol) that only indirectly connects (or let’s say, even tangentially connects) to the etiology of the disease or is a component of the disease. It is the difference between the smoke and the fire analogy. By lifestyle, diet, and exercise intervention what one gets is a multiple-factored influence on multiple etiological agents giving an outcome. Even though we might look at one risk factor, it is only a part of the whole puzzle, and statins are molecules that relate to some piece of that puzzle, but not the whole. Is that… am I saying something that sounds reasonable? JMW: I think so. I think what we are measuring is very rudimentary in terms of knowing what is really happening. I personally believe that measuring total cholesterol and LDL and HDL is something that we are doing right now, but I doubt we will be doing that in the future when we have a better measure of what the really important measures are. I think they are really going overboard in terms of looking at these things. Healthy people probably shouldn’t have their cholesterol measured because it can lead to anxiety and illness when someone is told that their cholesterol is high. Often when an individual is told their number is high, it is really just the average for the population. It is quite a surprising situation that we are in in terms of the way we are managing and measuring cholesterol. I don’t know if I’ve explained that very well… JB: No, I think you have explained it very well. Since most of the people who are hearing this are clinicians, they may be a little shaken by this discussion because of what they have been told or what they have read about the value, in primary prevention, of statins. You obviously are not only involved with the research, but you are a clinician as well. I guess my final question is what recommendation do you have for how to manage this information gap with patients? JMW: When I present this to physicians I always start off by telling them that it is going to cause them some cognitive dissonance. I sort of warn them and that probably helps them when they start to see the information. In terms of your patients, I think when we are dealing with healthy patients we should be talking to them about modifiable risk factors in terms of diet and exercise, and stopping smoking, and not worrying about measuring the surrogates and getting them concerned about their cholesterol. I actually wouldn’t measure cholesterol if a person hasn’t had it done already. If they have had it done, then I think you need to then look at that. In many cases, the patient with high cholesterol also has a high HDL. Again, I think that those people (healthy patients) really are not at significant risk at all and we certainly shouldn’t be considering trying to lower their cholesterol with drugs. I think we need to get away from this whole focus on measuring cholesterol. If we did, we would also do something about the line at the labs-I notice that every morning when I go by the lab there is a big line of people who are going in for their fasting lipid profiles and I think it is the wrong way to go at the present time. JB: I said I asked the last question, but I actually have another. Given the controversial nature of this, have you had any discussions with people who feel you are being irresponsible, or that you have no business saying this, or that it puts physicians at risk or patients at risk? What have you been confronted with? JMW: I have had people who have argued the opposite and said, “Well, it doesn’t matter whether it is primary or secondary prevention, we need to measure their risk factors and if they have an elevated risk factor we should be treating them.” And they don’t worry about the fact that the data doesn’t show any benefit in women… I just bring them back to the data and say, “Well, this is what the data shows.” I personally think it is irresponsible to be treating people based on risk factors that haven’t been studied in randomized trials and haven’t been demonstrated to really identify the people who need to be treated. I just tell people that they should be not treating people until doing further randomized trials to see whether the approach they are taking actually is rational. If they did that, they would find that it probably isn’t rational. JB: Have you had anyone that you feel has mounted a successful argument against your very intelligent and thoughtful argument about the lack of demonstrated low numbers to treat in these primary prevention trials when you split them out, or has everyone come up kind of dry when confronted with your observations? JMW: They haven’t, and I have challenged them to come up and show us that serious adverse events and total hospitalizations are decreased in primary prevention trials and they haven’t come up with the information. Not all of that information is in the public domain, so I think if in the trials (where it hasn’t been published) it was showing a positive effect then it would have come forward already. I am confident that there really isn’t any evidence out there that our approach is wrong. JB: Lastly (I know I keep saying “lastly” but you beg another important question), I presume that this is a class effect, whether it is atorvastatin or Zocor or Crestor or Prevacol, we are talking about something that cuts across all of the members that reside within the statin class? JMW: Right. I think there is pretty good evidence that the benefits are class effect. There is also pretty good evidence that the adverse effects are dose-related, and therefore the higher the dose and the more potent the statin that you are using, the more likely you are to have adverse events. I personally think patients should be taking the lowest dose that has been studied in trials. I think treating to targets has never been proven in randomized trials and so again, I think that whole concept is not a good approach to take because it hasn’t been studied. JB: In Japan, I know the cardiology community does not agree with the higher-dose statin therapy we use in the United States and their statin doses are much lower. They feel that regulating to lower dose is the preferable way of treatment. It seems that your concept is consistent with what they are doing in Japan. JMW: Yes, that’s so. Even in secondary prevention, I think (except in some rare circumstances) we should be using the lower doses that have been shown to be beneficial. In the trials there are not big differences in terms of the benefit (there are not big differences in the trials where they used less potent and lower dose statins as compared to the more potent and high dose statins). That is being borne out in some of the newer trials where they are using high doses. Genomics and Statins JB: I noticed in October of last year that the NIH in the United States released into the public domain the data on some 30,000 patients from the Framingham Study who had had full genome scans (some 500,000 SNPs, or single nucleotide polymorphisms, were evaluated in this database), which is supposedly going to lead to a new era of cardiovascular research where we’ll start to individualize treatment based upon unique patterns of unique genetic and epigenetic expression. Do you feel the genomic component of medicine that is emerging will help us to better understand, in a primary prevention perspective, what patients might be most likely to benefit from statins versus those that won’t? JMW: I personally don’t think it is likely to have a big effect, and it is going to be a long ways down the road before we know. I would advise that we be very careful. If some of these things appear to be identified in patients then we should test that and do a randomized trial to find out whether that bears out; we shouldn’t just jump onto the bandwagon and start identifying people and treating them blind based on that data. In every case, it needs to be, I think, tested in a randomized trial. If they did, say, identify a subgroup and did a randomized trial and demonstrated a benefit with a number needed to treat of 10 to 20, I would be the first one to say that this is something that we should be recommending for our patients, but at the present time that is not the case and so I think that is the message to patients. It is unfortunate, but the drugs just aren’t as effective as they are touted to be. JB: Once again, I think the message that you are communicating to us is so important. I mean, it has implications not just for statins, but really about how we evaluate the efficacy of all drugs used in primary prevention (where a patient is going to be taking them for long periods of time throughout their life). I think this really raises some questions that probably most of us were not sensitive to. I want to thank you. JMW: I agree with that completely. It is not specific to statins and we need to be thinking about it in terms of antihypertensive therapy as well as a lot of the things we do, for sure. JB: It seems like we are treating numbers now as the blood pressure recommendations have come down. It is more and more reasons to use ACE inhibitors or ERBs or whatever the class of antihypertensives are. The question is, do we have the long-term outcome studies demonstrating that we’ve reduced morbidity and mortality? Are we just changing numbers or are we really changing outcome? I think you’ve raised that question so eloquently in your analysis. This is going to be an interesting chapter in medicine that you have helped to open for us. JMW: Thank you. That is completely the case. All of these ideas we need to test properly in trials before we start doing them widely. JB: Thank you once again. We really appreciate you spending the time with us and, of course, your advocacy. Sometimes it’s not easy to speak out against what everybody assumes to be the facts. Sometimes the facts are in the moment of interpretation and you have shed some extraordinary new light on this whole important topic for us. JMW: Thank you. I have enjoyed talking with you. How is it that statins appear to be the most commonly used family of medications (29 billion dollars worth of them used a year), and yet an investigator from the University of British Columbia with a good academic background and solid publication record questions the assumed usefulness of statins as agents for primary prevention? When we look at advertisements that appear for statins in the top-line medical journals, or for statin-containing drugs like the new drug, Caduet, which is a combination of Norvasc and Lipitor, the advertisements are saying there is a 45{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction in myocardial infarction risk. These publications of statistical benefit in supposed primary prevention are dramatic–41{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} risk reduction for Lipitor in an advertisement that appeared in The New England Journal of Medicine and the Journal of the American Medical Association. One has to wonder how this data came about. It is not lies; the Food and Drug Administration has approved these claims. What is going on? As Dr. Wright has pointed out, it has to do with how you manicure and evaluate statistics. If you reduce the relative incidence from 2{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} to 1{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, that’s a 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction. The patient may not know that that means one out of one hundred less incidents; what they see is the number 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction. Dr. Wright points out that the problem is going from a statistical base to an individual base in trying to make an assessment of value. As he says in a BusinessWeek article titled “Do Cholesterol Drugs Do Any Good?” the number to treat (or NTT) for many of these statins, in primary prevention, is upwards of a hundred, meaning that you have to treat a hundred patients for five years or more to get one demonstrable reduction of an incident in cardiovascular disease. How does the NTT for statins contrast to a family of drugs that we know have very high therapeutic value, like antibiotics for a bacterial infection? With antibiotics, for every 11 patients you get 10 who benefit, so antibiotics have a very low number to treat (a number more like 10, not a number like 100). When you get to number-to-treat data sets on agents for therapeutics above 50, it is pretty much a statistical game, not an individual therapeutic efficacy game. Yet we see statins being used with extraordinary frequency as primary prevention agents, and treating the number (which is the cholesterol number) rather than treating the condition (i.e. the pathophysiology-the functional disturbance). So these are very, very interesting philosophical questions. As we examine blood cholesterol levels in contrast to their cerebrovascular disease (even Alzheimer’s disease) in older-age individuals, we find people from 80 years of age and older who have higher cholesterol have lower incidence of vascular disease and vascular dementia. People with very low cholesterols have increasing relative risk. So cholesterol, in and of itself is not a direct univariate relationship to vascular disease. There is a paper that appeared in the International Journal of Cardiology in 2007 in which the investigators talk about cholesterol in the blood really being a marker of nutritional status in mild to moderate heart failure.5 As people have low cholesterol, it is associated with low levels of microalbumin, meaning, basically, their pre-albumin levels are low, suggesting they are nutritionally compromised and they have low cholesterol because of a nutritional compromise (lowered anabolic function, lowered physiological nutritional status). So low cholesterol may be a risk factor, just as high cholesterol is, that is indicative (in this case, in an older-age population) of poor nutritional status with poor pre-albumin levels. Beyond Statins: A General Lack of Data for Primary Prevention of Many Conditions. Is a Systems Biology Approach the Answer? I think we are starting to look at this cholesterol story (the statin story) and drugs in primary prevention for chronic disease in an entirely different way. As you heard Dr. Wright point out, it is not just statins alone that are cause for concern. This model translates into other drugs used for primary prevention for which we don’t have good outcome data to examine whether they really do anything other than to lower a biomarker-whether they really affect outcome related to mortality or morbidity over the long term. This would be things ranging from whole families of antihypertension agents, fibrates, insulin-stimulating drugs, and anti-inflammatories. What are the real outcome variables that relate to the effectiveness of these drugs other than them just altering a biomarker? A number? This obviously speaks to a different philosophical approach to medicine, moving away from disease as a sine qua non, to looking at function. Those of you who have been listening toFunctional Medicine Update for some time probably knew I was going to go here at some point in this discussion because it once again points to the importance of looking at an emerging view of medical philosophy-a view based less on the pathophysiology (the end disease) and more on the path that goes there (the functional processes that resulted in disturbances that warped or altered the physiological web in such a way as to ultimately lead down a trajectory towards the disease). I was reminded of this emerging view when I read an interesting paper that came from some investigators at the Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School that was titled “Human Disease Classification in the Postgenomic Era: A Complex Systems Approach to Human Pathobiology.”6 This paper appeared in the journalMolecular Systems Biology in 2007 and I think it frames the whole basis upon which the functional medicine model has been built. The authors say that contemporary classification of human disease derives from observational correlation between pathologic analysis and clinical syndromes. Characterizing disease in this way establishes a nosology that has served clinicians well to the current time in which acute disease was the major focus. It depends on observational skills and simple laboratory skills to define the diagnosis using the presenting phenotype The sine qua non for many of us in our training was to become good diagnosticians. Yet this time-honored diagnostic strategy has significant shortcomings as we have moved into an era when chronic disease has become the dominant disease type because it reflects both a lack of sensitivity in identifying preclinical disease and a lack of specificity in defining disease unequivocally. The focus, then, is on viewing disease as a reflection of different clinical presentations and starting to look at the underlying causes of disease rather than just what we call them (this variable phenotypic expression), and of excessive reliance on kind of a reductionistic view in establishing diagnosis. The purpose, then, is to provide a logical basis for classifying human dysfunction that uses conventional reductionism, but also incorporates the nonreduction approach, which is a systems biology approach in medicine. It is this systems approach that I think is very important. Controversy over Homocysteine as a Biomarker One of the examples that we could use to describe this concept is the recent controversy concerning homocysteine as a biomarker for cardiovascular disease. Homocysteine has come under some challenge recently as to whether it really does represent a true risk factor to atherothrombosis. Some papers have been published that indicate that the homocysteine hypothesis of heart disease doesn’t hold up. Some trials have actually been completed which yield negative results (while homocysteine levels were reduced with vitamin B12 and folate therapy, the event rates were unchanged compared with a population treated with placebo in these studies). I think these studies have received a lot of attention in the media, so you may be familiar with them. The suggestion is that atherosclerosis is not a result of hyperhomocysteinemia. Another way of looking at the data from these studies is to examine homocysteine as a biomarker that reflects distortions in the physiologic web beyond that of just being a risk factor to cardiovascular disease. The homocysteine connection is not exclusively owned by cardiology. We recognize that the modulation of homocysteine by B12 and folate supplementation not only lowers homocysteine related to potential vascular and toxic injury, but also promotes DNA synthesis (thereby supporting cell proliferation), enhances methylation potential, increases the formation of S-adenosylmethionine (or SAM), and lowers S-adenosylhomocysteine, which can alter gene expression by modulating the methylation status of certain DNA promoter regions. There are many different functions that derive out of the alteration of the folate cycle, which is seen by a surrogate marker called homocysteine. Homocysteine is not just connected to cardiology; it is connected to neurology, oncology, endocrinology, obstetrics/gynecology, developmental biology, and pediatrics. All of these fields have some connection to that marker, homocysteine, which is reflective in the way it expresses itself in the web of interaction (the connection between genes and environment in that individual). In a traditional diagnostic view, we would say that hyperhomocystemia has to be strongly connected with a disease to be seen as real. In this new model of systems biology we would say that hyperhomocystemia is an indication of a distortion in the web of physiology modulated through the folate cycle that can express itself based on genetic uniqueness in a variety of different clinical entities depending upon that individual’s own susceptibility or their own physiological status. It might be seen as a neurologic, or it might be seen as an immunologic, or it might be seen as a cardiologic, or even as an obstetrical complication in some individuals. When we apply a systems biology approach to looking at dysfunction it is different from always tying one indicator to one disease type. This organizational network-this disease network concept-is a very, very important emerging underpinning that differentiates a functional medicine model (which is built on systems biology precepts) from that of a sine qua non, pathonemonic disease nomenclature model in which each disease is seen as independent and isolated, one from the other, and it is not connected across different disciplines. I believe that we can apply that back to this discussion we have had with Dr. Wright concerning statins and cardiovascular disease, but in order to understand how we need to do a quick bit of background work on the history of the cholesterol hypothesis for atherogenesis. Let’s quickly review how this all fits together. The History of Statins: Context for Dr. Wright’s Research The early history of statins and cholesterol was built on the interpretive history of this cholesterol controversy. It goes back to Anitschkov, the Russian physiologist who did work with white rabbits, feeding them a diet enriched with cholesterol. This was in 1913, while he was working at the Military Medical Academy in St. Petersburg. Feeding these white rabbits cholesterol dissolved in sunflower oil induced vascular lesions resembling those of human atherosclerosis, both grossly and microscopically. Dr. Anitschkov’s work had been based upon the research of one of his previous Russian colleagues (Igor Ignatowsky), who had been looking at the relationship between protein in the diet and atherosclerosis and actually making an assumption that high protein diets were atherogenic. When he used the high proteins diets in animals, he was actually using diets that had a lot of animal products in them that brought cholesterol and saturated fat as well as protein. Igor Ignatowsky was the first, then, to actually demonstrate that these diets would induce atherosclerosis in animals, and that then led Anitschkov (later) to use more purified materials in demonstrating the cholesterol hypothesis in rabbits. Interestingly, just to make a full circle of this, Ignatowsky actually took his work from a previous Nobel Prize-winning microbiologist whose name we are very familiar with and that is Elie Metchnikoff. Metchnikoff (who took over the Pasteur Institute after Dr. Louis Pasteur passed away, and was given the Nobel Prize in Medicine and Physiology for his discovery of aspects of the immune system) proposed that an excess of protein in the diet was toxic and somehow accelerated the aging process. By the way, he is also the person who talked about the use of yogurt installation through the rectum for the management of hospitalized patients and suggested that bacteria in the gut were very important in producing disease or health. A lot of the probiotic concepts were built on the immune strengthening properties that Dr. Metchnikoff observed in animals and later in humans at the Pasteur Institute. It is interesting how this whole history kind of fits together-Metchnikoff, Ignatowsky, Anitschkov-and the cholesterol model that emerged. From there, this lipid hypothesis model was considerably advanced by work that allowed for the differentiation of the way that cholesterol was packaged in the blood (work by Dr. E.H. Ahrens showing the impact of diet on blood cholesterol levels and how that ultimately resulted in atherogenesis). Later, the discovery of Dr. John Goffman related to the various lipoproteins led to our recognition that these lipid molecules were packaged in carriers called lipoproteins. At this point the LDL/HDL/VLDL nomenclature started to be developed. Now we are moving, obviously, into the 1960s. By the late 1960s, many clinicians and investigators were already convinced that hypercholesterolemia was an important factor in atherogenesis. The connection of fat in the blood and atherosclerosis was further promoted and amplified by the work of Dr. Ansel Keys, a pioneer in nutritional research at the University of Minnesota who was convinced that blood cholesterol levels were determined significantly by the amount and the nature of fat in the diet. He started talking about the polyunsaturated fatty acid concept versus saturated fats, so we started to get into this whole lipid domain. This was the era, by the way, when we left behind the concepts of Rudolph Virchow. Dr. Virchow, recall, was the German pathologist, the so-called “father” of pathology, who had observed in the 19th century that atherosclerosis appeared to be more of an inflammatory disorder. So the Virchow model was kind of left behind and the Anitschkov model (the lipid model) was advanced, and the cholesterol connection became much more important. Without knowing exactly how or if cholesterol did, in fact, serve as a primary etiological agent for coronary vascular disease, we came to the Framingham Study in Massachusetts (what later became known as the Framingham Heart Study), a pioneering evaluation of relative surrogate markers that associated themselves with increasing incidence of vascular disease as people aged. This led to our traditional association of cardiovascular risk factors with serum cholesterol, particularly bad LDL cholesterol being elevated and good HDL cholesterol being reduced. We start to get into this whole lipoprotein/cholesterol lipid model. Fortunately, a new technology was developed to make available finger-stick measurements of cholesterol. It could now be done at health fairs and shopping malls and everybody could suddenly know their number (their cholesterol number). This technology advancement was very helpful in making the concept more accessible to all people. And then, there was the discovery of statins and the connection to the red rice yeast fungal metabolites that were used as culinary agents in Japanese cooking, as well as the chalcones. Japanese chemists were able to lower cholesterol levels in animals when they were fed certain red rice yeast metabolites. That led to the extraction, isolation, purification, and ultimate structure proof of these molecules, and they became antihypercholesterolemic agents, which then got derivatized and modified in structure to make new-to-nature molecules by the drug companies. From Lovastatin and Nevacor was birthed a whole family of new, improved versions of these cholesterol-lowering agents originally derived from natural products (from the red rice yeast). The history is a pretty fascinating history if we go all the way back to the turn of the last century right up through the development of Lipitor, the blockbuster drug of today for modulating cholesterol de novo biosynthesis. All of the history leads us to lipid research intervention trials and to looking at what happens when you start intervening with these cholesterol-lowering agents. There are two approaches that have been used. One approach is the use of diet, lifestyle, and exercise. There is a huge body of literature that supports the value of this primary therapy, and that becomes the basis of what the National Institutes of Health now calls the first line of therapy, or the therapeutic lifestyle change program (TLC program), which is recommended to physicians for use with patients who have hyperlipidemias prior to the onset of intervention with a lipid-lowering drug. This treatment approach involves dietary modification, exercise, stress management, smoking cessation (obviously), and ideal body weight achievement. This approach has a demonstrated success in primary prevention with limited to no adverse side effects. The other approach is pharmacotherapy, which is to intervene with a cholesterol-lowering pharmacological agent. Here is where we come full circle back to the comments of Dr. Wright. He says that we jump very quickly into utilizing pharmacology for the management of a surrogate marker (cholesterol) without really knowing if a patient is individually at risk to a disease because not every patient with elevated cholesterol gets heart disease and not every patient with low cholesterol is absent to heart disease. We need to know more about the individual etiology–the functional status of the patient– rather than just go off a biomarker, because the drugs in and of themselves, as he points out, may have a limited benefit in primary prevention when applied in a general way, without knowing the individual risk that a particular person has. Statins have been made into over-the-counter (OTC) drugs in Britain, and there is even suggestion that they should be made available to children on a regular basis to bring their cholesterol levels down to levels that are considered ideal. These steps are being taken without a full understanding of exactly what we are we doing, what are we treating, what the long-term outcomes are-not just the biomarker change, but the actual health outcomes (morbidity and mortality). The above interpretive history of the cholesterol controversy may give us a little bit better understanding of the context by which Dr. Wright is delivering this information that he shared with us.7,8,9,10,11 There is another important and interesting part of this story. As the interpretive history of the cholesterol controversy emerged and statins were discovered and more fully investigated, it has become recognized that they operate, physiologically, in ways that are beyond that which was originally thought. Initially statins were thought to be HMG CoA reductase inhibitors (hydroxymethylglutaryl Co-enzyme A reductase inhibitors), the rate-limiting enzyme for cholesterol biosynthesis. It was thought that these molecules (these statin molecules) worked by lowering cholesterol, specifically by blocking the valonate polymerization to give rise to sterols that ultimately are derivatized into cholesterol itself. It is true that statins will lower the biosynthesis of cholesterol at the hepatic level. No question. It is also true that they will serve as HMG CoA reductase inhibitors. As such, they will then lower not only cholesterol in and of itself, but the intermediary molecules that are involved in the squalene pathway that are associated with the conversion of mevalonate ultimately into these tetracyclic diterpenoid molecules that we call steroids. So it has to do with sex steroids. It has to do with stress steroids. It has to do with the whole family of cholesterol and their derivatives that relate to membrane function and steroid synthesis. So there are many, many things that are involved with regulation of brain structure and function. All of these components of the synthesis of long-chained polyenoic molecules that are cyclized into steroids are modulated, modified, or reduced as a consequence of consumption of statins. It begs the question: what happens to physiological function if you limit all of these molecules in their biosynthesis? Are you influencing things other than just the potential cardiovascular relative risk of an elevated LDL? That is where the state of the art of discussion is now really focusing: to look at how these other things–geranyl pyrophosphate, farnesyl pyrophosphate, the farnesylation of molecules-are modulated or modified by the consumption of statins and what impact they may have over the long term on a person’s physiological function. One role of statins is LDL reduction. But it is interesting to note that if you go back to the story that Dr. Wright was sharing with us concerning Vytorin, (a drug that contains not only a statin, but also contains a cholesterol-binding substance that prevents cholesterol absorption from the diet) in clinical trials this drug was demonstrated to lower cholesterol LDL levels. The clinical outcome of that trial was that patients had an increased thickness of their artery wall and increased filtration of lipid with increased potential atherogenic risk. So even though LDL cholesterol was lowered, which is presumably desirable, the relative risk to atherogenic dysfunction was increased Are we sure we know everything we need to know about LDL cholesterol and atherosclerosis? Obviously the answer is no. In previous issues of Functional Medicine Update, I have reported that in cases where you had patients on aggressive statin therapy (this would be above 80 milligrams a day of atorvastatin), that you could lower their LDL cholesterol below 70 milligrams per deciliter, which is in a low-risk category. But yet if their hsCRP (their high-sensitivity CRP) still stayed elevated above 2, they had an increasing relative risk to a secondary event (this is in secondary prevention trials). So even though aggressive lowering of LDL with statins reduced the LDL below 70, if a patient’s hsCRP was above 2 milligrams per liter, they still had a highly significant increased relative risk to a secondary cardiovascular event (meaning it is more than just that of LDL, there is this inflammatory component as well). This relates, then, to a question whether statins might have anti-atherosclerotic effects beyond that of lowering LDL itself. Are they pleiotropic drugs? The answer to that question is emerging to be “yes.” The Pleiotropic Effects of Statins and Other Drugs With statins (as in the case of probably all medications), as we examine the mechanism of action in more detail we find out there is not just one thing that they do. With statins, it appears as if their effects are pleiotropic (multiple), with one effect being the blocking HMG CoA reductase. Other effects have to do with the influence on the synthesis of isoprenoids and the attachment for intercellular signaling molecules.. These post-translational effects have to do with modulation of GTP-binding proteins (guanosine triphosphate-binding proteins) that are involved with intercellular signal transduction. These are the trans-membrane-binding proteins that translate outside-inside information-the G proteins-that are modulated in their function by post-translational influences (like farnesylation). The connection with these farnesyl residues affect their function (and statins appear to influence this), and therefore might have wide-ranging influences on things other than cholesterol biosynthesis. I am now talking about immunomodulation, neuroprotection, and cellular senescence and inflammation.12,13,14,15 Do we really know how statins work in the individual? Maybe there are people who have specific types of high-risk physiological processes for which statins influence (through these pleiotropic mechanisms) function in very desirable way, whereas for other individuals in primary prevention, the alteration of these functions may have deleterious effects. Statins might alter these post-translational modifications of G proteins in such a way as to alter the response of some people and put them at higher risk (like the reduction of neurosteroids that might produce increasing risk to Alzheimer’s, which we have seen at least some suggestion of). Statins might increase the risk to altered intercellular replication associated with oncogenesis. They might have influence on immunological function in such a way as to produce deleterious outcome in some individuals. These are the kinds of questions that are now being raised about the altered functional status that statins might produce. These questions might also help us to understand some of the myopathy that develops with statins. We know blocking the synthesis of coenzyme Q10 (and lowering CoQ10 levels) is one of the adverse effects statins have. This alters mitochondrial oxidative redox function and can increase oxidative stress. Concern is spreading to many different areas. One emerging topic is the effect of statins on Rho proteins that are involved in G-protein signaling and how they influence expression activity and physiologic function. In 2008 inBiochemical Pharmacology, an article was published looking at the effect of lovastatin on Rho isoform expression activity and association with GMP dissociation inhibitors (the relationship to this intercellular signaling processes mitigated by statins).16 We know that endothelial dysfunction, oxidative stress, and inflammation is influenced in atherosclerosis and that statins could have an influence on that as well through these G-protein signaling events through farnesyl and post-translational modification of these proteins. And statins may ameliorate pulmonary hypertension versus Rho-Rho kinase signaling pathways. It is interesting to note that now statins are being seen to influence specific cellular kinase signaling agents that are involved with these Rho protein post-translational modifications and how they regulate intercellular signal transduction. Understanding the pleiotropic effects of statins (and related pharmacological approaches) is starting to evolve beyond the simple thought that statins were only working as HMG CoA reductase enzyme inhibitors. Mapping all of this against the comments of Dr. Wright, what does it say about the primary prevention applications of statins? That’s a very interesting and somewhat controversial question. Let’s follow the kind of precedent of Dr. Wright’s discussion and look at what an alternatives there might be to usingstatins for primary prevention in an asymptomatic individual. What about the National Institutes of Health Therapeutic Lifestyle Changes Program, which uses diet, lifestyle, and exercise as primary therapies, and holding statins for secondary prevention? Would this be considered irresponsible? Would it be best to apply these medicines-these statin molecules-with the presumption (in primary prevention) that we are going to forestall some outcome that would be a cardiovascular event? Or would it be best to focus our attention and energy onto really learning how to apply lifestyle, diet, and exercise therapies more effectively? These questions take us back to conditions that have cardiovascular risk, like cardiometabolic syndrome (the connection between hyperinsulinemia, endothelial dysfunction, and cardiovascular disease). Even in the face of normal blood cholesterol levels, people may carry a conferred, enhanced risk to vascular disease as a consequence of altered lipoprotein transport and hypertriglyceridemia and lowered HDL levels. A very interesting paper published in Clinical Pharmacology and Therapeutics looks at metabolic syndrome and cardiometabolic disease from a global epidemiology perspective to individualized medicine.17 What the authors point out in this wonderful review article is that in virtually every country that has been examined, as one starts to see increasing waist-to-hip ratio, increasing waist circumference, and increasing fasting triglyceride and low HDL levels, there is an increasing incidence of cardiovascular disease that you cannot tie directly to elevated blood cholesterol levels, but rather it is tied to insulin resistance and hyperinsulinemia. My review of the data seems to say it is consistent across all these countries: Brazil, Equador, Finland, France, Greece, India, Iran, Ireland, Latin America, New Zealand, Turkey, the United States, and Venezuela. This trend includes increasing blood pressure, increasing dyslipidemia, increasing sleep apnea, increasing systemic inflammation, increasing erectile dysfunction in males, increasing central adiposity. All of these things seem to map against increasing prevalence of cardiovascular disease. What is the best way of intervening? We are caught with the same conundrum, aren’t we, that we were talking about earlier? What do you do? You talk about the drugs that are used for the primary prevention/intervention related to cardiometabolic syndrome. If you look at the clinical trials that have been published about drugs for the prevention of cardiometabolic syndrome or even surgical intervention in the morbidly obese person, they have limited outcome data available and they all have limited success. Bariatric surgery in the morbidly obese person is probably the most efficacious, but for ambulatory medicine, the drugs have really not been able to demonstrate their success, be it either statins, fibrates, ACE inhibitors, or the other drugs that have been employed in the management of insulin resistance and metabolic syndrome. Again, what is the best approach? The best approach appears (once again) to be that of diet, lifestyle, and exercise intervention. Katherine Esposito has authored a very eloquent recent paper in Current Opinions in Lipidology talking about how the Mediterranean diet really represents the most efficacious, safe, and effective intervention for insulin resistance and cardiometabolic syndrome and the dyslipidemia associated with this condition (which is alteration of apo B to apo A-1 ratio, increasing apo B and a decreasing level of apo A-1, with increasing atherogenesis).18 There was a wonderful paper in the journal Circulation in 2008, talking about dietary intake and the development of metabolic syndrome and its connection to atherosclerotic risk.19Again it showed a complex diet (such as the Mediterranean diet) that is low in refined carbohydrate and high in whole grains, omega-3 and omega-9 fatty acids, and fruits and vegetables that are rich in phytochemicals is-by far and away-the most successful therapy and should be employed before one would even consider pharmacotherapy. By the same token, in the Journal of the American College of Cardiology, a very nice paper on dietary strategies for improving postprandial lipids, inflammation, and insulin levels was reported, and it again showed that a high fiber, plant-based diet, rich in vegetables and fruits, whole grains, legumes, and nuts, markedly blunted postprandial hyperinsulinemia and improved lipid dynamics and lipoproteins more effectively than pharmacotherapy intervention.20 It seems there are specific treatments for metabolic syndrome emerging. This was described in a recent review paper by Katherine Esposito in the American Journal of Clinical Nutrition in 2008.21 We are seeing first-line therapy (therapeutic lifestyle changes) become the standard of identity that takes us away from relying on intervention with pharmacological agents for which the long-term effects in primary prevention have not been adequately demonstrated, and for which there is adequate information suggesting potential adverse side effects that can occur (at least in sensitive individuals) that can limit the clinical effectiveness of these agents. I think we should recognize that the presaging comments of Dr. Wright that you’ve heard today in this issue of Functional Medicine Update are dramatic. They are earth-shaking. They are seismic in their implications. Not everybody aligns themselves behind Dr. Wright’s concepts, obviously. We have a lot of vested interest in the status quo. In fact, in the letters to the editor to The Lancet, there were some criticisms. How could he be so audacious to call into question the fact that the lipid-lowering therapies using statins weren’t effective in primary prevention? Of course, Dr. Wright says the following. “The people who criticize this work use the common excuse: that the primary prevention studies are not powered to detect changes in total mortality. In reality, our evaluation of the eight available trials for primary prevention using statins comprise more than 40,000 individuals of all ages, followed up on an average of five years. These pooled data are certainly powered to detect a reduction in mortality and failed to do so. As a consequence, we know there is an association between LDL cholesterol and coronary artery disease in some populations. However, one cannot assume that predicted benefits from epidemiological data will be achieved in drug intervention trials. The reason for that is that all drugs are double-edged swords and have harms as well as benefits. We must not so quickly forget the lesson from the Women’s Health Initiative trial in which a reduction in LDL cholesterol with combined estrogen-progestin therapy caused an increase in coronary heart disease events. We believe, as we explained in our comment, that in some subpopulations statins cause serious, unrecognized harm, which negates the benefit when the benefit is small. In most primary prevention settings, statins have a low therapeutic positive benefit. That is why we are calling for a detailed, subgroup analysis to be made available so that we and others can get a better idea of who is being harmed by primary prevention with statins.” I hope I have left you with some very strong “food for thought.” I look forward to visiting with you in May.

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Bibliography

1 Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet. 2007;369(9557):168-169.

2 Abramson J, Wright JM. Author’s reply. Lancet. 2007;369(9567):1078-1079.

3 Wright JM. Are the benefits of statins a class effect? CMAJ. 2005;172(9):1995-1196.

4 Carey J. Do cholesterol drugs do any good? BusinessWeek. January 28, 2008.

5 Araujo JP, Frioes F, Azevedo A, Lourenco P, Rocha-Goncalves F, et al. Cholesterol-a marker of nutritional status in mild to moderate heart failure. Int J Cardiol. 2007 Jul 20 [Epub ahead of print].

6 Loscalzo J, Kohane I, Barabasi AL. Human Disease classification in the postgenomic era: a complex systems approach to human pathobiology. Mol Syst Biol. 2007;3:124.Epub 2007 Jul 10.

7 Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I. J Lipid Res. 2004;45(9):1583-1593.

8 Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans. J Lipid Res. 2005;46(2):179-190.

9 Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia. J Lipid Res. 2005;46(10):2037-2051.

10 Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part IV: the 1984 Coronary Primary Prevention Trial ends-almost. J Lipid Res. 2006;47(1)1-14.

11 Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part V: the discovery of statins and the end of the controversy. J Lipid Res. 2006;47(7):1339-1351.

12 Alegret M, Silvestre JS. Pleiotropic effects of statins and related pharmacological experimental approaches. Methods Find Exp Clin Pharmacol. 2006;28(9):627-656.

13 Wang CY, Liu PY, Liao JK. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med. 2008;14(1):37-44.

14 Xing XQ, Gan Y, Wu SJ, Chen P, Zhou R, et al. Statins may ameliorate pulmonary hypertension via RhoA/Rho-kinase signaling pathway. Med Hypotheses. 2007;68:1108-1113.

15 Lahera V, Goicoechea M, Garcia de Vinuesa S, Miana M, de las Heras N, et al. Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis : beneficial effects of statins. Curr Med Chem. 2007;14(2):243-248.

16 Turner SJ, Zhuang S, Zhang T, Boss GR, Pilz RB. Effects of lovastatin on Rho isoform expression, activity, and association with guanine nucleotide dissociation inhibitors. Biochem Pharmacol. 2008;75(2):405-413.

17 Batsis JA, Nieto-Martinez RE, Lopez-Jimenez F. Metabolic syndrome: from global epidemiology to individualized medicine. Clin Pharmacol Ther. 2007;82(5):509-524.

18 Guigliano D, Esposito K. Mediterranean diet and metabolic diseases. Curr Opin Lipidol. 2008;19(1):63-68.

19 Lutsey PL, Steffen LM, Stevens J. Dietary intake and the development of the metabolic syndrome. The atherosclerosis risk in communities studies. Circulation. 2008;117:754-761.

20 O’Keefe JH, Gheewala NM, O’Keefe J. Dietary strategies for improving postprandial glucose, lipids, inflammation, and cardiovascular health. J Am Coll Cardiol. 2008;51(3):249-255.

21 Guigliano D, Ceriello A, Esposito K. Are there specific treatments for the metabolic syndrome? Am J Clin Nutr. 2008;87(1):8-11.

Welcome to Functional Medicine Update for May 2008. It is interesting and paradoxical that we’re told to “just say ‘no’” to drugs, and yet we seem to be the most medicated society that the world has ever seen. It seems like an interesting contradiction. For me this point was really brought home when I read a recent report. I was-I think-incredulous. I couldn’t believe that it was really true, but it had been brought to me by some of my most trusted colleagues. They said, “Jeff, are you aware of the fact that in surface waters in the United States you can now find a whole array of pharmaceutical drugs by just sampling the water we drink?” And I said, “Come on, that’s got to be an exaggeration. I don’t think that that is true.” I guess I shouldn’t have such a degree of skepticism when I’m listening to friends I trust because I went to the literature and there are some very interesting reports from highly responsible and capable analytic chemistry groups looking at the level of pharmaceutical compounds, both the direct compound and their metabolites, in surface waters, not only in the United States, but in Europe as well.1 Admittedly, the levels of these substances are very low and the technology we have available today is much more sensitive to picking up very low levels, but I think it still raises an interesting philosophical question about over-the-counter and prescription drugs: where do they go? We don’t metabolize drugs like we do food, where we burn enough to carbon dioxide, water, and urea, and some phosphate salts, and so forth. In terms of pharmaceuticals-because these are new-to-nature molecules that the body is not used to metabolizing-their excretory products (their metabolites) may be persistent (like with pesticides, where DDT gets converted to DDE, but DDE can stick around for a long period of time because it is not readily metabolized by microorganisms). Is there a difference between natural substances (to which our body has been exposed and developed metabolic and excretory pathways to manage over time) and new-to-nature molecules that our body is trying to manage through cytochrome P450s and conjugases resulting in excretory products that are different from what we see excreted after consuming nutrients from food? I think this question kind of sets the tone for the topic we are going to speak about today. We are going to have the opportunity to visit with a researcher of the month who has over 30 years of experience in the field of phytochemistry and who has one of the most impressive publication lists that you can find in the academic communities in America today. We had the privilege of recently speaking with Dr. Mary Ann Lila from the University of Illinois. She discussed the extraordinary work that she has been doing with her group on the role of various phytochemicals as genomic modulators of expression and how this relates to functional changes in the organism who consumes these phytochemicals. Following on that theme, we are going to hear from Dr. Mukhtar this month, the person who first discovered the active principals in green tea. Nowadays, everybody knows about EGCG (epigallocatechin gallate) and the chemopreventive effects of green tea. The socialization of this concept is interesting. People will feel good-feel that they have done the right thing-if they have their cup of green tea each day (no matter how stressful their life is and no matter how bad their diet is, if they had their cup of green tea, or even their green tea soda, they feel like they have done something good). Public awareness about green tea derived from the fundamentally solid work of Dr. Mukhtar and others who followed on from his discovery. Dr. Mukhtar has had an extraordinary footprint in the whole area of phytochemicals and chemoprevention and the roles they have in physiologic function. We’ll hear more later, but I just wanted to set the context by talking about this pharmaceutical concept: antibiotics, anticonvulsants, mood stabilizers, sex hormones, and anti-inflammatories have been found in drinking water. This impacts the water supply of at least 41 million Americans according to an Associated Press report in March of 2008. 2 Again, concentrations are low, but if we look at 24 major metropolitan areas, measurable quantities of hundreds of different pharmaceutical compounds and their metabolites are found in drinking water. I think we can say that no one really knows whether this is or is not a problem. Low levels of hormetic substances, as we have described, can have significant impact on function if they happen to influence very critical switching points (or nodes) within the genomic expression profile or the metabolic profile (the metabolome). Sometimes small amounts can have big effects. In fact, in some cases, this is probably where the biggest impact occurs on physiologic function–hitting these more sensitive switching places within our intermediary metabolism (the metabolic nodes, or what I sometimes like to call, euphemistically, “the metabolic acupuncture points,” the places that are most sensitive to modulations). We really just don’t know what effects low levels of complex arrays of these molecules and their metabolites have on cell function. We know (on marker organisms like phytoplankton and organisms in the aquatic ecosystem) that the effects appear to be real, but then we are not so sure-as it transfers up through the food chain-how that influences (if at all) humans. I still think it is alarming (probably a good word) to think that 62 major water providers, when tested, showed a number of compounds above the level of sensitivity of the methodology. Clearly, this concern will increase over time if more medications are used and we depend on pills as solutions. Before the age of pharmaceuticals, we depended on what has been called by Hippocates the “food-as-our-best-medicine” approach. How does that approach differ in terms of both physiological function and ecological sense of balance? If we consider a phytochemical that is present in a food that the body has been exposed to for millions of years, the metabolic path for its detoxification and its ultimate effect on the biosphere has had the chance to be processed through the most lengthy laboratory experiment ever been done: natural selection. Organisms (including the top of the food chain-humans-and those lower on the food chain) have had a chance to become exposed to these compounds, and therefore there may be something very different relative to not only the individual effects of these compounds on the marker organism (in this case human), but also the secondary effects that it has as it has been metabolized and excreted and its persistence in the environment. Most likely it is not persistent and it has the ability to be used or metabolized by other organisms. This is what some people consider the difference between synthetic chemicals and natural chemicals. It is not only the influence they have directly on the organism, but the secondary effects that they have through metabolism and on the biosphere when they are excreted. When you talk to the general public, an assumption can be made that when something is excreted, it is out of sight and out of mind. We took it in. We got rid of it. It is gone. Forget about it. But if this is something that is persistent and doesn’t have (in the environment) readily available metabolic pathways to detoxify it in organisms exposed to it in the biosphere, this persistence can lead to bioconcentration and accumulation, and it can ultimately affect offspring. We have seen this with xenoestrogens in the environment, certainly with DDT and DDE affecting the reproductive rate of birds. But now we are going beyond that to talk about pharmaceutical compounds and over-the-counter drugs, which may be having similar opportunity or potential for bioconcentration as a consequence of being in surface waters. This is a pretty remarkable step forward. Transitioning from that, then, to the theme of today (which is to kind of contrast new-to-nature molecules that are used as drugs to natural substances that have biological activity, meaning biological response modifiers derived from natural substances), we are led to a discussion about chemoprevention (and even therapeutics) as it relates to these compounds in various health conditions. I think one of the areas that has received some of the greatest exploration, at least observational and clinical overview over the years, are those plants that contain active ingredients that have what has been called an adaptogenic effect on human function. As a student of traditional pharmacology, I wondered early on what an adaptogen was. It sounded like a term that was almost just a buzz word or a catch word, not something generally understood within the field of pharmacology. But the more that I have had the chance to really gain a better understanding of what is meant by “adaptogen,” the more I understand the power and also the support for that word. Let’s look at what that means. An adaptogen is said to be a substance that helps the body adapt to a changing environment or stressful situation. This could be emotional stress, chemical stress, or heat stress. I guess you would say an adaptogen increases the resiliency of the organism (the so-called organ reserve capacity of the organism) to maintain homeostasis against a changing environment. Are there any examples we can pull out that would actually support this concept of adaptogenic substances? The answer is “yes” because when we talk adaptogens, what we are really talking about are molecules that interact with receptor sites or with various signaling processes in such a way as to, at low levels of stimulation, enhance or serve as agonists, and at high levels of stimulation of a specific pathway, lead to antagonist of that pathway. So this agonist/antagonist activity gives rise to kind of a schizophrenic personality of that molecular species, which then induces this adaptogenic capability, meaning a capacity to maintain homeostasis or homeodynamics against change. So if there is a low stimulation of a specific process, this compound may stimulate receptor-binding and activate the pathway (that way it is an agonist). Or if there is a high level of stimulation with many things sitting on the receptor site that are activating that pathway or that process, this substance can then serve as an antagonist for that receptor activity and could downregulate the function in a hyperfunctioning state, and therefore it would be seen as having this dual personality: depending upon need, it would lead to normalization of function. That is what we mean by an adaptogen. Examples of Adaptogens In the plant kingdom, many substances have been found to have this characteristic of agonist/antagonist activity (or what I am terming “adaptogen”). The best examples that probably come to mind are the isoflavone families of molecules that are found in soy or in red clover. We know the soy isoflavones (genistein and daidzein) have the principal effects of interacting with estrogen receptors to some extent, and as a consequence they can either stimulate activity of the estrogen receptor when it is underoccupied with its ligand, or they can antagonize the estrogen receptor by blocking or preventing the binding with an estrogen stimulator like 17beta-estradiol. So they can be an agonist in one case (low estrogen) and an antagonist in another case (high estrogen), so they are adaptogens in that respect (normalizing estrogens mode of activity at the estrogen receptor). I think that is one commonly understood example, but there are many, many other examples that are now being explored and being discovered where there are compounds (bioactive materials) in plant foods that actually increase the regulation of these receptor activities. Let’s look at ginseng. For years, ginseng has been considered an adaptogen-to be both yin and yang in traditional Chinese parlance. Recently, pharmacogenomics and the antiangiogenic-modulating and storage-like activities of the active principals in ginseng have been studied and have been found to be, again, this agonist/antagonist-type of characteristic. I am now quoting from a recent paper in Clinical Medicine in 2007 in which it was found that Panax ginseng actives, the ginsenosides, have a very profound effect to either serve as proangiogenic or antiangiogenic compounds, depending upon the specific state of function of that system.3 And they also can serve as a steroid receptor agonist or steroid receptor antagonist, and so they, again, can have this normalizing or adaptogenic effect. This may explain in part why many of these adaptogens seem to have a variety of clinical applications from modulating hormones, to modulating stress, to modulating oxidative reactions (meaning they are said to be antioxidants). They are said to have anti-anxiolytic activity. They are said to improve wound healing. They are said to be anti-ulcer. How can all these effects come from the same mixture of molecules? I think it has to do with the fact that these are mixtures within natural products. Although they may have remarkably strong specific interactions, they have weak potency. They have this ability to maintain metabolic degrees of freedom, whereas a new-to-nature drug has been screened for its very high affinity to certain endpoints and it has a very high potency, meaning very low IC50. It kind of nails these things very hard. It’s like driving the point home very strongly. These molecules that are found in nature, as a mixture, hit many things a little rather than a few things a lot. I think, as a consequence, you get a different mode of action, a different physiologic function. You get a different kind of molecular or metabolic degree of freedom. It maintains plasticity. That is what we would call adaptogen agonist/antagonist capability. It is an interesting and different kind of pharmacology. It still participates with molecular interactions and the ligand-receptor binding and how that interfaces with signal transduction and regulating expression of function, but it does so in a different way. A mixture of molecules may be a reasonably high affinity, but lower activity, hitting multiple sites a little rather than a few sites a lot. That characterizes both the difference in functional capability and also the difference potential in adverse side effects between these two classes of compounds. So it is not that one compound/class is bad (i.e. new-to-nature molecules) and one is good (i.e. natural-derived molecules). It is using the right set of molecules for the right application. If you want to hold on, own, and completely (without ambiguity) control and regulate a function, you probably want a high-affinity and also very potent molecule that comes out of the Physician’s Desk Reference that has been screened very exhaustively by people who are very knowledge about these high potency molecules. The emergency room, the critical care center, or acute medicine probably really benefit from having an array of molecules that have come through this kind of a screening process. On the other hand, for individuals with chronic conditions in which there is no one single thing that is causing the problem, but rather myriad imbalances in their web or network of physiology, then maybe hitting many things a little (using a mixture of natural products that have differing receptor interactions) is preferable to that of hitting a few things a lot. Again, it is using the right personality of the molecular species in order to produce the right effect. What I have said is that these substances that are derived from food or natural products that have these characteristics (agonist/antagonist) are secondary metabolites from the plant; they come off the genes of the plant. Ginsenosides are synthesized by the ginseng plant based on its genome, just as we would say that flavonoids are synthesized off of the genes of the plant producing them, or proanthocyanidins coming out of berries, or catechins coming out of the tea plant, or the glucosinolates coming out of the cruciferous family of vegetables. These are all secondary metabolites produced by plants in response to what appears to be perceived stress that that plant is under, and so the plant upregulates these anti-stress compounds to be manufactured within its own biosynthetic capability. When we look at glucosinolates, they have a specific function in the cruciferous vegetable family to help protect against predators. If we look at things like carotenoids and xanthophylls in plants, these photosensitizing pigments have the effect to protect against a stress called sunburn by trapping the sun’s energy in such a way as to prevent singlet oxygen damage and free radical injury caused by excessive sunburn. If you can imagine having your arms raised to the sun all summer long in a cornfield in Iowa that would be a pretty difficult situation. Every morning, seeing that sun come up, you’d probably say, “Oh no, not another day.” (Even with SPF50.) So the plants have these adaptive capabilities by upregulating their production of these phytochemicals to defend them against environmental stresses. Data from Experiments with Cultivars If we talk about the phytochemical composition of various fruits and vegetables, it is related, in part, to how they are grown. I was interested to see a paper in the Journal of Agriculture and Food Chemistry-this is in 2007-in which they were looking at the same cultivars of berries, some that were grown by traditional, what we might call “organic” agriculture methods, and another from the same cultivar in an agricultural system that used pesticides and herbicides and fertilizers that basically put the plant under pretty low stress (it didn’t have to worry about defending itself).4 And then they looked at the presence of these bioactive ingredients within the berries. Agents that were found to have influence on lowering inflammation (these were phenolic acids, anthocyanidins, proanthocyanidins, and also hypoglycemic agents). What they found is that the levels of these bioactive compounds-these secondary metabolites (phytochemicals) in the berries that were grown under the organic agriculture conditions (I mean stressed, obviously)–were higher in level per unit mass of the berries versus those that were grown under the less stressed fertilizer/pesticide/herbicide environmental conditions. I think we look at the value of our foods from the perspective of some of these native secondary metabolites and we have to ask, “How was the food raised?” and “What was the general content of the substance within the food?” not just “We know that a food has that phytochemical in it.” We would have to ask something about its condition of growing and harvesting and storing and so forth, and so we would have a potential variety of different levels, depending upon those variables. Notwithstanding all of that, however, I think you can see that what I am talking about is a different model for potential development of bioactive substances for modulating function from that of the traditional pharmacological model. We are talking about mixtures of molecules that are produced by plants naturally as a consequence of their defensive mechanism that then are consumed by humans in their diets or as natural product remedies, which then induce in the human a similar anti-stress response. As you might know from previous issues of Functional Medicine Update, from interviews with people like Dr. Christoph Westphal from Sirtris Pharma, the term that is applied to this concept is “xenohormesis”-foreign substances (i.e. plant-derived secondary metabolites) having a hormetic effect (meaning small amounts having a larger effect on function)-again going back to this concept I talked about earlier of influencing the so-called metabolic acupuncture points and having influence on function far greater than one would anticipate based on just the mass of the substance alone. The Clinical Application of Xenohormesis Now let me give you an example of that from clinical application. Let’s take a look at omega-3 fatty acid supplementation. We are told that it is good to consume about 1 to 2 grams a day of EPA (let’s even say 3 grams, if you wanted to be on the good side of the equation here). So let’s say 3 grams of eicosapentaenoic and docosahexaenoic acids (i.e. EPA and DHA). How does that really compare to the overall amount of fat that is in the body of a fairly fit and healthy individual? So let’s take the example of a 170-lb. male who has 15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} body fat. He would be pretty fit, pretty lean. And 15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of 170 pounds is about 25 pounds of fat (about 454 grams per pound, so we multiply 454 times 25 and we come out with about (I’m going to rough it out) 10,000 grams, say, of body fat. If we were to look at that for a second (10,000 grams) and we say, “Let’s see, we are consuming, as a supplement, 3 grams of EPA/DHA mixture a day-what’s 3 out of 10,000?” It is a rounding error. You don’t even see it. It is lost in the sea, right? And so you say, “Well, there’s no real reason, then, to supplement with EPA because clearly it is of no significance relative to the massive amount of stuff that we already have in our bodies (the 10,000 grams of other fats). But see, this is where xenohormesis plays a role because as we bring in these important fatty acids, omega-3 fatty acids, that have an impact that is different than that of the whole body burden of fat. It has a hormetic (small amount, bigger effect) effect. And so this would be a specific example of how hitting at the right place by the right concentration with the right form leads to a larger metabolic response. That theme holds true for a variety of potential substances in plant foods that could be hormetic that serve as chemopreventive agents-agents that help to defend against chronic, age-related diseases because they modulate function in such a way as to lead to adaptogenic response around a set point which is healthy physiology. That is one of the themes you are going to hear from Dr. Mukhtar as he tells his story, from the discovery of EGCG in green tea to now literally hundreds of other phytochemicals that have potential biological response modifying activities. Let’s look at traditional Chinese medicine, which is built on this concept of multiple agents in a complex mixture coming from natural sources and having impact on physiology, sometimes at a very low level. We even talk phytochemicals where the level of concentration is fairly small relative to, obviously, a chemically synthesized, purified single molecule drug. If we were to examine, then, from traditional Chinese medicine to rational cancer therapy, which was the topic of a paper in Trends in Molecular Medicine in 2007, we are led to recognize that many of these natural products and derivatives thereof belong to the standard repertoire that ultimately lead themselves into traditional cancer chemotherapy.5 It started off in natural products, in nature as mixtures, and over time we get more and more to a purified, drug-like, single molecule. Examples include things like the Vinca alkaloids, the taxanes, and the camptothecins. In recent years, the potential of natural products from plants, notably from medicinal plants used in traditional Chinese medicine, has been recognized by the scientific community in the Western world, and there have been recent developments in this field which have allowed for comparison of single molecules of high potency to mixtures of molecules of modest potency and the influence they have on various cancer cell models and tumor models in animals, trying to contrast the difference between chemoprevention and maybe chemotherapy. Traditional Chinese medicine holds an important position in primary health care in rural areas of China. It is also appreciated in urban and well-developed areas for its 5000 year-old tradition. The Chinese government has undertaken enormous efforts to modernize traditional Chinese medicine (TCM) by investing in capital and every level of scientific and clinical research, and trying to better understand the underlying principle of TCM. Western interest in TCM stems from the hope that it might complement Western medicine by providing different tools for different applications. Medicinal herbs play a very important role in TCM, and even in Western medicine many of our medicines were traditionally derived from green pharmacy, or natural products. However, medicinal plants gradually, over time, have lost their importance as pharmaceutical agents as synthetic chemistry progressed in Western countries entering the 20th century. We got to the point where single molecules became the dominant theme because it was easier to test a single molecule against a single end point using the double-blind, randomized, clinically controlled trial. Currently, there is seemingly a revival of interest in medicinal plants and an increasing scientific interest in bioactive natural products as chemical lead compounds for the generation of what might be considered semi-synthetic new derivatives. This would be where you would modulate or modify the natural product into a slightly different structure to make it a new-to-nature molecule that then can be patented and has maybe more financial growth and return-on-investment possibility. But we still have a very significant interest in the natural compounds that appear in the mixtures in their native state and how they influence function. At the pharmacological level, the different areas of classical pharmacy differ from this kind of view of TCM and the models that I was describing earlier: mixtures of molecules having smaller effect across many functions and leading to this hormetic adaptogenic response versus a hard-hitting single molecule producing a dominant effect on one pathway that has been screened for its ligand-receptor interaction. We start seeing some very interesting classical targets for these traditional Chinese medicine-derived materials. People are looking at genomic relationships, proteomic relationships, and metabolomic relationships There is now a lot of very good science being done on the mixtures of these natural products that have come through traditional history-5000 years of history-and asking, exactly, how do they work? What is different about their role and function from that, say, of a single, new-to-nature molecule in chemoprevention or in therapy? I think we are starting to see some dramatic steps forward in this, and some of these are being found to be extraordinarily interesting products related to modulating what we call the inflammatory pathway. As you probably know, the inflammatory pathway is really the inflammatory pathways. There is ever increasing recognition that inflammation is an underlying etiological contributor to virtually every age-related chronic disease-from such things as osteoporosis, coronary heart disease, arthritis, Alzheimer’s dementia, thyroiditis, metabolic syndrome, type 2 diabetes, peripheral neuropathy, nonalcoholic steatohepatitis or nonalcoholic fatty liver disease, even loss of muscle mass with aging through metabolic sarcopenia-all of these have an inflammation component. Dr. Claudio Franceschi has recently termed this “Inflammaging.” Inflammaging is an interesting kind of conjoined term that talks about the relative increase in biological aging as a consequence of underlying inflammation, and that this connection between inflammation and biological aging connects, then, to chronic disease. In a recent paper in an issue of the Nutrition Reviews, Dr. Franceschi says that this accelerated biological aging process that we now see as demonstrated through increased prevalence of various types of chronic disease has a very close connection with underlying inflammation.6 Centenarians, when examined, have very low levels of proinflammatory materials. Centenarians are very unique because they have actually fairly high levels of proinflammatory materials, but what they have is even higher levels of anti-inflammatory responsive markers. It is as if they have a very vigilant immune system, but it has been kept in control by having these regulatory breaks that are called anti-inflammatory molecules that buttress the inflammation/anti-inflammation pathways. It is as if they have a robust, healthy, and responsive system to infection and offenders. It is not suppressed. It is not denied its function. They have got the right regulatory balance between immunological activators and immunological attenuators. This is all, I think, an interesting observation because we often say, “Well, we want to regulate the immune system; we want to activate the immune system; or we want to downregulate inflammation.” But maybe what we want to do is make sure that we have the right balance between inflammatory and anti-inflammatory activities. Neuroinflammation in the Aging Population Clearly, one major area that is emerging to be very important in an aging population for this story is that of neurological aging. Neuroinflammation is becoming more and more recognized as a major concern. We recognize things like Gingko biloba have a whole variety of molecules in the complex mixture of natural products that modulate aspects of the inflammatory signaling process that might be selective to that of neurologic aging. But not solely neurologic aging, because we also see effects of Gingko biloba on liver function, reduction of liver oxidative stress, and inflammation. These constructs of mixtures of molecules from natural products that have unique effects on inflammation signaling is an emerging view in chemoprevention and what I might call chronic disease prevention. What are the implications of neuroinflammation on the pathogenesis and molecular diagnosis of Alzheimer’s disease? I’m now quoting from the Archives of Medical Research in 2008-an article that talks about cytokine production by the microglia of the brain.7 The brain’s immune system has a lot to do with the etiology of Alzheimer’s dementia. The glial cells communicate through inflammatory mechanisms with the neurons to lead to these hippocampal fibrillary tangles (neurofibrillary tangles) and ultimately the beta-amyloid that undergoes the conformational changes that leads to plaque. This is an oxidative stress and inflammatory-related pathway. We recognize that things like resveratrol (in peanut skins and in grapes) have an effect on pro-apoptotic effects and inflammatory effects. We recognize that that coupled together with the isoflavones that I discussed earlier (the genistein soy isoflavones) have very interesting roles as anti-inflammatory compounds that work synergistically. I am now quoting from a paper in the Journal of Nutrition in 2007 in which the authors demonstrated the extraordinary roles that resveratrol and genistein have in anti-inflammatory, anti-adipogenic, and anti-proapoptotic effects.8 We start to see complex interactions–it is not just one at a time and that is what makes this so difficult. That probably explains why things like omega-3 fatty acids (DHA and EPA) recently have been shown to improve cognitive performance among the elderly; we get mixtures of these molecules that influence complex physiological pathways that then lead to normalization of inflammatory pathway. I’m now referring to an article in the American Journal of Clinical Nutrition in 2007 about why an anti-inflammatory diet that is low in arachidonic acid and increased in omega-3 oils has been shown to be helpful in patients with rheumatoid arthritis, or a diet that is low in gluten-sensitizing protein is helpful in patients who have various forms of rheumatoid arthritis.9 I’m now actually quoting from papers that appeared in Rheumatology International in 2003 and Rheumatology in 2001.10 Two years after a vegetarian diet that had higher levels of omega-3 fatty acids and was low in gluten was introduced to rheumatoid arthritis patients, there was improvement in joint mobility and reduced pain (that’s Clinical Immunology, back in 1994).11 And immunology of the gut plays a very important role in lowered inflammation–this is “Immunity, Inflammation, and Allergy in the Gut,” a review that was in Science magazine in 2005.12 This article shows that probiotics and prebiotics play a very important role beyond that of the intestinal tract in lowering inflammation, so this whole concept of gastrointestinal restoration (what we call the “4R Program”-remove, replace, reinoculate, repair) relates to delivering lower inflammatory potential through the gut mucosal immune system. I am quoting now from a “Probiotic and Prebiotic Influence on Intestinal Inflammation” article that appeared in November 2007 inNutrition Reviews.13 Even in inflammatory bowel disease there is now very strong evidence that probiotics can be very helpful, producing extra hepatic (extra intestinal) reduction of inflammation as a consequence of probiotic supplementation. The gut bacteria flora is another important part of this “Inflammaging” concept and maintaining proper gut-immune function. Gut-immune activating substances, for many people, may be things like food-sensitizing proteins (like gluten-containing proteins) that increase gut-mucosal permeability, encourage the release across the gut mucosa of potential larger molecules, and can induce, then, inflammatory response. In fact, in a recent paper that just appeared in American Journal of Clinical Nutrition it was found that a high-fat meal, in apparently healthy people, induced alteration in gut-mucosal immune function such that in the blood, after the meal, bacterial lipopolysaccharide was seen. This is a low-grade form of endotoxemia, and it was associated with an increased output from white cells of tumor necrosis factor-alpha. This is a very important paper for those of us who have been speaking for years about the gut connection to the rest of the body and how diet might influence inflammation. This is the American Journal of Clinical Nutrition, volume 86, page 1286 in 2007.14 So the diet can influence the immune system directly or indirectly through the immune system. The complex array of phytochemicals in the diet can have roles on this whole inflammatory signaling process and can be organ-specific or generalized in impact. That couples back to the concept of chemoprevention and even management of chronic disease using complex arrays (mixtures of molecules) that hit a lot of things a little, rather than one thing a lot. So with that as a preliminary insight, let’s now move to our clinician/researcher of the month, where you will really get the full story.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Hasan Mukhtar, PhD Helfaer Professor of Cancer Research Director and Vice Chair for Research Department of Dermatology University of Wisconsin Medical Science Center, Room B-25 1300 University Avenue Madison, WI 53706 I am very pleased to have the opportunity to introduce our researcher of the month to you. I have been so fortunate over the last 27 years to speak with some of the world’s most renowned contributors to the development of the functional medicine concept, and certainly this month is no exception. Dr. Hasan Mukhtar is our special guest this month, and he has a resume and background second to none. I have been following his work for more than 10 years as it relates to natural products and the effects that they have within cellular physiological systems. As a Helfaer Professor of Cancer Research and the Director and Vice Chair for Research in the Department of Dermatology at the University of Wisconsin Medical Science Center, Dr. Mukhtar has authored and published more than 400 papers in this field. He is a paragon. He is an institution unto himself. Dr. Mukhtar started his work in India, where he was involved with work on cytochrome P450s and detoxification. He did his postdoctoral fellowship at the Medical College of Georgia and worked at the National Institute of Environmental Health Sciences at Research Triangle Park. Ultimately he came to his present position in the Department of Dermatology at the University of Wisconsin. Dr. Mukhtar is just an extraordinary investigator. He has mentored many students that have gone on to do their own work and become leaders in the field. I was very pleased to see that he wrote a piece for “Profiles and Legacies” at the request of the Journal of Cancer, Biology, and Therapy, which describes his background and his professional legacy.15 I think all of us wish we had as rich a resume and background as Dr. Mukhtar. His work on the editorial boards of 22 scientific journals in diversified fields including cancer, pharmacology, toxicology, biochemistry, dermatology, and photobiology is just kind of a snippet of the breadth of activities that he has had. One of the things that Dr. Mukhtar has been very actively involved in recently (and we will discuss this) is his work on prostate cancer prevention and management by custom tailoring of a chemopreventive regimen and how that relates to things like various bioactive ingredients in foods and spices and modulators of intercellular signal transduction through cellular processes that these molecules are identified to have. With all that as a very lengthy introduction, Dr. Mukhtar I really would like to welcome you to Functional Medicine Update and thank you for spending the time with us this morning. HM: Thank you very much and I am honored to be with you. I really appreciate the kind introduction you gave me. I never knew I had contributed that much; that is nice to know. JB: I think all we have to do is look at your resume for five minutes to know the amazing contributions that you have made. Let’s talk, if we can, a little bit about how you got started down this pathway of looking at natural products and evaluating their effects in a different way than maybe previous investigators had done. Obviously you had started off a little bit on this cytochrome P450 as a detoxification biotransformation system, but how did it lead you into what now has turned out to be this extraordinary career? Discovering the Health-promoting Effects of Polyphenols in Green Tea HM: I was always fascinated with the idea of prevention of diseases. I came to understand that in order to prevent any disease we need to understand what actually happens. During that course, I was fascinated with the idea of looking at natural products because I was made aware that most of the drugs we use today are derived from natural products. It seemed to me that nature gave us these plant products (botanicals, vegetables, fruits) to enjoy, and then endowed then with many agents (products to discover)– that can prevent many diseases. So that is how I began my career in this particular area: nature’s part in disease prevention. I began more than 25 or 30 years ago. Each time I looked into various systems, I found new things. Within the last 10 years, I think I was the first to show that polyphenols present in green tea may have some health-promoting effects. That work was started in 1988, from my lab, and it has become the talk of the town. “Green tea does this; green tea does that.” Many of the biological and cellular processes we have found are modified by the green-tea-containing agents. So that is a brief introduction. How would you like to continue on from that? JB: I think anyone who has read about nutrition at all, be they either in the science world or in the lay public, obviously has this green tea connection to health in mind. You only have to go to the refrigerator case of a supermarket and you see all these green tea products now that are coming out. If you are more science-based, you know about epigallocatechin galate and some of its effects and the whole nature of this discovery. What was the first discovery you made that kind of got you in to seeing some of the power that was within the composition of the green tea concentrate? HM: We made many observations with green tea: that green tea can prevent cancer development in animal model systems, especially upon the skin. But most important of that, in my judgment, was our 1997 publication in the Journal of the National Cancer Institute, where we showed that you can take a polyphenol from green tea, EGCG (which you talked about a few seconds ago-epigallocatechin galate), and put it in a cancer cell (any kind of cancer cell).16 These cancer cells undergo apoptosis, and apoptosis is nothing but programmed cell death where cells make a decision to die. What good is there if it does the same thing to the normal cells? We took the normal cells and put the same amount of the EGCG in them, which are those concentrations that are physiologically attainable, and nothing happened to those normal cells. So this was the first distinction that any dietary or botanical agent was shown to make cancer cells commit suicide at a concentration where nothing happens to the normal cells. This became a paradigm for our research that has lasted for more than 10 years now. And now we know hundreds of compounds have a similar kind of biological effect. JB: I have had the chance to read what I think is one of the most well-written reviews in this area that you authored (you were one of the principal authors), which appeared in Cancer Research in 2006 titled ” Targeting Multiple Signaling Pathways by Green Tea Polyphenol EGCG,” and one of the things that struck me (that a lot of people don’t seem to understand) is that one of your discoveries is that these molecules that are present in these natural product mixtures target multiple pathways.17 It is not like a traditional pharmacology discovery. Could you tell us a little bit about this? I think this is very interesting. The Importance of Targeting Multiple Pathways HM: It has been made clear by many, many investigators, including us, in the last 15 or 20 years, that the cancer cell adopts multiple pathways to survive and thrive. A single target agent is that you can kill or do something with that target, but the cancer cell is very clever. If that pathway is eliminated, it will adopt another pathway to grow and survive, so scientists have been looking for agents that can kill the cancer cell through many pathways. We have found that green tea polyphenols have the ability to target multiple pathways. Let’s say the cancer cell has 10 different routes through which it can survive (and I am not saying that it only has 10 routes). If you can only block one of these routes, there are still 9 routes to go. It has become clear that with most of these routes that cancer cells can adopt, green tea polyphenols are able to limit those. It looks like a jigsaw puzzle now: the cancer is trying to stay alive (if this pathway is eliminated, let’s go to another pathway). The moment it goes to another pathway it says, “Alright, here is also a blocker.” So this compound from green tea that we found can block most, if not all, pathways that lead to survival of the cancer cell. We say that it adopts a “multi-targeted” approach for inhibition of the cancer cell. JB: I think how you (in that paper) summarize some very complex pathways–the inhibition of NFkB signaling, the inhibition of MAP kinases, the inhibition of epidermal growth factor, the inhibition of overexpression of COX2, the inhibition of proteozome, the inhibition of vascular endothelial growth factor, metalloproteinases, urokinase plasminogen activator-I mean this was a very nice review in a short summary of tremendous biology that has only been discovered in the last, say, 10 to 15 years. HM: That’s true. I am not aware of any other naturally occurring agent that is so versatile in making the demise of the cancer cell through inhibition of many, many pathways which you described a few seconds ago. So the cancer cell finds itself in a dilemma: “No matter what happens, I have to die.” Let’s say there are 10 roads through which you can go and there is a block in every single road. You cannot go anywhere else. So that is the strategy that a single agent-green tea-is doing, and we are now learning that there are many, many more agents that have the same kind of ability, and many more agents derived from natural products, especially dietary products, which have the same kind of ability. So if we can, I will come back to what you were referring to in the beginning-that if we can develop a cocktail of agents, ultimately, that if we identify let’s say 20 different or 30 different pathways that are there which make the cancer cell survive, and let’s say green tea is able to inhibit 10 of those and other agents are able to inhibit 5 of those, and if we can use different agents and develop a cocktail, I think we will win in the end, to a great extent, by inhibiting the march of the cancer cell from one stage to another stage. JB: One of the things that you point out in your work is the remarkable discovery that these biologically active agents influence intercellular signal transduction and serve as kinase modulators through things like MAP kinases, the ERK J and K pathway, or through PI3 kinase. These seem like pretty remarkable, intimate relationships between the molecules and food and fundamental processes that translate outside information into inside genomic messages within cells and serve as transcription factors. Is this a fundamental discovery, do you think, that is changing our view in the biological sciences world? Developing a Cocktail of Agents to Inhibit Carcinogenesis HM: I think it is. Let’s imagine all these pathways you describe (MAP kinases and proteozome and this and that) as a network. We don’t know, really, how many of those are involved. Many of those have been discovered; many more will be discovered in the years to come. So it is a network of pathways that make the transformation of a normal cell to a malignant cell and, furthermore, the journey of the malignant cell to become an invasive cancer. So if we can discover all these pathways (complex pathways), which we are discovering left and right every single day, then our job is to put breaks along these pathways so that we can devise agents (a cocktail of agents) which can inhibit the cancer development process. With this idea in mind we are trying to develop a cocktail of agents to inhibit the process of carcinogenesis through the use of simple and inexpensive agents derived from natural products. JB: It seems very interesting to me that this is a philosophically different approach than that which has been seen in traditional pharmaceutical science, which is to take one molecule at a time and look at its very low IC50 high-potency activity on blocking a certain process. Here you are talking about mixtures of molecules that have more of a symphonic effect upon pathways of metabolic function. So it seems like a whole different strategy. Am I right in making that assumption? HM: The idea is so simple. For some of diseases, there is a defined pathway. Unfortunately, for cancer, we have learned the hard way that that is not the case. It is a very complex process; hundreds of thousands of genes are involved, hundreds of thousands of pathways are involved. So how in the world we can think that a single drug can ever be developed for the treatment of cancer? And that is a major hurdle for the treatment of cancer, in my judgment. Most importantly, the cancer of one site (one individual) may adopt a different pathway to develop and survive and thrive, whereas in another individual it can adopt a totally different pathway. That is why one drug that may be effective in one individual may fail in another individual. If we can give a cocktail of agents that will work through different pathways it is likely to succeed more effectively than a single agent. Research on the Prevention and Management of Prostate Cancer JB: Let’s move, then, from this kind of general discussion to some of the more recent, specific work that you have been doing on the prevention and management of human prostate cancer because that obviously is big area of therapeutic concern right now with the rising prevalence in males. I was reminded of another paper in 2007 from your group in Clinical Cancer Research on the combined inhibitory effects of green tea polyphenols and selective COX2 inhibitors and the growth of human prostate cancer cells.18 Tell us a little bit about how this is evolving, this cancer chemoprevention work that you are doing. HM: Same idea, even with prostate cancer. Processes involved somehow damage to the normal cells. Inflammation is the key there. Through that, some kind of inflammatory lesions are produced that then develop and travel through different pathways to cause cancer in the individual, which can adopt a different pathway through which cancer migrates and metastasizes. My lab is actively identifying the pathways which are apparent in the development of cancer of the prostate gland, and how can we develop or identify nontoxic, dietary inhibitors which we can mix together and hopefully stop the growth of the normal cells to inflammatory cells to cancer and, subsequently, metastasis of the prostate cancer. JB: So with that I am led to this most recent publication from your group that I have, which is in Chemical Biological Interactions, and is a 2008 publication talking about the prevention of prostate cancer through custom tailoring.19 In this paper you talk about the agents from, obviously, the green tea plant, and turmeric (which is curcumin), and pomegranate, and soy bean genistein, and cruciferous vegetables (indole-3 carbinol), and resveratrol from red grapes… HM: Initially we put the idea out there because the cancer cell adopts multiple pathways to survive and thrive. If we can identify in an individual, through a genomic and proteomic approach, what kinds of defects have occurred in genes (proteins, oncogenes, and similar response genes), then we have identified those genes and we can look up in our armamentarium of natural products and say, “Alright, you have 7 genes that are defective or 5 similar responses which have gone defective which are ultimately going to put you at the higher risk for development of prostate cancer.” We can find out the agents which can destroy these defects. So we need two kinds of information: we need to identify individual defects, and then we need to find what agents can fix those defects. Through that approach, we can make a customized cocktail and give it to individuals. This approach could be extremely effective in high risk individuals. Let’s say one brother has prostate cancer, then the other brother is likely at higher risk. If the father has prostate cancer, then the son is at higher risk. Same thing for breast cancer. If one sister has breast cancer, the other sister is at higher risk. If the mother has breast cancer, her daughter is at higher risk. Can we identify high risk individuals and start identifying their genetic profile? If these abnormalities are detected early on, we can to do something to fix those defects. How can we do it? We can develop a cocktail of agents and, say, use curcumin, green tea, pomegranate, whatever it is, and hopefully that can stall the defects that are occurring in a person at higher risk and hopefully those defects are repaired before the damage has taken place. JB: This is a very visionary concept: nutrigenomically based, personalized medicine or nutrition-that’s a really powerful concept. Do you feel from your work that one could actually get adequate levels of these nutrients into their diets to be of therapeutic value? HM: There’s a long way to go. I think, ultimately, we can succeed. At this stage we have no idea, and that is why human variability exists. That is why more work has to be done. That is why the personalized cocktail approach could be more effective because we may not be able to deliver the concentrations of one agent that could be effective, but we can mix up small amounts of different agents. The whole concept is like the multivitamin concept. I want to bring a “multi” natural product concept. JB: What do you think the next steps will be in making this become a clinically applicable concept? HM: I think we have to develop a cocktail and test it in human individuals who are at higher risk. We don’t have to wait until they develop cancer or not. We have to do some biomarker analysis, which are indicators of the likelihood of development of cancer. That is a multi-million dollar task. There is a long, long way to go. JB: Have you seen any receptivity to this being funded by our granting agencies so that people see the value of this? HM: Granting agencies look at things differently. There is a big barrier: to convince them because of the issues like availability (bioavailability), stability, interaction of one agent with another agent-those are the dogmas, those are the hurdles. I haven’t seen a shift in the way the way the funding agencies look at it. JB: We are very encouraged by the quality of the science that you are doing and perhaps acceptance will happen soon because it appears as if the model of treating things after you get them is not very efficient. I think the future, as you have described it, of nutrigenomic-based chemoprevention sounds to me like it has a huge amount to offer in the prevention and treatment and maybe management of these major chronic diseases. HM: Thank you very much. JB: I want to thank you so much for spending this time with us. I believe your work has set the tone for all the rest of us in hopefully moving to a different strategy as we see the future unfold. HM: It has been a privilege to be with you. We thank Dr. Mukhtar very much for his extraordinary comments. What a tremendous contribution his work and that of his colleagues has made over the years in helping us to understand this whole concept of the mechanism of chemoprevention and biological activity from natural products and food-derived, secondary chemicals. Traditional Medicine as Front-line Therapy for Millions of People Traditional medicine has continued to provide front-line pharmacotherapy for many millions of people worldwide and so I don’t think we should discount any of this as being kind of secondary importance; it has primary importance. Although application is often viewed with skepticism by the Western medical establishment, we know now that medicinal extracts used in ancient medicinal traditions such as Ayurveda and traditional Chinese medicine, are rich sources of therapeutic compounds for modulating function in areas of chronic illness. The transformation of traditional medicines into modern drugs has its origin in the archetypal examples of the antimalarial, quinine, and the antipyretic analgesic, aspirin, coming from willow bark. The Vinca plant was very important in developing and delivering various pharmacologically active compounds. The alkaline, quinine, was isolated in 1820 from the bark of several species of chincona and is thought to have been used by Peruvian Indians to suppress shivering since the 17th century in the treatment of malarial fevers. Similarly, we know aspirin was derived from salicylic acid and the bark of the willow tree, and used traditionally to treat fever and inflammation in many cultures worldwide for at least four millennia. The successes of these two early “blockbuster” natural molecules set the stage for ongoing discovery effects and efforts across the world with traditional medicinals. Compounds derived from natural medicinal extracts are appealing for several reasons: they are often stereochemically complex, multi- or macro-cyclic molecules with limited likelihood of prior chemical synthesis, and they tend to have interesting biologic properties. They have also been sieved through the laboratory of natural selection, so they have some history and relationship with our physiology. But perhaps most importantly, parent extracts have been clinically tested in this traditional milieu, in some cases over millennia, so there is this empirical understanding of their application. Despite these advances, however, the path from traditional medicines to Western pharmaceuticals is fraught with challenges as a consequence of different philosophies I mentioned in the introduction of this month’s Functional Medicine Update. We have a tendency to believe that new-to-nature molecules coming off the desktop of bench chemists, which show very high levels of activity (i.e. potency) are the preferable molecules to use because they have this supposed specificity and potency of action. However, as we have learned more over the last 10 years about the pleiotropic effects of many of these synthetic molecules that we use in pharmacotherapy, we find that the mechanism of action that we might have thought of as being singular is actually multifunctional, and therefore these hard-hitting, highly potent molecules don’t necessarily isolate their activity to just one gene or just one enzyme, but rather have effects that cut across many different functions in different tissues. That is what gives rise to the potential of adverse side effects over time of use because of this spreading effect of their activity. The natural-source molecules, as I said earlier, which may have lower potency, may hit many things a little rather than a few things a lot and therefore their risk to adverse side effects are often much lower than these synthetically derived molecules. But it doesn’t necessarily fit in to our logic from the pharmaceutical world, nor does it fit into the patent structure in that one cannot own a molecule in nature that has already been identified as a natural product. Many Studies on Natural Products If we look at things like artemisia (from the Artemesia annua) we know that it has a very interesting effect as an anti-malarial. There are many different groups that have been surveying. In fact, 81 clinical trials have looked at anti-malarials from artemisinin, and 31 charities and institutes, universities and companies that have studied it. We also see the role that has been studied in cytomegalo-virus infection (two different studies in that area). We go on to compounds that are derived from triptolide compounds from Wilfordia and from Celastrol. These are compounds derived from natural products that have been studied by the National Institutes of Arthritis and looked at for potential activity in autoimmune disease. Again, the mixtures of molecules seem to have a different effect than single molecules. I have been actively involved in published work as it relates to the complex array of molecules found in the lipophilic fractions of hops (the so-called Humulus lupulus). These molecules are called tetrahydroisoalpha acids and they also have very dramatic and interesting effects as mixtures of molecules on the kinase-regulated pathways that are associated with inflammatory disorders and arthritis. We can see that in natural products there exists a variety of very interesting inflammatory modulating substances that work by different mechanisms. Some of them are working by the traditional COX1 and COX2 inhibition activity (that is the cyclooxygenase 1 and 2 inhibitors like the nonsteroidal anti-inflammatory drugs work), and others work by different mechanisms, like the molecules derived as tetrahydrolized alpha acids from Humulus lupulus, by modulating the selective kinase signaling pathways that regulate the gene expression of the cassette of genes associated with inflammation that then downregulates the production in inflammatory-prone cells of the synthesis or the production of messenger RNA for the various inflammatory proteins. So it doesn’t block the enzyme, but rather it modulates the upstream activity of expression of these proteins in a cell-specific way. It is a similar situation with capsaisin, which has been used for chronic pain, postoperative pain, radiation-induced mucocitis, alopecia areata, Morton’s neuroma, and interstitial cystitis, we have seen clinical trials that have been done in each of those areas. In fact, 13 clinical trials have been published on capsaisin and chronic pain, showing that this hot factor that we find in spicy foods actually has a very interesting effect that modulates the pain receptor and pain signaling mechanism. The paradox is that the hotness that is associated with the capsaisin also retards the heat of pain that is related to inflammation. It is kind of an interesting ying-yang association with capsaisin. And then, of course, we see some very interesting things with curcumin, coming out the spice turmeric. Many clinical trials that are now being done-there are 6 clinical trials being done on chemoprevention of colon cancer with curcumin; there are 3 clinical trials on pancreatic cancer; Alzheimer’s disease, 2 clinical trials; and chemotherapy-induced mucocitis, multiple myeloma, psoriasis, and cystic fibrosis have all had clinical trials performed with curcumin. It is another interesting molecule, derived from nature, that has influence on signaling pathways associated with cell replication and with metastasis and also with inflammation.20 In an earlier issue of Functional Medicine Update, we recognized work that is being done on resveratrol, another very interesting molecule derived from peanut skins and grapes. Resveratrol has a very important role in modulating NAD-dependent deacetylases with epigenetic modulation of cellular genetic expression. It seems to control that set of genes that we often call the “longevity genes” that are influencing insulin sensitivity and inflammation, so here’s another interesting natural product that is within a mixture of molecules in its natural source. And the list obviously goes on; I’m just hitting the surface. Dr. Mukhtar did a brilliant job of helping us to understand this broad array of molecules and natural sources that have these interesting effects. If we summarize all this, it leads us to recognize that nature has possibly already been synthesizing molecules with safe and effective activity for the management of certain types of chronic disorders that are not yet severe enough that they require a pharmacological hit. At an earlier stage of a disorder, we are kind of “tickling” metabolic pathways (or the phenome) of the individual (which was the genome, the proteome, and the metabolome)-tickling it with a variety of lower potency but selective molecules that are derived from natural sources, and this may be the both safer and more effective way of managing function over time. I think this is where the juxtaposition of controversy really exists today–one side against the other, seemingly as if there is no common ground that can be found. I think there is a common ground because it is all about sharing similar concepts of pharmacology. It is all about sharing similar views of this interaction of a biologically active molecule with a cellular function to produce outcome. The controversy is about the orchestration of how that plays out, whether it is an orchestration of a smaller orchestral soloist that is playing very loud and giving a great maestro performance as might be a new-to-nature molecule, or whether it is a full orchestration that is playing together in timber and each voice is attenuated slightly to that of its neighbor to form the complex array of messages that we call the functional web of physiology. So I think in terms of different molecules for different applications, different thoughts for different needs, and that is where I believe the story really has a commonality of resting between the two sides. It is not that one view is right and the other view is wrong; they really share common attributes of function. It is about using the right thing at the right place and the right time. With the deciphering of the human genome, and looking at how genetic expression occurs and how substances are regulated through the complex kinase signaling pathway (taking outside messages and convert them into inside function)-all of that is leading to a resurrection of interest in natural products, the mixture that comes from substances that have been sieved through this large laboratory process called natural selection. I think that we are going to find that maybe the best molecules of all for chronic management of complaints and restitution of health comes from this laboratory of natural selection. I hope you have enjoyed Dr. Mukhtar and his comments and I look forward to sharing with you again next month.

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Bibliography

1 Besse JP, Garric J. Human pharmaceuticals in surface waters. Implementation of a prioritization methodology and application to the French situation. Toxicol Lett. 2008;176(2):104-123. 2 http://www.usatoday.com/news/nation/2008-03-10-drugs-tap-water_N.htm 3 Yue PY, Mak NK, Cheng YK, Leung KW, Ng TB, et al. Pharmacogenomics and the yin/yang actions of ginseng: anti-tumor, angiomodulating and steroid-like activities of ginsenosides.Chin Med. 2007;2:6. 4 Burns Kraft TF, Dey M, Rogers RB, Ribnicky DM, Gipp DM, et al. Phytochemical composition and metabolic performance-enhancing activity of dietary berries traditionally used by Native North Americans. J Agric Food Chem. 2008;56(3):654-660. 5 Efferth T, Li PCH, Badireenath Konkimalla VS, Kaina B. From traditional Chinese medicine to rational cancer therapy. Trends Mol Med. 2007;13(8):353-361. 6 Franceschi C. Inflammaging as a major characteristic of old people:can it be prevented or cured? Nutr Rev. 2007;65(12):S173-S176. 7 Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res. 2008;39(1):1-16. 8 Rayalam S, Della-Fera MA, Yang JY, Park HJ, Ambati S, et al. Resveratrol potentiates genistein’s antiadipogenic and proapoptotic effects in 3T3-L1 adipocytes. J Nutr. 2007;137(12):2668-2673. 9 Nurk E, Drevon CA, Refsum H, Solvoll K, Nygard O, et al. Cognitive performance among the elderly and dietary fish intake: the Hordaland Health Study. Am J Clin Nutr. 2007;86:1470-1478. 10 Hafstrom I, Ringertz B, Spangberg A, von Zweigbergk, Brannemark S, et al. A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatology. 2001;40:1175-1179. 11 Kjeldsen-Kragh J, Haugen M, Borchgrevink CF, Forre O. Vegetarian diet for patients with rheumatoid arthritis &ndash; status: two years after introduction of the diet. Clin Rheumatology. 1994;13(3):475-482. 12 MacDonald TT, Monteleone G. Immunity, Inflammation, and Allergy in the Gut. Science. 2005;307:1920-1925. 13 Lenoir-Wijnkoop, Sanders ME, Cabana MD, Caglar E, Corthier G, et al. Probiotic and prebiotic influence beyond the intestinal tract. Nutr Rev. 2007;65(11):469-489. 14 Erridge C, Attina T, Spickett CM, Webb DJ. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr. 2007;86:1286-1292. 15 Mukhtar H. Profiles and Legacies. Natural Produts: Nature’s Gift. Molecules for Cancer Prevention and Treatment. Cancer Biology & Therapy. 2007;6(9):e1-e4. 16 Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst. 1997;89(24):1881-1886. 17 Khan N, Afaq F, Saleem M, Ahmad N, Mukhtar H. Targeting multiple signaling pathways by green tea polyphenol (-)-Epigallocatechin-3-Gallate. Cancer Res. 2006;66(5):2500-2505. 18 Adhami VM, Malik A, Zaman N, Sarfaraz S, Siddiqui I, et al. Combined inhibitory effects of green tea polyphenols and selective cyclooxygenase-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo. Clin Cancer Res. 2007;13(5):1611-1619. 19 Siddiqui IA, Afaq F, Adhami VM, Mukhtar H. Prevention of prostate cancer through custom tailoring of chemopreventive regimen. Chem Biol Interact. 2008;171(2):122-132. 20 Corson TW, Crews CM. Molecular understanding and modern application of traditional medicines: triumphs and trials. Cell. 2007;130:769-774.

Welcome to Functional Medicine Update for June of 2008. In the last few issues, we have talked about ways that one can validate the safety and efficacy of interventions. The gold standard has traditionally been the randomized, double-blind, placebo-controlled trial. We have talked about the strengths and limitations of that type of methodology when you are looking at network or systems biology interaction, because the placebo-controlled trial is very suited for single-agent-against-single-outcome types of studies. When you are doing studies that relate to polygenomic complexity (with multiple interventions looking at multiple outcome variables), the randomized, double-blind, placebo-controlled trial becomes less useful in terms of defining the effectiveness of a hypothesis, or the outcome of a hypothesis, or the safety and efficacy of an intervention. A paper that demonstrates these limitations appeared in the British Medical Journal and was titled “Parachute Use to Prevent Death and Major Trauma Related to Gravitational Challenge: A Systematic Review of Randomized Controlled Trials.”1 This is by Gordon CS Smith and Jill Pell from the department of obstetrics and gynecology at Cambridge University and the Department of Public Health at Greater Glasgow (the institution of the National Health Service in Scotland) who I think did a marvelous job. In this article, the authors talk about how one would prove the efficacy and safety of the parachute under randomized controlled trial procedures. The conclusion of this study (which I think you will find fascinating) says the following: “As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomized controlled trials. Advocates of evidence-based medicine have criticized the adoption of interventions evaluated by only using observational data. We think that everyone might benefit if the most radical protagonists of evidence-based medicine organized and participated in a double-blind, randomized, placebo controlled crossover trial of the parachute.” I think that sets the tone for this month’s Functional Medicine Update. When we deal with systems biology-related issues, which are the focus of functional medicine, we are dealing with networks rather than pathways. We are dealing with interactions of complex, dendritic relationships (feedback pathways rather than single throughput steps that relate to A going to B), where it isn’t very amenable to a randomized, placebo-controlled intervention trial system. We are also looking at human individuals over many years of living, which have complex lives and very diverse genotypes. All of these variables play a role in modulating and modifying the outcome within a population-based group of what you might call safety and efficacy of any therapeutic. And when we are dealing with a functional medicine systems biology approach, we are generally dealing with multiple things going on simultaneously, not just holding all variables constant and modifying one thing, like the addition of one molecule (one new-to-nature-molecule). With the complexity of this kind of thinking, what is the better methodology? We have been talking about the development of this new way of treating data that is related complexity, which is complexity science; it is related to network thinking; it is related to nearest neighbor analysis, cluster analysis, artificial intelligence, non-parametric solutions that relate to polynomial types of polyvariant rather than univariant type of statistics, and looking at things in a nonsymmetrical universe. Not everything is Gaussian (mid-line, symmetrical, about the average point). With all of the realities of the world in which we are living today and how those realities map against chronic age-related diseases, it is forcing us into different ways of thinking. Dr. James Wright, in his extraordinary interview in the April issue of Functional Medicine Update, used the example of statins as agents for primary prevention of cardiovascular disease. We learned that the outcome is not so easy to evaluate when we start looking at number to treat and actual cost-effectiveness of use of statin drugs in the primary prevention of cardiovascular disease. Recently, a very interesting article titled “Future of Lucrative Cholesterol Drugs Murky,” appeared.2 This article says that physicians “are waiting for new preventive heart medicines beyond popular statin therapies, but a tough regulatory climate and fierce debate over the effectiveness of some of these newer drugs has clouded the future of cholesterol treatments. The uncertainty is roiling investors looking to cash in on what has traditionally been the most lucrative arena of the pharmaceutical sector. Sudden plunges in sales of newer cholesterol drugs, that had been expected to grow strongly for years, and unexpected US Food and Drug Administration rejections or delays of medicine have sparked deep declines in share prices. ‘Today investors are probably feeling like a successful investment in a new lipid franchise is something that is going to take a long time to materialize,’ said Leerink Swann, an analyst looking at the pharmaceutical industry. As you are probably aware, the Food and Drug Administration has received intense criticism over withdrawn drugs such as Merck’s painkiller Vioxx and GlaxoSmithKline’s diabetes PPAR-gamma agonist Avandia. There is now debate over extensive use of cholesterol medicines such as Vytorin. That drug, sold in a joint venture between Merck and Schering-Plough, is facing plunging sales following publication of a failed study. Patients are now questioning whether these medicines are really safe and effective. Although heart disease remains the number one killer in the United States and many patients need something in addition to statins to get their cholesterol to target levels, we are asking about the real return on investment for a person taking statins in primary prevention. Are there subtypes of individuals who are either genotypically or phenotypically more sensitive and responsive to statins than others? Would some people be better candidates who we would target in a personalized medicine approach? Should we target those people who would best respond, rather than using a drug with a group and looking at the average-a blockbuster mentality, “one-size-fits-all”- type of medication? All of these questions are really starting to come to the surface more and more frequently. Also related to this issue is the recent removal (or denial for acceptance) of the drug Torcetrapib by Pfizer, which was reputed to be a new HDL-elevating drug that would be added to statins to extend their therapeutic benefit. Studies found that although Torcetrapib did increase HDL, it also increased HDL of an inappropriate type. The drug didn’t lead to reduced incidence of heart attack, but actually increased cardiovascular accidents. Treating the physiology is what is important, not just treating a number. Of course, that is what we have been saying in functional medicine for nearly two decades: one needs to look at the functional outcomes that relate to any intervention and ask the question, do these functional outcomes relate to normalization of the physiological, physical, mental, emotional outcome of that patient and their performance level? As we move from blockbuster medicines to personalized medicine, this is becoming a theme we are seeing more and more frequently in the literature. An article just appeared in a new journal called Personalized Medicine that shows, once again, how this field is moving forward and is evolving very rapidly. This particular article that appeared in volume 1 of the new journal was titled “From Blockbuster Medicine to Personalized Medicine” and went on to say that the biggest challenges of the pharmaceutical companies in the 21st century will be to develop and deliver drugs that fit the individual patient’s biology and pathophysiology.3 This is what Roger Williams called “Biochemical Individuality” back in the 1940s. This change from blockbuster medicine to personalized medicine, the article says, “will, to a large extent, influence the way that drugs are going to be developed, marketed, and prescribed in the future. These changes can mean an end to the blockbuster philosophy and Big Pharma, and thereby impose major changes in company structures. The implementation of personalized medicine will be a step-wise process where the division of patients into biological subgroups will be the first important step.” I might say (parenthetically) that this has been the focus of the Institute for Functional Medicine and functional medicine for many years: trying to define the processes that relate to the underlying pathophysiologies and looking at the origins (rather than just the name) of the condition and its outcome as a pathophysiology. Going back to the article, the authors say “today this is already the situation for several cancer diseases, for example, breast cancer. In years to come we may see more and more drugs being prescribed based on the results from pharmacodiagnostic testing.” (That is looking at the genetics of the individual and how they respond to a specific therapeutic agent.) “Within cancer medicine, which has been at the forefront of this field, it is expected that in 10-15 years time very few drugs will be prescribed without such a test,” (pharmacodynamics, pharmacogenetics, and pharmacodiagnostics to type the individual to their medication). Now let me move away from this article to talk about the model that we have been describing and we are going to talk more about in this issue of Functional Medicine Update. We talked about the fact that in the laboratory of nature– this large experiment that has been going on for hundreds of millennia called natural selection–that we are starting to recognize that there are certain molecules that have emerged in our food supply and in our life in such a way as to speak to our genes and modulate both epigenetic and genetic expression. As such, these may be molecules that are well suited for normalization of function in people who have distorted physiological networks in their physiological function (such that any distortion at a point on the net then distorts the whole of the net). Pathways are really just abstracted snapshots in the web of life. With a systems biology approach to that network, we see it is composed of pathways that are all interacting in real time, and differentiate it from cell type to tissue type based upon the functional characteristics of that tissue or organ. These molecules in nature, the things that have been in our food supply system historically, have a relationship that has evolved with our signaling processes (the so-called intercellular signal transduction) to induce and to modulate certain cellular outcomes that lead to normalization of the web. As such, we call these hormetic effects, meaning small amounts of substances may have larger than expected effects on the system. And that hormetic effect-because these substances in our food are not natural to our human body (they are produced by plants, not by humans-they are what we would call “foreigners”)-we call xenohormesis. Xenohormesis means foreign molecules from plants (produced through the biosynthetic machinery of plants in response to their environment) that are then consumed by humans in complex diets and have a hormetic effect upon the regulatory nodes in our network of physiology. This hormetic effect leads to stability, or to organ reserve (to go back to a term we have talked about since 1980, when Dr. James Fries authored his classic paper in The New England Journal of Medicine on aging, natural death, and the compression of morbidity). The concept that we have certain molecules in our foods that have come up through natural selection and are smooth in the way they respond through signaling agents to induce-at the epigenetic or genetic expression level-influences on our network physiology to normalize function as xenohormetic agents is very powerful. I know I threw a lot of terms together in that sentence, and I may have lost some of you if you are not longtime listeners. This is a very, very new concept within cellular physiology, nutrition, and medicine and it is reframing our view of how nutrients might play a role in both prevention and management of chronic disease. This is very different than looking at new-to-nature molecules that block certain pathways, like an ACE inhibitor, or an SSRI, or an HMG-CoA-reductase inhibitor, or an H2 blocker. Here we are talking about agents that have evolved through time to modulate intercellular signal transduction at such a level as to lead to functional plasticity in the network, and more reserve capacity, and to help normalize the texture, composition, and shape of our complex web of physiology. This model-this xenohormesis model-that I am describing was first discussed by David Sinclair at Harvard, and now is gaining much more traction as we see other people picking up on the theme and doing research. It was recently further described in a new article by Sinclair and Howitz in the journal Cell, a very premier journal in cellular biology. This article appeared in a May 2008 issue under the title “Xenohormesis: Sensing the Chemical Cues of Other Species,” and the subject is how plant molecules interact with and modulate key regulators of mammalian physiology in ways that are beneficial to health.4 As described in this article, the proposal is that there are heterotrophs (animals and fungi) that are able to sense chemical cues synthesized by plants and other autotrophs in response to stress. The complex array of phytochemicals that are manufactured through the biosynthetic machinery of plants are made in response to stress in their environment, for which they produce their antistress compounds (like carotenoids and the whole family of flavonoids (including flavanols and anthocyanins), isoflavones, glucosinolates, and other polyphenols-the list goes on and on). Literally thousands of different phytochemicals are manufactured by plants specific to their species in response to stress in their environment. If not refined away, phytochemicals (in plant foods) are consumed by humans (heterotrophs), which can then affect function and may provide more reserve to adversity in changing environmental conditions. This is the organ reserve concept so once again we come around full circle to James Fries (through the understanding of gene expression, epigenetics, and the role that xenohormetic substances might have on them). Moving away from just looking for more new-to-nature molecules that can block or inhibit specific downstream pathways in physiology is a profound new concept. Here we are looking at upstream regulators (what you might call the regulatory units) in the net of physiology that has to do with this hormetic effect (small amounts of substances having larger effects on physiology). When we start looking at how this translates into clinical medicine, we have to recognize that there are many, many different functional regulatory systems in the body that can express dysfunction over time and that we later call a disease. In Functional Medicine Update, we have been focusing on things like the stress response in humans and the hypothalamus/pituitary/adrenal/thyroid axis and how that translates into a population of people who are stressed from environmental changes, time compression, less-than-high-quality diets, and chemicalization. All of these are things manifest through what Hans Selye called stress factors. They induce alteration in the network plasticity and network function to be then seen as a whole complex array of disorders: cardiovascular disease, hypertension, increased risk to cancer, musculoskeletal problems, digestive disorders, non-ulcer dyspepsia-the list goes on and on as it relates outcomes from these changes in the network of life Recently I put together a short presentation on this. It is available through Synthesis by Jeffrey Bland and is titled “Managing Adrenal and Thyroid Balance Associated with Stress.” I think this is a very nice review of this whole topic. It is a combination audio and visual program that reviews this complex clinical topic quite nicely for those of you who are looking to learn how this model I am describing (the functional medicine model) fits into both the recognition and management of chronic stress. It also really ties together with another product that we have just released through www.jeffreybland.com, which is “The Emerging Therapeutic Target: Improving Therapeutic Outcomes by Treating the Intersection of Osteoporosis, Cardiovascular Disease, Type 2 Diabetes, Arthritis, and Cancer.” This presentation also focuses on this intersection of mechanisms that relate to the outcome that we call disease at an earlier stage than waiting until histopathology is seen. Earlier intervention can lead to milder intervention and prevent the trajectory heading on towards the crisis disease (or the more acute disease). So these two products, “Managing Adrenal and Thyroid Balance Associated with Stress” and “The Emerging Therapeutic Target” are both a combination (audio plus visuals) products that provide an overview of these topics and give some news to use, clinically, in these two areas. If you are interested in finding out more about these, I refer you to our website, which is www.jeffreybland.com, or you can give us a call at 866-272-5789. If we take this concept I am describing-this hormetic concept, and how substances in our diet or substances in our environment influence our function-then it leads to recognize that the translation of messages from the outside world into interior functional changes in the body has something to do with how our book of life is read. Our book of life is our genome-23 chapters, written by our biological parents-which then gets translated ultimately into expression patterns that leads to our phenotype: how we look, act, feel, and function. What questions would you ask clinically? What is it that communicates those messages and how do they get translated into function? How can we therapeutically harness this conceptual framework in such a way as to produce more effective outcome in patients with chronic illness instead of just blocking downstream pathways with inhibiting drugs to manage symptoms? The answers are fairly complex and require more than just a few minutes of explanation, but let’s try to cut it down into individual piece parts that we can manage. Let’s first ask this question: what are we going to be measuring in order to understand where that patient is in the progression from optimal function to complete absence of function (which we call death)? This is where biomarkers become very important. Biomarkers are variables we can assess that give us some indication of the trajectory that person is traveling. The most classic example of a biomarker is blood pressure. We know that blood pressure, as it elevates, is associated with an increased incidence of cerebral vascular disease and coronary events and has detrimental effects on kidney function and vascular function. We would say that elevated blood pressure is a biomarker for later stage, more serious illness. Similarly, we might use a chemical biomarker, like total cholesterol or the cholesterol HDL ratio, as a way of assessing trajectory towards a relative risk to cardiovascular disease. We would not say the total-cholesterol-to-HDL ratio is a diagnostic criterion, but we would say that it is a prognostic evaluator, a biomarker of a trajectory towards the potential risk of vascular diseases. We might use something like an EKG (an electrocardiogram) to evaluate the functional integrity and organ reserve of the cardiovascular system under stress. Or we might use something like the power EEG (the electroencephalogram) to measure certain aspects of brain mapping and brain biochemistry, indirectly, by utilizing spectral analysis of the EEG. New technologies are being developed that allow for more precise understanding of regional aspects of metabolism in the brain and how that maps against regulatory features of things like brain inflammatory patterns, or ischemia in the brain, or altered neurochemistry of the brain. All of these measurements become functional biomarkers for evaluating trajectory towards more serious illness, and also become markers that can be used for tracking the success of intervention (by seeing normalization in these biomarkers, the assumption is that a patient is on a path towards improved outcome). Let’s look at something like metabolic syndrome (insulin resistance) as an example of a condition that is a syndrome before a disease. The concept of functional somatic syndromes and the preclinical stage of a disease is really where a lot of the action is. A metabolic syndrome/hyperinsulinemic patient may not yet have a diagnosed disease, but they have a risk to things like type 2 diabetes, cardiovascular disease, renal disease, stroke, certain forms of cancer (like breast, prostate, and colon cancer), or things like nonalcoholic steatohepatitis (NASH) with fatty liver infiltration if they don’t do something about their insulin resistance. All of these are manifestations of metabolic syndrome progressing to clinical disease states. How can we evaluate a patient’s status before they have an onset of these more severe conditions that require more aggressive intervention? The answer comes down to things like the triglyceride-to-HDL ratio as a surrogate marker. We can also look at the apolipoprotein A and apolipoprotein B levels to see what relative risk is because we now know that an apo B-to-A1 ratio, when it gets above 0.6 to 0.8, is a ratio associated with increasing incidence of vascular disease associated with insulin resistance. The ratio of apo B to apo A1 (that number when you divide apo B by apo A1, that quotient) should be less than or equal to 0.8. As this number gets larger, it is associated with an increasing relative incidence of vascular disease associated with insulin resistance. We can look at the particle number and the particle size in the lipids in the blood, either by NMR or by densitometry; we can actually measure particle size and particle number. We know that dense LDLs, as they grow in number, are associated with a much higher atherogenicity even if there is a reasonably low total cholesterol, and even if LDL, in and of itself, is reasonably low. So we would look at atherogenicity of the particles by looking at their size and number. All of these examples are relative biomarkers for evaluating the potential pathology downstream from insulin resistance. Once these markers are established, what is done to improve the function of the individual and improve their biomarker analysis? We talk about diet and lifestyle, of course (the so-called “first-line therapy” that the NIH talks about). Before you intervene with pharmacotherapy, the NIH guidelines say that we should first intervene for a period of three months with lifestyle and diet intervention to see if, in fact, we can normalize function before relegating the patient to pharmacotherapy. What type of dietary interventions would we use? We would get away from refined carbohydrate. We would get away from excessive lipid in the diet as saturated fat. We would lower total fat and increase the omega-3s and omega-9s within the diet. We would lower the amount of high fructose corn syrup sweeteners (in fact, I would say lower it to the point where it becomes an insignificant part of the total diet). Fructose Consumption as a Biomarker for Nonalcoholic Fatty Liver Disease It is more than just fructose in and of itself; it is a combination of fructose plus other ingredients that are found in high fructose corn syrup sweeteners that we are now seeing an increased intake of in the diet. There was an interesting paper just published in the Journal of Hepatology titled “Fructose Consumption as High Fructose Corn Syrup Sweetener is a Risk Factor for Nonalcoholic Fatty Liver Disease.”5 In this particular paper the authors looked at patients who had symptoms and signs and biomarkers associated with metabolic syndrome versus a control group. Then they looked at people with nonalcoholic fatty liver disease versus controls, and they found that those people who had NAFLD had a much higher intake of fructose coming from fructose corn syrup sweeteners. The amount they were consuming in their diet was about 100 grams per day (100 grams of fructose coming from high fructose corn syrup sweeteners). One hundred grams per day is a very, very high dose relative to what you would get from a normal diet as it relates to fructose. For instance, an apple has about 5 &ndash; 7 grams of fructose, so to give an apple equivalent, obviously to get 100 grams of fructose you would have to eat something like 20 apples. You could get 20 apples as apple juice, but it would be very difficult to get 20 apples worth of fructose eating whole apples. And, in fact, the apple also contains other agents that might help mollify or modify the way that fructose is actually metabolized. It is probably not even a very good example-comparing apples to high fructose corn syrup sweetener-because there you get the raw signal of fructose and its multimers versus the signal that you would get of fructose in apple or apple juice that is modified by many other phytochemicals. In this particular study, the authors go on to talk about the pathogenic mechanism underlying the development of nonalcoholic fatty liver disease, and they say that it may be associated with this excessive consumption of dietary fructose, particularly in people with specific genotypes that have unique polymorphisms of the enzyme fructokinase. In this study, they actually looked at hepatic messenger RNA expression of fructokinase and asked how it relates to those individuals who have NAFLD who consume this high dose of fructose as corn syrup sweeteners everyday in their diet. What the investigators found was that there was a dose-dependent increase in the expression of fructokinase, a protein inactivity associated with this high level of fructose intake as corn syrup sweeteners, and that that tracked back to specific genotypes that had higher genetic susceptibility to fructokinase activity. Again, a complex interaction among diet (among altered modified diet) and genotypes to give rise to a risk factor in a trajectory towards a disease that we call nonalcoholic fatty liver disease. I think this is a very nice example of the complex interaction of genes and environment from a functional medicine/systems biology perspective versus just looking at the outcome of a disease called NASH. The other thing I want to mention here is to make sure that we identify the difference between giving a highly chemicalized, purified form of high fructose corn syrup sweetener versus that of taking in fructose in a complex dietary array as a small constituent of the diet. We are going to get some monosaccharides and disaccharides in diets that are of natural origin. The question is, at what magnitude do we consume them? Do they elevate the risk factors of metabolic syndrome, and what are the other factors that come along with them in a complex diet that actually assist in their metabolism or in their regulation? That is where the complex diet story really becomes interesting from a systems biology perspective because the more we abstract and isolate constituents out of the diet and separate them into what Roger Williams talked about as “partition foods,” the more we get a different effect of that food than that in the natural state, where it was in a complex mixture in its natural origin. If you use the example of apple juice versus the same amount of fructose that comes from high fructose corn syrup sweetener, apple juice contains (if it is a full, whole-pressed apple) all sorts of lignans and polyphenols and other kinds of phytochemicals that modulate the metabolism of the nutrients like fructose that are found within the apple itself. I think these are the kinds of thinking patterns that are leading us into a state of understanding, even as it relates to all the published studies on nutrition that talk about “this nutrient produces this problem.” You have to say, “Well hold it. What was that nutrient delivered in? What matrix? Was that a purified chemicalized form of that nutrient that was then delivered in a very synthetic fashion into that individual animal’s diet to evaluate its outcome, or was it that same nutrient, in a complex whole form, at a modest level of intake, that then resulted in a different effect on its outcome?” With all of that in mind, let’s move this discussion to a specific clinical takeaway. I would like to move this into the molecular origins of cancer. Cancer comes about as a consequence of several different steps: initiation, progression or proliferation, metastasis, and then lastly angiogenesis, which is part of the metastatic process. What we recognize is that a cancer cell is a cell that has undergone dedifferentiation. It has become a juvenile embryonic-like cell that multiplies rapidly (an unregulated cell growth). It develops its own blood supply (angiogenesis) when the tumor cell mass gets to a certain size (about 3 millimeters). And then it starts to be able to spin off its brethren (which we call metastasis, where it can travel to distant sites and initiate growth elsewhere). This whole process is what we then term as the “cancer process.” How does the body manage to transform cells that might be developed over the course of living? It has an immune system (a recognition system) that tries to understand the presence of these foreign cells that have undergone transformation and excise them from the body prior to them getting a foothold and getting to a stage where they can actually undergo angiogenesis and metastasis. This has to do with the upregulation within these transformed cells with certain function expression patterns that relate to the caspase genes (the death genes) that cause apoptosis, or cellular suicide. A transformed cell is recognized within an immune system that is functioning optimally as a “funny” cell, as a cell that really should have no business there, and regulating its function through this natural excision process that we call the apoptotic process. When you get multiple hits, however, and you get accelerated initiation and you get processes that are involved with stimulating propagation, and you get regulatory factors in gene expression that relate to the ability for that mass to undergo angiogenesis, now you start getting double or triple hits on the system, and now the body’s regulatory mechanisms may not be able to keep up or compensate for this initiation process and this whole way that tumors ultimately develop into a clinical cancer. It all starts at a molecular stage, doesn’t it? Over the past decade, insights into the origins and behavior of human cancers have reshaped our understanding of these diseases. We now know that cancer is not singular, it is plural (cancers), and each cancer may have a different fingerprint based upon its genetic mutation that it has undergone within the book of life of that specific cell. And that specific cell’s regulatory change through a mutation either at the epigenetic or the genetic level can then result in certain dedifferentiated cell regulatory processes being obviated or exhibited, which then we ultimately see over time developing into a diagnosed cancer. What controls these personality characteristics of cells? In part these are controlled epigenetically (“epi” meaning “above the gene”), so not only are we talking about initiation being caused by mutation of a gene (like an oncogene that has undergone a mutation to kind of ignite its proliferation), but we also talk about the alteration of the epigenetic messages that sit on the regulatory regions of genes that actually control their function (like the stop-function gene regulators that we call methylated promoter regions). Undermethylation can increase the relative risk to carcinogen induction or initiation of tumors. Let me say it again: undermethylation of the promoter regions of specific genes (that is the silencing messages of genes) can lead then to the promotion of these processes. What we are going to learn from our clinician/researcher of the month is that one of the ways that you can actually examine this morphologically is by looking at the genome under the microscope for what is called genomic instability. Genomic instability is not just connected to the potential risk to cancer, but also the potential risk to virtually every age-related chronic disease. In fact, in The New England Journal of Medicine in January 2008, there was an interesting paper that talked about the molecular origins of cancer and looking at the genotype of the individual (as to their cancer susceptibility), looking at the genotype of cells that have undergone transformation (which are upregulated to cancer cells), and also looking at epigenetic dysregulation (where you have altered promoter region methylation or acetylation patterns that lead and result ultimately to higher expression of cancer).6 At one point, there was an interesting paper published in Advanced Cancer Research called “Epigenetic Theories of Cancer Initiation.”7 This article talked about hypomethylation and a methyl-deficient diet being a potential higher-initiation-to-cancer-type of regime because now that individual’s genome is more susceptible to carcinogenic injury and initiating tumors. If we start looking at a whole organism, are there ways of assessing the relative risk to cancer? At a functional level, are there ways of assessing the risk to heart disease or to autoimmune disease? This concept of genomic instability-our book of life, the most sacred thing that we should protect–becomes a very interesting focus as to how we might understand (early, before the appearance of these diseases) whether we are on the trajectory (and it may precede the onset of a disease by decades by recognizing an individual may have this genomic instability). Once you understand it, what do you do about it? Are there any ways of averting or changing your book of life from this unstable kind of state of injury into a protected, highly controlled, genomic regulatory region that then helps to prevent the environmental perturbation and these changes that ultimately lead to chronic disease? What you will learn from our clinician/researcher of the month is that, yes, the research indicates that here is where diets and specific nutrients may play a role in modulating genomic stability by helping to protect and to become able to express messages under very controlled conditions (one message at a time), rather than being susceptible to injury by mutagens or carcinogens or radiation, which then induces in them certain kinds of changes that ultimately lead to increasing risk to disease. This genomic instability is related not just to the exposure to outside caustic agents, like radiation and chemicals, but also internal agents that help to protect the genome, which are nutrient-derived, like methylation patterns that lead to methylation of the promoter regions, and silence specific genes that we don’t want to be over spoken, like oncogenes. This is a very dramatic step forward in our understanding, at an early stage, the functional changes that may ultimately relate to the appearance of age-related chronic diseases. When I say age-related, these agents can be in youth; they don’t have to be just in aged adults. It depends upon the relative susceptibility and exposure to the offending agents. What we are going to hear in this interview is how nutrients may actually help to counteract environmental carcinogen exposure, and how DNA hypomethylation increases the relative risk. I’m now quoting from a wonderful paper that Randy Jirtle and his colleagues from the Department of Radiation Oncology and the program in genetics and genomics at Duke University recently published. This article was in the Proceedings of the National Academy of Sciences, and these researchers showed that maternal nutrient supplementation in animals was capable of counteracting a carcinogen-induced DNA hypomethylation that led to very serious risk to cancer in these animals.8 By giving folate and B12 and other methylating nutrients, they were able to actually lower the relative risk to this carcinogenic chemical producing adverse effects. So here is diet neutralizing an adverse effect from the environment by protecting the epigenome. It is a very, very powerful new concept and this relates to what you are going to hear from our researcher of the month.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Michael Fenech, PhD Theme Director, Food and Nutrition Food Science Australia CSIRO Human Nutrition PO Box 10041 Adelaide, BC, SA 5000 Australia www.csiro.au Once again we are at that place in Functional Medicine Update that we all look forward to, which is our clinician/researcher of the month. Over the 27 years I have been doing this, I have had the honor to talk with many of the world’s leaders who are really carving out this paradigm-this frontier-that we are calling nutrition in the 21st century, or nutritional medicine, or maybe even health care in the 21st century. I am very privileged this month to interview Dr. Michael Fenech, who is a geneticist by background. He has a PhD in genetic toxicology from Flinders University of South Australia, with his thesis being about genetic damage in human lymphocytes assayed by a micronucleus technique. From there, Dr. Fenech became a senior principal research scientist at CSIRO Human Nutrition, Adelaide, and a visiting fellow at the Centre for Mental Health Research at the Australian National University in Canberra. He is a highly published and prolific scientist in the area of genomic stability/instability and its relationship to environment and nutrition. Many of you might be saying, “I’m not exactly sure what that means.” By the end of this interview, I can assure you that you are going to know a lot more about this than you did at the beginning. You are going to hear from someone I consider to be one of the world’s leading experts in this area. Dr. Fenech, thank you so much for joining us from all the way in Australia for Functional Medicine Update. I think maybe we’ll just start by asking how you got in the field of genomic stability/instability? Obviously your thesis (back in your PhD days) was down this path, but you must have been led into it with some interesting insight. MF: Although I ended up working in the genomic instability area, I was always intending to be a marine biologist. What really happened was an opportunity came up to do a PhD in Australia with Professor Alexander Morley at Flinders University. I grew up in Malta, which is a tiny island in the Mediterranean, and the opportunities for research were limited there, but I managed to get a scholarship to come and study in Australia. The opportunity that was presented to me was to work with Professor Alexander Morley. He is a hematologist, and he had an interest in the genetic basis or the origin of hematopoietic cancers. At that time, the mutation theory of cancer was a hot topic of interest. In Dr. Morley’s laboratory a variety of methods were being examined to study mutation in human blood cells, specifically the lymphocyte. My interest was also stimulated from the fact that I had been working for some years as a hospital scientist in hematology laboratories and that (together with my curiosity about genetics) led me to come to this laboratory, which is really where I did my PhD. JB: Well, I think the field is very fortunate that you were led in that direction. One of your more recent publications that I had the privilege of reading was a 2007 publication in Food and Chemical Toxicology titled “Genome, Health, Nutrigenomics, and Nutigenetics: Diagnosis and Nutritional Treatment of Genome Damage on an Individual Basis.”9 I shared that article with a number of the scientists in our group and they have all commented that they think this is high scholarship and a wonderfully written article that provokes all sorts of questions. Can you tell us a little bit about genomic stability and instability? What does this mean? Explanation of Genomic Instability MF: Okay. So going back to those early days when I was doing my PhD, the interest then was to look at environmental functions, both chemical and physical. The technique I was working on at the time was the micronucleus assay. This assay is really about a biomarker that tells you whether chromosomes are broken, or being lost, or not being properly segregated between daughter cells when they divide. In fact, hematologists have known about this particular biomarker for many years; it is known as a Howell-Jolly body in erythrocytes. These small nuclei, or micro nuclei, or Howell-Jolly bodies, as they are known to hematologists, increase when the organism (when the bone marrow) is exposed to either radiation of genotoxic chemicals, as well as due to deficiencies in nutrients required for DNA synthesis and repair such as folate and B12. I suppose it is from those early days that I was starting to get ideas in my head that maybe nutrition can be as important as environmental toxins, to measure in terms of the damage to the DNA or genome that may appear. JB: If we consider our book of life to be the genome, which needs to be protected both for our own integrity of mitosis as well as for our future generations, then this genomic instability, as you are implying, obviously has some fairly significant influences not only on genetics and future progeny, but also on individual cellular function and physiology of the host, I would presume? MF: Yes, exactly. I think that is a very critical point that you have mentioned. In reality, we know that only a small proportion of embryos actually succeed in developing into a fetus and into a healthy baby. Those of us who are here and living are actually quite lucky we were selected in utero to begin to be viable. That privilege really comes from the fact that the genome we were lucky enough to acquire from our parents happened to be a viable genome. The problem is, of course, that we start life as just one cell, and from that cell, millions and millions of others have to be copied and produced to create the organism, the child, the adolescent, and eventually the adult that defines us. I usually give the analogy of a photocopier: the more copies you make of the same original (making a copy of a copy of a copy), the less accurate is the image that we get with the more copies that are made. Furthermore, the quality of the copy depends on the toner and the photocopier. I consider the toner to be, perhaps, the nutrients required to make good copies of DNA in the cell. That is just my analogy. JB: I think that is a wonderful way of looking at it. This photocopying goes on everyday in our cells that are turning over during the course of our life, and also those copies (through developmental biology after fertilization of the egg) start going through this epigenetic development process, so you’ve got two levels upon which genomic stability or instability can play a role in the phenotype, it seems. Contributors to DNA Damage MF: Yes, that’s right. There are really many ways that the genome can be harmed, both at the base sequence level (that’s the sequence of the nucleotides in the DNA), as well as with gross chromosomal changes in the genome. These are usually due to breaks in the DNA and misrepair of those breaks so that different fragments of chromosomes get located in with other chromosomes, or a change in chromosome number, which again alters the gene dosage, and therefore ultimately the phenotype of the cell. When I give my presentations, I often show results, for example, of measurements that we can do with molecular probes, where we can identify the proportional cells, for example, which are triploid 4/chromosome 21, which is the Down’s syndrome genotype. People are often startled by the fact that each and every one of us actually has these types of cells in the body. Furthermore, we know that the frequency of these cells appearing in the body increases with age and also with folate deficiency. And all of this is really important to drive home the point that nutrition and aging are key factors that affect genome stability and the normal genome compliment of the cells. I think the more interesting aspect of this research is that we are finding that while ionizing radiation, of course, is a really important concern and a contributor to genome damage, also of concern is ultraviolet light and exposure to toxic chemicals such as mercury, which is of concern these days through its accumulation through consumption of fish and by other environmental routes. Surprisingly, what we find is that the impact of moderate deficiencies in micronutrients such as folate, which we have studied extensively, are as important as those induced by significant doses of these environmental carcinogens. These would be doses that would be considered unsafe. I think that is really the key point: that environmental exposures, while they are important, are not necessarily more important than the DNA damage that we can induce by dietary imbalance or deficiencies, as well as by other factors in lifestyle, such as alcohol consumption, which, again, is another important contributor to the DNA damage that we observed in people. JB: I would like to just make sure that our listeners picked up a very important point that you stated, which I think amplifies some of the things that we all learned about the role of nutrients such as folate and B12 and the hematopoietic system. We often read in textbooks how you assess nutritional deficiencies, thinking maybe that there is just one cell type. So we think, “Gee, I’ll look under the microscope at the blood and that is the only cell type that is going to be adversely influenced by this agent.” We put a nutritional deficiency disease like pernicious anemia, or macrocytic anemia, with a specific nutrient deficiency, and then we capture that in our mind as if that is the only effect. What you really said to us, I think is very important: that’s a marker cell type that is turning over from the bone marrow fairly rapidly, but it is not the only cell type influenced by these insufficiencies. Measuring DNA Damage in Lymphocytes MF: No, not at all. In fact, you have probably noticed from our literature that most of the work we have done relates to the lymphocyte, and more recently and increasingly, to the epithelial cell, which is easily accessible and therefore practical to use. The reason for looking at lymphocytes (apart from the fact that it is a very practical system to use) is because the lymphocytes can be easily isolated and stimulated to divide in culture, and therefore to express the DNA damage. The other key reason is, of course, the lymphocyte is a very important component of the immune response system. We know, in fact, that increased damage to the DNA and lymphocytes also correlates with a reduced capacity of these cells to function as immune cells and to increase the numbers. It is for these reasons, as well, that we specifically examine lymphocytes. Furthermore, we know that a depressed immune function is also an important component of the risk factors that relate to cancer. A lot of the work that we have been doing is related to understanding the nutritional requirements to maintain a healthy genome in lymphocytes using the micronucleus assay, as I mentioned before, and more recently, expanding this assay, which is actually known as the cytokinesis block micronucleus assay. We block cells in the binucleated stage (after they have completed nuclear division) because it is at this stage that you can observe the DNA damage accurately. With this procedure, apart from looking at the fragments or whole chromosomes that are left outside the main nuclei (and, hence, the term “micronuclei”), we also can measure bridges between the daughter nuclei, which is an indication of abnormal chromosomes with more than one centromere being pulled to the poles, as well as nuclear buds, which are these protrusions from the main nuclei, and are an indication of genome instability because this is the mechanism by which the nucleus attempts to eliminate amplified DNA, which is a hallmark of genomic instability. By genomic instability, we really mean chromosomal and molecular events that are causing a continuous and major change in the genome of that particular cell. This hallmark of genomic instability is exactly what we see in cancer cells, and we can measure it directly in human lymphocytes. JB: You just stated so many extraordinary things. Talk about densely packed information and content-rich words. That was very, very strong. Let me pick up on a few things and just to go back over them for emphasis. The first is the relationship between cellular function and genomic instability. I think for many people who have been trained for the pathomnemonic view (or let’s call it the histopathological view of medicine), they see disease often being as a “switch,” kind of either on or off. We either have something or we don’t, and this concept of degrading function over time that leads ultimately into what we, in medical taxonomy, later call a disease. That concept is fairly abstract in medicine. Clearly, the way you have described this tendency toward genomic instability that might be associated with biological aging (if I can use that term euphemistically because it doesn’t necessarily line up against the number of birthdays), and how that relates to cellular function, which then tracks against later pathology is a very big, different concept than the way that many people learned disease and health. The Genome Clinic Health Concept MF: Yes. What I have been trying to suggest and promote is this idea that we should consider an abnormally high level of genomic instability as a disease in itself. If we consider the genome to be the most fundamental component of the cell, and that determines the phenotype (the normal or abnormal phenotype of the cell), then we really ought to consider damage to the genome to probably be the most fundamental disease that we can actually diagnose and nutritionally prevent. That really is the basis of all the concepts that we have been developing in the past 5-10 years, which then leads automatically to the concept-the idea-that perhaps we should now be considering the dietary requirements of individuals and populations based on what is required to minimize damage to the DNA in human cells. And furthermore, this also leads to the Genome Health Clinic concept, which is more recently evolved from the other ideas. Perhaps the way forward in disease prevention from here onward should really be around the establishment of genome health clinics in which an individual has their DNA damage or genome stability index diagnosed, and based on that diagnosis, one can determine whether it is either low enough or too high, and given that, to intervene nutritionally to minimize the extent of genomic instability in the individual’s cells in the body. That is really where we are at, at the moment. We are currently taking this idea into practice through a small company here in Adelaide called Reach 100. It is a group of doctors who are interested in commercializing and taking this idea into practice at their anti-aging clinics. JB: When I look at this 2005 paper that you authored for Mutagenesis titled “The Genome Health Clinic and Genome Health Nutrigenomic Concepts,” it is mind expanding.10 It describes a vision for a paradigm shift in disease prevention that is based on the diagnosis and nutritional treatment of genome or epigenome damage on an individual basis. You have established a frontier that surrounds this assay-the cytokinesis block micronucleus assay-that allows one to have their own genomic stability/instability determined so that (presumably) one can titrate the individual need of nutrients to that person to manifest not only improved genomic stability, but therefore the myriad functional, metabolic, and proteomic changes that occur as a consequence of proper protection of your genome. It then ties together with this whole nutrition concept and you authored another paper (I think also in 2005) in Carcinogenesis titled “Low Intake of Calcium, Folate, Nicotinic Acid, Vitamin E, Retinol, Betacarotene, and High Intake of Pantothenic Acid, Biotin, Riboflavin are Associated with Increased Genomic Instability.”11 Maybe you can tell us a little about how this nutrient-specific research ties together with the assessment tool of genomic instability. MF: Our research, as well as that of a couple of other groups (for example, Professor Bruce Ames’ work is an inspiration with regards to this and the direction of our research), has indicated that a number of nutrients can have impact on the genome, either when they are deficient or in excess. I think this is actually very important because in the minds of many people, there is this idea that if a micronutrient or vitamin is good for you, the more the better. What we actually find is that is not the case. We know that with micronutrients, a U-shaped curve with regards to DNA damage is typical. An example where DNA damage may increase and vitamin intake may be excessive would be betacarotene. Although not published yet, we know that excessive organic selenium can increase DNA damage in cells. It is essential to be able to exactly identify, for an individual, not only the dose of each micronutrient that is required to maintain the genome in the healthiest state possible, but also the combination of micronutrients and their doses. That is really where the field is going. We are modeling that using virtual systems. In 2004, we published a paper in the Journal of Nutrition where we showed how this could be done.12 In this study, we also took into consideration the genotype of an individual. We took cells from people with a mutation in the methylenetetrahydrofolate reductase gene (MTHFR). This is a gene that determines how folate is used in the cells and whether the folate is used primarily to prevent the uracil getting into the DNA, or whether folate is used primarily to maintain methylation of cytosine in DNA, which can have different consequences to the genome stability in the first place. With too much uracil, there might be too many breaks in the DNA. In the second case, with not enough methylation of the DNA, especially in the centromeric sequences, this could lead to chromosome loss. In the study, we examined the cells of people who were either homozygous normal for the mutation at the 6 and the 7 locus, or who were homozygous mutant, and therefore had a slow variant (a slow activity enzyme, in this case). We examined how their cells interacted with either a low or high folate combined with a low or high riboflavin. It was very interesting to note that it was evident that the individuals with the MTHFR genotype showed a different genome instability profile than those with the normal variant. Furthermore, it was interesting that in a low folate background, when there was too much riboflavin, DNA damage actually increased. This indicated to us that it is really the interactions and the combinations that tell you what is going to happen in the cells. In this way, using these tools, we could define the combination for individuals where the DNA damage is minimized. What we are trying to do now is take that concept to the clinic. At this point in time we do not have enough knowledge to be able to say, based on genotype, what is the optimal nutritional combination to reduce DNA damage in an individual. Really, we can only rely on information we have from placebo-controlled trials that tell us this combination of nutrients or this other one could reduce DNA damage and then test whether that actually works in an individual. That is really where we are. We are also building up a database to know what the genetic basis is for an individual’s response to supplementation (for example, folate and B12, and why one individual differs from another). There could be a number of reasons. One reason could be, for example, a defect in the ability to absorb vitamin B12 or to metabolize it to the form that is actually active in the body. It is this information that we really need to build up to be able to provide targeted information to individuals. Functional RDA JB: As we look at the potential clinical application, it takes us to the potential development of what you alluded to in some of your papers as a “Functional RDA” that is based on genomic stability. You have some very nice articles where you postulated this concept and have also given evidence to why it may be valid, and how it ties together with preventing age-related diseases associated with genomic instability. Have any of your colleagues championed this idea along with you of a functionally based RDA? MF: I presented this idea at the International Congress of Nutrition in Vienna about six years ago. The concept is essentially found to be acceptable by the wider community in the field of nutrition. While it is not being specifically promoted as the way to do it (because there are many different ways that one can measure health in the body), when you look through the literature you will find that the number of papers investigating the impact of nutrition and vitamins on DNA damage has increased. There is no doubt that DNA damage is increasingly considered to be a key biomarker to assess not only the optimal requirement of nutrients, but also to identify the toxic dose. I think this is really one of the very nice aspects of using DNA damage as biomarkers because you can not only determine the optimum to reduce DNA damage, but you can also identify the doses at which DNA damage starts to be induced or increased when the nutrient is in excess. There are also wider aspects and applications that I haven’t mentioned, which are increasingly important. For example, this concept relates to the important issue of whether consuming too much red meat is a risk factor for colorectal cancer. As you know from the World Cancer Research Fund Report, there is a recommendation to reduce the extent of meat consumption because there is an association with increased risk for colorectal cancer. Another way that we have been using these assays is to try and define the genotoxicity of the bowel contents as a way of determining which dietary patterns are most likely to create a safe (or a lower) genotoxicity environment in the colon. In fact, this has happened. We have shown that you can actually extract the water from the feces and test the toxicity of that water, depending on the diet. You can actually see, in animal models, quite clearly that if you take the fecal material or the fecal water from a rat that is on the high-risk side for colorectal cancer, the extent of DNA damage induced by the fecal water is about seven times higher than that that you would observe on a diet that is considered at a low risk for colorectal cancer. So these are other ways that one can actually measure and assess genotoxicity in individuals. JB: You have talked very beautifully about the relationship between genomic instability and cancer. Obviously there is a connection to inflammation-things like heart disease and diabetes. But it also begs, in my mind, as I am listening to you, the question concerning damage to DNA and the immune system related to autoimmunity. Do you have any sense as to whether genomic instability might be connected also to immunological responses to this transformed foreign DNA? MF: There is evidence for this. We also obtained some direct evidence of immune responsiveness in the cytokinesis block micronucleus assay. The reason I say that is because we know that to do the assay in lymphocytes, we have to stimulate them with a mitogen. And the mitogenic response is a measure of immune responsiveness. We can actually measure this by counting the ratios of the mono- to-binucleated cells (and multinucleated cells) because of the nuclear division index. And we have been able to show that the mitogenic responsiveness is directly related to nutritional status, and in particular, to the levels of magnesium, zinc, selenium, and folate in the blood. Furthermore, it is also known that as the nuclear division index of lymphocytes is reduced, the higher the DNA damage in the cells. From our point of view-from our experience-it is clear that nutrition does have an impact not only on DNA damage, but also on the responsiveness of the lymphocytes. Furthermore, we know that a number of immune deficiency disorders, such as the ICF Syndrome, which is a syndrome that exhibits a defect in DNA methyltransferase, also exhibits DNA damage, as measured by this index. It is also known that genetic defects in genome maintenance, such as ataxia-telangiectasia gene mutation, also results in a deficiency in immune response and elevated DNA damage. There have also been studies done on autoimmune diseases, such as systemic lupus erythematosus and DNA damage that was elevated under these conditions (whether that is actually a direct cause or just a consequence of the disease process is not known). With regards to inflammation, there is no doubt at all that the oxidative stress that is generated in the inflammatory process, as well as by activated neutrophils, causes a lot of DNA damage and is measurable by this index. We have actually modeled this in vitro, and the extent of DNA damage produced by activated neutrophils is really very, very high and can be easily measured. JB: I know it is not fair to ask you to look into a crystal ball, but you are one among a small group of people in the world who probably have the best vision as to where this is heading. How long do you think it will take before this concept filters down into what might lead to effective clinical application? Do you think we are on the short edge, or do you think we are on the long frontier in terms of getting this concept into where it can really have meaningful effects on personalizing nutrition? MF: I think it is really at the beginning. I have been really surprised, though. About two years ago, we had a story about this concept told (shown on television). This really wasn’t our own initiative; we were actually approached to do this by the national science television program here known as Catalyst, which is a weekly program on new ideas in science and breaking new technologies. They approached us after they read one or two newspaper articles about our work, as well as some of the science articles. The story is known as “DNA Doctor” and I can make that available to anyone who is interested; it is also available on our website (on the CSIRO website). What happened was that we had a very strong response from a number of groups who wanted to take this idea to practice. Obviously CSIRO wasn’t keen to have just anyone take this idea into practice, so at the end of the day, our management decided to come to an arrangement with a group of doctors based here in Adelaide to put this idea into practice through their clinic, known as Reach 100. This is really an incubator activity that is going on for about 18 months not only to train the young doctors (of course, this idea is really being taken up by young doctors) with regards to these new concepts and ideas, but also to get a better understanding of what the expectations of the clients are and how we can communicate these results to the client. JB: I want to tell you that this-to me-has been one of the most fascinating interviews that we have had the privilege hearing in our 27 years. It opens up a whole frontier. We are going to keep in close contact with this work and with the Reach 100 group. I think this has the opportunity to really make tremendous positive contributions. Dr. Fenech, I want to thank you for allowing yourself, at this early morning time, to be involved with this and wish you the very best. We are going to be checking back with you. MF: Thanks very much for the opportunity, Jeffrey. I really enjoyed having the chance to discuss with you and with your colleagues the possibilities that emerge from this science. Thank you so much. JB: Thank you very much. My takeaway from this interview is this: it may be possible to evaluate our status before we actually end up with a diagnosis, at a point where we can actually intervene early to use complex lifestyle variables to modulate our genomic stability. We are going to take this model into next month’s issue with another clinician/researcher of the month, Dr. Devra Davis, and we are going to look at mechanisms of oncogenic cooperation in cancer initiation and propagation and how it inter-relates to metastasis and angiogenesis. I hope you will be able to take this theme from the June FMU and take it with you into July, where we are going to explore a whole different approach towards cancer chemoprevention using xenohormetic signaling.  

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Bibliography

1 Smith GCS, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomized controlled trials. BMJ. 2003;327:1458-1461. 2 Berkrot B. Future of lucrative cholesterol drugs murky. www.reuters.com. 3 Jorgenson JT. From blockbuster medicine to personalized medicine. Personalized Med. 2008;5(1):55-63. 4 Howitz KT, Sinclair DA. Xenohormesis: sensing the chemical cues of other species. Cell. 2008;133(3):387-391. 5 Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48(6):993-999. 6 Croce CM. Oncogenes and cancer. New Engl J Med. 2008;358(5):502-511. 7 Jaffe LF. Epigenetic theories of cancer initiation. Adv Cancer Res. 2003;90:209-230. 8 Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA. 2007;104(32):13056-13061. 9 Fenech M. Genome health nutrigenomics and nutrigenetics&mdash;diagnosis and nutritional treatment of genome damage on an individual basis. Food Chem Toxicol. 2008;46(4):1365-1370. 10 Fenech M. The genome health clinic and genome health nutrigenomics concepts: diagnosis and nutritional treatment of genome and epigenome damage on an individual basis. Mutagenesis. 2005;20(4):255-269. 11 Fenech M, Baghurst P, Luderer W, Turner J, Record S, et al. Low intake of calcium, folate, nicotinic acid, vitamin E, retinol, beta-carotene and high intake of pantothenic acid, biotin and riboflavin are significantly associated with increased genomic instability&mdash;results from a dietary intake and micronucleus index survey in South Australia. Carcinogenesis. 2005;26(5):991-999. 12 Kimura M, Umegaki K, Higuchi M, Thomas P, fenech M. Methylenetetrahydrofolate reductase C677T polymorphism, folic acid and riboflavin are important determinants of genome stability in cultured human lymphocytes. J Nutr. 2004;134(1):48-56.

Welcome to Functional Medicine Update for July 2008. I hope you will find this to be very robust and informative issue. We are going to be focusing on aspects of environmental carcinogenesis and nutrient relationships to chemoprevention and how these interrelate to topics we have been exploring this year in Functional Medicine Update. We are very fortunate to have as our clinician/researcher of the month a person whose name is very familiar to many of us and that is Dr. Devra Davis, who is the author of the recent best-selling book, The Secret History of the War on Cancer. I think you will find this to be a fascinating interview and discussion with an opinion leader who holds information and knowledge that most of us aspire to understand and know. She can help us get access to that information as we listen to her interview. I want to remind you that the Synthesis by Jeffrey Bland website is extending and expanding itself. We are doing a blog there, including a video blog to address some of the questions that come up in between each issue of our taping of Functional Medicine Update. Sometimes things might be in the news that people are inquiring about. I also give some opinions, and positions, and analysis of various bits of recent published data or clinical studies. You’ll find things like this on the www.JeffreyBland.com website. I also want to remind you that we have (through Synthesis) two new home study programs that I think you will find interesting. One is titled Managing Adrenal and Thyroid Balance Associated with Stress. You can find more information about it on the website. The second is The Emerging Therapeutic Target: Improving Therapeutic Outcomes by Treating the Intersection of Osteoporosis, Cardiovascular Disease, Type 2 Diabetes, Arthritis, and Cancer. If you want to find out more about either of those new products, you can find them on the www.JeffreyBland.com website. Let’s move, if we can, into this month’s topic, and that is an extension of our 2008 series on the concept of xenohormesis, the big “X” word. For those of you who are new to this discussion, what this refers to is a relationship. “Xeno” means foreign, and “hormesis” refers to a small amount of something having a larger effect than expected, so “xenohormesis” is a foreign substance having a bigger effect on physiological function than expected. Xenohormetic substances can either be injurious to physiological function (i.e. distort the web of physiology in such a way as to produce dysfunction that we later call disease) or they could be things that lead to improved homeodynamic balance or improved stability of the web of physiology and increase the resistance to environmental perturbation (i.e. enhance organ reserve). The term “xenohormesis” doesn’t imply a value term as it relates to good or bad. It implies an effect on physiology greater than that which you would anticipate based upon the amount of material. Since “xeno” refers to foreign, meaning coming from the outside environment, this could come from something like a petrochemical polyaromatic hydrocarbon, which would be a xenohormetic response that probably would be injurious to the web of physiology, or it could be a molecule that has come up through natural selection through a diet like flavonoid, an isoflavone, a polyphenol, a proanthocyanidin, that may have a positive impact on improving physiological function or stability of the web of physiology. There is a very interesting review paper that was just authored by Konrad Howitz and David Sinclair from Harvard University titled “Xenohormesis: Sensing the Chemical Cues of Other Species.”1 This appeared in the journal Cell in 2008. The authors talk about the fact that plants make substances of benefit to human health. Actually one-third of the current top twenty drugs in the market are plant-derived and have been modified to make them new to nature so they can be patented, but the ultimate pharmacophore that these drugs were built upon were molecules that were evolved in nature over natural selection processes that gave rise to interaction with human physiology in such a way as to have a xenohormetic effect, meaning modulate complex network physiological function. Probably the most classic example of a naturally derived drug has to do with Edward Stone testing the bark of the white willow (Salix alba) for treating fever; he concluded that it was very efficacious. Today, of course, aspirin is the most common drug of choice in the world at large for the management of many different maladies. It is interesting that the first drug derived from natural products that has now been used commercially for a couple of centuries has really turned out to be one of the most efficacious and probably (when used appropriately) safe. We started off on the right foot, I guess, in appropriating some of these things from nature as it relates to a purified material that was later appropriated into pharmacology as acetylsalicylic acid, which was the chemically modified derivative of the aspirin molecule (or the aspirin pharmacophore) found in the plant. In fact, there are 45,000 metric tons of acetylated derivatives of salicylic acid that are now consumed worldwide each year, which makes it a pretty remarkable compound. Beyond that, there is this view that these molecules that are found in plants can have direct modulation of key mammalian intercellular signal transduction processes (i.e. the processes by which our physiology is regulated). They are xenohormetic in the way they enhance the body’s response to stress. These are molecules like curcumin, from the spice turmeric, or something like the green tea polyphenolic epigallocatechin gallate. In red wines and peanut skins, resveratrol modulates various aspects of cell signaling through kinase modulation (protein kinase C delta or gamma, or phosphotidylinositol 3 kinase, or looking at its effect on SYK or BTK, the Burton tyrosine kinase). We are starting to recognize, at the mechanistic level, how these xenohormetic substances in foods have interfaced and interrelated with the symphonic orchestration of our physiology. The expression of genes into function occurs through interaction with these complex molecules that we eat in a diet with variety and color that are close to the earth (i.e. phytochemicals, by their very nature are derived from plants). It is these minimally processed, plant-derived foods that give rise to these xenohormetic substances. A number of extraordinary contributors to this field have discussed the evolution of this model on Functional Medicine Update over the last few months, and have advanced this whole conceptual framework of how a complex diet and these molecules interface with function. These are secondary metabolites that plants make as their own anti-stress molecules (the flavonoids, the carotenoids, and the xanthophylls). And these particular molecules then serve the plant to defend itself against environmental stress (insects, sunburn, parasites, infection, etc.). When we consume those plants that contain these complex phytochemicals, they then have influence on our function through these intercellular signal transduction processes in such a way as to modulate our network physiology and to increase stress resistance. Often we call these antioxidants, but they are much more than antioxidants. “Antioxidants” is kind of a general term that refers to the ability to quench free radical oxidation processes. But well below that, mechanistically, what we are starting to see is that these specific phytochemicals have very distinct and unique abilities, based upon the plant source and the individual shape of the molecules, to influence signal transduction at the mitochondrial level, at the cell cytosolic level, or even at the genomic expression level so that it influences the “trilogy of ‘omics” (genomics, proteomics, and metabolomics of the organism) and ultimately its phenomics (how it looks, acts, and feels). Nutrition is being seen to play a much bigger role on physiological function. By the opposite token, xenohormetic substances that are new to nature (synthetically modulated ingredients in our food like partially hydrogenated, trans-containing fats) have a different role to play on hormesis. Small amounts may have a more dramatic effect on distorting the web and producing alarm reactions-such things as inflammatory modulation in specific tissues. As I mentioned earlier, the term “xenohormesis” doesn’t necessarily mean either good or bad influence on physiology. What it means is that each of these molecules, small in amount, may have a bigger effect on regulatory nodes of physiology than we would have anticipated, and it could be a stabilizing influence, or it could be a destabilizing influence. Decoding the Molecular Origins of Cancer and Examining Chemoprevention How does this all relate to cancer? That is the main topic of this month’s discussion. If you think of the cancer process, as it has emerged to be seen over the last 30 years, it is a process with a series of steps, starting with initiation. Sometimes this is called mutagenesis or the tumor initiation process. Then there are a series of cellular alterations of function that lead to propagation with cell replication and a dedifferentiated state (a juvenile, embryonic-like state), rapidly dividing in a dedifferentiated state. From there it goes into a state of having to feed itself-the process of angiogenesis. Once you get beyond about a three millimeter tumor mass, fixed tumors or solid tumors have to have their own blood supply-the angiogenic process. And then, obviously, the last step, and the most lethal part of cancer, is its tendency to break off certain cells and find sites of infiltration in other tissues. We call this metastasis, and this metastatic process is often the lethal event associated with cancer. If we look at these particular processes (initiation, propagation, angiogenesis, and metastasis), each one has regulatory-control systems associated with it. One might say that cancer is a complex process of the interaction of the genes with the environment–the whole organism with their environment–that leads to these things that we see clinically (dedifferentiated, proliferative, metastatic cell lines). These cell lines start taking over and alter the energy economy of the host, ultimately creating the potential for a lethal event caused by starvation and by complete alteration of immunological function. With all of that as a context, how does chemoprevention really work in trying to prevent cancer at various stages (either at the initiation stage, at the propagation stage, at the angiogenic stage, or at the metastatic stage)? Clearly, the earlier that one can engage in prevention, the better off one is. If you can prevent initiation, you don’t have to worry about propagation, angiogenesis, and metastatic events. Obviously there must be regulatory controls at each of those steps in the process. If a tumor is already initiated-a cell is already initiated into a dedifferentiated state (an oncogenic state)-then you want to regulate the propagation (the angiogenic and the metastatic processes) so that that cell type will starve or will be attacked by the immune system in such a way that it will never go to the next stage of development. Part of this relationship of how tumors get started relates to mutations of the genes as a consequence of injury by a chemical or a radiation event, but also by epigenetic effects (as we have learned earlier in Functional Medicine Update), which mask and silence certain genes, or upregulate the expression of other genes. You would like-in theory-to silence your oncogenes and upregulate the expression of your tumor suppressor genes. It is like a way of putting “bookmarks” on the sections of your book of life that have to do with your oncogenes, saying “Do not read: X-rated.” And then you’d like to put “sticky notes” on the sections of your book of life (the chapters in your genes) that are associated with tumor suppressor gene activity and natural killer cell activity, and so forth. You would like this regulatory balance of gene expression at the epigenetic level. There are “sticky notes” and “paper clips” that are put on, in part, as a consequence of nutritional status. For instance, we know the “paper clips,” or the gene silencers, are related in part to methylation of the promoter regions of specific genes. And the methyl groups come by way of what? Through the folate cycle (through s-adenosylmethionine). Does elevated homocysteine have anything to do with a carcinogenic risk and the increased potential for initiation of a tumor when exposed to a carcinogen? The answer is “yes.” Animal studies have demonstrated that undermethylated promoter regions of oncogenes increases carcinogenic risk. That is why folate, B-12, B-6, and betaine become very important nutrients for modulating the gene silencing influence on oncogenes. That is why it is known that animals in a malnourished environment have a higher carcinogen risk (as it relates to pro-carcinogenesis); it is because of the fact that the oncogenes are not as silenced and their promoter regions are available. So that is one concept. The other concept relates to the activation of your tumor suppressor genes. You want to put the “read here” (sticky notes) on the promoter regions of those genes. One of the groups that causes “read here” are your acetyl groups. Acetylation of the histone and non-histone proteins, as well as the promoter regions, leads to an unfolding of the supercoil structure of the genome so that it can be accessed to read that specific chapter in your book of life. These acetyl groups are put on there as a consequence of available acetyl Co-A. You have to have proper bioenergetics. You have to have the proper Krebs cycle activity (mitochondrial bioenegetics) because if you are malnourished and you have poor mitochondrial function, you are acetyl Co-A deprived and you don’t have your acetyl groups available to be put on as “read me” sticky notes onto the histone proteins or onto your genome. We know that butyrate, a very interesting small molecule (short-chain fatty acid molecule), which is produced by gut fermentation of fibers, also has a very important role to play in regulating the “read me” messages on specific regions of your genome are associated with tumor suppression, so we recognize that proper in situ production of butyrate by gut fermentation (by bacteria) of non-digestible fibers (sometimes called prebiotics) is very important as a colon cancer chemopreventive. We have started to understand the mechanism of protection of a fiber-rich meal on colon carcinogenesis. We are starting to see how these concepts (the initiation, propagation, angiogenesis, and metastatic steps) actually translate into therapeutic potentials for prevention of cancer. We are really talking here about the molecular origins of cancer. There was a very nice editorial on this in The New England Journal of Medicine in 2008 that talked about how, over the last decade, insights into the origin and behavior of cancers have reshaped our understanding.2 The seminal feature of all this research seems to be the focus on how these steps of initiation, propagation, angiogenesis, and metastasis can be modulated at the cellular level. Maybe the most important thing we have learned since President Nixon stared the “war on cancer” is not necessarily how to treat cancer, but how better to prevent it based upon accessing the appropriate information to prevent initiation, propagation, angiogenesis, and metastasis. We are also starting to learn that “cancer” obviously is “cancers.” It is plural because these mutated cells are different from person to person. We have our own individual cancer that is part of the family of cancers, and so each mutated cell, which may be a mutated kinase or a mutated intercellular signal transduction agent, then plays out its personality slightly differently than other cancers. That is why no two patients are exactly the same when treated, even with the same chemotherapeutic drug or cancer therapy. It is a very, very interesting evolving field. It is almost like studying ecology, with a diversity of species in the environment (when we start talking about cancer, each one having a unique personality). We are starting to see cancer cell types being genotyped with gene arrays, and then specific types of molecules being used to arrest the mutated kinases in that specific tumor, for example, kinase-inhibiting drugs like Gleevec. It is a different approach toward cancer therapy. But if we back up well before the need for therapy to the chemoprevention stage, we can see that much of what we are starting to understand about the origin of cancer helps us to better understand how to design preventive and early-stage intervention approaches targeted to the initiation and propagation steps. Endogenous Origins of Cancer What about things that are endogenous to the human body that might be associated with cancer and its initiation? We think of exogenous substances, like pollutants (and we are going to hear from Dr. Devra Davis today in greater detail about the role that the environment plays in inducing the potential initiation and even propagation of cancer as a consequence of exposure to new foreign molecules), but what about endogenous substances? I am thinking of molecules, as an example, like sex steroid hormones. The one that has probably received the most attention is estrogens and the estrogenic metabolites, which are the hydroxylated estrogens and their quinone byproducts. As you have heard in the past from an eloquent interview with Dr. Eleanor Rogan from the University of Nebraska, we are now starting to recognize that initiation of cancer can result from endogenous injury caused by chemicals that are present in the normal physiology that undergo chemical transformation. In the case of estrogen, 17beta-estradiol can be hydroxylated to the 4-hydroxy estrogen by cytochrome P4501B1, which then can be oxidized to the 3,4 quinone. This 3,4 quinone derivative of estradiol, as we have learned from Dr. Rogan’s work, is extraordinarily electrophilic (meaning it seeks out an electron-dense region of the book of life — the DNA — and it chemically reacts with these electron-rich regions in our DNA molecules to produce these covalently-bound, apurinic bases, which then can avoid excision repair mechanisms and induce mutations and potential carcinogenesis). So here is a case where an endogenous molecule, 17beta-estradiol, undergoes an unusual type of physiological transformation process to form the 3,4 quinones. In the absence of proper protection, this transformation can then induce potential carcinogenesis in estrogen-sensitive tissues, which can be the breast, endometrium, ovary, etc. How does the body protect itself against this biotransformation process, at least to potential endogenous carcinogenesis? Dr. Rogan and the work of other people have identified the fact that there are many steps that can be protective. The body is not just laid naked and exposed to the 3,4 quinones. There is a glutathione conjugation that is possible at the previous step, prior to the intercolation step where you get the reaction of the 3,4 quinone with DNA. So, glutathione protection is important. We know that antioxidation states of the tissue plays a very important role in keeping the semi-quinone from oxidizing into the full 3,4 quinones, so redox potential of the cells, from antioxidants, is important. What types of phytochemicals can find themselves concentrated in tissues where these reactions are ongoing because there are different partition coefficients of different phytochemicals, and there are different transport mechanisms? They don’t appear within the same concentrations of all tissues. They have certain tissue affinities, so we might start saying it is not just antioxidants, in general, it is the tissue-specific effects of certain phytochemicals that help modulate the conversion of a semi-quinone into an injurious 3,4 estrogen quinone. I am going to a higher level of questioning about how we actually develop a science-based chemoprevention program. What would we harness in the way of specific nutrients for the prevention, say, of prostate cancer, or breast cancer, based on what we are learning about these mechanisms? The story I have just talked about with breast cancer and 3,4 quinones of estrogen also applies to prostate cancer in males, where estrogen is also produced in the prostate gland and can undergo oxidation to the 3,4 quinones, as we learned from Dr. Rogan, and can induce initiation of prostate cancer. Here is where sisters and brothers may have similar genes relative to risk, and it plays out in different ways (in gender-specific ways) in the breast in the sister and in the prostate in the brother. These are interesting epidemiological connections. Here is where mechanism and epidemiology tend to converge. Phytochemicals and Xenohometic Effects Can Reduce Risk We start asking questions. What are some of the kinds of phytochemicals that have been found to have xenohormetic effects of a positive nature in helping to reduce those events? We talk about things like epigallocatechin gallate in green tea. We talk about limonene, which is a monoterpine from citrus. We talk about curcurmin, but because it is not generally bioavailable, we ask is it the subtle effects curcurmin has on the immunological system that communicates to the breast and prostate? These are still questions that are being asked because we often assume that if there is an epidemiological connection between a phytochemical and a reduced incidence of cancer, the role of that phytochemical must be directly on that tissue. But now we are starting to see that maybe these things can also work indirectly through alterations in specific immunological function. Maybe the functional change occurs at the gastrointestinal mucosa by interaction of flavonoids that are not bioavailable, but influences, at a receptor site in the GI tract, a signaling mechanism that ultimately communicates to tissues at a distance. You’ll notice that this is a systems biology approach I am talking about, here, that relates to chemoprevention. It is not so simple as just a single molecule and a single end-point type of analysis. The mechanism of oncogenic cooperation in cancer initiation is what I have really been speaking to. There is a nice review paper on this whole concept that appeared in the Yale Journal of Biology and Medicine in 2006 that looks at cancer as a disease of extreme heterogeneity, where there are general principles that we can employ to try to prevent this initiation process, or to lower the oncogenic potential, no matter the specific of the gene characteristic of the cancer.3 This is the science-the “new” science, I believe-of nutrition and chemoprevention. For a simplified version of this whole discussion of cancer initiation and progression, there is a review paper that I found very intriguing in Theoretical Biology and Medical Modelling in 2006 that talks about cancer initiation and its progression, and really highlights the relationship between the host immune system, their gastrointestinal function, their biotransformational systems and how they can detoxify substances, and their genetic susceptibility or sensitivity based upon epigenetic and genetic loci of sensitivity giving rise to that person’s own individual risk to cancer based upon exposure to a substance.4 That is why this field is so complicated because you can’t just take an individual molecule and say it has a certain toxicity or a certain carcinogenic potential that is going to be equal in all people who are exposed to it. Cigarette smoking is probably the classic example. We know there are three-pack-per-day smokers who don’t get lung cancer, and yet there are people who are exposed to a much smaller level of secondary smoke and do get lung cancer. It has to do, again, with these multiple factors interacting. I’m not even talking, here, about covariables because we don’t just get exposed to one thing at a time, we get exposed to all sorts of things simultaneously — this symphonic orchestration. With all of that in mind, there is still a unifying mechanism by which we might think about preventing tumor initiation based upon the integrity of our epigenome and our genome and preventing genomic instability. I come back to the wonderful discussion we had with Dr. Michael Fenech about this morphological marker for biological aging and risk to age-related diseases–this genomic instability argument. Ercole Cavilieri and Eleanor Rogan authored a very nice paper titled “A Unifying Mechanism in the Initiation of Cancer and Other Diseases” that appeared in the Annals of New York Academy of Sciences in 2004 in which they talked about the fact that by offering an individual the exposure to the right mosaic of chemopreventive agents it helps to defend against initiating processes that lead to dedifferentiated cell replication that we call oncogenesis.5 The Important Role of Kinases I think we are starting to witness the emergence of a science base for cancer chemoprevention. You’ll notice that I have spoken, at several stages along this discussion, about a class of enzymes that are involved with this intercellular signal transduction process, meaning taking information from outside cells and communicating it to inside cells. These enzymes, whose name you are now fairly familiar with, are called kinases. Kinases are a family of over 500 different enzymes whose role it is to selectively phosphorylate (or put a phosphate group at a specific region on a macromolecule). Kinases are cell regulators in terms of function. There are kinases that work within the genome itself. There are kinases that work by modulating the epigenome. There are kinases that work in the cytosol to modulate, post-translationally, the function of proteins and enzymes. And then there are kinases that work within mitochondria that modulate the bioenergetics of the cell. So these kinases have very important roles to play in transducing signals from the outside world (meaning outside the cell) inside to the regulatory regions of the cell where function ultimately exists. I’ve talked about acetylation of the genome that leads to “read me here” type messages. I have talked about methylation that leads to gene silencing, like putting paper clips on certain chapters in your book of life. I also want to make sure you understand that these kinases that phosphorylate various regions of the genome and the histone proteins, ultimately also post-translationally modify active proteins within the cytosol of the cell. These are also very important regulators of the phenotype of the cell (its function). How does that have anything to do with carcinogenesis and tumor initiation or propagation? The dysregulation of kinases, or the mutation of kinases, has been, in the last 10 years, identified to be very closely associated with the process of cancer initiation and propagation. Regulation of kinase signaling has a very important role in chemoprevention. Why am I going into great detail on this? Because the work that we and many others have been doing over the past several years has identified that one of the roles that phytochemicals have in modulating cellular function is their role on specific kinases, and Mother Nature has produced a whole array of natural molecules in these complex diets that we consume that have specificity for modulating specific kinases. When we are eating foods of variety and a rich array of unprocessed ingredients (phytochemicals), we are eating a complex library of kinase-modulating substances that help to regulate the network of our physiology, the translation of outside messages to inside cellular function. I think that that is an important thing to keep in mind as it relates to how we think about nutrients because often we see studies being done in chemoprevention using one nutrient at a time, where we use a vitamin E or a betacarotene, or a vitamin C, one nutrient at a time, and then we ask, what is its outcome as a drug-like intervention in protection against a certain disease or event? Actually, that is not how the signature of our dietary information influences function in the broader sense. It is not a drug-like effect; it is a systems biology effect by this complex orchestration across families of interrelated kinases that then regulate genomic expression, that regulate intercellular signal transduction, and ultimately even bioenergetics at the mitochondrial level. This may appear overly technical for you, as you sit there with a patient and ask “What do I do?” The reason I am trying to make this a driving point is that the evidence that has accumulated over the last few years from clinical, animal, and basic science research is that these rich arrays of complex matrices of nutrients appears to have a different effect on physiological outcome than taking one nutrient at a time, or so-called meganutrition, looking at a more pharmacological approach of each nutrient at a time. Let’s use resveratrol as an example as it has been in the news quite a bit. We know that resveratrol is associated with chemoprevention of breast cancer from animal models. Is giving resveratrol at high dose an approach towards chemoprevention that would be justifiable? Obviously that is a pharmacological model. What about lower doses of resveratrol in combination with the multiple other phytochemicals that are found within, say peanut skins, or that are found within grapes, or found within foods that are rich in resveratrol? Does that have a different orchestration of effects when combined as a mixture than when you are using a single molecule in purified dose? It appears, once again, that what is emerging is these signatures of complex mixtures that influence intercellular signal transduction in the cancer initiation process have a different effect. Again, it comes back to eating variety, eating color, and using families of phytochemicals. Dr. Randy Jirtle, who is at the Department of Radiation and Oncology and the University Program of Genetics and Genomics at Duke University, is one of the fathers of the epigenetics field and has recently published, with his group, a very interesting paper in the Proceedings of the National Academy of Sciences about maternal nutrient supplementation of animals that had been exposed to a known carcinogen (bisphenol A-this is the plasticizer that has been of some concern in plastic bottles as it relates to potential carcinogenesis).6 When these animals are exposed to bisphenol A, it results in carcinogenesis. And when they supplemented these animals with specific nutrients that were involved with silencing oncogenes (that would be your methylating nutrients), they were able to basically show that there was compelling evidence that early developmental exposure to certain nutrients can help to neutralize the effect of later exposure to these carcinogens, or that early exposure to carcinogens in the absence of proper nutrient intake can imprint the genome to make it more susceptible in later life to carcinogens. It works both ways: poor nutrient intake imprints the genome in such a way as to make it more susceptible over life to cancer; proper nutrition during pregnancy silences the genes and makes the animal less susceptible throughout life to exposure to carcinogens. Are we doing both things simultaneously in our culture? Are we reducing the level of intake of specific nutrients that are necessary to protect against genetic expression that we associate with cancer while we are also increasing the exposure to carcinogens? This was the theme that Dr. Bruce Ames wrote about in his landmark article and cover discussion in Science magazine many years ago called “Dietary Carcinogens and Anticarcinogens,” saying that it seems that we are reducing our anticarcinogenic intake in our diet while we are increasing carcinogenic exposure.7 This construct, I think, is very important Let’s say that you initiated a tumor and it started to propagate and needed to undergo angiogenesis in order to feed itself. Are there natural antiangiogenic substances? Of course, the answer is yes. Dr. Judah Folkman, just recently passed away-he was the father of angiogenesis-and what a sad loss that was to the science and medical community. He had been working extraordinary hard over many years in trying to help the world understand the importance of angiogenesis and antiangiogenesis in tumor prevention and tumor treatment. We now recognize that in this angiogenic process of formation of blood supply to feed a tumor, there are many nutrients and phytochemicals that have been found to be antiangiogenic. There is a tremendous amount of work now ongoing as it relates to the role that various phytochemicals have, even after initiation has been established, to prevent angiogenesis and hopefully starve the tumor and make it more susceptible to the body’s immune system. Lastly, let’s talk about anti-metastatic agents and the things that are being studied with the hope of being able to prevent metastatic transformation of the tumor (which, as we said earlier, is one of the major concerns that one has in cancer–the metastatic event that leads to seeding in other parts of the body). This is the concept that we heard about from Dr. Hasan Mukhtar who was talking about cancer chemoprevention through dietary phytochemicals. We are starting to witness the emergence of this field, I think, around the major cancers to which nutrients appear to have a very important role–colon cancer, breast cancer, prostate cancer-as being right at the head of the list of those that seem to be very sensitive to nutrient modulation, both at the prevention and maybe even the early stage intervention levels. There are things to consider like Spez PC, the complex array of phytochemicals in Chinese herbs that, years ago, some thought helped in prostate cancer. Through the lens of today, maybe there are things in these complex mixtures that really do influence the processes of initiation, propagation, angiogenesis, and metastasis that frame a new way of approaching chemoprevention from a mechanistic approach. With that in mind, let’s turn it over to our clinician of the month.

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INTERVIEW TRANSCRIPT

Clinician of the Month Devra Lee Davis, PhD, MPH Center on Environmental Oncology University of Pittsburgh Cancer Institute 5150 Centre Avenue Pittsburgh, PA 15232 www.preventingcancernow.org Once again we are at that part of Functional Medicine Update that I know you-as well as I-really look forward to, and we won’t be disappointed this issue. We have a real treat in store-hearing from someone whose work I have followed for many years and I am very privileged to have the chance to interview her, Dr. Devra Lee Davis. The name probably even goes without further explanation. She is the author of a recent book, The Secret History of the War on Cancer, and before that the best-selling book When Smoke Ran Like Water. She has a series of extraordinary honors in her background, including being appointed by President Clinton to the Chemical Safety and Hazard Investigation Board. Dr. Davis has a BS in physiological psychology, an MA in sociology from the University of Pittsburgh, and a PhD in Science Studies from the University of Chicago as a Danforth Foundation Graduate Fellow. She has an MPH in epidemiology. She has taken a lot of tests in her life, I can tell that. Dr. Davis has authored more than 170 publications in books and journals, and her article in Scientific American on carcinogenicity and estrogen relationships was one of the foundations for my thinking. She is a member of the American Colleges of Toxicology and Epidemiology, and a visiting professor at the Department of Environmental Occupational Medicine at Mount Sinai Medical Center in New York. I won’t belabor this other than to say that we have a very credentialed and capable person who is going to speak to us on a topic that, for me, started when I first met Rachel Carson many years ago and was very heavily impacted by her book, Silent Spring. Later I interviewed Dr. Sandra Steingraber for Functional Medicine Update, who wrote what I thought was an absolutely fantastic book, Living Downstream. It is interesting to me that it seems like women scientists are more interested in this topic in men. Dr. Devra Lee Davis is also a female with great scientific credentials in this field. Maybe that’s their stewardship of the environment and a sense of mothering the world-I’m not sure-but it seems like the great thinkers in this field are of the female gender. Dr. Davis, it is really a pleasure to have you here today as an expert on this topic. We started down this road with Nixon’s war on cancer, and it doesn’t appear as if the outcome of that war was much different than other wars. It just continues on at a level of conflagration, but we have learned quite a bit, it seems (and you pointed this out beautifully in your book), on the area of chemoprevention, maybe more than actual treatment. This history seems to start somewhere back (according to your book) in Germany, with this bifurcation of thinking between the chemical industry and organic food. Can you tell us a little bit about how you got into this and how this all might fit together? Early Environmental Work Done in Nazi Germany DD: I was astonished to learn that actually under the Nazis there was a serious program to try to prevent smoking and reduce occupational carcinogens, and at the same time, the site of the world’s first organic gardens was at Dachau, where they were making organic honey and trying to encourage young Aryan women not to eat any refined flours and sugars. It was an astonishing thing to learn. It was part of their overall program of racial hygiene, the notion being that they would weed out “defectives” and produce a healthier breed of humans by not allowing German women to smoke or to eat bad food. JB: And this is at the same time when we saw the development of the chemical dye industry and the start of what was later to be the pharmaceutical industry. It is kind of an interesting paradox. DD: It is indeed. Germany was not united in many ways, although one thing that is kind of chilling to realize is that doctors were among the earliest and most ardent supporters of Hitler and of the idea that you could selectively decide who was fit to reproduce, and so they had programs for sterilizing–and later killing–people who they judged to be defective. Of course, among the most defective were the political dissidents, the Jews, the Catholic priests who didn’t agree with them-all of them were among those who were judged “unfit” to reproduce. JB: It is interesting. You point out something that I had never really thought about and that is the origin of the discipline of epidemiology, which allows us to see some of these associations in large population groups between an agent and an outcome. Tell us a little bit about how epidemiology grew out of this soil. DD: Well, there were some very astute scientists in Germany. In fact, until the early 1930s, Germany had won the most Nobel Prizes and German was considered the language of science. And among the excellent German scientists were people who began to look at patterns in time and space that disease created. They did the first epidemiology showing that tobacco clearly caused lung cancer, but they also observed workers and found that in workers who produced certain synthetic dyes, 100{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of them would develop bladder cancer in 20 years. They had a treasure of information, much of which has been ignored by the West, not just because of its questionable origins, but also because immediately after the war, American and British scientists went over and captured the records and the German scientists who had done this work and gathered that information for the Office of Secret Service (and the British counterpart, as well), but did not share it broadly with the governments or with the workers who were affected. JB: So there is a longstanding, almost social, history of lack of full disclosure and this concept that maybe it is best that the public doesn’t know, “we’ll just hold this information in trust,” leads to the ability to manipulate, it sounds like. DD: I think that’s right. After all, war crimes are what the losers get charged with. Right after World War II broke out, American companies actually gave the formula to make leaded gasoline to the Germans, the Japanese, and the Italians. Without that formula, they would not have been able to fight against American GIs. And, right after the war ended, Robert Kehoe, the medical director of the Ethyl Corporation, went over to Germany and collected information on what they knew about bladder cancer, and the role of synthetic dyes (diethylsilbestrol), and other things that we now understand were signals of industrial hazard. Very Early Work Linked Industrial Exposures to Cancer JB: It seems fascinating to me because I remember studying, back years ago when I took an epidemiology course, that Percival Pott, working with chimney sweeps, had come to the conclusion that testicular cancer had something to do with exposure to coal tar dye in chimneys. It seems like that preceded all of this, and yet it has taken these many years to uncover all of this. DD: Actually, I was astonished to learn that in 1936, shortly before World War II broke out, the world’s leading cancer scientists traveled to Brussels and agreed, at that time, that based on what was then known, coal tars (like those that lodge in the scrotum) were a cause of cancer (scrotal cancer) in chimney sweeps. They understood that cobalt and uranium mining caused cancer in workers. They knew that x-rays and solar radiation caused cancer, and if you painted hydrocarbons on the skin of animals and gave them solar radiation you could magnify the response. What was considered evidence of cancer in the 1930s was a combination of animal experiments and some human evidence. And what happened after the war was that epidemiology, as a discipline, became interpreted as the requirement before we could say something was causal. The effect of that was to make it necessary to wait until we had enough proof of human harm, in the form of dead or sick workers, or in the case of tobacco, people who clearly had been smoking for a long time. What that meant–because cancer has such a long latency, as you know–is that we were dooming one generation to be experimental subjects in order to decide whether we could try to protect the future generation. That is precisely what we did with tobacco epidemiology, so that not until the 1990s was government action started against tobacco, and when the war on cancer was launched by President Nixon in 1971, it was completely silent about tobacco, although the hazards of tobacco were known in the scientific community in the 1930s and 1940s. JB: You make such a really remarkable point in your book of helping us to understand the correlation or the association between smoking and lung cancer was brought really from Germany with some of the post-war “intelligencia” that we inherited after the war. It actually became kind of the seed of the anti-smoking research here in the United States, although obviously not heavily embraced by the tobacco industry. DD: Right. JB: Who was the gentleman that I think you spoke of that was one of the most charismatic people that carried the banner? That set up the Brunnemann Health Foundation research in Valhalla, NY? DD: Ernie Wynder was quite an interesting guy. He had been a young man in Germany, and he also was in the Secret Service and went over right after the war to collect information on what the Germans knew. And while he did that, and quite likely learned about their own research on tobacco and lung cancer, he never mentioned it in his own work, and in 1950 with a famous surgeon, he published work showing that people with lung cancer had been smokers. His work, and that of Doll and Hill, appeared in 1950 in the Journal of the American Medical Association. JB: It burst one of my bubbles when I read about Sir Richard Doll and what I thought were his extraordinary contributions to the birthing of modern epidemiology, and yet it looks like so many of those people were serving also with joint appointments as consultants to the tobacco industry, so some of the work, in terms of the interpretation, wasn’t maybe as clean as we might have liked it to be. DD: You know, it was very saddening for me to find that Richard Doll, who has been a hero of so many of us, had secretly accepted money from the asbestos industry, from the vinyl chloride industry, and from others throughout his career and didn’t disclose that funding. So he would publish findings that were quite friendly to the industry, without indicating that they were supporting his work, and we will never really know whether the funding had any influence on the positions that he took. Think about it. If he hadn’t cooperated with the asbestos industry, we would not have any data at all on asbestos. That is the challenge for modern epidemiology, as well. We have to have cooperation with industry to get information, and yet because the pendulum has swung so heavily in favor of protecting trade secrets, those trade secrets that a company maintains may have cost my father his life. And it is perfectly legal to keep information secret, but sometimes what is legal can be immoral. Slavery was legal. Apartheid was legal. But, obviously, today we think those things were immoral. And it was legal for Richard Doll to collect large sums of money from the chemical industry and not disclose it, when he published articles saying that vinyl chloride was not as big a danger as the World Health Organization, itself, had said just a few years earlier. And because it was Richard Doll, a man revered by many of us in public health research, when he reached that conclusion, people accepted it. Environmental Advocates Face Public Challenges JB: Going to a more recent time, I know you know even better than I about the vitriol that was written in The New England Journal of Medicine in the review of Living Downstream, Dr. Steingraber’s book. And it turned out on disclosure-in fact, I’m very pleased to say that the person who seemed to be the first whistleblower on the fact that the reviewer for her book in The New England Journal of Medicine was the toxicologist for the Grace Chemical Company (that he didn’t disclose)-that the first person to point that out was one of my friends, a medical doctor in southern Oregon who wrote a letter to the editor and finally exposed that that had been the case. I think they have said that they have changed their policy now as it relates to disclosure for reviewers. It seems like there is a history, here, of this happening. DD: Yes, there certainly is. I think that is where our democracy-as imperfect as it is-that is where interview programs like yours play a very valuable function because we are able to get information out. Steingraber’s book is a brilliant, brave, bold, and important book. It was very unfairly reviewed in The New England Journal of Medicine by someone who works for the Grace Company, the company that was responsible for massive pollution in an area of Massachusetts called Woburn, where there was so much pollution and so much illness that the people affected actually recovered damages. That’s an unusual situation. Most often when people are harmed by toxic materials, it is close to impossible to prove in a court of law what the cause of their harm was and it is becoming more and more difficult to do so. As I discuss in my book, The Secret History of the War on Cancer, the courts have increasingly made it very difficult for people who have been harmed by toxic substances for people to recover at all. JB: That leads me to your book and you as an author and you as an expert in the field. Obviously you have also engendered the wrath of those who don’t want this information to be fully disclosed. Tell us a little bit about your history. DD: Well, I’m still standing, but there is no question that there have been some unfair hits on my book. One appeared in The New Republic, much to my surprise, where the reviewer actually used material from my book without acknowledging that it had come from my book and accused me of being unscientific when I talked about the role of spiritual matters in helping people to heal and when I talked about my views that complementary and integrative medicine are very powerful tools that we do not fully understand that can often play a remarkable role in helping people recover and do well. When I discussed my friend Les Field, who is an extraordinary, seven-year ovarian cancer survivor (survivor of stage 3-B ovarian cancer), and the work that she did, the efforts of Donna Karan to promote yoga for cancer patients, all of these things, as you know very well, are fundamentally changing the nature of cancer care and the way we think about illness today. This reviewer thought that all of that was just terribly unscientific. JB: You have known and touched upon in your book a variety of very strong personalities who have also been similarly painted in a certain brush-people like Sam Epstein, who I have had the chance to meet, or Irving Selikoff-what has been your discussion with these people, as colleagues in this area? DD: We all owe Sam Epstein an enormous debt of gratitude. In 1980 he wrote The Politics of Cancer and the only problem he had was wrong timing. That was at the beginning of what turned out to be the Reagan revolution. Irving Selikoff, of course, really sets the standard for what good, solid research on asbestos dangers should look like and spent years tirelessly gathering records and working with the unions to document the damaging effect of low levels of asbestos and high levels of asbestos on the health of working men and women. I was very grateful that I was able to work with them earlier in my career as well. I think it is fair to say that they both suffered and were targets of attack. The situation for me now is actually a little bit different because I’m working in a major medical center, the University of Pittsburgh Medical Center. I think the reason why I still have a job is because my boss is Ronald Herberman, and Dr. Herberman is the discoverer of natural killer cells. He wrote one of the 100 Most Influential Scientific Papers of all time. He, himself, has had some unusual personal experiences. He and his brother both developed the same rare cancer of the blood as middle-aged adults. There is no record of this cancer in their family, and yet they had some very interesting exposures. Each of them, as boys, ran in pesticide spray in the fields of southern California, and they became doctors and researchers at a time when young men worked without any protective equipment, and they worked with some known carcinogens. We don’t know all of the things that contributed to the fact that both of these brothers, who are several years apart in age, came down with the same relatively rare cancer of the blood, but Dr. Herberman now is the director of the cancer institute where I work, and he has said to me, “Get the science right. We need to have a solid program looking at this.” And that is why we have the Center for Environmental Oncology now at the University of Pittsburgh Cancer Institute. We have a website, www.preventingcancernow.org. We have lots of materials available to your listeners about practical things they can do-if they need to treat fleas in their pets, or head lice in their children, there are ways to do this without poisoning them or putting their children at risk-and we have developed all of these materials at a major cancer center because growing numbers of doctors themselves, including my own boss now, understand that we have got to do a better job of reducing our use of things that put us at risk of developing cancer. Controversial Remarks by Dr. Bruce Ames JB: That was just so beautifully said, thank you. Once again, that is www.preventingcancernow.org site. We are on the throes of a discussion here that some element of controversy, which makes this very exciting. Let me throw another little wrinkle into the discussion and that is Bruce Ames, who I admire and respect very much as a biochemist, but who has taken a very strong position that carcinogens represent but an insignificant load relative to the overall body burden of potential cancer-producing substances and diet far outweighs the risk as it relates to environmental carcinogens. I know you have a different opinion. I’d like to have you share it with our listeners. DD: First let me say I share your view that Dr. Ames has done very important scientific work that we are all grateful for. Unfortunately, he has taken a very strong view in areas that he is not an expert in, namely epidemiology, and has suggested that current cancer burdens today are chiefly due to nutrition and smoking and have nothing to do with the environment. His view is wrong, and the reason it is wrong is that we now have evidence from current scientific work that prenatal exposures to very low levels of things like diethylstilbestrol or bisphenol A (a plasticizer) can have profound effects on reproductive capacity, on the health of animals, and ultimately on whether or not they get cancer and the types of cancer that they do get. The most recent evidence of this is work shows that the Agouti mouse, when exposed to bisphenol A prenatally, can develop at twice the size and a different color just if it has had one small exposure to bisphenol A at a critical period of organogenesis. That is extremely important work. It is parallel to work that was done by McLaughlin and others at the National Institutes of Environmental Health Sciences, where they showed that exposure to diethylstilbestrol, a synthetic estrogen first synthesized, by the way, in the 1930s, early in gestation can cause profound defects in offspring (male and female rats), and that those defects can be passed on to the third generation. And we now see an echo of that in human data generated by the National Cancer Institute that Dr. Ames may not be familiar with. The National Cancer Institute reported just this year that women whose mothers took diethystilbestrol when they were pregnant with them in the first trimester of that pregnancy, have double the risk of breast cancer when they reach age 40. So we now have had 40 years of time for the natural experiments unfortunately to become evident, that children are at risk from things that happened to them before they were born and that it can take 40 or 50 years for those risks to become evident. JB: This ties together very beautifully with the increasing understanding at the molecular biology/cellular biology level of epigenesis and how modulation of genomic tagging can then express different patterns, say tumor surveillance genes versus oncogenes, and how that can be passed on in the absence of mutations within the genome itself. DD: I think that is right. We know, for example, that if you look at identical twins and do chromosomal banding analysis, at age 3 they look pretty close to identical (monozygotic, coming from one egg). But by the time they reach age 50, if you look at those same chromosomal bands for methylation patterns, they don’t even necessarily look like they are related to one another (if you look at paired twins at age 50 compared to age 3). That is telling us something very simple and powerful: genes give us the gun; the environment pulls the trigger. But the epigenetic effect is really fascinating because that is where I think I’d like to know what you think about the evidence on breast cancer and hormone replacement therapy because some people say the downturn in breast cancer that we are seeing in older women (and it is a slight downturn) is due to the fact that fewer women are using synthetic hormone replacement therapy. If that’s true-and I state, if it is true-it is telling us that late-stage effects are working outside of genes (as in, epigenetically) to accelerate cell growth and cause the expression of cancer, or in this case, turning off that cell growth so that even though you stop exposure late in the process, you get a downturn in cancer. But the whole field of nutritional work with cancer is full of examples where nutritional factors seem to be able to turn off cancer processes, even when they are established already. Xenoestrogens: Collaborative Work with Dr. Leon Bradlow JB: Yes, and of course you are one of the experts in this field. Again, I had mentioned in my introduction the article that you had authored in Scientific American, and your co-author was the world-renowned steroid chemist Leon Bradlow.8 His work on estrogen metabolism has really created another whole spin on how estrogen might be related to alterations in carcinogenicity. DD: Indeed. We know, for example, that alcohol is a cause of breast cancer, but most people don’t realize that alcohol is highly estrogenic. That is why men who are alcoholics tend to have breasts, and alcohol stimulates the wrong hormone metabolism so that you get a higher amount of 16-alpha-hydroxyestrone relative to 2-hydroxyestrone, and the more 16-alpha (the more “bad” estrogen, if you will), the greater the risk of breast cancer, particularly in postmenopausal women. The question that Dr. Bradlow and I have addressed in some of the work we have done-and, God bless him, he is still doing work today, in his 80s-is whether there are synthetic materials, which we call xenoestrogens, that also can stimulate the production of the “bad” estrogen, 16-alpha hydroxyestrone. We did a study that showed that a certain number of synthetic organic chemicals including certain organochlorine pesticides clearly increase the amount of 16-alpha hydroxyestrogen. JB: This is a big presumption, which actually is not a good thing to do, but I’m going go into the unknown here and say if I could try to summarize a platform upon which this discussion rests, it is this concept of how our physiology, from the time of conception (maybe even pre-conception, with the sperm and the egg) is influenced in its ultimate phenotypic expression by the environment through what we might call stress factors, and that could be radiation, infection, chemicals, all these things that you were describing, which really-as you point out in the book-goes back to starting with Walter Cannon with homeostasis, and then Hans Selye with stress, and then more recently Bruce McEwen with allostatic load, so this construct of the environment as a stress factor to physiology seems like a very interesting convergence of thinking of which medicine hasn’t really adopted. DD: I think it is really important. You have been leading a revolution, as I think you know. People are going to look back in five or ten years and say “Remember when we used to give people pills for ills without asking what was in their body and what the status of their nutrition was, their proteins, their enzymatic repair?” We need to be smarter and look at where people live, and where they work, and what source of physiological and psychological stress they are under in order to understand how to help them heal. I think we have generally not done that because the part of scientific medicine that has been carried to extreme is the notion that we can medicalize and use medication to treat most ills. And while we can do a lot of good things with medication, oftentimes medication is masking what the underlying cause of the problem is, as you have written and told people very well. JB: So if you were to leave a soundbite here at the end of what we could take hours and hours to discuss with your depth of knowledge…if we try to get this into a soundbite, what message might you want to leave with physicians who are listening to this? DD: The dying words of Pasteur were “Remember the host.” Pasteur was the person, of course, credited with the germ theory of disease for understanding smallpox transmission, but as he lay dying, supposedly his last words were “Remember the host.” Look at where people work and live, and what they eat and do, and understand that that plays an important role in their health and their illness, and understand, therefore, that the Chinese model of medicine, where we look at the whole person, and we don’t simply look at the manifestation of illness, but ask how it evolved, is something we’ve got to take some good advice from. Looking at the whole conditions that contribute to the health and well-being of people becomes very important. Coming up now, we need to develop better methods for evaluating metal exposure; better methods for understanding historic experiences with nutrition, good and bad; and when we have those tools, we will be more effective in helping people stay well. JB: That’s beautiful. Once again, I want to re-emphasize, on your mandatory reading list, those of you who are listening, should be The Secret History of the War on Cancer. I think that no matter how much you think you know about this topic, you will take the next level of understanding by reading the book and also checking in on the website, www.preventingcancernow.org. I want to thank you, Dr. Davis. You have been very kind in giving us this time. I think you have given a lot of people impetus to take the next step in their education. DD: Thank you, Dr. Bland. I appreciate your work.  

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Welcome to Functional Medicine Update for August 2008. This is the age of personalized medicine. How do you implement personalized medicine? What does it really mean? How does it differ from that of pathomnemonically, pathophysiologically-based medicine? What are the tools and the algorithms that might differentiate a personalized medicine from that of a medicine that is focused on disease taxonomy? That is the topic of this month’s Functional Medicine Update. This month, our clinician/researcher of the month is one of the real experts in this area: Dr. Iris Bell. You will hear from her later in this edition. Before we get to Dr. Bell, let me set the context of the functional medicine model as it applies to personalized medicine, or individualized medicine, or what Dr. Roger Williams talked about many years ago, “biochemical individualized medicine,” or what Linus Pauling called “molecular medicine.” Whatever term we apply to this, we want to understand how it differentiates itself from that of the primacy in present, which is the diagnosis. The diagnosis is the affixation of a name (called a disease) to describe a set of conditions the patient presents with. The person then knows what to do because that disease connotes a specific therapy and it leads to this kind of taxonomic definition-almost Linnean definition-of how we see health and disease, a classification-type of mode The functional medicine model differentiates itself from the primacy of diagnosis by looking at the assessment of a patient from a different lens that includes antecedents, triggers, and mediators leading to signs and symptoms. You have heard this from me so many times over the years that it is probably ad nauseum. For those of you who might be new to this field, let me once again quickly review what I mean about the difference between differential diagnosis and the functional medicine assessment model. Functional Somatic Systems The functional medicine assessment model is looking for the unique characteristics that define a patient’s signs and symptoms, those things that led them into the healthcare system. Signs and symptoms obviously have differing levels of severity, duration, and frequency. Depending upon what threshold those particular signs and symptoms achieve relative to the patient’s own alarm systems (their propioreceptor systems or their noci ceptive systems), it ultimately triggers a sense of dysfunction in that patient that the patient understands through pain, fatigue, disability, and chronic problems. Often these are what we call functional somatic syndromes, and. they exist prior to the onset of a very well-defined, classically articulated disease. These syndromes have names like irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia syndrome, or essential hypertensive syndrome. The list is very long as it pertains to these things that precede the onset of a clean, histopathologically identifiable diagnosis. The functional medicine approach is to use the construct of antecedents. What does the patient actually have in their background (their genetic background, their health history, their social environment) that then sets the tone (the soil) for the triggering events that are like the inoculation of that medium with the precipitating factor? Some people call this the straw that broke the camel’s back. While there may have been an underlying reduction (or compromise) in organ reserve that the patient had, they were coping with it. It was only when this trigger (this precipitating factor) was present upon those antecedents that it gave rise to alteration in the web, the network of physiology, the trilogy of ‘omics, as we often call it (genomics, proteomics, and metabolomics). This trigger shifts the functional state of that patient into a new state of homeostasis (or homeodynamics) that is then a distorted component of their web of function. Mediators that work on target tissues and cells ultimately produce the signs and symptoms that lead to the dysfunctions that are labeled, at first, “functional somatic syndromes,” and then later become, over time, more acute and well-defined diseases. You’ll notice that this model has a kind of sequential staging component to it, starting at low-grade dysfunction that might be just molecular interactions. Maybe it is even at the interaction of energy within the cell, which then has a spreading effect over time: cell to a tissue, to an organ, to an organ system, and ultimately to a whole organism-type level of distortion that we ultimately can see with a measuring lens such as an x-ray, or a CAT scan, or a microscope. We ultimately can see that pathology. Or it may even be through biochemistry that we see pathology, by elevated levels of troponen, for instance, after a myocardial infarction, or elevated levels of protein in the urine with renal failure. These are all examples of the sequence of events that creates the personalization of that individual’s own dysfunction. Ultimately, this dysfunction comes to a point where it is called a disease, as if all people with that disease shared common pathways getting to it, and all people who have that disease have the same physiological dysfunction. I think we know that that is not true. From our experiences managing patients in the real world, we recognize that people come to their dysfunction from different mechanisms and they present with their diseases in different ways. This is the patient-centered approach to medicine that is the underpinning of functional medicine and how it relates to personalized medicine. In the Journal of the American Medical Association in December of 2006, a wonderful paper was published titled “A Systems Approach to Patient-Centered Care.”1 I think it is very important that the word “systems” was used in the introduction to this paper because systems biology is the new emerging construct upon which will rest our ability to understand how to deliver personalized medicine. We are looking for distortions in the systems that control biology of the individual. The new biology is looking at biological function within the organism as a system, not as it relates to pathways, but rather networks. I will come back to talk about that later. Helping Patients Achieve Self-Efficacy How do we get to a patient-centered care system? I think there is now more and more evidence to indicate that a personalized, patient-centered (or patient-focused) system is one that helps the patient to become self-efficacious. I am taking this term from Alberto Bandura at Stanford University, who has talked about self-efficacy. Ultimately, the objective is to assist the patient in knowing how to manage their own complex web of physiology. We start with intervention, to manage the specific signs and symptoms that led to the patient seeking out health care, but over time, the objective is to attempt to educate that patient about their own uniqueness in such a way that they become a self-regulator (they become self-efficacious). That is what is discussed in this article in JAMA: the attempt to achieve a system for patients to be involved with their own self-care by knowing what to do. It is very important to recognize that this is describing a system that is a distributive medical system. This is in contrast to a focused system that takes broad information and weaves it down into smaller and smaller bits of conclusions until we ultimately have a laser-like understanding of the specific histopathology of that disease in the absence of looking at some of the broader issues that may have led to the occurrence of that disease. What I am really talking about is a different philosophy than that of subspecialty medicine, which is knowing more and more about less and less, assuming that that will help us to better manage the patient. It is good to have a microscope when we are trying to examine things. Looking through a microscope would be an analogy for specialty medicine (knowing more and more about less and less). But it is also important to have a telescope, and to move back and to look at the whole system. The functional medicine approach towards personalization based on patient-centered care is built on this idea of a collapsing telescope-to-microscope, almost like an accordion. You move from a telescoping vision, looking at the ecology of the illness and the person within it by looking at antecedents, triggers, mediators, signs and symptoms, and then you go to the microscopic level, looking at the cellular pathology into a differential assessment of pathology. Personalized medicine is integrating those views together into a construct of systems biology, and the social network of the individual We are really talking about the emergence of a systems biology in human health and disease, rather than just the primacy of the disease in isolation. There are some very good articles that have been published recently on this whole construct. One was an editorial published in the Molecular Systems Biology in 2007.2 This editorial looks at how systems biology relates to human health and disease and what factors influence the functional capability of the individuals. Using new research techniques, the new biology that has been emerging integrates wide and divergent bits of data, everything from patient symptoms and past history, mediators that are analyzed and different fluids, and then ultimately coupling that information together with gene array data, proteomic data, and metabolomic data. Previously, this large, complex data array was too big to manage because we didn’t have the computing power, but now, with algorithms and computing power much greater than the past, this can be condensed down into an understanding of that individual system. That is where we are going. A Systems Biology Approach to Cancer Therapy I think the first step in this direction is starting to emerge from cancer therapy. In cancer therapy, we are-for the first time-starting to look at the unique genomics of the tumors of a patient and individualize the treatment based on mutated kinases, or specific characteristics, of the tissue type that is in the cancer of that patient, recognizing that cancer is really “cancers.” There are multiple genotypes and multiple phenotypes that go under one definition of a cancer. Therefore, out of the field of oncology is emerging a systems biology approach towards treatment. Drugs like Gleevec, for instance, which is a kinase-inhibiting drug that is being used for managing certain types of cancers, target a kinase that has become mutated and for which the drug is selective. These are signs of how we are starting to see the emergence of a systems biology approach towards therapeutics. In the area of pharmacogenomics, we are starting to see significant personalization. In the last ten years, it has become a requirement that drugs be labeled with the specific cytochrome P450s required for metabolism of those drugs (or how they are metabolized through the body), and also agents that might antagonize or influence the first-pass metabolism of these drugs that share the same cytochrome P450 detoxification pathway. Individual toxicity to a drug is based upon genetic polymorphisms of the detoxification enzymes, like cytochrome P4501A2, or cytochrome P4502D6, or cytochrome P4503A4, which are three common drug metabolizing phase I enzymes that have polymorphisms for which ultrarapid metabolizers or ultraslow metabolizers may respond in dramatically different ways than the wild type genotypes that have kind of “normal” Gaussian average detoxification first-pass metabolism. If you are an ultrafast metabolizer, obviously the therapeutic dose of a drug may need to be higher in order to get clinical outcome. By the same token, if you are a slow metabolizer, or you have an antagonistic second molecule that that same enzyme is trying to detoxify, then the dose that you are consuming might be producing a toxic body burden of that drug because it is undergoing slow first-pass detoxification and elimination. So we are seeing drugs now that are being tagged to their detoxification pharmacogenomics. I think this is really opening the door for patients to have their genotype of detoxification analyzed (or understood) before they’re given certain drugs that might produce a toxic effect if not properly metabolized. All of this is weaving itself into what has been called a systems biology approach to medicine, which leads to integrative biology and predictive biology. I think these are very important new terms that can be mapped against how we are seeing the etiology of disease and its potential management, particularly in the chronic disease area. With chronic diseases that have a long, latent etiology (going through preclinical into early clinical stages, and then going through different stages of severity), a different model is required than just the differential diagnosis model that we have with an acute disease presentation. The systems biology/integrative biology/predictive biology model leads us to a much better way of managing, early on, chronic complex disease than the differential diagnostic model because it maps itself against things like functional somatic syndromes and allows us to understand and explain, at a mechanistic level, using first principles in the new biology where the origin of that condition or that distortion of the web of life (or the web of function) of that patient came from so that it leads us into tailored, personalized intervention. Not just intervention for the average, but intervention for the individual. Of course, that’s the whole basis that we have been talking about (as it relates to functional medicine) for many years. An example that I think many people would use and is very well understood is methylenetetrahydrofolate reductase polymorphism (MTHFR). This is a key rate-limiting enzyme in the conversion of folic acid, ultimately, in 5-methyltetrahydrofolate, which then serves as part of the homocysteine recycling into the production of S-adenosylmethionine. S-adenosylmethionine (or SAM) is a very important methyl donor that has to do not only with methylation of neurotransmitters, methylation of hormones, methylation of phospholipids to produce myelin, but also with methylation of histone proteins in the genome, and it has to do with methylation of promoter region of genes. The availability of proper levels of S-adenosylmethionine has a very important role to play across a wide range of functions. This is probably why elevated homocysteine has an association with so many different conditions. Homocysteine is a surrogate marker for inappropriate conversion of homocysteine to methionine and the production of s-adenosylmethionine. Therefore, when we start looking at what conditions are associated with elevated homocysteine, it is not just atherosclerosis and cancer, but it is depression. We see it associated with Alzheimer’s disease. We see it associated with Down’s syndrome. We see it associated with hormone-related dysfunctions-hyperestrogenism and prostatic disorders in males. We see homocysteine elevations associated with arthritis. Why are so many diseases connected to one surrogate marker, an elevated level of homocysteine? It is because there are so many metabolic pathways that are dependent upon the availability of S-adenosylmethionine and how it regulates things like gene silencing, or epigenetic effects on the CpG islands of the promoter regions of genes that become methylated and silence those gene expression patterns, or it influences the production of intermediary biomolecules that are very important for cell signaling and cell regulation. So that pathway, which we call the homocysteine-folate pathway is really part of a regulatory network, and that is the point I think that differentiates the old model (which is associated with pathways) from the new model (which is associated with networks and a system that is unique to that person). For many people, the methylenetetrahydrofolate reductase polymorphism (the so-called C677T polymorphism), in which folic acid is not converted as rapidly into 5-methyltetrahydrofolate, may be a regulatory node. It is a weak spot; it is a pressure point; it is a-I’ve used this term advisedly-a “metabolic acupuncture point.” I hope you understand the analogy there. I’m not talking about a real acupuncture point; I’m talking about a point that has hormetic control of overall systems function. What do I mean by “hormetic” control? Hormesis is a word that refers to something in small amount having a much larger effect on the system than we would have predicted based on the amount. If you have a regulatory node in the web of physiology, and that is a highly sensitive regulatory node to a specific substance (in this case it might be folic acid or 5-methyltetrahydrofolate), it can induce a larger effect on function than we might have predicted, based upon the impact that it has on that critical switching point in physiology. So that’s our systems biology/integrative biology/predictive biology model that is emerging as a kind of counterpoint to the differential diagnosis and histopathology model. By the way, I was just describing commentary in the journal Cell, volume 121, page 505 in 2005.3 We now recognize that there is evidence of different metabolic phenotypes in humans. This has been discussed for years and years in the field of metabolic typing–trying to understand what differentiates a person, metabolically, from another. We are actually getting the tools now–for the first time–that really quantify metabolic phenotyping. There is a nice paper that was just published in the Proceedings of the National Academy of Sciences in 2008 titled “Evidence of Different Metabolic Phenotypes.”4 This was a study of metabolic responses to drugs, environmental chemicals, and diseases from a metabolomic perspective. Metabolic Fingerprints We know that metabolic fingerprints can be obtained by various analytical techniques (high pressure liquid chromatography, mass spectrometry, nuclear resonance, magnetic resonance spectroscopy). By looking at complex data sets of urine or blood, one is able to measure literally thousands of different metabolites. What you then can do is take a person from a baseline kind of evaluation of their metabolites, and you get a signature of their metabolites-kind of a metabolome (it’s like their web of metabolites). You stress the patient by giving them something that would challenge their physiology. It could be a glucose load, or it could be a protein load, or it could be a fatty acid load, or it could be a vitamin load. It could be any number of things, or it could be a chemical exposure. And then you examine, post-challenge, how that individual’s metabolome (that web) modifies or accommodates that challenge. You start to examine, then, the uniqueness of that person’s response to these environmental pressures. If you study that same thing across a wide range of people you can start to understand the biological variation in what we call metabolic phenotypes. That is the work that was described in the Proceedings of the National Academy of Sciences. Individual metabolic phenotypes exist; numerous studies report differentiation between individuals on the basis of a subject-specific response to particular stimuli, which helps us to better understand how things might categorize themselves in various individual classes. These classes are around the functional nature of the web, of the system, which is really what we have been looking at, and how we then look at the most important controlling parts of the web. Are there an infinite number of metabolic phenotypes? Theoretically, there are. In actual practice, what I think is more likely, is that they will tend to cluster themselves (or group themselves) into dominant pathways or patterns that are related to specific kinds of ways that genes speak to their environment. Recall, if you would, that we don’t get one gene at a time being expressed). They express themselves in families in response to a different environmental perturbation. These cassettes of genes are controlled in such a way that they ultimately influence metabolism, so we get these metabolic types that can emerge from this type of an analysis. This concept takes us away from the idea of disease being classified in a pathophysiological way into a complex systems biology way. There has been new evidence published in the last year or two on this concept of human disease classification in the post-genomic era moving away from human pathobiology as the classifying term. That is the way that we have basically defined the differential diagnosis that ends up in the ICD-9 codes into a new complex systems approach that looks at distortions of the web at a mechanistic level. In one of the recent papers in Molecular Systems Biology that I found fascinating, the authors looked at contemporary classification in terms of the disease and they mapped that against what is being understood in terms of each of those diseases having different mechanistic inputs, so actually, the systems biology approach gives you a finer granularity of understanding.5 Let me take this from the abstract to the real. Let’s look at cholesterol as an example. I think cholesterol is an interesting example because we are told that it should be minimized in people who have hyper-cholesterolemia, so these people are on dietary cholesterol restricted intakes. In the whole universe of individuals who have elevated blood cholesterol, what percentage of those people has elevated blood cholesterol principally as a consequence of elevated dietary cholesterol? That is a different question than the kind of statistical correlation between elevated dietary cholesterol and elevated blood cholesterol. Now we are going to the individual and asking what percentage of individuals in that set are those for which dietary cholesterol is a major determinant of their elevated blood cholesterol. It turns out, when you start looking at that and you look at what is called the ABC transporter, which is one of the controlling influences of how people regulate cholesterol biosynthesis in relationship to dietary cholesterol intake, you’ll find that about 10 percent of the population (approximately) are dietary cholesterol hyper-responders, meaning these are people for whom dietary cholesterol can really dramatically elevate their blood cholesterol. But for 90 percent of the population, their dietary cholesterol has a marginal and somewhat even insignificant effect upon their blood cholesterol. The elevated cholesterol in their blood is really more a consequence of de novo cholesterol biosynthesis, which is more related to other factors: hormones, macronutrients, toxins. The list is quite lengthy now that we have been putting onto it things that we know activate apolipoprotein synthesis and cholesterol de novo biosynthesis, which are seen in the blood as elevated cholesterol. This construct–that all people who have elevated blood cholesterol should be on a cholesterol-restricted diet–doesn’t really wash when you get to the personalized level. It is a similar situation with salt. We know that salt (sodium) is associated with hypertension, so it has been said that people who have hypertension should be on a sodium-restricted diet. But again we go back and we ask, how many individuals not in the average, but in the individual person, are those who are hyper-responders to sodium, with regard to sodium transport and the effects that it has on the renin-aldosterone system and ultimately in elevating blood pressure? When you start looking at that literature, again you come to recognize that somewhere between ten and twenty percent of the population who are hypertensive are sodium hyper-responders. The other members of the population (which are obviously the greater percentage) are those for whom sodium (even at average increased levels in the diet) are not the major determinant for their blood pressure. It may constitute a small part of their blood pressure elevation, but it is not the major criterion. Therefore, there are other factors that should be focused on in those individuals in order to personalize their program to improve outcome. This is the type of logic that is now coming from this systems biology approach: looking at the individual and how they respond to their environment rather than assuming that they are part of the group of averages. This is network biology-understanding the cell’s functional organization. Isn’t that an interesting title for a paper? “Network Biology: Understanding the Cell’s Functional Organization.” This is actually the title of a paper that appeared in Nature Review and Genetics in 2004.6 According to these authors, the key aim in this post-genomic era of research is to systematically categorize all molecules and interactions within a living cell. Ultimately, the goal is to see how the functional organizations of these molecules in the cell regulate (or are involved in the regulation of) the function of that cell, that collection of cells to become a tissue, a tissue to become an organ, an organ to organ system, and then eventually the individual. Networks Create Function We are starting to look at this network biology, the interaction of various pathways to form networks. And the networks, then, create the control of function. When you are evaluating a patient and you are looking at a blood test, you ought to be always thinking of that blood test in the context of all other blood tests and all other symptoms and signs, thinking of this as a system (a biological system), and then asking the question, when was the patient last well? Can the patient remember what triggering events might have been associated with the precipitation of whatever led them to come and seek professional health services? These concepts of antecedents and triggers leading to mediators and then ultimately to signs and symptoms gives a medical diagnostician a different way of approaching the detective work. Now what we are looking at is the distortion of the system that leads to the dysfunctional state, which is a steady state, I might add, in that patient, that we call their dysfunction or disease. That steady state is a new state of homeostasis around a new set of presumed markers, and these can become locked in over time. It is not like a bacterial infection that fulfills Cox postulates. In this case, when the patient gets over the precipitating trigger, they still have the residual effects of the dysfunction. It can be locked in for years and years and years until you break the cycle, and how do you break the cycle? You can do so by establishing a new state function for that person’s systems biology. You don’t do it by just changing one component; you find the regulatory nodes in their web that is creating a locked in feedback control system that produces this dysfunctional state. Now that is a very easy thing to say, but it may be much more complicated to deliver. How do you deliver it? It is going to be a distributive healthcare system that will allow that to occur because no one molecule, no one surgery, no one therapy, in and of itself, may free this whole system up. It may be a complex series of variables that modify the environment of that individual so as to send a different signal to their cells, tissues, organs, and organ systems to create a different relaxation of their web of physiology, moving from an alarm state into a state of normalcy. The person will go to a new homeostatic state of regulation, and the new one is the one associated with lowered dysfunction. I often argue very strongly that the path to deliver personalized medicine is not finding “the” therapy. The path is finding the way to interface multiple therapeutic interventions: diet, lifestyle, physical medicine, structural medicine, energy medicine. All of these things contribute to the inputs that are picked up by cells that create signals that associate themselves with their functional status. That then maps into genomics, proteomics, metabolomics, and ultimately into phenomics. This is really putting the “systems” back into systems biology. And this is a whole new way of viewing the way people become ill, how to understand the etiology of their illness, and how to work with them collaboratively to turn it the other direction. What we have been doing through the differential diagnosis model is using the diagnosis to find the treatment for that disease. In so doing-because we didn’t examine all the functional inputs of the uniqueness of that person’s illness-we may be masking, by uncoupling certain warning valves or smoke detectors that that person has. We use drugs that uncouple pain, or inflammation, or neurological function in such a way that the signals don’t get there, but the dysfunction of physiology is still present and it still has a trajectory towards increasing degrees of pathology. Putting the systems back into systems biology is to try to understand how we look at the whole-the system of the whole-rather than the system of pathways. I think what happened for many of us in our education is that we studied physiology and biochemistry on the basis of pathways that were provided on two-dimensional pieces of paper that we memorized and recited on demand. We got the view that somehow this was the way life worked. This view assumed that these pathways worked in isolation, and also that these pathways worked in equilibrium situations, neither of which are true in human physiology. A human is a non-linear, non-steady-state, dynamic system that is constantly responding to a changing environment by changing its physiology. Our whole systems approach has to be non-linear, and it has to be a dynamic system model. What we learned, when we learned our pathways, was a static system that is often unidirectional-A goes to B goes to C-and it is one that seems rigid and fixed in isolation. It gives us this concept of compartmentalized physiology.7 Putting the “systems” back into systems biology is a way of thinking as much as it is a way of acting. I believe very strongly that it is the way we think about things that ultimately determines how we act versus the converse, which is we act and then we think. So our perceptions-the lens upon which we sieve information-will determine the therapies that we use, or how we approach that patient, or how we define the etiology of their condition. With this in mind, there is this whole concept of scale-free networks. How do we view a person as an open-ended dynamic system responding to their environment in such a unique way as to give functional outcome? There is an interesting paper that appeared in Scientific American titled “Scale-free Networks” that describes the dendritic nature of physiology.8 It almost looks like a nerve map versus a pathway that goes A-to-B-to-C linearly. Feedback processes, both positive and negative, all leading to regulatory control, and we have to start thinking in this way. We have to look at our patients as a network, a biological system. Is personalized medicine finally arriving? That is the question. I would say, in 2008, the answer is yes. In Nature Biotechnology a very interesting paper was published that reviews how select companies are developing or partnering to develop personalized diagnostics.9This list is very long, Companies are developing ways of sequencing or evaluating either genomically, metabolomically, or proteomically individual uniqueness that will then develop new biomarkers for which personalization will ensue. This article actually talks about over 26 different laboratories that are engaged in different types of work, everything from the AmpliChip that is at LabCorp for measuring cytochrome P450s, to looking at the kinase mutations that are associated with various cancers that then lead to specific kinase inhibiting drug applications, to looking at cardiovascular disease risk factor biomarkers that are related to endothelial functional changes like phospholipase A2 (which we discussed in a previous issue of Functional Medicine Update). And all of these are tied together into very interesting systems of evaluation, using these biomarkers to look at prognosis and not just diagnosis. The next step is to map this against genetic variation. There is a lot of variation going on, isn’t there? We have two to three million SNPs (single nucleotide polymorphisms). Don’t we see everybody as a different person, and how will we ever gain mastery over this complexity? The answer is that some of these SNPs are going to be of little consequence in terms of the outcome to the patient and the phenotype. Others may be very important in modifying regulatory nodes, like the methylenetetrahydrofolate reductase polymorphism I described earlier. As we understand what SNPs have the most important role to play in modulating function, we then can develop biomarkers to assess both the genomics and the phenomics of that individual that then allows personalization of the program and also allows tracking of the success of the program. We are starting to see trials now being done looking at personalized approaches towards cancer therapy, like the HER polymorphism, or looking at BRCA1 and 2 polymorphisms related to breast cancer, and personalizing various types of things that would then allow treatment that is the medicine of the person rather than the medicine of the average. Let’s use an example of leukemia, and there is an interesting example in lymphoma as well. A hundred years ago, leukemia and lymphoma were just said to be diseases of the blood. Eighty years ago, we differentiated those into leukemia and lymphoma. Sixty years ago, they were differentiated into chronic leukemia, acute leukemia, preleukemia, incident lymphoma, and aggressive lymphoma. And now today, as a consequence of better understanding of the differentiation of these conditions, there are 38 different types of leukemia identified, and 51 types of lymphoma, all of which have different personalities and signatures requiring different personalized therapies. So if you can map that concept against what is going on in the whole nature of medicine, we are going from blockbuster medicine to personalized medicine. The age of one-drug-fits all is really going away and personalized medicine is becoming a dominant theme. In a recent issue of the journal titled Personalized Medicine, it was stated that one of the biggest challenges to biotechnology and pharmaceutical companies in the 21st century will be to develop and deliver therapeutics that fit the individual patient’s biology based upon this new systems biology approach.10 Do we have models for the study of whole systems, and what are the appropriate therapies that will personalize and produce better effective outcomes in the chronic disease state? It is that topic that we are going to be discussing with our clinician/researcher of the month, Dr. Iris Bell, who has been a prodigious researcher over many, many years in this area, and has authored an extraordinary paper titled “Models for the Study of Whole Systems” that appeared in Integrative Cancer Therapies in 2006.11 In this article, she and her colleague Mary Koithan said that the growing reliance on complex systems thinking in systems biology for research in the area of chronic disease affords a unique opportunity to bridge the gap between what we have traditionally called alternative or complementary medicine and the conventional medical world. We are going to learn much more from her as to how this actually plays out in the future of the clinic.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Iris R. Bell, MD, PhD Iris R. Bell Associates LLC 10645 N. Oracle Road Suite 121-126 Tucson, AZ 85737 www.irisbell.com I look forward to this section of Functional Medicine Update with great anticipation every month because it gives me the opportunity to speak personally with someone who I really admire and who has made some extraordinary contributions to the evolution our field, and also to learn from them. Certainly, we have another example this month on Functional Medicine Update because I have the privilege of introducing you to and talking with Dr. Iris Bell, who is a professor of family and community medicine and involved both with psychiatry and psychology in the integrative medical program at the University of Arizona in Tucson. You probably also know Dr. Bell, whose contributions go back many years in our field, as being a person who is looking at energy systems, looking at non-linear systems theory as it applies to medicine, has also done a tremendous amount of work in the underpinning of homeopathy. She has been very heavily funded by the National Institutes of Health, including a career grant. She has worked in publications to contribute more than 100 different scientific papers; she is highly authored in PubMed. She has done two dozen book chapters on her work. She has really been one of the sentinel contributors to our field over the last 20 years. Her forthcoming book for consumers is titled Getting Whole, Getting Well: Healing Holistically from Chronic Illness. It will be published this year. Dr. Bell, it is just such a privilege to have you as a Functional Medicine Update Clinician/Researcher of the Month. Let me start, first, with the question that I think everyone would like to know something about: how did you get into this field with the extraordinary background you have, both with your MD and PhD? Obviously there were many paths you could have chosen and you chose this path. How did it happen? IB: Thanks very much Jeff. I have always had a great deal of admiration for the work that you do also, so we’ll have a mutual congratulatory discussion here. When I first got into this field, I actually had the strong sense that that I wanted to study learning and memory in a psychobiology kind of way. I knew that I was very drawn to interdisciplinary work, even as I was starting college. I had to go around in a few different fields before I found a home. I majored in biology, but spent much more of my time in the psychology building learning psychophysiology. So that was really my background and my baseline. I, very soon in college, got a job in biofeedback research. The person who hired me, the professor there, said “I hope you don’t have a bias against the ability to voluntarily control the autonomic nervous system.” I said, “No, I don’t know anything about either.” I think that is one key point about all of this: just having an open mind and taking a look at what you see before you. You certainly have to be informed by what people show you and what the evidence accumulates in saying. But many times the interpretation of the evidence is far from simple. So after I did college, I knew I wanted to go to graduate school. I got involved in more psychophysiology research as part of a sleep laboratory at Stanford. It was really there that I was first introduced to some of the ideas of Theron Randolf and his groundbreaking work on food and chemical sensitivity. I had the opportunity to really delve into this field for many, many years, and actually made the decision as I was finishing graduate school that if I wanted to study human health (and I was getting plenty of advice) that I needed to go on to medical school. So I said, “Oh well, here’s another degree. Okay.” So I finished my PhD as I was starting medical school; a feat and trick that I would not recommend to most people. I then began to really look at this whole question. His [Theron Randolf’s] work was really so good at connecting the mind and the body, but also saying that there was a biological thread. There were demonstrable things going on in the background if you looked for them, and that, of course, led me even further into understanding a little bit more about nutrition. So, all of those areas became of interest to me. As I was starting medical school, I was confident that I was going to go into research on environmental medicine, which I ultimately did. But at the very beginning of the time I started to learn about that, I heard about this very controversial field called homeopathy. That opened up a whole different world of therapy for me, because up until that time I was very focused on understanding mechanisms and trying to explain to the world why low levels of environmental chemicals or common foods could actually make people sick. That continued to be a focus of my work for many years, but the door was opened to this whole notion of homeopathy that there might be ways of using some of the even more controversial therapies that were out there in the world of environmental medicine, such as the provocation/neutralization technique where they were able to turn symptoms on an off in what they called “miniature.” I saw how imperfect that system was when I was working in an allergist’s office in the summer between various semesters of school, but I also saw that it had a lot of potential. It [homeopathy] was inappropriately rejected by the mainstream community by using data that actually supported the likelihood that it had a significant effect beyond placebo. It was one of my first lessons in how human biases can get over into science. So in any event, at that point, I learned about homeopathy and I saw tremendous overlaps in the theory and the practice of homeopathy with many of the ideas that had been developed in an entirely different direction by Theron Randolf, who I think was really a very good practical observer, and then someone who put together these ideas into theoretical models. I never forgot his [Theron Randolf’s] bipolar, up-and-down diagram. He showed that when he gave someone a food or a chemical they were sensitive to at a time they were unmasked (by having withdrawn from it for four days) and then rechallenging, that the person could bounce back and forth between what he called stimulatory and depressive (or withdrawal) kinds of symptoms. His work was really seminal in that area of recognizing that reactions were not linear, that what the human being was capable of was very bipolar. And at the extreme, of course, there was manic depression, which he also reported seeing affected by his clinical diagnostic approach and ultimately by his treatment approach, which was avoidance. The thing that appealed to me about homeopathy was that it seemed to be a more intensively developed therapeutic system that would change the vulnerability (the inherent vulnerability) of the host to things in the environment. And I realized, after having really gone in depth into environmental medicine, that it could hit a wall where peoples’ quality of life was being compromised by having to not eat in any kind of simple way within the culture that they lived in and not be able to be out in the world, working and enjoying their families and their overall environment because of the health problems it brought up whenever they were out there exposed. And so that was what brought me through the whole thing. But all the way through all of that, I saw this kind of non-linear, up-and-down process that the human being was capable of. I saw that low doses of things, and things that were always being claimed to be nontoxic, and certainly scorned by the skeptics (when you said “Well, corn can make somebody manic,” and they would just laugh at you), that those kinds of ideas, that a small, supposedly innocuous dose could be interpreted by a particular individual’s body as being toxic for them, were just fascinating. To me, again, that was a non-linear kind of process. I’ll stop, at this moment, to sort of catch a breath and see if you have any questions about that. JB: Oh boy, you have just opened up so many extraordinary doors in that introduction. Just fascinating. What a panorama. Let’s back up just for a second. I find that many people who have come into our field don’t probably know, to the extent that they should, about Dr. Theron Randolf and his extraordinary contributions in this whole neutralization/titration concept. Maybe you could help us (for those who are maybe newer to the field) by describing Dr. Randolf-his work in Chicago and what that technique, in terms of patient management, evolved to become. Research of Dr. Theron Randolf IB: Sure. Dr. Randolf was very much a fundamentalist. He was part of a group of allergists, actually, who were very well trained in their particular field. He was open to the idea-his patients were really teaching him-that there seemed to be problems with certain foods, and then ultimately with foods that had been sprayed with chemicals. For example, some of his patients reported being able to eat an apple that had been grown organically, but not an apple that had been sprayed with pesticide or waxed. That expanded into a whole series of discoveries for him. His primary approach was to do what he called “unmasking the addiction to food” or really the habituation to a chemical that you are exposed to all the time. And so he would withdraw people. He actually, at one point, had a hospital unit where he would withdraw people from the usual diet and their environment and then challenge them with this item after 4 or 5 days. Typically they would feel worse at the beginning of this process, and then they would clear up and feel better than they had in a very long time. Then he would challenge them with this item, whether it be a food or a chemical, in a controlled setting, and show that he could produce these very hypersensitive flares of symptoms, acutely, that people would otherwise say didn’t happen for them if they were eating the food everyday or breathing the chemical everyday. Of course, this opened up the whole world of environmental medicine. His contribution was to even build further on the notion that diet could do this, to look at the entire world of environmental chemicals. As he was doing his work, there were other colleagues who developed even further this idea that you might be able to use allergenic extracts to produce this kind of effect. There was a series of developments, really, but what they did was take the allergenic extracts that were typically used by allergists of the time to inject people with small doses and supposedly produce an immunity. But in this case what they did was really dilutions (low-level dilutions) of these allergens, and certain dilutions would provoke symptoms, and the next dilution might actually shut off the symptoms in a five or ten minute period in the office. So that enabled Randolf and many of his colleagues to test people without putting them through this very demanding process that sometimes someone who is very debilitated really couldn’t undergo with the actual challenge in a hospital setting. They could take someone in an office and turn these symptoms on and off very quickly. Again, certain stronger dilutions would do it and then it was almost like there were harmonics, where the next dilution might remove the symptoms, the next one might provoke them again, and so on and so forth; a very fascinating process. If they were able to find a stable dose that shut off the symptoms, many allergists would then combine what they called neutralizing doses into a treatment bottle and send the people home to take this material, and they would do it either by injecting it under the skin or under the tongue (not injecting it under the tongue, but having them just dilute it under the tongue). They would use that as a treatment just before they would try to eat a food or be exposed to a chemical that they couldn’t otherwise avoid. JB: That’s a beautiful explanation. Of course, that leads, then, back to what you were talking about with non-linear systems, that we have this view (from the way we are trained in pharmacology) of this dose-response curve, that with each increasing dose you get an increasing response. It may be not totally linear, but we have this concept that 1, 2, 4, 8, 16, you know, kind of a geometric progression of dose response, and what you are saying here is that different doses may give very different responses, sometimes agonist and sometimes antagonist, which is very different than the traditional pharmacological model of linearity. IB: Absolutely, and it raises questions about what that can mean because we assume very simple lock-and-key kinds of mechanisms in the body. If that is the case, it means that the interpretation at the cellular level is different depending on exactly how much material is there. JB: So that leads to a term that we have used in Functional Medicine Update over the years, which you have a better understanding of than anyone that I know, and that’s the term “hormesis.” It refers to a small amount of something having a bigger biological effect than anticipated. How does this concept of hormesis play a role in explaining, mechanistically, these non-linear reactions? IB: It is fascinating to see that there have been these different, very well organized disciplines that have identified these concepts. Hormesis has grown up in the field of toxicology, where researchers have actually found–in hundreds of cases, and have published very good reviews of these in all kinds of papers–that the dose-response curves to many things, ranging from radiation to environmental chemicals to common drugs that are used in treatment of conditions. Typically, if you go down the scale of dosing and you get just below the lowest dose that can cause an adverse reaction, which is where you begin to see this phenomenon of hormesis, which is the evidence that there is a non-linear dose-response curve. This appears to be related, in part, with the more recent work that I have read about. The lower dose appears to not be enough to stimulate a toxic reaction in the person or in the animal, but what it does do is stimulate a compensatory, more homeostatic response, if you will, of the organism. So it strengthens the organism to a future exposure to that same material. Many of the simpler studies have been done. Really that whole phenomenon has not been adequately explored, experimentally, but many of the studies indicate that you might be able to stimulate this protective effect by giving a low dose of something, where the same material in a higher dose will trigger an adverse reaction. This appears not just to be dependent on immune system response, which is very interesting. JB: So that obviously is a beautiful segue into what, I think, was a seminal paper for our field that you authored with Carol Baldwin and Gary Schwartz back in 2002 in Alternative Therapies, which was titled “Translating a Non-linear Systems Theory Model for Homeopathy into Empirical Tests.”12 We then see something related to your interest in homeopathy, obviously, emerging out of this whole construct that you are describing. Maybe you can review for us or summarize for us this kind of next step you took into homeopathy. Insights on Homeopathy IB: Homeopathy is an enormous field unto itself. I thought environmental medicine would be controversial, but I was wrong. The world of homeopathy is even more controversial. There are several levels of issues in this field. What was fascinating to me was not continuing to be engaged with this whole argument about how a low dose can actually do something to an individual, which turns out to be interesting in itself, and actually relates to network theory within the non-linear, complex systems, science world. Just the whole notion of what is the human being doing when it heals? I went back to Randolf’s model of this bipolar reaction of people being able to go all the way in a stimulatory side. But as they recovered from an acute reaction, or as they recovered from chronic illness, he reported seeing that people, perhaps, might have more emotional or sleep-related problems and they were very severely affected, and then begin to recover through headaches and fatigue, and then ultimately things like runny noses, mucous membrane discharges, the nasal rhinitis kind of thing. And he saw this kind of cycle that people would go through. Well, homeopaths have seen and reported a very similar thing. They have a phenomenon that they have described for many years called “Hering’s Law of Cure,” where they say that a human being, in the process of healing naturally, rather than being forced into it by a drug, will actually go through a process of healing from above downward, from the more important organs inside outward, towards the skin, and in reverse order of time of the appearance of the symptoms. That very much fascinated me because it matched up and mapped onto what Randolf had reported and I had seen repeatedly in patients who were food and chemically sensitive: as you were recovering from a reaction you would begin to have these nasal discharges, and that is precisely what the homeopaths were claiming. So I started there, saying “Well, that’s a very interesting phenomenon because now I have people in two different fields observing the human being, and what must be true is that the human being has some truths about him or her that go past whatever discipline, or whatever glasses or lenses we are looking at the person with.” So homeopathy claims to be able to give a very low dose of an agent that is really drawn from animal, mineral, or plant materials and prepared in a very interesting way that is similar to allergenic extracts, but a little bit different. It involves serial dilution and what they call sucussion of the material. And the sucussion is very vigorous shaking, so it is probably even more vigorous and extended than what you might expect with an allergenic extract. And they will take the serial dilution out so far that there are no molecules at the source left, which is the source of the most intense debate about the plausibility of the field. However, it turns out that the sucussion apparently creates a network effect within the water molecules on the agent itself. Meanwhile, we have the person doing their illness pattern, really a phenomenology of mental, emotional, and physical symptoms. I encourage people to try to go to conferences where they can watch video tapes of patients who have been treated over a period of years, because the changes are truly transformational and there are so many of these cases out there. It seems very implausible that these are the claims of a misguided individual because we are talking about many different individuals worldwide reporting these same kind of phenomena, and actually being supported by a great deal of data that, again, gets overlooked and attacked by the skeptics. But what you see is people doing-living out-Hering’s Law of Cure in a most dramatic way. If someone has, for example, skin lesions all over their body, literally you will see a march of the skin lesion down the body and out towards the toes. You can see these video tapes of patients going through the treatment like that. There are many other even more dramatic situations with people with multiple sclerosis and other kinds of autoimmune diseases, particularly other kinds of allergy, asthma, seizure disorders, and so on, who seem to have this same kind of effect. People alternating between-Randolf observed this-severe depression and skin eruptions. But homeopathy appears to trigger the ability of the body to keep it moving towards the skin and then eventually resolve without pushing it to other parts of the body. One of the most interesting things that you learn from homeopathy is the notion that if you try to treat the body locally, whether you are using an alternative medicine approach or a drug, you could suppress the symptom, and by that they mean they are pushing the symptom from the local area where the manifestation was appearing back into the body, saying “Well sure, the only kind of manifestation the skin could do is a skin eruption.” But say you push it back in, the lung is capable of having asthma, or the brain is capable of having depression. So you are saying that there is a disease process that this individual has, which homeopathy recognizes. It is not an entity, by any means, but it recognizes that as a disease that the person has, which simply happens to manifest in all these different local parts, if you suppress illness, you are pushing it into more important organs. If you treat it homeopathically or find other methods of healing naturally, you should see it go the other way, and you should see the thicker organs (the more important organs) that are necessary for survival recovering first during a gradual process of the illness moving out towards the skin and then ultimately resolving. JB: That’s a fantastic explanation. I notice that you are co-author of what I think is a very nice paper in the journal Homeopathy in January 2008 titled “Homeopathy: Quackery or a Key to the Future of Medicine?”13 I found that article very insightful because we’re all responding, in part, to the Bausell book titled Snake Oil Science, which was published in 2007, in which he basically says there is no scientific support nor clinical justification for anything that is within the domain of complementary and alternative medicine. I presume you probably have an opinion, at least in summary, that you would share about that book? Facing CAM Skeptics IB: As a disclaimer, I have not read the book. I have heard about it. I have certainly read many of the arguments that are made from a skeptical perspective about many of these areas. I think that if somebody wants to shut off discussion and say we have what we are comfortable with and we will just stay with that, then it is up to them. But I think we have to really look at the fact that Western medicine has become completely focused on the reliance on pharmaceutical agents as a primary way to treat everything. One of the things that I have learned, even looking at the mainstream literature, is that people are beginning to realize that the human being is a complex system. It is a complex living, adaptive system, actually. It is too simple to try and take pharmaceutical research designs, such as randomized controlled trials, and not honor the nature of the alternative medicines being tested, show a negative result, which proves, in fact, that that particular intervention doesn’t work like a drug. And I am perfectly willing to accept that conclusion because most of these techniques do not. And then you can go on your way saying, “Well it doesn’t work like a drug and drugs are the only important thing,” so the important thing to look at is your assumption that mechanisms that are drug-like are the only way to look at the way healing can occur. We know that the mind and the body speak to each other. We know that you can have profound effects by simply changing the way you perceive a situation. If you get very excited and upset about a particular situation and the person next to you does not, your autonomic nervous system, your hormonal responses…they are all in a different state than the person standing next to you. You are in the same situation, but your response to that situation is different. The way of understanding that and the way of doing research on that is simply different than what you do to come up with a simplistic answer about alternative medicine. I simply disagree with the completely blanket conclusion that all of the evidence is completely missing or flawed about alternative medicine. I certainly agree that if we really take the material in this area seriously, we have a lot of work to do, and we have to develop rigorous methodological approaches to how to do this work, and we have to think more deeply about what it teaches us. Systems biologists, in the mainstream, are recognizing that they cannot tweak one gene and stop worrying about everything else that may happen, or even look for simply one genetic flaw in a particular phenomenologic condition because we find that there are multiple pathways to get to the same situation. There are multiple factors that take us to the same situation. What we end up with is really a clash of world views. I don’t know that we can easily convince another person who holds a different world view. I think for people who are open-minded you can explain that there are world views and what the implications are if you take a more relativistic point of view of how things interact with each other and how we are all part of networks: we are a network, we are part of larger networks, within our bodies we have microcosmic networks (the biochemical networks of the body). These all interact and communicate with each other to lead to what we call emergent properties of the system. These are the kinds of ideas that you can ignore, if you choose, if you are a skeptic of alternative medicine. But I think in many different areas of alternative medicine, it keeps bringing up this notion of a complex, adaptive system where there is interaction, where there are all sorts of astonishing and hard-to-predict outcomes. One of the problems, when you think about it, is that a drug can force a body to do a particular thing pretty much every time you give the drug. Many forms of alternative medicine are not even trying to do that; that’s not their claim. What they are trying to do is get the body to get back in balance so that the different parts are all communicating in a normal, healthy way, if you will. That is actually not that reproducible unto itself, and that is one of the biggest challenges we have as researchers in this field. We know that science wants reproducible phenomena. And yet, a complex system is never in exactly the same place that it was a few minutes ago, let alone a week ago, and that some things may not be easily reproducible because it is a subtle interaction of whatever stimulus you are giving with a therapy and the state of the individual at that moment in time. That is something that many of the skeptics, including that book, really keep ignoring. I think it is to their peril because there are so many amazing discoveries we have ahead of us if we open our minds to that possibility. JB: I think your explanation was absolutely eloquent and thank you. For those of you who want to read a little bit more about this, Dr. Bell and Dr. Mary Koithan have published/authored a paper titled “Models for the Study of Whole Systems” that appeared in Integrative Cancer Therapies in 2006, which kind of reviews exactly what you were talking about in a very nice summary fashion. I think you have set the tone for a whole different thought process about how we look at this interaction of environment with the individual to give rise to health or disease. Let me ask/go back to a point that you made earlier, which I think is a very critical point and that has to do with mechanisms of action. We have assumed, through our years of study, that there are these interactions that are kind of hard molecular interactions between a ligand and a receptor and they bind with a certain affinity coefficient and you can look at all the molecular interactions, you can model it in silico, and yet there is this concept that you are describing that poses maybe another way that things can interact other than just the dirty dancing of a close contact between a ligand and a receptor. What are your thoughts about these other mechanisms? Are there any hypotheses that you think are interesting? Computer Model Studies IB: There are a lot of computer model studies that are done in the field of complex systems science and network science. One of the interesting things, which I think needs to be explored and is beginning to be explored, quite honestly, in the systems biology world, is this idea that the global-this emergent-which is really more than the sum of the parts, basically, of the organism of a whole, appears to be able to communicate back and forth with the parts. We don’t always think about that because the parts have their own properties, but what we are saying about the larger system, which is really fairly self-organizing and has emergent properties that the parts don’t have, is that that global level of organization can communicate back down, if you will, the organizational scale into all the parts that contribute to it, and vice versa. In the world of acupuncture research, there are some interesting theories about how that communication could be going on that involves the connective tissue. I think one of the interesting concepts that the world of homeopathy raises is, are there properties of body water that are potentially more electromagnetic in nature that may actually be structured and communicating information at a whole other level than we usually think about at the molecular level? There are papers by people who are looking at the notion that water molecule structure, for example, helps proteins fold in a particular way. What if you were to change the information that those water molecules were providing so that they were actually changing protein configuration at a local level, but the larger signal was some larger piece of information that makes you you? It is more than just your genetic information per se. There is a lot of interesting evidence about socioeconomic status, even, affecting how we turn certain gene patterns on and off, and actually a low socioeconomic status early in life appears to be retained as a piece of information in the body for years at a time, such that there is a proinflammatory pattern years later. Again, there are studies showing this kind of thing. So we are not talking about something that is just some theory that I have come up with this week. We are talking about the notion that there may be acquired information over a lifetime, and even prenatally, that in fact can be communicated, change the way the genes express themselves and therefore the way the person exists, so they have the genetic potential for whatever. Even in twins we know that in one year one twin may get a particular illness, and it may take five years for the next twin to get it, and we know that has to be environmental. I think we have to think much more about the interaction between the environment and the organism and the organism and the parts in a flow kind of manner and look for what could possibly carry that information. JB: I can’t believe how the confluence of knowledge tends to run in streams and collect as tributaries, ultimately, to make a river. We were very fortunate to have Sandra Steingraber talking about Living Downstream a few years ago, and then last month we actually talked with Dr. Devra Davis. I’m sure you’re familiar with her work on environment and its interrelationships to epigenetics and how that triggers different kinds of physical and physiological changes. Again, going back in both of their examples to how little we really know about low levels of multiple things interacting with complex systems of polygenetic origin and what kind of tags and markers there are in our human genome that make us either receptive or not receptive to certain messages. This is a whole different way of looking at life than looking at it as a series of nodes on a metabolic pathway in two dimensions. IB: Right, exactly. JB: So can you leave us, as clinicians, with some thoughts about what would be the way to approach a patient who is sitting in the exam room, based upon this kind of a strategic thinking? How do you train students to even be prepared to be doctors who would be open to this information and filtering it in this way? IB: Obviously it is a large challenge, really because of the pharmaceutical mindset that we have right now in this country among many mainstream clinicians being trained. But there are many students who are open to these ideas. I think, probably, the main idea is to question the assumptions, because we struggle so hard, especially when we are a student, to learn something so we can excel at the test, showing that we grasp the information being offered. Go back and examine your assumptions. And go back and ask the question, are there other people who have thought in a different way about these assumptions, and starting with a somewhat different set of assumptions, have taken this whole idea of health and disease off in a different direction? What kinds of commonalities flow between the different approaches, be they alternative or conventional? Pay attention to your own observations. If they don’t match up with what the textbook says should be happening, then pay attention to what the patient is telling you. Pay attention to what their body is telling you. And try to understand that with fresh eyes instead of trying to impose a particular way of looking at that patient’s problems. JB: That’s a beautiful thought. Again, Dr. Iris Bell, I want to thank you for so many years of being a thought leader and also being willing to put yourself at some risk, professionally, and delve into these issues at a much deeper level, knowing that it is not the road easily or often traveled. What you have been able to do is to leave a path behind you that opens up the door for many other emerging practitioners to have some comfort and understanding that there are people like you, with your background, able to look at these things objectively and help guide us so that we have more tools in the tool kit. The functional medicine model that we have been describing for many years is really built around this whole network concept of systems biology, and I think your work is key and fundamental to understanding how this fits into the clinical world. Thank you so much for both sharing with us today and also for your years of contribution. IB: Thank you very much, Jeff. I certainly hope that you are as educated and informed by Dr. Bell’s comments as I. I think that was a very eloquent and courageous presentation. She covered a tremendous range of topics very eloquently. It really goes back to the functional medicine concept, I believe, of a patient-centered assessment and medicine looking at antecedents, triggers, mediators and how they interrelate to signs and symptoms, which is, as you know, the method of assessment that is described and taught within the functional medicine curriculum, versus the sine qua non being only that of diagnosis. Obviously Dr. Bell is talking about a non-linear, dynamic, complex system and network approach to looking at physiology that provides a conceptual basis that looks at the whole organism, this patient-centered organism. Complex systems theory then facilitates an understanding of and, hopefully, ability to move beyond the perplexing difficulties of reproducibility of the randomized clinical controlled trial. It allows us to look at this multidimensional world view of whole systems and how the environment interacts with the individual to produce an outcome, versus looking at each thing as piece parts and siloed thinking, one at a time. If we were to look at the clinical differences that Dr. Bell has described between whole systems, basic biology, and a conventional medicine approach, we might say, how does the evolving life course of a disease differ in these two views? In the concept of systems biology, diagnosis is related to a coherent pattern, really, of interaction of the disturbance of the individual in their environment to produce differing kinds of symptoms that have differing severities, duration, and frequency, versus the conventional medicine approach that each diagnosis, unrelated to and independent of other diagnoses. We look at systems patterns in this systems biology approach as expressions of global disturbances in the organism’s web of physiology. In a traditional model we might look at symptoms as local expressions of local disturbances versus this global disturbance. The outcomes that would be expected in a global well-being, energy and pattern model related to systems biology would be this whole organism treatment, versus, in a conventional medicine, more siloed thinking with differential diagnosis and elimination of the chief complaint and associated symptoms. As Dr. Bell said, maybe these would even drive those symptoms deeper by blocking them at certain levels. So there is a different philosophy, psychology, formalism, and basis of thinking. The old model, which is treating one thing one at a time, is not really consistent with human physiology nor biology. We need to move to a biologically based medicine, which I like to think is the functional medicine model. Thank you, Dr. Bell, so much for your extraordinary contributions to our education in this area. We’ll look forward to being with you next month.  

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Bibliography

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3 Liu ET. Systems biology, integrative biology, predictive biology. Cell. 2005;121:505-506.

4 Assfalg M, Bertini I, Colangiuli D, Luchinat C, Schafer H, et al. Evidence of different metabolic phenotypes in humans. Proc Natl Acad Sci. 2008;105(5):1420-1424.

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6 Barabasi AL, Oltvai ZN. Network biology: understanding the cell’s functional organization. Nat Rev Genetics. 2004;5:101-113.

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Welcome to Functional Medicine Update for September 2008. I am going to title this issue “Personalized Medicine and the Epigenome.” Hold onto your seat. This is going to be a very interesting discussion. In this issue we will have one of the world’s leading investigators in the area of nutritional epigenomics, Dr. Randy Jirtle, as our clinician/researcher of the month. I think you are going to be really pleased with the quality of the information that he shares with us. Before we get to Dr. Jirtle, I think it would useful to set a context. There has been a lot of fanfare and hoopla surrounding the age of personalized medicine that we are presumably moving into as a consequence of the decoding of the human genome. But as we get more into this topic we recognize the story is not quite as simple as we may have thought it to be back in the age of Watson and Crick and others who were looking at the triplet code that gave rise to our genetic lineage encoded within DNA. There is more to this genome story than just the linear sequence of nucleic acids along the polynucleotide chains of DNA. We now recognize that DNA chains are wrapped together, not only in the alpha helix, but also supercoiled and compacted into our genome. They are insulated and regulated in a very interesting geometric-almost artistic-way into the nucleosomes, where the nucleic acid material is bound up in a selective way with histone and nonhistone proteins that coat it. These proteins provide protection from the outside environment so that chemicals and radiation do not have ready access to our book of life. Locked deep in this vault, more secure than Fort Knox, is the encyclopedia that we call our genetic code. Unlocking the Epigenome Unlocking this code requires selective library card privileges. You can only check out one book at a time and read each book individually. Because every cell has the complete library, if we were reading all the books simultaneously, our liver would behave like our heart, our heart would behave like our stomach, and our stomach would behave like our skin. All would behave like one another and we would be a mess. We have to differentiate function within this complex array of tissues, and the way that happens through developmental biology is by silencing some of the messages (meaning putting “Don’t Read” messages on them, and putting “Read Here” messages on select portions of the genome that are related to the functions of that specific tissue type or cell type). These messages are encoded in what is called the epigenome. The epigenome (or “above” the genome) is the regulatory regions of the genome that allow for specific access to this book of life-our library, our encyclopedia. What has emerged in the last 10 to 20 years is that accessibility to this message that is locked into our genome is in part regulated by interaction with our environment. Environmental factors influence the regulation of the epigenome, which then, in turn, regulates accessibility to the read and don’t read messages of our book of life, our encyclopedia. Personalized medicine is emerging as a buzz word or a sound bite that I think relates to understanding function. It is more than just arming ourselves with the decoded human genome. It is also looking at how the epigenome allows access to these bits of information that are encoded within our genome so they can be expressed as messenger RNA and ultimately into protein. Through post-translation modification by phosphorylation, oxidation, or glycation, these proteins ultimately become functional proteins that then regulate structure and function of the cell, tissue, organ, organ system, and whole organism. This is a very different view of regulatory effects on function, and ultimately on health and disease, than previously held thinking that all answers would come from deciphering the human genome. Regulatory Effects of Environment on the Epigenome We are at the beginning of the story. What is beautiful about this beginning story of the epigenome and the regulatory effects that the environment plays is that there is a lot more plasticity and modifiability in outcome than we previously recognized. We can’t change our genes easily in the absence of mutation or molecular excision by genetic biology-related functions (by carving out a portion of the genome and inserting a new portion with molecular biology). So we can’t change the genes easily, but what can be changed much more readily is the epigenome, by modifying the environment. Stress reduction, regular exercise, lack of exposure to toxic chemicals, proper nutrition and micronutrient intake, and phytochemicals have all been found to modulate the structure and function of the epigenome. Such modulation allows access to certain regions of our genome that then get expressed or not expressed into the proteins that ultimately regulate our cellular function. It is a very interesting story that is unfolding. You are going to hear much more about that from Dr. Jirtle. “The Genome Gets Personal” is the title of a recent paper in the Journal of the American Medical Association.1 The authors of this article talk about the fact that we are looking much more seriously at gene loci that map against certain diseases, and we are understanding more now about single nucleotide polymorphisms (the variation of single-letter alphabet changes in our code of life and how they may relate to diseases). The next step is understanding expression because it is not enough just to know whether you have or don’t have the specific genetic susceptibility or strength. What is more important to know is if it is expressed into the phenotype and alters function in such a way as to result in health or disease. When we get personal with the genome, we have to take into account not only single nucleotide polymorphisms (or SNPs), but also how they are influenced in their expression by the epigenome and whether these SNPs sit in regions of cellular function that play principal roles in regulating outcome in the phenotype. This is more than just genetic screening. Another recent paper in the Journal of the American Medical Association talks about delivery of genomic medicine for common chronic adult diseases.2 The authors looked at how many titles have been published in the literature in the last few years in this area. It is over 10,000 titles that break themselves down into looking at outcomes of genomic medicine, consumer information needs, delivery of genomic medicine, and barriers and challenges to integrating genomic medicine into the practice of health care. The majority of these articles talk about multi-loci influences on the expression of chronic disease (multi-loci meaning there are not single genes that control the expression of the major chronic diseases: heart disease, cancer, diabetes, arthritis). Chronic diseases are not monozygotic types of situations. They are controlled and regulated by multiple genes working together as families (or what are called cassettes of genes) that ultimately take their messaging from an upstream boss-the reporter DNA, or the area of the genes that actually regulate their expression, so these are the regulatory regions of genes. And these regulatory regions control the expression of multiple genes upon certain environmental features and reside in a place within the genome that is quite unexpected: they reside in what used to be called the junk DNA. Years ago, I suggested that the term “junk DNA” presumed that this massive amount of DNA material found in our genome which didn’t seem to code for protein was just relics from a past history that had no functional impact on the individual. Another point I have made (based on many other authors’ work) is that the major difference between the genome of a human and all other plants and animals is the amount of junk DNA. If we look just at the coding regions of our genome, we find that we are 98.9{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} homologous with the chimpanzee. (A lot too close for some peoples’ comfort.) But the difference between the chimpanzee and humans relates to the amount of non-coding DNA (what used to be called the junk DNA). It has now been discovered that this is where many of the regulatory regions for genes reside, and so no longer should we be calling this junk DNA. These regulatory regions of genes are controlled upstream by the exposure they have to the ability to be expressed through epigenomic messaging (what we call silencing or activation). The epigenome lies on top of the regulatory regions of genes. These regions then promote the expression of downstream cassettes of genes that ultimately regulate a whole series of functions at the organismic level. A chronic disease is not a breakdown of one step, it is a dysfunction of the network of genes that regulate complex function. This is why chronic disease has multiple symptoms, not just one, because we are influencing many functions. The delivery of genomic medicine for common chronic adult diseases is going to have to tie itself very closely to better understanding how the environment influences the epigenome and ultimately the regulatory or promoter regions of genes. One of the groups looking at this very intensely is a group at Rosetta Informatics, a division of Merck. Dr. Eric Schadt is the director of this group in Seattle, and they have been-along with a number of other groups-investigating the role that these genome-wide functions have on correlation with chronic disease. The Wellcome Trust Consortium has put together now what is called the GWAS, the genome-wide association studies. These have been published and now there are data sets looking at 14,000 people with various diseases and 3000 controls. These diseases include things like schizophrenia, diabetes, Parkinson’s disease, and heart disease. One can go in and probe or query this GWAS database to see where linkages between disease and genomic and proteomic and metabolomic structure and function might reside. Dr. Schadt and his colleagues at Rosetta say you get a signpost from DNA that says there is something there, but you need to look beyond the signpost at how these are actually expressed in the function of the individual at these levels of protein expression and ultimately the regulation of metabolism. I am quoting from a recent article that appeared in Genome Technology in May 2008.3 Out of this derives the question: what environmental factors influence the expression of genes and the epigenome? That leads us, obviously, to one fundamentally shared principle that, as far as I know, every human being that has lived more than a day has had some experience with, and that is eating (i.e. nutrition). Nutrition is an environmental factor that influences epigenomics and gene expression. That leads us into the discussion of nutrigenomics. How does this relate to applications of clinical medicine? There are many papers that are being authored on this topic. One of note was in Pharmacogenomics in 2007 by Dr. Kaput and his colleagues and was titled “Nutrigenomics: Concepts and Applications in Clinical Medicine.”4 Dr. Kaput is now at the USDA nutrigenomics lab at the University of Arkansas. The authors point out that the maintenance of health and prevention and treatment of chronic diseases are influenced by many naturally occurring substances in foods, both macro- and micronutrients, as well as phytochemicals. In addition to supplying the substrates for producing energy (that is the caloric macronutrients: protein, carbohydrate, and fat), a large number of dietary substances (small molecules) are known to be bioactive. They alter the regulation of biological processes, and either directly or indirectly, they affect the expression of genetic information, translating down through the epigenome into the regulatory regions of genes and ultimately into gene expression. Nutrients and other accessory bioactive substances in foods, therefore may produce different physiological phenotypes among individuals due to genetic variability from person to person. Because of this genetic variability, no one diet will be optimal for all people because food is really information. Food influences the regulation of complex functional integrity at the cellular level based upon the genetic uniqueness of the individual. This sounds very much like Roger Williams and Linus Pauling, going back to the 1940s. Nutrigenomic concepts, research strategies, and clinical implementation are similar to and overlap those of another field in pharmaceutical medicine called phamacogenomics, which looks at the individual way that drugs are metabolized and utilized based on their genetic difference. Both fundamental to the treatment of disease and the maintenance of optimal health, so we are seeing a revolution in thinking about how to access, implement, and harness this genomic information. Dr. Steven Zeisel, who is with the Nutrition Research Institute, Department of Nutrition, at the School of Public Health and Medicine at the University of North Carolina, has authored a paper that helps to understand how this might translate to clinical application. This paper appeared in the American Journal of Clinical Nutrition in 2007 and was titled “Nutrigenomics and Metabolomics will Change Clinical Nutrition and Public Health Practice: Insights from Studies on Dietary Requirements for Choline.”5 His group has been looking very significantly at one of the B-complex vitamins, choline (trimethylglycine), and how it influences cellular function as a co-factor or as a nutrigenomic modulator. You might recall me mentioning this study in a previous edition of Functional Medicine Update. The authors found that metabolic syndrome, or insulin resistance, in part relates to individual nutrigenomic response to the nutrient, choline. Large variations in responses occur within populations as it relates to choline, far greater, probably, than we have acknowledged through the recommended dietary intake or the previous RDA levels. This biological diversity at the genomic level is consistent with what Roger Williams talked about with his concept of genetotropic disease back in 1949 in The Lancet. It is more consistent than the way that we have defined the RDAs and RDIs for substances based upon the amount required to prevent nutritional deficiency disorders. Dietary Effects of Choline on Cell Signaling and Network Physiology It would appear that even micronutrients have small implications on cellular physiology. In specific individuals, things like dietary choline might have larger effects on modulation of cell signaling and network physiology. Recall, if you would, that choline is a methyl transfer compound, that is, the transfer of methyl groups. DNA methylation usually occurs at cytosine bases that are followed by a guanosine, the CpG islands within our DNA regulatory regions. These are islands that then can be methylated by methylating agents, and choline is one source of methyl groups. In mammals, 60 to 90 percent of these CpG islands are methylated. When this modification occurs in the gene promoter region, expression is altered. We call this gene silencing. Gene silencing puts a paperclip on those genes and downregulates their expression. Increased methylation is usually associated with gene silencing or reduced gene expression because the methylated CpG islands attract capping proteins that hinder gene expression. These methylated CpG islands that have these capping proteins then induce gene expression in a different way. As I said, DNA is wrapped in proteins that are tightly packed together and they prevent access to the promoter sequence of genes. Methylation and a companion process called acetylation, and perhaps also biotinylation, of these histone proteins can either cause them to be silenced (as with methylation) or activated (like putting sticky notes on them as in the case of acetylation), creating channels through which transcription factors can pass and activate gene promoters. Transcription factors can be things like nuclear factor kappa B, which upregulates the cassette of genes that are associated with inflammation. If you produce more access to the gene messages of inflammation, a lower signal might induce a higher inflammatory response. You might want to silence those messages by reducing NFkB signaling as a transcription factor while you are upregulating tissue repair processes and the cassette of genes that are related to those effects. These are found to be, in part, related to nutritional status because epigenomics of methylation is tied to the availability of active methyl groups through S-adenosylmethionine, of which a precursor (or methyl contributor), is choline. So by silencing specific labile genes (or promoter regions of genes) that are associated with the expression of dysfunction, you can then silence those genes by improved methylation pattern. This is nutrition in the genomics era, and we can tie that together with things that relate to the benefit of specific diets. Why do certain historical diets seem to be associated with improved health and health outcomes? Dr. Jose Ordovas and his colleagues at the Tufts University Medical School Department of Nutrition and the Human Nutrition Center on Aging have been looking at this for some time and published an article in Molecular Nutrition and Food Research in 2007.6 In this article, they talk about how this epigenomic modulation by diet can influence cell signaling associated with insulin sensitivity and inflammation. This may account for why the Mediterranean diet, with its complex array of phytochemicals that help to modulate gene expression patterns by epigenomic patterning, can induce or produce a better clinical outcome relative to insulin stability. I think what we are starting to recognize is that diet is much more than just the prevention of deficiency disease. Diet is also functionally contributing specific markers for expression of messages that regulate the phenotype through the genome. Can you do preemptive nutrition of a proinflammatory state by using this information? That is what Dr. Philip Gillies talks about in a paper in Nutrition Reviews in 2007. –He says that nutrigenomics can provide nutrition sciences with a molecular basis for positioning nutritional bioactives, (functional foods, medical foods, and designer diets) to preemptively offset chronic disease.7 This preemptive model of nutrition consists of multiple interdependent parts, not a single pathway, but rather a web-like network that can be simplified into principal component axes. The axes that are most important-what I often call metabolic acupunctures points-are the nodes of the network. Placing a small amount of nutritional input at these nodes can have a large effect on function and can regulate the expression of cassettes of genes in such a way as to prevent states of dysfunction that we associate with chronic disease. As an example, omega-3 fatty acids are known to be epigenetic and nutrigenomic modulators that influence gene expression and functions at the protein level that are associated with inflammation and insulin resistance. Increasing, then, your omega-3 fatty acids downregulate the expression of those processes and upregulates signaling associated with proper insulin management. This leads us to the view that genes are not our destiny. What we need to look at is incorporating molecular medicine into clinical practice so we can modulate expression of genes in such a way as to produce the most important positive outcome. In all of our books of life-encyclopedias that regulate our expression-are found stories of Greek tragedy. Some people may have more of those embedded in their book of life than others, but all of us have them somewhere-an oncogene, or a series of genes that encode under certain environmental exposures to increase relative risk to a certain warp of the network of physiology that we associate with a disease. The question is how to silence those messages while upregulating and normalizing the function of the stories in our book of life that are related to expression of good health. In terms of how you manipulate these functions, the disease state often requires a pretty hard-hitting intervention. In the subchronic state, (well before you get to extreme histopathology of the disease), it may be a much more mild effect that is required in order to modulate these functional states at the epigenomic and genomic level. When we take a global snapshot of health care, the numbers of chronically ill people are escalating. We don’t have enough medical personnel and hospital facilities to handle all these people when they get to the stage of being in an acute disease state and people are receiving inadequate medical intervention. How do we manage that on the other side (not on demand, but on supply side)? Demand is once a person is sick. Supply is preventing the number of people who are going to need services. Medical practice patterns that are designed to provide quick and effective amelioration of signs and symptoms are frequently not an enduring solution to many health afflictions in the chronic disease state. The drugs that we employ in a chronic disease management program are often those that block certain signaling processes related to signs and symptoms, but don’t correct the underlying problem that relates to the ultimate histopathology. Unfolding evidence appears to support a genetic predisposition model for health and illness rather than this fatalistic predestination construct. These concepts of susceptibility are modifiable through epigenetic and environmental factors that have enormous potential to influence clinical outcomes. By understanding and applying fundamental clinical principles related to these emerging fields of molecular medicine, nutrigenomics, and the exposure to environmental factors, physicians of the future are going to be empowered to address causality of affliction and achieve sustained reduction in the incidence of more severe chronic disease. At this point, I am paraphrasing a wonderful article that is titled “Our Genes are Not our Destiny: Incorporating Molecular Medicine into Clinical Practice” by Steven Genuis, which was published in the Journal of Evaluation in Clinical Practice.8 We can nutritionally and environmentally modulate the disorders of aging by focusing our attention on genomic stability and epigenetic signaling. John Mathers, from the Human Nutrition Research Center at the School of Clinical Medical Sciences, University of Newcastle in Australia authored a nice article on this topic in the journal Mechanisms of Aging and Development in which he pointed out that dietary factors have a profound effect on many aspects of health, including aging.9 And now we start to recognize that the way they do this-I’m talking about biological aging now-is partly through interactions with the genome, which result in altered gene expression. Damage to genomic integrity that we call genomic instability is associated with virtually every disorder of aging, and nutrition plays a role in maintenance of genomic stability. As advances in the application of high-throughput genomic technologies in nutritional research evolve (the so-called nutrigenomic revolution), we are starting to witness a new approach to understanding the molecular mechanisms by which nutrition affects aging, well beyond what most of us learned in school (about the prevention of scurvy, beriberi, pellagra, xerophthalmia, and rickets). We are starting to see that epigenetic-modulated changes in gene expression are also extraordinarily important and occur throughout the lifespan. These changes may be more profound when occurring in the first phases of conception in utero, but actually can occur by altered methylation, phosphorylation, acetylation, and ubiquination pathways or processes throughout our whole life. What we have also learned is that our germ cells can be imprinted with our epigenomic tagging, or these methyl groups, or these acetyl groups. And those particular patterns, which may have been a result of what the individual was exposed to in their life, can then be passed on, in their germ cells, to their progeny, which means that you can have a very quick change in the phenotype of a population if you had a population change in their epigenome as a consequence of altered environment. This could be starvation. This could be hypernutrition. This could be environmental toxicity or radiation exposure. All of these can modulate and modify the epigenome in such a way as to set up an inheritance of that without even changing the code in your book of life. Now I recognize that this sounds Lysenko-like (like we are talking about adaptation). In the 21st century Lysenko doesn’t look quite as strange as he did in the 20th century, based upon the evolving understanding of the epigenome and how the environment can influence it. We are starting to recognize this might better explain how societal drift can occur in certain diseases very rapidly, like the question that has been asked so many times: why are we seeing such a rapid increase in autistic spectrum disorders in our population? Is it only as a consequence of better diagnosis? Or is it a consequence of some epigenomic changes that are occurring that regulate (in the developing nervous system of the child) different expression patterns into their phenotype? These are very powerful questions that bring us back to looking, hard, at the variables that can influence epigenomic structure and function and how it then can pass on those traits through hereditability-into progeny, generations, and influence their function and ultimately public health-type drift. To examine this construct of genomic uniqueness as encoded through single-nucleotide polymorphisms and how that interfaces with epigenomics and ultimately a chronic disease, there may be no better clinical example than the concept of the methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and their relationship to folic acid need and how that maps against homocysteine and ultimately into clinical incidence of atherosclerosis. As it emerges, the story appears to be more complicated than we previously thought because this homocysteine construct doesn’t appear to work unto itself in isolation as a single-point gene risk factor. Rather, it inter-relates with other genes in this cassette of genes that regulate a variety of functions, including apo E genes, cholesterol-ester transport genes, and fibrinogen genes. When you put all those together as a family of genes and look at polymorphisms within them and how folate needs related to MTHFR polymorphisms connect with fibrinogen polymorphisms, CEPT polymorphisms, and low HDL and apo E levels. What you find is that that clusters of genes, not single genes, are found to correlate with carotid intima media thickness (or CIMT) in healthy men. Individuals who have certain polymorphisms are at high risk to atherosclerotic disease as a consequence of shift in their web of physiology that makes them have a higher need for things like folate, exercise, and factors that might increase their HDL. It is a complex array, rather than single genes, that controls regulated function. We are talking about programs rather than drugs because single molecules will probably not do the trick. Folate is a single molecule. It can have an impact by itself, but it has a greater impact when it is embedded in a program that sets a net over this whole system that improves functional expression. I am now quoting from a paper in Clinical Genetics in 2001 that talks about this connection among different genetic propensities and ultimately the expression of carotid intima media thickness and risk to heart disease.10 The complex story of epigenomics and the relationship with methylation patterns and how that ties with the folate cycle and how that ties with methylenetetrahydrofolate reductase polymorphisms can weave itself right down into transgenerational amplification of various factors (where diets and lifestyles have been changing so rapidly as to alter the function of these particular expression patterns). Let’s say a diet that suddenly alters folate concentration or leads to an imbalance in nutrients that are required to modulate these processes can change methylation patterns of your epigenome. That changes the expression of cassettes of genes downstream, and now you get increased prevalence of certain disorders, like insulin resistance, metabolic syndrome, and cardiometabolic syndrome. Let’s look at obesity. Some think of obesity as being solely a consequence of too many calories. Recognized in developed nations for a decade, the obesity epidemic has become a worldwide phenomenon, and seems to influence all age groups, including women of child-bearing age. This has fueled concern that maybe-beyond the luxurious nature of calories-there is something that inter-relates dietary drifts with nutrigenomics. In a study using Agouti mice (which are mice that are genetically at risk to obesity and diabetes) the hypothesis that maternal obesity induces trangenerational amplification of obesity was tested. They took these animals that were genetically inbred to be obese, and they started changing the methylation patterns in their genome by supplementing them with folate and B-12, which increased methylation of their genome. What the researchers found is that the methyl donor supplementation prevented transgenerational amplification of obesity in these animals that were genetically at risk to obesity and diabetes. This is a pretty remarkable suggestion: certainly excessive calories do play an important role in contributing to the pandemic of obesity, but it may also be other shifts in our physiology as a consequence of epigenomic changes amplify susceptibility to obesity and make it more of a clinical risk factor. I am now quoting from a recent paper in the International Journal of Obesity in 2008, which I think is very, very fascinating.11 I want to emphasize again that this was an animal study (Agouti mice), but the finding was that by modulating their folate and methylation intake one can alter the transgenerational transfer of the risk to obesity. Imprinted and more equal. The imprinting of genes (silencing certain characteristics in the epigenome and amplifying other characteristics) has become a major theme in our understanding of how the genomic message is ultimately expressed. A paper in the American Scientist by Randy Jirtle and his colleague, Jennifer Weidman, talks beautifully about why perfectly good copies of important genes are silenced and what impact this has on the phenotype.12 Even more recently, Dr. Jirtle wrote a paper that appeared in Genome Research.13 This paper was on experimental identification of novel human imprinted genes and showed that some genes were much more susceptible to methylation and demethylation (putting methyl groups on and off) than other genes. These more labile genes are those related to control and regulation of environmental effects on the phenotype of the organism. Not all genes are equally influenced. This all leads us to environmental epigenomics and disease susceptibility. A very good collaborative paper by Randy Jirtle and Michael Skinner at Washington State University appeared in Nature Reviews and Genetics in 2007.14 In this paper, they showed that environmental toxicants at high levels can induce epigenomic changes that can then be passed on as heritable factors to the subsequent generations in animals, increasing disease susceptibility. If you think of our environment and what influence it is having on our health, this might play a role. Lastly, I want to mention a paper in Proceedings of the National Academy of Sciences by Dr. Jirtle and his colleagues, Dale Wang and Dana Dolinoy on supplementing pregnant animals with folate and B12 and looking at what it does to counteract the bisphenol A (BPA)-induced DNA hypomethylation associated with cancer in early development. 15 The results suggest you might be able to “neutralize” some of the relative risk to environmental chemicals by proper epigenomic tagging through nutrition. This is a revolution that we are going through-a revolution in thinking. The textbooks we have been learning from are incomplete and actually incorrect, relative to the new biology. You are going to hear from one of the world’s leaders about where we are going, Dr. Randy Jirtle.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Randy Jirtle, PhD Department of Radiation Oncology Duke University Medical Center Durham, NC 27710 jirtle@radonc.duke.edu Here we are, once again, at that portion of Functional Medicine Update that we all look forward to each month. You never know exactly what new revelation you’re going to have. We’ve had the opportunity to speak to people who are making the new medicine and the new biology a reality before our eyes. This month we are so privileged to have another member in that lineage. I think he will open the door for many of us as it relates to this discovery that looks at genetics from a perspective that is post-Mendelian and moves us away from genetic determinism into this, I guess you would call it, pluripotentiality in which the genes and the environment are speaking together to give rise to the outcome that we call our phenotype. Who better to introduce that topic to us than the person whose work has really brought this whole field to life, and that is Dr. Randy Jirtle from Duke University. As a professor of radiation oncology, you might think his focus would be strictly on cancer and how radiation influences oncogenesis and metastasis, and certainly that is part of his work. But beyond that was this extraordinary discovery that started us down another path, to some extent, and that is the work with the Agouti mouse that has received so much attention. His group supplemented pregnant Agouti mice, which we all know to be white fat mice, that we have all-in the field of obesity or in diabetes research-used at one time or another. These mice are predisposed to have hyperphasia and to get fat, diabetic, and have cancer and heart disease. When they supplemented these mice with folate and vitamin B12 at higher doses they found the offspring were animals that were a different color. So without changing the genes, they changed the expression of the genes to be a brown mottled color, and probably most interesting, they did not get obese and they did not get diabetes. This kind of shook the whole traditional hallowed halls of inbred animals and genetic determinism and raised some very, very remarkable questions, questions that are above genes (“epi” being the prefix and meaning “above”)-epigenetic questions. Dr. Jirtle’s work with his group has started to pave the way for us to understand something that has been probably understood at a “rules of reasonableness” level, but not at a molecular biology or molecular genetics level until the birthing of this field. Dr. Jirtle, such a privilege to have you on Functional Medicine Update. Help us understand how you came about doing the experiment with the Agouti mouse. Were you surprised at the outcome? The Phenomenon of Genomic Imprinting RJ: We got into this because I was really interested in the phenomenon of genomic imprinting, which is another class of genes (maybe we’ll have some time to talk about later on) that are regulated epigenetically. But there weren’t good ways to study the effects of environment and nutrition on that class of genes. This mouse model system was available and it had already been shown that nutritional supplements could change the phenotypes, or the colors, of these animals. What had not been shown, though, before our study in 2003 (this is work that was done by Robert Waterland when he was post-doc in the laboratory–he’s now down at Baylor), was what was the mechanism by which this occurred? What he showed very clearly is that the color of the animals was changed completely because of degree of methylation and the little bit of DNA that is upstream of the Agouti gene, which is a transposable element, a retrovirus that jumped into that position in this one specific strand of mice. In the animals that were brown, methyl donor supplementation dramatically increased the methylation at that level, and basically the Agouti gene went back to being regulated normally. The animals were brown and no longer became obese, nor did they get diabetes or cancer. We knew before that there was this connection between what an offspring is exposed to, very early in utero or during pregnancy, and adult disease susceptibility. What this experiment really did was demonstrate what was the memory, or the glue, or the gravity that held those two different time points together and it is basically epigenetic changes. JB: So for those who may not be quite as familiar with the terms epigenomics or epigenetics as others, can you kind of give us a quick summary/primer course on this concept of promoter regions of genes and histone proteins and the genome and how it gets signaled to be expressed? RJ: First of all, I like to use analogies because it is easier for me to understand. I really think of the genome as being comparable to the hardware of a computer. I think of the epigenome (which, as you said, means above the genome) as being comparable to the software that tells the computer when, where, and how to work. So epigenetic changes are basically changes that can be inherited during cell division that alter the function of these genes without changing the hardware, or the DNA sequences. So we are talking, really, about software programming of the genome. And there are two major, sort of, epigenetic-type phenomena that control expression of genes. There is obviously transcription factors that bind to promoter regions, which are the bits of DNA that are just upstream of the genes and telling the genes when, where, and how to work. But on top of that, also, is sort of a memory system that, in effect, either allows a gene to be functional and regulated, or to totally be non-functional. Those phenomena are DNA methylation and histone marks, or histone codes, that when they are, let’s say, methylated, for example, at the DNA, usually that means that the chromatin is condensed down. So, the transcription factors are the little fingers that go into those grooves of the DNA, and the gene is, in effect, turned off. Rationalizing the Work of Mendel JB: So, when we look at this concept that comes from Mendel, the dominant and recessive patterns of inheritance, which all of us kind of got exposed to probably early in grade school-that we had to reproduce pedigrees and look at various ways that dominance would kind of proceed over that of recessive traits-how do we rationalize these two things together? It seems like it almost throws into controversy the construct back to Lysenkoism? RJ: It only does if there is some ability for these marks to be transferred from generation to generation. When I said heritable, what I meant was heritable during cell division. But there is also evidence that these epigenetic marks are not always completely reset. I like to think of this like when I was a kid and played with these little etch-a-sketches. They were the plastic that went over the wax and you’d write on them and then you’d flip them up and all the marks are erased and you can start all over again. That is what happens in most situations, but occasionally at some locations that doesn’t happen. So in effect, what you now have is a legacy from the previous generation, and that legacy has now been created by the environment. So there is the possibility at certain genetic locations of being able to transfer this epigenetic information from generation to generation. If you are not continuously exposed to this, this should probably start dying out and being erased completely, but it is a way in which you can pass information to another generation about the environment that your parents and grandparents were exposed to. It is an adaptive mechanism. JB: It sounds like, in terms of timeline, that this adaptation can occur very rapidly in contrast to natural selection by mutation, which we think of as smoothing over millions of years. RJ: Right. There is a time compression component, which is something that would be very important because, for example, if you are in the middle of a famine it would be advantageous to be able to store energy more readily, and probably to be of smaller stature. We always focus on the negative aspects of this-in other words, disease susceptibility-but you wouldn’t have these types of problems (i.e. diseases) if, for example, probably you didn’t have a mismatch between the environment that you perceive you are going to be in versus what you find yourself in. This generation, now, or in the last couple of generations, might have been some of the only time in the history of humans where you can get a lot of calories, basically, in your diet, without expending virtually any energy. You can see that if you’d been in centuries and centuries of, say, very low nutritional status, that all of a sudden now you can get a lot of energy where a person could, if they were very efficient in storing energy, etc., you could become obese. JB: Like Neel’s “thrifty gene” concept, and like the Pima Indians that may have genetic selection for being more thrifty and therefore they are the yellow canaries? RJ: Correct. This adaptive system, now, can also be pushed too far. So if you are exposed to environmental toxicants, for example, that we maybe never were ever exposed to, you can see now you also have a system that you can push too far, to the point where it literally almost becomes broken. So it is not always just the mismatch that is the problem, sometimes you can really push it too far and create problems by the environment that you are being exposed to. Epigenomics and Disease Susceptibility JB: I think that review that you and Michael Skinner at Washington State University recently co-authored in Nature Genetics is absolutely spectacular, titled “Environmental Epigenomics and Disease Susceptibility,” because it certainly raises the question-well it actually comes from some work that you published previously in PNAS that was related to bisphenol A, which seems to be in the news recently, and DNA hypomethylation- how an environmental toxicant can influence methylation patterns and epigenetics? Maybe you could help us understand how this environmental connection fits into this whole scheme of changing disease patterns? Work with Agouti Mice and Bisphenol A RJ: Yes. Now you have a system that is adaptive and involves epigenetic changes in programming. This is work done by Dana Dolinoy, who is now going up to the University of Michigan and starting her own laboratory. These are really (I think) some very interesting experiments because she came from a toxicological background. She was interested in these compounds that are referred to as endocrine disruptors, so they are estrogenic compounds and they mimic estrogens. They are also referred to, sometimes, as non-genotoxic carcinogens. In other words, they don’t cause mutations, but yet in some animal models you get cancer formed from these compounds, and in this situation I think there is even evidence that you can get transmission of that from generation to generation. If you think of the Agouti mouse model that we use, it is almost the biosensor for determining whether environmental compounds are capable of altering the epigenome and whether they primarily cause decreased methylation or increased methylation. So when we use the methyl donors-from food, basically (food supplementation)-we found increased methylation and we shifted the distribution of the offspring’s coat color, let’s say, to brown. Normally, it sort of sits right in the middle, more sort of right at the Agouti (mottled-type animals are the most prevalent). So then we asked the question whether or not something like bisphenol A, which is a relatively strong estrogenic compound, can alter the epigenome, and Dana clearly showed that it caused hypomethylation. So now in this strain of animals, those animals become obese and would have a higher probability of developing diabetes and cancer in the future. So again, this is the first time when an environmental toxicant, or non-genotoxic agent has been looked at for its ability to alter the epigenome, and in this situation (in this mouse strain) we found that it caused hypomethylation, which is deleterious. JB: As I recall, in that work, in at least one of the papers that Dana Dolinoy and your group published, you also found that nutrient supplementation of the mother helped to counteract the bisphenol A-induced hypomethylation. Do I recall correctly? RJ: Yes, it almost gives you goosebumps, doesn’t it? JB: It does. RJ: I mean people have already said-a long, long, long time ago-that food is medicine. So what we did is-again, it sounds simple-we looked at the distributions of coat colors of animals’ offspring that were exposed, for example, to methyl donor supplements, or genistein, which is a weak phytoestrogen, a compound which we also demonstrated increased methylation. It has to do it through a different mechanism than, let’s say, folic acid because just genistein does not have a methyl group on in so it cannot donate methyl groups, but it is somehow enhancing the probability that those regions will be methylated. And so then we asked the very simple question: if the mother is exposed to a toxicant like bisphenol A in their diet, can you alter the effect of bisphenol A on the epigenome by supplementing the mother’s diet with either methyl donors like folic acid, choline, betaine, or vitamin B12, or genistein? What we showed is that indeed, with these concentrations, we could completely block the negative effect of bisphenol A on the epigenome in the offspring. JB: That is goosebumps. Quite honestly, it is like moving up to another platform for future studies, isn’t it? I recall, many years ago, Bruce Ames had a cover article in Science magazine that was titled “Dietary Carcinogens and Anticarcinogens,” where he was talking about the fact that there are substances within foods that can cause cancer, like aflatoxins, and then there are those substances in foods that may prevent cancer. This is prior to the epigenome discoveries that you’ve made, so it may help explain some of these anticarcinogen properties from a mechanistic level. RJ: I think it can, but I want to make a point real clear, here. I mean with the levels that we were using we were able to negate, in effect, the negative effects of bisphenol A. That doesn’t mean that all levels that people potentially are exposed to (to environmental toxicants and pollutants) could be counteracted by supplements in our diet because it could be very possible that you could totally overwhelm the system, also. But at the levels we were looking at, we were able to block completely the negative effect. JB: I want to go back, if I could, just for a second. You alluded to the fact earlier that methylation is one of these important processes to silence gene expression in certain loci within the genome and it has to do with methylation of these CpG islands and the promoter regions of genes, but you also said there are other mechanisms (phosphorylation is one) that presumably come through kinase activities, and now we recognize that kinases are regulated in part by the presence of various phytochemicals in the diet. So it sounds like we have a very complex network of potential interacting variables that regulate the epigenome’s kind of control mechanisms. RJ: Yes, that’s true. As I said, the histone code is much, much more complicated than DNA methylation and we primarily study DNA methylation because, in general, they tend to go hand and hand. If you have negative marks, in effect, on the histones (like deacetylation and that kind of thing, where you would have condensation of the chromatin), you usually have also hypermethylation. But it is very, very complex, and the two are working hand in hand. Right now, as I said, people are working and whole labs are working in one group (like histones, basically) and other groups of people tend to be working more with DNA methylation. Our lab tends to work more with DNA methylation because frankly it is a little bit easier to work with because you are still working with DNA. JB: So if we were to address the question that people have raised, which I think is a question, probably, without a complete answer at this point: if undermethylation is undesirable (and that means that you are not getting proper nutrition of these folate-cycle-supportive nutrients that regulate S-adenosylmethionine production) then what about too much B12 and folate and hypermethylation? Where are we on that and how does that relate to the homocysteine story? I’m sure all of this has come up in your discussions? RJ: Again, I’m not too much of a biochemist. I always work in analogies. I always use the analogy that a glass of wine might be good for your cardiovascular system, but a gallon a day sure isn’t. I think what you are talking about is that everything-the effects of compounds, even like folic acid-are going to be dependent upon the dose that you are exposed to per day, and potentially also even genetic mutations in ability to, in effect, metabolize these compounds. Some people might be more sensitive than others to the beneficial or negative effects of folic acid. I don’t think this story is done yet. I think everything is like this. If you get too much of something, it is not necessarily good. I always warn people, when I talk to reporters, and make it very clear, because in this country people tend to think if a little is good, a lot is really great. In this situation, we don’t know. We do know, for example, that as you get older your epigenome tends to become less stable so it might be advantageous, for example, to have higher levels of folic acid, etc., that would stabilize your epigenome. But we also know that cancer cells, for example, often the promoter regions of tumor suppressor genes are hypermethylated. So it is possible that having too high of doses could actually cause the formation of tumors. These issues just have not been worked out yet. JB: So when we look at the number of genes-let’s say, approximately, 25,000 genes in the human genome that are coding regions for proteins-how many of these genes are under the regulation of promoters that are controlled, in part, by methylation? Do we have any idea? RJ: I don’t personally have any idea. Any gene that is involved, potentially, in differentiation, the promoter regions will have been methylated very early. That is why, for example, a liver cell and a skin cell are going to have a different repertoire of genes that are functional. You have your housekeeping genes that tend to be functional probably in every cell, but then you are going to have specific genes that are involved in making a liver cell a liver cell, and a skin cell a skin cell. Those genes that are involved in that definitely will be methylated, probably in the promoter regions, to turn them off. That is why you can take a liver cell, for example, out of an animal and put it in a Petri dish and it still looks like a liver cell and works pretty much like a liver cell. It’s a memory system, basically. JB: You have raised a very interesting question, obviously, because if there are those imprints with methyl groups that are very tight and not likely to give up their legacy, then there may-by your suggestion-be some methylated regions that are more, maybe, labile to demethylation that can be put on and taken off. It would seem like both of those things are occurring within cells, some more labile than others. RJ: Right. And there are going to be other genes-I think of them as more equal than others-and, as I said, the group of genes that I am particularly interested in and our lab is working on very, very diligently right now are the genes that are called imprinted. The reason why this is also very, very important–and a point that we really haven’t made yet–is that the epigenome varies greatly between species. When we first started out the conversation we were talking about this viable yellow Agouti mouse, where you can switch from yellow to brown and even have calico-cat-looking mice that are in between. There are other strains from a C57 background (which is a strain of mice) that don’t have this transposable element. Upstream of the Agouti gene you are never going get these phenotypic changes in response, to, for example, methyl donor supplementation. So the point I am making here is that it is going to be very difficult, or more difficult, to extrapolate between species concerning the effects of environmental conditions on the epigenome concerning the role of how they affect phenotype between, let’s say, mouse and humans. Because the epigenome is different. As I always say, if we had the same epigenome as a mouse we would have a long tail and a snout and we don’t, right? JB: That’s right. RJ: They are very different. So the targets, the epigenetically labile targets, will potentially vary-not always-greatly between species, which makes it very, very important that we determine what are the epigenetic, or labile genes, within humans. JB: That’s a really fascinating idea. So, if we went to Indian corn as a analogy here, which has a lot of transposons, would you expect, then, the coloration from ear to ear of Indian corn to be highly variable related to the environment of that germinating ear of corn? RJ: Compared to… JB: To regular cultivars of corn, because you are linking the transposons to these more imprintable genome characteristics. RJ: Correct. Yes. The phenotype would be different because the transposable elements don’t even have to be in the same locations in different strains of corn, I would think. JB: That’s very, very interesting. Yes. Absolutely. RJ: I mean, that transposable element is upstream of the Agouti gene in the viable yellow mouse, but it is not upstream of the Agouti gene in a C57 mouse. And with imprinting, we know this now and there is good experimental work now with predicting the genes that have high probability of being imprinting in mouse and human, for example. We predict that about 600 or so in mouse and about 156 in humans, but what is even more important is the overlap is only 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, so the repertoires are very different. How is Dominance Determined? JB: If I could just take one step from this discussion to the question which has been on the mind of every kind of amateur geneticist: if we are diploid beings, getting one set of characteristics from our biological mother and another strand from our biological father, then who wins the battle to get expressed? We have always kind of thought of this kind of simplistically as “the stronger wins,” so whatever parent brought the characteristic that was dominant to the other wins, but this imprinting characteristics suggests that maybe there are other variables going on as to which strand of our DNA wins. RJ: Yes, I mean, let’s say, if you even went to the Agouti mouse kind of thing with transposable elements…in our system, we only have that transposable element and it is the copy that is inherited through the father; the mother’s does not have it. But if you had it on both copies, both chromosomes, you could have both copies turned off, one copy turned off, or none of them turned off. There is a lot of variability, here, in expression, just with that type of system. Now with imprinting it is even crazier because the turning off of a copy is dependent completely upon which parent you inherit it from. IGF2 is expressed only from the father’s copy, so always the mother’s copy of IGF2 is turned off. JB: That’s very interesting. RJ: So it is monoalleic expression in a parent-of-origin-dependent manner. So imprinted genes actually have a sex. Don’t you love it? JB: Absolutely. I would just like to ask you the obvious. What does this do to generations of geneticists as it relates to what we answered on test questions to get good grades? It sounds like there is a lot of stuff we have to correct here in terms of the way we look at genetics. RJ: Most genetics that we learned is correct, but there are some interesting things going on that don’t obey the standard Mendelian inheritance. Imprinting is one of them because, think about this, how do you-generation after generation-only have the mother’s copy turned off for IGF2 and another gene like (at least, in mice) IFG2 receptor, which is a degradation pathway for IGF2, only the mother’s copy is always expressed and the father’s copy is turned off. The inheritance of that is very, very different. In effect, what happens is the expression of the gene in this generation depends upon the environment that the gene found itself in the previous generation, either in a male or in a female. It is sort of Lamarckian, from that standpoint. The environment is very, very important in determining whether the gene is going to be expressed-totally dependent, in this case. JB: In your eloquent presentation that you provided in Ghost in Your Genes for the Nova program, at the close of that program-and, in fact, it is in one of your articles, as well-you have an advocacy, which is kind of maybe the consumer takeaway from all of the extraordinary, exciting scientific discovery work. And that advocacy is a little bit about how we see ourselves in the sea of our environment, both from emotion, chemical, air, water, food-all these various factors. Could you share that view with us? Different Definitions of “Environment” RJ: I’m not sure exactly what you are referring to. Are you saying about the time that I said everybody has a different definition of environment? JB: Yes, and that we have a responsibility, which I thought was a very interesting context. RJ: It’s true. I mean, we all have (particularly at universities where groups sometimes don’t seem to get along very much…)…you know, if you go to a nutritionist, their definition of environment is basically, you know, the food pyramid. If you go to a toxicologist, it is a super fund site. If you go to…I can’t remember what other one I used, even… JB: The psychologist, with stress? RJ: That’s right, because if you go to a psychologist it is the nurturing environment, and we now have examples, from all of these groups, of people who are doing these types of studies on epigenetics, that these environments are all impacting on the genome and the expression of genes through programming of the epigenome. If you think about the genome as being like the basis of the DNA, as I said, and you have a mutation in that gene, it is very deterministic in that when you have a mutation it is very hard to change that mutation back to normal. The problem is that people-all of us-I think we don’t like thinking about having things that determine what is going to happen to us. But with mutations, it tends to be very deterministic. With the epigenome, however, you can vary the programming somewhat by the environment that you create or that is created around you. The problem and the downside of an epigenome of basically someone having free will is there is also responsibility, and I don’t know if people particularly like that part of it. They like the fact that they are not determined, but I am not sure they like the part that there is some responsibility to make sure that your environment is…you know, that you don’t do things that potentially harm you or potentially generations of children after you. JB: So when we look at the body of data that has been collected to date related to methylation and we talk about factors that are related to the imprinting by methyl groups, and then factors that take methyl groups off, is there any sense as to whether it is easier at some of these more labile loci to put the methyls on or take them off or we are not sure yet about the kinetics of this process? RJ: We are not totally sure. The putting on of methyl groups is reasonably well established through the DNA methyl transferases with the de novo methyl transferases and the ones that maintain it once the marks have been placed, but the removal of methyl groups and how that is done is not totally clear yet. There is some controversy about how this is done. But it is clear that these methyl groups have to be removed because with Moshe Szyf and Michael Meaney’s work with licking rats, those areas originally methylated and the nurturing (the licking) of the mother results in the removal of methyl groups and that is a covalent bond that has to be broken and those methyl groups are gone and they are removed in specific areas that allow transcription factors, in this case, that bind upstream of the glucocorticoid receptor. And you have a completely different behavior now. JB: As I recall, that work at McGill showed the nurturing led to an imprinting so that the offspring, whether they were born to high-stress mothers or not, when they were with mothers that nurtured them by licking and grooming, they ended up being lower stress animals as they grew up. RJ: That’s correct. And if you didn’t know that the nurturing was doing this you would just assume that this was something that was being passed through the gametes (the egg or the sperm), right, inherited? But in this case it is not inherited like that, it is the nurturing behavior that is setting these marks, and then they are passed on to the next generation, depending upon what the mother was like. It is pretty amazing stuff. JB: I would say it is a fundamental shift in our paradigm that has such dramatic, below-the-water line implications for social design…I mean, for everything–our environment, nutrition, how we talk to one another, how we see ourselves. It seems like these things that we have maybe thought were inconsequential and they could just come and pass in the night could have lasting effects, so it is this whole concept of the selfish gene and what we are imprinting on the selfish gene…seems like it may make less selfish. RJ: It is modifying its selfishness, to a degree. It is going to have-I hate to say it-legal ramifications, too, I think. JB: I would imagine so. As a scientist, I know it’s not fair to put you on the spot, to look forward and kind of forecast out where this might go, but, you know we are talking to clinicians, principally, people who are seeing patients everyday and helping them make intelligent decisions about their lives. What would you say, at this point, is a responsible takeaway from all of this extraordinary work? RJ: You mean how clinicians will be treating diseases? JB: And how clinicians might language this to their patients in terms of people who have chronic lifestyle-related diseases. RJ: You mean changing their behavior, essentially? JB: Right, exactly. RJ: What is going to have to happen, I think, in order for people to, in a way, to sort of believe that this actually can occur, is it has to be situations where, for example, you have real problems that you can identify, that can be potentially reversed through psychotherapy, nurturing, that type of thing, and then have a readout of the epigenome where you show that you have actually changed the programming of genes, let’s say stress receptors or something like this. Why are the Agouti mice so important? They are the poster children for the importance of epigenetics because you can see it. And I think that is going to have to happen before people are going to be willing to change their behaviors-that you can show that this is what is going on, not only do you feel better, but you have made a permanent change in your programming. Not everybody is going to be impressed with this, but I think it is going to be impressive to a lot of people. I don’t think that is that far away, frankly. These types of studies are going to be done. And the other thing that is already being done is the use of what they call epigenetic therapy for the treatment of cancer. It is possible that some of those same things (or comparable things) will be used in the future, for example, to treat neurological disorders, which at this point is not really thought of much, but I think in the future this could be the case. We might be able to reprogram with the use of compounds that alter the epigenome. Future Research into the Epigenome JB: Unbelievably exciting. So in the call-to-action at the end of the Nova program there is the quest for deciphering the epigenome, but of course, as we know, this is complexity upon complexity, each cell being different, with regard to its epigenetic pattern. Where will we be, do you think, in the years to come with regard to taking bites of this apple of understanding the epigenome? RJ: Well, I mean, as you said, the epigenome is going to vary in time, and it is going to vary between different cell types because that is why there are different cell types, and it is obviously going to vary between species greatly, too, as we talked about before. So it is a massive undertaking, but I think we have got to start, basically, defining what those epigenomes are, and that is being done right now because there is a roadmap initiative from NIH to, in effect, do that. That is literally just starting right now. I think the first grant applications were submitted maybe about six months ago and I would imagine a half a year or so from now you will have the first laboratories that are going to be funded to, in effect, map out, beginning maybe with stem cells and going up through differentiation the various epigenomes. And those will be used as templates that other types of information can then be layered on top. In the next-I’m only guessing-few years, five years, whatever, there is going to be a lot more of this information available, and at that time, then, we should be able to start determining what is going one when a person has got, let’s say, schizophrenia or autism. Are there any of these regions that we now have defined that are specifically altered in the formation of those neurological disorders? I think that is going to be of great importance because you are not going to be treating it from an epigenetic standpoint until you know those diseases and disorders, for example, are, in part, caused by deprogramming of the epigenome. That is going to happen after we learn what the baseline is and we add additional information to it. That is what I see happening. JB: Well that’s an incredibly exciting frontier. I’d like to ask you one last quick question in the couple of minutes we have left. Probably this is a different kind of question than you have had with other interviews. This discovery you have made, in your group, clearly is one of those paradigm-shifting discoveries and it opens up the field in ways that maybe we didn’t recognize would happen until the discovery. How is it changing your life? What is the nature of how you see your work and your presence and your advocacy changing as a consequence of this extraordinary discovery? RJ: Well one thing it does is it makes it more complicated-which is nice-because you are asked to talk to a lot of different groups. I think a lot of the people who are working in the beginnings of this field of epigentics are basically out talking to people and telling them how important the whole field is-so you are busier, from that standpoint. And I have to admit-it sounds terrible-but I had foot surgery done in January, and as a consequence I really couldn’t travel, but just even having three or four months of not traveling has been very, very nice. So it has become more complicated from the standpoint of traveling and talking. I got into the field of epigenetics back in the early 90s because we identifiee IGF2 receptor as being a tumor suppressor gene. And right at that same time, Denise Barlow identified that exact gene as being imprinted. I had no clue what this was about. And when I read about it and realized what was going on, that one copy was always (in this case, one from the father) turned off and it was done epigenetically, I said to the people in the lab, and this was in the early 90s, “Within three years our whole laboratory will be in the field of epigenetics and genomic imprinting.” And that is what we have done with the ultimate thought of being able to define those genes in humans that are imprinted and potentially epigentically labile because if you only have one copy working, a single mutation, or a single epigenetic mutation, can actually totally alter the function of the gene. And from that standpoint, I really haven’t veered from that goal, and we are very, very close now, I think, to pulling that off and determining that subset of genes in humans that are imprinted, and as a consequence, are potentially targets for environmental nurturing, whatever-deregulation or regulation-by the environment. And as I said, when you can’t extrapolate readily from mice, for example, to humans, I think much of our research along these lines is going to have to migrate into humans. As I keep saying over and over and over, a mouse is not a human. And that is particularly true when you are talking about the epigenome. JB: Well I want to personally thank you on behalf of everyone that has had the pleasure of listening to this interview and all of your work, which is shift-shaping work. Thank you for your diligence. Thanks for you eloquence. And also thanks for your extraordinary commitment to the publications which keep coming out to help all of us who are novitiates in this field to be better educated. We really appreciate the work you are doing and what a marvelous contribution you are making. RJ: Well I very much appreciate you for inviting me to discuss our work because it is through very scholarly things like you produce that people understand better why this field is so important to human health and disease. JB: Thank you, Dr. Jirtle, very, very much Were you as taken by Dr. Jirtle’s comments as I? I think there are certain things that happen in your life that are frame-shifting, jaw-dropping experiences. Listening to him was certainly one of those for me. We are witnessing the rewriting of rules through the work of Eric Schadt at Rosetta Merck, and Randy Jirtle, and someone you are going to have the pleasure of hearing next month on FMU. I’ll give you a tidbit: Dr. Edward Calabrese will be speaking about hormesis. These people are rewriting the tablets from which students will learn the new biology that will become the new medicine that will become the new healthcare system that will be focused on function. Isn’t that an interesting word? Function. Not just pathology, but function. How does one maintain high-level function throughout the course of living? That is really the challenge to the new medicine: to deliver clinical outcomes that will improve patient function beyond that of just suppressing symptoms. We’ve milked a tremendous concept for over 60 years in pharmacology, which is a use of toxic molecules to block certain functions to induce the suppression of certain symptoms, and now we are into a new era, leveraging the new biology that will produce the new medicine that is related to improving function and transforming patient outcome. Pretty exciting era. Stay tuned for next month.

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Bibliography

1 Feero WG, Guttmacher AE, Collins FS. The genome gets personal-almost. JAMA. 2008;299(11):1351-1355. 2 Scheuner MT, Sieverding P, Shekelle PG. Delivery of genomic medicine for common chronic adult diseases. JAMA. 2008;299(11):1320-1334. 3 Salisbury MW. Looking for disease links. Genome Technology. May 2008:31-33. 4 Kaput J, Perlina A, Hatipoglu B, Bartholomew A, Nikolsky Y. Nutrigenomics: concepts and applications to pharmacogenomics and clinical medicine. Pharmacogenomics. 2007;8(4):369-390. 5 Zeisel SH. Nutrigenomics and metabolomics will change clinical nutrition and public health practice: insights from studies on dietary requirements for choline. Am J Clin Nutr. 2007;86(3):542-548. 6 Ordovas JM, Kaput J, Corella D. Nutrition in the genomics era: cardiovascular disease risk and the Mediterranean diet. Mol Nutr Food Res. 2007;51:1293-1299. 7 Gillies PJ. Preemptive nutrition of pro-inflammatory states: a nutrigenomic model. Nutr Rev. 2007;65(12):S217-S220. 8 Genuis SJ. Our genes are not our destiny: incorporating molecular medicine into clinical practice. J Eval Clin Pract. 2008;14(1):94-102. Review. 9 Mathers JC. Nutritional modulation of ageing:genomic and epigenetic approaches. Mech Ageing Dev. 2006;127(6):584-589. 10 Pallaud C, Sass C, Zannad F, Siest G, Visvikis S. APOC3, CETP, fibrinogen, and MTHFR are genetic determinants of carotid intima-media thickness in healthy men (the Stanislas Cohort). Clin Genet. 2001;59:316-324. 11 Waterland RA, Travisano M, Tahiliani KG, Rached MT, Mirza S. Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes (Lond). 2008. [Epub ahead of print] 12 Jirtle RL, Weidman JR. Imprinted and more equal. American Scientist. March-April 2007:143-149. 13 Luedi PP, Dietrich FS, Weidman JR, Bosko JM, Jirtle RL, Hartemink AJ. Computational and experimental identification of novel human imprinted genes. Genome Res. 2007;17(12):1723-1730. 14 Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007;8(4):253-262. 15 Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci. 2007;104(32):13056-13061.

Welcome to Functional Medicine Update for October 2008. Small is beautiful. A classic book of that title told us how great things can often happen with small events. Sometimes we over emphasize the importance of big events in shaping our destiny, when we really should be looking at how small, very important, catalytic events create great institutional changes, cultural changes, and changes in the shifting sands of technology. That’s the theme of this month’s Functional Medicine Update: How the concept of small is beautiful applies to health care. I am going to look at this concept within the cell, within the tissue, within the organ, within the organ system, and within the whole organism. How does small translate into beautiful? How does small translate into dysfunction? How does small translate into disease? I think these are interesting questions. You are probably asking, “What does Jeff mean by small?” Over the course of the next 90 minutes, we’ll be looking at how small translates into what we call hormesis. Hormesis is an interesting term. You probably are familiar with it from previous issues of Functional Medicine Update. In this issue, we have the fortune of hearing from someone who is arguably the most well-known person in the field of hormesis. He has published in excess of 400 articles in the peer-reviewed literature in this area, and lives, breathes, and conceives how hormesis plays a role in shaping systems. I’ll save his name for awhile as a carrot to keep us going through this issue, but I think you are going to be fascinated to hear this interview with a world leader in the areas of hormesis and nutritional hormesis. Hormesis, as a term, refers to small things having large effects (unexpected large effects) on the outcome of a system. Just for context, if we look at hormesis in social terms, we could look at India in the period where there was unrest between the British and the Indian population and there was an emerging potential civil war. Ghandi argued for non-violence and he used as his symbol for cultural change in creating independence for India a very small idea: the spinning wheel. The spinning wheel: let’s gain economic independence and weave our own cloth. The spinning wheel became the small icon for a great cultural movement that transformed India. If I could stretch the definition of hormesis slightly into social systems, that would be an example of small is beautiful. A small idea, even a small implement (the personal, peddle-pushed sewing machine), became the increment of change that ultimately created what we see as the independence of India I think there are many, many examples one can think of throughout history-social, technological, and scientific history-that would exemplify this concept of a small factor having an unexpected large effect on outcome. The first question we are going to raise this month in Functional Medicine Update: how do small levels of specific agents have unexpectedly significant effects on health? That is question number one. A corollary to that question is: if these substances can have an unexpectedly large effect on health, do those effects always hit directly where you see the histopathology, or are they removed from the histopathology, then radiating back an effect that lowers the disease? Let me say it a different way. We could reframe this to say: is the origin of a certain disease a result of action at a distance to the diagnosis of the histopathology, which is created by some hormetic alteration in the system of biological function of that organism? This probably sounds very esoteric and highbrow, and so let me kind of distill it down to ground here and try to get it into a clinically meaningful package. The system of differential diagnosis is the basis of the international classification of diseases (or ICD9 code) and the CPT code used for reimbursement for those therapeutics is built around the construct that histopathology defines disease. If you can see it, taste it, and feel it, then that is where the disease resides and that is what you are treating (what you see under the microscope, or under the CAT scan, or what you see visually), and that these particular associations between a disease and its treatment are intimately linked in cause-and-effect-type relationships. So a person who has a heart attack has a heart disease. A person who has a stroke has a brain disease. A person who has inflammatory bowel disease has an intestinal disease. You go to the site of histopathology and when you treat that disease, you are treating that histopathology, so that’s a one-to-one kind of construct (cause and effect). Here is the question I am raising: if there are hormetic influences in physiology (meaning a small agent has an unexpected large effect on outcome), could that effect then influence far distant from where you might expect it (the outcome that we call a disease)? Rather than treat “the” disease, you move back to the hormetic event. We might call this the physiological acupuncture point, to use a metaphor. This thinking I’m delivering to you is dependent on the underpinning of a mechanism by which something at a distance could weave its way through the wires of living, or the tendrils of life, or the web of function, to influence the disease at a distance. As an example, we might say dementia is the result of a brain disease; or we could say dementia is tied to a physiological acupuncture point of the immune system that is distantly related to how the gastrointestinal lymphoid tissue (or the immune system of the gut) is functioning. So, ipso facto; the gut is connected to the brain. By properly treating the gut-immune system to normalize its functional integrity, the outcome at a distance through this hormetic effect would be a lower risk of dementia. You are not treating the dementia, rather you are treating the underlying factors that connect to it through what we call a systems biology matrix, or network. Could it be by understanding where the critical switching points are in that complex web, and by putting what you might call aikido-type attention to those web hubs, that you would then be able to produce an unexpected and large effect in the patient’s outcome? Rather than saying more is better in therapy, we are saying less is better as long as attention is focused on the appropriate regulatory center that connects to that ultimate disease or condition that we are trying to manage. I hope I’m not losing you in the course of this discussion. I know it is kind of complex and maybe esoteric, but I believe you’ll see how I’m going to develop this in connection with our clinician/researcher of the month, and how this plays out in clinical practice. Hopefully the concept will gain more clinical utility as we continue. Just as a review, the two questions that I believe are very important to think about when you see a patient with chronic, complex disease and are then developing the management plan and therapeutic armamentarium for intervention are: (1) How do small levels of various agents have unexpectedly large effects on health outcome? And, (2) Could the origin of certain diseases be a result of action distant to the diagnosis of the histopathology that we see of that disease itself (meaning by managing the alterations at regulatory centers that are tied through this web of function, of which hormesis plays a role in the regulatory network)? With that as the construct, let’s now get to the topic. Let’s go right down a clinical path for this debate and talk about something that probably, for most people, is in the back of their minds as a connection, but maybe not to the extent that it deserves as we are doing assessment and diagnosis of patients who present with complex, chronic diseases. I’m now talking about the oral cavity and its connection to the cardiovascular system, it’s connection to the immune system, and it’s connection to the systemic inflammatory system. We have spoken in Functional Medicine Update for years about the relationship of the gastrointestinal system to the inflammatory immune system, but we haven’t spent as much time (I’ve only alluded periodically) on the relationship between oral health and the oral cavity to the gastrointestinal and hepatic and systemic and neuronal-related immune system. The oral cavity is an area where the outside world touches the inside physiology. It is like the nose in its connection to the dendrites of the brain. The oral cavity is rich in organisms; it is moist; it is warm; it’s got all sorts of food available; and, therefore, there is a lot of metabolic activity going on within the gingiva and the connective tissues associated with teeth and jaw. Periodontal disease is one of the most significant causes of loss of teeth in the adult population, even in the developed world. We might ask the question, is periodontal disease isolated as an oral health problem, disconnected from any kind of other subspecialty in health care? As if, somehow, the head (or the oral cavity) was cut off at the neck and had no connection, systemically, to the rest of the body? What has been emerging over the last five years with greater and greater degrees of understanding at the basic science and clinical levels is that there is a very distinct connection between the status of immunological function in the oral cavity and immunological and inflammatory status systemically. Let’s cut to the chase here. Recall, if you would, that the bacteria in the oral cavity, as contrasted in mass to the bacteria in the gastrointestinal tract are but very, very small. The mass of bacteria in the intestinal tract, for an average human being, is around a kilogram (over 2 pounds). You can imagine if your oral cavity was laden with 2 pounds of bacteria you’d be a mess, so, the number of bacteria is very, very small. Therefore, you might say, “Well, except for regional effects, the small number of bacteria could have very little effect upon systemic health.” But using the hormetic model that I was describing earlier, could it be possible that this small number of bacteria in the right place at the right time and the right species could activate the immune system in such a way that it sends signals (action at a distance, so to speak) to other immune regulatory tissues that then sets the stage or poises those tissues to have their own altered physiological status that leads them into a state of alarm and ultimately into chronic disease? Could the oral cavity, through alteration in its inflammatory-mediated function, produce a chronic state of inflammatory stress on other organs at a distance, for which maybe the patient doesn’t even have severe periodontal disease, but they have other diseases that then we try to treat as if they were localized diseases? Oral Data from the Physician’s Health Study A recent paper in The Lancet, certainly raises that question very nicely. It was a 2008 paper titled “Periodontal Disease, Tooth Loss, and Cancer Risk in Male Health Professionals: A Prospective Cohort Study.”1 This was a fairly large and well done study started back in 1986 when US male health professionals, aged 40-75 years, were responding to questionnaires posted by the Department of Nutrition (the Walter Willett Physician’s Health Study). In addition to the baseline questionnaire, follow-up questionnaires were posted to all living participants every two years and dietary questionnaires every four years in the study. At baseline, the participants were asked whether they had a history of periodontal disease with bone loss. Participants also reported the number of natural teeth at baseline and any tooth loss during the previous two years was reported on the follow-up questionnaire, so we got kind of a serial prospective history. Smoking status and history of smoking were obtained. Other kinds of parameters related to food frequency. Questionnaire data were assembled with a 131-item, semi-quantitative, food frequency questionnaire. Any disease indices were all recorded over this period of time as well, with participants reporting on any new cancer diagnosis on follow-up questionnaires. This study enrolled 48,375 men with median follow-up of 17.7 years from, as I said, 1986 to January 31, 2004. Participants diagnosed with cancer before 1986 and those with missing data on periodontal disease were excluded. There were 5720 incident cancer cases that were documented during that period, excluding non-melanoma skin cancer and non-aggressive prostate cancer. The five most common cancers were colorectal cancer, melanoma of the skin, lung, bladder, and advanced prostate. After adjusting for known risk factors, including detailed smoking history and dietary factors, participants with a history of periodontal disease had an increased risk of total cancer compared with those with no history of periodontal disease. By cancer sites, significant associations for those with a history of periodontal disease were noted for lung, kidney, pancreas, with relative rates of increase for pancreas about one-and-a-half fold over controls with no periodontal disease, kidney about one-and-a-half fold, and lung about 1.36 fold. This is not insignificant. In fact, it reaches a level of high significance. The interpretation of the study was that periodontal disease was associated with a small but significant increase in overall cancer risk which persisted in people that never even smoked. The associations recorded for lung cancer are probably because of residual confounded by smoking, but with the other cancers, it appears as if there is a very strong link to action at a distance. You have to ask questions: What role would oral infection have on systemic risk to cancer? How is there an inflammation risk? What has to do with genomic stability when you have high inflammatory burden or high bacterial debris burden? We go back to the interview that we had with Dr. Michael Fenech, which was a very, very powerful interview about one of the most important biomarkers for age-related dysfunction in all animals, including humans: genomic instability. Genomic instability can occur through many different mechanisms, as you heard from the eloquent discussion with Dr. Fenech. Is this chronic state of inflammation occurring as a result of the oral cavity having bacterial action and debris that incites a systemic immune inflammatory response? Is this one of the additional layers of risk in this systems biology web of living in which we all live that then increases the relative risk in people that may have certain genetic susceptibilities to specific cancers? This kind of thing I’m describing takes us away from looking at the origin of the disease as being its histopathology and where the site and locus of that disease resides, to moving to distant sites to look at where regulatory mechanisms may influence, through a cause-and-effect relationship, the signaling to that disease (the alteration in function at that tissue, ultimately, that is not obvious at first look, but rather is only obvious when you start backing up and looking at these interrelationships). Gingival Health an Indicator of Overall Systemic Tissue Health The same type of theme I am talking about with periodontal disease is also seen as it relates to gingivitis in a slightly different model related to atherosclerosis. I want to take us beyond just looking at the cancer connection to periodontal disease to also looking at gingival health, which is the soft tissue around the teeth (the tissue of the gums). This tissue is an indicator not solely of poor oral hygiene, but it is also an indicator of overall systemic tissue health. In a paper that was in the International Journal of Clinical Practice in April of 2007, investigators were looking at the relationship between gingival health status in renal transplant recipients and whether there was a relationship between gingival health, systemic inflammation, and atherosclerosis.2 They used carotid intima-media thickness (CIMT) as a surrogate marker for looking at relative risk to atherosclerotic disease (this is the thickening of the carotid artery intima-media boundary), which is indirectly related to the atherosclerotic process. What these investigators found was a very close correlation between increased CIMT values in those individuals who had gingivitis and poor gingival health. One might raise the question: is poor gingival health a cause or an effect of an overall relationship then to cardiovascular disease risk? Could it be that other factors lower systemic health in such a way that the radiating effect of that (the halo effect, so to speak, or the shadow) is to alter all soft tissue functional health because you have induced a state of poor tissue performance? With gingivitis, what you see clinically if you look in the oral cavity (even with people who might be brushing and flossing and getting regular preventive care) is that they’ve got bleeding gums and they’ve got all sorts of issues related to tissue integrity. Could, therefore, the gingival and gingival health be a reflection (kind of a surrogate marker) of overall tissue health? Gingival tissue, just like mucosal tissue of the body elsewhere, is a rapidly turning over tissue that reflects the changes that are occurring within the environment of that person-their nutritional status, their stress, their sleep patterns. When we look at gingival tissue, we need to look at more than just whether they brush and floss. We are looking at a whole environment of that person that constructs their tissue integrity. I think this is another interesting example of how a disease (cardiovascular disease) is connected to a distant sign which may be ultimately reflective of a systemic shift in the web of physiology. Predispositions are based upon the genetic uniqueness of that patient, and what we see later as diseases come downstream as a consequence of these outcomes. So asking the right questions, making the right assessments, moving upstream becomes very important. Do we look in the mouth? Do we ask questions about tooth loss? Do we connect with the dental community or oral health community to recognize these things are all interrelated? Does oral health connect to the gastrointestinal health? Are we looking at all these various focal points (or let’s call them balance points) upon which immune system integrity can be seen? I think these are very, very interesting things. Then, of course, we go to the skin and the eyes, right? These are other tissues that are very related to quick changes in status with an altered environment. We had a very wonderful interview with Dr. Valori Treloar this year on the dermatological connections to insulin resistance and dysglycemia, again showing how this is a radiating effect. You might say, “Well, the skin is the skin, so we’ll treat the skin.” But the skin is a reflection of this web, which then may go back to specific regulatory nodes in this complex web, and these regulatory nodes are where hormetic effects might have a great unexpected impact on outcome, either positive or negative. The regulatory nodes are the places where you have the greatest amount of potential leverage to create gene expression changes, to create outcome at cell physiological levels. So often we use the kind of karate mechanism in medicine: let’s break the brick by using the biggest arsenal of weapons we have, versus maybe a different philosophy which is the aikido concept of moving to the regulatory network and using the right energy, or right kind of therapeutic at the right dose, under the right conditions to radiate this influence to influence the whole system Let me, if I can, take the construct I have just talked about (oral health and its effects on systemic outcome in multiple diseases) and look at things that we might say at first blush are seemingly very hard to understand. For example, how could omega-3 fatty acids influence so many different factors, from cardiovascular health, to ocular health, to brain health, to immunological function and inflammation when the amount that has been found in clinical studies to influence these functions in an adult human is about 3 to 6 grams a day? Let’s put this in context. What does 3 to 6 grams a day of omega-3 fatty acids (usually referring to eicosopentaenoic and/or docosahexaenoic (EPA or DHA)) really mean? If you look at the amount of fat in the whole body, we would say that these are forms of fat. These are fatty acids that become part of triglycerides that are part of our fat storage. If we have an average 70 kilogram person (~150 to 160 lb person) and they are reasonably fit, they carry about 20 percent of their body mass as fat. Let’s say that’s 20 percent of 70 kilograms. What is that? That’s 14 kilograms, would you agree? Fourteen kilograms is how many grams? That is 14,000 grams? Fourteen thousand grams. And what did we just say was the dose per day of a fatty acid that would have influence on function? We said it was 3 to 6 grams. Now, what percentage of 14,000 grams is 3 to 6 grams of fatty acids? It is so small it is a rounding error to the right of the decimal point. If you were to look at this from a straight physiological (kind of mass action) effect, you might say, “Well hold it, in the face of the fat reading everyday and the amount of fat in our body, 3 to 6 grams of additional fat will have no effect. It will just be lost in the sea of other fats.” But we know that it does have an effect. And how does it have an effect? Just asking that question opens the door to a new possible discovery because maybe it has its effect because its effect is small in amount but big in outcome. It is like Schumacher’s Small is Beautiful. It is like the spinning wheel of Ghandi. A small effect on a regulatory network produces a big effect by recruitment of what goes on downstream. That’s a very interesting concept, isn’t it? You might say it prompts many questions about how various constituents of foods could influence function, and not just fatty acids. In a complex minimally processed diet, aren’t we eating literally tens of thousand of different small molecules that in amount are small, but could have a big effect on regulatory networks, and therefore the potential for hormesis could be large? Do you see where we are going with this discussion? In other words, for years we have discounted the amount of these secondary phytochemicals and other stuff that wasn’t vitamins or minerals, that weren’t part of the essential family of nutrients, as having irrelevance in human physiology. But what we are now saying is by a different way of sieving or a different way of focusing this information, maybe some of these molecules that were excluded as of being of value could have much broader effects when we look at them as potential modulators of regulatory nodes within the complex physiological matrix (small is beautiful) because there are new mechanisms of understanding that have emerged that are related to systems biology There are many, many places we could apply this thinking, but I’m just choosing a few examples to try to illustrate clinically how this could play out. Let’s look at the July issue of Nature Reviews of Neuroscience. There is a wonderful review paper in that issue titled “Brain Foods: The Effects of Nutrients on Brain Function.”3 This is a nice review paper authored by Fernando Gomez-Pinilla, and he says it has been suspected that the relative abundance of specific nutrients can affect cognitive processes and emotions, however, newly described influences of dietary factors now looking at their influence on neuronal function and synaptic plasticity have revealed some of the vital mechanisms that are responsible for the action of the low level of these substances on brain health and mental functions. They also–he says–influence indirectly through the modulation of gut hormones. These gut hormones can serve as putative neurotransmitters, entering the brain and then altering brain function itself, which influences cognitive ability. So it is not just the direct effect, but it is also the secondary effect, where you modulate at the gut level (with specific phytochemicals) the gut function, which then sends a signal through a neurohormone (a gut hormone). Remember that the gut is the second brain, which then influences brain function. It is a much more complex construct than we may have laid it out to be in the past. Dr. Gomez-Pinilla goes on to say that using this molecular basis the effects of food and nutrients on cognition helps us to determine how best to manipulate diet and the constituents of it in order to increase the resistance of neurons to insults and promote mental fitness. This clearly takes us to things like type 3 diabetes, doesn’t it? This has been in the news recently. Type 3 diabetes is the diabetes associated with Alzheimer’s disease and cognitive decline, where insulin becomes toxic to the brain and is associated with the production of neurofibrillary tangles and tau proteins, which then is associated with the pathophysiology of hippocampal functional loss and Alzheimer’s disease. We now even give a name to it–as I said, it is not just insulin resistance, it is “type 3” diabetes. Someone can own part of that in the neurology field, but these functional states know no disciplines and boundaries among subspecialties of medicine. They can influence the whole of the biological web, and they can do so hormetically, by small levels producing big effects on function across distance. It may seem to you that what I am saying is fairly simple and very obvious. But I would suggest that maybe this is a much more profound, altered way of thinking about health and disease than most of us learned in school when we came up through the international classification of disease (ICD9) and its companion, CPT coding, for treatment. We are now really taking a bigger picture, a bigger snapshot, of the interconnectedness of these systems, and we are asking, where, in this interconnectedness, might small effects of specific things have big influence on outcome? It is in these regulatory nodes that I talked about earlier. Food has classically been perceived as a means to provide energy and building material to the body. We learned from Casimir Funk, the Goldbergers, Albert Szent-Gyorgyi, and others, that there are these small molecules that we call “vitamines,” or vitamins. These are life-giving amines that are necessary to prevent deficiency of diseases like scurvy, beriberi, pellagra, xerophthalmia, and rickets; protein for kwashiorkor and and marasmus. Food is relegated to energy and material construction of our connective tissue and bones, and these small regulatory micronutrients are there along with trace minerals to activate enzymes and produce our function. But research over the past years has provided exciting evidence that there are other mechanisms by which nutrients and the array of phytochemicals (thousands of them) can influence molecular systems and mechanisms that maintain things like mental function. We talked about omega-3 fatty acids. Certainly our level of understanding about these nutrients has increased. As we have reduced our intake of omega-3 fats, we have seen adverse effects (maladaptive effects) on our physiology. In fact, if you look just at major depression on an age- and country-adjusted type of format, there are some very interesting studies published showing that those countries that have the highest level of fish consumption (meaning the highest level of omega-3 fats and other nutrients in fish) have a logarithmically decreased incidence of depression versus those countries that receive or consume the lowest amount of fish. An association like that doesn’t prove causality, but it is certainly worthy of some attention, isn’t it? You start asking, “What are these things?” Maybe it is just different in diagnosis, or maybe it is just a different way people manage depression in the Orient versus Germany. Maybe it is Seasonal Affective Disorder. There are myriad variables, here, but I just want to throw out one variable: omega-3 fatty acids. There are studies in animals that show if you remove omega-3 fatty acids from the diet, cognitive ability goes down, memory goes down, and depression (staying unresponsive to the environment) goes up. If you supplement these animals with omega-3 fatty acids, you get improvement in all those functions. The association of animal models with an epidemiological association in humans doesn’t prove causality, but these are certainly very strong connections, particularly with new mechanistic understandings of how omega-3 fatty acids alter brain-derived neurotrophic factor (or BDNF) and improve, then, things that are associated with mood, mind, memory and behavior in animal-controlled studies. It mimics the effects that SSRIs have anti-depressants. In other words, the natural way our brain regulates affect and mood is through the regulation of BDNF and adrenaline receptors and activity. I think there is a strong argument for connection of mechanism to epidemiology to animal studies. What about gut hormones? Certainly we see with gut hormones the relationship of cognition and things like insulin-like growth factor and glucogon-like peptide 1 (or GLP-1), which then have effects on brain function, not just solely on gut function, or pancreas, or liver function. What nutrients then influence GLP-1 release? That’s starting to be understood now and research is being published. I could go on and on and on. This is a very nice review paper for those of you who might wonder how this field of nutritional hormesis is emerging in the relationship to brain function and how that ties to brain food. It is certainly, again, another step in understanding this. The gut connection really takes us into this whole issue of nutrigenomics and gut health and how they are connected together. The gastrointestinal associated immune system has kind of this regulatory node effect upon other portions of the body; it is not just the sole purview of the gastroenterologist, but a part of the overall functioning of the whole body as it relates to the immune system. A very nice paper was just published in Mutation Research titled “Nutrigenomics and Gut Health”4 This article is about this whole concept of single nucleotide polymorphisms and the human variability in response to signaling from the diet and how that influences, then, gut immune function, which influences not only localized inflammatory conditions of the gut, but systemic problems that relate to altering the web of function. This takes us, lastly, to this question of nutritional hormesis and plant phytochemicals. There is a very nice paper that appeared in Science magazine in 2008 titled “Plant Stress Profiles.”5In this article the authors mirror the construct that we’ve been developing for you in Functional Medicine Update for the last year: when a plant is under stress, it upregulates the activity of certain genes that are involved with its stress response. These genes then regulate the production of secondary metabolites that we call phytochemicals. A plant that is more stressed has a higher phytochemical production, which then helps it to defend itself against things like high solar intensity of the summer, or stress like drought, or stress like mold, or insect predation. The plant will upregulate the synthesis of agents that come off the anti-stress genes, and these agents are things like flavonoids and epigallocatechin gallate (ECGC), or things like theaflavins, or things like various families of isoflavones. These molecules, when consumed by humans, have interesting hormetic effects on regulating stress response at different organ systems or tissues. This is a whole different way, obviously, of looking at nutrition, because now we are talking about almost a kind of a co-evolution relationship between plants and humans in which plants under stress produce agents that humans (when consumed) use as anti-stress compounds for improving functional integrity of their outcome. You might say, “Well aren’t those just antioxidants, all those things you talked about?” To me, “antioxidants” is just a generic term for lack of explanation of mechanism. The ability to trap oxidants is really more related to how they are regulating those processes at the cellular physiological level that are correlated with reactive oxygen species, which has to do with mitochondrial function, electron transport function, the proteome, and how the cells, tissues and organs are functioning at a level of regulatory control (bioenergetics). So I think that we are more than just trapping oxidant radicals. That’s a fairly simple-minded explanation for what’s really going on with these phytochemicals Our research group recently published a paper that appeared in the Canadian Journal of Physiology and Pharmacology.6 We looked at the combination of various phytochemicals for the modulation of inflammatory condition from in vitro to animals and finally into humans, kind of a three-level series of studies. We were able to demonstrate that specific ratios of various phytochemicals modulated at the proteomic level the appearance of inflammatory markers. We went through the in vitro work with cell lines, and then into the animal model, and finally into the humans, and these phytochemicals mapped right into the human with the same effect: these plant-derived materials that were specific ratios of ingredients from olive leaves, and from rosemary spice, and from hops were capable of actually eliminating some of these inflammatory signals at a distance in humans. So I think you are seeing the emergence of a whole new construct. This construct has been reviewed in a nice review paper that Dr. Deanna Minich and I coauthored that recently appeared in Nutrition Reviews in the August issue, 2008, titled “Dietary Management of the Metabolic Syndrome: Beyond Macronutrients.”7 In this paper we look at how these various phytochemicals serve as hormetic agents to modulate insulin signaling and signal transduction. I hope I have tee’d you up for the opportunity to meet the person who, as I said, is arguably the father of modern nutritional hormesis, Dr. Edward Calabrese, Dr. Calabrese is with the Department of Public Health, Environmental Health Sciences, at the University of Massachusetts, and has just authored a fascinating review titled “Hormesis: Why it is Important to Toxicology and Toxicologists” that appears in Environmental Toxicology and Chemistry in 2008.8 You will hear from him how important this construct is for all of us to understand as we are developing both the assessment and therapeutics of patients who have distortions of their systems biology that appears as chronic disease. With that, here is Dr. Calabrese.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Edward J. Calabrese, PhD Department of Public Health Environmental Health Sciences Morrill I, N344 University of Massachusetts Amherst, MA 01003 As you know, we look forward to this section, the clinician / researcher of the month, in each issue of Functional Medicine Update. For the last 27 years, we to have some of the world’s leading pioneers and innovators discussing things that really are changing our view of medicine and physiology. In this issue, we have a person who I believe is really an icon in the field. I have had the privilege of following his published work for more than 25 years; he has been publishing since 1976. I am talking about Dr. Edward Calabrese, who is a board-certified toxicologist, a professor of toxicology, and the chair of the environmental health sciences program at the University of Massachusetts School of Public Health. Anybody who has been in the field of environmental toxicology knows Dr. Calabrese’s work. He is, as I said, an icon. He has researched extensively in the area of host factors affecting susceptibility to pollutants, and is the author of more than 600 papers in scholarly journals, and actually has had funding for his research exceeding 30 million dollars over the past 30 years. Dr. Calabrese is an author of 26 books, 40 monographs and conference proceedings, and has given 500 invited presentations at major conferences and university seminars. I think you get the drift that we are talking about a person who is an expert in this field. He has been actively involved in helping us understand the role that environmental agents and various types of pharmacoactive substances have on physiology through this process that he is going to be describing. You have heard me review this subject in past Functional Medicine Update, but certainly not at the depth nor understanding of Dr. Calabrese; it is the concept of hormesis. Dr. Calabrese, we really would like to welcome you to Functional Medicine Update. I think, right out of the box, probably the first thing is just to ask you the simple question: could you define for us what hormesis means, so we’ll all have a similar point of reference? Hormesis: Low-Dose Stimulation/High-Dose Inhibition EC: Thank you very much and it’s my pleasure to be here. I define hormesis as a dose-response phenomenon, characterized by a low-dose stimulation and a high-dose inhibition. This dose-response relationship has specific quantitative characteristics. The low-dose stimulation is very modest, usually at maximum it does not exceed about 30 to 60 percent greater than the controls. The width of the stimulation is a bit more variable, but typically is about 10- to 20-fold below what I would call the traditional pharmacological or toxicological threshold. The hormetic response is one that has been observed for a long time and derived its name from researchers at the University of Idaho in 1943 who were studying the effects of extracts from the red cedar plant on the growth of fungi (they were concerned with the rotting of the wood). Both of these individuals went on to biomedical fame. One, John Ehrlich, became the co-discover, later on, of chloramphenicol, and the other, Chester Southam, became very well known after he got his MD from Columbia in the area of immune responses, immune antigens, and tumors. So there is a medical linkage to its origin. JB: I think this concept is so dramatically important because it shifts our frame of reference away from that which most of us learned in our pharmacology courses about the nature of a dose-response relationship. We all kind of got the sense that there was this linear relationship (or nearly linear relationship) between the dose of a substance and its response. In terms of most views this was kind of a straight line or maybe even a slightly curved relationship (a sigmoidal relationship), but not a relationship that at some lower concentration might shift its whole personality, going from either an antagonist or an agonist to the opposite (to become an agonist or antagonist). This concept of hormesis seems like it flies right in the face of what virtually everyone has learned as their traditional pharmacology. Early Dispute between Traditional Medicine and Homeopathy EC: Yes, it is hard to believe that the field of biomedical science could actually get the most fundamental pillar of the discipline wrong, and it is upon which our pharmaceutical and governmental regulations on the environmental side are based. Yet, actually, I believe this is true. The reason for this is a complicated set of factors. Back in the early part of the 20th century there were several things going on. One was a phenomenal dispute between traditional medicine (what we call traditional medicine) and homeopathy. A fellow by the name of Dr. Hugo Schultz in northern Germany in the late 1880s had discovered, while studying the effects of disinfectants on yeast, that at low doses they seemed to have stimulated the metabolism of the yeast, but at higher doses they inhibited it. Schultz believed that he had uncovered the explanatory principle of homeopathy and he became very–you might say–active in advocating this. I would say he became a lead spokesman for the homeopathic community, even though Schultz was very traditionally trained. In this (really) war of two medical titans (traditional medicine and homeopathy), we know how the battle came out: traditional medicine actually won. Schultz, because he took sides in this matter, became the object of a lot of criticism. The criticism that was leveled at him really came in its most poignant form out of leading intelligentsia of the British pharmacologists of the 1920s and 1930s, led by a really great pharmacologist by the name of Alfred Joseph Clark. He viciously attacked Schultz in his writings and, unfortunately and unfairly, linked him to the high delusionist wing of homeopathy, and in many other ways associated him with extremism and quackery, which was really, for the most part, totally unfair. I believe the reason why this went on was that ultimately homeopathy had to be defeated in this economic battle. Development of the Threshold Dose Response Model Once the attack went on Schultz, I believe that Clark and his other associates had to come up with an alternative dose-response model which actually seemed to fit the data, and that was the threshold dose-response data. In fact, Clark and some other colleagues helped to develop the probic dose-response model and then they biomathematically forced the modeling to always be constrained to be above the control and to approach the control, in effect denying the possibility that hormesis or biphasic dose could exist. This perspective became institutionalized and within a developing governmental apparatus at the time (within the US FDA and over in Europe), and appeared in the major textbooks. The next thing you know, the threshold model was then the biphasic hormesis model. All our testing schemes were based upon a threshold model, which required essentially just a few doses (high doses) in an assumption that a threshold would be easily extrapolated to. If you only have two or three doses when you do hazard assessment and risk assessment, it is always going to be next to impossible to see the hormetic stimulation. Development of the Biphasic Dose Response Model What that meant was out of sight, out of mind, and that is essentially what was perpetuated all throughout the remainder of the 20th century. And so all of our-essentially-national toxicology program testing, the prior work before that, was all based upon an assumption of a dose-response that I believe was incorrect. When individuals (either because of their own interests or because of other reasons) studied many doses, and doses in lower-dose arms, they began to see that there was this biphasic dose response that was developing. It is very difficult to prove because this low-dose stimulation is actually a very modest stimulation, whereas I mentioned before the maximum stimulatory response is only about 30 to 60 percent above the control. If you have a high background variability in your control animals you can easily ascribe that to chance or it maybe chance itself, but if you only have one dose that happens to fall into that below-threshold zone, you’d most likely just discount it. I got into this because (just to add a little personal aspect) many years ago, as an undergraduate taking a course in plant physiology, I was conducting an experiment in which I was to evaluate the dose-response relationship of a growth inhibitor in the plant (we were studying peppermint plants). It was just to evaluate a dose-dependent response. In our experiments, the professor came in one day and said, “Something unusual is happening, there is a growth stimulation taking place which is not suppose to happen (it is just suppose to be an inhibition).” He wanted to know if somebody would come back at the end of the semester to do the study over again and of course I was the only one who had the interest and went back. This time we did it exactly the way he said we should, and from looking at my notebook it appeared to be that we actually made a dilution error when making up stock solutions, and so we actually gave our plants about 10-fold less than they should have received. When we combined our low doses with his high doses we got this nice inverted, U-shaped dose-response of a low-dose stimulation high-dose inhibition. He made me extend that study and replicate it probably eight different times, in soil, getting the same results all the time, then extending it over into the world of hydroponics, where we got the same low-dose stimulation high-dose inhibition. And even though I had never heard of the term “hormesis” we published the work calling it a low-dose stimulation/high-dose inhibition. That is really where I got my initial insights, and then ultimately have built upon this in a much more extensive way looking at lots of other peoples’ research experience, in which they surprisingly showed the same phenomenon. It wasn’t just occurring in plants with growth inhibitors, it was occurring in all cell types (with microbes, with viruses, all kinds of nerve cells, and any kind of tissue that you might want to consider). When you really look at the broad spectrum of the responsiveness (looking at a broad range of concentrations or doses), you typically will find that low-dose stimulation and high-dose inhibition, and it has a lot of implications for the medical world because the medical world is dealing with the pharmaceutical industry and the chemical industry-we’ve built industries upon killing things. It could be using insecticides, or antibiotics, or disinfectants, anti-tumor drugs-these all act at the high end of the dose-response spectrum. They are effective because they kill things. However, hormetic stimulation is really below that toxic threshold, and what I think the hormetic stimulation is actually measuring is biological performance, which is really very different than measuring toxicity at the higher level. By performance I mean you could take a look at extensions for longevity, for growing hair, it could be for increasing memory, increasing cognition, strengthening bones-many different types of biological activities, which all fall, for me, under the broader rubric of biological performance. And it is in that area of biological performance where there are many, many different kinds of opportunities that certainly the pharmaceutical world, but also many other aspects of society, are interested in. Cap on Capacity to Increase Biological Performance And the interesting thing here is that when you look at the thousands and thousands of cases that we have found of hormesis that are in our hormesis database (we have probably close to 9000 now), the one thing you find that is a real constant here is the modest increase that you have in that low-dose stimulation. What that really means is that our capacity to increase biological performance on just about every parameter that I know can only be modestly increased, and that is by 30 to 60 percent. And so when people talk about a drug to improve memory, the most you are going to get out of a drug is an increase of 30 to 60 percent. In bone strength by about the same, increase in hair growth, the same, increase in whatever parameter that you want to look at, even if you have two drugs that interact synergistically, they will still be capped, they will not be able to exceed that amount. They may be able to get there by lesser doses, but I believe that there is a cap, and I believe that that is imposed by constraints imposed by biological plasticity across all biological tissue, from plants, to microbes, to invertebrates and vertebrates. This puts many constraints on what pharmaceutical companies can achieve. You might like to think, “Oh, gee, I can make it more difficult to have a seizure occur by giving a drug that increases the threshold by which a seizure could occur,” but the most you can increase a threshold is in the modest 30 to 60 percent, and the same for all these other parameters. This creates numerous opportunities for us, but we are also working within the constraints of biological plasticity. JB: Oh boy, there are so many incredible things you just left us with. Talk about high-density information. Let me go back and pick up just a few of the pearls you laid before us. Let’s go back to this homeopathy question. When you look at the data in this really beautiful review paper that you just had published in Environmental Toxicology and Chemistry in 2008 titled “Homesis: Why it is Important to Toxicology and Toxicologists,” you present quite an array of data from different types of studies showing this low-dose stimulatory effect and then a high-dose inhibitory effect with things like mercury, cadmium, various pharmaceutical compounds. I notice that at the low dose, often the doses extrapolate back to, say, 10-7 molar, or something like that, but in homeopathy, often the doses have much higher dilution than that. In fact, even mathematically they might exceed Avogadro’s numbers, so it seems like there must be a range in which you still have to have active enough molecules in order to do this, or can we extrapolate this all the way back to zero? EC: Well, you certain can extrapolate it back to zero, and this would be really incompatible with what I would call the high dilutionist wing, so to speak, of homeopathy. I would have to say that there are many homeopathic medications that are in the measurable zone, so to speak. I’m not saying that these would show hormetic effects in those treatments or not, one would have to look at it, but you do have to have enough of a concentration to, let’s say, activate receptors on different cells to initiate a process of activation. Generally speaking, there would be a threshold, for the most part, that has to be exceeded before you could initiate the hormetic response. JB: That really answers that question very nicely. It seems that there is an analogy here-and maybe I am overly extrapolating-but knowing a little bit about immunology… in the area of immunization, there is this thing called low-zone tolerance versus high-dose energy. This is the whole theory of immunopotentiation, or developing an immunization, that you get this low-zone tolerance. That seems like it is very much a diluted dose, generally, of the hapten or the antigenic substance that at a higher dose would produce an inflammatory or energenic response. Is there an analogy here somehow between what we see in the immune area and what we are seeing in the hormetic area? Hormetic Effects on the Immune System EC: In the immune area-and I have looked at that, not so much with vaccines, but I have looked at it within the context of agents that could modulate immune response-this is looking at a wide range of chemical agents, therapeutic agents, as well as physical agents, including various types of radiation. In this area there is an amazing capacity to enhance immune function for almost any kind of immune endpoint that you could imagine. Studies have demonstrated that in the biomedical literature, and I published, actually, a very comprehensive review of that in 2005 in Critical Reviews in Toxicology.9 But the important thing here is when you activate the immune system within an hormetic context, it still actually conforms to the constraints that I mentioned, and that is that the maximum stimulatory response is still only modest, and is about 30 to 60 percent greater than the control background. I have to say, in the literature that I have looked at, about 80 percent of the cases where the people who commented on the clinical implications of their findings argued that these would be consistent with enhancing health. In about 20 percent of the cases, the activation of the immune system within an hormetic sense was thought to actually have some adverse health implications. It could be any of a variety of potential endpoints, such as enhancing an autoimmune response. However, for four out of five, the response was to be supportive of health, but that depends, obviously, on what system you are trying to study and the endpoint that you are interested in. But there is no question that the immune system is one in which hormetic effects have been extensively studied. JB: Another interesting pearl you left us with was this concept about biological performance and the takeaway, and you describe this in several of your papers, that there is some advantage to modest stress of physiological systems to produce plasticity or to produce functional performance. That would include things like exercise, or calorie restriction, or all these variables that we are describing that maybe even a low level of what might be considered xenobiotics in the environment that induce, then, this plasticity through this hormetic effect. Is that a logical takeaway from this discussion? EC: Yes, it is. It seems as though biological systems, to be optimized, need to be stressed. This stress can come in many different forms. It can come in the form of low-level exercise, it can come in the form of oxidant stress, it can come as a result of even hypoxic stress, and dietary restriction is another. There are many different ways to achieve this enhancement in different systems. The bottom line is that in essentially all of those cases, what happens is that it makes the cell system or the individual much more resistant to any subsequent follow-up stress. JB: So this obviously begs a question which I know you have been looking at for many years, and from your writings it appears as if we are still in search of a definitive answer. That is related to mechanism. How-at low dose-do we shift over to what appears to be an entirely different mechanism from the same substance that produced, at a higher dose, say, an inhibitory effect? So it becomes an agonist at a very low dose and an antagonist at a high dose? EC: This has been looked at and documented with a lot of detail in actually a good number of receptor systems, and that is that the same agonist that is able to activate, let’s say, pathway one will, at a higher concentration, actually activate the opposite pathway. In so doing, it provides a regulatory framework to, in effect, keep the system properly functioning, but also to give it the flexibility to operate within a zone of performance. What you would have on a cell, is two receptor sub-types that that agonist can bind to. One may have much greater affinity to it, and the other has much less affinity by having many more receptors. So one pathway gets activated at low doses, and the other pathway takes over at higher doses. In so doing, you end up (if you plot it out by doing an experiment) having a beautiful biphasic dose response. Actually, that would happen very much so in toxicology experiments where you might give a very broad range of lead, or cadmium, or mercury, or something else. What they are going to do is change very widely the concentrations of different types of agonists and what that is going to do. Is it just going to create a whole series of biphasic dose-response relationships? That is why I think these hormetic dose responses are so common when one actually looks at a broad range of doses within well-designed studies. JB: So that then leads us to a very interesting example of the potential clinical application of what you are describing. I notice that you have authored a number of very interesting papers recently about the potential application of this hormesis concept in functional neurology and improving neurologic function. Could you describe a little bit about your thoughts in that area? Neuroscience and Hormesis EC: The area of neuroscience and hormesis is one that I have just spent three years looking at. I have fourteen papers that are now being published in the journal Critical Reviews in Toxicology. By the end of the summer all fourteen will be officially out. For example, if you take a look at the field of, let’s say, anxiolytic drugs and you look at the animal models that are being used in these studies (for example, mice and rats), they tend to be very much liking to be where it is dark and not liking to be where it is light, probably because they are afraid of being (in their evolutionary history) essentially gobbled up by a hawk or something like this. And so the pharmaceutical researchers, what they try to do is they see that (from an anxiety point of view) trying to get a rat to go into the light is actually like getting me to drive to New York City (I would have great anxiety). You don’t want to do it. The animal doesn’t want to go out into the light. But if you can get the animal to do what it doesn’t want to do-what is very, very stressful for him-that’s what you are trying to achieve with an anxiolytic drug. What you would do is take the drug and you give the animal a choice to go into a darkened alley or a lightened alley, and with the anti-anxiety drugs, you can see that you can actually get the animal to spend more time in the lighted zone at low doses than at higher doses, when it actually drops down and spends more time in the dark zone. When it goes into the lighted zone it is a measure of a reduction in anxiety, but when it goes and spends more time in a dark zone, it is actually a sign of increased anxiety. That is how these dose-response relationships actually follow the quantitative features of the hormetic dose response. In fact, the anti-anxiety response in the animal model is exactly a hormetic dose response, and the pharmaceutical companies, themselves, actually choose the dose for the therapeutic zone based upon that low-dose stimulation, and without them even knowing what they are doing (with respect to hormesis), they are actually using hormesis to pick the right chemical and then to use a hormetic zone for their therapeutic range. One could then look at the whole spectrum of anti-anxiety drugs as being a clear example of how major pharmaceuticals are making billions and billions of dollars by applying the hormesis principles to a main core of their business. And the same actually is true for anti-seizure drugs. If you take an anti-seizure drug, what it is really supposed to do is make it harder for seizures to occur. You can induce seizures in animal models with certain chemicals, and then when you come in with your treatment modality, that treatment chemical, if it can increase the threshold by which a normal seizure inducer causes seizures, then you basically have a good chemical. What you find is that it causes an increase in the threshold at low doses, but then decreases the threshold for the induction of seizures at higher doses, again very much within the context of a hormetic dose response with the same quantitative features, and this gets replicated to just about every other effect within the pharmaceutical realm in which the industry is interested in performance rather than toxicity. Essentially, the hormetic concept is actually well integrated within this, but without it actually being recognized that this is the same… this dose-response, which is occurring for anti-anxiolytic drugs, is occurring for seizures, is occurring with respect to stroke, is occurring with respect to pain, is occurring with respect to neuroprotection, growing neurons, and also with regards to many other aspects that we see in the biomedical world. It is actually, I believe a dose-response principle that has never been recognized before and has been missed because of the hyperspecialization to which biomedical science has had to drift into. JB: So that leads to a very nice segue. I don’t want to lead you into an area that you are uncomfortable with, but that’s the whole concept of nutritional hormesis. We know that nutrients have interesting biological response-modifying capabilities. They can serve as intercellular signal transduction agents but yet we are told they are very low dose compared to new-to-nature molecules that come off the benchtop of medicinal chemists. So people would say, “Well, nutrition is really not a medicine as such, it is really dealing with other factors that are preventing anemia or preventing scurvy, beriberi, pellagra, xerophthalmia, rickets, kwashiorkor, marasmus, and that’s a whole different field from that of pharmacology. But yet it would seem, from what you’ve said, that these nutrients, which may be considered low dose in a pharmacological model of toxicity may have a performance-related function at hormesis that might be very different. Am I saying something that has any credence? EC: Yes, I think you are, and that is-I believe-there is being shown in a lot of ongoing research that, in fact, various types of nutrients have hormetic effects that go beyond what I am going to call the normal features upon which they were described as being an essential nutrient. This could relate to activation of different types of biological systems that they may have. It could be neurological. It could be any kind of factor. You can also have certain nutrients that could actually inhibit what I call hormetic effects. For example, people used to be afraid of oxidant stress because of it, perhaps, affecting mutagenicity and other end points, but, in fact, low levels of oxidant stress provide the messaging that goes on in every single cell that we have in the body. It could be that with a desire to expose oneself to massive amounts of antioxidants actually could shut down an hormetic response if, in fact, the level of oxidant intake was too great. So I think there is going to be some balancing of intake to result in an optimized type of response. This is a bit avant garde, but that is emerging, and every time it is seen it is a surprise. It is not really a surprise if you have been following the hormetic literature. JB: Dr. Calabrese, let’s go back, say, to 1967, to an article that Linus Pauling authored in Science magazine titled “Orthomolecular Psychiatry” in which he talks a little bit about this concept of molecular medicine from a nutritional perspective. And later Bruce Ames picked this up in a very nice review article that he authored in the American Journal of Clinical Nutrition in which it was discussed that high doses of specific nutrients can modulate cofactors in intermediary metabolism by mass action that then pushes sloppy equilibrium towards completion and improved function.10 That’s one role that nutrients might have as cofactors that stimulate enzyme activity at a higher dose. I think what you are suggesting (and I think the literature supports this) is that there may be other phytochemicals and other nutrients in foods that work by a different mechanism than just apo enzyme-halo enzyme relationships, that work through these hormetic receptor transduction processes that may be better at lower dose than higher dose. EC: I believe that’s true, and these are going to be found for trace elements, even things such as cerium, lanthanum, neodynium, agents that we normally, you know, rare herbs that we normally wouldn’t study because we have the impression that they are so low in concentration that they are not biologically important. Or other factors like that. And it depends on the system. Even toxic metals, for example, such as mercury and lead, even though they are not considered essential nutrients, you can find in many different systems that these actually can be used to have a positive impact on the biological response going way back to-I would say-the early decades of the 20th century where investigators have shown that low levels of such stressor agents could enhance plant growth at low dose and inhibit it at higher. The same with microbes as well. I think that it is expansive in terms of the intellectual breadth that it offers us because we have oftentimes had biases against either a certain chemical, or against a certain process, but really when you open your mind and actually follow the data rather than your own ideas, it actually creates a whole set of new opportunities for you, research-wise. I think that is what this low-dose domain is doing. JB: This has just been a fascinating discussion with you. Obviously we could go on for hours and hours, this is just amazing. But in the last few minutes, I would like to just get maybe a summary from you, as you look at the horizon-I know this is asking for a level of clairvoyance that is not very fair-what this is doing as changing the perspective, the frame-shift that interfaces with network biology (or systems biology) in a unique way, this whole view that we don’t really see the body as a collection of pathways, but we are really a part of a network and applying stress to the network then modulates its functional integrity. If we take that model and then we look at how your discoveries influence environmental toxicology, pharmacology, and clinical therapeutics, what would you say is going to happen here in the next period of time, looking out at the horizon? The Future: Looking for Patterns of Dose Response EC: I think what is going to happen-what I hope happens, anyway-is that somehow our highly specialized trend in medicine (and science, in general) is able to stand back and to take a look at general strategies which have been selected for that help us in adapting to all sorts of environmental stresses that we have. In fact, we have a dose response that is, in many ways, truncated into a high zone and a low zone, and the low zone actually deals with performance. How do we maximize that and what are the constraints? I think if we begin to see this from the plant world, to the microbe world, all the way to the human behaviors, we begin to see such integrative simplicities, even, for example, when you take a look at male sexual performance drugs that are advertised on television, or the memory drugs, or anything that we see. They all actually conform to an inverted U-shaped dose response, and the dose response actually has the same quantitative features. You have to sit back and ask yourself, could all of this have happened by chance that all these end points, that all these organisms, and all these chemicals, that they somehow have adopted the same quantitative features of the dose response? In my opinion, they obviously couldn’t have. This must be something that has been highly selected for over time, that it is placed to our species (and all species’) advantage, and you have to ask yourself, how did we miss it? Why do we continue to miss it? How is it serving us (as a society) to continue to miss it? And how do we overcome this to our collective advantage? My greatest fear was that this trend that I have been working on would actually be totally missed because the system rewards hyper-specialization, where the person in microbiology actually doesn’t talk to the person who does animal physiology, who doesn’t talk to the person who does behavioral pharmacology, who doesn’t talk to the geneticist, and yet if you look at all these patterns of dose response, they actually are highly consistent and follow the same basic framework. It is like missing a fundamental biological principle. We would never think that that was possible. But I actually think that this is the big issue. Modern science doesn’t have a built-in failsafe to protect it from missing a basic scientific principle. JB: I can’t tell you, Dr. Calabrese, how we have appreciated this. Your articulate summary of a huge body of work has just been overwhelming. I think you have left every listener of this reeling with some of their past preconceptions and reflections on what this all means. Thank you very much. We have started into the age of hormesis thanks to you and I really appreciate it. EC: Thank you very much. I certainly hope you found the discussion with Dr. Calabrese to be as innovative, provocative, and stimulating as I did. I think it encapsulates a tremendous amount of both good science and rich history that we can leverage in how we see patients with chronic disease and how we manage them. As I mentioned to you earlier, Dr. Minich and I authored a review paper on metabolic syndrome that incorporates many of these principals that just appeared in Nutrition Reviews, August 2008 issue, titled “Dietary Management of the Metabolic Syndrome: Beyond Macronutrients.” In this particular article, which I think is reasonably well referenced (about 183 references, I believe), we talk about the work that is both ongoing in our nutrigenomics MetaProteomics research lab and the papers that we published out of that research the last few years, but also the body at large of work that is going on related to signaling effects and how nutrients serve as signaling agents, as if they are speaking to the genes through these regulatory intercellular signal transduction networks. I think this construct (that a little amount of something can have a large effect on function) traces all the way back to the rich origins of homeopathy. But you still need to look at this in the construct that these regulatory nodes are the places that you have the highest sensitivity to functional changes, so a little can be a lot, and a lot can be less, because you can actually start having altered function. So it is the right amount. Maybe the body has been getting the right amount by eating a complex diet rich in these substances that are coming from stressed plants, and so we are starting to emerge, maybe, a different construct, that for chronic disease, the best therapeutics are utilizing nutritional hormesis with foods of variety and foods of complexity.

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Welcome to Functional Medicine Update for November 2008. In this issue, we are once again looking at the complex issue of modulating the neuroendocrineimmune system with therapy. In past editions, we have had several extraordinary leaders in the field talk about things like bio-identical hormone replacement therapy. We are going to have a chance to have an update on this topic. The reason I continue to revisit this subject is because it is an evolving field and it’s a rapidly changing field in our understanding. I think the more opinions and the more leadership we get in this area the better off we are in being able to really manage this process and provide the patient with the best information. This month we have had the privilege of visiting with Dr. Jane Murray who is going to be discussing a very remarkable monograph that the group Women in Balance has put together on this topic. Before we get to the interview, I want to say some things about women’s health in general and the push towards hormone replacement therapy. I’d like to provide some context. There is now evolving information indicating there is wide diversity at the genetic and metabolic level among both women and men. The concept of biochemical individuality that Roger Williams talked about all the way back in the late 1940s (and Linus Pauling, with his concept of orthomolecular medicine) is starting to really gain traction as we learn more about the transcription, translation, and the outcome of the human genome into the phenotype of the individual. The Role of Single Nucleotide Polymorphisms in Women’s Health With regard to hormone replacement therapy and managing women as they go through perimenopause, and into menopausal and post-menopausal years, we start to recognize that women respond very differently based on the principles of epigenomics and genomics through the pre-menopausal and into the post-menopausal period. A lot of this has to do with SNPs (single nucleotide polymorphisms) that modulate the way that various compounds travel through the body and are biotransformed and excreted, and also how they interact with receptor sites and are engaged in intercellular signal transduction. They communicate through information as hormonal materials to change/regulate cellular function. So there is a wide diversity of responses. Some of the most critical single nucleotide polymorphisms that relate to women’s health are now starting to be identified. Of course, this is giving birth to a whole new field of molecular genetics as applied to the female reproductive system, particularly coming out of the area of breast cancer in which certain single nucleotide polymorphisms are being identified to have higher associations with breast cancer risk and responsiveness to certain chemotherapeutic drugs, particularly certain kinases within the kinase inhibition family of drugs, like Gleevec. Conflicting Information from the Women’s Health Initiative We are starting to see a move from “medicine of the average” to “medicine of the individual.” This shift might help us understand some of the apparent conflicting information around the Women’s Health Initiative studies that were done with mixed equine estrogens and progestins in the management of women’s health throughout the menopausal period. It appeared as if many women had no adverse side effects from intervention with mixed conjugated equine estrogens and progestins, whereas other women had increased risk. Overall, the weighted average (as if there was an average woman) was not good, but if you looked at certain cohorts within that full spectrum of women in these studies, you find that there were some who faired very poorly and others who faired reasonably well or even well. How do we identify those who didn’t respond so well? What is uniquely different about them? Various genes and their single polymorphisms that are unique to those who are more at risk are starting to be seen as part of the story, like possibly Leiden Factor V. In women with these specific SNPs (these polymorphisms), there is an increased risk of thrombolytic and thromboembolic risk. I think we want to stratify many of these data sets into looking at individual characteristics of groups of women who may be at differing relative risk. This moves us from the age of the blockbuster drugs (the class effect of “one-size-fits-all”) to the new age of gene-targeted agents (which might be considered “microbusters”). Targeted agents are more focused on individual characteristics, and they allow clinicians to stay away from those at risk and only give them to those people who have appropriate need. Hormone Replacement Therapy and Risk of Venous Thromboembolism I think this links very directly to a whole variety of recent published studies, but one that I think exemplifies this that I want to share with you has the title “Hormone Replacement Therapy and Risk of Venous Thromboembolism in Postmenopausal Women.”1 This was a systematic review and meta-analysis of a variety of published studies on the role of hormone replacement therapy on the risk to venous thromboembolism. I think this article is very well done. It appeared in the British Medical Journal in 2008. We recognize that hormone replacement therapy has been shown to improve the quality of life for some women who have hypoestrogenic symptoms (vaginal dryness, night sweats, even some of the cognition and depression dysphoria symptoms), but then we buttress that against (or juxtapose it against) the relative data that has come out of the Women’s Health Initiative looking at mixed conjugated equine estrogen and progestins and their effect on cardiovascular outcome, which was not too good, on average. The authors of this article started to look at the meta-analysis and the randomized trials from a larger kind of study perspective. What they concluded was that estrogen replacement does increase the risk of venous thromboembolism when given as oral mixed conjugated equine estrogens, especially during the first year of treatment when averaged across all individuals. The women most highly at risk may be those who carry the Leiden Factor V polymorphism. That is the overarching view from summarizing eight observational studies and nine randomized controlled trials that have been published to date. Research on Hormonal Delivery Systems According to these researchers, transdermal estrogen was found to be much safer with respect to thrombotic risk. They go on to say that more data are required to investigate differences in risk across the wide variety of hormone regimes, looking at bioidentical versus synthetic progestins, using conjugated equine estrogens versus native estrogens to the human specie, and also how it relates to different types of progesterones, and progestogens, and progestins, as well, which play different roles. I think the 2008 view is that there is still a lot of confusion. We still haven’t nailed all this down, but what has emerged is that we need to look at the individual woman. We shouldn’t be using a general “rules of the road” or “one-size-fits-all” mentality. We have to really look at how each woman responds. What are her unique genetic characteristics, and how do those, then, influence outcome when she is exposed to exogenous hormone replacement therapy? I think that is going to require a different level of knowledge. Many therapists have basically been just administering these agents on a standard dose regime without really recognizing the diversity of different ways that women respond: how they metabolize estrogens, producing more or less of the 4-, or 16-, or 2-hydroxyestrogens; how these estrogens travel through the detoxification process and get eliminated; how the progestins differ in their physiological response from the nature-identical progesterone. All of these factors are further complicated by the delivery systems: transcutaneous versus vaginal versus oral (these play very different roles), or time release versus immediate release. You have many, many moving parts, many variables. The woman, herself, is the key to this puzzle. She is the person for whom these treatments are designed, and amelioration of symptoms is not enough to really understand how she is responding. We need to take a snapshot of a woman’s response that is much more unique to her individual genetics and biochemistry. Diet is an Important Environmental Modifier This discussion leads to the question of whether we can modify or modulate the way a woman responds to her native and/or exogenous hormones based upon the environment in which she finds herself. One of the most important environmental modifiers that has appeared in a lot of the discussion we’ve had in Functional Medicine Update over the years is diet. Are there specific dietary principles that would have salutary effects on modulating hormones, and receptors, and the information (the signals) that are transduced from those hormones in the perimenopause or the menopausal period that would both help to improve symptoms in menopause while also regulating health outcomes in the woman? In our society today, a woman may live nearly half her life in the absence of having her menstrual period. The questions we want to ask a modern woman about her health, postmenopausally, are very different than if the mean average life expectancy of women was 55. What we are really asking is how do we sustain good health for a century or more in a woman? That’s a different question that requires different answers than maybe we would have used some 50 years ago. How does diet play a role in modulating these effects and maintenance of proper cardiovascular, neurological, musculoskeletal health in the case of a postmenopausal situation? I would like to address that question in a slightly more non-traditional way than perhaps you have heard before. We could jump to an answer that involves looking at specific diets that have been associated with long life and good health in women (transnational studies and things like the Japanese Women’s Study, which used food anthropological records, and examined what happened when Japanese women moved from their traditional diet to a Westernized diet). What happens to the disease patterns in these women? Those are important bits of information, but I want to move down a level in our discussion here. I want to use the same type of logic that women use about hormone replacement therapy to talk about constituents of the diet, meaning in hormone replacement therapy we are talking about specific small molecules interacting with specific receptor sites to induce, in that woman, specific signals in a tissue-specific way to then promote things like what we call (generally), health (brain health, or heart health, or skeletal health). How does that actually occur? Are there small molecules found within foods in a complex array of minimally processed things that were close to the earth, in which they were grown and harvested, that would have similar types of signaling principles to that which we talk about with hormones, and can either affect in a positive or a negative way, the way that hormones are used by the body? I hope I’m contextualizing this for you, as a listener, in a way that you understand. Rather than looking at it as a gross effect of diet on women’s health, what I want to look at is the same thing that we would with hormones: the interaction of small molecules (that in this case are found in diet versus, in the alternative case, found as small molecules in the hormonal system), and what influence they have on this crosstalk-this orchestration-of outcome of function in women from menopause right on through the end of their lives. When I raise that question, it sounds a lot like this principle that you have been hearing me develop in Functional Medicine Update: hormesis. What small molecules are present in foods that have a hormetic effect, meaning small amounts of things having an unexpected large effect on outcome? This is a “small builds large,” “small is beautiful” kind of conceptual framework. Beneficial Roles of Hormetic Phytochemicals There is compelling evidence from epidemiological studies that indicate beneficial roles of various hormetic-type phytochemicals that are found within a complex food-supply system that help to protect against virtually all the chronic diseases (cancer, heart disease, inflammatory disorders, and so forth). Emerging findings suggest that several of these dietary phytochemicals also benefit the nervous system, and when consumed regularly, may also reduce the risk of what we consider age-related neurological disorders such as Alzheimer’s and Parkinson’s diseases. We are starting to ask more detailed questions about the principal characteristics-the signatures of a diet that a woman might consume postmenopausally–that will have the beneficial effects on regulating her function, even with the declining level of estrogens or progestins due to ovarian… what’s called ovarian failure (I don’t really think it’s failure… )… ovarian alteration of function with age, and still results in maintenance of health. In other words, compressing disease and rectangularizing the health span, so to speak. The evidence supporting the health benefits of vegetables and fruits, which we have been talking about for years in Functional Medicine Update, provides a strong rationale for the identification of what these specific phytochemicals are that are responsible for modulating a variety of different functions. We now have the assay procedures that are starting to develop to do screening, and we have the animal models, and we ultimately even have the human clinical trials that would allow us to examine what type of diets are augmented and what kinds of phytochemicals would induce or promote proper function in the postmenopausal woman, just as we would set up clinical trials for looking at the difference between a nature identical (or bioidentical) estrogen to that of the mixed conjugated equine estrogens, which contain the B-ring unsaturated estrogens that are not natural to a woman’s body and are found only in pregnant mare’s urine. We could do a similar type of study with the molecular signatures of these phytochemicals to that which we might consider doing in a pharmacology experiment with the hormones. The difference, however, in this model, is that the hormetic effects of these phytochemicals are often seen to be more powerful (or I would call it synergistic), when they are combined together. We are hitting multiple things a little at a time to create an orchestral change of outcome, versus hitting one thing very hard, which is the general tendency towards drugs or pharmacology, where we come in with a single molecule like a jackhammer and we hit a specific functional status of metabolism or cellular biology. Are there studies that are now being done to look at the effects of sub-toxic doses of these phytochemicals that are derived from specific plant foods that modulate the principles that are associated with health of women as they go through the period of menopause? The answer is an absolute “yes” to that. I think it is a fascinating chapter that we are opening up that allows us to ask these questions at a slightly higher level of scrutiny and have the methodologies to actually provide answers as to how things work and what levels are beneficial, and even what genotypes might be most valuable or most sensitive to these particular alterations as it relates to their functional changes. Articles in Support of Phytochemicals I’m now actually indirectly quoting from a very nice new article that was authored by Mark Mattson and his colleagues that appeared in Neuromolecular Medicine in 2008.2 In this particular article, the authors are talking about how to lower the risk to brain-related dysfunctions in age through regulation of various neurological states of function with phytochemicals, but we can identify the same thing as it is being published in the area of cardiovascular disease and also with bone health. In fact, there is a wonderful paper authored by RM Ortega in Public Health Nutrition.3 This article is about components of the Mediterranean diet and how these phytochemicals have direct impact upon the health of individuals who are suffering from things like dysinsulinism, or indications of osteoporosis (or at least osteopenia), and how specific functional characteristics of the Mediterranean diet can play a role in modulation of these functional outcomes. You’ll notice that this is a different way of framing the diet-health connection. I really like a paper that appeared recently titled “Local Food and Cardioprotection: The Role of Phytochemicals.”4 This article looked at how specific families of plant-derived materials that are in our diets for millennia (so-called proven safe by food consumption), have a dramatic effect on all of the principles that we associate with the aging cardiovascular system, meaning they help to retard the dysfunction of the cardiovascular system with time-things like components of extra virgin olive oil, lycopene in tomatoes, and certain spices that we’ll talk about-all of which play very important roles in modulating cellular physiology. Before we leap to the construct that we need to have a hormone that has been replaced by either synthetic or natural methods-before we jump to that–maybe we ought to be looking at how the personalities of specific plant-derived and animal-derived nutrients can influence these functions in such a way as to limit or lower the need for hormone replacement. Let me discuss a classic example; it is one that is emerging that I think is quite fascinating. If we look historically at the French paradox, and we contrast that to northern latitude countries that didn’t have available grapes and therefore they didn’t have wine, their alternative, as you probably know, was beer. There are cultures that, historically, have consumed beer as a replacement for wine because wine wasn’t available. What you find when you look at the actual epidemiological outcome of these populations that were consuming high hop-derived related beer is that health benefits had some very significant similarities to that of individuals who consumed wine and red grapes. People started actually looking into this question of beer and health, just like wine and health, as part of the French paradox, and they found that there were a series of compounds within the hopping of beer that could have effect on the female reproductive system. Rather than being the agents that were commonly called the bittering agents of beer, which have names like the alpha and beta acids, these compounds that were manufactured biosynthetically by the hops plants are called the chalcones, or the 8-prenylated chalcones. These particular families of compounds, which are found in hoppy beers have an “estrogenic-like” effect. In fact, there is evidence to indicate that one of these compounds called 8-prenylnaringenin, which is a prenylated chalcone from hops, has an estrogenicity that, in female animal studies, is just about one order of magnitude lower than 17-beta estradiol. However, it has other signaling properties that 17-beta estradiol does not have that may be beneficial in modulating things like nuclear regulatory factor 2 and how that influences the expression of genes associated with detoxification. It has multiple personality types, so to speak. It is not only an estrogenic molecule, but it also influences other aspects of the cellular function, including detoxification. If we look at things like genistein, which as you know is a soy isoflavone that has estrogenic properties, or resveratrol (our red wine compound that has estrogenic properties), or 8-prenylnaringenin (the 8-prenylated chalcone found in hops in beer), these have all been found, recently, to be agents for not only cardioprotection, but protection against osteopenia and osteoporosis. When I say this, you’ll notice I’m talking about women’s health after menopause, like it was an estrogen and having multiple effects. The difference, however, is that these particular compounds derive from soy (as for genistein), or reseveratrol (from red grapes and peanut skins), or 8-prenylnaringenins (from hops), do not have the same mitotic stimulatory index as does 17-beta estradiol, and certainly have a vastly different effect on the production of the 8-hydroxy estrogens as does the family of equine estrogens, the B-ring unsaturated estrogens, found in mixed conjugated equine estrogens. What I am saying is that they have the potential to be safer with modulating effects that may be synergistic. If we talk about what a Mediterranean diet looks like, it might have soy protein containing genistein. It might have red grapes and red wine containing resveratrol. And it might have some beer-derived components like the hop-derived 8-prenylated chalcones. It obviously has fibers. It has a whole array of other phytochemicals that also participate as antioxidants and regulators of cellular function, so we are starting to get a multiple-voiced, orchestrated approach towards modulating those things that are associated with the menopause. It is interesting to note that when Dr. Deanna Minich and I authored the recent paper that appeared in Nutrition Reviews (this was the August 2008 issue-an article that was on nutrients modulating metabolic syndrome beyond macronutrients), we talked about phytochemicals, these same phytochemicals that I have just described (genistein, resveratrol, and hops-derived materials) also replicated to improve insulin signaling and to regulate inflammation.5 We are cutting across multiple functions. These phytochemicals have voices, so to speak, that when worked together, help to regulate function in a positive way. The question we come to, again, is: have any studies been done to look, head on head, in intervention trials, at a diet that is constructed to have the right kinds of molecules in it to send the right signals to induce appropriate regulation of bone physiology, cardiovascular physiology, neurological physiology, immunological physiology, in a natural source complete diet versus that of using hormone replacement therapy? The answer to that is “no.” No such study has yet been done or published that I have seen. There have been some gross nutritional intervention trials that have been done, but not optimizing the signaling of some of these phytochemicals that play this role. By the way, for those of you who are interested, this comparison of the phytohormones genistein, resveratrol, and 8-prenylnaringenin as agents for preventing osteoporosis appeared recently in the journal Planta Medica in July 2008.6 It is a very nice review paper looking at the studies being done on bone density using animals (these are female animals) in which they were supplemented with either 17-beta estradiol 3 benzoate as an active control, or genistein, or resveratrol, or 8-prenylnaringenin, or a combination of the three (genistein, resveratrol, 8-prenylnaringenin), and then looking at bone density in these animals after intervention. The results showed very significant improvement in bone integrity, or bone density, and skeletal strength, which was actually measured in these animals because the animals were sacrificed and they looked at their skeletal bone strength. They found that these have a very positive role in helping to prevent the deterioration of bone integrity and, simultaneously, also have a positive and salutary effect on things like serum lipids, cardiovascular health, and neurological health. I think what we are seeing is a new emerging view. Maybe we shouldn’t rush too quickly to jump on the bandwagon of hormone replacement therapy until we’ve had the opportunity to walk through how to optimize dietary intervention for each woman, knowing that when we get into hormone therapy there may be certain genotypes, like Leiden Factor V polymorphism individuals, who have very high risk to estrogen if supplemented because of thromboembolic disorders. You’ll notice that I mentioned soy. Soy is a big controversy, isn’t it? To say the least, it has been on the big board (the marquee) for discussion. We have heard recently that soy, because of its estrogenic characteristics, may encourage issues related to breast cancer in women or prostate cancer in men. It may be related to digestive disorders. It may be a highly allergic food and induce, then, immunological dysfunctions. It seems like everyday there is some voice out there finding a new way to criticize the incorporation of soy-based foods within the diet. I think we need to put this in some context because for every voice there is another voice that is a counter voice. When we look at the weight of the evidence of one voice versus the other in this area of soy, what do we see? There is a very nice review that appeared in Atherosclerosis in August 2008 titled “Nutritional and Nutraceutical Approaches to Dyslipidemia and Atherosclerosis Prevention.”7 The authors of this paper focus on dietary proteins and they look at different protein sources, like whey-based proteins, or wheat-based proteins, or soy-based proteins, or milk-derived proteins like casein. They ask questions as to the differences in influence that these particular proteins have on functional health over time. The authors of this paper are quite well-known collaborators in this whole area, including James Anderson from the University of Kentucky, who has been very well-published over the years in terms of nutritional endocrinology, and Cesare Sirtori, who is also very well known and a nutritional pharmacologist at the University of Milano. In this particular paper, these colleagues review what is really happening and what has been published in the literature. When they look at soy proteins and the risk/benefit of soy protein inclusion in the diet, it is quite, I think, a very realistic perspective for us to take away. What they point out is that soy proteins are unique in their composition as contrasted to animal proteins because of their high arginine content relative to their lysine content. As contrasted to animal proteins that are generally higher in lysine and lower in arginine and higher in sulfur amino acids, the soy proteins are uniquely different in their composition, having higher arginine and lower lysine. This arginine composition seems to be one of the contributors to the effect that soy protein has on regulating things like endothelial nitric oxide synthase activity and influencing in a positive way vascular compliance, lowering blood pressure, and improving endothelial function within the vasculature. But beyond the individual amino acids-and here’s where the story gets very, very interesting and I hope I can say this so that it is cogent and understandable-the proteins that are within soy, when partially hydrolyzed by the gut digestive process, liberate little oligopeptides that now have been identified to have influence, on their own, as information molecules that are differing than the breakdown products of other food proteins. They set up cellular signals across the GI signaling process to induce things systemically that have salutary effects on inflammation, cholesterol levels, lipid biosynthesis, and metabolism. Research on the Absorption of Intact Proteins We have now kind of moved into a new era of looking not only at the intact proteins and their amino acid composition (which has been a historical way we have looked at dietary protein physiology), to now looking at the information content within dietary proteins as a consequence of their partial digestion and the potential adherence or binding of those proteomic molecules or smaller polypeptides with receptors that trigger new signals that have new structure-function relationships. I know what I just said is pretty dramatic because most of us learned that dietary protein nutriture was based principally on the digestion of protein down to its requisite amino acids, and then the absorption of those amino acids into the plasma, and those would then be resynthesized on the other side of the gut wall to produce the body’s native proteins. It was told to us that there was no absorption of intact protein from our food. What is now being seen, however, is that small fragments of the intact protein can be absorbed to the extent that they can have impact upon cellular signaling across the gut mucosal wall and, as such, across the lumen they can then influence, systemically, through action at a distance, these signaling processes. This is a revolutionary change in thinking in both nutrition and physiology. Once we start accepting there may be dietary proteins that have differing signaling properties beyond that of the amino acids from which they are made that then influence systemic function, we now have a whole new ballpark opening up and a new ball game relative to how you utilize specific dietary proteins to modulate function. That seems to be what is occurring in the relative understanding of how soy protein differs from that of animal protein because you can take the exact composition of amino acids found in soy protein and administer those to animals in the same amount that you had given the native protein, and you will get different physiological outcomes in terms of lowering serum lipids, lowering inflammation, and modifying vascular endothelial function. It is more than just the amino acids, themselves. It is also the composition of the amino acids as they are found along the chain that when delivered in smaller fragments have differing effects on function. I think that that is a pretty powerful concept. When we talk about protein, it’s a family of all sorts of different molecules, just like when we talk about gluten. Gluten is a generic term for a class of molecules which run similar in electrophoresis, but underneath that peak-that electrophoretic peak-reside many, many different molecules that all make up the family that we call gluten. Some of those molecules may have different effects on the immune system than others, so we generalize it to say gluten, but it may be that you can have gluten in your diet that was free of one those protein fractions and it would not produce a gluten response, whereas there may be one or a smaller factor of offending gluten molecules within that family that trigger, then, specific immunologic effects by receptor-binding. I’m trying to get you to sense that we are seeing shifting sand right now, shifting understanding. With regard to soy protein, we know there are specific fractions that have the most health beneficial effects, and that these, then, lower LDL in animals, they lower total cholesterol, they increase HDL slightly, and they lower CRP (C-reactive protein). We can say these are positive benefits that are accrued to soy protein as a protein, itself. I’m not even talking about the other phytochemicals, like the beta-sitosterol or stigmasterol (the neutral plant sterols). I’m not talking about isoflavones, like genistein or daidzein. I’m not talking about lignans that have additional effects like those that are metabolized to equol. I’m just talking about the protein, in and of itself. When people say now that soy protein is dangerous, or bad, or has adverse health effects, I just don’t think it stacks up at all against the weight of evidence in the literature that is now getting much more precise as to how these particular characteristics in soy protein, in a full complement of materials, influences physiological function. It may have hypotensive effects and cause the vasculature to relax by increasing endothelial nitric oxide synthase activity. It has ACE-inhibition effects by modulating angiotensin-converting enzyme activity to help regulate blood pressure. Recent Papers on Soy Protein Intervention As always, I want to emphasize everything in moderation, but I think this backlash against soy is a very ill-founded approach. It may prevent many women from consuming soy in their diet, and as such have a detrimental effect or a lower-than-desirable effect on how diet will influence their function (cardiovascular, neurologic, and skeletal function) post-menopausally. There is a very nice meta-analysis on the effects of soy protein containing isoflavones and lipid profiles that was published in the American Journal of Clinical Nutrition in 2005.8 The authors of this article looked at 23 randomized controlled trials published from 1995 to 2002 on soy protein intervention in humans (these are all human trials) to examine the effect on cholesterol (LDL cholesterol), triglycerides, HDL, and oxidative stress factors. What they found was that soy protein in its intact form, containing isoflavones, significantly reduced total serum cholesterol, LDL cholesterol and triglycerides, and increased HDL. The changes were related to the level (about 25 grams a day), the duration of intake, the sex (females having a positive impact), and the initial lipid levels. Those who had the highest lipid levels had the most positive effects. There is even a more recent paper that I think you’ll find interesting, again talking about post-menopausal women and the effect of soy protein on modulating their function. This is a systematic review looking at randomized control trials in humans and the association between the intake of 25 grams of soy protein a day and the effect on blood cholesterol and appeared in the Atherosclerosis in 2008.9 After looking at an extensive amount of literature, these authors report that the inclusion of modest amounts of soy protein (at least 25 grams a day) into the diets of adults with mild hypercholesterolemia, (which is often seen in the post-menopausal woman), resulted in reductions in LDL. I just don’t buy this model that has been talked about with phytochemically-enhanced diets-that Mediterranean diets and soy protein-containing programs are somehow not desirable for women as they move from perimenopause into menopause. If we were to optimize dietary variables and introduce women to these diet and lifestyle programs with exercise and stress management, the discussion about bioidentical hormone replacement would be a lot less important because many of these women who have need can modulate or modify it just by lifestyle and diet intervention alone. If there was still need to modify symptoms such as vaginal dryness, or night sweats, or dysphoria, you could use an appropriate amount of a bioidentical hormone. I think that’s the approach we are moving toward.. Research on Red Rice Yeast Let’s look at traditional Chinese medicine. There is a condiment that has been used in Chinese cooking for years that modulates cardiovascular health, and we call it red rice yeast. Red rice yeast is a condiment in the traditional Chinese sense. The fungus grows on rice and produces not only the red color, but it also produces a class of compounds called monacolins, one of which is related to lovastatin, or the cholesterol-lowering agent that acts via its effect on HMG-CoA reductase. Many studies have been published on the effects that red rice yeast has on coronary events in the Chinese population. A secondary prevention trial was just published in the American Journal of Cardiology looking at the effect of red rice yeast on Chinese men and women who had previously had a heart attack, and compared the secondary heart attack incidence in 5000 patients versus those who would have been on traditional pharmacological statin therapy.10 They found that the individuals on a daily intake of red rice yeast actually had a lowered level of secondary heart attacks. I think there is so much yet to be learned about how these molecules in nature modulate function at the cellular level and go through similar mechanisms of actions. The difference is they don’t work as a sledgehammer; they work by modulating, or tickling, metabolism to produce altered function. With that in mind, let’s go to our extraordinary clinician of the month to take this to the next level of discussion about bioavailable hormones.

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INTERVIEW TRANSCRIPT Clinician/Researcher of the Month Jane Murray, MD Women in Balance PO Box 12004 Overland Park, KS 66282 www.womeninbalance.org Here we are back at that section of Functional Medicine Update that we look forward to every month and that is our clinician or researcher of the month component. We are privileged this month to have a leader in a field that is at the forefront of our discussions about the transitions that occur as a person ages into middle-age and beyond. One of these issues, of course, has to do with the transition into menopause for women and the transition into climacteric for men. What are the various things we can do to assist that transition to be as healthy as possible and to compress morbidity and increase life expectancy? We are very privileged to have Dr. Jane Murray, who will be sharing with us some work that she has been doing with Women in Balance on the state of the science of bioidentical hormones for mid-life women, which I think, for all of us, is a very important ongoing discussion. We have had a number of discussions about this in Functional Medicine Update over the last few years, but I think you are going to find this interview takes it to the next level of discussion. Let me give you a quick introduction of Dr. Murray. She is at the Sastun Center for Integrative Health Care in Overland Park, Kansas. I first had the privilege of meeting her through the Institute for Functional Medicine, when she was the Chair of the Department of Family Medicine at the University of Kansas Medical Center. Dr. Murray is obviously one of those people we hold at high esteem as a functional medicine expert. She has also worked with the American Academy of Family Practice; she and Dr. David Jones actually gave a course at one of their recent meetings on functional medicine in the family practice environment. She was the Chair of the AAFP course in Complementary and Alternative Practices in 1999 and core faculty in the AAFP Fundamentals of Management. Dr. Murray comes with a very broad and deep understanding of the issues surrounding family practice and also how that interfaces with healthcare issues throughout the lifecycle. Today we are particularly going to focus on this issue of mid-life women. With that as a brief introduction, Dr. Murray, I would like to introduce you once again to Functional Medicine Update, and thanks so much, Jane, for being with us. JM: Well, Jeff, it’s a true honor to be able to have a conversation with you, someone who has been such a leader and that we all learn so much from. Thank you for inviting me. A New Publication on Bioidentical Hormones JB: This review paper that you and your colleagues have been working on, which, as I mentioned briefly, is the state of the science of bioidentical hormones for mid-life women&hellip;really below what’s written is a tremendous amount of experience that you and your colleagues have clinically, as well as a very deep amount of information from both clinical and basic research science. I think before we jump right in to that review, maybe you can just give us some introduction to your historical experience with hormonal issues and women going through the menopause. Women in Balance: A National, Nonprofit Organization JM: Okay. I think all of us, as clinicians, really think of ourselves as students, and many times patients are our best teachers. About 15 years ago, when I was not, myself, quite in the mid-life transition yet, I had a series of mid-life women who really were very interested in having as much information as possible about their transition and were doing some things that I had not been exposed to with their hormone therapy. Specifically, they were using some bioidentical and compounded hormones. I got curious and started to look into this whole new field of individualizing medicines for patients and became very fascinated. I had not learned about compounded medications. I was not very familiar, at that time, with bioidentical hormones and what they were. So, again, as often happens, my patients really spurred me to learn more. And the more I learned, the more fascinated I became. In the late 90s I started reading things-articles, research papers-about progesterone, in particular, and how it was very different from synthetic progestins such as medroxyprogestone acetate that was being used commonly in hormone therapy for women. And I was sort of shocked that this wasn’t more widely known, this very clear, cogent research data about the differentiation between these two forms and some of the actual improvement in benefits for patients in using the real (in this case, progesterone) hormones. I actually kind of got so interested I wrote a little paper that was published in a primary care journal about progesterone and its benefits, and that kind of took its own legs and got me introduced to some other people who were very interested in the field and we started meeting and talking and decided that really women needed more information, and clinicians needed more good, unbiased, clear information about the various hormone options women might have and why some might actually be physiologically superior to others. After a lot of conversations and meetings and discussion, we decided to start a national nonprofit organization called Women in Balance, which I can talk more about if you are interested. JB: Yes, I would, but before we get to that, I always find it fascinating that people who rise to be the leaders in a discipline (and you certainly fulfill that definition) have very nonlinear paths to how they got to a certain point in their life that we all respect as their leadership position. I find it interesting that you started off at UCLA, and you went up through what obviously is the “southern California” experience, with family practice residency at the Santa Monica Hospital Medical Center. Then you became the Director of the Division of Education for AAFP (so you become kind of institutional medicine as well as your clinical medicine), and you move on from there to Kansas, which might not be seen (for most people) as the kind of commonplace transition. You end up in this family practice residency chair position at the department of family medicine, University of Kansas Medical Center, and then later into private practice, and now in your center. How did you get guided through these experiences? It is very interesting because it doesn’t seem like a linear path. JM: No. Well, you know, I think in primary care and family medicine, you have to be sort of interested in the broad picture, and I always was. Going through medical school, I liked every rotation, and what I liked was the people and the patients and trying to see if I could put things together for them from different fields and different specialties. For myself, I always felt that trying to do a narrow specialty would be way too constricting and not as beneficial as if I could maybe pluck information and experience from a variety of areas. What has resonated so much with me over the last, maybe, eight years since I’ve been exposed to functional medicine and your fine work is that there are just exceptional mind-expanding opportunities to see how we can take the individual patient and look at them in the bigger, broader perspective and not worry about labels, but worry about what is happening with them and what they need. I think what I found, through my whole experience in all of these different venues, was people being very unique and situations being very unique and needing to pull experience and knowledge from a variety of areas, whether it was running a meeting in the family medicine department or meeting with the other chairs or putting together educational programs for the Academy of Family Physicians. It helped to have a breadth of experience to be able to be effective in those areas. You know, you keep referring to me as an expert&hellip;I just feel like I’m a lifelong student and I’m always trying to learn and pick up new information and be more well-rounded and be able to do a better job with patients. I would say that that has been what has driven me. As a young resident, I would listen to patients tell me that their back pain was better with their chiropractor, which, you know, back in the 80s was not something that doctors really recommended a great deal-“Go see your chiropractor.” I was always a little bit of a rebel. I got into a little bit of trouble for not using enough drugs in my residency and maybe not a high enough dose-“Oh my goodness, you’re telling a patient it is alright to go to a chiropractor?” My response would be, “Well, you know what? It’s helping them, and it’s helping them in a different way and a better way than anything I have been able to do.” So I think that’s what we want: helping people. That’s really been my trajectory: to take the best of whatever we can find and see if we can help someone. JB: That then helps us to understand, obviously, the segue to the next point, which is probably why you and your colleagues decided to spend the time and energy to form Women in Balance. It just seems like an extension-the interface and links. Tell us a little bit about that. JM: We all felt that women were getting information primarily from healthcare providers about their options for mid-life transitions. At this moment, we are talking about hormones, but there is certainly a broader palette of options than hormones. The standard of care would be to go to your gynecologist, your family physician, or your internist once a year for your pap smear. If you are having some hot flashes and your periods are changing you get a prescription for something-say Prempro-and, you know, then you would hear “Have a nice year. I’ll see you next year for your next pap smear.” For women we are seeing now (as you mentioned, the baby boomers who are aging and coming into this whole mid-life and beyond timeframe), that is really not an acceptable option. You don’t just give someone a prescription and say have a nice time. They want a conversation. They want to know what this medicine does. What are the risks and benefits? What are the other options that aren’t this? We kept talking to patients, and friends, and colleagues about their frustration with health care. They don’t want to just take horse urine. They want to know what else might be available. We really felt that in a way there was kind of an injustice for women that they were not having access to the full range of information and therapies, largely because the information that doctors receive about healthcare options comes from continuing education programs and other opportunities that are highly pharmaceutical-company driven. The things that pharmaceutical companies don’t know about or don’t sell are not as often (or have not, maybe, until more recently) been what doctors learn about. We felt there needed to be some kind of an opportunity, and we basically created a website that has tools, information, resources, primarily for women, but also for healthcare providers interested in caring for women, to really put forth what some of the options might be. One of the big interests that we have had and that stemmed from that paper that I wrote a long time ago about is the differences between progesterone and synthetic progestins; we need to know more about this. When patients would say, “Well, my doctor says there is no research about these bioidentical hormones,” we felt that that was a significant inaccuracy. One of the first things we put on our website was the research that has been done (the papers that have been published) about bioidentical progesterone and bioidentical estrogen, and what we do know so that there at least is some data to support that there isn’t zero science in this field. Now we are moving forward and developing tools for women to use when conversing with their clinicians about hormone options, and very soon (hopefully by the end of the year 2008), we will have a practitioner locator for women who want to have a physician/clinician who is somewhat knowledgeable in this area and at least willing to have a conversation with them. JB: So obviously you need to tell us the URL for this website… JM: Yes! It is www.womeninbalance.org. JB: Great. And it is all run together? JM: All run together: www.womeninbalance.org. Polarized Views of Hormone Replacement Therapy JB: You hear this interesting discussion that is going on right now. I have heard it back and forth among clinicians as I travel around the country. Some people say, “You know, going through the menopause is a natural process of transition that has been going on–it is the circadian rhythms of life–in women since time in memoriam. We didn’t have access to all of these hormone replacement things before and women did just fine, so why do even need to consider this? It’s a natural process.” And then on the other side (I’m giving the two polar extremes here just to make a point), people are saying, “You know, women need to be supported with every possible thing we can think of so that their physiology will look like that of a 30-year old or a 25-year old. If you expect them to live healthily out to 100 years, then you’ve got to use the whole pharmacopeia.” Could you kind of characterize where Women in Balance is in that continuum? JM: Yes, and I think that’s a good polarization, as you have said. Certainly there are women who live a very healthy lifestyle. They have always taken good care of themselves. They are balanced in mind, body, and spirit, and many times they don’t experience a great deal of difficulty (disruption of their life, their sleep, their mood). They are able to transition what can be a bumpy path for some very gracefully and very easily and they don’t need to do anything pharmacologic at all. That would certainly be, I think, our ideal situation. Then there are women who are very disabled by hot flashes and night sweats and their sleep is terribly interrupted and so then the next day they are fatigued and they don’t focus well. They can’t do their jobs. They can’t care for their families. And so there is a wide spectrum here and I think it comes back to we need to practice individualized medicine and take a person where they are at and help them find their way (it’s their own way) through this trajectory, but we have some tools and some experiences that might be helpful to them. Hormone “Therapy” Rather Than “Replacement” What I find in my practice (and I think the view of our organization, Women in Balance, is) is that balance is everything, and to find your own balance is a very individual path and it might involve changing your diet, changing your lifestyle, getting more exercise, seeing a therapist if you are having stress-related emotional issues, doing some mind-body practices with calming yourself and balancing and being sure you do some good self-care. And then sometimes we need to help some of the symptoms that people are having with some kind of hormone supplementation. We’re not really calling it “replacement” any more; we are calling it hormone therapy now. It’s the broad array of the hormones that women might have deficiencies in or symptoms related to their being out of balance. We take that individual person and help them find what they might need for a period of time (months to years). And then, of course, there is a whole other arena of women’s health research: finding some actual (perhaps) benefits from replacing or supplementing hormones relative to density for years, which we have known about for years, and now we are getting into some other areas, such as preventing cardiovascular disease, if we start some of these hormones early in the transition, and maybe even some brain protection. So there is beginning to be scientific and clinical arguments being made that, “Gee, you’re right. We could keep people healthier and happier through their next 40 years if we could balance their hormones better.” I don’t know that anybody knows what the right answer is. My approach with patients is to say, “Well, if it looks like you are a candidate and that hormones might be helpful to you and we can talk about, perhaps, what we think the safest ways to use them are, then we’ll have this conversation at least every year, because the state of the science will change, the state of you will change, and we’ll see if we want to continue, or change your regimen, or add something new, take something away, see how things are going.” This is a very big moving target. We are getting new and more exciting research all the time about the risks and benefits and the options about hormone therapy, and we need to have a lot more information than we have to make the best choices. But, you know, we are kind stuck in the here and now and we have to practice medicine with the information we have and try to use it in the best way. JB: I think you have said so many fantastic things in that very, very condensed and dense bit of information you shared with us. Let me go back and pick up a few things. First of all, I think what you said (matter of factly) is probably, for the average listener, a pretty big deal because I think it implies something quite different. You said that we’ve changed our terminology from hormone replacement to hormone therapy. That, to me, connotes (and raises the question), what does therapy mean? And you went on to say, then, that has to do with personalization and the fact that we have changes that are going on through time. There is not just a formula or a recipe. It is not just a woman of a certain age with a certain dose-response. You basically are looking at a much more complex array. You are basically treating the web of that individual. JM: Exactly. JB: These are very big conceptual changes, aren’t they, than the way that most practitioners were trained in school around differential diagnosis and seeing menopause maybe as a disease that you treat? Mid-Life Brings Development Issues JM: A disease with, “Here’s our three tools that we have to treat it.” Absolutely. It is so much a web, and this is one of the reasons I love this field and I am kind of passionate about working with women in this transition time because it is exactly the web. There is so much going on with a woman and a man, even (and we don’t have time to talk about men’s hormones), with the aging process, with the changes in hormones, with the changes in life responsibilities. For many of my patients, their teenagers are going off to college and their parents are going into nursing homes all at the same time. They are having more stresses with their own work environment. They are being subjected, possibly, to ageism in their corporate structures. They are possibly reevaluating the whole purpose of their life. In fact, mid-life has developmental issues just like every stage of development from birth through death. One of the developmental issues at mid-life is, “What’s my purpose?” And very often people find, you know, “this work I’m doing isn’t what I wanted to be doing. This isn’t what I want my legacy to be.” And so they are having a lot of emotional angst and self-exploration and there is a tremendous amount of anxiety, and depression, and worry, and doubt along with all of these hormonal changes and family situations. It is the perfect, ripe opportunity for working with the web and thinking about how one aspect of this person’s life experience is affecting something else. JB: With that as a context, let’s now go down a level into the reality of what this might mean. You talked about what I call the three “big Bs:” bone, brain, and breast. And we could tie that also to cardiovascular, so we maybe have the “big four.” Do you need to assess using diagnostic profiling or some kind of clinical/biochemical testing before you get involved with this, or can you use symptoms as your guide? The Complexity of Hormone Testing JM: I would say it depends. I think certainly the whole issue of hormone testing we could spend hours discussing. Women who are over about 45, I honestly don’t think we need to even bother checking something like progesterone because it is going to be very low and we might as well not waste their money because you just don’t ovulate, you don’t make progesterone, and there is no point in checking for that. Checking various estrogen levels might be something useful to do, but honestly I think a woman is her own best bioassay, probably, for estrogen levels. Is there vaginal dryness? Are there vasomotor symptoms? Those are the biggies that tell us that there is estrogen deficiency. It doesn’t really matter if her estrogen level is “x” in her blood, or saliva, or urine. If she’s got these symptoms, we are probably going to do some things to help improve her estrogenation. Now some of that can be done with diet and with exercise and so forth, but perhaps a little local vaginal estrogen, if that’s the biggest problem. If libido is an issue, I will probably, personally, never give anybody testosterone without knowing that their level is deficient, because that has a lot more intricacies in treatment than some of the other hormones do. I think what you might test is worth thinking about, and, you know, not just looking at hormones, but also cholesterol and blood sugar. Does she have metabolic syndrome? What’s your thyroid doing? How’s her adrenal gland? All of these things are very important in terms of finding balance, and it isn’t all just about estrogen and progesterone. I think, again, you sort of take it individually. What is the scope of symptoms here? Can we maybe even try some things empirically? A little bit of bioidentical estrogen, a little bit of bioidentical progesterone&hellip;get the sleep better, get the vasomotor symptoms better, then sort of see where we are. Now, is she ready to work on some of her emotional issues? Now is she ready to exercise more? She’s sleeping better, she’s got more energy, can she think about changing some of her eating patterns? Again, you really have to take it from an individual perspective. The Importance of Re-checking Levels Now, having said that, I will say that one of the things that got me intrigued about looking at how I did hormone treatment differently a number of years ago was that it occurred to me that we’ve got people on estrogen replacement therapy, and then we never check them. We never think that it is important to know what is going on biochemically with them. We don’t even give people refills of thyroid medication without checking their TSH at least every year; that’s mainstream medicine. Yet we give women Premarin for years on end without ever asking, “What’s their estrogen level?” So I started (again, about 15 years ago) checking people’s total estrogen level on regular doses of Premarin, and for some people these levels would come back 3-,4-,5-times higher than any physiologic needed to treat symptoms. And I got to thinking that maybe it is those kinds of patients in whom we are overstimulating breast receptors, and maybe those are the patients who are likely to have problems with breast cancer, and uterine bleeding, and so forth. Even though the state of the science of testing for hormone replacement doses is still very much in its infancy, it just got me thinking that it is probably not totally responsible to give people a drug and never check to see if it’s the right dose. Even though I would (maybe), personally, start somebody on something empirically, I might want to check down the road, periodically, to make sure they are still in a safe physiologic range on the replacement doses or the treatment doses. JB: So now a number of questions derive from that that are very important. When you are testing, do you test plasma, or do you test urine, or a combination? What is the timing of your testing? When do you draw samples? Evaluating Different Delivery Systems JM: Exactly. I used to think I knew how to do this a number of years ago, and of course, every year it gets more and more difficult. The more you know, the less you know. It turns out that probably what kind of testing one does depends on many factors. What’s the delivery system? If a person, for example, is using a transdermal estradiol or progesterone, the way we do the serum test is to draw blood and spin off the red cells and measure it in the serum. Well, when you put, particularly, estrogen and progesterone on transdermally, the hormone is picked up by the capillaries in the subcutaneous tissues and carried around to the various receptor sites throughout the body, and the red cell membrane holds these hormones and releases them at the tissue level, so we get good tissue responses. But when we measure serum levels, we have thrown away the red cells and there’s not much left in the serum. So then we think, “Oh my gosh, these levels are so miniscule. These hormones aren’t doing anything.” So for transdermal delivery systems, we may need to think about saliva or urine or capillary blood testing rather than serum testing. If we are doing something that is a transmucosal delivery system like a lozenge or a sublingual drop, which some of the compounding pharmacies are very good at making, then testing saliva is kind of difficult because those hormones are now concentrated in the salivary glands, so saliva levels will be very inordinately high. Like I said, I used to think, “Oh yeah, well, we’ll just check your levels, you know, halfway between doses. If you’re taking a dose once a day, we’ll do it at 12 hours. If you are taking a dose of something twice a day, we’ll do it at 6 hours.” And that stood me in very good stead until I started realizing from the work of Frank Stanczyk, for example, at the University of Southern California, a reproductive endocrinologist. Basic science has discovered this issue with progesterone transdermally being attached to red cells and then serum levels are pretty useless. I think this is a whole arena that just cries out for more data, more research, more study, and more standardization of the testing modalities as well because they’re not as standardized as maybe a blood sugar or a potassium level might be. This isn’t unique, either. In fact, I think it was a recent Functional Medicine Update that talked about how even cholesterol levels vary from lab to lab and from day to day. One cholesterol level may not tell the whole story about someone’s cholesterol. So this whole idea of testing I think is very important, but it is not the be all and end all. The whole chapter has not been written on what’s the right way to test, how to test, who to test, when to test. This is still very anecdotal. You talk to 10 different clinicians and you’ll get 10 different models of how they are doing testing because there is really no textbook on this yet. JB: So that leads me, then, to the question of once you have made your clinical judgment and you’re going to use a bioidentical estrogen, do you use 17-beta estradiol, transdermally? Do you use a mixture of estrone and estradiol, now knowing that we’ve got some questions about estriol? (Probably you’re not using that.) Give us some thought about where you go from there. JM: Yes, that’s a very good question. Again, the more data we get, the more complicated this seems to become. When I sit with a new patient and we talk about options, I tell her my preference would be to use a bioidentical estrogen because it sits on your receptors properly. There are three bioidentical estrogens, we know: estriol, estradiol, estrone. Estradiol is probably the most potent. It is the one that has the most studies. When you look at all the research, there is some from Europe and Japan about estriol. Estradiol has probably had more data. It turns out that now we are finding that giving estrogen of any kind-bioidentical or otherwise-orally versus transdermally makes a big difference in vascular inflammatory markers, thrombotic tendencies, blood vessel reactivity. Probably from 5 to 8 years now of good research, it looks like transdermal delivery of estrogen is probably, in the whole, much safer, and that we get a better inflammatory and thrombosis profile when we use patches, or creams, or gels through the skin, or some non-oral estrogen preparation, so the estrogen itself doesn’t go through the liver and then stimulate the liver to make all these various proteins that may not have the best outcome for us. Again, that’s another whole layer. What’s the right delivery system? What’s the right molecule? I think the issue about estrogen is that we haven’t been comparing apples to apples. We’ve got oral estrogens (equine estrogens). There are oral estradiols. But we only really have transdermal 17-beta estradiol. There are not too many other available (commercially or compounded) estrogens that are not at least partly estradiol. So we’re not comparing transdermal conjugated equine estrogen to transdermal estradiol. That’s kind of a just a scientific flaw. However, there is a huge amount of information about the difference between progesterone and all of the synthetic progestins that just don’t have the biochemical and physiologic benefits that real progesterone has, and that’s whether it is given orally, transdermally, transmucosally, or any other way. Progesterone is just so far superior in everything that is in the research to the synthetic progestins that I almost don’t why we even use medroxyprogesterone acetate or any of the other synthetic progestins at this point in our medical knowledge. JB: Let me just give a parenthetical and see if this washes with you. I think we use medroxyprogesterone acetate because in the way that the bioassay was set up to evaluate progestin activity, it was set-up with a rat uterine assay that was very, very sensitive to the chemical nature of those progestins. So if you start to develop a bioassay that selects for certain activities, which may have to do with pregnancy, then it starts to make that molecule look like it is preferential to others because you forgot about all the other activities that the other molecules might have had if you ran different bioassays. Large-Scale French Studies Yielding Important Data JM: Exactly. And we do know that all the synthetic progestins and real progesterone do protect the uterus in a very similar way and they are all safe and effective for that in that regard. However, the synthetic progestins are not safe in pregnancy, whereas real progesterone, of course, we use it to preserve pregnancy in women who have recurrent early miscarriages. But you are right. The science is coming out now about all of the other things progesterone does in the body in terms of some very powerful data about breast cancer and looking at different hormone combinations. Even the Women’s Health Initiative was halted in the arm that had conjugated equine estrogens and medroxyprogesterone acetate, but not in the arm with the estrogen alone. There was a very large study out of France in 2005 (Fournier’s group) that looked at over 90,000 women on a variety of estrogen and progestin/progesterone combinations and the relative risk of breast cancer after five years.11 In the women on any estrogen plus a synthetic progestin, there was about 1.4 relative risk to women on nothing. The relative risk for women on any estrogen preparation and actual progesterone was 0.9. So they did not conclude that there was a protective benefit for progesterone in breast cancer, but it certainly did not increase the risk. That, to me, is a piece of information that I think is incredibly powerful and that was an incredibly huge study; I don’t think anyone can argue with the power of it. Other things are coming out that are so fascinating about progesterone regarding the nervous system. It turns out glial cells in the brain make progesterone, and that progesterone is a pro-myelinating hormone that is necessary for the nervous system to function well. Again, this is information out of France. There was a huge paper from 2007 from a group at the University of Paris looking at all of the neuroendocrine effects of progesterone and why it probably is a preferential part of hormone therapy in lieu of synthetic progestins in terms of helping keep GABA receptors healthy and prevent brain degenerative diseases related to aging and so forth.12 Again, this information is in its infancy, but it is just fascinating. I think you are right that when you look at that one uterine animal model assay, yes, the synthetic progestins are great. But when you look at all these other effects-and we haven’t even talked about cardiovascular yet-progesterone is just head and shoulders above anything synthetic that we know of yet. JB: Yes, and I think you hit on something (again, there’s just so many topics that you have hit on that could be deep drilled for hours): this whole neuroactive sterol area which seems to be emerging and then how that relates to statins and whether there is some (in certain sensitive individuals) adverse effect of statins on reducing the precursors to these neuroactive sterols and what effect that could have on affect in mood, brain, and so forth&hellip; JM: Absolutely, yes, and memory. JB: You are hitting on such fascinating areas. You know, when we go back to Robert Wood Wilson and Feminine Forever and read that book today (which is disgusting, I might add, but if we can force ourselves through it&hellip;), what we recognize is so much of what seemed to be (in the way it was presented) factual information was really spun so seriously, and it affected generations, really almost three decades of thinking about this whole topic. JM: Yes. JB: Let me, if I can, talk about one other ADR (adverse drug reaction), which I know has come up because you alluded to it: thrombotic risks pertaining to hormone therapy. It seems like one of the ways that the Women’s Health Initiative has now been stratified and analyzed is to look at women who have certain single nucleotide polymorphisms that make them more susceptible to the coagulation problems associated with hormones. Can you tell us a little bit about how your thoughts relate to those women who may be unique in their SNPs pertaining to these coagulation parameters? Contraindications for Estrogen JM: Yes, absolutely. Certainly, whenever we would contemplate using an intervention with anybody, including bioidentical hormones, we have to think about contraindications. So with a person who has a history of antiphospholipid antibodies, antithrombin III, or Factor V Leiden genetic predispositions, we know that adding estrogen of any kind to that mix could precipitate problems with thrombosis. Those are the kinds of patients we’d want to be particularly careful with whether we even went down that road of hormones with them or not. So you are right, and I think this whole idea of pharmacogenomics and finding out an individual person’s risk for developing a problem with a drug is going to help us a great deal in knowing what is safe and what might not be safe for a person. As kind of a little aside, there is a great deal of information coming out, and even stratifying, as you said, the Women’s Health Initiative, about the age at which hormones are started probably making a big difference in cardiovascular risk. This doesn’t relate to the women with higher thrombotic genetic risks, but the blood vessels actually change as we age. In the Women’s Health Initiative, where we all know the average age was 62, these women had a little bit more risk of thrombolic stroke and cardiovascular events. But the younger women, when those early 50-year-old women in the Women’s Health Initiative were pulled out, did not have this increased risk. It looks as if early intervention, if we are going to do it for cardiovascular protection, is quite important. I think the results of the ELITE trial coming out of USC that is in process now looking at early versus late administration of estrogen and the KEEP Study (estrogen and progesterone intervention trial) that is being looked at in a multicenter trial, when those come out in a 2010, I think we’ll have some very good information about this whole timing issue of when to start hormones if we are going to do it. JB: Obviously we could carry this conversation on for hours&hellip; JM: Days! JB: You have all of that information just sitting in reserve-you could do that-but unfortunately we are going to have to draw this to a close. Maybe you could just give us your thoughts as you look forward to the future as to where you see the future of managing postmenopausal health may take us. JM: I’m hoping more and more clinicians will be willing to have a longer conversation with patients because that is what women want. They want to know: what are their options, what are their choices, what can they be doing? I’m hoping the future of menopause health management will really include a lot of self-care that women are doing themselves (lifestyle, in particular). I would hope that we would continue to have good, high-quality research with all of the questions that are still left very much unanswered after the Women’s Health Initiative. That was not the definitive women’s health hormone study by any means, and just in our conversation today we have brought up dozens of questions we still have that we need answers for. I also think we haven’t looked enough at the role of the adrenal and thyroid parts of the endocrine system and how they affect a woman’s experience of this mid-life transition, and that I hope we can flesh out and develop much more clearly. And then I sort of briefly mentioned the whole life cycle and developmental issues that happen at this stage. We don’t have a lot of information and ways to really help women through all of this. I hope that the mind-body aspects that are so critical at this time can also become a really standard part of our armamentarium with women in mid-life and beyond. JM: Dr. Murray, I can’t tell you how much we appreciate this. If this is not titillating everybody’s neurons then we’ve got a little problem with neuronal deficiency because this was really a tremendously interesting and evocative presentation. I want to again recommend that people check into the website, www.womeninbalance.org. I think it is a tremendous resource. And this new state of the art science review paper that you are going to be publishing I think will put another step in the road forward. Thank you for all of your hard work and being the clinician you are and being willing to share with us. JM: Jeff, it’s my honor. Thank you so much. In the course of this issue of Functional Medicine Update, I hope your takeaway might be that there are things we can tell women responsibly now as they go through their menopausal period about the risk/benefit trade-offs of various kinds of intervention trials, but that starting with lifestyle and diet intervention, and getting them on a therapeutic lifestyle change program, is-without question-the first and most important way of starting down this road before we start adding exogenous things in. Then, on top of that, let’s know something about that individual woman. Let’s make sure we are just not treating her as the average; treat her as the i 1 Canonico M, Plu-Bureau G, Lowe GDO, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336(7655):1227-1231. 2 Son TG, Camandola S, Mattson MP. Hormetic Dietary Phytochemicals. Neuromolecular Med. 2008 June 10. [Epub ahead of print] 3 Ortega RM. Importance of functional foods in the Mediterranean diet. Public Health Nutr. 2006;9(8A):1136-1140. Review. 4 Visioli F, Bogan P, Grande S, Detopoulou V, Manios Y, Galli C. Local food and cardioprotection: the role of phytochemicals. Forum Nutr. 2006;59:116-129. Review. 5 Minich DM, Bland JS. Dietary management of the metabolic syndrome beyond macronutrients. Nutr Rev. 2008;66(8):429-444. 6 Sehmisch S, Hammer F, Christoffel J, Seidlova-Wuttke D, Tezval M, et al. Comparison of the phytohormones genistein, resveratrol and 8-prenylnaringenin as agents for preventing osteoporosis. Planta Med. 2008;74(8):794-801. 7 Sirtori CR, Galli C, Anderson JW, Arnoldi A. Nutritional and nutraceutical approaches to dyslipidemia and atherosclerosis prevention: focus on dietary proteins. Atherosclerosis. 2008 Jul 1. [Epub ahead of print] 8 Zhan S, Ho SC. Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am J Clin Nutr. 2005;81:397-408. 9 Harland JI, Haffner TA. Systematic review, meta-analysis and regression of randomized controlled trials reporting an association between and intake of circa 25 g soya protein per day and blood cholesterol. Atherosclerosis. 2008;200:13-27. 10 Lu Z, Kou W, Du B, Wu Y, Zhao S, et al. Effect of xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol. 2008;101:1689-1693. 11 Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114(3):448-454. 12 Schumacher M, Guennoun R, Ghoumari A, Massaad C, Robert F, et al. Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev. 2007;28(4):387-439. ndividual. Look at her metabolism. Look at her genetics. Look at her history. And make prudent choices based upon the information that you have heard beautifully shared with you today

Welcome to Functional Medicine Update for December 2008. Can you believe that we are ending another extraordinary year? The evolution of functional medicine over the last 26 years has been truly remarkable. December’s issue is going to focus on epigenetics/epigenomics and how it relates to the future of medicine. We had the privilege of learning about this with Dr. Randy Jirtle, and I think we are now going to the next level by focusing on environmental epigenetics. Environmental epigenetics (as described by our researcher of the month, Dr. Michael Skinner) is another component that ties environmental exposures to nutritional factors, lifestyle, and the expression of chronic disease entities, which then can change patterns of morbidity over time due to the heritable opportunities that these epigenetic marks pass down through the generations. I think there is a lot of alarm that can come from the observations you will learn about in this issue, but there is also a lot of hope for change in the future. As we move into 2009, an epic period of change in the world’s history may be right ahead of us, certainly with the change in the United States government and all the things that are going on internationally. I think this topic we are discussing this month in Functional Medicine Update(a very small part of it-a microcosm) illustrates the remarkable nature of change that is occurring across all sectors–politics, economics, science, medicine, and so forth. With that as a prelude, let me just quickly remind you what we mean by epigenetics. As you know, it is the post-mitotic modulation (or the change in the DNA marks) that then allow only certain portions of our book of life to be expressed; all regions of our genome are not equally readable after epigenetic modulation. This has to do with either putting methyl groups on certain regions of the genome, or putting acetyl groups on the histone proteins that encode the compaction of our DNA genetic information and open up regions of the DNA so that they can be read (so these would be “Read Here” notes versus the “Don’t Read Here” notes that methyl groups impart). Webinar Series on Nutritional Epigenomics As some of you may know, I have just completed a two-part webinar series on basic nutritional epigenomics. This series will be available through Synthesis for those of you who are interested in doing more in-depth study on this emerging topic. I think this is a very, very important topic for reasons that we’ll be discussing this month. Emerging evidence obviously suggests a key role for epigenetics in a variety of human diseases, including inflammatory and even neoplastic disorders. The epigenome is modified by all sorts of environmental factors throughout life, of which nutrition is one and that’s why we called it “Nutritional Epigenomics.” Environmental xenobiotics or foreign chemicals can have a role to play in modulating the epigenome, and that’s what we will be discussing this month with Dr. Skinner: autoimmune and neoplastic consequences of cumulative epigenomic or epigenetic dysregulation that occurs throughout life. We want to protect our book of life against putting marks that start reading the wrong chapters. There are individuals who live in cultures that have a history of long life (the so-called blue zones of our world, where centenarians are common). These are places where, maybe, the epigenetic marks that occur throughout life are not being placed on the regions of the book of life that would cause bad stories to be read and good stories, (like tumor suppressor genes) to be silenced. Protecting the Epigenome from Genomic Instability I think this model that is emerging gives a different view of the concept of diet, lifestyle, and environment related to health. It suggests (as we learned from Dr. Fenech earlier in 2008) that we want to protect our genome against genomic instability (agents that would cause it to be less able to keep the integrity of our message alive and well). Altered epigenomic marks or epigenetic marks would, in fact, influence the stability of the message and its integrity of being read in the right way. We now recognize that there are a variety of dietary factors that influence this process of epigenetics and the “Stop” messages or the “Read Here” messages (the DNA methylation and acetylation messages). Those messages interrelate with diseases like autoimmune disease, cancer, diabetes, and heart disease. One condition that has been studied a great deal is colorectal cancer. Colorectal cancer is the most common cancer in nonsmokers and it poses a significant health burden. Observational studies have tended to support the impact of environmental factors, especially diet, on colorectal carcinogenesis. This is because the colon is like a conduit that is picking up the debris from our diet, and also the secondary byproducts from bacterial fermentation and the transference or the alteration of these materials into secondary chemicals that may cause injury at the cellular level. We have started to look very seriously within the cells of the mucosal lining. We find that the cells exposed in the colon to these various chemicals in the gut can undergo altered genomic/epigenomic marks, the so-called DNA methylation. This is DNA methylation that is thought to occur at least as commonly as inactivation of tumor suppressor genes. In fact, compared with other human cancers, promoter gene methylation occurs most commonly within the gastrointestinal tract. This is very recent work that has been discovered, and an article on this was published in the journal Epigenetics (it has its own journal now) in 2008.1So emerging data suggest, then, that direct influence of micronutrients (for example, folic acid and selenium, as well as other methyl-donating nutrients) interact with toxins and can alter DNA methylation in the colon mucosal cells and alter, then, the potential for epigenetic silencing of tumor suppressing genes. This recent research suggests such interactions are likely to have a mechanistic impact on colorectal cancer carcinogenesis through these pathways and offer potential therapeutic benefit for dietary alteration and even selective nutrient supplementation through nutraceuticals. You might say, “Are these epigenetic effects the same in all individuals?” Of course, the answer to that is “no” because we have to superimpose the concept of nutritional modulation of these epigenetic marks on the concept of genetic diversity (single nucleotide polymorphisms, the so-called SNP model). Although we only have about 25,000 genes in our human genome that code for proteins, we have several million different variations on a theme called single nucleotide polymorphisms that are single letter alphabet changes in these stories that relate to those genes. These single letter alphabet changes sometimes may be benign, but other times they may produce a variant protein that has differing functional characteristics. You could say there are different degrees of susceptibility to epigenomic changes based upon differing SNPs. This is making the field even more complicated. Epigenetics provides a potential explanation for how environmental factors modify the risk for common diseases. Individual variation in DNA methylation and epigenetic regulation has been reported at specific genomic regions, including transposable elements called transposons, genomically imprinted genes, and the inactive X chromosomes in females. Understanding of the factors that contribute to these inter-individual epigenetic variations is still emerging, but they do appear to relate, then, back to specific single nucleotide polymorphisms, or SNPs, that have unique diet and lifestyle sensitivity for their modulation. As Dr. Jirtle told us in his interview earlier in 2008, of these 25,000 genes within our human genome, there are probably just a few-maybe a few hundred at most-that are very sensitive to epigenetic changes in the adult cells (meaning genetic messages that can be epigenetically modified in the adult). Those are the genes that we probably really want to spend our time learning more about because those are the epigenetic changes that can be both wiped clean and replaced with new marks, and we can do something to actually alter the marks themselves. There is now some preliminary clinical evidence showing that when individuals with specific types of cancer are given a drug that modifies epigenetic marks (e.g., by wiping the slate clean, so to speak) such as removing the silencing of tumor suppressor genes, there has been remission.. That certainly gets us to think very significantly about where the future might be in therapeutic medicine, but it also gets us to think about the role that everyday living plays in putting marks on and taking marks off of our genome to allow the good messages to be read and messages that we want to save for a rainy day (that hopefully never comes) to be silenced The Important Role of Kinases in Intercellular Signal Transduction In terms of dietary manipulation related to methylation patterns, you might jump too much on the bandwagon of folate, B6, B12, betaine as being the answer because we know there are many other variables and factors that influence these epigenetically modulated pathways. The signal that alters or stages the epigenetic marks is a signal that we call intercellular signal transduction. With this process, something that occurs outside the cell that triggers a series of events that transfer through the cytoskeleton of the cell, all the way into the genomic message locked deep within the nucleus of the cell in our book of life-this vault, this library that is more secure than Fort Knox by orders of magnitude-and allows, then, for the structure of our genome to be modified epigenetically by the placement of these marks (these methyl groups or these acetyl groups). The intercellular signal transduction process that communicates the outside world to the inside of the cell is regulated in part through a family of enzymes that I have discussed with you in the past called kinases. There are over 500 of these, and they participate in kind of a complex relay race, passing along the baton through the cytoplasm of the cell and ultimately through the nuclear envelope into specific regions (promoter regions) of genes to modulate their function. Diet Plays a Role in Modulating Kinase Activity You might ask, “Does diet play a role in modulating kinase activity?” The answer is yes. It has now being discovered that there are many phytochemicals and nutrients that may play roles in augmenting or modulating kinase function within cells, which can then influence epigenomic remodeling of the genome. These are post-translational modifications that may influence what we call our nucleosome. The nucleosome is the complex unit structure that compacts and compresses the DNA message and locks it away safely within the cells so it is not easily accessible to injury from chemicals or radiation. The nucleosome is kind of a secure “vault.” These post-translational modifications of the nucleosome occur through these processes that are kinase modulated and can also connect to things called NAD-dependent histone deacetylases or acetylases. Resveratrol is an Example of a Phytochemical with Epigenetic Control One of the phytochemicals that has a rich history and certainly has been in the news and speaks to the nucleosome in this capacity (to the NAD-dependent histone deacetylase) is resveratrol. This is related to the paradox of the French wine syndrome and this whole construct of phytochemicals playing a role in modulating the sirtuin genes, which are the so-called longevity genes. These genes are modulated through the epigenetic control that resveratrol has on this NAD-dependent histone deacetylase. When modified, this causes the compaction or the change in the reading structure of the genome. It allows different chapters to be read or not read, so this is an epigenetic modulation that is seen in the adult by the exposure to resveratrol. Resveratrol is just one of many phytochemicals that are being identified to have effects on epigenomic modulation. I want to emphasize that the resveratrol work has principally been done, at this point, in very simple eukaryotic cell systems or in animals. We haven’t yet seen the proof of concept in humans, but there is evidence, at least from the preliminary data, suggesting that this resveratrol or phytochemical connection to the NAD-dependent deacetylases that modulate histone protein epigenomics is real and can have influences over time on the functionality of gene expression. I’m throwing a lot of words out there, aren’t I? For those of you not molecular biologists or cell biologists this may appear very complicated, but I hope you are getting the drift of where the science is going. We are continuing to see how diet has an information signature that is much more complete, robust, and sophisticated than we previously thought. And this diet and environment connection to genetic expression is tied, in part, to cellular processes that translate these outside messages into epigenetic modulation of the genome that not only is going to influence that existing cell in its present state, but (if it occurs in a germ cell) is also transmissible to the next generation. That’s the big “a-ha.” This concept may suggest that a changing environment can produce a transmissible factor very quickly, without having to rely on mutational injury to the genome as Darwinian natural selection might have suggested. This may occur very quickly by epigenetic modulation through these environmental factors, and we’ll be hearing much more about this from Dr. Skinner. We’ve got both positive and negative influences of epigenetics on outcome, as it relates to health. Dietary manipulation can influence these post-mitotic, or let’s call it epigenetic regulatory pathways (the histone deacetylation and acetylation pathways, and the methylation/demethylation and the phosphorylation pathways), all of which can play roles in modulating how our book of life is going to be read. Maternal Nutrition Influences Disease Susceptibility Later in Life Epidemiological and experimental studies have pointed toward maternal nutrition as a very major player during prenatal development in influencing disease susceptibility later in life. The reason for this is clearly tied to these epigenomic or epigenetic changes. This was reviewed beautifully in the Annual Review of Nutrition in 2008.2 This article discusses the influence of dietary sources on epigenetic programming during pregnancy. These messages can be passed on to the progeny as marks that alter the way their genes will be expressed throughout the course of their life unless they are able to wipe off those marks and replace them with new marks. Again, it has to do with sometimes aggressive lifestyle changes in behavior to reprogram and repattern some of these epigenetic systems. That is really where we are starting to see significant work going on now. What does it take to modulate an epigenetic mark at one of these susceptible gene regulatory units? I think we can say we don’t have the full answer to that question. The evidence would suggest that there are therapeutic opportunities for changing the course of expression. This is a very optimistic sense of the future. It doesn’t lead to our belief of determinism; it leads to the view that aggressive intervention can remodel the ability of our book of life to be expressed in more favorable ways. An article about this effect of in utero and early life conditions on adult health and disease was published in the New England Journal of Medicine in 2008.3 Really it is about tying back to epigenetic programming or patterning what went on with the sperm and the egg prior to conception and then what happened in utero relative to the placement of epigenetic marks. Some questions that come out of this are: can this explain things like the rising prevalence of autistic spectrum disorder?; or can this explain the rising incidence of hyperactivity disorder?; or can it explain the rising incidence of things like asthma? All of these have been identified in animal models to have epigenetic relationships. Are we silencing certain genes and activating other genes to be expressed through these epigenetic environmental influences? These are very interesting questions. We are trying to learn not only where the effects occur, but how we can then replace those kind of marks with the marks in the right place on the genome to create the right (or more favorable) outcome. Does Epigenetics Play a Role in Metabolic Syndrome? People are talking now about epigenetic modulation in cancer metabolism. What about chronic diseases? Can you modulate a condition as broad based as metabolic syndrome, which we know has multiple genes that are influencing multiple functions? The American Journal of Clinical Nutrition featured a very interesting article in 2007 looking at epigenetic modulation and the effect of metabolic syndrome.4 The article talked about how hyperinsulinemia and high insulin levels alter, post-mitotically, the epigenetic marks on the genome. In so doing, this causes regulation of expression in such a way as to induce higher inflammation, dyslipidemia, and vascular-related issues, which are things that we see clinically expressing themselves as type 2 diabetes, or cardiovascular disease, or even cancer, associated with hyperinsulinemia. This raises a whole different view, doesn’t it? It is a view about intervention that pertains to how to create the right marks in the right places (these epigenetic marks) to regulate the gene expression and to optimally produce outcome in the environment that is changing. This an environment in which we are being exposed to more and more things that are not native to the human species, but new within as little as a hundred years ago. We are having to develop new ways of modulating the effect of these exposures. The Influence of B Vitamins on Epigenetics What about B vitamins? Can we say that cultures that have low B vitamin intake, like concentration camp victims or prisoners of war, during starvation or famine, modulate the epigenome through lowered effect on genome methylation, acetylation, and phosphorylation? The answer appears to be yes. If you go back and look at individuals during time periods that were influenced by low nutrient intake, there is an influence on disease causality throughout the generations. This was discussed in an article in the Proceedings of the Nutrition Society in 2007.5 This is the whole construct that temporal insufficiency of nutrients that modulate various critical epigenetic pathways can influence not only the immediacy of that person’s health, but more importantly, the long-term outcome of their health, and maybe even passed on to progeny. What I’m really talking about here is a structural approach for, kind of, functional modules: looking at the body as a biological network and how it interacts with its environment. This is a very different view than looking at single agents and single outcomes. This is the approach of looking at body function and health outcome as large biological networks in which cellular function interacts with the environment in such a way as to influence both immediate and long-term outcomes. If we cast this approach against the past view of nutrition, nutritional supplementation, and nutritional pharmacology, it kind of re-contextualizes much of what we have been thinking for the last 30 years (actually it is probably more like the last 50 years). I recently authored a paper that appeared in Alternative Therapies in the September/October 2008 issue titled “The Future of Nutritional Pharmacology.”6 In that particular article I suggested that we go back and review the work of pioneers like Dr. Roger Williams, Dr. Linus Pauling, Dr.Abram Hoffer, and Dr. Kilmer McCully. So many discoveries, so many observations that were criticized heavily and were argued against by the “people in the know” at the time, are now being re-evaluated in light of nutritional epigenetics revolution. That is, how nutrients may not only influence the direct metabolism (i.e., metabolomics) through their effects as co-factors or antioxidants, but also their effect long-term on the signature of information that appears in the epigenome and how it regulates genetic expression and controls the proteosome, ultimately moving out into the metabolome, is now an area of interest. I think we are really at a threshold-a very powerful threshold where we are taking this information and tying it together with our understanding of single nucleotide polymorphisms and diversity. We are going to be seeing many, many more genetic evaluations being done on people to try to personalize therapy, and coupling these two together to develop a construct that is the personalized medicine approach for that individual. We now see that genetic tests are beginning to play a role in pharmacogenomics, in which people are being genetically typed for certain drug treatments. We are also seeing how the genotyping is being used to predict responsiveness of certain cancers to specific chemotherapy drugs. And now there are new organizations like 23andMe. Their website is 23andMe.com. They have a very robust website that is connecting a specific individual’s genomic uniqueness to the world gene base to look at geneology. This is a very, very interesting trend that is occurring, and it is occurring, in this case, outside of traditional medicine. Molecular geneticists are behind this particular company, 23andMe. It is giving a whole different level of understanding of an individual’s ancestry, legacy and past history. It is not just about advice to eat broccoli and exercise any more, but this whole connection between the specific strengths and weaknesses within the genomic uniqueness of the person that tie together with their nutrition and lifestyle patterns to give rise to their outcome. This is obviously a threshold. It is a revolution. When you hear Dr. Skinner you are going to learn more about how the environment is also a major component. And then various dietary substances can modulate this process hormetically. We had a wonderful conversation with Dr. Calabrese earlier this year in which he talked about nutritional hormesis and how small amounts of some substances working at regulatory nodes have larger effects than we expect on outcomes. Resveratrol is an example, and I have also talked about our own research that relates to the iso-alpha acids from Humulus lupulus (hops), which has a dramatic effect upon the regulatory networks that associate with inflammation and insulin signaling. There are also the effects you see hormetically from things like ginger (gingerols), or in licorice (some of the constituents in licorice have effects upon gene modulation through these regulatory nodes). Small amounts of intake can have much broader effects on physiology than we expect, through these hormetic mechanisms. Hormetic Dietary Phytochemicals and their Role in Prevention of Neurodegenerative Diseases There is a very nice paper that appeared in Neuromolecular Medicine just recently in 2008 that describes how hormetic dietary phytochemicals might play a role in prevention of neurodegenerative diseases through alteration of the regulatory pathways associated with apoptosis, neurofibrillary tangle formation, and beta amyloid accumulation with Alzheimer’s disease, and how these phytochemicals can help reduce toxins that induce oxidative stress and free radical injury.7 These phytochemicals include things like epigallocatechin gallate from green tea. We certainly see a tremendous amount of research coming out in that area. We also hear about various flavonoids that are associated with activation of the pathways associated with detoxification of foreign chemicals. I think this field is emerging to be more than just a cursory interest and is starting to translate down into clinical applications. Let me close this discussion by focusing on things like the Mediterranean diet. We know the Mediterranean diet is very complex. It is rich in phytochemicals; it is nutrient dense. It is amazing the number of papers that are being published just within the past year or so on the Mediterranean diet composition on function and gene expression. The rich array of phytochemicals in the Mediterranean diet play a significant role in imparting some of its clinical benefit, including improved insulin sensitivity, improved cardioprotection, and reduction of risk to inflammation. This may also translate into things like lowered risk to Alzheimer’s through what is called type 3 diabetes, which is an insulin resistance situation that affects neurochemistry. We recognize that there are various dietary proteins within the Mediterranean diet that also play a role. This is a complex diet with many different factors, not one of which on its own has this influence; it is the full dietary array has impact on the cell signaling function. Differing proteins have differing effects, not just as a consequence of their amino acid composition alone, but as a consequence of the fact that sequences of amino acids and proteins can impart different signals to the regulatory pathways. What did I just say? What I just said is that the sequence of amino acids in specific dietary proteins can modulate signaling pathways that are different than that of just individual amino acids in that protein by themselves. In the past we have always considered dietary protein was just delivery of amino acids because it is digested down to its requisite amino acids and absorbed as amino acids; we didn’t think there was any functional characteristics of the intact protein or the partially hydrolyzed protein. This whole model is changing. It is being recognized that there are receptor sites on the surface of the GI system that can pick up information from small partial hydrolysate molecules in the digesta that can impart information to the immune or inflammatory system. This is new information suggesting the composition of proteins in the diet may play regulatory roles. This might explain things like how gluten from grains with alpha gliadin could have an inflammatory potential. They are made up of the same amino acids as other proteins, right? Why do they have a problem that other proteins don’t? It is because of the structure/function relationships they have with specific genetic uniquenesses along receptor sites on the gut that activate transglutaminase or have different effects on the inflammatory pathway. I want you to be thinking that these generic food families we talk about-carbohydrate, protein, and fat-are very limited in their usefulness when we are trying to design individual diets. The personalities and signatures of each of the components of protein, carbohydrate, and fat can have very dramatic, important roles to play in how they are witnessed, or seen, or read by the body. These bioactive components in food can modulate signaling in very, very important ways and can lead to altered bioenergetics and altered mitochondrial function. They can lead to different adipocyte function and engage in altered energy that leads to storage (storage we call obesity). So obesity may not be just solely a consequence of eating luxurious calorie diets. It may be a consequence of eating disinformation and inducing, in cellular physiology, altered epigenetic and proteomic/metabolomic outcomes. As I said, the Mediterranean diet is a complex diet with many different dietary signatures. It is an orchestra with all the components: the strings, the woodwinds, the percussion, and the brass all playing together. It is the harmonious orchestration of that whole orchestra that gives rise to the effects on how genes are expressed across multiple tissues in men and women. There was a very nice paper about the rationale and evidence for the Mediterranean diet that was authored by Michel de Lorgeril and Patricia Salen; this paper talks about the extraordinary benefit that the Mediterranean diet has as a consequence of these dietary signatures.8 I think we are really starting to witness a changing paradigm-a paradigm that says lifestyle and diet intervention is a primary therapy. What we often call therapeutic lifestyle change, or TLC program, is a primary therapy for the management of complex metabolic disorders in which there is a distortion in the web of physiology rather than just a single point problem of necessity of blocking one enzyme, like using an ACE inhibitor, or using an H2 blocker, or using an HMG co-A-reductase inhibitor. We are talking about a much more complex modulation of the system (the network system), and the environment and the agents within the environment (beyond diet) play roles in sending signals as well. These are things like bisphenol A, which you probably know has been implicated recently in a whole range of metabolic, age-related disorders-a recent paper in the Journal of the American Medical Association brought that to our attention.9,10 Bisphenol A is a plasticizer found in many different plastics. We might say, “A very small concentration isn’t insignificant, is it?” But if you take the concept of hormesis (hormesis being small amounts having much bigger effects than expected), what has been found is that in animals, there are influences of this very small concentration on cellular signaling and cellular function, and when you look epidemiologically in humans, you find the same thing; it appears to correlate. We have the good, bad, and the ugly: cellular signaling, depending upon what the environmental exposures are and how they get translated through things like genomic stability or instability through epigenetic tagging, through the whole concept of transcription and ultimately into the formation of protein (the post-translational modification of protein), how that regulates metabolism and how metabolism eventually plays out to give rise to function. At every step along the way this system our environment is interfacing with those regulatory units to create our outcome. The way that we have basically managed this in medicine is to think, “Let’s step in with a drug, which is a single molecule and block one function related to one end point so we’ll create a good outcome.” And then we wonder, “When we gave that single molecule, that person actually had what we call unexpected adverse symptoms. Where did they come from? I thought we were blocking only one function, one isoform of one enzyme or something of this nature.” We find that our receptor sites for that specific functional characteristic on cells and tissues other than that which we wanted to treat, so we start getting action at a distance that gives rise to these other effects. What we are really looking at now is a different philosophy–a different approach–and when people adhere to Mediterranean-type diets it leads to a reduction in the prevalence of clustered risk factors and clustered biomarkers, not just one biomarker: total cholesterol goes down, HDL goes up, LDL-C goes down, triglycerides go down, apo lipoprotein A goes up, apo lipoprotein B goes down. There are multiple things going on that indicate that we have changed the web of physiology. By the way, this is recently discussed in a very nice paper in the European Society for Cardiology on the role of the Mediterranean-type diet in reducing the multiple risk factors associated with cardiovascular disease.11 It has also been found that the Mediterranean diet has a positive effect on bone mass in a sample of Mediterranean women, as well, as we might expect because we are modulating the web of physiology. This was published in 2008 in Nutrition.12 Hopefully we have set the stage for the wonderful interview we are going to have with Dr. Michael Skinner, who is really going to take us beyond the diet connection into the environment connection–to epigenetics and how that regulates function potentially throughout life and how those things ultimately translate into not only the immediacy of impact in the health of the individual, but also potential future generations. Obviously, the most sensitive period of life is during fetal development and infancy, and those times (or generations) may be the biomarkers of our society: how are we modulating the epigenetics of these individuals, either in utero or in infancy? How does that translate a legacy through the generations of altered functional status? And then that begs the question: what do we do to remove the marks that we don’t want in certain places and put marks back where we need them? Stay tuned. You are in for a very exciting tour with Dr. Michael Skinner.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Michael Skinner, PhD Center for Reproductive Biology School of Molecular Biosciences Washington State University Pullman, WA 99164 www.skinner.wsu.edu www.biotechnology.wsu.edu www.reproduction.wsu.edu You all know how excited I am to this part of our monthly Functional Medicine Update, which is our clinician/researcher of the month section. It is here that we really learn what is happening at the forefront, at the cutting edge, at what I like to think is the leading-not the bleeding-edge, as it pertains to looking out the windshield rather than the rearview mirror of where medicine is going rather than where it has come from. As you know, in 2008, we have had the opportunity to talk with some people who are really creating a whole new vista, a whole new perspective. I would call it a post-Mendelian perspective of medicine-or a post-Darwinian perspective, even. We’re not going to be disappointed this issue because we have another one of those seminal contributors to the evolution of this field, Dr. Michael Skinner. Dr. Skinner and I share some degree lineage here, through our location. He is a professor at Washington State University in the School of Molecular Biosciences Center for Reproductive Biology. Also, I notice he is a graduate in chemistry from Reed College. I actually taught at Reed College for a year, so I have an Oregon affinity for him as well. That’s probably where the similarity stops because his science has far surpassed that which I could have expected in my professional lifetime. He has done some extraordinary things. The first paper of his that I had the pleasure of reading, which really got me on to following his work more closely, was published in the June 2005 issue of Science magazine titled “Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility,” which, as you’ll hear through his voice, is the start of a whole interesting collaborative field.13 We heard a little bit about it from Randy Jirtle, but you are really going to get a sense from Dr. Skinner, I think, of how the environment influences not only the health of the F-zero generation (meaning us) but our progeny. Is this hormesis effect that we talked about with Dr. Calabrese really anything of clinical interest or is it just really an esoteric concept? If it is of clinical interest, how does it affect future generations? With that as a context, Dr. Skinner I would like to welcome you to Functional Medicine Update. Thank you for your time. I guess my first question would be, how did you get into the area of environmental molecular toxicology? MS: Thanks for the opportunity to participate. It’s a pleasure. I would say I’m not an environmental toxicologist by training, for sure. We stumbled into this. Many major studies or observations in science you would call serendipitous. I will kind of go through it quickly, but yes, this was a serendipitous observation that led us down this path-something we would not have predicted. I am actually a reproductive biologist. I have studied the development of the testis and the ovary for many years, in terms of the basic molecular and cellular control of their function. We were studying sex determination during embryonic development and looking at testis development. To investigate that further I decided to try some environmental compounds (some endocrine disruptors) to treat a pregnant mother to see if we could interfere with or alter sex determination. We put forward a series of experiments in vitro and in test tubes and everything appeared to work really well (it looked like we were getting effects), but then when we did in vivo where we simply injected a pregnant mother (we used a rat as a model), we basically didn’t see any change in the sex determination. We didn’t see any alteration in testis development. And, in fact, we looked out through puberty development up to the adult and we really didn’t get an effect. Most people would say that was a negative experiment (essentially the experiment didn’t work). But then there was a serendipitous observation: the adults, after they matured, developed a testis defect on most of the spermatogenic cells undergoing spermatogenesis that are eventually going to turn into sperm; they started dying in the testis. They would undergo apoptosis and die. It was a sub-fertile sort of condition. We actually published that article and put it out and we thought that was pretty much it. There was a postdoctoral fellow in my lab-her name is Andrea Cupp-and she came in the office one day upset because she accidentally had bred the F1 generation animal to make an F2. We didn’t really plan that experiment, so we hadn’t planned on using the animals that way. I said, “Don’t worry about it. Just go ahead and look at the phenotype (what the testis looked like in that F2).” Lo and behold, it had the same phenotype. Greater than 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the males had this hermatogenic cell defect. She came back and said that was going on. I didn’t quite understand because the only animal exposed to the toxin was a very transient exposure during sex determination of the mother. She went back and repeated it a number of times. Basically, we took it out to the fourth generation and we found that this became a transgenerational male defect in spermatogenesis that went out four generations and greater than 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of animals in each generation were affected. So this would not follow a normal Mendelian genetic sort of trend, and having 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the males of all those different generations also would not follow normal DNA sequence mutation events either. So this turned out to be a transgenerational disease state. As those animals age it turns out that they develop a whole series of diseases-prostate disease, kidney disease, immune abnormalities, and a whole series of tumors, including breast tumors, as well. About 85-90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the animals would develop one disease or more, so this was an extremely high level of disease. The only animal exposed to the environmental factor was a pregnant mother, four generations later causing a disease state, so this is a transgenerational disease state. The only real way to do this, mechanistically, is epigenetics, which I can describe for you. It turned out to be a non-Mendelian sort of approach. It turns out what we were doing was reprogramming the germ line during that embryonic development during sex determination and permanently imprinting DNA methylation marks on the DNA, which then became permanently programmed such that that sperm would pass forward to each generation this disease phenotype. It turned out to be an epigenetic transgenerational disease phenomenon. JB: You know, when I hear people like yourself–primary discoverers of major new paradigms–it often just flows off their lips so eloquently and so smoothly, but behind the scenes are all sorts of extraordinary seismic events in the body of knowledge, which often doesn’t undergo transition easily. We hold onto our beliefs (even scientists) very, very strongly. When we talk about non-Mendelian and alterations of phenotypic expression from non-mutational changes in DNA, how did that get responded to by your colleagues? MS: That was the hypothesis I put forward and then we actually had to do experimental studies to show that we were not causing a DNA sequence mutation. We did some experiments recently using some genomic approaches to show that indeed there are no increases in point mutations. We had to also show that there was a DNA methylation change in the germ line in the sperm, itself. Originally, four years ago, we did much more cruder approaches than what are available today. Today we take much more elegant molecular approaches. Basically we had to show that the DNA was getting methylated differently, and that was carried forward for four generations. So we had to have that experiment in hand before anyone would let us state that this could be an epigenetic phenomenon. It took us several years to actually get that done. JB: After having completed that work-by the way, as I was mentioning to you, I have had the privilege of reading 17 of your papers, which are just really excellent science, just doing the heavy lifting of this work-after you completed that and published it, was there a general sense of “a-ha,” or did you find there was still a push-back and people trying to find fault with the work? Or did they look at other investigators (we’ve had a chance to talk with Randy Jirtle and the Agouti mouse model) and maybe they started to see that there was collaborative discovery… how did that actually transition for you? MS: The same year that we published this article in Science there was another article published on twins (identical twins) basically having different disease frequencies even though the same genetics were there.14 As those twins age in different regions from where they were raised they would develop different disease frequencies, suggesting an environmental impact on disease development. So that suggested, again, an environmental impact, and one of those investigators actually looked at the epigenome of a cell type showing that it was different between those twins, even though the genetics was the same. That came out at the same time, so that was supportive evidence that indeed epigenetics may be the mode of action for environmental factors on genome activity. Randy Jirtle has been studying for a long time the Agouti mouse locus and he had also found environmental impacts on that locus, so he had done that previously, and more recently he’s done the same thing with some environmental toxicant-type substances. Approximately eight months or so later, there was a fellow named Marcus Pembrey in England who did a study (he was more of an epidemiologist).15 They looked at a famine case where several generations after the famine they had increased disease frequency versus controls in a European population (sort of archival epidemiology). That supported the concept that an environment would affect an epigenetic phenomenon that may go forward in terms of disease. So all of those things sort of broke within about a year, and when all the multiple things started breaking more of the scientific community started to accept that something was probably going on. But I must say, from the beginning even up to now, we still get a push back by the genetic community because it is a fairly built in dogma to our current scientific paradigm that genetics really is the principal cause for disease. What our data would suggest is it is a factor, but epigenetics probably has an equally important role. JB: With that in mind, now you start birthing a new field (or new discipline) within science. It is always interesting when you start seeing that happen how many people attend the first meeting. You start forming a foundation or an institute or a society and you have a group of epigeneticists that have maybe come from different disciplines but you are similarly bonded together by a similar observation or a shared observation. Tell us a little bit about the birthing of the field of epigenetics, because clearly you were one of the first guys as a club member. MS: Epigenetics has been around for awhile. Just to give you a little history, there was a fellow named Conrad Waddington in the 1940s that came up with the term “epigenetics.” He came up with regards to environment-gene interactions that generated phenotype, and that was done back in the 40s. It was mostly theoretical, and he had some very nice papers around that. That sort of concept, however, was set aside for several decades, and in the mid-70s, the first epigenetic phenomena called DNA methylation, where cytosine residues and DNA get methylated was identified by Holliday in the mid-70s. Then in the late 80s/early 90s, imprinted genes came around and also histone modifications, and so for about a decade and a half (almost two decades) the concept of having things around the DNA that regulate genome activity independent of sequence has been known. The new phenomena that came out around the time we published was that environmental factors that could actually affect disease has been known for quite awhile by epidemiologists that have been telling us that for decades, but we really didn’t have a mechanism to pinpoint how the environment could regulate the DNA since most things don’t change DNA sequence. So our study and subsequent studies have started to show that epigenetics probably is the main mechanism by which the environment can influence genome activity. That’s really what’s pushed. So the field of environmental toxicology is fairly mature; there is a big population of people in it. And the field of epigenetics is reasonably mature as well. What we did is sort of brought those two together, and so now most environmental people are moving towards doing epigenetic-type studies. In addition, people in the field of disease, or epidemiology, or just interested in disease etiology, started moving that way (whether it be cancer researchers or whatever disease they have an interest in) because they’ve started to get the concept that epigenetics may be a factor in those diseases. I think it was multiple fields sort of merging on a central theme where epigenetics clearly was the bridge between them. JB: You know, the tradition of toxicology is built around Tolman’s laws and this kind of linear dose-response model of extrapolating back to the origins of zero-zero effects, so you have some kind of straight line or curvilinear response. This epigenetic-environment connection suggests (at least, to me, as I read the papers) that this may be a nonlinear extrapolation back to the origin and there may be some profound unexpected effects at low concentrations, which sounds a little like this hormesis concept. Am I at all moving down the right path in this kind of connection? MS: In part. Clearly the newer concepts over the past few years (for example, in the area of using bisphenol A and so forth) have shown that extremely low doses below what you would anticipate for receptor binding, that those very low doses have physiological effects that are actually either lost or are different at higher doses that you’d expect would be more appropriate to binder receptors. Fred von Saal (with bisphenol A) has been talking about that for a number of years. So that type of activity has been going on, and that is a factor in terms of how much it would take to regulate an epigenetic effect versus how much it would take to regulate a physiological response. Those two things can be quite different. It may take a very little amount to affect epigenetics, which indirectly, then, would affect the physiology. Unless you know the direct target for the substance you are interested in, it’s a little bit difficult to go after dose. But probably more important for epigenetics is this is really getting towards the heart of developmental biology, so the fetal basis of adult-onset disease. What it looks like is early life exposures, when an organ system is undergoing a rapid development, is susceptible to environmental factors, changing its epigenome. It then turns around and changes the transcriptome, and eventually that could potentially lead to a disease later in life. So it is much more of a developmental phenomenon, more so than we previously appreciated in disease etiology. JB: People undoubtedly ask you the question-I mean, there are many questions I’ve asked you, but one that come to mind from what you just said is: how about cells that have differentiated and are beyond the state of a germ cell, so they are in some form of mitotic division by cell repair and turnover, but they are not in the germ cell state? Is the organism, at that point in the lifecycle, susceptible to epigenetic effects, or is it only that where you have a rapidly dividing fertilized ovum? MS: Certainly the most sensitive period for exposures is in utero, in the fetus. The next density of area would be early postnatally (when you are a very young individual). The next step would be pubertal development. And then, as an adult, you are relatively insensitive to most things (this is just general toxicology). And then as an aged adult, that’s when a lot of those adult-onset diseases develop. So generally, as adults, we are not as sensitive to environmental effects because of that very process. Those cells are differentiated. Even though we might cause some damage to a tissue, they can repair themselves and so forth, but it’s not a developmental process. Therefore, the reason those early ages are more susceptible is organ systems are rapidly developing, so it doesn’t take much to shift that development a little bit to then eventually cause a disease as an adult. JB: In the compounds that you have seen that cause these effects, are they trans-placentally transferred and can it have extrapolation to human, or is that still an area for controversy? MS: Depending on what time during development, many compounds can actually go across and reach the fetus. There is not a barrier, per se. As the fetus gets older, there becomes more of a barrier. Yes, the compounds we are using can get across that. Bisphenol A, the phthalates, lots of the environmental compounds actually can get across that. The question is whether the amount exposed to the mother, and the amount that gets across, has a physiological effect on the fetus. Those are questions that have not been rigorously looked at in a toxicology manner in terms of levels and metabolism and so forth. For our purposes, we’re using (and this is important) the vinclozolin, which is the principal compound we use, and which is the most commonly used fungicide worldwide in the fruit industry, including the wine and apple industries. It is a compound that basically, in occupational exposures and potentially the water supply around these sources, could be available. It breaks down relatively rapidly. There have been a few toxicology-type studies done to show that it takes reasonably high levels to cause an effect. The level that we use exceeds what you would expect in the environment. We also use injections (interperitoneal injections) so we can control the dose, which is also not your typical exposure route. We are strictly using this as a pharmacologic agent to induce an epigenetic transgenerational disease so we can study that basic molecular process of how a compound may influence epigenetics, which then can promote disease onset. With basic information on a molecular level, then you can go back and do much more sophisticated toxicology than doing classic toxicology, in terms of looking at a dose and a phenotype. So that’s the approach I think that we are going to end up taking in the future: taking more molecular approaches to study environmental toxicology. JB: With that in mind, and the fact that methylation patterns are changing upon exposure to these compounds. It raises the question, obviously, as to whether there are other covariables that relate to the regulation of these methylation patterns, and the one that is obvious that people think about is the folate cycle and 5-methyltetrathydrofolate through S-adenosylmethionine. Are there any ways, with nutrients, to modulate the relative sensitivity of these agents on methylation patterns? MS: Sure. Clearly folate, which is the methyl donor (rides the methyl donor, eventually) for DNA methylation is (and there are a couple of things that will do that)… basically, if there were sufficient amounts around, then you’d get a normal sort of methylation. If there were insufficient amounts around, then you actually may get an effect on methylation that could be abnormal. However, if there was too much around, you could also get an effect that would be detrimental. So putting in additives like folate, you potentially might protect for some things, but you also could turn around and induce others. For example, it has recently been shown that excess folate can actually induce asthma and immune abnormalities in a rodent model, and potentially there is a correlation. Having too little is bad and having too much is bad, so you have to be careful, when considering those additives, of exactly what you are doing. I think that the field is a little bit premature to actually start using that information to suggest how humans supplement their diets. I suspect in the future, however, that type of thing can be used potentially as a protective-type agent to environmental things, but we just simply need more data before we know exactly how to use them. In other words, what I like to stress is there could be equally as much harm done from putting in too much than having not enough. JB: So when we take this extraordinary discovery that you and your colleagues have made and we map that against (or superimpose it, or intermix it) with the developing field of nutrigenomics and the recognition of how many single nucleotide polymorphisms exist, it both raises the complexity and it also gives us understanding of points of differentiation moving away from the Gaussian representation of the human. How do you see nutrigenomics interfacing with this concept of epigenomics? MS: I have been using endocrine disrupters to induce these types of phenomena, and so those are environmental compounds that are sort of readily in our environment. But another major environmental factor that will induce this type of phenomena is nutrition. Caloric restriction in the embryo has been shown in both animal and now human models to actually influence disease onset later in life-things like diabetes, obesity, and so forth. Nutrition is clearly, during pregnancy and early postnatally, a significant factor in terms of environmental factors that will affect your eventual adult onset disease. Understanding that more-understanding what is bad and what is good-will be a significant impact of the nutritional field. I think that is one of the major areas that we are going to expand, and now just in the last year or so there has been some epigenetics linked to those nutritional effects that they are looking at. I think it will be very important, and we just need to get more molecular information on how the nutrient supply is affecting sort of the programming of the epigenome. JB: In previous discussions we have had the privilege of talking to Dr. Bruce Ames and Michael Fenech and different conversations about factors related to genomic stability which then translates into phenotypic changes. Do these differing methylation patterns then alter the degree of genomic stability in such a way as to have effects that I guess you would call global effects on metabolic disorders? MS: It has actually been known for a while. Particularly, the cancer field is one of the first ones to come out with the concept that the epigenome can influence genome stability, and so the transformation process in a cancer can actually be influenced initially by whether you have a normal or abnormal epigenome. There are a number of laboratories studying that in the realm of cancers, on several different types of cancers. And so, yes. This is where I would sort of step out and make the speculation that I don’t see very many diseases in the human condition that would not have an early-life effect, (having a reprogramming of the epigenome) that then has some sort of susceptibility to an eventual sort of disease onset, and that includes cancer. Now which one comes first, whether it is a genetic susceptibility or whether it is an epigenetic-induced susceptibility, I don’t know. It is probably some combination of the two. I guess what I am saying is, I don’t believe it is now possible to think about genetics as the only source for disease or susceptibility. It is going to be a combination of the epigenome and genetics, and so it will be a combination of epigenetics and genetics that is going to fully explain disease etiology susceptibility and what diseases you are going to get. JB: I may be asking a question here that is inappropriate and please tell me if it is because I’m not asking you to speculate beyond that with which you are comfortable. When we take what you just said and we kind of weave it into society today, we can see there are some conditions within our population in children that are increasing quite dramatically relative to what they were even 40 years ago, which are hard to explain on the basis of just maybe Mendelian types of traditional views. Two I am thinking about are ASD (autistic spectrum disorder) and the other is NALFD (nonalcoholic fatty liver disease) which, when I was in medical school in the 60s we were told that wouldn’t probably ever be seen very frequently, and now we are seeing it quite frequently. Both of those kind of speak to the liver and the brain, something of lipophillic nature that could modulate things like epigenomics. I’m using wide brush strokes here so you can certainly censor me. Do you think any of this that we are seeing in society, beyond that of just better diagnosis, relates to some of these potential things that you’ve discovered? MS: Yes. I think there are a number of aspects of disease which suggest a significant environmental impact. The first is if you go anywhere in the world, every region has a different disease frequency, even if you have similar genetics. Sometimes if you take a person early in life and put them in another area they actually develop the disease frequency where they move to, suggesting environmental impact. The second most compelling sort of argument is the increase in the disease frequency for nearly every disease over the past two or three decades, sometimes going from 1-2{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} up to 15-20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the population. That kind of an increase within that short of a period has to be an environmentally induced phenomena; it cannot be a simple Mendelian genetic sort of issue. So, yes, I think when you see a dramatic increase in something like autism (the rate it has gone up), there is sort of an argument that clearly diagnosis is an issue (the efficiency of it), but if you can count that, you still have an increase in the disease that has to be an environmentally induced. Now one area that neuroscientists have been talking about for over a decade is they have not been able to explain neurodegenerative diseases very well using genetics. Actually there are very few genetically-based neurodegenerative diseases, but epigenetics could explain a great deal of that and they have been speculating that for awhile. I think the role that epigenetics plays in the brain may be very important. JB: With that in mind, let me go to an example that you probably are familiar with because it seems like it is almost directly mapped to your discoveries and work and, again, I may be extrapolating ad absurdum here. I’m talking about David Jacobs/Duk Lee’s work, which you probably are familiar with, looking at an association between serum concentrations of persistent organic pollutants and insulin resistance, metabolic syndrome, and type 2 diabetes16 in which they find, by looking at NHANES 3 data (the National Health and Nutrition Examination 3 data for the US) that there actually is no strong statistical correlation between obesity or elevated BMI and diabetes in the absence of people having high normal or elevated GGTP in their serology (gamma glutamyl transpeptidase), which is a surrogate marker (it appears, from work that has been published over the last few years) for exposure to environmental toxicants or xenobiotics that upregulate the use of glutathione and cause the body to compensate by enhancing glutathione synthesis. It suggests from this-and again I want to emphasize “suggests”-that there is a connection between persistent organic pollutants (POPs) and disease, which then begs the question: how do these POPs influence disease? To me, the explanation is tied to your discoveries. And then we take that one step farther and look at the Journal of the American Medical Association, in the September 17 issue this year, at the paper that Ian Lang and his colleagues published on the association between urinary bisphenol A concentrations with a complex range of medical disorders and laboratory abnormalities, which again seems to suggest that we’re seeing these chronic metabolic diseases. In fact, the editorial that follows it even emphasizes that-that from nontraditional dose-response type relationships of exposure that are influencing a wide panorama of diseases, and they seem very prevalent in people with high normal GGTP levels in their serology. To me, this sounds like a clinical indicator for what you have observed in your studies. Am I at all making an association that has any reasonable connection? MS: I think you are on the nose. For example, diabetes and obesity is clearly a metabolic syndrome-it’s a metabolic disease-and it is fairly well established as to the etiology of the disease. The brain has a significant role in the regulation of metabolic disease as well. I think you are, overall, influencing the system (the entire system of metabolism), and some of the outcomes of that are various diseases like diabetes or obesity. Clearly, the data to suggest nutrient support, environmental factors, and environmental compounds can influence those types of diseases is there. I think, yes, it could be that metabolic disease is clearly more of an environmentally influenced phenomenon. If that’s the case, then I would suggest that it is going to be an earlier life exposure causing a sort of programming event that later in life causes an abnormal metabolism, which then subsequently leads to the adult onset disease. I think that that overall trend is there. The proof now will be to actually go in and look at what is the exposure, showing the epigenetic changes, how that influences the metabolism, which then correlates to the disease. So I think you are definitely correct in your hypothesis, and now we just need more sort of a systems approach to actually approach it. JB: I know that you are actively involved in some of that systems biology-type research. Could you kind of give us a glimpse into the future as where you see your (and your colleagues’) work heading, knowing that this is very complex? This is like trying to eat the elephant in a single bite. MS: I can give you two examples of two ongoing studies right now, and then I can speculate sort of what this might be leading to in the future. The first: we have done a series of experiments where we did this exposure in utero to this endocrine disruptor. And this exposure occurred during sex determination, so we affected gonadal development and the germ line development. And it also occurs during brain development, when the brain is actually developing, as well. So we speculated that we’d have some significant brain effects. So we have taken three generations removed from the exposure (brains) and found that indeed the brains, in several different regions, have different transcriptomes (what sets of genes are expressed). Hundreds of genes are actually changed, and it is a transgenerational thing because it goes between generations, the same set of genes being affected. This transgenerational transcriptome would then likely lead to some sort of neural abnormality. When we have done behavioral studies on these animals, indeed what we found was that the females have a statistically significant higher level of anxiety, and the males have a statistically lower level of anxiety and are higher risk takers. So there is a behavioral effect on those animals, and it is opposite between male and female, and it is linked to the brain transcriptome and this early life, transgenerational exposure. That is a study that we are putting out, sort of showing that through an epigenetic change in the germ line we can actually alter brain development and subsequent behavior, so this is sort of providing that systems link from neuroscience to sort of this environmental exposure. That is a current study that we are sort of in the midst of putting out. The other corresponding study was in 2007. We published an article on a similar type of phenomenon showing sex preference (or mate preference) in sexual selection was actually altered in the males and females as well-again, a brain-initiated function.17 I think that whole issue that you brought up earlier on how the brain may be involved in the diseases associated with abnormalities in the brain could be epigenetic… we’re moving in that direction. In a second series of studies we are doing a much more genome-wide approach and moving towards the human to actually look at the epigenome in the human and mapping some of these epigenetic changes, both in the germ line and in somatic tissues to see if we can identify epigenetic biomarkers. This is where you’d have a DNA methylation change in the DNA, or a group of them, that may correlate to a specific disease or another. The potential to have these epigenetic biomarkers as diagnostics for the disease to then go in and potentially (early in life) identify that you have a 95{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} chance that 20 years from now you are going to develop this disease (that type of a sort of epigenetic biomarker). This is a much more of a developmental effect. In the past, we have never had the ability to have those early-stage diagnostics. So the future could be that when you are in your 20s you would have your epigenome mapped, and because of certain biomarkers you might have, you could predict what diseases you may get later in life. Instead of waiting for the disease to develop to treat it, when you are in your 30s or 40s, prior to the disease onset, you could potentially map what changes are happening in that tissue, and therapeutically treat them to prevent the disease from developing. This would lead us down the path to preventive medicine, and the ability to do that would be having these early-stage diagnostic markers that could be epigenetic biomarkers that would be linked to those diseases. I think that potentially will be the future of medicine: going from a reactionary medicine situation to a more preventative medicine situation. The key, really, is a better understanding of the etiology of the disease, including the epigenome. JB: That’s a really fascinating vision for the future. I have to say, just parenthetically, that is certainly consistent with what we have tried to structure as out functional medicine model as it pertains to the connection between genes and environment and outcome. I’d like to close with just one question and I don’t want this to sound alarmist because I think there is always a tendency, probably, when people hear this work that it sounds a little doom and gloomish… I’d like to phrase it in a slightly different way. We all know that this article that appeared in the New England Journal of Medicine in 2005 that was a consortium group of high profile individuals that wrote about future life expectancy and suggested that the lifespan of our children born today maybe shorter than that of their parents, on a statistical average, which would be the first time in the history of the United States.18 This is at a time when we are spending twice per capita on health care than any country in the developed world (we are 30-something in health outcomes according to the World Health Organization). That then brings the question up: if you get the diminishing returns of a model indicating that maybe your model is broken or needs modification, and if transitions occur with the epigenome and we start to see it mapping against certain diseases, what do we do in our curriculum? What do we do in our society to educate people about how the decisions that are made everyday influence not only that which we are living, but that which subsequent generations will live? Is it through the science? Is it through public activism? How would you see this transmitting into a cultural change? MS: Well, it’s a combination. Ten years ago, if you basically asked a scientist that question they would tell you that you will have to focus on the DNA sequence and the genetics and that is pretty much going to be your answer. I think clearly that that is part of the answer, but we had this huge black box, which now epigenetic may help fill, that just develops and stands in terms of its application. So I don’t think you can ever say that science is fully aware of everything we need to know about disease or health. I think you need to move the science forward to develop those new insights–things we didn’t expect-to help answer some of those paradigms or conundrums that we couldn’t explain. Part of our movement forward, in terms of improving our health, will be to advance the science, and so as a society we are going to have to support basic research and moving that science forward, otherwise we will simply get into a situation where we think we know how everything works, but probably we don’t. That will be the first. The other thing that scientists need to do, which your program does for physicians but we probably need to take it to the more public level, is the scientists need to educate the public about some of these fast-paced, moving scientific advancements, so that they are aware of the situation. I think if the general community realized that things like caloric restriction during pregnancy may actually induce obesity or a diabetes situation in their children there would be a consideration or a request from the health community on what they should or shouldn’t do to avoid that. So just educating the public about these scientific advances is probably something we should do in the sciences as well. So those are the two things I would suggest, on a societal level. We do definitely need to move the science forward, but we also need to educate the public more. JB: I can’t tell you how much I appreciate you spending the time with us, and also the diligence and the difficult that you have done in bringing this whole field up with your colleagues to the level of understanding that you have. It’s clearly obvious that we have a lot of work ahead of us. I guess the good news is if you can put these imprints on and you can take them off and this leads to some degree of plasticity versus the deterministic view of Mendelian genetics, so I guess that’s the nice part of the story: if we can clean up our mess, we can also clean up our epigenome. MS: Generally, knowing more of the basic reasons why things happen helps us actually fix the problems, correct? JB: Yes. Dr. Skinner, thank you very, very much. We wish you the best in your continued work. We will be following it very, very closely. MS: Thanks very much and I appreciate the opportunity.  

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1 Arasaradnam RP, Commane DM, Bradburn D, Mathers JC. A review of dietary factors and its influence on DNA methylation in colorectal carcinogenesis. Epigenetics. 2008;3(4):193-198. 2 Delage B, Dashwood RH. Dietary manipulation of histone structure and function. Annu Rev Nutr. 2008;28:347-366. 3 Gluckman, PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):61-73. 4 Ross SA, Milner JA. Epigenetic modulation and cancer: effect of metabolic syndrome? Am J Clin Nutr. 2007;86(3):s872-877. 5 Haggarty P, B-vitamins, genotypes and disease causality. Proc Nutr Soc. 2007;66(4):539-547. 6 Bland J. The future of nutritional pharmacology. Altern Ther Health Med. 2008:14(5):12-14. 7 Son TG, Camandola S, Mattson MP. Hormetic dietary phytochemicals. Neuromolecular Med. 2008 Jun 10. [Epub ahead of print] 8 De Lorgeril M, Salen P. The Mediterranean diet: rationale and evidence for its benefit. Curr Atheroscler Rep. 2008;10(6):518-522. 9 Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, et al. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA. 2008;300(11):1303-1310. 10 Vom Saal FS, Myers JP. Bisphenol A and risk of metabolic disorders. JAMA. 2008;300(11):1303-1310. 11 Sanchez-Tainta A, Estruch R, Bullo M, Corella D, Gomez-Gracia E, et al. Adherence to a Mediterranean-type diet and reduced prevalence of clustered cardiovascular risk factors in a cohort of 3,204 high-risk patients. Eur J Cardiovasc Prev Rehabil. 2008;15(5):589-593. 12 Kontogianni MD, Melistas L, Yannakoulia M, Malagaris I, Panagiotakos DB, Yiannakouris N. Association between dietary patterns and indices of bone mass in a sample of Mediterranean women. Nutrition. 2008 Oct 10. [Epub ahead of print] 13 Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2006;308(5727):1466-1469. 14 Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. July;102(30):10604-10609. 15 Kaati G, Bygren LO, Pembrey M, Sjöström M. Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet. 2007;25(7):784-790. 16 Lee DH, Lee IK, Porta M, Steffes M, Jacobs DR Jr. Relationship between serum concentrations of persistent organic pollutants and the prevalence of metabolic syndrome among non-diabetic adults: results from the National Health and Nutrition Examination Survey 1999-2002. Diabetologia. 2007;50(9):1841-1851. 17 Crews D, Gore AC, Hsu TS, Dangleben NL, Spinetta M, et al. Transgenerational epigenetic imprints on mate preference. Proc Natl Acad Sci USA. 2007;104(14):5942-5946. 18 Olshansky SJ, Passaro DJ, Hershow RC, Layden J, Carnes BA, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005;352(11):1138-1145.

Welcome to Functional Medicine Update for January 2007. I look forward to the first of every year, and consider how Functional Medicine Update will evolve. With this issue, we are starting with a high standard of identity for 2007. I believe you will find this month to be an unprecedented example of what we consider excellence. We are going to have the longest discussion with the researcher/clinician of the month that we have ever had in our 25-year history. This discussion embodies so much of what Functional Medicine Update has been throughout its 25 years. It couples the best of science with clinical insight, and addresses the integration of many different findings from different fields into the understanding of a principal fundamental mechanism that underlies many diseases and cuts across multiple subspecialties of medicine. I think it is that we feel functional medicine provides an opportunity to understand: how traditional diagnostic medicine (with the sine non quo being the pursuit of the diagnosis) so often loses the forest for the trees. For those of you who may be starting new with us this year, let me just quickly tell you a little bit about Functional Medicine Update. As I mentioned, Mr. Jay Johnson, my colleague, and I have been doing this now for 25 years-it will be our 25th anniversary as we come up to the middle of this year. As a consequence of this long-standing opportunity, we have had the pleasure, privilege, and illumination of interviewing some of the world’s great agents of change in this field of health care and medicine. People who are valiant in what they are doing-warriors and pioneers and trendsetters, who have been mind changers in allowing us to understand the origin of chronic, age-related diseases in different ways that potentially lead to improved patient outcomes. Functional Medicine Update started off many years ago as Metabolic Update , then it went to Preventive Medicine Update. Finally it evolved (a little over 10 years ago) into Functional Medicine Update, and we feel that the standard of identity for the product has continued to improve over this last decade. Functional medicine has been described as a different way of looking at the etiology and management of disease from a functional perspective. The management of Functional Medicine Update is now through a group called Synthesis. Synthesis is my own company, and Trish Eury is our manager. Our website is www.jeffreybland.com. The reason the administration ofFunctional Medicine Update was transitioned out of The Institute for Functional Medicine in 2006 is because to keep FMU embedded within an institution that is CME accredited would have required that this product be edited, peer-certified, and reviewed by an outside review board. Doing this (I think) would have caused us to lose the tone of what we have been trying to achieve over the 25 years, which is for FMU to be Jeff Bland’s view of what is happening within the field of health care. Our objective is to connect science with clinical work, and put it into the context of the words of the scientist and clinicians that are doing it. To be bridled by the guidelines of peer oversight through the ACCME and to try to define it as Category I credit would be different from this objective and alter how FMU provides early assessment and understanding of information that is on the front edge of evolution in clinical medicine as driven by science. It is with this in mind that we have now taken over the responsibility for the content, editing, and format of Functional Medicine Update. You will see, I think, some interesting changes, starting with a feature called “Hot Breaking News” that will lead off every issue. For Hot Breaking News this month, I want to focus on three quick topics. The first, which has been heavily in the news, is the vitamin D question. How much vitamin D do people need? We spent a lot of time talking about the vitamin D connection. I have interviewed Michael Holick, Colleen Hayes, and Robert Heaney, all of whom were helpful in helping us to understand much more about vitamin D and its connection to many different conditions. Vitamin D Status: Evidence Suggests the Optimal Level Should Be Increased We now recognize the best current assessment method for vitamin D status is the level in the plasma or serum of 25-hydroxyvitamin D3. These variables help us to better understand what level of vitamin D intake the patient needs to maintain proper function. It has often been said that anything above 20 nanomole per liter (nmol/L) is satisfactory. I think it is now being more and more recognized that this level (at the low end of normal reference range) is actually suboptimal, relative to physiological function for most people, and that the clinician should try to achieve a range between 40-55 nmol/L in order for the patient to have better function. This is what the evidence suggests. Some investigators suggest that clinical conditions may improve at levels up to 80 nmol/L, but I think the data from the literature would support that a target level should be in the 40 to 55 nmol/L. For those of you who would like to read more about this, a nice review paper on this subject appeared in the Journal of the American College ofNutrition in 2006. 1 I would also suggest that one needs patience, as a clinician, to raise the level of 25-hydroxyvitamin D3 in a patient’s serum; it may take several months on supplementation of 2000 or more IUs per day of vitamin D3 in order to raise that 25-hydroxy level to 40-55 nmol/L range. The toxicity of vitamin D is related to the hypercalcemic effect, and to excessive levels of the hormonal form, 1,25-dihydroxy cholecalciferol. The marker for that is the plasma or serum level of the 25-hydroxy cholecalciferol. As long as serum calcium is not elevated, there is a proper calcium-phosphorus ratio in the serum and the level of 25-hydroxyvitamin D3 does not get excessive; this is why I am suggesting 40-55 nmol/L. In this situation, you should be able to continue to supplement a patient to the level of sufficiency. Fish Oil and Fish Consumption: Does the Risk of Mercury Toxicity Outweigh the Potential Health Benefits of Omega-3 Fatty Acids? Our next Hot Breaking News topic relates to fish oils and fish, and the question of a trade off between mercury toxicity versus the advantages of omega-3 fatty acids. There has been quite a bit of discussion over the last few years about how much benefit is achieved if we supplement patients with fish oil or we have them eat more fish because of the potential exposure mercury, which in and of itself is a health risk factor. Are we trading a benefit to an adverse risk? This subject was revisited in an article that appeared in the Journal of the AmericanMedical Association in 2006. 2 It is a nice review, I think, of the relative cardiovascular incidence and mortality rate in people who eat fish, as well as looking at other co-variables of health risk associated with fish consumption and how that interrelates with total methylmercury exposure and other problems (immunological problems or oxidative problems related to mercury exposure coming from fish or even from fish oils that might contain mercury). First of all, I should tell you that both mercury and pesticides in fish oils should have been removed by proper processing. When you use a fish oil supplement, obviously it is very important to make sure it has a standard of identity from independent laboratories that demonstrate it is free (to below the level of detectability) of standard biocides. A whole list of these are conveniently tested by toxicological laboratories, as well as, of course, heavy metals, particularly mercury. This is a standard of identity that I think clinicians should always demand of their supplier for fish oil supplements; to see an assay from an independent lab to demonstrate that it is below the level of detectability for biocides-things like dioxins, PCBs, herbicides and so forth, and also heavy metals. With regard to fish, you can’t do that. You can’t go to your fish store and demand an assay of all the biologicals and the heavy metals. But what the recent JAMA review paper points out is that even with the imperfection of our oceans (as it relates to bioconcentration or accumulation of some of these toxins in higher carnivores in the ocean, like tuna and swordfish) the health benefits from increasing fish consumption appear to greatly outweigh the health risks. There is strong evidence for this. For women of childbearing age, however, and certainly pre-pregnancy, one might be very cautious about consumption of those fish that are the biggest accumulators of mercury (fish like swordfish and tuna).There are already some recommendations to limit consumption of these. With regard to fish oils, however, because these can be purified, one can use them safely as long as they have been demonstrated to be free of bioconcentrated toxins or heavy metals. Neutralization of the Acidogenic Western Diet Lastly, there has been a question about the acid or ash or alkaline components of the diet-how these influence things like detoxification, renal function, cardiovascular function, endothelial function, and insulin sensitivity. One hundred years ago, it was suggested that by increasing amounts of animal protein, refined sugars, and fats in the diet increase the acid load on the body, which has deleterious effects on function, and that eating a more complex carbohydrate, vegetable, and fruit-rich diet (which is an alkalizing diet) has a positive benefit on health outcome. This has been re-examined in a number of papers recently, and it does appear that neutralization of the acidogenic western diet does, in fact, improve bone mass, insulin sensitivity, and endothelial function. I am quoting now from a recent paper that was published in the Journal of the American Society ofNephrology that shows (by using calcium citrate and potassium citrate as neutralizers of the acidogenic diet) that there was improved bone mass in postmenopausal women with osteopenia. 3 We also know that acid-based status affects renal magnesium losses in healthy elderly people, so as you alkalize the diet, the individual retains more magnesium (plasma magnesium goes up). This is another benefit to an alkaline-ash diet; this is from the Journal of Nutrition in 2006. 4 Lastly, an interesting paper appeared in Medical Hypotheses about how acid-based balance may influence insulin sensitivity, reducing insulin resistance by modulating cortisol output. 5 With that in mind, let’s move from our Hot Breaking News section over to the extraordinary voyage/journey we are going to take with our researcher of the month.

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INTERVIEW TRANSCRIPT Clinician/Researcher of the Month S. Jill James, PhD University of Arkansas for Medical Sciences Arkansas Children’s Hospital Research Institute 800 Marshall Street Little Rock, AR 72202 I look forward each month with great anticipation to our opportunity to speak with a leader, clinician, or researcher. I can honestly say that I have looked forward for many months to this opportunity to talk with Dr. Sandra Jill James. Let me quickly tell you a little bit about my first contact with the work of Dr. James, which I’m sure she’ll tell us more about. I was at a meeting at the Institutes for the Achievement of Human Potential, where I have been a member of the scientific advisory board for many years. It is an institute in Philadelphia founded by Glenn Doman-who was the first winner of the Linus Pauling Functional Medicine Award-and his colleagues 50 years ago to work with brain-injured children and their families. The institution has developed extraordinary ways of improving performance and function in these children. I have personally witnessed what I would consider to be miracles there with kids who were speechless, sightless, and unable to be really self-moving and under control, who-many years later, with extraordinary efforts on the part of their parents through these programs-have been able to achieve extraordinary function, sometimes high-level function, including gymnastics and playing concert violin and doing Shakespeare. It has just been quite amazing. A Serendipitous Meeting As I was at one of these meetings, I met a very amazing woman, Laurette, who was the mother of a daughter who had leukemia. This was probably not your average mother in terms of her advocacy (or the lengths that she would take her advocacy) for her daughter. Her daughter, who was receiving repetitive treatments with anti-folate chemotherapeutic drugs (I think methotrexate, and other medications like that), ended up having seizure disorders, which is not an uncommon secondary side effect from these treatments. Laurette asked the attending oncologist and physicians if this side effect could be reduced or removed. They didn’t have a lot of clues about this, so she went on her own into the literature world (being a sleuth for information), and eventually hit on Dr. James’ work. As you’ll learn more about, this work has to do with folate, the methylation pathways, homocysteine, and all these variables, but at a different level to neurologic function. And so Laurette came back to the people at the hospital with reams of information. They said it was very interesting intellectual stuff, but it didn’t really relate to the practice of clinical medicine and her daughter. Laurette made a big case of this and her advocacy was undaunted. She said that her daughter should be treated with folic acid and other methylating nutrients and that this would reduce the seizure disorders. So the debate went on and on. The products Laurette was requesting were not available in formulary, so the hospital staff couldn’t really prescribe them, and so Laurette fought through that to get them on formulary. The long and short of it was that through her advocacy and through mobilizing the work of Dr. James and others, Laurette was able to better manage these problems with her daughter in terms of seizure disorders. Laurette said to me, “You really have to meet this Dr. James. She is really the leader in this field. If you don’t, then you aren’t doing your work very well.” Needless to say, Laurette is quite an advocate. I have been looking forward to this interview because I have been following Dr. James’ work. She is a Mills College graduate in biology who went on to get her PhD in nutritional biochemistry after traveling through Berkeley to UCLA, where she got her PhD. She has been in the area of research and development, and the Division of Biochemical Toxicology at the Food and Drug Administration (FDA) National Center for Toxicological Research, as well as a professor (now, of pediatrics since 2003) at the University of Arkansas School of Medicine. We have some interesting interweavings in our histories because I also followed the Berkeley-UCLA-ultimately UCI path in my undergraduate life, and I did quite a bit of lecturing at the University of Arkansas School of Medicine on nutritional biochemistry back in the late 1970s. I guess we have kind of had this interesting web of interaction on a number of intellectual levels. It is very extraordinary that we finally have a chance to meet together on Functional Medicine Update. Dr. James, what a privilege to have you today and thank you for spending time with us. JJ:     Thank you. It’s my pleasure. JB:     In looking at your publication record, what I see (as I kind of take the broad brush) is an extraordinary example of the evolution of a scientist and the implications of their work on many fields as they recognize the spreading effect. I’d like to go back to where this all started for you, and show how it has built up to have a tremendous application across many different functional-what we might even consider disease etiology-conditions. This, of course, fits into our functional medicine model so beautifully, because we have often told our doctors that the differentiation between functional medicine and traditional diagnostic medicine is that we are less concerned about what we call it (i.e., the diagnosis as a disease) and more concerned about mechanisms (because people have processes, they don’t have diseases). The dysfunctional processes are what give rise to what we codify (to make it simpler to understand and memorize) as a disease. I think your history really is a tremendous example of the functional medicine model, because by understanding more and more about a process-in this case transsulfuration and the methylation pathways-we can see how it applies to so many different conditions that cut across a whole variety of different subspecialties of medicine. You are, in many senses, what we would consider the premier functional medicine researcher. With that as a kind of introduction, let me go back to where-for me-this all started. In 1971, I read a paper in the Lancet authored by Dr. Smithells in England, who was talking about B vitamins and neural tube defects and spina bifida offspring from women who apparently had functional vitamin B deficiencies. He talked about folate and B12 as important nutrients, and when he supplemented women who had previously given birth to children with NTDs or spina bifida, this really significantly reduced the frequency of another offspring having that problem. That was a very controversial area for the better part of 25 years. It was only through the later understanding of mechanisms that we started to see how spina bifida could be associated with folate problems and how that related to folate polymorphisms. That now takes us to your work and your initial publications on methylation. Could you tell a little bit about DNA strand breaks, radiation diet, heavy metals, calorie restriction, and the folate cycle? The Methylation-Transsulfuration Pathway JJ:     Okay. It has been quite a journey, researching this metabolic pathway. I first became involved with it in graduate school at UCLA. This is the methylation transsulfuration pathway. We started out in a rat model, using what is called a lipotrope-deficient diet (it is folate, methionine, and choline deficient). It is well known that over time, with diet change only, hepatocellular carcinoma can be induced. So that is where we started, looking at the livers of these animals that were put on this methyl-deficient (or lipotrope-deficient) diet. Looking at DNA Strand Breaks and Uracil Misincorporation We looked at strand breaks and how this diet affects the pathway. That was an interesting finding. The shift in the metabolites in this pathway (looking at the folate side), showed us that the dUMP, which is the precursor for thymidylate synthesis, was increased, and the dTTP (the thymidylate product) was decreased. This work was actually very early, and subsequently Bruce Ames looked at that same pathway. We had seen the strand breaks, and he followed that with the finding that there was actually uracil misincorporation. Again, this is all just diet and shift in these pathways so that this ratio of the uracil precursor (the dUMP to the thymidylate product) was increased. So what happens when the DNA polymerase doesn’t differentiate dUTP from dTTP? It misincorporates the uracil. That is interesting in itself, but we think that the real problem is that there is a uracil glycosylase that will get rid of that uracil and leave a break. So that was a big insight into one of the mechanisms (again, I’m very mechanistically oriented). We thought this might be a mechanism associated with how this carcinogenesis process works and this might contribute to preneoplastic state. So that’s where we started, looking at liver cancer in rats. JB:     I recall from some of your publications that you looked at different ways of inducing DNA changes, like radiation and heavy metal exposure (like nickel), and you also even did a number of studies on calorie restriction as a protective intervention in animals. Studies on Calorie Restriction as a Protective Intervention in Animals JJ:     Yes. That was an interesting finding. Trying to understand-again, this is nutritionally related and cancer, which is where I started-why caloric restriction is protective and is associated with an increased lifespan (at least in rodents) and recently, in The New York Times, apparently in primates, as well. Did you see that? JB:     Yes, I did. JJ:     It was interesting-the fat monkey and the slim monkey and the slim monkey looked so much better and was so much more active. So, we were interested in the mechanism. If you look at rats in a cage, you can tell immediately which ones are the calorically restricted because they are zooming around the cage, they are looking for food, and they are much more active than the slobs who have all the food they want and are just getting fatter and fatter, not worrying about food so they are just gaining weight and not exercising. It occurred to me that maybe (and it was just kind of a flash moment) it could be that because there are fewer calories available, the body senses that loss (or restriction in calories) and will induce an apoptotic event in the most vulnerable cells. And so that was our hypothesis, that maybe what’s happening and what is protective with caloric restriction is that the vulnerable (the preneoplastic) cells (which are well known to be most vulnerable to apoptosis), when you pull the calories, those cells go first. That paper was in Cancer Research, where we actually looked at the level of apoptotic bodies in the livers of calorie-restricted rats compared to the ad libitum fed and found a clear increase in the level of apoptosis, which did support our theory. 6 An Alternate Theory about Calorie Restriction I have another theory about caloric restriction, which is kind of the inverse and I think is equally interesting. It may be that we are not looking at the effect of calorie restriction extending lifespan, but rather we are looking at the effect of overnutrition reducing lifespan. This depends on which side you take as your control. If you take the overfed (the ad lib fed) animals as your control, then it looks like caloric restriction is extending lifespan. However, it is equally valid, I think, to take the calorically-restricted animals as the more normal, because they are (that’s what mice and rats do-look for food and they are not ad lib fed), and you take them as the control, then what you are really studying is the life-shortening effect of too many calories. So that was kind our take at that level, at that pathway. JB:     Let’s talk a little bit about the assessment of alterations in the transsulfuration/transmethylation pathway. I know you have talked about glutathione and you have talked about S-adenosylhomocysteine. There are some ratios that look like they might be interesting from an assessment perspective, like the GSH to GSSG ratio, or the S-adenosylhomocysteine to S-adenosylmethionine ratio. Could you tell us a little bit about those? JJ:     Yes. Again, as I said, this pathway has been my life. It has taken me on a wonderful and fascinating journey. The transmethylation is basically the methionine cycle, which I think you are all very familiar with. What we did is take the methionine cycle through S-adenosylmethionine to S-adenosylhomocysteine to homocysteine. Then we took it down further. Taking the Transsulfuration Pathway to Glutathione If you take from homocysteine, now you enter the transsulfuration pathway. Most graphs (if you look at the diagrams and papers) will end at cysteine. What we did is say, “Wait a minute. We need to go all the way down to glutathione.” That was really illuminating for us. What we have looked at in Down syndrome and cystic fibrosis and now, most recently, in autism is how the transmethylation pathway interfaces with the transsulfuration, taking it all the way down to glutathione. This has been really fascinating to us because there is a lot of regulation that intersects those two pathways. For instance, methionine, which is at the top (it is the product of methionine synthase), that is the essential amino acid. What the methionine cycle is basically doing is it is a clever way the cell has to recycle or conserve this essential amino acid. It’s basically through methionine synthase and the methyl group from 5-methylfolate. It’s a way to keep that methionine level high and that’s critically important for the viability of the cell, for not only protein synthesis, but these essential methylation reactions because methionine then leads to S-adenosylmethionine, the major methyl donor for a multitude of methyl transferase reactions-essential DNA methylation, RNA methylation, protein methylation, phospholipid methylation, creatine, and neurotransmitters. SAM (S-adenosylmethionine) is absolutely essential to keep that up, which requires the methionine. The methionine cycle is keeping methionine up, which then feeds to this essential methyl donor. Once it gives up its methyl group, it then becomes S-adenosylhomocysteine (SAH), which is then rapidly hydrolyzed to homocysteine. The next step is from homocysteine down through the transsulfuration to cysteine. Cysteine, recall, is the rate-limiting amino acid for glutathione synthesis. Now if we go back up to the methionine cycle, the S-adenosylmethionine is an important regulator of CBS (cystathionine beta-synthase) which is the enzyme that pulls homocysteine down transsulfuration. When it is high, it upregulates CBS (when SAM is high you get an upregulation, which pulls homocysteine down to glutathione, which is good). There is that interaction, then, through SAM levels, of regulating the transsulfuration pathway. So keeping methionine levels high-the other important point here-is that methionine, through this pathway, down through CBS and transsulfuration, provides 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the cysteine for glutathione synthesis. That transmethylation-transsulfuration pathway is not only important for methylation reactions, but also as a precursor to get methionine all the way down to cysteine, and that is what leads us into glutathione. We go from methionine being high, and it is going to keep cysteine levels up. Cysteine is the rate-limiting amino acid for glutathione synthesis, and so now the whole transmethylation-transsulfuration works together, and that is actually reciprocal. When glutathione needs are high, transsulfuration is upregulated so that the SAM and homocysteine and the cysteine levels are pushed down that pathway so we can fortify the glutathione levels, which are so important for a multitude of viable options for the cell, including what we call the reducing environment inside the cell (that is what allows multiple redox-sensitive enzymes to work well). You have got to have adequate high levels of glutathione in the cell so that those enzymes are redox functional and active. It is important for the integrity of the cell membrane, for membrane signal transduction, and for gene expression. Glutathione is an Important Detoxification Mechanism for the Cell Glutathione is an absolutely fascinating molecule. It is important, as you know, as a free radical scavenger. It is well known to be the major antioxidant, or free radical scavenger, inside the cell. It is also important for detoxification; this is less known but equally important, and brings in an environmental aspect. Glutathione is actually a tripeptide: glycine, cysteine, and glutamate. It is the cysteine (and remember, that’s the rate-limiting amino acid for glutathione synthesis) component in the glutathione and, specifically, the SH, or thiol group, that’s the active part of glutathione; it donates that hydrogen from the SH, or sulfhydryl group. Well that sulfhydryl group, on glutathione, is a magnet for heavy metals. And, again, we are bringing the pathway now to an environmentally important pathway. That SH group will bind mercury, lead, arsenic, cadmium-it is a magnet for heavy metals. Once bound by glutathione, that heavy metal now is inactive (it can’t damage the cell). So glutathione is an important detoxification mechanism for the cell, and that conjugant of glutathione, then, is further metabolized and is excreted from the body in the bile and also in the urine. It is not only the major detox mechanism, it is the way that the metals are excreted, and it is actually the natural chelator of the body, if you want to think about it that way. We have sort of taken our transsulfuration down to being very interested in the glutathione and what we call redox ratio. JB:     We could spend days going through this in great detail and I know you could fill those days very eloquently with us. It sounds like there is a connection between this oxidative stress reaction that occurs when you can’t detoxify oxygen and nitrogen free radicals, so your glutathione to glutathione disulfide (that’s the reduced-to-oxidized-glutathione ratio) goes down as your apparent conversion of SAM, ultimately, down into incorporated cysteine for glutathione synthesis is compromised. So that would then suggest, I think, that there is a connection between oxidative stress and glutathione synthesis and interruptions in the transsulfuration pathway. Do you see, then, increased levels of 8OHdG (8-hydroxydeoxy-guanosine) in animals or humans when there is a diminution of the reduced glutathione levels? JJ:     We haven’t done that. However, we have just gotten a 5-year NIH grant and that will be part of what we’ll do. Our grant is more focused on autism, but it is the same thing. We see a low GSH-GSSG ratio and whether that is associated with 8-deoxy-guanosine is a fascinating question. My bet is that it should be. JB:     That, then, also opens our thoughts because we have heard so much about homocysteine as a marker for interruptions in this pathway (at least a surrogate marker). And then there is literature that you have described in some of your publications suggesting that S-adenosylhomocysteine might be a more sensitive marker. Could you tell us a little about the homocysteine connection, as a marker to defects in this pathway? The Relationship between Homocysteine and S-adenosylhomocysteine (SAH) JJ:     Yes. That is a very interesting area. We were interested in the SAH reaction. What we showed (I think in a Journal of Biological Chemisty paper, I think in 2000) is that when homocysteine is elevated,that comes from S-adenosylhomocysteine to homocysteine and adenosine. 7 That is the sole source of homocysteine in the body (that one reaction). It turns out that that reaction is actually reversible. That is getting to be better known, but it was not really fully appreciated early on. The only reason that that methionine cycle proceeds in the clockwise direction, if you will, from homocysteine then back through to methionine synthase (the reason the SAH hydrolase reaction proceeds in that hydrolytic direction) is because the products (homocysteine and adenosine) are rapidly removed. The metabolism is set up to keep those levels low. The homocysteine gets sucked into methionine synthase or sucked down into the transsulfuration pathway. Adenosine goes on to adenosine kinase or adenosine deaminase. So the products of the SAH hydrolase reaction, under normal physiologic conditions, are kept very low. That keeps that SAH hydrolase reaction going in the hydrolytic direction. However, under pathologic conditions, where homocysteine is elevated, or adenosine is elevated, that SAH hydrolase reaction will reverse, and, in fact, the thermodynamics of that reaction actually favor the reverse direction (from homocysteine back up to S-adenosylhomocysteine, or SAH). We showed that in our paper-actually a very nice relationship-that as homocysteine is elevated, so is SAH. But the real punch line is that SAH is a potent product inhibitor of all of the methyltransferases, and it is involved in, for instance, DNA methyltransferase, which was our particular interest at the time. When SAH with homocysteine levels go up, it backs up and SAH levels go up and then the hypothesis is-and it has been shown in multiple in vitro studies-that the SAH will inhibit the methyltransferase and cause a decrease in the methylation potential or capacity. And so in that paper, we showed also that the DNA methylation level decreased as SAH went up. I think that is where it has actually been reproduced, and now there is a lot of talk and theory (which I think is still at the theory level, but certainly worth pursuing) that maybe homocysteine is just a marker and it is really the SAH (which inevitably has to go up when homocysteine goes up because of the thermodynamics of that reaction) and the SAH well known effect on phospholipid methyltransferase, DNA methyltransferase, and protein methyltransferase. We are getting into a whole new area that could be related to an increase in homocysteine, but is actually an indirect downstream product of an increase in homocysteine. I think that’s still in its infancy, but there is an awful lot of active work going on now looking at methylation changes (whether it be protein, DNA, etc.) associated with elevated homocysteine. JB:     For the clinician, who is probably the major listener of this, is it still valid or valuable for homocysteine assessment to be done as a surrogate marker? JJ:     Absolutely. Mechanism is where we are delving now. Without question, homocysteine is much, much easier to measure than S-adenosylhomocysteine. I’m not even sure that it is commercially available. This is done in the research lab. We have HPLC with electrochemical detection, which actually was a breakthrough because SAH levels in the plasma (readily available to clinicians) is very, very low and very difficult to pick up with fluorescence. But it absolutely holds that if you see an elevation in homocysteine, you can assume that the SAH is up. You can also assume that if you lower homocysteine with intervention such as folate, B12, B6, or betaine and get homocysteine down, SAH came down as well. So you really don’t have to measure SAH. That whole area of trying to understand the mechanism behind atherogenesis or carcinogenesis, for instance, may or may not be important to the clinician directly. If you can get the homocysteine down you are going to get the SAH down, and that is what is important, clinically. The mechanism-whether a hypomethylation is involved with atherogenesis or carcinogenesis-that’s kind of a research area. JB:     I hope that our listeners are hearing that you are delivering on my introduction. You have cut this discussion across a number of potential clinical conditions, including cardiology. We have talked about neurology. We are going to talk about developmental biology. We are obviously talking about areas of endocrinology. It is a pretty fascinating that we have even talked about oncology (carcinogenesis). Mechanisms are probably where the action is in medicine. The outcomes that we call disease are really the secondary effects from altered mechanisms. You are making this point very, very clear. Let’s go back now. The clinicians who are listening have survived through some very arduous biochemistry, so now the payoff is to talk a little bit about the applications. Earlier in your career, you started applying this concept to Down syndrome, looking at some of these polymorphisms of the folate cycle, like methylenetetrahydrofolate reductase and catechol-O- methyltransferase. Can you tell us that chapter in your history? Down Syndrome and Polymorphisms of the Folate Cycle JJ:     Yes. That was, again, serendipitous. A colleague called who was involved in Down syndrome research, and pointed out that the cystathionine beta-synthase gene is on chromosome 21, and it overexpressed, obviously, because there are 3 copies of CBS in children with Down syndrome. This perked my interest because, of course, that’s part of our pathway (and, again, that’s the beginning of the transsulfuration pathway). So we were interested in looking at children with Down syndrome (to examine whether this pathway was altered). We did find alterations in the pathway. We also looked at cells (the blastoid cell lines) from children with Down syndrome. What we see with Down’s kids is that homocysteine is low because it is being pulled down the transsulfuration pathway with the overexpression of CBS. But, interestingly, we also found the glutathione levels were low, which you might not expect with overexpression of CBS. It turns out that superoxide dismutase (which leads to hydrogen peroxide) is also on 21 and that is overexpressed, and so we did see some oxidative stress in the children (the GSH-GSSG ratio being decreased), but (again) for a very different reason (secondary to another gene on chromosome 21). We also were interested in the parents, and looked at the frequency of the MTHFR polymorphism (the 677T). This was actually a surprise. We just thought it might be interesting and it was a huge payoff. It was actually very controversial when our paper first came out. Most geneticists involved with Down syndrome thought there really wasn’t a genetic cause, but that it was somatic. What we found was a significant increase in the 677PT. The hypothesis (and I always have to have a mechanistic hypothesis to get interested in a project) was that basically Down syndrome is a nondisjunction event 95{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the time in the mother (two chromosomes don’t separate properly). Thinking about that and the folate cycle was the rationale behind even thinking about looking at MTHFR. It turns out that where methyl groups are most concentrated is in the pericentromeric repeats (CG repeats) around the centromer. I hypothesized that if the mothers had a MTHFR polymorphism, that should affect the methylation of the DNA, and where most methyl groups are is in this pericentromeric region. 8 With fewer methyl groups in the centromeric region, what happens is that the DNA is in a more open configuration and more likely to tangle and may, somehow, be involved (mechanistically) with why those chromosomes aren’t segregating properly. That was the rationale. We came out with this paper and it was very controversial. It usually takes 5 to 10 years before a hypothesis is replicated or not. The good news is that it is being replicated. And actually even more interesting, other genes that are involved in this pathway are now being found to be elevated (in MTRR and MTHR1298-other polymorphisms affecting the same pathway that would affect methylation). Data are coming out of different countries now that really seems to support that we were on the right track. Subsequent to that paper (our paper with this kind of far out hypothesis), came several papers showing that, in fact, the MTHFR677TT is clearly associated with DNA hypomethylation, which would fit with our hypothesis that maybe it is the methylation around the centromer that is involved with the nondisjunction event. JB:     I think this is an enormous bit of science and discovery. Over time, this will probably weave its way down in the same way Smithells’ early observational association between B vitamins and neural tube defects has changed our thinking about epigenetic effects of nutrition on gene expression and developmental biology. Your work is just right at the cornerstone of that and I really want to compliment you and your colleagues. Before we jump to autism (I know a lot of our listeners are very excited about hearing about your recent work in that area), I want to quickly cover a couple of sound bytes that I know are part of your publication record. One is the postmenopausal woman. Looking at lymphocyte DNA methylation patterns, do we have any relationship, do you think, of functional folate, B12, and B6 insufficiency in the postmenopausal woman who is eating the standard American diet? JJ:     Are you talking about an estrogen effect? JB:     I’m talking about the paper that you published in 1998 in the Journalof Nutrition where you looked at lymphocyte methylation patterns in postmenopausal women. I thought it was quite interesting. Elevated Homocysteine in Postmenopausal Women JJ:     That was the SAH paper, I believe. We were showing that elevated homocysteine could be associated with the postmenopausal state. This actually goes back to the difference between men and women and their homocysteine levels. It is known that men have higher homocysteine levels than women, all the way up to menopause. It is fascinating to me what that could mean. Estrogen upregulates the methionine cycle, believe it or not. When the MAT is increased, methionine synthase is increased (and this is in rats as well as humans). The methionine cycle is much more efficient in women, and that may be the reason why we see lower homocysteine levels in women at all ages up to menopause, and then the difference is less. Somehow estrogen-and it could be, again, by upregulating the methionine cycle-keeps homocysteine low. I think that was the paper where we were showing when homocysteine went up, SAH levels went up and the DNA methylation was affected. 9 It is, again, back to a relationship between the homocysteine level being elevated and backing up to increase the SAH, which affects methylation. JB:     What really struck me about your paper was multiparametered input into postmenopausal women and their risk to cardiovascular disease and cancer and neurological deficits. The cause may be more than just the lack of estrogen, in and of itself. There may be a number of other secondary variables like alterations in methylation pathways, which may be modifiable factors if we can just look at these from a different perspective. I think your work is very helpful in that regard. This is such an extraordinary and important topic I think we would be remiss if we didn’t also address the work you did on the p53 tumor suppressor gene and how that relates to methylation and the folate cycle. This question about whether folate supplementation in women is increasing or decreasing the risk to breast cancer is a very interesting topic right now. Could you tell us a little about your work on p53 tumor suppressor gene and methylation? Methylation and the p53 Tumor Suppressor Gene JJ:     Yes. Again, this was in our rats on the choline, methionine, folate-deficient diet-looking in their livers for methylation changes. We picked the p53 gene because it is a well known tumor suppressor gene that should be expressed highly as a tumor suppressor gene (when it is working). We were interested in whether the methylation pattern would change with this diet (again, the concept that just alone could affect changes in DNA methylation and gene expression). As background, I guess you need to know that where DNA methylation works, generally, is in the promoter region of genes. When we talk about DNA methylation we are talking about cytosine methylation. It is a methyltransferase that is taking a methyl group from SAM and putting it on the number five position of cytosine (at CG dinucleotide-that’s the target). This is really how tissue-specific gene expression is produced and maintained. These patterns of methylation are set down very early in development (during embryonic development). If a gene is methylated, it is turned off. That is the way it should be in a tissue-specific manner. We want the albumin gene to be turned on in the liver, but not in the kidney. So what you see is a hypomethylated promoter for the albumin gene in the liver; that means it is going to be turned on. Whereas in an inappropriate tissue (like the kidney), that same gene (because all cells have all the same genes) is hypermethylated and turned off. DNA methylation is really a way that tissue-specific gene expression occurs. What we found with our diet (which we showed previously) is that it will cause global (what we call “global”) DNA hypomethylation. That means there is a loss of methyl groups in the DNA, globally (when you look at the whole DNA). It is fascinating and complicated, unfortunately, that when there is a global loss of methyl groups, it is accompanied by (and this is paradoxical) a local or regional hypermethylation and turning off of inappropriate genes. JB:     I apologize.I had to interrupt you in the middle of your sentence for technical reasons. Could you continue your thought about this methylation pattern? JJ:     Right. You were asking about the p53 gene. It was another step after the strand breaks: looking (in a rat model) at totally and nutritionally-induced carcinogenesis (really a nutritional-deficiency-induced carcinogenesis). We looked at a common tumor suppressor gene (p53). I was explaining that what we found is that when you have a global loss of methylation, it can often be associated with a promoter region hypermethylation. Although complicated, it is basically a dysregulation of methylation. We looked at the promoter region of the p53 gene and saw an increase in methyl groups, and that (when the promoter is methylated) is turned off. This finding fit into a mechanistic approach to this diet-induced carcinogenesis: maybe the methyl groups were dysregulated and turned off in a very important tumor suppressor gene-the p53 gene. This was an important tumor suppressor gene that was turned off by diet. JB:     I want to highlight one last clinical tidbit from your publication record. It has to do with the methylation patterns of phosphotidylethanolamine to phosphotidylcholine and how that relates to construction of cellular membranes that you had described earlier, including phospholipids that are associated with myelin. I know you have had at least one paper where you looked at undermethylation and its relationship (in an animal model, maybe) to MS, which we consider a dymyelinating condition. Is there any emerging thought that methylation may play a role in some of these neurologic autoimmune disorders? Phospholipid Methylation: The Role of Methylation in Neurologic Autoimmune Disorders JJ:     Yes. Actually we looked at DNA methylation because that was kind of our emphasis in this rat model. Frankly, I think phospholipid methylation and protein methylation are going to be affected more quickly than DNA methylation. You are not going to get a change in DNA methylation unless you’ve got cell turnover, which is fairly slow. Phospholipid turnover is very rapid, and protein turnover is also rapid (or more rapid than DNA). I think it is phospholipids methylation where you’d see changes in the availability either of the SAM (the methyl donor) or the product inhibitor inhibiting the methyltransferase. I would think that phospholipid methyltransferase would be the most sensitive. We did a study-it was actually on cystic fibrosis, not MS-looking at that ratio in children with cystic fibrosis. 10 Once again, it was kind of a serendipitous observation that homocysteine levels were elevated in these children with cystic fibrosis. I felt this must mean that SAH levels were also elevated. When we looked, sure enough they were, because the two go hand in hand. If you see elevated homocysteine, you can assume SAH is also up. My collaborator, Sheila Innis, at the University of British Columbia, is a phospholipids expert. She measured the ratio of phosphoethanolamine to phosphocholine, the precursor of phosphotidylethanolamine methyltransferase (the PEMT), and found that indeed the phosphoethanolamine, the precursor, was elevated, and the product, phosphotidylcholine was decreased. So that was evidence, then, that the phosphotidylethanolamine methyltransferase (or the methyltransferase involved in membrane lipid turnover) was indeed affected by changes in homocysteine. JB:     Thank you. That’s very interesting. Now let’s turn to what people have been waiting on the edge of their seats for. I will read a quote from one of your recent papers. “The current study was promoted by the serendipitous observation in a previous study that the metabolic profiles of dizygotic twins, one with Down syndrome and one with autism, were virtually identical with respect to methionine cycle and transsulfuation metabolites.” 11 Here we go. Now we go in to ASD (Autistic Spectrum Disorder). JJ:     Let’s go back to Laurette, where we started, because Laurette has just been instrumental in my life. This is a mother. Her child has Down syndrome, and developed leukemia. I got a telephone call out of the blue from this mother, who was obviously well read. She really had no biochemistry background, and it was fun because she couldn’t really say the words right, but she knew what she was talking about. We formed a wonderful relationship, helping her child get through chemo, because children with Down syndrome are very sensitive to methotrexate. We formed this wonderful relationship, which has held today. So through that Down’s project, and through Laurette, we were doing a study (as I mentioned previously) looking at this pathway in children with Down syndrome. As researchers, one of the problems we have in doing human studies (in children, especially) is the availability of normal control children. I had a great idea. The mothers of these Down’s children were so helpful and so grateful. I asked them if they could bring in a normal sib. Usually this wouldn’t be a good control, but for Trisomy 21, it is a fine control. And, of course, the moms were more than happy to bring in the group of kids, so we got a lot of controls. A Unique Set of Twins Leads to Autism Research One mom had twins, and one twin had Down’s and the other twin had autism (no Down’s, but just autism). That is what triggered my interest in Down syndrome. It was truly an N of 1, but it was so unusual. I couldn’t tell which one was the control; I had to call to ask. It was usually very obvious which child was the control child. Based on that N of 1, and with Laurette’s help, we decided to follow up. Was this was a fluke (something had been wrong) or was it real? So it was truly serendipitous that I got to autism through Down’s and through Laurette. She arranged a physician in Buffalo, and I said I needed 10 plasma samples from autistic children. Laurette, bless her heart (her daughter was somewhat autistic, as well as Down’s, as well as getting through leukemia, so she’s been through the gamut), had relations with the autism community there and arranged and got 10 plasma samples. We repeated our profile and it was so consistent I really didn’t believe it. I called the physician back (kind of embarrassed) and said, “You know, Paul, I’m not sure I believe this data because it is too consistent, and you don’t see that in humans, generally.” I asked him for another 10 plasma samples, and again (with Laurette’s help), they sent me a second 10 samples. The results were the same (a little more variation, but basically the same pattern). That launched me, full speed, into autism and I haven’t quit yet and don’t intend to. That is how we got started. JB:     We are very happy to hear that you have just gotten started because the work you are doing is absolutely pioneering. The first paper that I saw out of your group, which is a collaborative paper with Dr. James Neubrander (and it was very kind of you to have Laurette as a coauthor) was the one in the American Journal of Clinical Nutrition in 2004 (vol. 80, pg 1611) titled, “Metabolic Biomarkers of Increased Oxidative Stress and Impaired Methylation Capacity in Children with Autism.” And then more recently, a 2006 paper that you might want to tell us about. I think it is an absolutely fantastic contribution to our understanding of this subject. This paper is titled, “Metabolic Endophenotype and Related Genotypes are Associated with Oxidative Stress in Children with Autism,” and I think it takes this discussion to the next level. 12 Maybe you could tell us a little bit about that? JJ:     Okay. In the first paper (in the Journal of Nutrition) we discussed a small intervention trial that was fascinating. I had been looking at using trimethylglycine and folinic acid in the Down’s kids. We decided to try that in the autistic kids as well, because what we want to do is bring up their methionine, cysteine, and glutathione levels. So we initiated the folinic acid TMG in a small subset (and this was part of the publication). And then Dr. Neubrander came out with the methyl B12 information, so we added the methyl B12. So in that first paper, there is a small subset of 8 kids that we took through this intervention with folinic trimethylglycine and methyl B12. With 3 months of intervention, we were able to bring up methionine, SAM, and glutathione levels in these children. But, again, that was a very small study, and we were just looking at the biochemistry; we did not have any behavioral outcome as part of it. We are following up now at Arkansas Children’s Hospital Research Institute (where I work), repeating that intervention with the methyl B12 and folinic, and we are doing a behavioral evaluation (before and after treatment). That will be very interesting because (just anecdotally), I know you know (through Dr. Neubrander), the methyl B12 does seem to have a dramatic effect in many children, behaviorally. That’s the next step with that project. The more recent paper in the American Journal of Medical Genetics was a follow-up to our research on 20 kids-the first 10 (that I didn’t believe) and then the second 10 (that I did believe); that was an N of 20. In this more recent paper we have an N of 80 children, and this is through many of the physicians that are involved in the Defeat Autism Now movement (and they are coauthors as well), who helped get the plasma and sent it to us for analysis. So now it seems this is a much more powerful statement; we have 80 autistic children compared to 73 controls. Now we can see what the real variability is when we look at a much larger population. Basically, it was the same story (much more variation, but, again, it was the same story in most of the children). Recent Study Reveals Low Methionine Levels in Autistic Children What we see-and this gives us so much insight into this imbalance in metabolism and what it might mean for etiology and for treatment targets-is a decrease in methionine levels, and that was highly statistically significant. In the paper, I break it into subgroups because the mean difference was significant (statistically), but within that mean (if you look at a subset), what we found is that half of those kids had extremely low methionine levels. That was kind of our approach. The mean differences were exactly as we had seen in the previously smaller set, but now that we have a larger group I can get more definitive because, as you know, autism is highly heterogeneous. We were really interested in what subset of kids was severely affected, and could we isolate that subset and then look at their behavior and try to make some sense of biomarkers versus behavior. What we found, again, was similar: decrease in methionine (very reproducibly), decrease in its product (S-adenosylmethionine) in about 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, and then an increase in S-adenosylhomocysteine (the product/methylation inhibitor) in about 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. Even though the mean difference was statistically significant, it was really a subset that I would consider functionally affected by the elevated SAH (which would affect their methylation). So then, of course, the ratio was decreased. We look at this ratio as the best indicator of methylation capacity because you have a low methyl donor (SAM) and (in a subset of the kids) a high SAH; that is a set-up for methylation problems. That was a new finding that we thought was very interesting. If we look at the transsulfuration pathway, low cysteine is highly consistent. As I said, it is the precursor for glutathione synthesis. You would anticipate (with low cysteine) that you would have low glutathione, and we did see that as well. I think the most interesting (and the strongest) indicator that these children are under oxidative stress is the increase in plasma GSSG (that is the disulfide oxidized form of glutathione-it is the spent form that has given up its hydrogens and it is not being converted back to the active GSH as rapidly as it should be). The only reason that GSSG would be increased in the plasma is if there is a problem intracellularly. What the cell will do as a last-ditch effort when it can’t keep up and that absolutely essential redox ratio begins to creep into a dangerous level is to get rid of that GSSG-export it, get it out of there, reduce the denominator-and keep that essential redox ratio in a good range. When we see an elevated GSSG in the plasma that is proof positive that there was a problem inside the cell, which is where we are really interested, mechanistically. That, I think, was our strongest indication that many of these children appear to be under chronic oxidative stress. JB:     I think we are all applauding as we are listening to you talk. This is, again, a history of scientific evolution. It is really extraordinary to listen to this journey through your story. As we close, I would like to talk just briefly about how (in functional medicine) we might interpret some of your discoveries. As I said in the introduction, we are less concerned with the diagnosis and more concerned about the imbalances, defects, or alterations in basic physiological mechanisms. Our assessment is more focused on antecedents, triggers, and mediators that give rise to signs and symptoms. You have been talking at length throughout this whole discussion (and through your many, many studies) about antecedents-genetic variabilities that may point a direction towards an increasing risk or prevalence to a condition. Then we have to talk about a trigger that would take that antecedent and convert it into a different expression pattern. These markers you are describing (like elevated S-adenosylhomocysteine, or lowered levels of glutathione in the reduced state, or elevated glutathione disulfide in the plasma) are the so-called mediators or markers that give rise ultimately to a complex metabolic event that leads to the signs and symptoms of certain conditions. Knowing that we have these antecedents that are emerging, does this, then, allow us (you being at the principal hub of this wheel) to understand something about this triggers? I’m thinking about thimerasol and the connection (or the Andy Wakefield work) with lymphoid nodular hyperplasia and GI-immune relationships, or certain other kinds of environmental triggers that might encourage the expression of these patterns that give rise to these unique oxidative injuries in the nervous systems of certain children. Considering Autism as an Environmentally Sensitive Metabolic Imblance JJ:     Basically what we have is a phenotype. When you look at the metabolic profile that gives you (in my mind) the sum total of the genes and the environment for that individual. It gives you clues about genetic susceptibilities. We have found (it was part of our most recent paper in the American Journal of Medical Genetics), several polymorphisms that are increased in autistic children that might be responsible for this abnormal profile. The profile, itself, gives us clues possibly to etiology, as well. The problem with autism, intellectually, I think, for many physicians, is that it is a behavioral diagnosis and so you are thinking neuro; you are thinking brain. We are introducing a metabolic component, and that means it is going to affect systemically; it is going to affect beyond the brain because that pathway is in every single cell of the body. It brings out the possibility that if this is a genetic predisposition to this metabolic imbalance that is very environmentally sensitive, that maybe we are affecting more than the brain. In fact, maybe the brain is downstream. We know there is a significant GI component through Wakefield’s work. We know there is a significant immune component to autism and there have been multiple studies looking at immune imbalance in autistic children, most recently related to thimerasol. Issac Pessah, at the M.I.N.D Institute, has shown that thimerasol in very low levels affects antigen-presenting cells (the dendritic cells). Because glutathione is the major detox for heavy metals, if it is low in these kids, you would expect they would have a reduced ability to detox environmental exposures and that is where we get in to the environmental components and the environmental sensitivity of this pathway. What this would mean is given an exposure, with their lowered glutathione levels, these children would be less able to detoxify. 13 They are also going to have a reduced homeostatic reserve. You can think of it that way. Basically, these children have a fragile, environmentally sensitive, metabolic imbalance, and when exposed to environmental toxicants, they are going to be the most vulnerable. That is really scary because we are all exposed. Autism is often referred to as the canary in the coal mine. If, genetically (and possibly through this pathway), they are more sensitive because they are less able to detox, and if we don’t do something about the environment, the next level is going to be affected, and the next level. Bringing Attention to the Need for Environmental Testing I think you may have seen that recent release in the Lancet about Dr. Grandjean (from Harvard) who is coming out with a paper making the point that just so desperately needs to be made that there are a lot of chemicals in our environment that have never been tested in our children for developmental problems. 14 This is a huge advance that this is coming out. Why do we have so many neurodevelopmental problems in children today? Could it be the environment? This new paper in the Lancet really makes that point and hopefully will open some eyes in the government in terms of research. We need to understand the impact, developmentally, on the nervous system of all these chemicals that are in our environment now. JB:     I can’t tell you how much we have appreciated this. This is the first of our 2007 editions and this couldn’t be more noteworthy precedent to start the year with. Your work is just pioneering and I know it reflects many, many other investigators that have collaborated with you. It is a community of evolution in thought. In the course of this discussion we have touched on Down syndrome, neural tube defects, spina bifida, autistic spectrum disorders, leukemia, coronary heart disease, cancer, and MD. All of these are connected to these mechanisms you are describing. I think it is fascinating to watch the transformation in medicine. I really believe that the age of the primacy of diagnosis is fading and that we are seeing the emergence of understanding fundamental mechanisms and the dysfunctions in those mechanisms as being what will create both the prevention and treatment of these conditions in a more successful way. Your work is certainly helping to guide us in that direction. Thank you for giving us so much time. It has just been extraordinary. We are going to follow this journey and your evolution as it moves forward. Understanding Autism as a Medical Condition JJ:     Thank you. I did want to make one last point regarding autism to the clinicians, and that is that I think all of this-our work and the work of others-is beginning to change the view of autism-that it is much more than a neuropsychiatric condition, that there is systemic involvement. There are real medical problems-gastroenterology and immunology-in these kids, and if we can treat them, they are going to get better. That is a whole other area that I think is so important in the transition to understanding to autism more as a medical condition rather than a neuropsychiatric disorder, and treating those medical problems with the children and some of them can get better. It’s wonderful. JB:     We thank you. That’s a very wonderful, optimistic view where we are heading. And we thank all of your collaborators-these are all pioneers that have really often fought against the standard of fear and the belief systems of the age which are sometimes difficult to overcome, and have done so at some personal peril. I think this is what will make great revolutions in our future. A lot of children who have been adversely affected hopefully in the future will be protected. JJ:     I hope so too. JB:     Thank you so very, very much. JJ:     You’re quite welcome. It is my pleasure.

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Bibliography

1 Viljakainen HT, Palssa A, Karkkainen M, Jakobsen J, Lamberg-Allardt C. How much vitamin D3 do the elderly need? J Am Coll Nutr. 2006 Oct;25(5):429-435. 2 Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health. JAMA. 2006 Oct 18;296(15):1885-1999. 3 Jehle S, Zanetti A, Muser J, Hulter H, Krapf R. Partial neutralization of the acidogenic western diet with potassium citrate increases bone mass in postmenopausal women with osteopenia. J Am Soc Nephrol. 2006 Nov;17(11):3213-3222. 4 Rylander R, Remer T, Berkemeyer S, Vormann J. Acid-base status affects renal magnesium losses in healthy, elderly persons 5 McCarty MF. Acid-base balance may influence risk for insulin resistance syndrome by modulating cortisol output. Med Hypotheses. 2005;64(2):380-384. 6 James SJ, Muskhelishvili L. Rates of apoptosis and proliferation vary with calorie intake and may influence incidence of spontaneous hepatoma in C57BL/6 x C3H F1 mice. Cancer Res. 1994 Nov 1;54(21):5508-5510. 7 Yi P, Melnyk S, Pogribna M, Pogribny IP, Hine RJ, James SJ. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem. 2000 Sep 22;275(38):29318-29323. 8 James SJ. Maternal metabolic phenotype and risk of Down syndrome: beyond genetics. Am J Med Genet A. 2004 May 15;127(1):1-4. 9 Jacob RA, Gretz DM, Taylor PC, James SJ, Pogribny IP, et al. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J Nutr. 1998 Jul;128(7):1204-1212. 10 Chen AH, Innis SM, Davidson AG, James SJ. Phosphatidylcholine and lysophosphatidylcholine excretion is increased in children with cystic fibrosis and is associated with plasma homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine. Am J Clin Nutr. 2005 Mar;81(3):686-691. 11 James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80:1611-1617. 12 James SJ, Melnyk S, Jernigan S, Cleves M, Halsted CH, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141(8):947-956. 13 James SJ, Slikker W 3rd, Melnyk S, New E, Pogribna, et al. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors. Neurotoxicology. 2005 Jan;26(1):1-8. 14 Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet. 2006 Dec 16;368(9553):2167-2178.

Welcome to Functional Medicine Update for February 2007. We have changed our format for 2007. The first section you will hear is Hot Breaking News, then we’ll move into our main topic. In this issue, we will be focusing on bioidentical hormone replacement therapy. We are very fortunate to have an expert in this area as our Clinician of the Month: Dr. Bethany Hays. Dr. Hays will be sharing her thoughts with us, based on her 30 years of experience in the field of obstetrics and gynecology. The last section of the issue will feature questions and answers that come from subscribers like you. Let’s start right in to Hot Breaking News. There are two topics that I think have some interest right now that I would like to talk about; the first is related to calcium and prostate cancer. A number of papers have been published recently on this subject, in which an inverse relationship between the two (increasing calcium, decreasing prostate cancer incidence) is discussed. Calcium Intake and Prostate Cancer One such paper is a prospective study of calcium intake and the incidence in fatal prostate cancer that appeared in Cancer Epidemiology, Biomarkers and Prevention. 1 In this study, the authors found that calcium intake exceeding 1500 milligrams a day in men was associated with higher risk of advanced and fatal prostate cancer. I think this is very interesting. In the past, we have said that higher calcium was associated with a lowered incidence of prostate cancer. The results of this study showed that men with the highest intake of dairy products and calcium were more likely to develop prostate cancer than men with the lowest intake, although the relative risk appeared to be fairly small (the difference in relative risk). Why is this? I think that the mechanism that is emerging is that when you get very high calcium, you start depressing the production of parathyroid hormone. When you alter the calcium phosphate ratios in tissues, you get an altered effect on vitamin D metabolism. What happens is you start lowering the amount of vitamin D converted to 25-hydroxy and then ultimately 1,25 dihydroxycholecalciferol. There is a need to better understand the inverse relationship between vitamin D and prostate cancer that has emerged over the last couple of years. Men who have low levels of serum 25-hydroxyvitamin D3-when I say low levels, I mean below 50 nanomols per liter (nM/L)-are men who have increasing relative risk (apparently) to prostate cancer. You can drive down the conversion of cholecalciferol vitamin D into the hormonal form through the intake of very high levels of calcium. There is most likely a zone of effective calcium intake that is probably somewhere between 800 and 1200 milligrams a day in males. When you get above 1500 milligrams, it appears (at least from an epidemiological perspective) as if you are on the downside of a bell-shaped curve. In order to fully answer this question, we’d like to see data related to increased calcium intake or different incremental calcium intake in males and the level of 25-hydroxy and 1,25 dihydroxy D3. That information would better allow us to make this association at a mechanistic level. From the present state of our associative knowledge through epidemiological evaluation, it appears that a high level of calcium intake in males is associated with potentially lowered active hormonal form of vitamins D and has a higher tracking with regard to prostate cancer incidence. I think we need to keep our eyes on this because we know there is a very important correlation between vitamin D conversion to its 1,25-dihydroxycholecalciferol form and lowered incidence of prostate cancer. For clinicians, I think we want to emphasize the importance of doing serum analysis of 25-hydroxyvitamin D3. The data suggests that we would like this level to be in the range of about 80 nanomols per liter; anything below 50 we would consider to be in the suspect area (even though the normal laboratory range often goes to 20 or below, which most of us-in terms of functional vitamin D physiology-would consider too low to promote proper function). Lactoferrin and Gastrointestinal Physiological Function Let’s move to another interesting Hot Breaking News item: an example of an orally consumed bioactive that influences gastrointestinal physiological function. I think we are learning more and more about certain agents that can be administered orally that have functional properties in the GI tract to help normalize gastrointestinal immunological or mucosal function. The specific agent I am referring to here is derived from milk (particularly bovine milk) and is found at high levels in colostrum: Lactoferrin. You may be familiar with lactoferrin as an iron-containing protein that is found in small levels in the immune fraction of milk. It is a very important agent in milk for inducing proper immune defense in offspring, and it also has an extraordinary ability to help stabilize immunological function in older-age animals, including humans. Recently, a study was published looking at Helicobacter pylori eradication.2 This study was an open, randomized, multi-center trial using bovine-derived lactoferrin administered to humans. This was lactoferrin taken with triple therapy. I think this is an interesting example of augmentive medicine, or functional medicine. Lactoferrin was once thought to mainly act as a transport of iron to the blood, but now we recognize that it really has a very powerful effect on immunological function of the gastrointestinal tract and interacts with the MALT (the mucosal-associated lymphoid tissue). As such, in the upper GI, it helps to reduce the potential of opportunistic infection with helicobacter pylori, which of course is a very important agent in the etiology of gastritis, gastroduodenal ulcer, and gastric cancer. I think this is a specific example of a more general theme, and that theme is that there are bioactive agents in various foods that have immunological reactivity within the gastrointestinal immune system. This is part of the list of potential therapeutic agents we have available in administration of the 4R Program (the gastrointestinal restoration program). The first “R” is Remove-removing allergens and toxic agents. The subsequent three “R’s” are Replace (that would be stomach acid and pancreatic enzymes, where necessary), Reinoculate (the use of probiotics and prebiotics), and Repair. We might consider lactoferrin to be part of the Repair category because this involves using nutrients such as arginine, L-glutamine, pantothenic acid, vitamin E, and zinc to help repair gastrointestinal immune integrity. That’s the Hot Breaking News for this month, so let’s move into the discussion of focus for this issue, which is bioidentical hormones, or functional endocrinology. I was very taken by a book that won the New York Times Science Book of the Year Award two years ago titled, Merchants of Immortality, authored by Steven S. Hall. 3 This is a very well-researched book. It speaks to the development of our understanding of cell aging and how it has been appropriated into the biotech community, specifically in the areas of investment and technology. It may be that this topic has been misappropriated (or prematurely appropriated) into the general sales of overexaggerated (probably) longevity or anti-aging. This book was a 2003 book published by Houghton Mifflin. On the subject of human life extension, there are real and exciting things happening at the molecular biology level, the cell biology level, and even at the animal biology level. We’ll talk more about those things throughout the course of 2007. There is also, however, the opportunity for exploitation and exaggeration. People sometimes pay money for things that really don’t deliver or may even lead to adverse outcomes. That takes us to another popular book-a 2006 publication titled Ageless: The Naked Truth about Bioidentical Hormones.4 A Recent Controversy over Bioidentical Hormones A science-based book like Merchants of Immortality is highly documented from first-tier publications. A book like Ageless is based on anecdotal testimony and personal experience, and somehow what may be an N of one can get extrapolated to the population at large. I think we need to be somewhat concerned about this Ageless concept, which basically promotes the idea that we can administer hormones in a very safe fashion as long as they are bioidentical to those naturally produced by the body; that only synthetic hormones produce adverse side effects or outcomes. I think this idea could lead people down problematic roads and I want to discuss that. There are safe and effective ways for utilizing hormone replacement therapy. But to assume that these substances that have very high activities at very low doses (on cellular proliferation, cellular turnover, and gene expression) can be used with no worry about overdose is truly an exaggeration of fact. The ideas promoted in this book have led to a backlash. A number of press releases and media services have covered the controversy over bioidenticals, and almost all the periodicals have advocated for intervention by the Food and Drug Administration (FDA). The College of Obstetrics and Gynecology has become so alarmed that they have now mounted publicity campaigns to warn patients about the risk of excessive hormone exposure. We are into a very dynamic period of reevaluation of what is safe and effective as it pertains to hormone replacement therapy in the perimenopausal or postmenopausal woman, or in the climacteric male. I’m not speaking to situations where there is growth hormone deficiency in children, or there is a very significant hormone deficiency in adults (which can lead to a number of endocrinopathies). I am speaking now to the natural transition in hormones that occurs as a consequence of “normal” aging, what level of replacement would be required (if any), and if needed, what would be used? This is the topic that we are going to be discussing in this issue of Functional Medicine Update. To put this into context (as it relates to the risk/benefit/safety profile), I want to cite a recent paper that appeared in the Journal of the National Cancer Institute in 2006 titled, “Endogenous Steroid Hormone Concentrations and the Risk of Breast Cancer Among Premenopausal Women.” 5 The question the authors are asking is, does estrogen produced by women naturally (and all the other hormones that come with it) have anything to do with relative risk to breast cancer? We’re not talking about exogenously administered hormones; we are talking about endogenous hormones-I want to emphasize that. If a bioidentical estrogen was completely safe, would we say it didn’t matter whether a woman had high estrogens or low estrogens-that, in fact, she would be at the same low risk if it is bioidentical? I think most of you know the conclusions of this study are quite clear. The levels of circulating estrogens and androgens found in women may be important in the etiology of premenopausal breast cancer. Those women who had the higher levels of estrogens are the women who had a relative risk that was about two-fold higher than those women who had the more normal levels of estrogen (again, these are endogenous estrogens). Higher levels of total and free testosterone and androstenedione (these are the androgens in the menstrual cycle) were associated with modest, non-statistically significant increases in overall risk to breast cancer, whereas the increases in estrone/estrone sulfate were not seen to increase risk. But if we look at estradiol, we had a much higher risk to breast cancer. So estrogen as estradiol, which is very mitogenic (it is a substance that causes cellular proliferation), does associate itself (as an endogenous hormone) with increasing relative risk. I don’t think we can say this about hormones at large, but when we start looking at individual contributors such as estradiol, we certainly see that high levels are associated with increased risk. I think the concept that bioidentical hormones are safe and synthetic hormones are dangerous is specious and not correct. It’s about balance. It’s about metabolism. And it’s about cellular activity. These are the things that really relate to the question of safety versus risk. If we look at ovarian cancer risk (this is the recent association of a diet and its relationship to hormone metabolism and cancer risk), I think it is a very interesting evolving story. It seems that one of the major determinants for how hormones interact with the body and ultimately mitigate relative risk is through diet and lifestyle. Although we can’t directly control our hormones as they get secreted from glands, we can control the fate of those hormones as it relates to their metabolism, their excretion, their cellular effects, and their transport through dietary and lifestyle variables. This information is taken from an article in the Journal of the National Cancer Institute, which talks about the fact that long durations of unopposed estrogens (and of estrogen plus progestin) are associated with increased ovarian cancer risk. 6 However, these particular types of relative risk may be modulated or modified by dietary intervention, for example, by going more to a vegan diet with a higher density of phytochemical-rich foods-whole grains, fruits, and vegetables. Many studies have been published on this subject, with some suggesting that vegetarian women have faster turnover of hormones, lower estrogen levels, and lowered incidence of hormone-related cancers. I think we need to put the diet component in perspective as a very important variable. We also need to look at not only at estrogen, but also the balance with androgens and progesterone. There are progesterone receptor sites on virtually every tissue, and certainly on breast cells. Progesterone can be proliferative, even in the bioidentical form. There is an interesting recent paper that just appeared on a cancer link of genes regulating estrogen effect on breast cells, showing an inter-relationship. 7 I think we need to be cautious about the use of progesterone (which is often used to balance estrogen) because excessive progesterone signaling can also induce cell proliferation. I’m talking about bioidentical progesterone, here, not progestins (the synthetic variants thereof). What roles do various nutrients found in the diet play in either reducing the relative risk to hormone-related cancers or to increasing the risk? An interesting paradoxical observation has been made recently that has to do with folic acid. We know that folic acid, vitamin B12, vitamin B6, and betaine are all very important for support of the folate cycle. The folate cycle is the cycle that generates active methyl groups through S-adenosylmethionine. S-adenosylmethionine then serves as the donor of methyl transfer reactions that are useful through the enzyme catechol-O-methyltransferase (or COMT) to partially metabolize estrogens to form the methoxylated estrogens. This would be like the conversion of 2-hydroxyestrone or 2-hydroxyestradiol into 2-methoxy compounds. These methoxylated estrogens are antiproliferative and they may be seen as (kind of) estrogen’s break. Think of estradiol as a cellular accelerator (meaning it increases the turnover of cells, the replication of cells, and their division). In physiology, for every accelerator you always have a repressor or a break (that’s the yin and yang upon which physiology is built). One of the breaks of estrogen’s induction of cellular replication is the methoxylated estrogen, 2-methoxyestradiol. So the balance between estradiol and 2-methoxyestradiol is very important in regulating aspects of cellular turnover and cell cycling. First is the hydroxylation of estrogen to form the 2-hydroxy compound by cytochrome P450 1A2, then the hydroxyestrogen gets methylated by S-adenosylmethionine. You would assume, then, that it is desirable for a woman to have proper folate, B12, B6, and betaine nutritional support for proper methylation of her estrogens, and that has been proven correct in a number of studies. But the question is what happens if you give very high levels of folate? Does that have any effect that is continuously beneficial, or is there a bell-shaped curve? This is where the controversy starts to exist. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial I’m now quoting from a review article that appeared in NutritionReviews in 2006. The title of this article is, “Does a High Folate Intake Increase the Risk of Breast Cancer?” 8 Although not uniformly consistent, there is an epidemiological series of studies that generally suggests an inverse association between dietary intake and blood measurements of folate and breast cancer risk. However, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial has recently reported for the first time a potential harmful effect of too high a folate intake on breast cancer risk. We’ve generally said that the higher the folate, the lower the incidence of colorectal, ovarian, prostate, and lung cancer. But now this new study says that with too high a level there was a statistical association with an increased risk. In this study, the risk of developing breast cancer was significantly increased by 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in women who reported supplemental folic acid intake compared with those that reported just normal dietary intake of folate. Although food folate intake was not significantly related to breast cancer, total folate intake (mainly from folic acid supplements) significantly was associated with increased breast cancer incidence by 32{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. So then the question is, why? Is there any reasonable rationalization for this? There is no real compelling supportive evidence at this point as to how (mechanistically) these associations tie together; however, we have to take this with some degree of sobriety because the data was published and was of concern. Folate Appears to Possess Dual Modulatory Effects on Carcinogenesis I think this story of folate, methylation, the pleotrophic effects of folate, whether there is a difference between folic acid from a supplement versus food folates (polyglutamyl folates), and whether 5-methyltetrahydrafolic acid has a different effect than folic acid are all questions that remain to be better understood. Certainly I think we recognize that folate appears to possess dual modulatory effects on carcinogenesis. We know that folate deficiency has an inhibitory effect on carcinogenesis, whereas high folate has a promoting effect on the progression of established neoplasms. Folate deficiency in certain normal tissues appears to predispose them to neoplastic transformation and modest supplemental levels suppress, whereas supraphysiological doses of supplementation may enhance the development of tumors. As an essential cofactor for the de novo biosynthesis of purines and thymidylate, folate plays an important role in DNA synthesis. Folate may also modulate DNA methylation, which is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity, in chromosomal modifications related to gene expression, and also in protection against mutational injury. So proper folate intake is very important for supporting proper methylation and these epigenetic effects that folate has, as well as its effects on DNA repair mechanisms. What happens when you give supraphysiological doses of folate? How does it promote rapidly replicating preneoplastic cells to increase their cellular turnover and cell cycling? The mechanism that is emerging-it’s still in the early stages-is that associated tumor promoting effect may be due to the enhanced de novo methylation of CpG islands of the tumor suppressor genes with consequent gene inactivation, which could result, then, in tumor progression. I want to, again, put this in the context that this is early stage news, but I think it is well worth looking at because we know most every substance has a dose-response, parabolic-type of curve. Too low a level is not good, too high a level is not good, and somewhere in the middle is where we should be and that’s certainly true for all nutrients. As we look at this folate connection, it may not be that if a little is good then a whole lot more is better; it may be finding the right folate level to support proper methylation of hormones and proper conversion of homocysteine to S-adenosylhomocysteine and then ultimately onto SAM (S-adenosylmethionine and the methylated derivatives). How do you clinically evaluate this? One method that is used as a surrogate marker is homocysteine. If you have a patient with elevated homocysteine (I believe that is above, say, 8 or 9 micromol/L), that may be a patient who is then going to benefit from folate B6, B12, and betaine supplementation. You want that homocysteine to be in the range of 4 to 7, or 4 to 8, and you can use that as a surrogate marker for folate B12, B6, and betaine. Let’s move from this discussion over to looking at a review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risk. There is a review that was published in Alternative Medicine Reviews in 2006 authored by Deborah Moskowitz on this topic. 9 When we talk about bioidentical hormones, we are talking about 17-beta estradiol, estrone, estriol. We are talking about progesterone as contrasted with progestins. And we are talking about testosterone. These would be considered your bioidentical hormone replacement substances. Bioidentical versus Synthetic Hormones When we start examining the relative risk/benefit, certainly I think we have to look at things like route of administration, dose, and formulation. I believe the overwhelming evidence is that for safe and effective use, bioidentical hormones are preferred over synthetic hormones, especially if an individual will use replacement for many years, as is often the case-going through perimenopause into menopause. This does not necessarily connote that all women have to be on hormone replacement therapy, but we are talking about the relative risk/benefit based on literature. It appears we have much better evidence that bioidentical hormones, in the right range of concentration and administered correctly, have a higher safety profile. Transdermal versus Oral Hormone Administration In terms of administration, there is some interesting new information. I’m now quoting from a recent paper in the journal Maturitis in which the authors looked at hormone replacement therapy (estrogen and progesterone), contrasting transdermal versus oral hormone therapy. 10 In this particular study, the findings were that transdermal (or even the intravaginal administration) had a much more beneficial effect-a safer effect-than the oral administration route. This also seems to be the case in a recent paper that appeared in Arteriosclerosis, Thrombosis, and Vascular Biology that contrasted the effect of oral versus transdermal estrogen on serum amyloid A and high density lipoprotein serum amyloid A in postmenopausal women. 11 These are proteins (SAA) that are associated with inflammation and also with cognitive dysfunctional neuroinflammation. So the question is, is there any difference between the route of administration of estrogens and the effect they have on SAA (serum amyloid A protein)? Oral estrogen was found to increase serum amyloid A and alter HDL composition to contain a higher level of SAA protein, whereas the transdermal administration did not have this same effect. These findings appear to argue for the use of a transdermal estrogen that would avoid first-pass conversion in the liver and would have a more favorable effect on cardiovascular outcomes. There is a wide body of literature on the benefit of transdermal over oral administration. I don’t think I need to take you through all of the data, but certainly we see-as it relates to metabolism-the more favorable effect on inflammation. You see a lot of studies showing elevated CRPs after oral administration and you don’t see that with transdermal administration. We see changes in fibrinolytic activity with oral that we don’t see with transdermal. We see changes in lipoproteins (adverse changes in lipoproteins) with oral that we don’t see with transdermal. So it seems to really argue fairly strongly for the transdermal route of administration. Assuming that a woman can absorb transdermally, there are different vehicles to help transport. There is also intervaginal transmucosal transport, and Dr. Hays will talk a little bit about that in this particular issue. Personalized Hormone Replacement Formulations Now we’ll talk about formulations, and of course that gets into compounding pharmacies and compounding the right formulation of bioidentical hormones. There is some discussion of this in the journal Integrative Medicine in 2006. 12 This is a place where the practitioner can work very closely with the compounding pharmacist to produce a specific formulation that would personalize the bioidentical hormone replacement therapy for each woman. I think it is important to recognize that personalization is probably what should be done and not every woman absolutely requires hormone replacement therapy to lead a healthy life. For those women who do get hormone replacement therapy, tailoring it to their own specific needs is critically important. Dr. Hays will talk about this in greater detail as part of our clinician of the month discussion. In fact, she has authored an interesting paper that gives an overview to this whole field titled, “Giving Menopause It’s Proper Place.” 13 This was published in Integrative Medicine in 2006. Her article goes through the whole concept of menopause, knowing about estrogen and where it is going and how it reacts with a woman’s body, and then finding the right balance. She will speak to this in greater detail in our interview with her. It is not just administration of the hormone substances in and of themselves that is important, it is also how those substances interact with receptors and how these receptors then signal cellular activity. Many estrogen-related receptors are now being seen as targets in cancer and other metabolic disorders, so estrogen has a crosstalk with many other cellular functions, including (as I already mentioned) inflammatory functions, insulin signaling functions, and relationships to detoxification. Many cellular functions have (in the web of interaction) a relationship to estrogen and its reactivity. There is a review paper about estrogen-related receptors and their relationship to cellular function that appeared in Current Topics in MedicinalChemistry in 2006. 14 I think the very important takeaway is that estrogen-receptor-targeted therapeutics are now showing success in not only the treatment of breast cancer, but orphaned estrogen related receptors have also become novel targets for future development because these are receptors that are different than the traditional estrogen receptor alpha and estrogen receptor beta. ERa is the receptor that is traditionally activated be 17b-estradiol. It is involved with cellular cycling and cellular proliferation. It is the receptor that is most often upregulated in oncogenesis. The estrogen receptor b is more associated with bone metabolism and this appears to be the differentiation of the SERMs, tamoxifen and raloxifen, and estrogens. The SERMs apparently have more effects on ERb, although these effects are mixed slightly as it relates to modulatory effect (their selective estrogen response modulators). We now recognize that there are effects that compounds have beyond that of just the traditional estrogen receptor alpha and beta, which are called the estrogen-related receptors, or ERRs. This is a very interesting family of receptors whose agonist or antagonist can crosstalk with the estrogen receptors, and so you might have amelioration of estrogen-related symptoms without ever directly affecting the estrogen receptor with that ligand. We now know this crosstalk takes place across such processes as cellular detoxification, and that ties together the estrogen activity with things like nuclear regulatory factor 2, or NRF2, which is a ligand-dependant interaction with estrogen that then helps to regulate detoxification functions. This could be occurring both as a consequence of stimulation of estrogen receptors directly and of nuclear receptors that influence then the gene expression of the detoxifying enzymes. What I am really trying to say is that if we look at how to modulate estrogen’s effects on the body, part of it is modulating the actual level of estrogen in the body as measured by serology or a urine 24 analysis, and part of it is really regulating the responsiveness of estrogen by how it affects receptors and how it is metabolized and excreted. This takes us to the concept of how diet may influence estrogen, not just directly through modulation of estrogen receptor a and b, but also through these ERR pathways (through the estrogen-related receptor pathways). There is an interesting paper published in the Journal ofEndocrinology in the latter part of 2006 titled “Selective Activation of Estrogen Receptor b Transcriptional Pathways by Herbal Extract.” 15 In this paper, the authors show that some of the bioactive phytoestrogens in various plant foods don’t work strictly through ERa or b, but work through these ERR pathways (the Estrogen-Related Receptors) that then modulate things like flushing and night sweats without having a direct cell proliferative effect. Study on Use of a Phytoestrogenic Substance to Alleviate Menopausal Symptoms Recently, a prospective randomized double-blind, placebo-controlled use of a standardized extract to alleviate menopausal discomfort was reported. This was using a substance derived from Humulus lupulus (hops). A fraction from the hops plant, the so-called hydrophilic fraction (the water-soluble fraction) from spent hops, was shown, when concentrated, to have a very interesting menopause symptom reducing outcome, without apparently having a direct serious effect on activation of the estrogen ERa mechanism. This study was published in Maturitas in 2006. 16 It is a very interesting report of this highly “phytoestrogenic” substance from hops. It is about 100 times more phytoestrogenic than that of genistein (about ten-fold less estrogenic than 17-b-estradiol), but it doesn’t appear to have the cellular proliferative effects that estradiol does, so it make work through other mechanisms (through these ERR mechanisms or other crosstalk mechanisms), or even maybe a mixed effect through alpha and beta estrogen receptor agonist activities and these other response elements. What I’m really trying to get you to understand is that the complex diet that contains a rich array of phytochemicals may be one of the best tools (clinically) for managing estrogen-related dysfunctions or hormone-related dysfunctions in perimenopausal and menopausal women. It may actually be a much safer approach or at least a first-step before we introduce bioidentical hormone therapy because of the complications in trying to measure hormones and stabilize activities when they are given exogenously. By modulating the diet, we may then induce proper cell signaling and allow the woman’s natural estrogen, progesterone, or androgens to be properly regulated through hormone binding globulin, through cell receptive mechanisms, and ultimately through cell signaling. I think this sets a context for what we want to speak to with Dr. Hays: How do you take all of this extraordinary information that is emerging around bioidentical hormones and apply it in a crucial area (30 million women will be going through menopause over the next 10 years). These women are questioning what to do (if anything), what is safe and effective, and what will give them better long-term health outcome. Those are the questions we will be addressing when we talk with our expert, Dr. Hays. I want to contextualize that this conceptualization that hormone therapy will alleviate symptoms is built around the principle that we understand how those hormones are signaling, what cells are being influenced, and how safe and effective outcomes are differentiated. As we really dig deep into the literature, we find that we are still at a very early stage in our understanding of the complex web of interactions. The concept of “Doing less can do more” may be a good watchword. Maybe rather than jump in and try to do watch repair with a jackhammer, we ought to be treading very carefully, using the least aggressive therapy possible to modulate symptoms that are associated with menopause. With that, let’s turn to Dr. Hays and talk about her clinical expertise in this area.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Bethany Hays, MD, FACOG True North Health Center 202 US Route 1 Falmouth, ME 04105 www.truenorthhealthcenter.org In this issue of Functional Medicine Update, we’ve been focusing on what I call functional endocrinology, or the relationship-specifically, in this case-to hormone replacement therapy (the bioidentical hormone story). We are very fortunate to have as our clinician of the month this month an expert in the field, Dr. Bethany Hays. Many of you know of Dr. Hays if you are in our field of functional medicine. She is a leader in the area of women’s health issues, has been a teacher at the functional medicine Symposia and Applying Functional Medicine in Clinical Practice training programs, an author, and the founder and director of the True North clinic consortium (which has a functional medicine underpinning) in Maine. I’ve had the privilege of visiting her facility and meeting her colleagues. It is just a remarkable way to apply functional medicine in a clinical setting-using a comprehensive, multifactorial group of practitioners to address these very complex issues from a central theme. Dr. Hays (for those of you not familiar with her background) went to Wellesley, where she graduated with a major in philosophy, which is probably why she is such a good medical doctor, because she started off with the right underpinning-a broad base of humanities understanding. From there she went on to Baylor College of Medicine and to her OB/GYN residency at the Baylor-affiliated hospitals, and she has been in practice for more than 20 years. She is the mother of three sons (all adults now) and is involved with their complex lives. So she is one of these superwomen who has many things going on and seems to do them very adroitly; we can only envy those skills. Dr. Hays, it is wonderful to have you as a clinician on Functional MedicineUpdate, and to have a chance to talk about this controversial but very important area of hormone replacement therapy. BH:     Thanks, Jeff. I’m happy to be here. Different Theories of Why Hormones Decline JB:     I want to start, if I could, with three questions (or comments/statements) that have been made in recent literature meant for the general public, which often then brings women to doctors to ask about hormone replacement or bioidentical hormone replacement therapy. I’d like to get your opinion of these three statements because they are made as statements of fact, but I think we both (probably) would question the factual veracity. Statement #1 is: We age because our hormones decline; our hormones don’t decline because we age. I think I’ll take each of these three separately. What’s your thought about that statement of purported fact? BH:    Well, I’d like to see some evidence of either part of that statement. The first part is, “We age because our hormones decline.” I’m not sure that is a true representation of what is going on. I suspect that our hormones decline in order to allow us to age well. In other words, I think the hormones of our younger years, particularly the premenopausal hormones of women, are toxic-level hormones that allow us to reproduce. Then when we don’t need to be reproducing anymore, we’re allowed to have normal levels of hormones so that we can age gracefully and not end up with the toxicities that those high levels of hormones produce. The second part is, “Our hormones don’t decline because we age.” I think our hormones probably decline in part by intention (as I said, in order to age gracefully), and then there’s the abnormal decline in our hormones that are due to toxins in the environment, poor metabolism of hormones, and hormone attack from autoimmune disease that attacks the glands. JB:     That segues nicely into the second statement that has been made as if it were a statement of fact, and that is: Bioidentical hormone replacement is the only answer to ward off illness, weight gain, and other symptoms of hormonal decline that occur during menopause. BH:     I think that’s clearly not true because we all know some 93-year-old women who are sharp as tacks-driving their own cars, running their own households, not obese, not sitting in wheelchairs somewhere without their brains intact. So, clearly, it is possible to do that without hormone replacement therapy if you have the right environment in which to bathe your genes. That environment would include a clean, balanced diet, movement (stretching your muscles and moving your muscles so that they stay oxygenated and don’t tighten up and affect joints), and a positive attitude. I think people stay alive a long time for two reasons. One is because they are very connected to their physiology. And the other is because they are very connected to their future. If you have a reason to be alive a week from now, a month from now, or ten years from now, you are much more likely to be alive then than if you can’t see any reason to be alive. JB:     That’s a wonderful statement and I think it bears on the last statement that has been thrown out into the universe as a statement of fact, which is questionable. That is, “Without hormone replacement, we will end up as mere shells of our former selves.” This sounds a little bit like post-Robert Wilson, Feminine Forever, in the ’60s. BH:     It does, doesn’t it? It brings to mind this advertisement for hormone replacement from 15 years ago, with a woman looking out over parched land, and the title is, “The fate of the untreated menopause.” I think where we need to be headed is healthy aging. We need to be looking at what we’ve done to our environment. We need to be looking at what we’ve done to our food supply. We need to be looking at what we’ve done to women to make them feel worthless once they go through menopause. JB:     That’s magnificent. So let’s move from that discussion/platform to another. What players are we really talking about when we talk about hormone replacement therapy? Of course, there’s quite a large array of hormones, but the ones that are most commonly discussed when we talk about bioidentical hormone replacement therapy are things like the estrogens-estradiol, estrone, estriol, progesterone, testosterone. We might include dehydroepiandosterone, cortisol, thyroxin and triiodothyronine (for thyroid), insulin, and maybe even human growth hormone (in some subsets). When we start going down that laundry list, from your very rich experience (and now the work that you are doing at True North), how do these different hormone substances fit into the development of a comprehensive program for a woman who is having some complicated symptoms that grow out of her menopause transition? Why Women Seek Hormone Therapy BH:     I think, first of all, women tend to come for hormone therapy because they are having symptoms, not because they are worried about the fate of the untreated menopause. The symptoms they are having, primarily, are problems with their brains. They are having problems with hot flashes; they are having trouble with insomnia; they are having trouble with cognition, memory, and sometimes depression. The balance of hormones is critical to the function of the brain. When you note that one-third to half of women have had hysterectomy at a average age of…it used to be 35, now it’s a little bit older than that, you know that a lot of women either are missing their ovaries (about half of those women), or have had damage to their ovarian blood supply by severing the utero-ovarian ligament at the time you remove the uterus. So, a significant proportion of the population is not going through normal menopause. I think another group that we are not yet able to clearly define is women who have autoimmune destruction of the ovary. And the reason we can’t define that is because there are so many antigens involved with the ovary that the researchers can’t really come up with an appropriate panel of antigens to look for antibodies for them. We have largely ignored that as a cause for abnormal menopause. When I see a menopausal woman, the first thing I want to do is measure her hormone levels. This is an easy thing to do because these hormone levels are fluctuating, particularly at the time when women come in for hormone replacement, which is often in perimenopause, and not actually in complete menopause. So they come in and they are having problems, but what they are really having problems with is the inability of their hormones to dance with each other. They don’t have enough reserve in several of their organ systems to allow an easy transition to menopause. These hormone levels go up one day, they are down the next, they’re up the next day, they’re down the next day…The brain doesn’t have time to adjust to those changes in hormones, so they are having symptoms. Because you can get rid of those symptoms by nailing estrogen to the ceiling (by giving high doses of estrogen), we’ve come to believe that if women have any complaints you just give them estrogen. And, boy, have I seen some women on high doses of estrogen with complications of that. The Importance of Measuring Hormones before Therapy What I do is start with a measurement, so that we have some idea of what’s going on. And I don’t just measure estrogen. I measure estrogen, estrone, estriol. I measure testosterone, progesterone, DHEA. I measure sex hormone-binding globulin. I measure the 2-to-16 hydroxyestrogen metabolites. I’d like to be able to measure more than that, but that’s what I can get, reasonably-priced, in a pretty well-accepted laboratory environment. So, I start with measuring them. Then, if they are low, the first question I ask is, “Why are they low?” Are they low because the ovary is missing? Are they low because the ovary is underproducing? Or are they low because that ovary is dancing with another hormone that is too high? In this case, the treatment would not be to raise the level of estrogen, it would be to lower the level of the hormone that is too high. So I go at it in a systematic manner. If I decide I’m going to replace the hormone because it is low and because I think I know the reason why it is low, I get informed consent from my patient. The data in the literature is so constantly changing that what may be considered standard of care today is going to change tomorrow. You need to have documentation in your chart that you have talked about these issues with patients; that they understand the risks they are taking; and they agreed to those risks. Then, we start with low levels of the hormone regimen I prefer, and then we recheck the levels to make sure than we are in the right range. That’s sort of (in a nutshell) the approach I take. JB:     Good. Could I interrupt and just ask a question quickly because I know a lot of clinicians probably would like your answer to this? In measuring these, obviously you have different compartments you could measure, or different fluids you could measure. You could measure serum, you could measure urine, or you could measure saliva. Is there a preemptory biological fluid you select, or do you vary that based upon what you are trying to answer relative to each of those hormones? BH:     I do check different fluids depending on the hormone I’m checking. With regard to estrogen, I usually use blood. The reason I use blood is because of two things. One thing is that I have found more data in the literature about what normal levels look like. And the second thing is it is often covered by insurance and so patients can get their insurance to pay for it. I think you can use other fluids to measure those hormone levels, provided you get good at knowing what the fluctuations look like in that fluid-what levels you would expect to find in different clinical settings-so that you know when you are looking at a hormone that doesn’t look right. So if I measure a hormone and I’m looking at a woman whose got high estrogen symptoms, and I measure her estrogen level and it’s very low, I know that I’ve picked a trough instead of a peak, and I need to, perhaps, repeat those hormone levels, or think through, “Why would her estrogen level be low with symptoms of elevated estrogen?” JB:     You’ve helped us all to really understand-those of us who have had the pleasure of attending your courses-because you’ve showed some very interesting data on perimenopause that shows exactly what you are saying as it pertains to estradiol levels in a perimenopausal woman who is maybe showing the symptoms of estrogen excursions. At one point of the analysis her estrogens are very low, but at another her estriol is very high. As you said, depending on where you point to freeze frame, you might get a very different sense of what the level is. BH:     That’s really true. I think you have to remember that it’s probably the overall area under the curve that’s going to influence things like breast cancer, uterine cancer, and perhaps bone loss. When you have an area under the curve analysis of perimenopause, you see that perimenopausal women (early in the transition) actually have higher levels of estrogen than they did when they were ovulating and having regular periods. I think perimenopause is a potentially dangerous time, and it is dangerous because you have higher levels of estrogen, so if you’re not metabolizing them well, you are creating chemicals that can induce breast cancers. And it is dangerous because you will (at the same time) be having symptoms of this fluctuation of estrogen that produces brain symptoms and some doctor is going to come along and say, “Oh, you are having hot flashes so you must be menopausal, so let’s put you on estrogen….” And now you have added to the risk. JB:     I think you raised a very important point that we need to probably emphasize for our listeners, and that’s the question of pharmacogenetics and metabolism of these hormones. What is being discovered is that there is a lot more variability among people (among women, in this case) as to how they process through their bodies these hormones. So the construct that a single dose on body surface area will be tolerated in the same way by all women is a pretty specious argument, so that argues for your personalization approach, it would seem. The Role of Genomics in Hormone Therapy BH:    I think that’s really true. Now that we have some genomics available to us in laboratories that are clinically available, you begin to see why so many people don’t respond the way you expect them to with hormones. If you are not paying attention to how they metabolize hormones, these are the cytochrome enzymes that are detoxifying enzymes, which implies to me that the human body sees estrogen as a toxin. The other thing it implies is that nanogram amounts of estrogen suffice, whereas microgram amounts of progesterone and milligram amounts of DHEA are produced, but picogram amounts of estrogen are produced daily. This is a potentially dangerous and toxic chemical and the body has many layers that it puts between that active molecule and the cell systems that are being affected by it. If those layers of protection are not working properly because of your genetics, or because of your environment, or because of your food, then giving a hormone is, I think, potentially a very dangerous undertaking. JB:     So let’s now talk a little bit about the delivery system because I know there is still a lot of question as to what’s the best way of introducing hormones when you are doing replacement therapy. Is it oral, is it vaginal, or is it some kind of transdermal? What is your opinion of this first-pass detoxification based on route of administration? Do you have a thought as to what is the best way of administering these hormones? BH:     Yes, I do. I think some hormones are safer to take orally, but the way glands administer hormones is directly into the circulation. Something that administers the hormone more directly into the circulation without as much metabolic transformation would be more physiologic. This is so complex because these hormones dance with each other and the levels are constantly changing. I am very humble about my ability to mimic Mother Nature, but I try. I try to do the best I can to do it the way Mother Nature does it. So, with estrogen, I think there is good data now that says transdermal estrogens are much safer than oral estrogens, partly because you don’t get a first-pass effect through the liver, and partly because you can administer one-tenth of the dose. I think progesterone (because it is rapidly metabolized both into downstream hormones and into metabolites, some of which are active, like allopregnenolone, which is a brain-active chemical that is calming)…because progesterone disappears so rapidly, it is very easy to get the impression that you can give very high doses of progesterone, and because it doesn’t change the levels of progesterone, it’s perfectly safe. But, in fact, you better be measuring some of those downstream hormones and making sure that you’re not changing the level of estrogen or the level of testosterone when you give high doses of progesterone. So I tend to prefer the bioidentical hormones, and I prefer the transdermal route. Then you get into the trouble of, how do you get women to absorb transdermally? Some women don’t absorb very well transdermally. Then you can go to a vaginal route of administration, but the vaginal route of administration you absorb much more rapidly. In fact, I see estradiol, given transvaginally, doesn’t change the estradiol level very much, but, boy, it runs up the 2 and 16-hydroxy metabolites significantly. And I think that could potentially be an issue in women with breast cancer, for instance. The Chronobiology of Hormone Administration JB:     You raised the question of chronobiology. Hormones are secreted, as you indicated, more on a pulsatile basis, not statically throughout the day. Do you try to mimic that cycle when you have women administer bioidentical hormones, or do you do it in a static dosing regime? BH:      If you mean the day-to-day, minute-to-minute pulsations, I don’t think we can mimic that because I don’t think anyone has ever been able to document what those look like. I know that from day to day, estrogen levels will fluctuate dramatically, but I don’t know if they are fluctuating from second to second, or from minute to minute, or from hour to hour, and I don’t think there’s any administration technique that mimics a fluctuation along those lines. So I admit that I am giving a hormone once (sometimes twice) a day, and getting a curve that doesn’t look much like physiology. But until somebody makes the delivery system that does that, or documents for me what levels I should be getting fluctuations of, I have to go with a cruder system. As far as the fluctuations of the hormones across the month, I think the evidence is (when you have premenopausal levels of estrogen) it is safer to give progesterone in a sequential manner, but when you have normal postmenopausal levels of estrogen (and I emphasize “normal”), the progesterone is supposed to come from the adrenals; it’s already there. You probably don’t have to administer progesterone at all, as long as your adrenals are healthy. But then, how many women in our culture have healthy adrenals after menopause? I don’t know, but I don’t think it’s a lot. So, yes, if you’re not making enough progesterone from the adrenals, you’d better add that in. And then what happens to it? If you’ve got the enzymes upregulated to make stress hormones, you’re going to put progesterone in and get cortisol out. All these things have to come into play. If you’re not working on stress reduction with that woman, you’re going to put a lot of progesterone in and get a lot of cortisol out. JB:     So now we ask the question about form of dose. We’ve obviously heard a lot in this field about compounds, or formulations such as Bi-Est or Tri-Est. Do you have any kind of inclination as to what is the best formulation to be using? Creating a Healthy Balance BH:     I think estrone and estriol are part of the normal metabolism of estradiol. So I don’t think you have to put them in. I think if you put estradiol in, it is going to get converted very rapidly to estrone. If you have estrone, it is going to get sulfated to estrone sulfate. It is also going to get bound to sex-hormone-binding globulin. And then it’s going to get converted to 2 and 16-hydroxyestrogen, and the 16-hydroxyestrogen is going get converted to estriol. I think a lot of people think you should administer all three of those, thinking that if you can create a healthy balance of those three chemicals, that you will decrease the risk of, say, breast cancer. But I think that healthy balance comes from the cytochrome P450 enzymes that are metabolizing estradiol, not from the level of estrone, estriol, estradiol. So what you want to do, if you want to have the correct balance of those three, is not administer some artificial balance of them, but work on the metabolism so that you’re metabolizing them appropriately. How Diet Influences Hormones JB:     Well, given that, then I think my next question follows very logically. In your experience, what role does diet have in influencing these hormones (this dance of hormones you are describing)? Things like lignans, isoflavones, omega-3 fatty acids, enteric bacterial function-is this a major player? BH:    It has everything to do with it. As you’ve taught me, we bathe our genes in the food we eat. If we’re eating food that our genetics evolved with to create a healthy organism and create healthy aging, our genes are going to listen to that food and metabolize these hormones appropriately and we’re not going to see the problems. It is only when you eat the standard American diet, which is high in carbohydrates, high in chemicals, high in empty calories, and low in vegetable proteins, lignans, isoflavones-all of the things that you just listed-that we get into these aberrant ways of metabolizing these hormones that produce problems. JB:     I was very intrigued-I’m sure you were, as well-about the paper that appeared in JAMA a couple of years ago, showing a statistically significant increase in breast cancer in women who had repetitive antibiotic exposure. 17 It certainly argues for a gut-hormone connection, I would say, through that data. BH:     Absolutely. There are a number of pathogens in the gastrointestinal tract which affect beta-glucuronidase. Glucuronidation of estrogen is one of the three main Phase II detoxification pathways, along with methylation (which we really need to be paying attention to given how many people have problems with methylation and activation of B vitamins), and sulfation, given the number of people who don’t have enough sulfate groups in their diet, or can’t access those sulfate groups because they have genetic abnormalities in sulfation. JB:     So that, then, leads to a clinical challenge that I know you deal with all the time in this personalization of hormone therapy in women that really need it and that’s the body composition issue. We recognize that high levels of adipocyte hypertrophy can increase these adipocytokines, which, then, increase regional cortisol. They influence insulin signaling, they have effect on inflammatory mediators, and they also influence the production of the 4-hydroxy estrogens. How do you handle hormone replacement in women who have, say, elevated percent body fat? Hormone Replacement in Women with Elevated Percentage of Body Fat BH:     The first thing is that we have a very aggressive program at True North to get those women on a diet that helps them to lose weight and create a healthier metabolism. We don’t just say, “Well, you should go lose weight,” and then leave them hanging out to dry. We give them programs; we give them information; we give them consultation; we do bioimpedance analysis to show them how they are doing; we have cooking classes to really show them what it looks like when you are eating good food and how fabulous the food can taste. So we have a lot of support to change that situation of obesity. Then there’s the big problem of obesity that I see in women at mid-life, which is really stress. We have a number of programs that help people to deal with stress-mindfulness-based stress reduction, yoga, meditation, HeartMath-there are a panoply of ideas out there if you can get patients to understand that their obesity is related to their stress and their stress is important to change, now, at mid-life. If you change those patterns of behavior at mid-life when you really have your body yelling at you to do that, then you’re going to be able to modulate your stress according to your adrenal reserves for the rest of your life, which in my opinion is why women live a long time. JB:     You’ve given me a variety of very important insights, one of which has to do with breast density and lobular structure of the breast and how that might individualize relative risk in certain women. Is this an area that you also look at as a risk factor and deal with in terms of personalization of the program for a woman? Progesterone and Breast Cancer Risk BH:    I think the differentiation of the breast, which occurs under the influence of the hormones of pregnancy and lactation, does allow a woman to go through a period of increased risk, but eventually get to a situation of decreased risk for breast cancer. If she goes through that period of increased risk and then out to decreased risk when she is young, she’s much less likely to get breast cancer. If she goes through it in her late 30s or 40s, she’s got more abnormal cells that she may stimulate into a cancer. However, if she gets beyond the first year or two after the pregnancy without getting a breast cancer, then she’s got the same protection that a younger woman would have from having a baby. And that protection is that the terminal ducts become lobular ducts, which then are resistant to the growth stimulation that produces ductal breast cancers. It is beginning to look like the progestin issue is related to lobular cancers. Those lobules may continue to be able to be stimulated by progestins or progesterone, and that’s part of what I’m beginning to be really interested in about the differences between premenopausal and postmenopausal administration of progesterone, and the difference in administration of progesterone in normal cells versus cancer cells (or precancerous cells, perhaps), and the influence of progesterone on the non-hormonal growth factors like EGF, IGF-1, and insulin, which I think is clearly a factor in the production of breast cancers in women. JB:     So with all of this in mind (which you’ve done a marvelous job of summarizing for us), what is a good assessment panel that you would recommend for women? I know a lot of women think mammography (followed serially to see if there is any relative risk). Or maybe it is vaginal cytology. Or maybe it is chemistry, like a 2-16 estrogen quotient. What do you do to help women allay some of their fear or to give them kind of a longitudinal assessment profile? High-frequency/Low-penetrance Genes Can Be Modified BH:     I do recommend mammograms, although clearly mammograms are not prevention, they are early diagnosis. And there are a lot of false positives in mammography, so it is not an ideal form of risk assessment. Family history is important, but there are two sides to that. One is the low-frequency/high-penetrance genes like the BRCA breast cancer gene, and the other is the high-frequency/low-penetrance genes like the cytochrome P450 enzymes, the glutathione transferase enzyme or methyltransferase, MTHFR. If you stack enough of them up against yourself, you’re going to have as high a risk of breast cancer maybe as a woman with a BRCA gene. What I love about that is the BRCA gene is not something you can change. You’ve got that gene and you’re stuck with it. But the high-frequency/low-penetrance genes are amenable to change. They are amenable to modifying with diet, lifestyle, exercise, and stress reduction. So, instead of just sitting on the railroad tracks and waiting for the train to hit you, you can move off to the side and let the train go past you, and I really like that image. So I tell women that if you’ve noticed that the light at the end of the tunnel is a train, it’s time to start getting off to the side. I will do the 2,16 hydroxy metabolites, and then I also (if I can get patients to buy into having more information about their genetics) will get a genetic profile that gives me some of these high-frequency/low-penetrance genes. And then women sort of feel like they’ve taken charge; they’ve taken control of their metabolism and their genetics and their lives and they are not just sitting on the track waiting to be hit. JB:     So, I guess my concluding question, could be (obviously) a question that would open hours of discussion. I know that you have more than enough resources to fill those hours, but I think we need to summarize. If a person is listening to this and they are saying, “I’ve been doing hormone replacement therapy and now you have raised a lot of questions and now I’m not as sure about what I was doing before because you’ve opened up all sorts of new perspectives that I wasn’t considering before,” what would be your recommendation? How do you get down the road to feel comfortable in the way you are managing women? Asking the Right Questions BH:     I would say if you feel that way after hearing this, you’re a very smart physician. I think this is a very complex area and we’ve been far too casual about it. Going through the Robert Wilson era and then the era of where we gave hormones to everyone and nobody had done the proper studies to know that we were producing problems for women, should be a lesson to us about how carefully we should tread when we are changing hormones. Because all these hormones dance with each other, if you change one then you are changing potentially all of them. So I would say that you need to have a logical reason to know why that hormone should be replaced. Has the gland been removed? Is it being destroyed by antibodies? If not, why isn’t it producing the way it ought to be? I have no problem with transiently mucking around in it-you know, changing the levels of hormones-in order to get a woman sleeping, for instance, so you can get her adrenals calmed down, or in order to deal with issues that are related to her thyroid until you get the toxins out of her environment. I don’t have a problem with that as long as you are simultaneously working on the whole picture (in the background) to get her healthier. Otherwise, I think you may be kidding yourself that you’re increasing her longevity by adding some of these hormones in, as we found out with the Women’s Health Initiative. JB:     I want to thank you. I’m saying what is clearly obvious: your patients are very privileged to have access to True North and your skill. I would like to think that we could form a functionally based medicine where these opportunities would be available throughout the whole of the country. We really appreciate you sharing with us what I think is a very thoughtful and rational perspective on this whole concept of bioidentical hormone replacement. We wish you the very best and look forward to visiting with you again, Bethany, real soon. BH:     Thanks, Jeff, and thanks for all the wonderful information that I have received from you and that you have put out into the world because it really has changed my life. If my patients are benefiting, it is because of what I’ve gotten from functional medicine. JB:Well thank you very much. Best to you and we’ll talk to you soon. As part of our new format for 2007 for Functional Medicine Update, we are finishing each issue with questions from you-the listener participants. We have an interesting start to this with a question that relates to the sulfites in red wine as the cause of the “red wine headache” syndrome. This is a specific question to a more general theme that I would like to speak to. Red Wine and Symptoms of Sulfite Sensitivity We have often attributed these sulfite-related headaches to an allergy-like response because individuals have inabilities to properly metabolize sulfites, so that begs the question: how does sulfite get metabolized? It is done through an enzyme called sulfite oxidase. Sulfite oxidase is a molybdenum-containing enzyme, and as a consequence this is one of the few examples where molybdenum is an essential nutrient for physiological function. In the case where an individual has a sulfite oxidase slow spot, then it would indicate that he or she may need to either remove the sulfites from his or her diet or, possibly to increase the molybdenum content of his or her diet through nutritional supplement or foods. Generally around 200 to 300 micrograms of molybdenum is considered to be in the safe and effective range. We can’t say that all individuals, with molybdenum supplementation alone, will get benefits; it may also be reducing the sulfite load from the food as well. We also recognize that vitamin B6 plays a role in the sulfite oxidase pathway, as well, so sometimes the administration of B6 along with molybdenum and magnesium will help to eliminate (or at least reduce) the sulfite sensitivity. But again, in extreme cases of sensitivity, even small doses can produce very large physiologic responses, so clearly the person needs to be very conscious about sulfite exposure. Beyond sulfite, however, in red wine, there is another series of phytochemicals that often mimic what people think to be sulfite sensitivity. These are the ethylamines, like phenylethylamine which is a dopamine-like conjuger. These particular amine-like compounds-organic amines-are vasoconstrictive and can induce, then, vascular changes (including small vessel changes) and produce headaches. One of the other things that we see in red wine, cheese, chocolate, and bananas is the phenethylamine-like compounds, which then require monoamine oxidase the detoxifying enzyme. If you look at the package insert for MAO-inhibiting drugs they say that while you are on these medications to be cautious about consuming foods that contain these amine-like substances. The reason for this is that the vascular response could produce headaches. If you have a genetic polymorphism of monoamine oxidase that makes that a slow step in the detoxification of amine-like substances that come from food, then you are more sensitive to these foods in a normal diet, of which red wine may be another member of that family because it contains these ethylamine-like substances. I don’t believe we should jump to the conclusion that headaches only come from sulfite; they can also come from these bioactive amines, and of course they can also come from the overuse of alcohol as well (we should probably throw that in there, as it pertains to the response to any alcoholic beverage). In the case, specifically, of red wine-induced headaches, however, I think it is probably a combination of sulfite sensitivity and other factors. As you know, in asthmatics, there is an increased risk to sulfite sensitivity-this tends to be a covariable constitutional issue-and so you generally have a higher level of red wine sensitivity in asthmatics. We know that sulfite sensitivity includes symptoms of skin rash, redness, hives, itching, flushing, and tingling, but we also recognize that these can be associated with other vasoactive substances. Differentiation of red wine syndrome as a headache probably is more related to that of the phenylethylamines. Red wine syndrome as it relates flushing and to the vasomotor effects is probably more related to the sulfites. I would differentiate those two classes of responses to wine or chocolate or bananas or cheese, with the sulfites being more the skin erythemas (hive and itching), and the problems related to headaches more coming from the bioactive amines. This is clearly an indication of unique detoxification-again, through monoamine oxidase. It means that person is less able to metabolize their adrenaline as well, so they are more sensitive to states of hyperadrenaline, like stress. So all this kind of fits together in a pattern, I believe, that is related to lifestyle, diet, and specific nutrients for modulating these pathways. I hope that’s helpful in answering that question, and please do send in your questions (email them into our website) to Functional Medicine Update, and we’ll be pleased to put the answers onto upcoming issues. This concludes the February issue of 2007. The website address, for those of you unfamiliar with it, is www.jeffreybland.com.

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Bibliography

1 Giovannucci E, et al. A prospective study of calcium intake and incident and fatal prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006;15(2):203-210. 2 Di Marlo F, et al. Bovine lactoferrin for Helicobacter pylori eradication: an open, randomized, multicentre study. Aliment Pharmacol Ther. 2006;23(8):1235-1240. 3 Hall SS. Merchants of Immortality: Chasing the Dream of Human Life Extension. 2003. Houghton Mifflin Company, New York, NY. 4 Somers S. Ageless: The Naked Truth about Bioidentical Hormones. 2006. Crown Publishers, New York, NY. 5 Eliassen AH, Missmer SA, Tworoger SS, Spiegelman D, Barbieri RL, et al. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst. 2006;98(19):1406-1415. 6 Lacey Jr. JV, Brinton LA, Leitzmann MF, Mouw T, Hollenbeck A, et al. Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health-AARP diet and health study cohort. J Natl Cancer Inst. 2006;98(19):1397-1405. 7 Seppa N. Cancer link: gene regulates progesterone effect on breast cells. Science News. 2006;170(23):355. 8 Kim YI. Does a high folate intake increase the risk of breast cancer? Nutr Rev. 2006;64(10):468-475. 9 Moskowitz D. A comprehensive review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risks. Altern Med Rev. 2006;11(3):208-223. 10 Modena MG, Sismondi P, Mueck AO, Kuttenn F, de Lignieres B, et al. New evidence regarding hormone replacement therapies is urgently required: transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits. Maturitas. 2005;52(1):1-10. 11 Abbas A, Fadel PJ, Wang Z, Arbique D, Jialal I, et al. Contrasting effects of oral versus transdermal estrogen on serum amyloid A (SAA) and high-density lipoprotein-SAA in postmenopausal women. Arterioscler Thromb Vasc Biol. 2004;24:164-167. 12 Benda W. Bioidentical hormones set the current political stage. Integrative Med. 2006;5(5):58-61. 13 Hays B. Giving menopause its proper place. Integrative Med. 2006;5(5):32-35. 14 Ariazi EA, Jordan VC. Estrogen-related receptors as emerging targets in cancer and metabolic disorders. Curr Top Med Chem. 2006;6(3):181-202. 15 Cvoro A, Paruthiyil S, Jones J, Tzagarakis-Foster C, Clegg NJ, et al. Selective activation of estrogen receptor b transcriptional pathways by an herbal extract. Endocrinology. 2007;148(2):538-547. 16 Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. 2006;54(2):164-175. 17 Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA, et al. Antibiotic use in relation to the risk of breast cancer. JAMA. 2004;291:827-835.

Welcome to March 2007 Functional Medicine Update. Have you ever stood at a corner knowing that when the light turns and you cross the street you are going to have an experience on the other side that you didn’t expect? That is how I feel as we head into this issue of FunctionalMedicine Update. I feel we are standing-all of us-on the corner of a paradigm shift in medicine. This month’s clinician/researcher of the month, Dr. Jorn Dyerberg, is one of the two discoverers of the fish oil concept. You will hear how he and his colleague, Dr. Bang, came to the remarkable discovery that fats in the diet of Greenland Eskimos were associated with a lowered risk of disease (which was totally alien and contrary to any opinion at that time because it was felt that all fat was dangerous to the vascular system). That discovery in the 1960s is typical of the mounting evidence before us as we stand on this corner waiting for the paradigm shift in medicine to occur. I will go through this information with you and describe just the tip of the iceberg of what has been changing over the last month or two in the field of health care-things that you see, feel, hear about, and are experiencing in your own practices. You will recognize that we are all standing on a street corner, waiting for the light to change. And when we do walk, we are going in a different direction than we’ve been taking in medicine over the past 50 years. Let’s start this month with a recent editorial that appeared in the New EnglandJournal of Medicine in 2006 that was titled “Dangerous Deception-Hiding the Evidence of Adverse Drug Effects.” 1 This is by Jerry Avorn from Harvard, who has written very eloquently about the field of drug safety and has done quite a bit of work-in fact, he is the author of a best-selling book on this topic. This editorial demonstrates why we are at a corner waiting for the light to change. I quote, “September 30 is becoming a day of infamy for drug safety.” It was on September 30, 2004 that Merck announced that rofecoxib (Vioxx) doubled the risk of myocardial infarction and stroke. The company withdrew the drug from the market after 5 years of use and more than 20 million patients, representing more than 3 billion dollars in annual sales. This action was a consequence of reports by a number of investigators. Adverse Reactions Recently Linked to Aprotinin In a similar, more recent situation, Mangano et al. found that patients who were given various drugs ended up with very serious difficulties. 2 The Mangano et al. study was looking not at Vioxx, but rather at aprotinin, which was approved in 1993. Further evaluation of this drug showed that patients undergoing uncomplicated coronary artery surgery who were given aprotinin had a 55{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} increase in the incidence of myocardial infarction or heart failure, and a 181{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} increase in the incidence of stroke or encephalopathy. One has to wonder how a drug could be approved that would later show dramatic adverse side effects. Another editorial appeared in The NewEngland Journal of Medicine in 2006 titled “Observational Studies of Drug Safety-Aprotinin and the Absence of Transparency.” 3 This editorial, authored by William Hiatt, goes on to talk about how we could miss-based upon the mechanisms of evaluation for drug safety-a potential series of side effects from aprotinin when used in clinical practice, a drug that was used routinely in the operating rooms of all hospitals that were doing the CABG (Coronary Artery Bypass Surgery). On the date of September 30, 2004, when Merck announced the recall of Vioxx, it further strengthened concerns about the way in which drug safety is determined. The recall of Vioxx opened up questions about the major classes of medications (both prescription and over-the-counter) that are used commonly for the management of many chronic-related health problems. At the head of this list are medications used to treat inflammation, which we now recognize represent the underlying etiology for so many of the chronic, age-related diseases. And then we might start looking at things like cardiovascular outcomes with diclofenac, or even something simple, like ibuprofen. Long-term NSAID Use and Cardiovascular Disease A study was reported in The Lancet in 2006 that looked at cardiovascular outcomes in patients with osteoarthritis and rheumatoid arthritis taking nonsteroidal anti-inflammatory drugs (this was the Multinational Arthritis Long-term Programme [MEDAL]). 4 What the investigators found was that there were not only increasing incidences of upper gastrointestinal clinical events (i.e. gastric hemorrhaging and bleeding), but also increased incidence of cardiovascular disease in individuals who were taking (over a long period of time) these nonspecific cyclo-oxygenase-inhibiting drugs. This suggests a general effect, with the impact seen most significantly on those drugs that have the highest efficacy, like rofecoxib. Rofecoxib was a marvelous drug for what it was designed to do: manage acute inflammatory pain for a very short period of time in people who have elevated, upregulated, inducible COX-2 activities. Unfortunately, these medications got extended into long-term chronic management of garden-variety pain and inflammation. This started producing (in susceptible individuals) the outcome predicted by Fitzgerald and others, which was the blocking of constitutive COX-2 activities in the vascular endothelium and lowering prostacylin (PGI2) production, inducing increased thromboxane and lowering the platelet anti-adhesive effects of prostacyclin, leading to clotting (with stroke) and heart attack. There is an ever-growing story of cyclo-oxygenase inhibition that is not so pretty. It is not just gastrointestinal risk that leads to 12,000-15,000 deaths a year from acute bleeding, but it is also the chronic effects on the vascular endothelium blocking prostanoids (a constituent of cyclo-oxygenase derivatives) that can induce relative risks that were never seen before. It is no wonder that a paper appeared in the Journal of the American MedicalAssociation in 1997 that suggested that the 4 th-6 th leading cause of death in America is adverse drug reactions (to appropriate medications given to patients in hospital situations by well-trained professionals). We had missed this over the many years because if you don’t ask the questions you don’t find the answer. It was assumed that people in hospitals often died, so we didn’t look for the possibility that death was amplified, or aggravated, or accelerated by medications given and the results these medications had on a person’s unique biochemistry, or physiology, or genetics to produce an adverse outcome as serious as death. This ever-growing story about things that could produce adverse effects over the long term includes chronic drug use. I’m quoting now from an editorial that appeared in The Lancet in 2006 called “The Ever Growing Story of Cyclo-oxygenase Inhibition.” 5 Have we taken into account the risk-benefit trade-off on long-term management of chronic disease with new-to-nature molecules? Possibly there is a different kind of approach required if you are going to have a patient on therapy for months, years, or maybe even decades than that which you would use for a patient under short-term therapy in the emergency room or with an acute situation, or for whom the therapy is administered, the condition resolves, and the therapy is taken away. FDA Recommends NSAIDS Carry Warning Labels about Long-term Use Even those conditions that are associated with the use of over-the-counter anti-inflammatories are now being questioned as potentially of some concern. You have probably seen recently that the Food and Drug Administration (FDA) has proposed sterner warning labels for acetaminophen, aspirin, and ibuprofen, again cautioning Americans who take these non-prescriptive, nonsteroidal anti-inflammatory pain relievers of potentially serious side effects. Although they say that they remain safe and effective when used as directed (meaning short-term use), the Food and Drug Administration has said overdoses or long-term use can cause serious liver damage or even death. With aspirin, ibuprofen, or NSAIDs there is a risk of not only GI bleeding and kidney injury, but also increasing concern about cardiovascular disease risk. So what I am really saying is that this is not insignificant. In fact, with acetaminophen, there is an estimated 56,000 people who go to the emergency room each year, making it the most common drug adverse side effect that produces acute symptoms, and these are not people who intentionally overdose. Many of these people are taking the doses that are recommended on the label, but they have unique biochemistry in the way they metabolize the compound, or they are poorly nourished, or they are drinking alcohol, which aggravates metabolism, producing toxic metabolites like NAPQI, which is the metabolite that has to be conjugated with glutathione in the liver. If glutathione is not adequately available, it becomes a hepatotoxic intermediate. We are starting to see dramatic changes in our thinking about the risk-benefit, or the safety relationships, of the use of pharmaceuticals over long term. What do we do? People are growing older and do have chronic health problems, and we would like to think there is some remediation available. In an article in Medical Hypotheses in 2006, Dr. H.R. Hellstrom says it is likely that the risk of cardiovascular events and gastrointestinal adverse effects from COX-2 inhibitors (or COX inhibitors) can be reduced significantly by lifestyle preventative measurements. 6 Maybe there are things that we can do to improve our diet and our lifestyle that would make our bodies more tolerant to these medications, or maybe greatly reduce (or remove entirely) the need for them. Often in life, as we are standing at the crosswalk waiting for the signal to say “Walk,” we might wonder if some driver who is not paying attention to the red light will come rushing through the crosswalk. So before we step off-even before the sign says, “Walk”-we probably look both ways. By similar token, as it relates to where medicine is going, before we step off onto the walkway that represents the corridor down the pharmaceutical pathway, we might want to look both ways and ask, “Is there something coming?” If so, we might want to stay on that corner or travel in the other direction. It is this question that we are going to be talking about because certainly this story is not just related to cardiovascular or anti-inflammatory drugs; it has a spreading message. We saw disillusionment in the minds of millions of women when the Women’s Health Initiative data on mixed conjugated equine estrogens and progestins was published, demonstrating that not only did these compounds not reduce the risk of heart disease (as had been told to women for many years), but they may have increased the incidence in specific women of heart disease, increased the incidence of cognitive decline, and had adverse effects upon immune system function. This disillusionment was extraordinary and led to (starting in early 2000) a reduction in the number of women taking hormone replacement therapy using equine estrogens and progestins. At the end of 2006, we saw-as maybe a fortuitous association, but maybe also a cause and effect-a dramatic report that for the first time in more than 15 years, data now indicates that the incidence of new cases of breast cancer are declining. 7 Now this may be fortuitous and just one of those random associations with women ceasing to use hormone replacement therapy with equine estrogens and progestins. Or there may be something very significant that we should pay attention to about medicalizing and pharmaceuticalizing a natural process called menopause, and that possibly there are other ways that we would want to cross the street using a different crosswalk that would utilize other substances that are less potentially adverse, mitogenic, and cell-replicative-more traditional substances that have been used and sold to women for managing hot flushes and night sweats. Statin Use is Becoming Pandemic A more recent part of this story has to do with our excitement-almost an infatuation-for statins and the lowering of LDL cholesterol. We have seen this statin concept become so pandemic that it is almost required that a mid-life individual be on statins for promoting good health and longevity. In fact, it has been suggested that even youth possibly be administered statins prophylactically to lower cholesterol and purportedly reduce the incidence of cardiovascular disease as these children grow older. There has also been a recognition that if we could lower LDL while raising the favorable HDL cholesterol, we might have the best of all worlds (to decrease LDL cholesterol to 70 milligrams per deciliter or lower and increase HDL cholesterol above 50 would be a tremendously positive outcome). Torcetrapib: Optimism Turns to Disillusionment People have been looking for pro-HDL drugs that will activate the HDL-synthesizing machinery of the body. There was extraordinary excitement around a new drug that would, in fact, increase HDL cholesterol levels. It activated cholesteryl ester transfer protein (CETP). When I say “activated” what I really mean is that it reduced its function (the CETP), which then increased the effect on the body to regulate HDL (it increased the HDL form of cholesterol). This particular molecule, Torcetrapib, was eventually approved as a drug sold by Pfizer as a way of working with statins (Atorvastatin or Lipitor) to lower LDL while increasing HDL. Not too long ago, we saw investor news in the pharmaceutical industry hailing and regaling the excitement about Torcetrapib, which was being promoted as an amazing new contribution to cardiovascular risk reduction and an amazing new profit generator for Pfizer. I’m now quoting from a press release in Investor Weekly that appeared just a little over a year ago, encouraging people to be very excited about this new drug and the combination of Atorvastatin and Torcetrapib.8 Use and sale of these products was expected to increase (and obviously increase profit for the company selling it), and it was presented as a good investor opportunity. So the CEPT inhibitor, Torcetrapib, and an LDL-reduction statin, Atorvastatin, looked like a wonderful recipe. As we moved into 2007, that extraordinary optimism has been dashed on the rocks of disillusionment. Even though there was 800 million dollars invested into Torcetrapib, evidence adverse effects in some individuals has been found, and the drug has now been withdrawn from the market due to safety. Why didn’t an FDA ethics committee intervene and why didn’t we know about this? Certainly something went wrong. Two senior Pfizer people said that trial results showed 82 patients taking Torcetrapib had died over the life of the trial versus 51 who were taking Lipitor alone. Torcetrapib was supposed to be combined with Lipitor and sold as a combination drug, but it doesn’t look like it is ever going to make it to the market and be the success it had been proposed to be. Did this result in-or at least contribute to-the recent news (in 2007) that job cuts are ahead for Pfizer? They are going to be domestically cutting their workforce down by 20,000 employees. They are going to be closing 5 plants and different research laboratories and production systems. This is a complex issue not just related to Torcetrapib alone, but related to pressure from generics, things coming off patent, and lack of an effective pipeline. 9, 10 What I am really suggesting to you is that as we stand on the street corner waiting for the crosswalk light to come on, the world of medications is changing under us. In fact, one might say that Torcetrapib is really just kind of a case study of the change that is occurring within the field of pharmaceuticals. “Big Pharma,” with its blockbuster medicines, is at a watershed that it has never really experienced before because of adverse side effects popping up in long-term surveillance trials. Are We Entering the Age of the “Minibuster?” It is very expensive to get drugs into the pipeline; the medicolegal system has put tremendous emphasis on improving safety profiles. We recognize from pharmacogenomics that people are different from one another and it cannot be expected that everyone will respond to a drugs the same way (as we used to think). It is more than just body surface area; it is related to cytochrome P450 and conjugation effects on how drugs are detoxified and how receptors are activated that results in tremendous genetic variation. We can’t just wipe away adverse drug responses as being atypical and unexpected; they are (in certain genotypes) expected and reproducible. We may be moving from the age of the blockbuster to the age of the “minibuster”-drugs that are more targeted to specific genotypes, or limited away from those people who have adverse risk genotypes, like certain polymorphisms (the cytochrome P450s). This changes prescribing patterns. This changes marketing. This changes sales. This makes it much more complicated to deliver a product that everybody embraces and it is good for all. This is the start of a new day of therapeutics in medicine. As the “Walk” light comes on and we start crossing the street-having looked both ways-we might find that the landscape on the other side has already changed by the time we get there. With this as a backdrop, let’s look at recent concerns in health care ( like the epidemic increase in dysinsulinism, diabetes, heart disease relative risk, and other problems that occur from the inflammatory conditions of altered insulin signaling). We recognize we are facing a global crisis for which we don’t have (at present) a good solution that comes out of pharmaceutical science. It’s as if we need a different model. It’s as if the old model (molecules from the bench of lab chemists) is not necessarily well-suited to the management of long-term chronic problems. The pharmacopoeia that has been developed, which is very powerful for use in the emergency room or the critical care unit, may be a strategy for developing new molecules or medicines that is counter to long-term safety and good outcome. What we have attempted to do is manage chronic disease (which constitutes 78{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of our healthcare expenditures) with drugs that were designed for short-term use for the management of acute problems without knowing what the long-term safety effects are when use of those drugs extends to decades of living. The first real test population for the effects of long-term use is the people who take them. Without any science upon which we can base the safety and effectiveness of drugs over the long term, the construct is starting to be recognized that maybe we are not really practicing scientific medicine when we extend use of short-term, high-potency drugs used effectively for crisis management into long-term patient care. This is a belief system not founded in real science; it is founded on the belief (or faith) that these drugs are going to be effective and safe, only to learn later that these products (many times) have shown to have less than acceptable safety or even efficacy profiles. There is more and more evidence that indicates diabetes is becoming a worldwide epidemic of the 21 st century. This is discussed beautifully in a recent editorial that appeared in The Lancet in 2006 in which it is shown that the global burden of ischemic heart disease and stroke (beyond that of just type 2 diabetes) is much higher than we recognized in terms of burden of disease globally. 11 In addition to 959,000 deaths annually that were directly assigned to diabetes, there are 1,490,000 deaths from ischemic heart disease and 709,000 deaths from stroke attributable to elevated blood sugar, accounting for 21{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} and 13{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of all deaths from these conditions. It’s like seeing the emperor with no clothes, finally, by shining light on him and he’s not that attractive; this is a serious problem. The data I just cited is from an article titled “Global and Regional Mortality from Ischaemic Heart Disease and Stroke Attributable to High-than-optimal Blood Glucose Concentration: Comparable Risk Assessment.” This appeared in The Lancet in 2006. 12 What do you do? What are the drugs? What are the therapies? How do we stem the tide? Before we walk across the street, where do we want to put our feet? A very provocative study was recently published that I think helps us with some path finding in this area. The Finnish Diabetes Prevention Study looked at sustained reduction in the incidence of type 2 diabetes. 13 There wasn’t a drug or a specific pharmaceutical used in this particular intervention. What was used was lifestyle intervention with diet, exercise, and counseling. Sustained Lifestyle Changes Can Result in a Reduction of Diabetes Incidence In this particular study, 172 middle-aged men and 350 women with impaired glucose tolerance were randomly assigned to either an intensive lifestyle intervention or control group. After a median of 4 years of active intervention, patients who were still free of diabetes were further followed for a median of three years (with a total, then, of about 7 years). Diabetes incidence, body weight, physical activity, and dietary intake of fat, saturated fat, and fiber were measured. The bottom line is that there was a statistically significant reduction in type 2 diabetes in the individuals who complied with lifestyle intervention as their primary mode of therapy. In fact, per 100-person-years, there was a statistically significant reduction in type 2 diabetes in the P < .0001 level, indicating a 43{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction in relative risk (or almost approaching half reduction risk over those people that didn’t engage). There is presently no drug therapy that will accomplish that outcome. Lifestyle intervention (the authors concluded), in people at high risk for type 2 diabetes, resulted in sustained lifestyle changes and a reduction of diabetes incidence, which remained after the individual lifestyle counseling was stopped for the duration of the 7 years of the study. Trial Involving a Thiazolidinedione Drug Let’s look at drug studies as contrasted to lifestyle studies for the management of these chronic illnesses (when I say “lifestyle” I am talking about diet, exercise, and stress management-types of programs). In a recent issue of the Journal of the American Medical Association in 2006, a study was published in which investigators (in a randomized, double-blind, placebo-controlled, multicenter trial) were looking at patients with type 2 diabetes and how their carotid artery wall was thickening over the course of intervention with a thiazolidinedione drug, pioglitazone. 14 This particular study (conducted over 18 months) showed that pioglitazone slowed progression of coronary intima-mediated thickness (CIMT) compared with using a first-generation diabetes drug, which was a sulfonylurea. The study authors came to the conclusion that there maybe an advantage to using a thiozolidinedione or a peroxisome proliferators-activated receptor (PPAR) agonist over using a traditional sulfanylurea because the progression is slowed down. How Does Lifestyle Intervention Compare to Metformin Use? How does this compare to the implementation of a Mediterranean Diet, exercise, and stress reduction? What is the relative outcome in cardiovascular disease comparing the two? There was a paper published in The New England Journal of Medicine several years ago comparing metformin against lifestyle intervention in patients with type 2 diabetes.15 This paper showed that both improved function, but that lifestyle, diet, exercise, stress reduction was superior to metformin. The more we do these comparative studies, looking at how we modulate function-drug versus diet and lifestyle-the more we may become convinced that the best therapies are things that seem so simple, but are maybe unattractive because they don’t sound exciting. It is easier to get something out of a bottle and take a pill a day than it is to have to do something by altering cellular signaling and cellular messaging by practicing good health. In a recent issue of The New England Journal of Medicine, the question of whether thiazolidinediones are really the initial treatment of choice for type 2 diabetics is discussed (given some of the evidence that is emerging). 16 The author of the piece says that there does appear to be some emerging evidence of value, but there are also some adverse effects (like weight gain) that occur with thiazolidinedione drugs. The relative cost of these medications-their profiles of adverse events and their potential risk and benefits-need to be considered very closely before using them as the first line of therapy. It is suggested that with the modest glycemic benefit weighed against the risk of fluid retention and weight gain and higher cost, possibly we ought to stay with our traditional drugs like metformin for initiating pharmacotherapy for type 2 diabetes. The author does not talk about the fact that maybe both of these are not the primary therapies of choice. Maybe what we should be looking at are molecules that signal appropriate functional changes to the body, which are also the molecules that have come through the most significant and long-term laboratory study ever done-natural selection. These are molecules that have been associated with foods that historically have been associated with a low incidence of chronic, age-related diseases. Maybe we are looking in the wrong place for the molecules of choice. There is an analogy you might have heard of about a man who has lost his car keys. He is bent under a street lamp at night trying to find them. Another man comes over to help him and says, “Can I help you look?” And the first guys says, “Oh yeah, but don’t look here because I think I lost them over there where it is dark.” So the second man asks him, “Well, why are you looking under the street lamp, then?” He says, “Well, it’s the only place I can see.” I think that analogy relates to some of the things we are doing in medicine right now. So before we step across the street when the “Walk” light comes on, let’s make sure that we are traveling to the right side-that it is really the direction that we want to head. In cases of very severe insulin resistance and metabolic syndrome associated with nonalcoholic steatohepatitis, you have fatty liver infiltration with an elevated liver enzyme profile. We are now seeing this in medicine for the first time with any prevalence. I can’t remember 30 years ago (when I first started in this field) ever really seeing people who had nonalcoholic steatohepatitis. However now it is very frequent (even in younger people) to have these marginal liver enzyme elevations as a consequence of lipotoxicity from the infiltration of fat into the liver associated with insulin resistance. There was a recent paper in The New England Journal of Medicine addressing the question of whether pioglitazone (one of the thiazolidinedione PPAR-gamma agonist drugs) is really the medication of choice for the management of, nonalcoholic steatohepatitis (NASH), the more acute form of metabolic syndrome.17 In patients who had elevated liver enzymes and were administered pioglitazone, it did lead to metabolic and histologic improvement. However, in the editorial that follows (again weighing risk/benefit), the author, Arthur McCullough, goes on to say this evidence is promising, but not ready (yet) for prime time because of the potential risk of using these drugs over many years for chronic management.18 We recognize that these age-related increases in circulating inflammatory markers and altered insulin signaling really occur well before the onset of obesity, or elevated blood pressure, or elevated blood lipid. I think this is an important observation because we often think that these conditions are all caused by obesity and we wait until the patient is obese before we intervene with drugs. Now there is ever-increasing evidence to suggest that the early trajectories of these dysfunctions are associated with increased inflammatory markers: C-reactive protein, interleukin-6, interleukin-18, secretory intercellular adhesion molecule 1 (ICAM-1). All of these increase in the blood well before one starts to see increasing body mass index, increasing blood pressure with vascular endothelial resistance, and elevated blood lipid concentrations. Possibly, the effects are the outcome that we call obesity and the causes are things that have occurred within the subtle cell signaling processes of the body. These processes ultimately regulate function associated with heart disease, diabetes, and stroke that we see as changes in body composition like obesity, diabetes, heart disease (dyslipidemia), and, in fact, even in arthritis management. Introduction of TNF Agents Increases Concern about Malignancy You probably have seen there is some evidence now that autoimmune antibody-blocking agents (like the TNF-alpha blocking agents) may have some adverse effects in individuals when used for an extended period of time. In a recent article that appeared the Journal of Arthritis Research and Therapy in 2006, the authors say that the introduction of anti-tumor necrosis factor (TNF) agents and their now wide-spread use has resulted in increasing concern about malignancy and suppression of the immune system with opportunistic infection, including things like tuberculosis.19 In addition, a recent meta-analysis of randomized clinical trials raised concerns about an increased rate of malignancy and infection in RA patients who were treated with these anti-tumor necrosis factor monoclonal antibodies. Again, it is risk/benefit trade-off we are talking about. Are there different approaches that we might use to modulate these effects? The different approaches often come out of functional medicine and we have been talking about them for more than 25 years on this series. For instance, we now recognize that oral supplementation with things like Lactobacillus acidophilus (a probiotic which was not considered in the mainstream of medicine) can modulate intestinal pain in chronic irritable bowel syndrome because it alters opioid and cannabinoid receptor activities through modification of cellular signaling. These friendly bacteria set up a relationship with the gut mucosal receptors that sends up signals that downregulate the message of alarm that we then see as pain and as cramping. How many drug targets are there? We are starting to recognize that the pharmaceutical industry is looking for ways of modifying cellular signaling because it is this signaling that ultimately controls (downstream) the production of tissue pathology. In an interesting paper that recently appeared in Nature Reviews in 2006, the authors talk about the fact that the pharmaceutical industry is now recognizing they need to find ways of modifying upstream events by modifying cell signaling, and they probably need multiple activities that are working simultaneously.20 More than one molecule; mixtures of molecules. This is a whole different approach in pharmaceutical science than we have historically seen, which has traditionally been one molecule for one outcome. When we look at how cell signaling influences chronic disease, we see emerging from The New England Journal of Medicine in 2006, a report that the asthma epidemic is associated with triggering events in gene response that produce multiple signaling outcomes that we see as inflammation.21 Another article states that the new therapies for asthma will be things that modulate cellular signaling. I am now quoting from Trends in Molecular Medicine (a recent article by Peter Barnes that talks about the modification of these signaling pathways that are called kinases).22 Kinase Modulators will be New Therapeutic Agents Similarly with neurodegenerative diseases, understanding the molecular causes of Parkinson’s disease leads us back to understanding adverse cellular signaling of inflammatory nature, with oxidative stress and neuronal injury, and that the new therapeutic agents will be kinase modulators that are specific to the brain signaling process and reducing the inflammatory signals. 23 And even in the case of things like menopause symptoms and the risk to breast cancer, endometrial cancer, bone loss, and cardiovascular disease in women. I’m now quoting from a recent article in Newsweek magazine (January 18, 2007 issue) titled “Understanding Menopause.” 24 These authors talk about using a lifestyle intervention diet to modulate hormone signaling. Such a diet would include the brassinoid vegetables-the cruciferous vegetables that contain glucosinolates that modulate hormonal metabolism, cell receptivity, and hormone signaling. There was an interesting article in a recent issue of Science magazine that discussed how brassinosteroid signaling can modulate hormonal metabolism and effects at cell surfaces. 25 We are seeing a transition in medicine occurring right before our eyes. There is really no better way to understand this than to hear the fatty acid story that we are going to learn about from our clinician/researcher of the month, Dr. Jorn Dyerberg. Dr. Dyerberg is a professor of medicine. He is one of the two pioneers in omega-3 fatty acid research who, in the 1960s and 70s, visited remote Eskimo settlements in Greenland and showed that the reason the low occurrence of ischemic heart disease was seen in these populations was due to the consumption of diets that were very high in omega-3 fatty acids from seals and fish. What we will learn from Dr. Dyerbeg is how this observation really frames a whole different paradigm in pharmacology and medicine that takes us away from new-to-nature molecules from the benches of synthetic chemists to those molecules in nature that might really modulate function, reducing the risk and incidence, and maybe even source of chronic, age-related diseases.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jorn Dyerberg, MD Medical and Scientific Advisor Marine Nutriceutical Corp/Napro-Pharma AS Norway We are here today with Dr. Jorn Dyerberg, a professor of medicine from Denmark who has done an extraordinary volume of work related to essential fatty acids and health, particularly focusing on cardiovascular disease. For those of you who may be unfamiliar with this, the story goes back more that four decades with Dr. Dyerberg and his colleague, Dr. Bang. I think this discovery will ultimately prove to be one of the great “a-ha’s” that has occurred within the fields of nutrition and medicine and will save many millions of people from having unnecessary cardiovascular disease and a host of other chronic ailments. The question really is: Where did the concept come from? Dr. Dyerberg, from your experience, obviously a good idea ultimately rolls forward to become a change in thinking. How did this all start for you? Pioneering Work in Greenland JD:    It started way back-as you just said-nearly 40 years ago (in the 1960s) when I was a resident in Dr. Bang’s department at a city hospital in Denmark. In our medical journal, there was a lead article pointing at our Danish citizens in Greenland, the Eskimos (because Greenland was a part of Denmark), stressing that in spite or their dietary habits (meaning, coming from the sea, from seals and whales with a high amount of fat), in spite of this diet high in fat, they had an extraordinarily low incidence of coronary heart disease. How come? The lead article said it was an obligation for the Danish medical society to go into that question before it was too late (meaning, before Westernized civilization, accompanied by high incidence of coronary heart disease, took over up there in the remote areas of Greenland). And Dr. Bang and I were fascinated by that story and said we would go up there and try to (if we could) elucidate that problem. For me, as a young doctor, it was, of course, an opportunity for going deep into some esoteric aspects of medical science, but also an opportunity to go and see these remote areas of the world and meet people, and that could be a fascinating experience. We arranged for our first expedition, which was in 1970. It wasn’t that easy to get the money for that because not very many people supported nutritional science and not very many believed that there could be something to gain out of going up and seeing what diseases this tiny tribe of people had. But we managed to collect, I guess, $85,000, and that covered our expenditures for two months up there and we collected blood from the Eskimos. We found out that they had a favorable lipid profile, but not to an extent that could explain why the number of heart attacks was as low as it was. So, we got sort of an explanation, but not the explanation we had expected. We were (rather strange enough) able to also analyze the fatty acid content of their blood. We had 130 samples of blood from Eskimos who were fasting. Dr. Bang said, “These are the only samples in the world. We have to do everything on them.” And then we did fatty acids. And up came two fatty acids we had never heard about-two peaks on our chromatogram. And we said, “What are these?” I actually had to go to America-to Minneapolis to the Hormel Institute-to visit Dr. Ralph Holman, who was the expert (at that time, he has retired now) in identifying strange fatty acids. And he knew about some omega-3 long-chain fatty acids (which I had never heard about)-docosahexaenoic acid and eicosapentaenoic acid. And he gave me standard samples that I could bring back home and identify that these were high in Eskimo blood. And we published that in the American Journal of Clinical Nutrition. At the same time, in the early 70s, Swedish and British researchers found out that prostaglandins that regulated blood clotting could be generated from omega-6 fatty acids. And suddenly we got the idea: What if, from our omega-3 long-chain fatty acids, there also would be generated prostaglandins that regulate blood clotting at another level (from a land-based food, polyunsaturated diet)? So we wanted to answer that because we had a lab able to do that in Britain. We ended up finding out that prostaglandins coming from eicosapentaenoic acid did not promote blood clotting to the extent of omega-6. We published that in the late 70s and from there on-that moment, that paper in The Lancet-the interest in omega-3 polyunsats started, but rather slowly. It has been sort of a disappointment how long it has taken the medical community to divert from medicine to nutrition. JB:     Yes, and I think there has been, always, the pushback of nay-sayers who don’t want to accept new discoveries. They will say things like, “How do we know the Greenland Eskimo would not have died because, basically with other causes of death, they must have a lower/shorter life expectancy. It is a harsh climate.” Or, “How do we know they didn’t die of something else, like strokes, so their heart attacks are low but maybe their cancer or stroke rates are high?” So you get all these secondary questions that obscure the primary observation. How did you deal with some of these other questions? Epidemiological Data Confirms Early Findings JD:     Yes. We had to deal with them in an experimental way. The medical community has already dealt with them in epidemiological studies-major studies from the US actually document it. I am now thinking of, for example, the Nurses’ Health Study from the Boston area from Dr. Willett’s group. They came up with epidemiological data showing that nurses who had a high consumption of omega-3 did not have bleeding, but rather had a low incidence of thrombotic episodes, which supports the idea that we brought forward. JB:     It is my belief-and I’ve said it in a number of presentations that I have given over the years-that your discovery is as important to public health as any singular discovery that I have heard of in the area of nutritional medicine. Certainly it is worthy of the Nobel Prize. It is interesting to note that Dr. Samuelson at Karolinska won a Nobel Prize for his discovery of the prostanoids that derive out of the arachidonic omega-6 family. I am wondering why you feel (philosophically) the fathers of all this work haven’t been seen by the Nobel Committee to have the same degree of importance because it seems to me that this discovery of Samuelson on prostanoids really is more amplified in importance because of your discovery. JD:     Yes, but of course, they were the first to show that from polyunsats belonging to the omega-6 family, there were generated prostaglandins that regulated hemostasis. Then we made sort of a parallel thing. We said, “Couldn’t it be so that another family of prostaglandins could do the same thing but in another direction?” And we managed to prove this. It is maybe fair enough that those who got on that trail first were the ones that got the laureate. Thank you for suggesting the idea, but I think that’s the reason. Heart Rate Variability JB:     Let’s, if we can, follow on with the importance of your discoveries, because I think it plays out in so many ways in health. I know you have looked at things like heart rate variability, which I find is a fascinating surrogate marker for an indicator of cardiovascular function and how EPA and DHA play a role in heart rate variability. Could you tell us a little bit about that? JD:     Yes, and not only heart rate variability, but also heart rate. There were two major studies performed during the 1990s-the DART Study and the GISSI Study-giving omega-3 (either fish diets or omega-3 supplements) to patients who had had a coronary event, showing that in the groups given fish oil supplementation, the sudden cardiac death rate fell dramatically (up to 45{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in the large study which included more than 11,000 patients). Sudden cardiac death is due to fibrillation of the heart, so we speculated about whether omega-3 fatty acids in any way had an influence on the heart beating/rhythm. An indicator of proneness to cardiac fibrillation and sudden cardiac death is your heart’s ability to change its rate, its adaptability to stress and rest and functional demands. And this can be measured by putting a record on your heart for 24 hours, which we did in several studies, and found that we could improve heart rate variability in patients who had had a coronary heart attack. To me, as a professor of nutrition, even more interesting was that if we took Danes who were normal, healthy, young males and measured their heart rate variability, we could improve that by giving them fish oil supplementation. This indicated that our Danish diet (which is far richer in fish and omega-3 than the American diet, on average) was below the optimal level. JB:     So that raises the question: What is the range of optimal level of intake of EPA and DHA? I know you have said that you can’t just get there by cutting out omega-6s, you have to have adequate levels of omega-3s. What do you find? Is There an Optimal Range for EPA and DHA Intake? JD:     Yes, there has been a lot of talk about the range between omega-3 and omega-6, and of course this can be used as a measure, but range means that you can also determine the range both by the denominator and the numerator. And, of course, you cannot improve the amount of omega-3 by decreasing the amount of omega-6. Even if we have (maybe) too high a consumption of omega-6 fatty acids, it is still necessary that you feed your system the omega-3s because you can’t make them yourself. And what is the optimal range or level? To be honest, we do not know. What we know is that 1-2 grams a day does a lot of benefit. So today we’ll say that this is a good dosage to aim for. JB:     Can we go back, just for a second, to your extraordinary discoveries about heart rate and heart rate variability? We have often talked about the fact that as people get sicker and they lose function, their physiological degrees of freedom are diminished. In fact, in a hospital, the worst kind of EKG is one that is totally rigid and has very low variability. In fact the most simple EKG is a flat line, so as an EKG gets more simplistic, you are moving towards less physiological degrees of freedom. That bears on the whole question of how something like essential fatty acids (or the omega-3) can improve physiological degrees of freedom across many different disease states, not just vascular disease. So could you tell us a little bit about the discoveries and things like neurology and rheumatology and endocrinology? Functional Aspects of Fatty Acids JD:     Of course, but first I want to stress what you just said. These fatty acids are built into every cell membrane in our body. They aren’t there just for fun; they are doing something. What they are doing we do not know in great detail yet, but we are starting to have sort of a sense of it because it modulates the cell membrane’s flexibility and it modulates the functional spots in the cell membranes-the ionic channels and things like that. And besides that, they have functional aspects of themselves. For example, in the brain and in the retina, DHA has functional aspects. Our brain is rather rich, and our retina is very rich, in DHA. It has been interesting to follow that. Deficiencies in long-chain omega-3 fatty acids are associated with disorders in our nervous system, for example, depression, Alzheimer’s disease, and ADHD in kids. Also, intervention trials have proven that there could be a therapeutic effect of giving it to people with these types of disorders. Rather recently, the Framingham data study group published their data on Alzheimer’s and found that what corresponds to a daily intake of .180 milligrams of DHA is associated with a 47{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} less risk of developing Alzheimer’s in elderly people over a 9-year period. This is not an intervention trial; this is observational data. These are rather solid data that I (as a nutritionist) have enough from to base my recommendation to the public because I know I’m not doing any harm; I’m increasing beneficial effects. JB:     So when people hear this it sounds overwhelmingly persuasive that we should be doing something to improve our omega-3 intake. For a lot of people fish is either not accessible all year long or they don’t like fish, so what do they do? JD:     As a nutritionist, of course, I always start with the diet (rich in fish, having 2 or 3 servings a week). This is related to a lower rate of coronary heart events. But then, if you can’t buy the fish or if you don’t like the fish (there are a lot of taste differences-personally, I love fish), the only way is to buy good quality supplement capsules or liquids and add that to your health maintenance in a daily amount of 1-2 grams (in prophylactic terms, for a normal person). JB:     So when we talk about high quality-I think that term, for a lot of people who may be unfamiliar with the process may be nonspecific-what kind of things in quality do we actually look for when we talk about fatty acid supplements? Concern about Pollutants in Fish JD:     High purity. No oxidation. No level of toxic pollutants. Unfortunately, we know the human race (mankind) pollutes a lot, even the seas, so some fish will have a high level of pollutants (mercury, dioxins-you name it), depending on where they come from. I’m not saying that fish (in that aspect) is unhealthy, but, if you go for the fish oils, you can meet products that do not qualify as good and reasonable products. I always advocate to my patients to not take the cheapest offer; go for quality-things that you know are good. I, myself, have always had relationships with good producers (I’m sorry I can’t name names). JB:     When we look at these fish oil supplement products, I note that they come in two kinds of general forms. They come in a triglyceride form, which would be considered kind of your normal dietary form, and then they have ester forms-ethyl esters, methyl esters, etc. Is there any difference between these two that you are familiar with? Different Forms of Fish Oil Supplements JD:      Yes, chemically, great differences. When you eat a fish or a seal (we don’t eat a lot of seals you and I, but the Eskimos did), it is in a triglyceride form, which is a natural form of fat that we absorb; they are ingested, split by the enzymes in the intestine, and absorbed as monoglycerides and as free fatty acids. These products contain a medium amount of omega-3s. You can enrich those triglycerides to improve their content (chemically) so that instead of one there will be two omega-3 fatty acids in the triglycerides. To me that is a reasonable way to make supplementation. You can do it in other ways. You can isolate the fatty acids as free fatty acids and they are well-absorbed. The thing with the free fatty acids is that they are rather odd tasting; they are rough to take. Quality oil is actually low in free fatty acids. In the mouth free fatty acids can form soaps, so they do not have the best taste and therefore compliance (in my studies) was not good using free fatty acids. And then, again, you can make ethyl esters, which is a chemical derivative of a fatty acid that is not as well absorbed, but is reasonably well absorbed. These are the products you can use. JB:     One of the things I’d like to appeal to you (as an expert in the field) to help us to understand from the vast experience that you have had, is why you think it takes so long for something that seems to have such reasonableness associated with it (with so many studies-epidemiological, animal, human, intervention trials&hellip;) to finally have stickiness. Do you have some sense as to why this is so? JD:     To be honest, I have to blame my own profession (the doctors) because nutrition is not of high esteem and it is not an essential part of the education of a medical doctor. It has been rather a low priority thing for a doctor to deal with nutrition. A doctor likes operations and medication, prescribing a pill (which, of course, is what he is there for and should do for disorders, but in prophylactic terms, I think nutrition has a far higher impact and is far more essential). The thing with nutrition is that it is not a part of the doctor’s education process, and the impact from the pharmaceutical industry has put nutrition at a lower esteem level than pharmaceutical intervention. To be honest, I think that is simply the reason, but-again-I see a conversion. I see that the nutritional aspect of medicine is gaining impact nowadays. JB:     There are obviously myriad questions we would love to explore with you, but because of the limited time I will just ask one last question. You are speaking now, principally, to professionals who are dealing with patients everyday and are making decisions or helping those patients to make decisions about their life. If you were to send a message to them from your 40+ years of experience, what would you like them to know in terms of takeaway? JD:     That the Western diet has been unbalanced with respect to the 2 components of essential fatty acids essential in our diet. This has been in favor of the omega-6. Besides many other things to consider in nutritional learning (to keep a good body weight, to refrain from drinking too much alcohol, to refrain from smoking, and to keep our physical exercise up), you should also be aware that you should increase your intake of omega-3 fatty acids. JB:     Dr. Dyerberg, I want to thank you both for this time and for the 40 years of hard work and diligence in helping us to understand this very important concept. JD:     Thank you. It has been my pleasure to be here in your lovely city. What was your takeaway from this extraordinary discussion of Dr. Dyerberg’s discovery with Dr. Bang? Of this Eskimo connection with low cardiovascular disease to their dietary omega-3 lipid intake? My takeaway is that this is a dramatic example of the power of nutrigenomics-a new model that is emerging in medicine that will frame a new therapeutic paradigm as we move into the remainder of this 21 st century. There is a dynamic two-way interaction between nutrition and the human genome. This interaction determines genetic expression and the metabolic response ultimately affecting an individual’s health status. These molecules that are found in diet have been sieved and screened through the laboratory of natural selection over millennia. What Dr. Dyerberg really recognized in this study was that the diets of these Greenland Eskimos that contained these high levels of omega-3 fatty acids were somehow speaking to their genes in such a way as to create an outcome called lowered cardiovascular incidence. They, in part, were genetic expression modulators. Since the 1960s, considerable work has mounted concerning this concept of dietary lipids and gene expression. One recent paper that speaks to this, demonstrating how the field is advancing, appeared in the Proceedings of theNational Academy of Sciences. It is a very interesting paper that describes how omega-3 fatty acid, docosahexaenoic acid (DHA), attenuates endothelial cyclooxygenase-2 induction through modulation of kinases-these signaling pathways that control gene expression, in this case Protein Kinase C Epsilon (PKCe ).26 You’ll notice I’ve just gone back 180° to pick up what we were talking about earlier in this issue of Functional Medicine Update. Our diet contains constituents that speak to our genes in such a way as to regulate function through intercellular signal transduction. This process is mediated through the cell by way of these relay-race runners we call kinases. By modulating the kinases through receptors that sit on the surface of cells that pick up the information from our diet and lifestyle, it then causes the genes to read different chapters in the book of life, different stories. In this case, omega-3 DHA causes the cells that are inflammatory in nature to read a story called anti-inflammation by upregulating the synthesis of cyclooxygenase-2. So I think we are starting to see some very interesting underlying mechanisms put to the long-respected association between certain dietary principles and lowered incidence of chronic disease, making these seem as molecules of tremendous potential (both safety and effectiveness) in modulating function over years of living. This concept that nutrition is a key environmental factor in the pathogenesis and progression of diet-related diseases takes us beyond nutrigenomics into this whole concept of cellular signaling. We said earlier that the type 2 diabetes, or obesity, or heart disease condition is preceded by altered cellular signaling that occurs years-maybe even decades-before an individual actually gets the disease and is diagnosed (and then given a drug as a prescription). In an article that is titled, “Dietary Lipids and Gene Expression” (this appeared in Biochemical SocietyTransactions), the authors describe how modulation of proinflammatory signals occurs by eating molecules in our diet that signal anti-inflammatory processes. 27 Another example of this that you may be familiar with is the mounting evidence that vitamin D is more than just a bone vitamin; it is an environmental factor influencing the whole of the immune system, including the effects on inflammation and autoimmune disease prevalence. In a recent issue of Experimental Biology in Medicine, the authors of a review discuss the increasing evidence pointing to a link between vitamin D and autoimmunity, with increased vitamin D intakes decreasing the incidence and severity of autoimmune disease. 28 In fact, we recognize that this particular association has to do with the increasing level (or activity) of 1,25-dihydroxyvitamin D3 (or cholecalciferol), the hormonal form of vitamin D in the blood, which is produced from 25-hydroxyvitamin D, and that is what we should be measuring in the blood of patients to maintain (or assess) the level of sufficiency of vitamin D. We would like that 25-hydroxy level in the blood (25-hydroxyvitamin D3) to be at a level that is considered ideal or optimal, which is in the area of 80-120 nmol/L. If you are doing a vitamin D assessment in your patient, you would like the level to be between 80 and 120 nmol/L. To give you an idea of what that means, if your lab is reporting the data in nanograms per milliliter, that is 32-48 ng/mL is that equivalency (of 80-120 nmol/L). We like to think of getting our patients up around 50 ng/mL of their vitamin D hormonal 25-hydroxy form. You can do that by both administering higher levels of vitamin D and following their 25-hydroxy serum level, and also give them simultaneously the soy isoflavone, genistein. Now why is that important? Because it appears that genistein upregulates the enzyme that is responsible in the gut mucosa for producing 25-hydroxyvitamin D, and it downregulates the expression of the enzyme that is responsible for detoxifying (or metabolizing) the 25-hydroxy D. So if you want to increase your 25-hydroxy D metabolism, the combination of genistein plus vitamin D can be helpful. This comes from a recent paper in the Journal of Nutrition (a supplement edition).29 This may, in part, explain why women who ate a traditional oriental diet didn’t have high levels of bone loss and osteoporosis until they started eating a more Westernized diet. Although they got low calcium (they weren’t dairy-product consumers, but they got adequate calcium), they got high vitamin D from fish and high soy isoflavones that activated calcium-binding protein and the effect 1,25-dihydroxyvitamin D3 has as an anti-inflammatory (reducing inflammatory signaling on the bone remodeling unit-the osteoclast). Vitamin D Status and Colon Cancer We also recognize that 25-hydroxy D is important as expressed in human vascular smooth muscle cells. It is very important in maintaining proper anti-inflammatory activity in the vascular wall and is also activated by the presence of genistein. We know that same thing holds true in colon cancer cells. In fact, statistical evidence suggests that one of the major risk factor reductions can occur in colon cancer by improving vitamin D status. I’m now quoting from a recent paper that appeared in the Journal of Endocrinology in 2006 that talks about the fact that genistein, as a phytoestrogen, regulates transcription and translation of vitamin D receptor and lowers colon cancer incidence. 30 In fact in a more recent paper in the Journal of Nutrition, talked about nutrients that regulate colonic vitamin D system and the relevance for human colonic malignancy, and how the proper vitamin D nutriture and epigenetic control of the hydroxylase enzyme, by having adequate soy isoflavone genistein present, can lower the relative risk of colon cancer. 31 Vitamin D Status and Prostate Cancer In addition, in a Molecular and Cellular Endocrinology paper, authors showed that genistein potentiates the growth inhibitory effects of 1,25-dihydroxy D3 in human prostate cancer cells, and, therefore, it is not just vascular endothelium and it is not just colonic cells, it is also prostate cells that all seem to really benefit from proper vitamin D hormonal signaling. 32 And then, of course, a more recent paper than these appeared in the latter portion of December 2006 in the Journal of the American Medical Association titled, “Serum 25-Hydroxyvitamin D Levels and the Risk of Multiple Sclerosis.” 33 This article describes a prospective, nested, case-controlled study among more than 7 million US military personnel who had serum samples stored in the Department of Defense Serum Repository. The authors examined whether there was an association between multiple sclerosis cases identified through Army and Navy disability databases from 1992 through 2004 and vitamin D serum 25-hydroxy levels. What they found was that the results of the study suggest a high circulating level of vitamin D as 25-hydroxyvitamin D was associated with a lowered risk of multiple sclerosis, a neurological inflammatory disorder. You’ll notice there is a theme-about signaling molecules that are present in the diet that have been sieved through natural selection over years of living. In the pharmaceutical world, what we are starting to see is an attempt to try to find molecules that will alter these fundamental cell signaling hubs that regulate gene expression, inflammation, and the risk to chronic diseases. A review appeared in Nature Reviews in 2006 that I think is quite profound (related to this association) was titled, “PI3Kg Inhibition: Towards an ‘Aspirin of the 21 st Century?’” 34 What the authors talk about is that these PI3Kg inhibitors are promising drug targets for the management of inflammatory disease. If you actually page through this article, you’ll find a magnificent diagram that describes how many different disorders are associated with altered PI3Kg activity-things such as sepsis, cutaneous and systemic anaphylaxis, allergy, chronic obstructive pulmonary disorders, stress remodeling and heart failure, thromboembolism, and lymphocyte chemotaxis abilities related to immune dysfunctions. All of these have something to do with inflammatory relationships and diseases like systemic lupus erythematosus, atherosclerosis, pancreatitis, asthma, allergy disease, hypertension, multiple sclerosis, and chronic obstructive pulmonary disease. All of those are associated with dysfunctions of the signaling pathways of PI3Kg , so the pharmaceutical industry is out searching for new-to-nature molecules that can modulate the cell signaling across this range of clinical applications. When we have screened constituents from nature foods, we have found there are many natural PI3K g inhibitors (or modulators). We call them selective kinase response modulators that can (and have, historically) done this by the consumption of diets that are rich in phytochemicals. So, we ask, where are the best molecules for the management of chronic problems, before they become acute? Could it be that we have taken these things out of our diets and lifestyles and added, in their place, things that stimulate altered kinase signaling to produce the trajectory toward the pathologies we see? Before you step across the street, and the sign says “Walk,” let’s make sure we know where we are walking. Indole-3-Carbinol (I3C) and Diindolylmethane (DIM) Going back, if we could, to hormonal effects in menopause, this raises the question, doesn’t it, about the brassica vegetables or the cruciferous vegetable glucosinolates? One of those glucosinolates that alters cellular signaling is called indole-3-carbinol (I3C) and there have been some very interesting questions as to whether I3C can reduce changes in cervical intraepithelial in situ neoplasia. It could be that extrapolates to other food components that modify cellular signaling. There was an article published recently in the Journal of Nutrition in 2006 in which the author, Karen Auborn, talks about how I3C and its congener, diindolylmethane (DIM), derived from cruciferous vegetables, help modulate insulin metabolism and insulin signaling by reducing both the 16-hydroxyestrogens and other proinflammatory estrogens, including the 4-hydroxy, at the expense of making more of the 2-hydroxyestrogens, which are antimitotic and not proinflammatory. 35 By eating more cruciferous vegetables, women can modify their hormonal metabolism. Maybe some of the problems women have with estrogen is not estradiol, estrone, or estriol, but is related to these altered estrogen metabolites-these hydroxylated estrogens (the 16- and the 4-hydroxyestrogens). Maybe these problems can be reduced in their severity and concern by consuming indole-3-carbinol or diindolylmethane. This same argument, by the way, would hold true for males with prostate-related problems. There is emerging evidence to suggest that some prostate difficulties are associated with altered estrogen metabolism in males, as are breast problems associated with altered estrogen metabolism in females. In an interesting paper that appeared in Integrative Cancer Therapies titled, “Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy,” the authors talk about these kinase regulators that are found in foods, like the glucosinolates. 36 These kinase regulators can modulate multiple kinase pathways that send appropriate signals to the genes that downregulate mitotic effects, cell cycling, cause DNA repair mechanisms to be enhanced, produce antioxidant effects that lower DNA damage, itself, and improve metabolism of hormonal messengers that cause cellular division. You’ll notice we are seeing a change in our thinking of one molecule at a time for one condition (which has been the nature of pharmacology) to multiple molecules to modulate complex pathways that then regulate cellular signaling and ultimately gene expression and cellular function. We have been controlled this way, historically, by way of the diets we have eaten. Foods contain complex ingredients that modulate these functions, no one of which works as a drug that powerfully, but together, they synergistically function by modulating these hub-like signaling pathways that we call kinases. I think it is a dramatic change in our thinking. When we look at the whole story of hormonal effects and with the ever-increasing number of postmenopausal women, we are seeing more and more the question as to what hormones to replace. What should I be using? Bi-Est? Or should I be using Tri-Est, or transdermal estradiol, or testosterone and progesterone replacement therapy (these are the bioidentical hormone replacement therapeutics)? Each of those has a role in the medicine of our future, but before we go there, there is this whole question as to how diet and lifestyle modulates the hormonal production, metabolism, receptor sensitivity, and ultimately cellular signaling. I believe that as we gain more insight into this topic, we are starting to see that the first stage of intervention should be that of modifying diet and lifestyle, because across every one of these chronic diseases, when put head-to-head against drugs or other therapies, these have proven to be more safe and more effective in modulating these chronic, early-stage problems that we associate with age-related diseases. I think this is the emergence of an amazing new chapter in pharmacology. Rather than just looking for molecules that block one endpoint and create, then, a single variable outcome, we are looking for complex arrays of molecules that hit (much more gently) multiple pathways, manipulating their function, and creating a stability or a modulation of gene expression that then normalizes their function. The analogy I often think of is the difference between monoculture, as a form of agriculture, and the complex rainforest. In monoculture, which is basically one crop over tens of thousands of acres, one bug, one blight, or one drought can jeopardize the whole of your ecosystem. You have to constantly shore it up with fertilizers, biocides, pesticides, herbicides-all sorts of things-to keep that crop stable. In the rainforest, which is very diverse, with multiple pathways going on all the time and multiple species, what you have is a stabilization of function. If one species is under jeopardy, others can take its place. There are many different tributaries for function to maintain stability. And that is the way we have evolved (our physiology) over time: multiple pathways, each one contributing a little to the overall symbiotic/synergistic balance, and the diets we have eaten are complex molecules that speak to those processes to lead normalization of function against the changing environment. I hope as we close this issue of Functional Medicine Update and we consider the wonderful comments of Dr. Dyerberg, we see that we are witnessing a change in the direction, the path, and the future of medicine. And as the “Walk” light comes on and we start across the street, having looked both ways, I think we’ll find that the landscape on the other side of the street will be very different, leading to a much more effective and safe form of therapy for chronic, age-related diseases. Thank you very much. We’ll look forward to visiting with you in April.

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Welcome to the April 2007 edition of Functional Medicine Update. In this edition we are going to focus on what truly is a functional medicine concern, chronic fatigue syndrome. We have discussed chronic fatigue syndrome throughout the last 15 years of Functional Medicine Update with some of the world’s leaders in this area, and we have attempted to try to find out more about the emerging understanding of the etiology and treatment options for this very complex energy-deficit-related family of disorders. Only recently, have we started to see meta-analysis studies done and various clinical randomized trials published that have helped us to understand that chronic fatigue syndrome is not a disease, per se, but rather it is a complex condition-a state of energy deficit-that ranges with differing degrees of severity, duration, and frequency from patient to patient. It should not be thought of as a single entity, but rather as a kind of resting place for a series of multiple etiologies that contribute (in the outcome of that patient) what appear to be immunological deficiencies or dysfunctions, alterations in the hypothalamus-pituitary-adrenal/thyroid axis, changes in musculoskeletal function, changes in cardiac function, and a general alteration in the systemic ways that the web of physiological function is balanced. It is this complexity that makes chronic fatigue syndrome (or “syndromes” probably would be more be more appropriate) a condition of the 21 st century. To understand the etiology of this condition, one has to look at the interface between genes, environment, lifestyle, and diet, and through that we will better understand both where it has come from and possibly what to do. Each patient will undoubtedly require some form of personalized therapy based upon his or her own unique manifestation of the condition. This sounds like a systems approach to patient-centered health care, and of course that is one of the fundamental tenets of the functional medicine discipline. Functional medicine is built around the precept of web-like interaction-what we call homeodynamic interaction-among different parts that give rise to what we call our function. Recently in the Journal of the American Medical Association there was an editorial titled “A Systems Approach to Patient-Centered Care.”1 In this particular editorial, the authors outlined some of the tenets they felt are required to deliver a systems-related, patient-centered care system. The criteria described in this article sounded very reminiscent of many topics we have been discussing in Functional Medicine Update for 20-plus years. The authors suggest the necessity of redesigning the system to include better access and continuity of patients to the healthcare system in continuity within their own patient management needs; the need to find ways of keeping patients involved, engaged, and committed to long-term therapies that are associated with the remediation of chronic disease; and the need for increasing opportunities for patients to participate in their own care process. When a patient is a participant in his or her own process, he or she starts owning their condition to a greater extent. He or she invests energy into his or her own care and recovery then gets seen as a positive healing force. This is obviously a very important part of the functional medicine model: with patient-centered care, you try to engage the patient in his or her own natural process of recovery and healing. Tools for Patients with Chronic Disease The authors suggest that tools to facilitate setting an agenda for patients with chronic disease help patients become more active, especially those who present without having new complaints. Agenda cards have been used in Europe as an application of how a patient can denote where they started and track their performance over time. This provides a positive feedback process to show patients they are making progress against what might be considered a long-term chronic disability or dysfunction. The cards can contain statements of improvement to help a patient remember where he or she started. Often over a course of therapy that may require months of intervention, patients can forget how bad they felt when they started treatment, and they are just still focusing on the one or two symptoms that are nagging, forgetting that they’ve taken out multiple tacks and they only have but one tack next. (This is Dr. Sidney Baker’s Tack Rule: If you sit on two tacks, taking one tack out does not reduce the pain by 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}.) We have to start looking at ways of managing expectations in these patients and helping them to chart their own process toward recovery and getting them involved in their own healing process. Self-Management Support for Patients The third area that is discussed in this article is to provide self-management support so that the patient actually understands their therapy and there are things that they can do, rather than taking a new-to-nature molecule that they don’t really understand how it works in their body and expecting to have a miraculous recovery. We are teaching them how to employ things that they can do everyday that they will see the results of-eating, exercising, thinking, breathing, relaxing, and staying away from toxic exposures. All of these things are, I guess, what you would call rules of reasonableness. The patient can actually understand these things and they can become the master of his or her own destiny, or the master of his or her own universe, we might say. Coordination of Patient Care The last point they talk about with this patient-centered systems approach is to coordinate care among different practitioners and to recognize that most patients with chronic illness have distributive problems that require distributive systems. No one practitioner is a master of all therapies that are necessary for that patient, so coordinating the best treatment program for each patient may require multiple practitioners with different expertise. In concluding this article the authors state, “…ensuring open access to and continuity with clinicians, improving opportunities for patients and families to participate in their care process, providing active self-management support, and coordinating care among settings are among the basic system redesign components that can result in an optimal care environment from the patient’s point of view, as well as that of the clinician’s.” Of course, those are all tenets the functional medicine model has been championing for some time. The question is: How do you bring into this model the most recent discoveries? We are going through an epic period of discovery right now at the basic sciences, the biological sciences, and the clinical sciences level. Many things are happening everyday that may have tremendous impact on improving patient outcome in the areas of certain chronic diseases. How do we translate these discoveries that are occurring in clinics and laboratories into effective patient-management programs without waiting 2 decades for them to filter through a cumbersome process of screening and being written into textbooks and ultimately become a standard of practice? And how do we, then, make sure that we don’t move things too quickly and prematurely into clinical practice, before they have been adequately demonstrated to be safe as well as effective? These are really questions that are at the forefront of what has been called “translational medicine.” Translational medicine is taking the systems biology approach to medicine and translating new discoveries into clinical applications. There are now whole institutes of translational medicine being built. Pennsylvania has the Institute for Translational Medicine and Therapeutics (ITMAT), just recently opened at the University of Pennsylvania School of Medicine. Trying to get things more rapidly into clinical practice is a trend we are now seeing that could facilitate improved patient outcomes. NIH has invested roughly 70 million dollars in the clinical translational medicine approach and trying to find ways to take new concepts and get them more quickly and effectively into integrative practice.2 ,3 A question I was recently asked by one of our FMU listeners is an example of this desire for the integration of new concepts. The question (paraphrased) is, “How long is it going to take for medicine to recognize there is something about vitamin D status and multiple sclerosis that should be put into clinical practice?” Of course, that is part of the whole new discovery frontier related to the role that vitamin D has beyond that of just a bone hormone (or a bone vitamin), where we are now recognizing it has complex and very important influences upon the neuroendocrine immune system function. One might ask, “We’ve heard about this work that has been done on vitamin D and its relationship to multiple sclerosis. We had a major presentation at one of our recent Symposia for the Institute for Functional Medicine about this. Why is it taking so long to get it into practice?” Fortunately, we are seeing translational medicine start to accelerate the process to some degree. I was very pleased to see an article in the Journal of the American Medical Association titled “Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis.”4 This article discussed the results of a study suggesting that high-circulating levels of 25-hydroxyvitamin D are associated with a lower risk of multiple sclerosis. This is in a case-controlled study protocol, again looking at serum levels of 25-hydroxyvitamin D as the assessment tool. They broke this down to the higher quintiles of 25-hydroxyvitamin D (which is greater than 99 nmol/L), and they found that these had a very significantly lower incidence (in fact, for whites, a 41{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction in multiple sclerosis incidence for every increase of 50 nmol/L vitamin D). There does seem to be an emerging translation of this observation that we heard about some 8 to 10 years ago into more prominent clinical understanding. But there is still so much that is happening on the frontier of basic discoveries and clinical discoveries, and it takes so long to get it into the limelight and be up on the platform of understanding by the clinicians. There is a need for this translation trend to occur and to accelerate. We are starting to see some fundamental new discoveries around chronic fatigue syndrome that may allow for better patient intervention and more successful outcome. In this issue ofFunctional Medicine Update we are going to be exposed to one of these interesting new observations and developments through the eyes, ears, and brain of one of our great conceptualizers in the field of chronic fatigue syndrome and functional medicine, Dr. Paul Cheney, who you will hear from later. Before we get to Dr. Cheney, however, let’s do a quick review of what is known about chronic fatigue syndrome in early 2007. Recently in the Journal of the American Medical Association , there was a summary/quick editorial comment about chronic fatigue syndrome answers being sought.5 It says what I think most of us recognize: for 20 years, we have been trying to understand better this clinical entity, chronic fatigue syndrome, but it still remains a very puzzling condition. Dr. Julie Gerberding, the Director for the Centers for Disease Control and Prevention (CDC), says, “Sometimes people question if Chronic Fatigue Syndrome is real or not real.” In addition to demonstrating that this illness is real, researchers are now uncovering potential triggers and treatments. That is where we are going to be focusing the energy and emphasis in this issue of Functional Medicine Update. Data from the Wichita Chronic Fatigue Syndrome Surveillance Study Some information has emerged from the Wichita Chronic Fatigue Syndrome Surveillance Study, which was launched by the CDC researchers in 1997. Investigators collected information on 90,000 individuals in Wichita, Kansas and conducted extensive clinical assessments of about 7000. The group found that the age that was most affected include individuals between 40 and 59 years, that an incidence of about 373 per 100,000 women are affected (which is about 4 times the rate found in men, by the way, so there seems to be a higher prevalence in women, reminiscent of what we also see as the difference between genders in the prevalence of autoimmune diseases; maybe it is coincidental, but it is certainly an interesting observation), and that the prevalence was even higher in non-white women (they are affected more than white women at a rate of 495 per 100,000 as compared to 352 per 100,000). This was published by Reyes et al. in the Archives of Internal Medicine.6 Monitoring patients with chronic fatigue syndrome in Wichita revealed that the disease may be associated with both genetic and environmental determinants, which is the way we have been describing this condition for the last 15 years on Functional Medicine Update . Efforts to decipher the causes have found that many cases may be linked to stress and childhood trauma. In a case-controlled study of 43 adults with chronic fatigue syndrome and 60 non-fatigue controls, it was found that exposure to childhood trauma was associated with a 3- to 8-fold increased risk for chronic fatigue syndrome across different trauma types, including emotional, physical, and sexual abuse, and physical neglect. This data was published in the Archives of General Psychiatry in 2006.7 The authors of this article suggest that studies analyzing the psychological and neurobiological mechanisms that link childhood adversity to chronic fatigue syndrome risk may provide targets for prevention.Once again we are reminded (in a chronic fatigue example) of the functional medicine model. In the functional medicine model, the environment (the psychosocial/emotional environment) in which each individual is bathing his or her genes with experiences is represented by the embedded roots of a tree. Being impoverished, as we have learned, is more than just being deficient of having money. Being impoverished means having no attribution, no love, no support, feeling at risk or not at home-all of these things have direct effects upon gene expression patterns and ultimate physiological function. We are starting to recognize that there is at least some correlation between psychographic patterns, emotional patterns, experiences in life, and chronic fatigue syndrome. Recently published results from a prospective case-controlled study found that higher emotional instability and self-reported stress were reported to be a very significant risk factor for chronic fatigue syndrome. This was also in Archives of General Psychiatry in 2006.8“There are now over 4000 published studies that show that there are underlying biological abnormalities in patients with chronic fatigue syndrome.” This is a direct quote from a recent presentation that Dr. Anthony Komaroff of Harvard Medical School made on chronic fatigue syndrome. He was actually interviewed about his understanding of chronic fatigue syndrome in Functional Medicine Update (he was in our September 2003 edition). What we are starting to witness the understanding that this is a multiple-etiology condition with multiple biological mechanisms that are ongoing, and we shouldn’t look at it as a single disease caused by a single agent. Among the suspected causes are mechanisms that relate to impairments in metabolism and dysfunction of the immune and nervous system. These are things we’ll be talking about in greater detail with Dr. Cheney. A Comprehensive Meta-Analysis of Treatment Approaches to Chronic Fatigue Syndrome If we were to summarize all interventions for the treatment, management, and rehabilitation of patients with chronic fatigue syndrome and do kind of an updated systematic review, what would it tell us? I have the benefit of being able to borrow from a very nice paper that was recently published in the Journal of the Royal Society of Medicine.9 The authors have done an elegant job in reviewing and grading the quality of the research on all the chronic fatigue randomized controlled trials (RCTs) that have been published to date. This is a very nicely done paper that gives a wealth of very good “news to use,” as it relates to what is known in the literature about successful interventions for chronic fatigue syndrome. The first thing that can be said (in looking at the tables that are provided in this paper) is that most of the pharmacological interventions that have been used have not been successful. In fact, when the researchers grade the validity scores of these various studies, these pharmacological intervention trials mostly have very low-graded scores (meaning they didn’t really work much better than placebo). Many different drugst have been attempted, including SSRIs, corticosteroids, anti-virals, and immunologically active agents. The quality of the research outcomes related to these drugs are marginal at best, I think we can say. There are some modalities, however, that seem to suggestd improvement after therapy (against placebo). The first is cognitive behavioral therapy (CBT). There are multiple studies that seem to all demonstrate improvement. The other is what we would call graded exercise therapy. There are five RCTs that concluded that graded exercise therapy is a promising intervention. Those, along with the three relevant randomized control trials on cognitive behavioral therapy, appear to be the best clinical outcome studies that have been published to date with regard to chronic fatigue syndrome. You’ll notice that we are dealing with elements that modify the psychosocial and psychological environment of the patient, as well as try to improve exercise tolerance, which has something to do with energy dynamics in the individual. We’ll come back and talk with Dr. Cheney a little bit about these two suggested positive therapies. The next therapy that rose up in the meta-analysis — which reviewed about 10,768 publications published on interventions surrounding chronic fatigue syndrome (that was the number of papers reviewed for this meta-analysis) and selected 70 that met the selection criteria –, was the use of inosine pranobex. A couple of clinical trials seem to demonstrate improvement in patients with the use of inosine pranobex, although there were side effects with this treatment. Inosine is an orthomolecular material that tends to improve cardiac function. We’ll also talk a little with Dr. Cheney about this. Other papers (2) describe some positive benefit using hydrocortisone given at fairly low dose (these are physiological doses of hydrocortisone). This is very reminiscent of what Dr. Mck. Jeffries talked about in his book, Safe Uses of Cortisol , many years ago. Two other reports talked about DHEA. Those appear to be of marginal clinical significance. One study was in women who had low libidos, low sense of well-being, and fatigue-related symptoms. DHEA supplementation at 30 mg/d had some improved outcome versus placebo. Another series of trials that looked encouraging were related to homeopathic preparations (there is some suggestion that certain homeopathics might have benefit in this condition, as well ascetyl-L-carnitine and propionyl-L-carnitine, which have shown some positive effect given at the doses of 1000 or so mg/d. Finally (probably rising up to a higher level of clinical significance relative to the meta-analysis of published studies) there are essential fatty acids in the omega-3 family, and also magnesium (probably essential fatty acids having more clinical validity than does magnesium, but both do have some evidence of clinical value based upon this meta-analysis study). What I have really started to develop here is kind of a multi-focal approach. There is no one magic bullet that is going to lead to complete remediation of chronic fatigue syndrome. At this point, we really don’t have any single therapy you can give all patients with this condition. Determining treatment requires a much more complex review of systems and (I would say) a functional medicine approach (looking at the web and what we call the matrix) to understand how an alteration in a patient’s web of physiological function might result in these energy-deficit-disorder-like symptoms. One of the things that we obviously have heard much about over the years related to chronic fatigue syndrome is that it has an infection-related component. It could be a viral infection, or it could be some kind of a stealth organism. There is now some evidence suggesting that there are very small vectors that are associated with Lyme disease that can actually be found inside mitochondria and may “infect” mitochondria. This isthe discovery of an Australian postdoctoral candidate, Nate Lo, who was working at the University of Milan.10 He was looking at this whole Lyme disease situation and found what he thought were microbes living inside the mitochondria of patients who had Lyme disease. Now his finding has been confirmed by other investigators. Scott O’Neill, a specialist in invertebrate endosymbiotics and head of the School of Integrative Science at the University of Queensland, said this was a very novel observation and that it was surprising to see a bacterial species living inside the mitochondria, which itself was a bacterium (in its progenitor history), but it looks like it is potentially significant. So, again, we might have some unusual types of organisms that can infect cells at even the subcellular level and can induce, then, mitochondrial disruption, bioenergetic catastrophe, and oxidative stress. We have talked about vectors playing a role, but it is more than just an infectious agent; there are other things going on. These small virus-like subparticles (or bacterial parovirus or infections) don’t explain the whole of chronic fatigue syndrome. It seems to be a multifactoral condition with stress, and the preceding life history of the individual going all the way back to their childhood, and exposure to xenobiotics, and gut dysbiosis, and alterations in hepatic detoxification systems, and alterations in oxidative stress and redox potential-these are all parts of the complexity of this condition. Erythrocyte Metabolism, Oxygen Delivery, and Erythrocyte Shape May be Linked to Chronic Fatigue Syndrome In a recent paper from 2007 in Archives of Medical Research, Ross Richards and his colleagues discuss evidence of oxidative damage that has been observed in the red blood cells of chronic fatigue syndrome patients.11 With reticulocyte alterations, the cells undergo membrane deformation. These authors also reported finding more stomatocytes in the blood of patients with chronic fatigue than expected. These are examples of what happens with oxidative stress. The authors looked at malondialdehyde levels and reduced glutathione levels and correlated that with the alteration in red cell confirmation in patients with chronic fatigue syndrome versus healthy control subjects. They concluded there is a strong likelihood that the increase in erythrocyte alterations is associated with the presence of stomatocytes, and that oxidative free radicals may be implicated in the pathogenesis of chronic fatigue syndrome. Therefore, erythrocyte metabolism, oxygen delivery, and erythrocyte shape are all linked. A deformed erythrocyte can’t deliver as much oxygen. It is less efficient in transporting an essential nutrient (which oxygen is), and it may actually participate then in free radical initiative reactions as a consequence of promiscuous oxygen in various forms such as hydrogen peroxide, singlet oxygen, superoxide, or even hydroxyl radical. We have really talked, here, about oxygen as being implicated somehow-about oxygen not being where it should be at the level it should be to be used effectively for oxidative phosphorylation. This idea brings into play the whole question of mitochondrial medicine. Is there some correlation between a mitochondrial dysfunction and chronic fatigue syndrome? We’ve seen many reports over the years that have implicated (or at least suggested) that. There is a report that appeared in Cell Metabolism in 2006 titled, “Mitochondrial Medicine: A Metabolic Perspective on the Pathology of Oxidative Phosphorylation Disorders.”12 We know in examples of severe inborn errors of mitochondrial function that you have extraordinary muscle-related fatigue problems and cognitive dysfunction. That is the outer edge, probably, of the mitochondria dysfunctions. But what where you get injuries to mitochondrial DNA and you get mitochondrial deletions that are produced not as a consequence of genetic alterations, but induced problems through environmental exposures (these induced OXPHOS disorders)? That is what is discussed in this particular review. How these disorders of mitochondrial function may associate themselves with what we see as fatigue in various tissues and functional alterations in tissues, like cognitive decline, or energy problems, or even resulting in things like a blood sugar abnormality through alterations in adenosine monophosphate kinase, which is coupled with ATP formation in the mitochondria, which can induce, then, a type 2 diabetic-like situation. In chronic fatigue patients you often see abnormal blood sugar regulation, and you see what appears to be metabolic syndrome (even type 2 diabetic-like situations).13 This is a very complex web of distortion that is often present in the patient with chronic fatigue syndrome. It seems to tie together things that relate to environmental exposures, potential infections, alterations of the immune system, and alterations in oxygen delivery and utilization in the cell, which then subsequently ties together with mitochondrial oxidative stress and cellular injury. Trying to find the answer may be less important than trying to find the environment in which function can be reestablished. We have talked about this as being graded (or a sequence of severities). Chronic fatigue syndrome does not present with one type of severity; it can range from fairly mild to life-threatening (in which cardiomyopathy may ultimately be contributing to risk of death). We start to see much more connection between this mitochondrial function, oxygen utilization and oxidative phosphorylation, and how that connects to the neuroendocrineimmune system function and how the environment may contribute to alteration in this functional state. I think it is very important to put into this oversight or review the cognitive behavioral therapy and graded exercise therapy components. In both of these cases, we are dealing with situations that may go way back in the life experience of an individual; back into childhood, or maybe even infancy. Certain situations related to deprivation or impoverishment or poverty (in the broadest sense of the word) has influenced energy transmission systems in such a way as to make them more vulnerable or susceptible to things like environmental exposures, or pathogenic organisms, or gut dysbiosis, or all these other factors that we seem to associate with the spreading effect or the multiple layer effect that we call later chronic fatigue syndrome. Mitochondrial dysfunction and oxidative stress relate to so many different organ- and tissue-specific dysfunctions. We can talk about the sarcomeres and the myocytes related to muscle dysfunction. We can talk about neuronal mitochondrial oxidative dysfunction that relates to neurodegenerative diseases and cognitive dysfunction. We can talk about energy deficit disorders in the beta cells of the pancreas that leads to apoptosis and decline in number, which ultimately is associated with type 2 diabetes. You notice this is a central theme that cuts across many age-related chronic diseases.14,15 Mitochondrial Resuscitation Can you do anything to repair these processes once they are in place? This is what we discussed with Dr. Martin Pall on Functional Medicine Update on two occasions. At Washington State University, Dr. Pall has been looking at these oxidative injuries that are associated with chronic fatigue syndrome and trying to introduce ways of resuscitating proper mitochondrial function (that’s a term that we have actually borrowed from Dr. Paul Cheney, who talked about mitochondrial resuscitation some 15 years ago). If you look at the papers that have been published in this area since Dr. Pall published his papers on oxidative stress, mitochondrial dysfunction, and chronic fatigue syndrome, we see papers like the one that appeared in Free Radical Biology & Medicine in 2005.16 It talks about the role that mitochondrial function decline has in aged animals and that long-term intervention with N-acetylcysteine, N-acetylcarnitine, and Co-enzyme-Q10 had a positive effect on these aging animals to improve mitochondrial function. This is very reminiscent of what Dr. Bruce Ames (who we interviewed on Functional Medicine Update a number of years ago) has been speaking about with his work as well: using N-acetylcarnitine, N-acetylcysteine, and Co-enzyme-Q10 to try to improve oxidative chemistry in the mitochondria, improve redox function, and lower oxidative stress. I don’t think, in and of itself, this intervention is the cure to chronic fatigue syndrome, but it may be part of the puzzle as we try to eliminate those factors that induce oxidative injury and improve intake of those agents that help buttress proper redox control within the mitochondria and oxidative chemistry. As we’ll see from the presentation of Dr. Cheney, this concept has a much broader implication (both anatomically and physiologically) than just looking at the subcellular organelle called the mitochondria. We have to look at the whole of how the body accommodates the alteration and the utilization of oxygen and the delivery of oxygen-how that is seen through the range of symptoms from early-stage fatigue all the way (possibly) up through the most pathological states of chronic fatigue syndrome. With that as a context, what we are really speaking to here is a functional medicine web. It is a web of understanding of agents that might either induce alterations in function or improve function within this neuroendocrineimmune system. We have learned that one thing that could cause dysfunction of energy processing centers (which has been part of our diet for some time) is trans-containing fats. I take some small degree of pleasure in recognizing that we started talking (on Functional Medicine Update ) about the potential concerns about trans fats in our food supply over 20 years ago. It wasn’t considered very fashionable at that point. In fact, there was some criticism that was levied against us for suggesting that this partially hydrogenated vegetable oil material called trans fats had anything other than a nutritional benefit. But over the years, obviously, this has changed its complexion considerably, and there is now the general consensus that excessive intake of trans fats in the diet has a deleterious effect on health. It is starting to be recognized that trans fats may affect not only heart function and mitochondrial function, but also possibly the developing fetus or even conception. It has recently been suggested that trans fats in a woman’s diet may actually have an adverse effect on conception ability. This whole trans fat/conception (or fertility) relationship is recent work; this was a study done by individuals at the Harvard School of Public Health in Boston (Walt Willett’s group). The study looked at 18,555 women trying to conceive and found 438 cases of ovulatory problems. The researchers found that women who took 2{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of their energy intake from trans fats instead of carbohydrates or polyunsaturated fats had a 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} greater risk of infertility through lack of ovulation. Those women whose energy came from trans fats instead of monounsaturated or polyunsaturated fats were twice as likely to have problems as those individuals were eating what we consider a diet low in trans fats. Dr. Jorge Chavarro said, “It’s really a small amount of fats that we observed having a significant effect on infertility.” This finding was the surprise of the study. This paper (published in the American Journal of ClinicalNutrition) suggested that women wanting to conceive should watch their trans fat consumption. Trans fat consumption is also related to the appearance of polycystic ovary syndrome (PCOS) because it has an adverse effect on energy production, insulin stability, and androgen/estrogen balance.17,18 We are starting to witness a redefinition of what might be considered toxic effects. Trans fats would not be a direct toxin to the extent that if you fed them to animals they would have LD50 that would suggest they immediately be removed from the diet, but rather they are modulators of function in such a way as to produce an outcome that we call dysfunction. In this case the dysfunction is an energy deficit in certain tissues that then has significant effects on things like pregnancy. We might consider this a disruptor at some level. We know disruptors are out there in the environment as both symbiotic and xenobiotic materials. We have heard a lot about endocrine disruptors triggering fertility problems in multiple generations and we have often thought of those as being things like fungicides and pesticides, which are known to be toxic to animals. But now there seems to be a darker side, because various chemicals used in agriculture can also cause fertility defects in animals, and these seem to be able to be passed down to subsequent generations by an epigenetic effect. A recent paper appeared in Science Magazine titled, “Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility.”19 This article and others specifically look at male fertility and sperm-related defects that seem to be passed down in subsequent generations.20 We could have xenobiotic (foreign) molecules and also symbiotic molecules (maybe more natural to our food supply). I guess we could argue whether you would call trans fats xenobiotic or not. All of these messages that our body is receiving can modulate our function. You then have varying genotypes that respond to these in differing ways of sensitivity (the “yellow canary syndrome,” as it is said). And then we get these statistical changes in distribution of certain outcomes. In the case of reproductive biology, as I have talked about, a 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} greater risk of infertility through lack of ovulation in women who had higher than 2{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} trans fats in their diet. If we were to start assembling a list of everything known to potentially have an adverse effect upon cellular function that we are exposed to, how long would the list be? That can be a total load effect on the energy processing centers of cells. Now add new organisms, infection, and altered immunological function. From that is born what we call chronic fatigue syndrome. With all of this in mind, I think it sets a very nice stage for taking the next step in our evolution of understanding and that is with Dr. Cheney as our guide. He is a person who has helped us over the last two decades to better understand the complexity of chronic fatigue syndrome and ways that we might throw a net over it so we can actually improve clinical outcome in patients. With that in mind, let’s move to our discussion with Dr. Paul Cheney. The price to download the video without the watermark and use it in your production is 197 euro: Yes I am interested.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Paul Cheney, MD, PhD The Cheney Clinic 1 Vanderbilt Park Drive Asheville, NC 28803 We are very fortunate (to say the least) to have as our clinician/researcher of the month this month, Dr. Paul Cheney. Some of you undoubtedly know the name. He is an icon in the field of functional medicine and in the area of chronic fatigue syndrome research. We actually had the pleasure of first introducing Paul Cheney to the Functional Medicine Update audience in January 1994. I can’t believe that 13 years has gone by. It is stunning to me how fast time travels; it’s a little bit scary and disconcerting. For someone like Dr. Cheney, I guess that’s not too unexpected because he was a nuclear physicist, so he was familiar with the quantum world well before he went to medical school. If you are not familiar with Dr. Cheney, let me introduce him through the writings of Hillary Johnson, who wrote a very interesting book on the history of chronic fatigue syndrome titled Osler’s Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic (it was published in 1996).21 To kind of personalize Dr. Cheney and his background, I want to quote a little bit from a section of Ms. Johnson’s book. The author talks about Incline Village in Nevada, which is a place where Paul and his colleague were practicing a number of years ago. She says, “Neighbors liked to speculate about her financial lineage. A few confused souls were amused by the notion that the heir to the West’s largest raisin dynasty lived among them. To those people she was ‘Mrs. California Raisin.’ To most of the citizens of Incline Village, however, she was just one more rich person who spent her summers in a town on the rim of Lake Tahoe. In truth, she was not the raisin heiress; she was married to a prosperous oilman, and each winter the couple returned to their home in Houston. Her life was one of ease and affluence. When her health began to fail in late August, she went directly to the Cheney-Peterson Medical Office on Alder Street in Incline Village. A number of such folk residing in the mountain hamlet routinely packed their overnight bags when they wanted to see a doctor and headed for the Reno airport an hour away. However much Incline was loaded with wonders of the natural world, it had-for years-been short on doctors, until it had the benefit of getting Dr. Daniel Peterson and Dr. Paul Cheney as the principal physicians serving the community. It was not entirely surprising, then, when her fatigue struck-this intense and sudden fatigue-that the oilman’s wife went directly to the medical offices on Alder Street of Dr. Cheney and Dr. Peterson.” And so it goes on, then, to talk about this remarkable group, and Dr. Cheney, specifically, saying that Dr. Cheney was one of those unusual people who had a penchant to learn and was constantly searching. Dr. Cheney decided to enter medicine when he was already a Duke University-educated PhD in nuclear physics. His conversion from physics to medicine occurred when he realized his entrance into the provocative would be through the latter. “The golden age of physics was the first after the century, said Dr. Cheney. “Medicine is in the second half.” Upon graduation from Emory University’s distinguished medical school, Dr. Cheney formed a general practice. He became, really, one of the first people to make observations of this condition that seemed to follow on from the HIV story in the early 80s, which was to be called chronic fatigue syndrome. Dr. Cheney, today, is in Asheville, North Carolina with the Cheney Clinic, which is specializing in chronic disease care. He has a curriculum vitae that is very long and rich, as you can imagine, with his background and his board certification in internal medicine and his work in immunology at the Centers for Disease Control (CDC). Dr. Cheney has worked extensively in trying to develop methods of understanding of the etiology of chronic fatigue syndrome and has probably seen more chronic fatigue syndrome patients than any other practitioner (I would say) living. He has patients from over 48 states and 20 foreign countries, and has done extensive research in the area going back into the late 80s, early 90s. It is with a great amount of pride that we welcome you once again, Paul, to Functional Medicine Update . I think it is quite timely now (13 years down the road since our last visit with you) to do a check-in because you have gone through a very interesting evolution and refinement of your own thought about this condition that we know to be very complex for which the CDC says there is no known (yet) unequivocal origin or etiology. I think these most recent discoveries that you have made and observations that you are bringing to the attention of the medical world put this whole condition into a slightly different framework. So, once again, Paul, thanks for being with us and welcome to FunctionalMedicine Update in 2007. PC: Thank you, Jeff. JB: Let me, if I can, start with your story, because as we were talking about it not too long ago, your story (since we last visited) has been very dramatic and (I think) almost paradigmatic in terms of the discoveries you have made. I’d like you to tell your story, as you see it-where you’ve come in your knowledge since 1994. A Community Outbreak of CFS in 1985 PC: Well, of course, everything has a beginning. My beginning with this was the witnessing of the epidemic in a small community on the north shore of Lake Tahoe in 1985 (actually it was the late fall of ’84, but it peaked in May of ’85). That was an epiphany for me. I had never seen an epidemic like that before, of middle-aged adults (average age 38) coming down with a mononucleosis-like illness and then failing to recover from it. It is unusual to see epidemics in adults of mono. It seemed like mono, but yet, it had certain features about it that appeared later that made me wonder whether it was or wasn’t. Having witnessed that epidemic, I was always impressed that this disease had a (usually-in stories that people tell you) defined onset, usually with a viral-like onset. Mono is not the only type of viral onset. There are also other types of flu-like or even encephalitic-like onsets. Then there is a certain population that do not have abrupt onset. That was sort of the beginning of it and from there I (as most people would) began to look at what I would call the microbial onset (or causality) of this disease. Looking for Causality It seemed (in the beginning) that that might bear fruit. Responses, for example, to IV acyclovir that we were seeing clinically, and other features of laboratory testing strongly suggested some sort of viral etiology. But, unfortunately, it appeared more and more over time that although viral onset might be important, it was not the center of gravity of this illness. And so then I evolved sort of an epiphany (in the mid-90s) where I began to look further a field from a sort of single-agent cause. Maybe it’s some sort of process that is a trigger in some way. And we began looking at the immune system. We began looking at the GI tract, which seemed to be potentially involved in this illness in terms of xenobiotic stress and distress. And we began looking at nutritional approaches and broader methodologies of dealing with chronic complex illness. And that’s when I met you and met the functional medicine movement, and I really got attracted by that conceptual framework of complex chronic disease and how it might be addressed. From there, however, after many years of working in nutritional aspects of this illness and gut management and so forth, I was still puzzled by the refractory nature of this disease and how well some people respond (most people didn’t, or if they responded, they may not respond for long). I began to evolve into the idea that maybe there was a deep-seated energy problem somewhere at the cell level, and although it was difficult to find out, exactly, the locust of control of that defect, it seemed to be what I would call “Rome.” (All roads led to it, and maybe there were many roads. And many roads led from it.) But somewhere in this disease there had to be a locust of control-some core problem that everybody had. You could get there for different reasons and you could emanate from there with different complications, but there would be a core. A Personal Illness Leads to Considerations of Low Cardiac Output It was at that time-at that moment, when I began to think about that-that I became ill myself with an abrupt onset of what would be called an idiopathic cardiomyopathy (following a mercury removal, interestingly, from my teeth, combined with a viral infection in the fall of 2000). By 2001, I was in congestive heart failure. Through a steady decline of approximately 3 years, I began to sort of slowly exit out, functionally, from medicine, until my transplant occurred in October of ’03. On return to practice in July of ’04, someone handed me a paper across the table. It was written by Natelson and Peckerman and published. It showed that about 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of chronic fatigue syndrome patients had low cardiac output. I, of course, was intimately familiar with what happens and how you feel and body system issues related to cardiac output. I had just gone through it in spades and knew all about it. I began to reflect on the fact that many of my symptoms of low cardiac output including gastrointestinal disturbances, inability to eat, food intolerances, xenobiotic stress, chemical sensitivities, and drug sensitivities actually could be explained by low cardiac output state. I began to wonder how this might be related to chronic fatigue syndrome, because until that moment, I had never thought of this disease as a low cardiac output state. I did not understand how that might be, in fact, related to energy, anyway. At that moment, I decided to recapitulate Peckerman’s article. I obtained a research-grade impedance cardiograph machine and began to do studies.-Indeed, Peckerman is absolutely correct, except in my patient population, 82{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} had low cardiac output compared to control groups, as opposed to their 48{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. That is merely reflective of the fact that we have a sicker patient population. Diastolic Dysfunction a Common Thread among Study Patients I was puzzled, though. If they had a low cardiac output, why didn’t they end up like I did? Why did they seem to not go on to death, or even (as far as we know) have any abnormalities on echocardiography (such as I did)? I picked out those with the lowest cardiac output on impedance and had about 5 or them echoed all in a row, in different parts of the country, and received the echo reports all about the same time. They all said, essentially, “Normal ejection fraction, normal chamber size, normal wall thickness, no valvular problems. But it mentioned a phrase at the bottom: “There is type 1 diastolic dysfunction.” It was present on all of these people. I was sort of struck by that. Partly, I didn’t know what that meant-“diastolic dysfunction.” I called up a cardiology friend and said, “What does that mean?” He said it is a problem you can see in aging; you can see it in hypertension; and you can see it in diabetes (where the wall compliance is affected). But (he said) the underlying mechanism involved in diastology is an energy problem. I asked him to repeat that because I wanted to make sure I heard him. He said, “Yes, diastolic dysfunction is what the heart looks like when it does not have energy at the cell level.” I said, “Well, I’ll be damned.” Expanded Studies on CFS Patients I began a journey that started, next, with the acquisition of a high-technology echocardiograph machine made by General Electric, and began to look at over 100 consecutive patients. Depending on how you define “diastolic dysfunction” (there are different definitions in different hands), the range of diastolic dysfunction ranges from 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} (on the low end, if you have a more strict criteria) up to 97{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} (if you use a less strict criteria). So, indeed, these patients do have diastolic dysfunction. It characterizes their disease. And diastolic dysfunction is not necessarily an “old person’s” disease. These patients are not hypertensive, nor are they diabetic, therefore the only reasonable explanation for their diastology is that they have an underlying energy defect. I began to investigate the different parameters of echocardiography that lends itself to understanding energy. There are several parameters measured in milliseconds, or ratios that are very energy-sensitive. And if you look at these parameters, they are very strikingly abnormal. It is very suggestive (in my opinion) of a deep-seated energy defect expressing itself in the heart. When you have diastolic dysfunction, of course, you fail to fill properly. And a pump is a pump is a pump. A pump has two functions: to receive blood, from which it then pumps. There may be pump failure, or there could be a filling failure (you can’t pump out what you don’t fill with). And the heart is no different; if there is a failure to fill, there will be consequences, in terms of output. What has been intriguing to me, in this long journey, is that the human physiological response to a lack of filling is to squeeze harder and to squeeze faster. Therefore, there are a lot of interesting things on the echo that suggest to me that a lot of these patients are compensating for this filling problem by hyperadrenergic tone, both by chronotropy and inotropy, driven (probably) by the adrenergic system, including the contents of the vasomotor center in the brain, primarily norepinephrine, but also supplemented by the adrenal glands, including epinephrine and norepinephrine, and perhaps cortisol. And so a model began to arise of a deep-seated energy problem, reflecting itself (partially, but not exclusively) in the heart, and that that defect is compensated for, in human physiology, by hyperadrenergenic tone, and as long as that is satisfactory, you may not even experience low cardiac output symptomatology. But when you see hyperadrenergic failure or exhaustion, which will obviously come to most in time, at least, then you will express the problems related to low cardiac output. That can begin to generate many of the symptoms we see in this illness. The next problem that I faced was (after identifying the energy problem) determining where the locust of control was, exactly. And I cannot, Jeff, exactly tell you-I guess it is my non-linear thinking; I don’t know how this came to me; it probably came to me by just holding several ideas that were not linearly connected all at the same time and deducing that maybe something could explain all of this. I noticed there was a defect on echo when these patients are tilted into the upright position, they cavitate their left atrium. I also noted that they had elevated pulmonary pressures by measurement of the tricuspid regurgitant pulmonary gradient, which is an indirect measure of pulmonary pressure (they had elevated pulmonary pressure in about 15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}), and about 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} had left atrial cavitation. Physiological Evidence of a Lack of Oxygen I was fumbling through Google search engines, and found that left atrial cavitation is a feature of high altitude climbing. It is found in people in hypobaric oxygen chamber in which they are echoed. They show that the higher the altitude, the greater the degree of left atrial cavitation, and the greater the degree of pulmonary pressure elevation, suggesting that high altitudes produced effects on echo reminiscent of what I was seeing in chronic fatigue syndrome. That gave me the first clue that maybe this may have something to do with oxygen (or the lack of it). At the same time, I also was intrigued by an article I read about the contraindication to neurosurgery if you have a patent foramen ovale (PFO). Neurosurgery is often done with the head-up/body-down position, so the surgeons can gain access to the brain, and in that upright position (which is similar to what I do on tilt) there is an increased incidence of PFO-driven air emboli to the brain in neurosurgery, which is why you don’t take someone to surgery who has an active PFO. So all of this was being held in my brain at the same time, and I suddenly decided to look for whether or not there was a patent foramen ovale (PFO) in these patients because they had several interesting features that might suggest that they might have a PFO. One is their cavitating left atrium, which means they could be getting a very low pressure-sudden low pressure-drop on the left side of the atrium, combined with pulmonary pressures elevated on the right side, sufficient to give a pressure gradient from right to left, blowing past the septum foramen, allowing a hole to open up (which is normally open in utero, but typically closes at birth). And so I decided to look for this and lo and behold, 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of these patients have a PFO in their hearts. They have evidence by saline bubble contrast echocardiography of a hole that exists, and they typically shunt from right to left, very similar to what you see in fetuses, which is, of course, a continuous hole. Whereas about two-thirds of patients, the hole is only evoked by Valsalva, which quickly and transiently increases the pressure differential, right to left, blowing past the septum primum. A whopping one-third of the patients were shunting constantly across-in effect, they have a functional ASD-suggesting that there is a significant pressure differential problem in a continuous fashion from right to left. At that moment, I began to view this disease as some sort of problem in oxygen because what mountain climbers and fetuses have in common is that they lack oxygen at the cell level. In the case the climber, the lack of oxygen is due to the fact that there is not enough oxygen at the altitude they are at. In the infant’s case, the lack of oxygen is due to the fact that they are in the uterus, where the partial pressure of oxygen is about equal to Mount Everest, and then that combined with the fetal hemoglobin, which causes a left shift. (Or in the first 8 weeks, neonatal hemoglobin which causes a really big left shift.) They may be at almost a facultative anaerobe. The reason they are that way is, in part, because they have not yet coded for the enzymes that handle oxygen; they have not been coded and they are not coded for until about 35 weeks (5 weeks before they are born). And so I began to view this disease as sort of somewhere between a fetus, on the one hand, in which maybe oxygen can’t get in because it is being kept out because of a defect in the handling systems for oxygen, or like a mountain climber, in which some other external problem is blocking oxygen from entering. That began to evolve into my current idea from this work, which is that this disease is a disorder of energy, and the locust of control of that defect in energy lies at the level of oxygen handling. The putative defect in the mitochondria may not really lie within the mitochondria itself, but rather perhaps in some enzymes within its inner mitochondrial membranes or even outside the mitochondria that handle the oxidative byproducts of oxidation phosphorylation, particularly superoxide. I’m drawn to that idea because of the physiology of infants (of neonates/fetuses), that is, they evolve their oxygen-handling systems late in pregnancy, and until those systems are well-developed, giving them oxygen can actually kill them. That is why you don’t give high doses of oxygen to newborns, especially preemies born before the age of 35 weeks, gestational time. To sort of link this together-this string of ideas-I decided to administer oxygen to these patients and monitor several things. First, I would monitor their PFO status, because if they were acting like babies (or fetuses), then we should be able to modulate the PFO grade (it can be graded from 1 to 5, depending on the number of bubbles that you see). I also monitored the energetic characteristics of the echo in response to oxygen therapy. Lo and behold, nearly all of these patients have near-total closure or partial closure of their PFOs with 15 minutes of 4-liters-per-minute oxygen. They act just exactly like fetuses act in response to oxygen. Secondly, in terms of their energetic response to oxygen, about half of them seem to get better with oxygen, making them look more like mountain climbers, and about half of them get worse with oxygen, making them look more like fetuses. So the patients seem to be split into those who look like they can’t get oxygen in for some external reason, and about half of them look like fetuses-trying to keep oxygen out lest they get killed by oxidative stress. That led me, finally, to ask what possibly could cause a defect in this central handling system for oxygen. The only thing I have been able to come up with that seems to reflect my own experiences going back to Lake Tahoe days is viruses (and the best model for this, of course, is the HIV virus). HIV codes for a peptide called the TAT protein. Is has been recently published (in the last few years) that TAT protein specifically inhibits superoxide dismutase (SOD) and the glutathione peroxidase systems, which are exactly the systems that babies do not code for until 35 weeks of gestational time. Therefore, these viruses that are involved or associated with this disease may be acting to downregulate these oxygen-handling systems, rendering these patients (functionally) into fetuses (in terms of their ability to handle oxygen). This process is actually keeping oxygen out of the system. I’m not sure of the exact mechanism of that, but it may actually be at the sense mechanism, just as it is in fetuses. They keep oxygen out to keep from getting killed by it, but in so doing, they equilibrate at a lower energy state, thereby (meaning) that chronic fatigue syndrome is not the problem; it is a sense response to a deeper problem in oxygen handling. So that is sort of a very short order, I guess, of the sequence of my thinking and how it has evolved over the years since Lake Tahoe. JB: Well, I want to compliment you. That was the most eloquent and beautifully understandable explanation of a very complex process. Even those of us who are not cardiologists would, I think, be able to follow that explanation very well. There are a number of obvious questions. We could probably go on for hours and hours with question and answer response, here, because there are so many things that are raised by your observations and extraordinary thinking. Let’s ask the most obvious questions based upon the observations that you have made and the way you have assembled this information (which, I think, based on the presentations that you have made recently and I believe the data you have assembled looks very compelling). When we suggest-from a functional medicine model-that removal of agents that might precipitate this transition resulting in a PFO in these patients is one part of the potential therapy, the other part would be trying to find a way to enhance both oxygen delivery and detoxification of oxygen’s secondary metabolites. Knowing that if this is kind of a functional ischemic event, you get this whole xanthine oxidase conversion and you get a bunch of secondary oxidants that result, so you basically have an oxygen burden paradox that too little oxygen is the time of greatest oxygen stress, which seems very paradoxical to many people, but that is actually what happens during ischemic events. So it seems like your observations may call for two things, one of which is identifying the agent that initiates this PFO transition, and the second is trying to prevent (to the extent possible) the toxic effects of ischemic outcome. PC: Yes. I understand your thinking and I agree. The first order of business is to understand (as best as one can) how the locust of control of this, which I believe is centered (I think) at the level of superoxide handling (that sequential step-SOD) and then either down two pathways: glutathione peroxidase to water or catalase pathway to water. I believe that is the best locust of control that I can come to. There may be other loci in this, but I like this pathway because that is the pathway inhibited by viruses. Therefore, I’m inclined to go there because that is the clinical scenario that I have been branded with since Lake Tahoe. How do I bring viruses into this mix? They don’t have to be specific viruses, mind you-just any microbe that has learned how to downregulate the redox state for its own survival, and therefore, this is one mechanism they do. Now if that’s the case, then we have to figure out how we can resuscitate that locust of control. Does resuscitation mean that we can induce the coding of those enzymes at the gene level someway somehow, and secondly, could the agent that is doing this be inhibited in some way so that perhaps you get resurrection at that locust of control because the virus that is inhibiting it is inhibited? Readapting to a New Reality And then you have to turn your attention to the consequences of all this, which are two-fold. One consequence, of course, is that you have significant oxidative stress involved, and so there are all kinds of things to do for that. On a deeper level, though, there is something that I think is worth mentioning because it was a definite epiphany to me and may be very involved here. When I had my heart transplant and they congratulated me for having a 25-year-old heart pumping 10 liters a minute, as opposed to my old dying heart pumping 2 liters per minute, they said, “You are now the owner of a brand new heart that is completely normal and, since that’s your only problem, we fixed you.” And I said, “Well if I’m so fixed, how come I feel so bad?” And they said, “Well, that’s because it takes years and years to adapt to a 2-liter-per-minute flow, and it make take… ” get this… “years for you to readapt to a 10-liter-per-minute flow.” The body has to adapt to defend itself, and then it cannot readapt quickly when you change the primary problem. Therefore, the other hurdle for getting people better, I think, is-even if you fix their locust of control-to get them rapidly to readapt to that new reality. Because if you don’t do that, they may take years, and maybe never readapt to the reality that you have generated for them, and that may be because they phenotypically adapted. For so many years they lose their way back, or they even have genotypic problems that may have supervened, so they may have new genes in play (mutated or otherwise) through the allo insertion regions so they have to be genotypically transformed. That may, therefore, bring into play such things as stem cell approaches. There is more to this than simply fixing the locust of control. You then have to figure out how to get these people who have been sick for 10, 20, and even 30 years back to some level of normality, even after you have fixed their central problem. And that is a problem I am extremely interested in because I think that is the problem of all chronic medical illnesses: How do you get people to readapt to the new reality that you have created for them? JB: I think that’s really a fantastic way of moving to my last question. As you look at the number of studies that have been published (of which there are many) on chronic fatigue syndrome with different interventions, we can come to conclusion that there is no magic bullet (obviously), and that it looks like a multifactoral condition (as you’ve described it). But there are 2 therapies (of those that have been tried) that seem to have the greatest number of potential positive hits from RCTs and those are cognitive behavioral therapy and graded exercise therapy. There are something like 6 or 7 trials on each of those that show some positive nature. So, if we map those against your discoveries, would you be able to make a connection as to how cognitive-behavioral therapy and graded exercise therapy could connect to this? Opinions on Cognitive Behavioral Therapy, Graded Exercise, and Rebreathing PC: I think it is easier to make a connection with cognitive behavioral therapy, and maybe one to graded exercise. I’m reminded of an experiment I recently read about where 10 people were asked to hold in their hands a vial of suspended white cells in a physiologic buffer. Five of them were asked to think bad/negative thoughts and five of them were asked to think good/positive thoughts. And then they took the vials that they were holding and they analyzed the DNA and found that the DNA transcription sites were very open and there was much more mRNA transcription being done in the ones with happy thoughts, and that the genes were being shut down in those who were thinking bad thoughts. So I think, perhaps, one’s mental attitude affects the phenotypic expression of your entire genome. So I think cognitive behavioral therapy might act there. In terms of exercise therapy, one of the greatest stimulants to the handling systems for oxygen is, in fact, oxygen itself. Indeed, it seems reasonable that oxygen-the mere production of superoxide itself-would actually stimulate the very enzyme systems designed to handle it, and therefore, as long as the system is graded, one might see a benefit (I suspect). But what bothers me about this is that it would be so easy to cross over the line. If there is an absolute inhibition in defect in oxygen handling, and you force oxygen into these people by exercising them, then you can do significant damage. I am always reminded when I rounded medical school as a young intern with J. Willis Hearst (a cardiologist), we came upon a bed with someone who had idiopathic cardiomyopathy. He warned us to never ever exercise someone with cardiomyopathy because you would kill them. I always remembered that. And so, I think in a system in which there could be a deep-seated energetic, shall we say, “metabolic cardiomyopathy,” they may not be able to handle significant oxygen loads any better than a baby born 6 weeks premature (34 weeks gestational time) would be damaged irreparably by excess oxygen. I think that is why I am a little concerned about graded exercise therapy, per se. For every person that you might help with it, you could irreparably hurt 2 others. JB: Yes. And I think you have pointed out in previous discussions and in your writings that chronic fatigue syndrome is kind of a generic catch-all for a whole variety of different degrees of severity. So we have people that have kind of a garden-variety fatigue that have called themselves chronic fatigue patients all the way up through the patients that you often see, which are very severely impaired and often the cause of their death will be something related to these energy-deficit disorders. Sometimes it is defining what we are talking about, I guess, as it relates to the patient and where they are in that sequence. PC: Yes, exactly. I wonder, in my own mind, how I would differentiate those who should be submitted, for example, to graded exercise versus those who should be not presented for such therapy. I would do it simply by looking at how they respond to oxygen. There are several ways to analyze how someone responds to oxygen. The one that we use here is we simply look at how the heart responds using the most energetically sensitive parameter, called the “Isovolumetric Relaxation Time” (measured in milliseconds). And if, on oxygen, that IVRT goes up, they should not be submitted to exercise, because that is saying that oxygen is making their heart worse. If, on the other hand, that IVRT goes down, that would be an oxygen-tolerant person; they are actually benefiting and it is almost like giving oxygen to a high-altitude climber (he suddenly feels like it is manna from heaven). And that person I think might do very well on a graded exercise. In my practice, it is bisected about 50-50. Fifty percent look like mountain climbers and would probably benefit from oxygen loading (by exercise or any other way), and 50 percent looks like they are getting creamed by it. That could change over time, I suspect. If you have other interventions in mind they may not be fixed in time, but that is an example of why I think the blanket statement that exercise for this disease is good in all cases is simply untenable. JB: Paul, as you are speaking I am reminded of a conversation we had years ago with Glenn Doman, who is the co-founder of the Institutes for the Achievement of Human Potential in Philadelphia. He talks about how with his kids that often have certain types of brain injuries, using this rebreathing technique, where they mask these children and they then get an increased carbon dioxide level, which then improves oxygen delivery and they train them to do this (the parents, actually, are trained to train the child). He feels that is a very effective way of increasing the oxygen environment in the central nervous system. Have you ever thought about this rebreathing concept? PC: Yes, I have. Here, again, I get a little concerned. When you undergo rebreathing approaches, you basically shift the oxygen hemoglobin dissociation curve to the right because as you are rebreathing the CO2 you are shifting the PH and you are actually offloading oxygen at a greater rate. That would be a very bad idea if someone is oxygen toxic. One of the interesting things, Jeff-one of the things we have observed-is that if you administer oxygen to these patients and monitor their breathing rates, we get three different varieties of breathing responses to the administration of low-dose oxygen. In one group, they start to pant, and in one case, the panting was 130 breaths per minute on the administration of oxygen. In another patient, the administration of oxygen resulted in the cessation of breathing and they became obtunded. In the administration of oxygen of a third set they seemed to just not be bothered by it; their breathing rate remained identical. So I think there is a very odd distribution of responses to oxygen. One group actually almost seems to act like someone that is in such a chronic hypoxic state that they no longer are CO2-driven; they are oxygen-driven. Just like the chronic COPD person; you put them on oxygen and they actually stop breathing. And another group, when you give them oxygen, they hyperventilate to the point that they actually countermand the excess oxygen by vasoconstricting to keep the oxygen you are giving them out of the cell. And a third group that seems to handle it rather more normally. So I think, again, that in disease that we are talking about here-chronic fatigue syndrome and other diseases that affect energy systems-if the locust of control lies at the level of the handling of oxygen, then the use of oxygen is very problematic. JB: I think you have done just an absolutely superb job of defining (at a fundamental level) what we would call in our parlance a functional illness. To define a pathophysiology is probably going to be not as important an understanding as you helping us to understand the mechanisms that relate to this dysfunction. Paul, I want to thank you. This has been quite a journey you have been on and to share this with us has been extraordinarily important. I know this is just a weigh station along your continued discovery process and we hope we can check back in. We’re so pleased that you are feeling better and that you are part of our community. You are a major contributor and we wish you well. I just thank you so much for doing all that you are doing with your patients. PC:Thanks very much, Jeff. JB: Thank you.  

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Welcome to Functional Medicine Update for May 2007. We had the decade of the brain in the 1990s, but certainly we are continuously learning more as to what brain dysfunction originates from and how it relates to functional medicine. When we talk about hyperactivity attention disorders, autism, depression, dysphoria, and some cases of Alzheimer’s dementia and cognitive dysfunction, we are talking about web of dysfunction that is not isolated in the brain itself. This web is signaled through much of the body: through the gut immune system, hepatic function, and vascular function. It is the interaction of those systems together in this functional web that gives rise to what we call neurological problems. There is even the environment and the perception of the environment-the epigenetic effects that occur through the process of modifying kinases and gene expression and signaling pathways. Traumatic life experiences, post-traumatic stress syndrome, violence, rejection, the feeling of no attribution or no love are translated through the same receptor sites and same signal transduction pathways and give rise to an amplified effect on the neuroimmune system that we see as these so-called neurological problems. This is a very complex web giving rise to the challenge for professionals to figure out therapeutic approaches towards neurological difficulties. It is more than a single path to enlightenment; it is more than just one agent causing one disease. The application of functional medicine can help us to unravel and tease apart the multiple etiological factors that contribute to these dysfunctions.. Metabolic Syndrome and its Relationship to Cognitive Decline There is no better example of this, I think, than the emerging story that surrounds metabolic syndrome and its relationship to the type of cognitive decline that we often call non-Alzheimer’s, or even Alzheimer’s-like, dementia. Many in the medical world first became aware of this relationship in 2004 when the article titled, “The Metabolic Syndrome, Inflammation, and Risk of Cognitive Decline,” was published in the Journal of the American Medical Association.1 The investigators were headed by Kristine Yaffe and included researchers at the Department of Psychiatry and Neurology and Epidemiology (as well as Geriatrics) at the University of California San Francisco School of Medicine, and also the National Institutes of Aging in Baltimore, MD. This collaborative study looked at the effect of a five-year prospective observational evaluation conducted from 1997 to 2002 at two community clinic sites. Participants totaled 2632 black and white elders (mean age, 74 years), and investigators tried to tease apart whether there was an association between metabolic syndrome (or insulin resistance/hyperinsulinemia) and loss of cognitive function. The conclusion of this study was quite dramatic for individuals who were unaware of this connection between insulin resistance, inflammation, and brain function. The findings of the study supported the hypothesis that metabolic syndrome contributes significantly to cognitive impairment in elders, primarily in those with very high levels of inflammation (as measured by increased levels of high sensitivity C-reactive protein above 1 gram per liter). The Role of High Insulin on Neurological Function and Inflammation The observation suggesting a relationship of elevation in inflammatory markers associated with metabolic syndrome and cognitive decline encouraged the research world to move at a faster pace to try and understand the mechanisms by which this could occur. A key relationship that was addressed was about what role high insulin would have on neurological function and inflammation. It is not an obvious connection in that we think of the brain as not being an insulin-requiring organ. It is now recognized that neurons have insulin receptor sites and that insulin activates at high levels of signal transduction NF&kappa;B transcription. NF&kappa;B plays an important role in stimulating gene expression of proinflammatory cytokines like tumor necrosis factor &alpha; and interleukin-6. This has been published in many different papers, including that of Benoliel, et al. in the Journal of Cellular Science in 1997.2 ,3 This hyperinsulinemia connection to inflammation is becoming a very well understood gene expression outcome from high levels of insulin signaling. Studies implicate an inflammatory process in the pathogenesis of insulin resistance associated with many disorders, including central obesity with increased visceral adipose tissue accumulation, and in type 2 diabetes as well. As you have high levels of insulin, there is an activation of inhibitor kappa kinase beta (IKK beta) which then phosphorylates inhibitor kappa B, causing that to disassociate from the NF-kappa B complex, allowing NF-kappa B then to gain access to the genome, where it sits down on specific portions of your book of life (your genes) and causes them to be read. These stories that are read are the pro-inflammatory cytokines, including the cyclooxygenase enzymes and the production of proinflammatory prostaglandins. Insulin plays a very important role in modulating or mediating these immunological effects.4 Data have shown that mononuclear cells are able to be activated into a proinflammatory state with an increase with NF-kappa B binding, and that high plasma levels of free fatty acids can activate mononuclear cells to produce more proinflammatory mediators. High levels of free fatty acids are associated with metabolic syndrome and hyperinsulinemia, and insulin resistance is a function of inflammatory mediators. A number of papers have been published demonstrating this, including one that discussed circulating mononuclear cells and the proinflammatory condition associated with hyperinsulinemia. This article was in Circulation in 2004.5,6 Free Fatty Acids Associated with Hyperinsulinemia We know high levels of free fatty acids associated with hyperinsulinemia can result in lipid accumulation in tissues, such as the liver and in muscle. This can lead to localized tissue inflammatory signaling that causes apoptosis of cells in those tissues and loss of cell mass (in the liver, leading to hepatic inflammation through NF-kappa B activation). We don’t think of the brain as becoming engorged with fat (it is not a tissue that we would normally associate with accumulation of triglycerides), but the same process of high levels of fatty acids that initiates the triggering of the proinflammatory mediators can have an effect across the blood-brain barrier and increase neuronal inflammatory response. It is both the direct and indirect effects of insulin through the inflammatory pathways that may be associated with the hyperinsulinemic state and metabolic syndrome and cognitive decline. In the Journal of theAmerican Medical Association in 2006 there was a review titled, “Insulin Effects Weigh Heavy on the Brain.”7 This article/review talked about insulin’s best known role (as regulator of blood glucose and fatty acid storage), but also how it acts in the brain to aid memory and thinking. When insulin regulation is disrupted (as it is in many common medical conditions including diabetes) the risk for cognitive impairment rises. Insulin dysregulation sets the stage for certain neurodegenerative disorders, particularly various forms of Alzheimer’s disease, as was discovered by Dr. Suzanne Craft, professor of psychiatry at the University of Washington, Seattle. Craft and her colleagues have been studying the link between insulin and memory for the past decade. Their research is suggesting potential approaches to treat, delay, or even protect against Alzheimer’s disease associated with hyperinsulinemia and altered insulin signaling. In normal physiology, and also when administered peripherally at optimal doses, insulin can enhance memory. Craft’s team have found evidence that hyperinsulinemia is associated with inflammation in the brain and triggers the accumulation of the 42-peptide form of beta-amyloid, the precursor of amyloid plaques that are found in certain brain regions and are a hallmark of Alzheimer’s disease. She has several publications in the journal Neurology about these findings.8 Insulin Resistance, Type 2 Diabetes, and Inflammation as Risk Factors for Alzheimer’s Disease So evidence now implicates insulin resistance, type 2 diabetes, and inflammation as risk factors for Alzheimer’s disease. A high level of insulin seems to boost beta-amyloid levels and induce, then, this inflammatory state. This has become so well-recognized that recently, in the Journal of Alzheimer’s Disease, an article was published titled, “Impaired Insulin and Insulin-like Growth Factor Expression and Signaling Mechanisms in Alzheimer’s Disease-Is This Type 3 Diabetes?”9 They are actually starting to name this condition of hyperinsulinemia associated with Alzheimer’s disease and loss of cognitive function as a type 3 diabetes. In this article the authors say, “The strikingly reduced central nervous system expression of genes encoding insulin, insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 1 receptor (IGF-1R) as well as the insulin and IGF-1 receptors, suggests that Alzheimer’s disease may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes and therefore might be termed, ‘Type 3 diabetes’.” Again, this was in the Journal of Alzheimer’s Disease in 2005. This brings us to the question, “How does one clinically evaluate the relative risk to cognitive decline and memory problems that are associated with insulin resistance/hyperinsulinemia?” In the past we thought we were just evaluating the potential risk to type 2 diabetes. Now we are looking at the risk to potential neurological dysfunction, and also to cardiac disease. Let’s do a quick review of the kind of clinical markers we think are important for evaluating the relative risk of a patient having hyperinsulinemia/insulin resistance. First of all, elevated serum triglycerides, generally graded at 130 milligram per deciliter. We might put under that another clinical parameter that is not normally measured, but maybe even has a higher clinical specificity to metabolic syndrome, and that is high serum free fatty acid levels. Free fatty acids, as you know, are the debris (or the breakdown products) of triglycerides. When triglyceride lipase, an enzyme that is present in plasma, operates on triglycerides, it liberates free fatty acids. This condition of high free fatty acids is tightly related to hyperinsulinemia in metabolic syndrome, even more so than that of serum triglycerides (although we would say fasting elevation of serum triglycerides is a good surrogate marker). The second evaluative tool that is commonly used for evaluating the presence of metabolic syndrome is depressed high-density lipoprotein cholesterol, or lowered HDL levels. These would be males less than 40, females less than 50. Now that would beg the question, what, then, about the ratio of triglycerides to HDL? If we associate metabolic syndrome with elevated triglycerides and reduced HDL, then wouldn’t the ratio of triglycerides to HDL even be a more sensitive marker? And that seems to be, “Yes,” to that particular question. With serum triglyceride-to-HDL-level ratios greater than 4 to 1, you have increasing relative presence of insulin resistance. If you were to do euglycemic insulin clamp experiments on a person with an elevated triglyceride-to-HDL ratio, you would undoubtedly find that this person has insulin resistance. So, again, the ratio of serum triglyceride-to-HDL, when greater than 4, and with increasing levels of that ratio. Let’s take an example of a person with triglycerides at 160 and an HDL of 40. That would be a 4-to-1 ratio. If it goes up to a fasting triglyceride of 200 and an HDL of 40, that is a 5-to-1 ratio; that would be more evidence of metabolic syndrome and insulin resistance. If we went to serum fasting triglycerides of 240 and an HDL of 30, now you have an 8-to-1 ratio, and that would be even (obviously) more relative risk to metabolic syndrome and hyperinsulinemia. So the serum triglyceride-to-HDL ratio is a reasonably good surrogate marker for metabolic syndrome/insulin resistance. We have also put on the list (obviously) elevated high-sensitivity C-reactive protein (or HSCRP). Greater than 0.9 to 1 milligram per liter is suggested to be a relative risk factor to the inflammatory component, which is associated with metabolic syndrome. The next is hemoglobin A1c (or glycosylated hemoglobin). We recognize that glycosylated hemoglobin has a very strong correlation to poor blood sugar control in the diabetic, but it also has been found (as a consequence of glycemic variability) to be associated with increasing risk to hyperinsulinemia/metabolic syndrome when it is marginally elevated (still within the normal range, but at the high end of normal range). In fact, it has been said that glycosylated hemoglobins greater than 5.5 percent of total hemoglobin may represent independent risk factors that are associated with the metabolic syndrome. I am now quoting from a recent paper that appeared in the Journal of theAmerican Medical Association in 2006.10 So marginally elevated glycosylated hemoglobins (or hemoglobin A1c) increase levels of high-sensitivity C-reactive protein. There was a nice paper that discussed insulin resistance and its relationship to elevated CRP in Metabolism and Clinical ExperimentalMedicine in 2005.11 To continue our list of risk factors, we have elevated percent body fat, which is an anthropometric measurement and (as you probably know) can be done by bioimpedance analysis or hydrostatic weighing or even using the qualitative test of body mass index ratio (height-to-weight ratio). Next is elevated waist-to-hip ratio, generally greater than 1, using a tape measure, basically, to measure waist and hip measurements. To make it easier, we recognize that elevated waist circumference with men greater than 40 inches and women greater than 35 has a very strong correlation with metabolic syndrome. Next is moderately elevated systolic and/or diastolic blood pressure, greater than 130/85; this is another risk factor to metabolic syndrome. Elevated uric acid in fasting plasma is another indication of metabolic syndrome (hyperuricemia). And then, of course, the last one (when we start viewing cardio-metabolic risk associated with metabolic syndrome) is elevated apolipoproteins. These are factors that are emerging to have major clinical significance of relative risk assessment in the early stage. The two that have been in the news most recently are apolipoprotein B and apolipoprotein A-1 measurements. I want to speak a little bit, if I can, to atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance. I think it is this new area that has really gained a lot of prominence and we can connect, then, the heart to the brain to the liver to the pancreas through the assessment of these dyslipidemic transitions that occur with metabolic syndrome. Scott Grundy, who is a very well-known champion for the metabolic syndrome concept (Professor of Internal Medicine and Director of the Center for Human Nutrition at the University of Texas Southwestern Medical Center in Dallas) has recently authored a very nice review in Clinical Cornerstone titled, “Atherogenic Dyslipidemia Associated with Metabolic Syndrome and Insulin Resistance.”12 In this article Dr. Grundy writes, “Atherogenic dyslipidemia, a component of metabolic syndrome, is characterized by high levels of apolipoprotein B-containing lipoproteins… and a reduced level of HDL lipoprotein cholesterol.” A Review of Apolipoprotein Let’s mention (for review) what we mean by apolipoprotein. As I’m sure you recognize, lipids (which are fats-be it triglycerides or cholesterol) are not well solublized in water. The blood is made principally of water, so that would be like trying to dissolve oil in water. In order to transport these fats, which are critically important as both energy substrates and as messenger molecule precursors (as with the cholesterol that gets converted into things like not only bile acids, but hormones), there has to be a transport system, and the way that that transport system is manifest is through the body’s ability to produce specific detergent-like molecules that are called apolipoproteins. Proteins can be like detergents. They can have a nonpolar component and a polar component to make them both fat- and water-soluble. They can bind specific types of fats, just like detergent does in your washing machine, and allow them to be solublized into the blood. This process of forming these apolipoproteins is not a random process. The body doesn’t make at random different detergent molecules; it makes specific molecules to transport specific types of fats and these apolipoproteins have names such as A, B, C, D, E, and they have different compositions. These proteins trap and bind specific types of fats (cholesterol and triglycerides of different sizes and different shapes), and they then deliver them to specific receptors on the cell surface, triggered by the unique affinity between a specific apolipoprotein and a specific cell membrane receptor site. So it is not just random delivery of fats to cells. The fats are delivered in a very prepackaged and preprogrammed way through the communication between the apolipoprotein and the cell surface membrane receptor. This is an important concept because I think in the past it has been felt that fats are the cause of heart disease-that when we have fats in the blood, somehow they glob on to the artery wall and they produce these plaques (like depositing grease debris on the side of a vessel), but that is actually not the process of atherogenesis. It is much more specific, related to intercellular communication between agents that are in the outside environments that get translated into the interior of the cells that make up the various layers within the artery wall that initiate the injury to the artery and are associated with what is called atherogenesis. These apolipoproteins are able to deliver different messages to the artery wall cells (the vascular endothelium) and even into the internal portions of the vascular wall. Apolipoprotein physiology may be as important as the amount of fat that is floating around in your blood, And, the composition and communication of these apolipoproteins is very strictly regulated by environmental factors that signal the synthesis of these apolipoproteins. It could be hormones that initiate this. One of the hormones, obviously, is insulin. It could be sex steroid hormones, like testosterone, androgens, and progesterone, and also estrogens. These hormones influence the synthesis of specific types of apolipoproteins. We also know that environmental factors (such as stress) can modulate apolipoproteins, so here we get into behavioral neurology and behavioral cardiology, in which we start seeing how we think about our environment may influence, then, how our body synthesizes these specific transport proteins that ultimately deliver different messages and fats along the surfaces of different cell types. So the apolipoproteins are a very important player in cardiovascular function, and they are not just passive transport “detergent” molecules; they actually have their own personalities and their own distinctive influence on vascular dynamics. If we start talking about apolipoprotein A or B or E, we are talking about not just the fats that they transport, but also the message that they, in fact, bring by themselves as these bioactive transport proteins. When Dr. Scott Grundy is talking about atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance, he is saying that these apolipoprotein B particles are manifest at higher levels during states of hyperinsulinemia and they then transport various types of fats that include LDL remnants and small atherogenic LDL particles to the artery wall, where they can participate in what is called cardiometabolic syndrome. Cardiometabolic syndrome is a fairly new term that tries to define how people who do not have the traditional risk factors for cardiovascular disease, such as frank hypertension or elevated levels of cholesterol or smokers or diagnosed diabetics, may still be at significant risk to cardiovascular disease because they have this underlying (kind of smoldering) metabolic syndrome/hyperinsulinemia that alters their apolipoprotein distribution and alters the delivery of certain messages of their vascular wall cells and their vascular endothelium. Specialists in metabolic syndrome and preventive cardiology are working closely together to try to understand this connection. There is a review paper, authored by Nathan Wong, on this topic that appeared in Metabolic Syndrome andRelated Disorders in 2006.13 This article discusses the importance of doing an assessment in cardiology for the presence of insulin resistance/hyperinsulinemia so that you can pick up this cholesterol-independent component of risk to cardiovascular disease. In this article, it is suggested that a great percentage of people that died by sudden coronary events and did not have the traditional precedent risk factors to heart disease were those who really carried with them this metabolic syndrome/hyperinsulinemia that put them at risk (unknowingly). Unless you analyze this risk, you are not likely to see it. This is a little bit like the example of blood pressure and stroke. No one really understood the correlation between elevated blood pressure and stroke risk until the development of the sphygomometer (the blood pressure measuring cuff), which then was able to actually measure relative risk and show an association between elevated blood pressure and stroke risk. By the same token, if you are not measuring these cardiometabolic risk factors that I’ve described, such as elevated fasting triglycerides, reduced HDL, the blood pressure changes, the body mass changes with central adiposity and a waist-to-hip increase, and even the apolipoprotein alteration that I’m now describing, you are not likely to understand that patient is at risk. The apoB/apoA-I Ratio is a Strong Risk Factor for Cardiovascular Disease What has emerged is the apoB/apoA-I ratio is a strong new risk factor for cardiovascular disease and a target for therapy that is associated with the risk to metabolic syndrome and hyperinsulinemia. I’m now quoting from the Journal of InternalMedicine. This is a nice review paper by Walldius and Jungner, who have been principal researchers in this field for some time.14 What is apolipoproteinA-I? If apolipoproteinB transports the atherogenic-dense LDL particles and remnants of LDL, the apoA-I is the converse: it transports the backbone of what we call the HDL particle. HDL is involved with cholesterol efflux from the artery wall. It is like an unloaded flat-bed truck that arrives at the cell well. The apolipoprotein binds at the membrane of that receptor site, and then is involved with “loading up” the flatbed truck with cholesterol by effluxing it out of the cell and then taking it through the bloodstream to a place where it can be metabolized, converted into bile acids, and ultimately excreted in the bile (or made up as part of bile as the cholesterol esters). The apoA-I is an important apolipoprotein for cholesterol efflux, whereas apolipoproteinB is associated with delivery of cholesterol and lipids to the cell, so it is influx. So you want your apolipoproteinB level to be low because you don’t want to deliver too much lipid to the cell itself, and you’d like your apolipoproteinA-I level to be high (that is, you have more available flatbed trucks to efflux the cholesterol out of the cell). When I say A-I, I want you to understand that is capital “A” dash “I.” We are not thinking about apolipoprotein little “a.” Little “a” is a subtype and that is an atherogenic apolipoprotein as contrasted with apo capital “A” “I,” which is an antiatherogenic lipoprotein. So the ratio of apoB/apoA-I you would like to go down, right? You would like it to be low. And when I say “low,” I would suggest that number means less than or equal to 0.7 (the lower the better). So as your number goes from 0.7 to 0.8, that is increasing atherogenic risk associated with cardiometabolic syndrome. I would go on to suggest that based on Dr. Craft’s and others’ work, that that would also suggest increased risk to cognitive decline and Alzheimer’s plaque and other kinds of dysinsulinism that is associated with altered neurological function (central neurological function). We shouldn’t just focus solely on the effect of an altered apoB/apoA-I ratio as being cardiometabolic. We should also think of it in terms of neurometabolic as well. If we were to compare apolipoproteinB/A-I ratios in subjects with (versus those without) metabolic syndrome, you might ask, is there a difference? Can you differentiate the two, based upon their ratios? As I’ve said, there is now very strong evidence that the apoB/apoA-I ratio predicts cardiovascular risk factor better than any of the cholesterol indices (that would be cholesterol HDL levels, for instance, or LDL levels). In a more recent study that I’m quoting from (which is found in the AmericanJournal of Cardiology in 2006), investigators wanted to evaluate the apoB/apoA-I ratio related to metabolic syndrome.15 They analyzed 2964 subjects, mean age 48 years, about 1516 men and 1448 women, from the National Health and Nutrition Examination Survey III, with apolipoprotein data that were evaluated for metabolic syndrome and its components. The metabolic syndrome was defined according to the criteria of the National Cholesterol Education Program Adult Treatment Panel III. In this study, the mean values of the apo B to apo A-I ratio in subjects with and without the metabolic syndrome were compared. Overall, the median distribution of the apo B to apo A-I ratio was significantly greater in subjects with the ATCP III metabolic syndrome than those without. In fact, the difference was at the P < 0001 significance (a highly significant difference in differentiating between those with metabolic syndrome versus those without). In conclusion, this particular study finds that the apo B to apo A-I ratio is strongly associated with the presence of metabolic syndrome and can be used as a early- stage interventional risk factor marker for what they call cardiometabolic syndrome, but we might also call it neurometabolic syndrome because of the emerging connection between hyperinsulinemia and neurological dysfunction. When you look more in depth at what we know about apo B and apo A-I, it really is a very fascinating story. Just to review for you, over the last three decades it has been recognized that a high level of total blood cholesterol (particularly in the form of LDL cholesterol) is a major risk factor for developing coronary heart disease.As we look at more recent research, our understanding of lipoprotein functions and metabolism has been expanded. A considerable portion of patients with atherosclerotic disease have levels of LDL cholesterol and total cholesterol that are actually within the recommended range, and some patients who achieve significant LDL cholesterol reduction with lipid-lowering therapies still develop cardiovascular disease. Other lipid parameters associated with cardiovascular risk are these lipoprotein subfractions that are components of the lipoprotein particles that include protein and fat together. We talk about apolipoprotein B existing in two forms: apo B-48 and apo B-100. Apo B-48 is synthesized in the intestine, where it is complexed with dietary triglyceride and free cholesterol absorbed from the gut lumen to form chylomicron particles that are generally cleared postprandially very quickly out of the blood within the first few hours after eating. Apo B-100, however, is synthesized in the liver and is present in LDL intermediate density lipoproteins and very low density lipoprotein particles. Only one apo B molecule is present in each of the lipoprotein particles, and therefore the total apo B value indicates the total number of potentially atherogenic lipoproteins. Apo B is essential for the binding of LDL particles to the LDL receptor, allowing cells to internalize LDL. An excess of apo B-containing particles is the main trigger of the atherogenic process. Individuals with seemingly low or normal LDL cholesterol levels can still be at increased risk of cardiovascular events. In these patients, the risk of cardiovascular events appears to be more closely related to the increased number of small density LDL particles, in addition to hypertriglyceridemia, and low levels of the protective HDL cholesterol. This is a combination that we know as the atherogenic lipid triad, and it is associated with metabolic syndrome and hyperinsulinemia. Target levels for apo B have now been included in a table on the treatment goals of the National Cholesterol Education Program ATP III Guidelines. Patients with diabetes or the metabolic syndrome can have normal LDL cholesterol levels, but possess aspects of atherogenic lipid profiles that are associated with a high ratio of the apo B/apo A-I. Apo A-I acts as a co-factor for lecithin acyl cholesterol transferase, which is important in removing excess cholesterol from tissues and incorporating it into HDL for first transport to the liver. Furthermore, apo A-I is the ligand for the ATP-binding cassette protein, which is called the ABC protein (ABC A-I), and hence is involved in the docking procedure by which excess cholesterol in peripheral cells is externalized to HDL for further reversed cholesterol transport, either directly or indirectly, via LDL back to the liver for metabolism. HDL exists as particles of different sizes, with HDL-2 being the largest and containing the most lipid in its core, and having the highest efflux capacity for cholesterol. Apo A-I is a very strong predictor of HDL cholesterol 2 levels: high levels of apo A-I mean high levels of HDL 2. Apolipoprotein little “a,” as contrasted to capital “A-I,” is bound to LDL to form this apolipoprotein(a) LpA, which shares 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of its amino acid sequence with plasminogen, and competitively binds as surface binding and activation of plasminogen. Elevated LpA has been associated with arterial wall thickening, and high blood concentrations of apo a have been suggested as a risk factor for atherosclerosis. But in evaluating all the risk factors, it appears as if elevated apo A-I is the most strongly associated with a decreased risk to cardiovascular disease. Elevation of apo B is associated with an increased risk of cardiovascular disease. The apo B level was found to be the best predictor of the extent of cardiovascular disease after correction for age, as assessed by the number of stenotic arteries, and was the only statistically significant predictor of the presence of cardiovascular disease in patients without frank dyslipidemia. This is why we keep saying that the apo B/apo A-I ratio is a very interesting prognostic marker for not just cardiometabolic syndrome, but also neurometabolic syndrome associated with hyperinsulinemia. There are a number of prospective studies that have evaluated this association, including the AMORIS Study. Compared with subjects in the lowest quartile, those in the highest quartile in this study, for apo B, had almost a three-fold increase in risk to cardiovascular disease. For the apo B to apo A-I ratio, the increase in risk was almost four-fold in men and three-fold in women, for those who had the highest quintile ratio of apo B to apo A-I. So we are talking about significant increases in relative risk as defined by the apo B to apo A-I relative ratio. In multivariate analyses, high apo B levels and the high apo B to apo A-I ratio, and low levels of apo A-I, were stronger predictors of risk than LDL cholesterol, total cholesterol, and triglyceride levels alone. Based on all these findings, the ratio of apo B to apo A-I, meaning the balance between potentially atherogenic cholesterol-rich apo B-containing particles and the antiatherogenic apo A-I-rich particles, is proposed as the best integrated measure of cardiac risk associated with lipoproteins, and closely associates itself with metabolic syndrome and insulin resistance. Values of apo B should be less than 1.2 grams per liter, and for apo A-I, should be greater than 1.2 grams per liter. This is why I have said that the ratio for optimal function of the cardiovascular system should be a ratio of 0.7 or less between apo B and apo A-I. Thus, in those at the greatest risk, a target apo B level below 0.9 grams per liter is recommended, regardless of gender. Regarding cut-off values for apo B/apo A-I ratios, I said we would like it to be 0.7 or lower. I think you can see that we are talking about a new emerging risk factor that not just ties itself solely to that of cardiometabolic risk, but also to the relative risk to neurologic problems. This will be described in much greater detail by our clinician of the month, Dr. Jay Lombard, a neurologist and a psychiatrist who really helps us to understand this broad connection in the web (the functional web) between hyperinsulinemia, inflammation, and other risk factors that are associated with neurodegenerative diseases. As I close, I would like to think that we have all come to the same point here at the end of this discussion. There are a variety of surrogate markers that are used clinically for evaluating the presence of hyperinsulinemia, such as the elevated triglyceride HDL ratio, elevated waist-to-hip ratio, elevated waist, elevated percent body fat, increased uric acid, increased blood pressure, increased high sensitivity CRP, and increased marginal elevations of percent glycosylated hemoglobin or hemoglobin A-IC. But if we add to that the relative evaluation of apo B to apo A-I ratio, we might now form a panel of evaluative tools that really is helpful in looking much earlier at the potential risk to not just diabetes and cardiovascular disease, but also neurodegenerative problems that are associated with hyperinsulinemia, insulin resistance, and the deposition of beta amyloid plaque. We are going to discuss this now with our clinician of the month, Dr. Jay Lombard.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month JayLombard, DO Chief of Neurology Bronx Lebanon Hospital 1276 Fulton Avenue Bronx, NY 10456 This month I’m very privileged to have a long-standing friend, colleague, and a person I have tremendous respect for (and admiration for, professionally), as our clinician/researcher of the month, Dr. Jay Lombard. Dr. Lombard is the Chief of Neurology at Bronx Lebanon Hospital and is an Assistant Clinical Professor of Neurology at Cornell Medical School. He is dual boarded in both psychiatry and neurology, and has been a friend and colleague for more than 25 years (since we first met in Rhinebeck, New York at the Omega Institute). Jay’s career has really spanned a tremendous swath of clinical experience and he has managed some of the sickest of the sick. He has been able to bring tremendous vision and integration of various practice management and techniques into his skill set, and I think he has framed (for many of us) the model of what integrative, open-minded, lifelong learning in medicine really means. Jay, it is wonderful to have you as a clinician of the month on FunctionalMedicine Update. You call yourself a behavioral neurologist and I think that is a very interesting term, so for the sake of our listeners, could you help us understand what that term means? Defining Behavioral Neurology JL: Behavioral neurology is, I think, the recognition that many disorders we encounter in our daily life in clinical practice have, in many ways, a direct relationship with our brains, our moods, and our emotional states. In terms of the specifics of what a behavioral neurologist is, my practice (and other neurologists who practice this way) is focused on disorders like autism and attention deficit disorder (t one extreme of the lifespan), and then Alzheimer’s and dementias and cognitive problems (t the other extreme). It is also, I think, recognition of how critical emotional states are to our overall physiology. JB: I think that is a very interesting and important part of the whole mind-body connection. There are still (believe it or not-in the 21st century) people who separate the mind from the body and try to dissect each component as if they were separate channels or silos of non-interacting function. Certainly from the functional medicine perspective and from your practice (in the way you have both treated patients and been a teacher) there is a very significant integration/marriage between the two. It seems, as I have listened to you, you can separate behavior from neurological function, and so it is a chicken-and-egg argument. JL: That’s right. It is probably a top-down and a bottom-up approach–the appreciation that mood states and emotional states can clearly affect our physiology. This is something that I have spoken to many physicians about just recently-this concept of neurocardiology and neuroimmunology. There is very strong data, both epidemiological as well as physiological, on how alteration in brain states increase vulnerability to specific disorders. But I think the other piece of that, which is clearly as important as the bottom-up approach, is how systemic variables (whether it is dysbiosis or immune dysregulation) affect mood and cognition. There is a reciprocal, interdependent relationship between brain and body function that goes bidirectionally. JB: Your books have been very instrumental in my learning in this field. Brain Wellness Plan, which was I think your first book (published by Kensington Press), and more recently, Balance Your Brain (a Wiley book). The books describe behavioral neurology from a perspective that the average reader can understand. I know in your research and in your practice you have been involved with brain imaging and neuropsychopharmacology, and many of your patients that you deal with at the neurology component of Bronx Lebanon Hospital are very seriously ill. It sounds like you have had the opportunity (professionally) to cover the whole waterfront. Is this an advantage to you, do you believe, in bringing perspective to manage problems? JL: I certainly hope so. I mean, it is something one can never fully feel on top of because of the complexities of these relationships and the learning curve is continuous. There is never a day that goes by in which some unique aspect about this relationship reveals itself in some unexpected way. Choosing neurology as a profession in many ways is a blessing and a curse. The blessing is that you never fully can understand exactly what is happening and that is exciting, but it can also be terrifying when you appreciate the magnitude of those effects. JB: For my definition, you are really kind of in the pinnacle of practicing functional neurology, and I think that is further supported by the reviews that you have had when you have been an instructor at the Neurology Module (from the Institute for Functional Medicine). In those presentations you have often talked about case histories and experience you’ve had. Can you share with us the kind of patients you see, or, through the eyes of some of your patients, some of the problems that you’ve encountered that describe how we would kind of contextualize behavioral neurology? Research on Angiotensin Receptors in the Brain JL: I think you can choose any number of examples of this relationship. Something I think you may find quite interesting, Jeff, is the area of research that I am pursuing currently, which is the recognition of angiotensin receptors in the brain. For the listeners who are familiar with angiotensin, it is clearly something that cardiologists pay attention to because of its regulation of blood pressure, and it has a diverse effect on renal function, in terms of increasing sodium and water resorption. It increases vasoconstriction. It increases catecholine production, particularly norepinephrine. It has this very ubiquitous effect across many different organ systems and has not been thought about as being critical in brain function. This is a gross oversight, I think, on the part of both researchers and clinicians. In fact, angiotensin has effects on the brain and is involved in the stress response, specifically what happens during periods of time when people are in a fight-or-flight situation or in depression. It also has applicability for what I believe are a number of neurodevelopmental disorders, like autism. Looking at this key effect or molecule (if you will) angiotensin, and ways that it is implicated in both systemic disorders and also neurological disorders, I think provides us with a quite unique opportunity and window into understanding how to modulate this hormone, both for body problems (which is already being done through specific types of compounds like the ACE inhibitors and the angiotensin-receptor blockers), and also for mood and anxiety. What is particularly interesting about angiotensin is that it is directly influenced by vitamin D levels. Something I think really caught my eye (in terms of looking at something nutritional and something that can be easily assessed which has been overlooked) is that vitamin D levels are inversely proportional to angiotensin. The lower a patient’s vitamin D levels are, the higher angiotension (and particularly plasma renin levels are). Conversely, if we administer vitamin D (let’s say to either a human or to an animal), we can lower angiotensin and plasma renin. This has implications for many, many disorders, not just the cardiac diseases in which vitamin D levels have been demonstrated to be lower in patients with congestive heart failure. For instance, vitamin D levels are also lower in stroke patients and in MS patients. Recently we have uncovered what we think are some very significant abnormalities in vitamin D in autism as well. It is a very exciting area, which integrates both functional medicine and mind-body medicine. JB: That is a very interesting observation that I was unaware of. A number of years ago, I had the chance to present at Dr. Mark Houston’s conference on hypertension at Vanderbilt University Medical School. One of the co-presenters there was a gentleman who had been researching angiotensin for 20 years and was talking about angiotensin receptor blockers and angiotensin converting enzyme inhibitor drugs as being anti-aging drugs because he felt that angiotensin was one of the critical factors associated with accelerated biological aging of the heart vasculature and brain. He was showing how low-dose use of these ARBs and ACE inhibitors actually could be seen (from animal studies) as preventing age-related deterioration. What is the story from your perspective on these pharmaceuticals that have been used to modulate angiotensin? JL: I think there are clearly animal studies in which (particularly if you administer the angiotensin receptor blocking agents to animals prior to inducing a very traumatic type of stimulus)you can block a lot of the stress response. This is opening the door to looking at possibly using these agents for treating stress-related disorders like post-traumatic stress disorder or other disorders that you would normally not think of using an ARB for. Obviously the concern, I think (with ARB use particularly), is using them for purposes beyond what they are intended to be used for, and specifically what it is that has gone awry in our physiology that has created this disturbance in angiotensin to begin with. I think that is where the vitamin D story is quite interesting. If we look downstream at how angiotensin modulates a variety of pathophysiological processes, particularly interesting is a matrix protein that is highly expressed in blood vessels called thrombospondin. Thrombospondin is an atherogenic protein that is highly upregulated during ischemic events, whether it is acute ischemic events or chronic ischemic events. What happens once thrombospondin is activated is it sets into motion a cascade that actually works particularly on transforming growth factor and other proinflammatory cytokines. What is interesting about this whole cascade is that the ARB drugs, like Losartan and other drugs, are actually thrombospondin-inhibitors; that is, they can block this immune response by virtue of downregulating the thrombospondin. So, they have an effect that is both anti-inflammatory and anti-ischemic. With regard to vitamin D, particularly to the ARBs, one wonders if vitamin D is an endogenous ARB-acting agent. That’s something that I think we should be looking at. Nutraceuticals as Natural ACE Inhibitors JB: I have noticed there are a couple of nutraceuticals that have been developed and recently marketed to be natural ACE inhibitors. They are specific peptides of fish protein hydrolysate and casein hydrolysate. Do you have any clinical experience or thoughts about those? JL: The bonito, right? JB: Yes, bonito peptide. JL: I haven’t. I’ve not actually looked at those, but that would be an interesting compound to study to see if some of these anti-anxiety and anti-inflammatory effects that one sees with vitamin D would also be seen with the bonito peptide. I can tell you (just empirically) that I have seen many patients who are diagnosed with these very low vitamin D levels who do quite well (from a behavioral neurology perspective) with vitamin D supplementation. Again, I think the mechanism of action here is that it is acting as an endogenous angiotensin receptor blocker. I don’t know whether the bonito peptides have that same effect or not. JB: It has been very interesting to listen to you over the years because you can bring so many different disciplines into your presentations and into your perspectives. People listening might say, “I wonder what kind of training Dr. Lombard had?” If a person is on the path to gain mastery in this area, could you share with us the kind of training and postgraduate education prepared you with this perspective? JL: I think first and foremost one should go to as many Jeff Bland seminars as possible, and I mean that sincerely. You are singularly the one person that allowed me to open my eyes to these very beautiful molecular events that are occurring beyond the surface of how we think of physiology and pathophysiology and pharmacology-to always ask, what’s the next layer? It is like peeling the onion. I’ll call you the first “onion peeler,” Jeff. I use that onion-peeling approach to my psychiatry training and my neurology training. With any disorder I would look at (whether it was schizophrenia or depression or bipolar disease, Alzheimer’s or Parkinson’s), I would keep asking the question, “Okay, this is what we know. What is it that is the next layer below that that is creating that disturbance and so on and so on?” You end up at a very molecular level, looking predominantly intracellularly at mitochondrial energetics, specifically how all this relates to not just the mitochondria, but also peroxisomes, which I think is another area that we are bound to hear a lot more about in regards to its anti-inflammatory effects, cell survival, and the relationship of peroxisomes to mitochondrial function. This idea that the mitochondria are so instrumental in increasing vulnerability to disease by an energetic phenomena was something that I think you saw a long, long time ago and has come to fruition amongst many research scientists across a diverse span of disciplines, whether it is cardiology or neurology or psychiatry. As you mentioned in the introduction, in traditional medicine we all look at our separate silos. The cardiologists don’t really think about talking to neurologists or to the immunologists. To really get to the bottom of the fundamental elements of disease, as well as the introduction of positive health phenomena, we have to break down those walls and have each of the disciplines talk to each other and realize that we are talking the same language. As an example, I’ll be talking in ’07. I had to kind of brush up on my immunology because it is not something that I am as familiar with as the literature in neurology and psychiatry. I was specifically looking at what kind of biochemical cascade occurs as a result of T cell activation (when it is actually responding to an antigen). That cascade is identical to the cascade that occurs when a neuronal cell is depolarized. It is identical. There is this depolarization of the neuron with influx of calcium, and activation of these proinflammatory cytokines like TGF, caspaces, and all of those immunogenic enzymes. Identical. So here you have this biochemical pathway in immunology which is completely the same as the biochemical cascade that occurs when a neuronal cell is being excessively depolarized and perhaps going into an apoptotic mode. That really struck me as, “Wow, this is like a string theory, these identical modes of operation.” If you think about it, it makes sense. Nature is redundant. Nature likes to use what works and it is parsimonious in its execution of biochemical pathways. Neuronal Hyperexcitation JB: You have raised a very interesting topic that I know is on the minds of a lot of people, even those who have only done a cursory review of the recent neurology literature. This is the association between certain neurodegenerative problems and what is called neuronal hyperexcitation (or NMDA excitation). Can you tell us a little bit about this? I know you have spoken very eloquently and (I think) very beautifully as to how that whole pathway can be triggered by environmental agents (the NMDA excitotoxic pathway)? JL: Sure. That’s something that has really expanded in the last ten years in terms of its appreciation for the involvement of excitotoxic pathways in a variety of neurological problems, not just Alzheimer’s and Parkinson’s disease, but also in MS, ALS (or Lou Gehrig’s disease), diabetic neuropathies, epilepsy, bipolar disease, and autism. These-what I call the final common pathways of excitatory NMDA pathways in which glutamate is upregulated-occur (there are many roads that lead to Rome) particularly through the arachidonic acid pathway. When we have a diet that is high in the omega-6 arachidonic acid content, this leads to an excess expression of NMDA receptors. Arachidonic acid blocks glutamate reuptake, so when glutamate is found in high concentrations in the synapses, it binds to the NMDA receptor and sets into motion these pro-apoptotic or neuro-inflammatory pathways that appear to be linked to a variety of neurological diseases. One may say, “Well, how does that make sense because MS is very different than ALS?” This is true, but the explanation is that the phenotype is different because the disease process is occurring in different types of tissue, but the biochemical processes may be similar. For instance, bipolar disease and epilepsy are very different. Epilepsy is obviously a seizure disorder and bipolar disease is not a seizure disorder, but these glutamate pathways are disturbed in such a way that they are upregulated (in both diseases). Depending on which area of the brain in which that abnormal expression is reflected will give you the particular phenotype of the disorder. Is that clear? I’m not sure if I’m explaining that properly. MSG and L-Glutamine JB: Yes, it is, very much so. There are two molecules that have been in the news quite a bit and may connect to this NMDA glutamate excitation. One is MSG and the other is L-glutamine. Can you give us your top-line thoughts about each of those? There are people who are very concerned about MSG relative to this neurohyperexcitation, and there are those who will say if you supplement with L-glutamine you stimulate that same pathway. JL: Right. This question comes up a lot in the seminars-concern about creating an excess glutamate state in patients inadvertently by glutamine administration. There is really no data to support that that is the case at all, for several reasons. First of all, glutamine is used both for the synthesis of GABA and glutamate. In fact, those two neurotransmitters, which are diametrically opposed in regards to their physiological function, are in many ways mirror images of each other. Glutamate is used as the immediate precursor for GABA, which is kind of interesting (the poison [if you will] and the cure are within the same metabolic pathway). I think in regards to glutamine, specifically, there is no concern in my mind that giving glutamine to patients can theoretically increase glutamate in the brain. The MSG story, I think, is something that is more complicated. I have read some data in which they have tried to confirm if giving MSG exogenously would increase glutamate receptors through these kind of in vitro analyses of brains of rats, for instance. They were not able to actually activate glutamate receptors through MSG administration. That conclusion (from that particular study) was that MSG did not have a bearing on brain glutamate receptors. I’m not sure if I believe that, but that’s what the data currently demonstrate. I think one of the points to keep in mind here (and this is one of the difficulties in doing any kind of neurological research) is the blood/brain barrier. We have this barrier to prevent these kinds of problems. If MSG were able (through oral ingestion) to penetrate the blood-brain barrier, then I think it is a different game than if it is not able to enter the blood-brain barrier. The same thing may be true to a lesser extent with L-glutamine. It is also true, by the way, with GABA administration. On the therapeutic end, the same limitations apply, and that is that GABA does not cross the blood-brain barrier very well. So I think that there is this concept of blood-brain barrier or neurologically privileged biochemical milieu that makes these questions a little bit less of a concern than one would have at first glance. JB: You have raised a very interesting point that I actually had never thought about until you mentioned it. It has to do with the gut, which some call (as we interviewed Dr. Gershon several years ago) the second brain because it shares so many of the putative messaging compounds that the brain produces as neuroregulators. The gut doesn’t really have the barrier, in terms of the blood-brain barrier, as that kind of compartmentalization that the brain itself has. Is it possible that some of the things that we think are neuroactive are really operating through gut-signaling phenomena? JL: I think there is no question that there is signaling that takes place between peripheral biochemical factors and neurological factors, particularly as it relates to gut peptides like CCK, secretin, and other peptides. It has effects in changing brain signaling without directly crossing the blood-brain barrier, so I think that the subtext of your question is-if I’m reading this properly-is that, yes, it may be true that MSG does not cross the blood-brain barrier, and that glutamine or oral GABA don’t, but is it possible that signals can be communicated through some biochemical cascade indirectly, without those molecules directly crossing the blood-brain barrier. I think the answer is we don’t know, but certainly (in my mind) it makes sense, and (to add another level of complexity to this) the blood-brain barrier itself is disturbed in many disease processes. For instance, in MS patients (particularly with disease exacerbations), one of the biggest problems is that the blood-brain barrier is more porous than in people who don’t have MS. I hate to contradict myself because that is probably what some of your listeners are thinking right now, but I think the blood-brain barrier, itself, is disturbed by many systemic disease processes that changes the equation in regards to, perhaps, our thinking that something is not getting across the blood-brain barrier. I hate to say it, but there is really no easy answer to some of the questions that you are bringing up. Many people like to have simple yes or no answers or responses to these kinds of questions, but there are more “we don’t knows” in the fields of neurology and psychiatry than there are “yes, definitely” or “no, definitely.” That is, again, the blessing and curse of being in this field of medicine. JB: I know you have talked a little bit about the serotonergic pathways and how the gut secretes (I think) nearly two-thirds of the body’s serotonin. People have asked the question, “What happens if you do gastric bypass for morbid obesity and you put to rest your gut? Are you altering serotonergic peripheral metabolism in such a way that it has a whole-body effect?” Do you have any thoughts about that? Serotonergic Peripheral Metabolism Following Gastric Bypass Surgery JL: I have some empirical observations. Many people (patients of mine) who have undergone gastric bypass have done really horribly after surgery. One can certainly posit that by taking away that reservoir of not just serotonergic neurotransmission, but also a huge amount of different gastrointestinal hormones and peptides, that you have disrupted their milieu, and that has consequences toone’s health that we don’t even know about yet. Just on empirical observation, many of my patients actually have gotten sicker post-gastric bypass, and one wonders if that is the mechanism of action of why that has happened. JB: I want to go back and pick up something you said earlier about vitamin D. I have recently been following a blog that has been discussing the potential that vitamin D excess may have very serious adverse effects and that people should be managed to have low vitamin D levels because vitamin D has a serious of adverse triggering effects on the neuroimmune system. Have you followed this discussion at all? This contrarian view about vitamin D, (which I personally don’t share) seems to be picking up steam. I am wondering if you have heard about it? The Goldilocks Principle JL: I haven’t seen that literature. I think there is one thing to keep in mind with all of functional medicine in general, and this very much applies specifically to neurology and psychiatry. When we do any kind of intervention, whether it is pharmacological or nutraceutical, we have what I call it the “Goldilocks Principle”-it can’t be a little too cold or a little too hot, it has to be just the right temperature. I think that concept applies to vitamin D administration. Low vitamin D has (in my mind) many pathophysiological consequences related to neurology and psychiatry. It relates to its effects on angiotensin and also on other pathways, including IL-10, and also its effects on brain serotonin receptors. One can imagine that there are probably issues with high vitamin D (excess vitamin D). From a purely “Medical School 101” lecture, in some cases it can raise calcium and make patients hypercalcemic, and that is certainly a serious consequence without going into even more sophisticated explanations about vitamin D toxicosis. Beyond just that obvious concern about vitamin D intoxication are the anti-inflammatory effects of vitamin D-that high doses may predispose to one’s vulnerability to diseases related to immune suppression. I think you have to look at this as a dose-range concept, not just for vitamin D, but for anything we do exogenously to patients at a biochemical level. JB: I think that’s a very good watchword. I think Mike Holick and Colleen Hayes who have talked more about trying to get patients into the 40-50 nanograms per/mL 25-hydroxyvitamin D level and keep them in that range is a very good watchword rather than trying to say more is better. JL: Absolutely. JB: Could you tell us a little bit about your experience in behavioral neurology with natural products? You know we hear a lot of remarkable claims about certain botanical medicines and so forth. Obviously, ginko-biloba has gotten a huge amount of press, but there are many others (huperzine and others). Can you give us a sense, from your experience, where some of this really weighs out? Huperzine and Studies on Alzheimer’s Disease JL: Well, you mentioned huperzine, and I think huperzine (in my mind) is going to be one of the most phenomenal stories in natural medicine in the next several years if it has not already caught steam. Huperzine, as many people know, is a natural compound from Chinese club moss that was used in China as a botanical. Years back, the Mayo Clinic discovered that huperzine possessed an effect which enhances brain acetylcholine levels by blocking an enzyme known as acetylcholine esterase and began studying it for Alzheimer’s disease. Now the NIH is involved in some large-scale phase two studies with huperzine for Alzheimer’s. The preliminary data looks very promising. The other effect of huperzine, in addition to its effects as an acetylcholine agonist for the brain, is that it also acts as an NMDA antagonist, so it has an effect on upregulating acetylcholine and downregulating glutamate. It has an effect that is beyond its effect on just cognition. In this area, by the way-just as an aside which I also think is very interesting-there is a researcher not too far from where I practice at Northshore Medical Center by the name of Dr. Pavlov (and I think he may actually be related to the original Pavlov), who has done some very eloquent research on central cholinergic mechanisms having an anti-inflammatory effect. By stimulating central acetylcholine neurotransmission, one can decrease production of tumor necrosis factor and other proinflammatory cytokines. It is another area I think is emerging as one of these surprise findings of how the brain and the immune system are communicating indirectly through these very complex signaling mechanisms. I think huperzine is one example. To answer your question in (hopefully) a not too circuitous way, Jeff, there are tons of compounds that surprise me in terms of their efficacy. I think what is interesting in neurology and psychiatry is that the effects are not subtle. When you have an effect on something, when you take an autistic child, for instance, or you take an Alzheimer’s patient or a Parkinson’s patient and you do an intervention, the effects are very obvious. There are no grey areas here-people either do a lot better, or they don’t have an effect. When one challenges a patient with an intervention, whether it is pharmaceutical or nutraceutical, their report and their response is the harshest critic that one can have for a treatment. I tell patients this exactly. I say, “You are the harshest critic of a treatment-the response that you have. Nothing is more objective than how you feel after we do something or by taking something to help you with a problem.” JB: I’d like to do a little bit of a soundbyte with you here and get your quick vignette on each of these natural products, from your experience. Let’s go to gingko-biloba with memory. What is your experience? JL: Mixed. I think there are patients who have had benefit and there are patients who haven’t had benefit. The patients who I have seen benefit with it have reported it as increasing attentional mechanisms, and I have seen it help in patients who have microvascular ischemic disease. I have not seen much benefit in Alzheimer’s disease. JB: St. John’s Wort and depression. JL: I think it is an effective herb for depression. I have used it for mild to moderate depression. I have been reluctant to use it in more severe types of depression, but I think for dysthymic disorder, which is sort of a chronic low-grade depression, I find that it is at least as moderately effective as a typical SSRI or other traditional antidepressant drug. JB: Valerian and sleep. JL: I have found it not effective. JB: B-12 and folate for dysphoria and mild depression. JL: I have found methylfolate helpful for depression. I think the difference between methylfolate and folic acid is that the methylfolate is a preferred form to cross the blood-brain barrier. I have seen definite effects, not just in depression, but also in ADHD patients with methylfolate. JB: Ginseng and stress-related phenomena. JL: That’s a tough one. I have not been overly satisfied with my patients with ginseng. I actually looked at ginseng particularly for ADHD because it has some effects on dopamine receptors as a dopamine agonist, but I know that I’m certainly not a ginseng expert and what I have learned is that there are many different types of ginseng-red ginseng and white ginseng, for cold versus hot conditions. I think that I would defer to my acupuncturist and Chinese herbal medicine doctor to give better opinions on ginseng in this area. JB: Any botanical medicines you have found that are helpful in the area of stress-related dysfunction? JL: I think passion flower is one of my favorite herbal treatments because I think we need to pay attention to sleep hygiene as a key element. I think sleep is the single best anti-inflammatory agent known to man-better than Motrin, better than Advil, better than any nonsteroidal. I think that we as clinicians do not understand or appreciate sleep and its critical effects in acting as an anti-inflammatory agent, and anything we can do to restore a patient to a proper sleep can have an effect not just on their mental status, but also on their physical well-being. Passion flower is certainly one of the things that I have found extremely effective to help patients with sleep. JB: We have just a couple of minutes left and I’d like to at least touch upon something you said earlier. There is an emerging recognition of the importance of insulin resistance (hyperinsulinemia) and its relationship to dementia. I know you have had quite a bit of insight into that. Can you share some thoughts with us? Insulin Resistance and Dementia JL: How much time do we have left? I think this is one of the most phenomenally interesting areas of medicine that is emerging-that insulin resistance is a key factor, not just in one’s risk of developing dementia, but a number of neurological, psychiatric, and systemic diseases, including cardiovascular disease. Beyond just the spectrum of diabetes, insulin resistance is a fundamental disturbance in a pathway that leads to these very catastrophic disorders. In regard to Alzheimer’s disease, particularly, both Suzanne DeLaMonte at Brown University and Dennis Selko at Mass General (who are both very esteemed Alzheimer’s researchers) have done a lot of the groundbreaking basic science work on detecting that insulin resistance is indeed a critical pathological disturbance in dementia and this is supported by epidemiological data. Patients who are diabetic or pre-diabetic have a greater risk of developing Alzheimer’s disease, and anything we can do for our patients to improve insulin resistance, whether it be physical exercise or nutraceuticals or even the PPAR agents, such as the omega-3 fatty acids which have an effect on peroxisome proliferator-activated proteins, have effects as anti-inflammatory agents and neuroprotective effect by virtue of improving insulin signaling. JB: Do you feel there is any difference between docosahexanoic acid and eicosopentaenoic acid in that regard, or is it that as long as get the long-chain omega-3s? JL: I think the latter is probably true. I think there is more DHA expression in the brain than there is EPA. DHA is in high concentrations in both the retina and in synaptic vesicles, so as a neurologist, my interest is predominantly in DHA as a vital agent for neuroprotection. But I think that both EPA and DHA are certainly relevant because of their similarities and structure as their pleuripotent role in metabolic pathways, both in inflammation, platelet aggregation, neurotransmission, and peroxisomal activation. There are so many different ways that these compounds are found to be so vital to our healthy physiology that if I was on a deserted island and could take only one nutraceutical with me, it probably would be EPA/DHA for my patients. JB: Jay, I can’t tell you how much I’ve appreciated this. I know our listeners have as well. We have covered quite a wide domain here of discussion and you’ve done it eloquently, as always. I think it is a testament to your background and the birth of your understanding. Thank you very much. I know your patients have certainly valued from your years of training and perspective. I know you treat everybody from the sickest of the sick to the walking wounded and that requires many different skills and tools in your toolkit. You certainly fit and, I think, exemplify what we can a functional neurologist. Thank you so much for being with us. Continued good work and we’ll look forward to talking with you soon. JL: Thank you, Jeff. My pleasure.

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Bibliography

1 Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292(18):2237-2242. 2 Benoliel AM, Kahn-Perles B, Imbert J, Verrando P. Insulin stimulates haptotactic migration of human epidermal keratinocytes through activation of NF-kappa B transcription factor. J Cell Sci. 1997;110:2089-2097. 3 Kurokouchi K, Kambe F, Yasukawa K, Izumi R, Ishiguro N, et al. J Bone Miner Res. 1998;13(8):1290-1299. 4 Shoelson SE, Lee J, Yuan M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord. 2003;27 Suppl 3:S49-S52. 5 Ghanim H, et al. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation. 2004;110(12):1564-1571. 6 Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, et al. Local and systematic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappa B. Nat Med. 2005;11(2):183-190. 7 Friedrich MJ. Insulin effects weigh heavy on the brain. JAMA. 2006;296(14):1717-1718. 8 Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol. 2005;62(10):1539-1544. 9 Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease-is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80. 10 Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications. JAMA. 2006;295(14):1707-1708. 11 Behre CJ, Fagerberg B, Hulten LM, Hulthe J. The reciprocal association of adiopocytokines with insulin resistance and C-reactive protein in clinically healthy men. Metabolism. 2005;28(3):125-127. 12 Grundy SM. Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance. Clin Cornerstone. 2006;8 Suppl 1:S21-27. 13 Wong ND. The metabolic syndrome and preventive cardiology: working together to reduce cardiometabolic risks. Metabolic Syndrome and Related Disorders. 2006;4(4):233-236. 14 Walldius G, Jungner I. The apoB/apoA-I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy-a review of the evidence. J Intern Med. 2006;259(5):493-519. 15 Sierra-Johnson J, Somers VK, Kuniyoshi FHS, Garza CA, Isley WL, et al. Comparison of apolipoprotein-B/apolipoprotein-AI in subjects with versus without the metabolic syndrome. Am J Cardiol. 2006;98(10):1369-1373.

This is the 25 th anniversary edition of Functional Medicine Update for June 2007, volume 27, number 6. Here is Dr. Jeffrey Bland. Jeff, after a quarter of a century, from June of 1982, we are still putting this out every month. Jay, I can’t tell you what this means. Twenty-five years and it seems like a lot has happened in our world-certainly our world individually, collectively, and globally. It has been a privilege to share this mic with you over these 25 years. Thank you so much. My voice has become synonymous with yours, so I guess we are linked. At the birthing of this audio magazine, we were in the halcyon days of what was called the “blockbuster era” of pharmacology. I find it to be very interesting that now-in the 25 thanniversary June 2007 issue-that we are now looking at what the New England Journalof Medicine says in a recent editorial is the “Demise of the blockbuster?”1 In the last 25 years, we have seen the rising tide of the most profitable industry in America-the pharmaceutical industry. It has taken over much of our economy, and now we are starting to witness what appears to be the waning tide of a dominant theme of that industry: the development of the one billion dollar-per-year product called the “blockbuster.” This New England Journal of Medicine article, authored by David Cutler, says that the stoppage of the clinical trials of the cholesterol drug, Torceptrapib, by Pfizer in March 2007 resulted in Pfizer’s stock market value falling by 21 billion dollars overnight. Similarly, when Merck removed Vioxx from the shelves, their market value fell 25 billion dollars. These pharmaceuticals were both (supposedly one was and one was to become) blockbuster drugs. As you probably know, blockbusters have become increasingly important over the last 25 years for the profitability of the pharmaceutical industry. In the year 2000, 17 drugs brought in more than one billion dollars each in global sales. And in 2005, 94 drugs met this threshold. This increase over five years was very significant. Lipitor (atorvastatin), obviously, heads the list of blockbuster drugs with 13 billion dollars of annual sales, but there are many other medications that you probably recognize that fall into this category. These include Zoloft, Norvasc, Nexium, Singulair, Zocor, Advair, Plavix, and Effexsor. You’ll notice that these blockbuster drugs fall into interesting categories. We have SSRIs for depression. We have cholesterol-lowering drugs. We have drugs that relate to the management of vascular endothelial function, calcium channel blockers, anti-inflammatories, and anti-platelet agents. It is a very interesting family of drugs that you might even suggest would be called lifestyle drugs to some extent because they are all managing disorders of lifestyle in our population, as well as things that relate to either physiological or emotional dysfunctions that occur from the environment-gene connection. Factors Contributing to the Demise of the Blockbuster Drug We are starting to (as Dr. Cutler says) witness the demise of the blockbuster as a consequence of what he thinks are three factors. One factor is economic-companies becoming better at discovering and producing medications that fall into a class (so no one owns a class anymore). This tends to dilute the class, so a company may have the first statin (like Merck did with Nevacor), but then quickly it is filled in with many other companies, diluting the overall market size for each of the individual companies. The second issue is equity and access. The article states that even Medicare’s prescription drug benefit cannot be afforded by all people, and with the current cost trends (if they continue), Americans are likely to lose their tolerance for paying substantially more for drugs. As a consequence, we are starting to see a lowered use of drugs, and people starting to make decisions. “Do I really want to pay that large co-pay or pay for that drug entirely out of my pocket?” The third factor, of course, is what we call biochemical individuality-the recognition that pharmacogenomics and genetics are playing a role. Not all people respond to a one-size-fits-all type of drug as the blockbuster concept assumes. Different adverse side effects are produced in people with different cytochrome P450 polymorphisms. This realization changes prescribing patterns relative to potential adverse risk. If you look at the most significant singular cause of death-cardiovascular disease-you might say that these blockbusters have certainly helped to lower the incidence of major killer diseases as it relates to benefit-to-risk trade-off. I was very intrigued when I saw an editorial in the Journal of the American Medical Association titled, “The International Pandemic of Chronic Cardiovascular Disease.”2 It stated some things that I was unfamiliar with. I wasn’t aware of the fact that during the final decades of the 20 th century, even with the major medical advances made in the prevention of cardiovascular disease by the increasing application of statin drugs, that while there have been reductions in overall cardiovascular death rates, the overall incidence of acute myocardial infarction (or heart attack) has not declined and has actually increased over this period of time among women. If we take that global, we see there is an ever-increasing epidemic of cardiovascular disease in cultures like China, which was not genetically protected against cardiovascular disease (they were protected by the fact that their diets were cardioprotective relative to now transitioning to the Western diet and lifestyle which is cardio-risk). The construct that we are winning huge battles against the war of cardiovascular disease by the application of these drugs like statins doesn’t bear out when we look at the data. There is another paper that was recently published in JAMA that supports this, I think quite dramatically. The authors of this article looked at atherosclerotic arterial disease mortality rates after one-year follow-up in both primary and secondary prevention-type studies. Their findings also indicate that the incidence of MI continues to increase while the number of sudden cardiovascular death cases goes down.3 What we end up with is an increase in the number of chronically diseased people who have had a first heart attack. We have to learn how to manage these people. Whereas before they may have expired with their cardiovascular event, now they are able to be kept alive. And so they are not a mortality statistic, but they are a chronic disease statistic, and now we have to learn how to manage that condition as a chronic disease after a heart attack. Secondary prevention becomes a very big part of the new medicine. Of course, statins have been used both for primary and secondary prevention, as have many other of the vascular-related drugs-the ACE inhibitors, the calcium channel blockers, the beta-blockers. One might ask about the data supporting the efficacy of these drugs over the long term versus lifestyle/diet intervention. Those questions have led to the National Institutes of Health making its proclamation that we should be engaging in first-line therapy, which is to intervene with lifestyle, diet, and exercise before intervening with drugs. If we can get a patient to comply with lifestyle and diet intervention, these are safe and effective ways of ameliorating both first potential risk to heart attack and subsequent secondary events. Common Adverse Effects of Statin Use What are some of the adverse risks associated with things like statin therapies? We have all heard (at least anecdotally) that patients often get these diffuse neuromuscular symptoms-tingling and twitches, zips and zaps, and pains like a myalgia. In extreme cases, which, fortunately, are infrequent, we get rhabdomyolysis and loss of muscle; this is very serious and could even be life-threatening. For most patients, the symptoms are more subtle. They are musculoskeletal and neuromuscular issues. But there is another series of potential adverse side effects that I think are on the horizon for a population employing statins on a routine basis. In Britain, you can get statins over-the-counter without prescription at lower dose. There are even some who are advocating that young adolescents start taking statins to lower their cholesterol. This has become a family of medications with very wide use. What are the effects of lowering cholesterol? Decreased Libido in Males Associated with the Use of Statins One effect that has emerged that I find interesting. This was published in the British Journal of ClinicalPharmacology recently-a report on decreased libido in males associated with the use of HMG-CoA-reductase inhibitors (or statins).4 The reason for it (presumably) is that by lowering the pool of cholesterol, which is the precursor for the formation of steroid hormones, you induce an endocrine dysfunction by lowering androgens and producing hypotestosterone. In this particular paper, the authors said that in looking at two of the eight patients who had decreased libido during the use of HMG-CoA-reductase statin drugs, they found low testosterone levels. Again, I think we ought to be looking beyond just vascular effects into the other dynamics of cholesterol. Cholesterol has some principally important roles to play beyond as a precursor to hormones (the steroid hormone family). Cholesterol also serves as a very important precursor to bile acids (the deoxycholic acid), necessary for proper fat digestion, metabolism, and as a critical component of membranes (to lead to proper membrane morphology and therefore intercellular signaling). Biochemistry Review: Cerebrosterols What are some of the downstream metabolites of cholesterol in the body? They are not just solely related to the steroid hormones that we are familiar with (like testosterone and estrogen), but they also get metabolized into things like cerebrosterols. I think this is a very interesting part of the story. In a recent review of cholesterol biochemistry that appeared in the journal, Lipids, in 2007, there was a review of cerebrosterol, which is a 24S-hydroxycholesterol.5 It was identified more than a half century ago, and it was given the name cerebrosterol due to the fact that it was abundant in the brain. It was shown that the mechanism by which cholesterol is eliminated from the mammalian brain involves a hydroxylation into the cerebrosterol, followed by diffusion of the steroid over the blood-brain barrier. Cerebrosterol actually has some structure-function relationships with brain chemistry. Because of this, could we be modifying active intercellular signal communication agents by lowering cholesterol beyond that which would be considered optimal for that individual? If so, we might, then, induce alterations in some secondary metabolites of cholesterol that could produce action at a distance (in this case, maybe functional changes in brain chemistry). We have known for some time that people with very low cholesterol (lower than optimal) are individuals who have higher suicide rates. There has never been a direct cause-and-effect link that has been established-it has more been an association-but it does call forth some suggestions as to how we could modify bioactive mediator substances that are derived from cholesterol by lowering overall body cholesterol to too low a level. This suggests that there may be a U-shaped cholesterol-optimal function association-too low a level of cholesterol maybe putting a patient at risk to a variety of different issues related to cardiovascular secondary effects. This would be things like mood, and memory, and affect, and also things that are related to steroid hormones (as I was mentioning earlier, androgen deficiencies). And then too high a level of cholesterol, particularly in the atherogenic lipoproteins, obviously is associated with primary risk to vascular injury and vascular disease. There is this kind of bell-shaped relationship between cholesterol levels and function, with too low a level not being possibly good, and too high a level not being good. What is optimal? That would come back (obviously) to the individual and their own physiology. Cholesterol dynamics plays an important role; it determines how fast cholesterol turns over and gets excreted. Whether cholesterol is taken in from the diet or it is biosynthesized (with a majority of the cholesterol in our blood coming from that biosynthesized in the intestine and liver, de novo), the way it is eliminated principally from the body is by conversion into biosalts and then excretion in the feces as bile. Phytosterols and Cholesterol Absorption How do you facilitate improved GI turnover of cholesterol? You get into things like phytosterols (found in plants) that are cholesterol mimetics and bind cholesterol and help eliminate it from the GI tract (and bind bile acids, as well). A complex diet contains phytosterols, beta-sitosterol, and coumesterol. These have been identified with lowered LDL cholesterol levels and improved digestive function and reduced lipidemia. A recent article about phytosterols, cholesterol absorption, and healthy diets in the journal, Lipids, describes how important plant foods that contain these phytosterols are.6 Soy is known to have a very high level of phytosterols; flax has a reasonable amount of phytosterols in the whole form; oats have a reasonable amount of both beta glucan and phytosterols. With the use of phytosterols, we start seeing improved turnover of cholesterol and the favorable dynamics it has. There are ways our body has developed a relationship with our natural environment and our food supply system over millennia to regulate these dynamics, and we have altered this relationship by changing our diet and our lifestyle. And then we step in with drugs that lower a variable (that is, cholesterol) by blocking an enzyme (HMG-CoA-reductase). We may, then, be on the other side of the bell-shaped curve, and we may actually get some disadvantageous effects of that. I haven’t even spoken yet about the effects cholesterol has on co-enzyme Q10. Co-enzyme Q10 is derived from biosynthesis from mevalonate, which is the pathway that is blocked by statins. A lowered co-enzyme Q10 level may have effects on antioxidant defense systems and cardiovascular function. The cholesterol story is a much more complex story than it was made out to be in 1982 when we started to see Nevacor become the molecule of choice for saving people against the risk of cardiovascular disease. I think we have evolved and have come a long way in understanding this story. The theme of this month’s Functional MedicineUpdate is to look at a broader functional perspective. The functional medicine model has, in the last 25 years, had richness in its own evolution. It is now understood that things are connected, one-to-the-other, in a web-like pattern, and that we can’t really pull apart and tease out one variable in human physiology and look at it in isolation. We now recognize that diseases are interconnected through mechanisms, and that the concept of disease is losing some of its formality and some of its specificity because we recognize there is no such thing as an independent, “clean” disease that is uniquely the same in all patients that have that label attached to them (that diagnosis). What have we learned in 25 years about the role diet plays in modulating these functions? As blockbuster drugs have been developed to regulate, or control, or fix certain aspects of our broken physiology, what is the alternative view as biosciences have evolved over 25 years and as the systems biology approach to physiology has stared to become more clear? Through this work, we have learned that our diet plays a very important role (as does our lifestyle) in signaling to our genes how they are expressed. Our genes are the templates that have pluripotentiality (meaning they can be expressed in multiple ways) to give different outcomes based upon the environmental messages that the genes are receiving. Although we can’t change (as an individual) our genes, we can change the messages that are received by our genes and how that signals alternative function, in terms of what we call the phenotype (the outcome of the individual). Diet plays an interesting role because it is not just the foods that we eat in the moment. The information from our diet washes over our genes and creates a phenotype that reshapes us-our physiognomy and our physiology-and this occurs over decades of living. People generally tend to eat diets that are consistent for many years, and so the shaping of gene expression patterns occurs as an outcome from that information that those foods are bringing. The information molecules in food are macronutrients. They are vitamins and minerals. They are accessory nutrients. They are phytochemicals. And they are all this rich tapestry of information sent to our genes over time. We know diets today are very luxurious in calories. We have super-sized our diets. We also know that the information we are super-sizing is information that often is received by our genes as disinformation, or incoherent information. This disinformation can produce an alarm reaction in the way our genes respond. There is some question as to whether the best way of managing the risk to chronic disease is maybe to stop eating so much. This question leadsto the calorie restriction concept. More than 60 years ago, Clive McKay at Cornell University made the observation that when he put animals on a calorie restricted diet (about 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of their calories restricted), it increased their lifespan and compressed the diseases of age so they also had an improved health span. Based on his observations, he suggested that calorie restriction might be a way of extending lifespan. The calorie restriction concept has become well-respected in physiology as being the only demonstrable and reproducible way of extending lifespan in animals. It hasn’t been proven entirely in humans, but it certainly has been shown that calorie restriction in primates (monkeys) results in increased lifespan and a reduction in the diseases of aging, including cardiovascular disease, arthritis, and other things of that nature. Calorie restriction is not micronutrient restriction. It is not under nutrition relative to the quality of the diet, but rather it relates to the quantity of the diet. Could you introduce a calorie restricted diet to a population that is used to a luxurious diet (sometimes a smorgasbord-type of diet) and achieve the same benefits that have been seen in animals? In our world where food is part of our recreation, most people have a tough time complying with a calorie restricted diet and becoming part of a study of this type. Alternative Day Calorie Restriction Could Increase Compliance Could we, then, rather than go to a total calorie restriction, go to some kind of alternative day calorie restriction? Could that be more modifiable (every other day, or twice a week), and would you see any benefit? Recently, an interesting paper was published in Free Radical Biology and Medicine, in which researchers looked at patients with asthma.7 These were individuals who were overweight, had asthma, and obviously had an inflammatory condition with increased oxidative stress, as measured by different markers. The researchers measured peak expiratory flow, and they correlated that with quality of life questionnaires and the asthma rating scale. They also correlated the data with oxidative stress indicators. The patients were put on an alternative-day calorie restriction program (meaning one day they would eat an adlib diet, and the next day they would be on a calorie restricted program, and it would alternate one day after the other). The results were very interesting. A rapid and sustained beneficial effect of the alternative-day calorie restricted diet on the underlying disease processes was demonstrated. Oxidative stress markers went down, clinical symptoms improved, quality of life improved, and FEV1 (forced expiratory volume at 1 second) improved dramatically. These results suggest that this might be a novel approach for therapeutic intervention in this disorder. You could conceive all sorts of interesting ways of packaging a clinical program (a dietary and lifestyle program) that would be an alternative-day, calorie restriction program. Why calorie restriction? What is going on? This, of course, is a very interesting topic of investigation right now. In the March 7, 2007 issue of the Journal of theAmerican Medical Association, there was an editorial titled, “Aging Adiposity and Calorie Restriction.”8 In this particular paper, the authors did a kind of meta-analysis of PubMed from 1966 to 2006, using search terms that included calorie restriction, dietary restriction, aging, longevity, lifespan, adiposity, and obesity. They then reviewed all the reports that have been published under those topics, correlated the information, and tried to come up with an understanding as to what the trajectory of the literature is. Is it heading us down the road to say there is something here-there’s some gold in them thar’ hills? Or is this just an interesting intellectual observation? What they came to as a conclusion in this evaluation of the literature was that calorie restriction in adult men and women does seem to result in beneficial metabolic, hormonal, and functional changes. But we are not yet sure about the precise amount of calorie restriction that has to be achieved, or how much body fat mass has to be lost, to enhance the optimal outcome and to improve longevity. But it does appear, from the weight of the evidence at this point, that there is something there. There is gold in them thar’ hills, but we just may not know yet where the mother lode is: exactly how to package this in a clinical program that will lead to high compliance with optimal benefits. The information that is brought forth in the diet modifies all sorts of gene expression patterns and we get a whole series of altered postprandial messenger molecules: insulin, glucagon, insulin-like growth factor, somatostatin, cholecytostokinin… the list goes one and on and on. All these regulators connect the brain to the gut, to the pancreas, to the muscles, to the liver, to the adipocytes, to our endocrine system, and ultimately even to our central nervous and peripheral nervous system. There is this wonderful kind of orchestration that occurs after eating. In a postprandial state, these messenger molecules tickle specific receptors that modulate, then, gene expression patterns through a family of enzymes that we have talked about in previous editions of FunctionalMedicine Update: the kinase families that are kind of the translators of this outside information to inside gene expression alteration. Diet has a very, very big role to play. Diet, exercise, and stress management all trigger and signal through these pathways altered or modulated gene expression that then (over years) regulates the physiognomy and the physiology of the individual. SIR2 Gene Expression and Calorie Restriction Dr. David Sinclair at Harvard University has been involved with some interesting studies looking at specific phytochemicals. Out of the tens of thousands phytochemicals that are in food, he is looking at one-resveratrol-which we have heard about in red wine and peanut skin. What Dr. Sinclair’s group has been looking at is the effect that resveratrol has on the gene family expression of the SIR2 genes. SIR2 gene expression has been associated with the beneficial effects of calorie restriction. By restricting calories, resveratrol sends a signal to the SIR2 family of genes that are engaged in regulating aspects of metabolic control associated with longevity. Dr. Sinclair has been asking the question, can you modulate SIR2 not just by calorie restriction alone, but by also signaling with specific phytochemicals? Resveratrol, given at high dose to animals, has been found to produce a similar effect in terms of SIR2 gene expression as that of calorie restriction. So now the question is, could we then add supplemental levels of specific phytochemicals to our diet that would give them a mimicking effect to that of calorie restriction to make the compliance with this program both convenient and higher? There is a nice review of this potential target for calorie restriction mimetics, the SIR2 gene, that in Trends in Molecular Medicine.9 The article talks at length about how studies (starting with Sacromyses cerevisiae [yeast], from there moving to the flatworm [Caenorhabditis elegans], and now moving into animal studies) have shown that a specific phytochemical (in this case, resveratrol) can modulate SIR2 in the same manner as calorie restriction. The SIR2 gene is the so-called Silent Information Regulator 2 gene and it is known to help regulate lifespan and mediate the effects of calorie restriction, and it seems to have a mimetic (as I mentioned) of a phytochemical when given in high doses. Are there other phytochemicals in foods that help regulate specific gene expression patterns associated with longevity, lower oxidative injury, improve hormonal regulation, and may actually help fight the epidemic we are seeing in insulin resistance and type 2 diabetes? I just recently authored a paper titled, “Type 2 Diabetes and Heart Disease: All Roads Lead Through Altered Insulin Signaling.”10 This paper appeared in the Townsend Letter in the May 2007 issue. In this article, I try to describe what is happening right now. Information is exploding concerning how dietary variables and principles can modulate these signaling pathways that affect insulin signaling and ultimately modify gene expression through things like the insulin receptor substrate 1, and through various kinases like glycogen synthase kinase 3, phosphatidylinositol kinase gamma and delta, and ultimately protein kinase C beta 2 epsilon. All of these regulators of various functional materials within our diet can have the ultimate outcome on insulin signaling. What does this all mean? What it might mean is that it is not just a case of eating too much. It is a case of eating too much of the wrong thing. We are sending the wrong signals to these gene response modulating pathways-these receptors that are facilitated through kinases, that ultimately then signal into the gene a phenotype that is associated with lowered longevity and increased risk to age-related chronic illness. Let me give you a specific example that I think is interesting. The example is soy in its full state. Soy is a very complex plant food. It has many, many different constituents, including the protein, carbohydrates, and fatty acids, but it also has a rich array of phytochemicals like isoflavones and lignans, and these all play very important roles in regulating aspects of cell signaling. I already previously mentioned phytosterols like beta-sitosterol within soy that have these effects as well. With metabolic syndrome, there are a couple of things you should be aware of clinically that may not be well understood. Metabolic syndrome has a connection to many different clinical presentations, but one that is emerging (and seems almost epidemic in its increase) is obstructive sleep apnea. As you probably know, people with sleep apnea have to be on breathing assistance machines (or CPAP machines) at night. It has often been said that sleep apnea is a very strong risk factor to cardiovascular disease. If you think about what is going on at night when a person is going through apneic events, they are actually in a state of brain ischemia. It is like they are starving from a lack of a critical nutrient (oxygen) in their brain, and that is the time that produces the highest degree of cerebral oxidative stress. It is a paradox that low oxygen produces increased oxidative stress. We spoke years ago about the mechanism by which that occurs, but just suffice it to say that whereas our body doesn’t need to eat for weeks sometimes, and we don’t need to drink for days, if we don’t have oxygen or air for minutes, we are in trouble and it produces very serious brain ischemic events leading to oxidative injury. With obstructive sleep apnea, you get left ventricular hypertrophy as the heart tries to compensate for this oxidative problem. Obstructive sleep apnea is independently associated with metabolic syndrome, even in the absence of obesity. Often we think this is just an obesity-related problem, but there can be people with metabolic syndrome with sleep apnea who do not have high BMIs. I am quoting from a recent paper in CardiovascularDiabetology.12 Obesity, metabolic syndrome, and sleep apnea are all pro-inflammatory states. We don’t necessarily have to be obese in order to get some of these pro-inflammatory problems, but there is a high correlation, obviously, between metabolic syndrome and obesity. This correlation is discussed in an issue of ObesityReviews.13 In a group of Chinese adults in Hong Kong, treatment of metabolic syndrome led to improved sleep patterns and lowered apnea (this study was published inRespiratory Medicine).14 Alterations in brain chemistry brought about by metabolic syndrome seem to account for the connection with obstructive sleep apnea. Just as there are very important connections between metabolic syndrome and sleep disorders, so too is metabolic syndrome also connected to problems of erectile dysfunction in males. There is more and more evidence demonstrating that metabolic syndrome/insulin resistance connects with vascular endothelial dysfunction, which is connected to problems of erectile function in males, and so a lot of men are treating their metabolic syndrome with sildenafil. These men think they need assistance from a drug (Viagra), when really the surrogate problem that underlies this real problem is that of vascular endothelial dysfunction associated with metabolic syndrome. If you treat the metabolic syndrome effectively, erectile function improves and vascular endothelial function also improves. Metabolic syndrome and hyperinsulinemia is also associated with nonalcoholic steatohepatitis. By properly managing blood sugar and insulin through dietary and lifestyle intervention, we can also lower the potential risk to fatty liver, which (as you probably know) is the major cause of liver failure and the need for liver transplant. And there is another variable beyond just stabilizing insulin sensitivity. There is also the food toxicity connection through what we might call allergic-like responses and autoimmune complexed disorder. This is seen in patients who have severe liver disease and fatty infiltration. In one study, a gluten-free diet was found to reverse elevated liver enzymes in these patients. This study is described in a very interesting paper in Gastroenterology that suggests that if a patient has elevated liver enzymes of unknown origin, you might put them on a gluten-exclusion diet and that might have beneficial effects on their liver function.15 So we are starting to see a tremendously interesting evolution of this whole field and recognizing that what we eat connects so much to our signaling mechanisms. Here is an interesting example of why we should be looking at the enteric bacteria in our gut that connects signals to the rest of our body. I found this paper in Brain Behavior and Immunity in 2007 titled, “Infection-induced Viscerosensory Signals from the Gut Enhance Anxiety: Implications for Psychoneuroimmunology.”16The article indicates that infection in the gut may have an adverse effect on signals that go out systemically and affect brain chemistry, producing an altered sense of mood. In fact, there is now evidence that bioactive components from various hydrolysates of protein, like tryptic hydrolysates from bovine milk alpha S1 casein, have a positive effect on mood in individuals and reduces stress-related responses. What an unbelievable thing we are learning: that diet contains all these potential signaling substances. To think that a tryptic hydrolysate from a milk protein (a bovine milk protein) could, in fact, help us to manage stress and lower anxiety (be an anxiolytic) is just a truly remarkable step forward in our understanding of the role that diet plays on function. With all of this in mind, we are very pleased to have a world expert to share with us his almost 30 years of experience in this field of how nutrients within the diet and various active principals play roles in modulating function.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jeffrey Blumberg, PhD, FACN, CNS Director, Antioxidants Research Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging Professor, Friedman School of Nutrition Science and Policy Tufts University 711 Washington Street Boston, MA 02111 What better way is there to celebrate a 25 th anniversary than to have one of the pioneers and true icons in the area of antioxidant research, Dr. Jeffrey Blumberg, as our researcher of the month? Many of you are well aware of Dr. Blumberg’s contributions to the field, going back many, many years. Just quickly, for those of you not familiar with his background, Dr. Blumberg received his bachelor’s in pharmacy and a BS in psychology from Washington State University (WSU) back in the late 60s, and then went on to get a PhD in pharmacology from Vanderbilt University School of Medicine. He did postdoc training in the areas of nucleic acid, biochemistry, and nutrition, and ended up working at the Jean Mayer USDA Human Nutrition Center and Aging at Tufts. He is a professor in the Friedman School of Nutrition Science and Policy, at Tufts University and is the director of the antioxidant area of research at Tufts. Dr. Blumberg has a rich portfolio of publications in top-level journals. One article that influenced medical world opinions and perspectives about antioxidants was an article that he principally authored that appeared in the Journal of the American Medical Association in 1997 titled, “Vitamin E Supplementation and in vivo Immune Responses in Healthy, Elderly Subjects.”17 This was a randomized, controlled trial that we actually reviewed on Preventive Medicine Update back in those days. The conclusions of that particular paper indicated that vitamin E supplementation could enhance certain clinically relevant in vivo indices of T-cell-mediated function in healthy, elderly people, and that there were no adverse effects observed at that level of vitamin E supplementation. That is just one of many, many papers-in fact, over 100 publications according to my counting-that Dr. Blumberg has authored. One of his recent papers that I hope we’ll get a chance to talk briefly about is in the Journal of the Society for Integrative Oncology this year. Dr. Blumberg and his investigating group are looking at a question we have all asked: Do antioxidants supplements during radiotherapy (or chemotherapy) have any effect on the outcome?18 An animal trial that was just published is part of the answer to that story. Dr. Blumberg, thanks so much for joining us on Functional Medicine Update. JBlumberg: It’s my pleasure to be with you. JBland: To set the context for our listeners, who are principally practicing healthcare providers around the world, it might be interesting for them to hear a little bit of a thumbnail from you about what got you into this field and how you got started down this road of looking at and then becoming a world expert in the area of antioxidant physiology. JBlumberg: Well, it’s a long story and has a lot to do with serendipity. I actually had been doing research in environmental toxicology and was looking at some common pathways for a number of different pollutants, which was lipid peroxidation. When the opportunity came to move to the Tufts Human Nutrition Research Center on Aging and I had to start doing more nutrition research, I was asked by the founding director of the Tufts Center what I was feeding my experimental animals when exposing them to these toxicants. I asked, “What difference does it make what’s in their diet?” And that was my first real lesson in nutrition, and then I learned all about the power of antioxidants to protect us not only from exogenous free radical peroxidant sources, but from endogenous production of these toxic compounds as well. Now, about 27 years later, I know just a bit more about it. JBland: To say the least. If you could let people kind of have an insight as to what goes on at the Tufts and Human USDA Nutrition Center on Aging it might be interesting for them to understand the collaborative group you have there, which is quite impressive. Tufts Human Nutrition Research Center on Aging JBlumberg: We have about 200 faculty and staff here. As you may recall, from ancient history, when the recommended dietary allowances were established for different age groups, there were RDAs for pregnant women and for toddlers and for adolescents and adults, and then there was a group of RDAs called “51-plus years,” as though the nutrient requirements for people over the age of 51 (61, 71, 91, 101) were all the same, and although I don’t think anybody believed that was the case, there was simply no data available to indicate how nutrient requirements changed as we got older. The institute here at Tufts was established back in 1981 to ask the question, “Using people who are older, what are your requirements for essential nutrients? And now that we are increasingly looking at a variety of phytochemicals as well, what are the requirements to promote health and reduce the risk for chronic disease in people who are 70, or 80, or 90 already? In those early days (before 1980), the assumption was that as you grow older, obviously your requirements for a nutrient goes down because you are more sedentary, you lose weight, you don’t eat as much, and you just don’t need as much. What we have found, of course, is that exactly the opposite is the case for a variety of reasons, some being age-related impairments in the ability to absorb nutrients or metabolize nutrients. The requirements for nutrients for older people oftentimes go up and go up substantially as we get older. JBland: For the sake of, again, our listeners who may be unfamiliar with the range of things that you have been involved with, I’d just like to highlight a couple of the many-180 or so-publications that you have authored. You have been recently in the European Journal of Clinical Nutrition with an article on the effect oat beta-glucan on blood pressure, carbohydrate metabolism, and biomarkers of oxidative stress. You published a review of South African herbal teas, and also a review of the bioactivity and potential health benefit of peppermint tea, and yet another review on the health benefits of chamomile tea. You have also looked at age-related associations between acute exercise-induced interleukin-6 and oxidative stress in humans. The work that you have done and published on cocoa and how it affects blood pressure and endothelial function and insulin resistance (collaborative work with a group in Italy) is (I think) fascinating. Flavonoids from almond skins and the effects they have with vitamins C and E is another topic you have written about. Lutein and zeaxanthin and their roles in disease prevention, and on and on and on… I just want people to recognize the breadth of experience that you bring from the many different collaborative research projects and individual research projects you have pioneered. Phytochemicals and Zoochemicals: The Forefront of Nutrition Science JBlumberg: Thank you. I would tell you that part of this has to do with just staying at the forefront of where nutrition science is going. We are entering a new era, where we are beginning to recognize that there is so much potential from the so-called non-essential nutrients. Vitamins and minerals clearly are very important and we are learning so much about how fatty acids can affect health as well, particularly some of the omega-3 fatty acids (for example, in ratios with the omega-6 fatty acids and so on). There is this enormous area with virtually tens of thousands of phytochemicals (and I would add even zoochemicals) that we are now learning that are part of our diet and can have a huge impact in the promotion of health and the prevention of chronic diseases. Whether they are carotenoids, flavonoids, or stilbenes, we have all of these tantalizing studies that tell us how important these molecules are. It is very interesting, then, to look at what some people like to call complementary or alternative medicine and find that some of these very nutrients that we find in herbal teas and some fruits and vegetables and whole grains, in fact are important components in the practice of Ayurvedic medicine, traditional Chinese medicine, and Native American medicine. We are actually at the cutting edge, while also going back a millennia or two in traditional medical practices to find out what the bioactive ingredients are in all of these plant components that are used. Controversial Study Linking Antioxidants and Mortality in JAMA JBland: With that great context, now we go to the thorny side of this discussion, and that has to do with what appears to be an ever increasing body of literature that has been published in first-tier journals that suggests that antioxidants (at least as they have been used in these trials) may not have beneficial effects and may even have deleterious effects. This controversy dates back to the beta carotene smokers study in Finland — that we had the chance to discuss some years ago on Functional Medicine Update — right up to the recent and highly publicized discussion concerning the JAMA paper that appeared February 28, 2007 titled, “Mortality and Randomized Trials of Antioxidants Supplements for Primary and Secondary Prevention.”19 The authors of this paper stated that treatment with beta carotene, vitamin A, and vitamin E may increase mortality, and the potential roles of vitamin C and selenium on mortality need further study. This has raised a pretty large flag for many people within the healthcare community about the safety and relative risk of antioxidants. Could you help us to kind of understand the origin of this meta-analysis/systematic review? When you talk about reviews and meta-analyses, we know there are always different ways of interpreting data, so maybe you can help guide us in this area? JBlumberg: Vitamin studies always seem to stir controversy, particularly in JAMA or the New England Journal of Medicine. In part this is because these publications like to choose controversial studies when they publish anything about nutrition. While there has been controversy about some of these vitamins, they certainly have never stimulated visions of death like this study by Bjelakovic and his colleagues in Denmark. I would tell you that this is such a fundamentally flawed study that the conclusions are of no value at all, but I have to place it first in a somewhat larger context because you talked about how many of these antioxidant clinical trials have been-at best-disappointing in having null outcomes, and in some cases in a meta-analysis like this particular one in JAMA, suggesting terrific harm is being done. I would like to tell you that it is my viewpoint that with many of these null outcomes of antioxidants, you really have to understand that these were secondary prevention trials. That is, these trials were conducted using people who already had a disease, most commonly either some form of cancer or heart disease, and then they were given the antioxidant supplements, which might have been a single compound like vitamin E, or sometimes just a few antioxidants like beta carotene plus vitamin C plus vitamin E, and even those. There have been few trials where they tried to look at more than one antioxidant at a time. The promise of antioxidants has always been in the prevention of chronic disease, as opposed to the therapeutic treatment and the reversal of established lesions like in atherosclerosis or in tumorogenesis. So, in some respects, it is not too surprising that even with all of the many, many, many observational studies that show that healthy people who take antioxidant supplements are at a lower risk for many chronic diseases, including Alzheimer’s disease and other age-related dementias, that when you do a study in people with cancer or heart disease, the compounds (these antioxidants) are not so successful in reversing the disease. They never really were established to reverse disease; they have always been about preventing them. Moreover, there is another confounding factor that I think most people fail to realize about these studies. As an example, in several studies of patients with heart disease who were given vitamin E, the results showed (in most all of these studies) that vitamin E didn’t prevent a secondary cardiac event like a myocardial infact, but people think these are studies about vitamin E. The real question being asked in these studies is: Does the antioxidant supplement, like vitamin E, when given with anti-platelet drugs, beta blockers, calcium channel blockers, ACE inhibitors, anti-coagulants, diuretics, statins, and other drugs significantly reduce the risk for reoccurrence of an event in the presence of this polypharmacy regimen? Frankly, in my view, that is asking an awful lot of any vitamin-to prove that it is substantially more efficacious than six or seven well-established drugs. JBland: I think that is really insightful. It always strikes me as interesting when I look at these papers-there are a couple of things that you have alluded to that are very interesting-that first of all, given the flaws in the way that these studies are done, how do they end up in a tier one journal? One expects, with a very high rejection rate, that you’d only get the crème de la crème of papers. That’s question number one. Question number two is: Why is there not a contextualization of these types of studies in the broad array of research with many of these papers that have been done by you and your groups that show very positive roles of intervention in human trials? It seems like there is never a balance in this discussion. JBlumberg: I agree. I think if you really want to find a number of very high quality research studies that deal with the efficacy and the safety of dietary patterns and specific nutrients and dietary supplements and so on, there are a number of wonderful, peer-reviewed, scientific journals in the nutrition field that do publish them on a regular basis. But when you get to some other journals, such as JAMA or the New England Journal of Medicine, and you do a survey of those nutrition articles they publish, you’ll come to a quick conclusion that they seem almost always to publish only very controversial and very negative results. They tend to reject studies that are published elsewhere that show the benefits of nutrition. But let me further address this recent JAMA article by Bjelakovic and his colleagues in Denmark that looked at all-cause mortality in people taking antioxidant supplements.I want to clarify something. I would just remind you that almost every single one of those clinical trials of antioxidant supplements was, in fact, a secondary prevention clinical trial. I’ll summarize it briefly. What they did originally was to identify 1663 clinical trials of antioxidant supplements. Then they excluded 848 of those trials that were looking at more acute outcomes like infectious disease or some cancer outcomes that they decided they didn’t want to consider. So then they had 1815 trials to review, but then they excluded 747 of those trials because they had no deaths. So they had 747 trials of antioxidant supplements that showed antioxidant supplements are not associated with any mortality, but because they were interested in mortality, they didn’t look at any studies that had no deaths, which is a very interesting bias in approaching this. Then they ended up with 68 trials that they decided to actually put into their meta-analysis, but when they came to reaching their conclusions, they excluded 21 trials that they felt didn’t meet their high standards for methodological protocol, and therefore they called studies with “high bias,” so they excluded those from their analysis. So they really only looked at 47 trials, but 21 of those trials looked at selenium, which actually was associated with reduction in all-cause mortality, so they excluded those from their final analysis. So in the end, of the 1663 trials that they had identified (looking at antioxidant supplements), they based their conclusions on 26 clinical trials. Well, that is cherry picking the data. You can draw any conclusion you want if you only pick studies that already show the conclusion that you would like to reach. I suspect this might be the case because this very group published an article in Lancet three years ago that looked at antioxidant supplement studies in cancer trials and they came to exactly the same conclusion that antioxidants actually kill you instead of help you, but they did that by eliminating what they considered to be any study that showed a benefit and had no harm because those studies were of low methodologic quality. I think it is a deeply flawed meta-analysis that is allowed because of the esteem-the gold standard-that randomized clinical trials are considered to be. The fact that they reached this conclusion and said it was based on randomized clinical trials is, I think, totally fallacious. They managed to ignore most of the clinical trials that have been published, and they did not consider this in the context of what we know from experimental studies, from observational studies, which have established the safety of these compounds. They had to ignore that to come up with a conclusion that simply had no coherence with any other published studies and what we know. It was certainly controversial. It got a lot of headlines. It was covered in most every newspaper in the world, even though it was completely inconsistent with all known studies about antioxidants. And nobody asked the question, what is the importance of all-cause mortality? What were people actually dying of, that you say that antioxidants now kill you? Well, they didn’t bother to tell us. In fact, if you go back to the individual studies, all-cause mortality, of course, means death for any reason-death from heart disease, hip fracture, infectious disease, cancer, suicide, homicide, drowning, automobile accidents-all of those causes and others were included in this analysis. I would suggest that there is no biological plausibility that if you take an antioxidant supplement you are more likely to be in an automobile accident and die, and yet this paper did exactly that. And so I find a difficulty in drawing any meaningful conclusions from such a highly biased and flawed study. JBland: Thank you very much. Very eloquent interpretation and evaluation of the work. The two questions that I commonly have asked to me by clinicians that have been confronted with patients who have asked about this study are: Number 1, what do I tell my patients when they ask me about the safety of vitamin C, E, A, or carotenoid supplements?; and 2, should I be telling them to take these supplements really as a mixture of complex phytochemicals in food or is it still adequate to say good diet plus taking these individual nutrients as supplements? JBlumberg: Well, as I indicated, this study is not coherent with everything we know. The Institute of Medicine has established tolerable upper levels for most all of the essential vitamins, including vitamin C and vitamin E and the mineral, selenium. And those numbers are much higher than this particular article suggests. I guess I would like to make one other point, and that is that this meta-analysis violated some of the basic statistical principles of meta-analysis, which is that you are supposed to compare comparable things. But, they included in their studies clinical trials that lasted 28 days, some lasted 12 years. Some were studies of doses as low as 10 IU of vitamin E, others as high as 5000 IU of vitamin E. But they put them all together and compared them. Some were studies of vitamin E (where they attributed deaths to vitamin E) that they didn’t mention actually had 5, 6, or 7 other nutrients also given in the supplement. It just makes no sense. I think when clinicians are faced with highly controversial studies like this, that the first response-and I think it should always be the first response-is that you should not make either a medical decision or a lifestyle change based on one, single study. And of course, this study by Bjelakovic wasn’t even a new study; it is a meta-analysis of old studies. One study can always be misleading, and certainly this one study is, but what we do know from the totality of evidence that has been collected over many decades from many different research approaches, including clinical experience, is that antioxidants in our diet, antioxidants in dietary supplements or in functional or fortified foods, are quite safe, even at doses that I don’t happen to think one needs to go to (really very high doses I don’t think are necessary to achieve their benefits). But they are beneficial, and they have been shown to be safe. The Institute of Medicine says that you can consume 2000 milligrams of vitamin C a day and it is perfectly safe, although if you go over, you may actually develop loose stools, which I’m not quite sure is a very serious toxic side effect, but there is a consensus about how safe vitamin C is. There is a consensus from The Institute of Medicine that doses up to 1500 IU of vitamin E a day are completely without harm, even though we actually have long-term (five-year-long studies-randomized clinical trials) using 2000 IU of vitamin E where there were no adverse events and no effect on all-cause mortality, either. JBland: So when we look at the relative benefit-we’ve been talking about risk, but now I go to many of your studies and that of your colleagues looking at the benefit, particularly in older-age individuals and individuals on various exercise programs-there seems to be (now that we are focused so much on risk) the loss of understanding that there is a lot of work out there that suggests benefit at doses that would not be extraordinary, but intakes that are within the 400 IU range. Many Trials Have Shown Benefits of Antioxidant Use JBlumberg: Oh, absolutely. Again, if you want to stick to randomized clinical trials, the age-related eye disease study showed that an antioxidant combination of vitamin E at 400 IU, vitamin C at 500 IU, plus selenium, zinc, and copper reduced the risk of age-related macular degeneration-an untreatable form of blindness in older people-by 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. We know from studies that my colleagues and I have done that vitamin E supplements at 200 IU in older people can reduce significantly the incidence of upper respiratory tract infections, which (by the way) just happen to be the fourth leading cause of death in older people. We know from the recent Women’s Health Study that older women (over the age of 60) had a 25{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction in the risk of cardiovascular mortality from taking 300 IU of vitamin E every other day for 10 years. And this doesn’t even get to the greater number of observational studies that really have been looking at healthy younger adults who take these supplements for a long period of time and then seem to be at lower risk for a variety of chronic diseases, although most of the emphasis has been on cancer, cardiovascular disease, and some eye diseases like cataracts and AMD. There are lots of studies showing benefit and safety, including some randomized clinical trials, but the most positive data comes from observational studies because they are looking really at the role of these antioxidants in primary prevention, whereas the randomized clinical trials (and I do want to be candid that many of those randomized clinical trials have failed to find a benefit, although none have really found harm, and when harm has been found… for example, there was one study that showed vitamin E was associated with an increased risk of congestive heart failure, and I do believe that study found that, but if you look at every other randomized clinical trial of vitamin E supplements, there is no evidence of that happening, so I just think it was a fluke). Some of the time, these kinds of events can happen, but they only happen in one study. As you know, when you can repeat a study, or when no other study has come up with that same observation, then it is really not credible to say, “Aha, vitamin E causes congestive heart failure.” It doesn’t. One study, one time, and no other studies ever have shown that effect. But when people want to write articles and talk about the harm of these compounds, they will cite the one study that supports their contention. Synthetic Tocopherols vs. Natural Source Tocopherols JBland: One of the things that we often hear, and I’m sure you’ve heard this question many times, is that studies not only have differing lengths of time and different patient intake criteria, but they also use different levels and different amounts and different types of the nutrients, and I have often heard the question, is there a difference between the all-racemic synthetic tocopherols and the RRR natural source vitamin E? I guess the question is, do you feel that some of these studies have confounding variables as it relates to the source of these ingredients? JBlumberg: I think many of these studies have a large number of confounding variables, but I wouldn’t overstate the difference between the synthetic and the natural source forms of vitamin E. There is a difference. The natural source form is much more bioavailable and much more potent than the synthetic form. But we know from trials that have used the synthetic form, and from observational studies that have looked at people using that synthetic form, that the synthetic form works. It doesn’t work-perhaps-as well, or it requires higher doses to get the same efficacy, but I think the things that confound some of these studies much more are other variables that have not been looked at. There is a very interesting recent paper that has just come out trying to identify the effective dose of vitamin E to lower levels of isoprostanes. This is a validated biomarker of damage to lipids and lipid peroxidation. Because many of the studies that have been done (the randomized clinical trials that have failed to find an effect) said, “Well, we’re testing vitamin E as an antioxidant,” and then they didn’t find a beneficial effect, but they actually never tested whether, in fact, they got an antioxidant effect, particularly in patients who had very high levels of oxidative stress because of their diabetes, their smoking addiction, the presence of heart disease, and so on. But we are finding, in fact, that in these patients, we may need much higher doses than the 200-400 IU that are used in many studies of vitamin E. If we are looking at sick patient populations, this study was suggesting that we’d need over 1000 IU to achieve a reduction in the plasma levels of isoprostanes. JBland: That’s fascinating. I’m reminded of the work that Maret Traber at the Pauling Institute and Bruce Ames have done down in Northern California that have at least suggested that with vitamin E the inclusion of some of these other forms (other than the alpha form, specifically I’m speaking of the gamma form here) may have some additional benefit. Plants make mostly gamma and yet we supplement mostly with alpha. Do you have any thoughts about how that field is evolving? JBlumberg: I think we certainly are finding that other forms of tocopherols and tocotrienols (closely related cousins to the tocopherols) do have bioactivity, including gamma tocopherol, which has a unique ability that alpha tocopherol does not have: to quench reactive nitrogen species. However, I think it is important to recognize that while we consume, in the American diet, about five times more gamma tocopherol, in part because we get a lot of that from soy beans and corn oil that are in our diets, that in fact if you look at our plasma, we have five times more alpha tocopherol than gamma tocopherol because our liver discriminates in the absorption of vitamin E against all forms of vitamin E and preferentially absorbs the alpha tocopherol form and packages that into lipoproteins for distribution throughout the body. This does not mean that non-alpha tocopherol forms of vitamin E have no bioactivity or that they are not important. We think they do play unique roles, but the human requirement for vitamin E is based on alpha tocopherol now because of the identification of very specific hepatic transfer proteins that deliver alpha tocopherol, specifically, in to our body. So that’s really our highest requirement, but again, I don’t want to suggest that there is not some very exciting research suggesting that some of the other forms of tocopherol might now play some very interesting and unique roles, independent of that of their antioxidant functions. JBland: And when we look at carotene, I recall the paper that was published many years ago that kind of challenged us to look under double-blind, randomized, clinical-controlled trials as to whether beta carotene, in supplemental form, could be a cancer chemopreventive agent. And then more recently, the work of Walt Willett and his group at Harvard in a kind of epidemiological study, looking at the relationship of vitamin A, which is obviously the metabolite of carotenoids in humans, and its relationship to fracture (spontaneous bone fractures at high levels of vitamin A intake). Is there a different story, do you believe, that is emerging around the carotenoid and the retinoid family than we see in the vitamin E story? JBlumberg: Yes, I do think it is a different story, but it is really important to understand the difference between beta carotene, or other pro-vitamin A carotenoids, and pre-formed vitamin A, or retinol. We’ve actually known for some long time that high doses of retinol (pre-formed vitamin A) can be quite toxic. The Institute of Medicine’s tolerable upper level for vitamin A suggests it is one of the more toxic vitamins; that is, it is the difference between its required intake and the lowest observed adverse effects is a relatively small margin of only about 5-fold, whereas for many nutrients we have 20-, 100-, 1000-fold differences between requirements and adverse effects. But what we do know is that pro-vitamin A compounds, like beta-carotene, are really remarkably safe because they are converted into vitamin A only to the extent that the body requires it, and then what you see is the accumulation of the carotenoid rather than accumulation of retinol, so it is very safe to meet your needs through as high a dose as you’d like of pro-vitamin A carotenoids like beta carotene or beta cryptoxanthin. But, as you mentioned a couple of times, studies have shown that high doses of beta carotene in heavy smokers does increase their risk for lung cancer, in contrast to the observational data that suggests that people who had high levels of dietary beta carotene intake for long periods actually had a reduced risk of lung cancer. There is no doubt that the results of the alpha tocopherol/beta carotene study in Finland, or the carotenoid and retinol efficacy trial done in the United States, showed that high doses of beta carotene given to people who have extraordinarily high oxidative stress due to 30 years of smoking do have an increased risk, but even if you look the subgroup analyses of those studies, the increased risk for cancer was not just in smokers, it was in the heaviest smokers (those smoking 2 packs or more a day) and who (by the way) were drinking at least 3-5 alcoholic beverages a day, so that toxicity of high doses of beta-carotene (these were doses that increased beta carotene levels up to 60-fold higher than you could ever achieve from diet or low-dose supplement). But this adverse effect of beta carotene is really an interaction with high levels of oxidative stress through heavy smoking, plus high levels of oxidative stress and liver damage due to alcoholism. And we know from experimental studies that have been done more recently, that this adverse effect doesn’t occur when in the presence of additional levels of vitamin C and vitamin E. The recycling of these compounds and the sparing of one on another to prevent the eccentric cleavage, that is, the abnormal breakdown of beta carotene, which is the actual toxic principal in these cases, does not happen when the antioxidant status of other compounds in this very complicated defense network are there as well. So, it is true that if you take this one beta carotene molecule outside of the antioxidant defense network, provide it at very high levels to people at extraordinary levels of oxidative stress, you do get an adverse effect that is real, I don’t think that necessarily is a message that translates well to people who are otherwise healthy-not smokers, not alcoholics, and are eating pretty good diets or taking other antioxidant supplements that complement the carotenoids. JBland: That was a brilliant answer. Thank you-very, very complete. We’ve just got a minute left, Dr. Blumberg, and maybe I could just close by asking you one last question. Given all that you have talked about, and our increasing sophistication and understanding, do you feel that we are witnessing the end of an era related to how nutrient supplements have been viewed and moving into a new era? JBlumberg: Absolutely. I am very excited by the advances being made today in nutrition science. We are now looking at compounds that we didn’t even know about-or barely knew about-in the past, like resveratrol, a stilbene that is found in grapes and red wine and peanuts. We are learning much more about the complex array of somewhere between five and ten thousand different flavonoids and their antioxidant effects. But even more importantly, what we are learning about-and I think this is very important for the design of new research studies-is that antioxidants are unusual in being classified by their putative mechanism of action. What we actually know is that antioxidants, like many other nutrients, are multifunctional molecules. And while it is true they have antioxidant actions, they have a number of other mechanisms for bioactivity that may, in fact, importantly underlie some of their health-promoting benefits. JBland: Well I can’t tell you how much we appreciate this. You have given us more time than I know you probably had available, but we appreciate your sacrifice of time. What a great way to celebrate our 25 th anniversary of Functional Medicine Update with your very lucid and global perspective. Thank you so much. JBlumberg: You are very welcome. Well, Jeff, this wraps of 25 years of doing the update every month. It has been a rewarding and fulfilling journey (at least it has for me). What do you see for the next 25? Jay, I really share that extraordinary feeling about the future with you. I think what we have started to witness is what was just an apparition for us 25 years ago: the hope that we would ultimately start to understand the role that nutrients play in both prevention and management of complex chronic health problems, the compression of morbidity, and the achievement of the benefit that we have been looking for: to allow people to live to the limits of their biologically determined lifespan so they could maybe have two or three careers in a life, and if they practiced the right things, they could actually achieve those kind of helpings that were given within their genes. I think that this concept of signaling, and kinases, and gene expression is witnessing the birth of a whole new view of the role that diet, nutrition, and lifestyle play in modulating our function. And we’ll make this, over the next 25 years (if we can be so lucky as to continue), a voice for the new medicine that is emerging. It has really been a privilege to be a part of this with you over the past 25 years and I look forward to the next.  

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1 Cutler DM. The demise of the blockbuster? N Engl J Med. 2007;356(13):1292-1293. 2 McDermott MM. The international pandemic of chronic cardiovascular disease. JAMA. 2007;297(11):1253-1255. 3 Steg PG, Bhatt DL, Wilson PW, D’Agostino R, Ohman EM, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;297(11):1197-1206. 4 De Graaf L, Brouwers AHPM, Diemont WL. Is decreased libido associated with the use of HMG-CoA-reductase inhibitors? Br J Clin Pharmacol. 2004;58(3):326-328. 5 Bjorkhem I. Rediscovery of cerebrosterol. Lipids. 2007;42:5-14. 6 Ostlund Jr. RE. Phytosterols, cholesterol absorption and healthy diets. Lipids. 2007;42:41-45. 7 Johnson JB, Summer W, Cutler RG, Martin B, Hyun DH, et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med. 2007;42(5):665-674. 8 Fontana L, Klein S. Aging, adiposity, and calorie restriction. JAMA;297(9):986-994. 9 Chen D, Guarente L. SIR2: a potential target for calorie restriction mimetics. Trends in Molecular Medicine. 2007;13(2):64-71. 10 Bland J. Type 2 diabetes and heart disease: all roads lead through altered insulin signaling. Townsend Letter. May 2007:72-74. 11 Azadbakht L, Kimiagar M, Mehrabi Y, Esmaillzadeh A, Padyab M, et al. Soy inclusion in the diet improves features of the metabolic syndrome: a randomized crossover study in postmenopausal women. Am J Clin Nutr. 2007;85:735-741. 12 Gruber A, Horwood F, Sithole J, Ali NJ, Idris I. Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state. Cardiovasc Diabetol. 2006;5:22. 13 Alam I, Lewis K, Stephens JW, Baxter JN. Obesity, metabolic syndrome and sleep apnoea: all pro-inflammatory states. Obes Rev. 2007;8(2):119-127. 14 Lam JCM, Lam B, Lam C, Fong D, Wang JKL, et al. Obstructive sleep apnea and the metabolic syndrome in community-based Chinese adults in Hon Kong. Respir Med. 2006;100(6):980-987. 15 Kaukinen K, Halme L, Collin P, Farkkila M, Maki M, et al. Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology. 2002;122:881-888. 16 Goehler LE, Lyte M, Gaykema RP. Infection-induced viserosensory signals from the gut enhance anxiety: implications for psychoneuroimmunology. Brain Behav Immun. 2007 Apr 9; [Epub ahead of print]. 17 Meydani SN, Meydani M, Blumberg JB, Leka LS, Siber G, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. JAMA. 1997;277(17):1380-1386. 18 Lawenda BD, Smith DE, Xu L, Niemierko A, Silverstein JR, et al. Do the dietary supplements epigallocatechin gallate or vitamin E cause a radiomodifying response on tumors in vivo? A pilot study with murine breast carcinoma. J Soc Integr Oncol. 2007;5(1):11-17. 19 Bjelakovic G, Nikolova D, Gluud L, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. JAMA. 2007;297(8):842-857.

Welcome to Functional Medicine Update for July 2007. We are in store for an exciting time together on this edition. We are fortunate to have with us one of the world’s leaders in the fields of cholesterologenesis and atherogenesis. He is going to open some new doors for us in understanding the prevention and management of atherosclerotic disease. Before we hear from him, I want to set the stage by talking about the concept of atherogenesis (or the origin of atherosclerosis) from a lifestyle, gene, and nutritional perspective. Before I get started I’d like to say a couple of quick things about two new educational products we put together. The first is a compiled and edited collection on autism. Over the last couple of years, I have had the good fortune to interview some world leaders in the study of autistic spectrum disease etiology. We excerpted four interviews and compiled them with my comments to provide an overview of what is going on in this field. You can get more information by checking our website, www.jeffreybland.com , or you can call the Synthesis office on our toll-free number. The second audio course we have is a seminar on insulin resistance. It is called Beyond Metabolic Syndrome . I think you’ll find this seminar helpful and useful from a clinical perspective if you are interested in understanding how to better recognize and manage insulin resistance/metabolic syndrome beyond just the pre-diabetes conditions, that is, into cardiovascular disease, dementia, relationships to autoimmune disease, and how that inter-relates to inflammatory conditions. Again, there are two new educational products available from Synthesis. The first is our autism collection, which is on four CDs, and the second is the Beyond Metabolic Syndromeseminar, which is on six CDs. Both products are available through Synthesis by either contacting the jeffreybland.com webpage or contacting our toll-free number. By the way, seminar courses like Beyond Metabolic Syndrome not only include the audio, but also the visuals (the Powerpoint slides) that I discuss throughout the course of the seminar. Now let’s move to the main topic of this issue of Functional Medicine Update: functional cardiology. If we were to sub-categorize it even more, we might call it functional HDL and LDL physiology. Obviously most of us have some familiarity with the use of lipid measurements in assessing relative risk to cardiovascular disease, the total cholesterol (LDL cholesterol and HDL cholesterol) analysis. An understanding of these dynamics at a level that gives us a new insight into the personality of lipids and how they relate to atherogenesis and vascular health is emerging, and it is that focus that I want to take you through in this issue of Functional Medicine Update. There is going to be some language that is probably new to you, but there is also going to be some news to use: how we might use things like the apoB-to-apoA-1 ratio as an assessment tool for evaluating cardiac risk; how we might use the subfractions of HDL; and how we might look at dense versus buoyant LDL particles in terms of atherogenicity. This will be an update on what I call functional cardiology through the lens of lipoproteins and apolipoproteins. In order to do justice to this, let me take us back to the 19th century. I want to speak about the father of modern pathology, Rudolph Virchow. As you probably know, he was the person who was credited with starting our categorization of pathology into a discipline in medicine. He published his masterpiece, Cellular Pathology as Based upon Physiological and Pathological Histology, back in the late 19th century. He wrote that the cell is the ultimate irreducible form of every living element. Dr. Virchow was (in some senses) the father of cellular biology and cellular pathology, as well as the father of overall organ pathology. The reason I think this is an interesting part of the story and relevant to this issue of Functional Medicine Update is that when Dr. Virchow was looking at atherosclerotic disease back at the end of the 19th century (which was very uncommon at that time), he did gross pathology, looking at the coronary arteries of patients who had heart disease. He visualized the arteries as being injured. It looked like there was a wound and that the wound had tried to heal, forming what we now call a plaque, but then looked like a scab. And so he came to the concept that atherosclerosis was really an inflammatory condition, like a wound on the inside of the artery wall. In the early 20th century, a Russian physiologist by the name of Anichkov had a slightly different view of the origin of atherosclerosis. He was able to take white rabbits and feed them high-cholesterol and high-fat diets and induce, then, this plaque on the arteries that was associated with atherosclerosis. And so the cholesterol hypothesis was born out of the Anichkov work, and the injury and inflammatory model was born out of the observations of Virchow. From those two emerged the dominant intellectual lineage in terms of the origin, treatment, and prevention of vascular disease. The emphasis was more focused on the cholesterol hypothesis than on the inflammation hypothesis of Virchow’s. Cholesterol seemed to be the sine qua non for the etiology of atherosclerosis. But then later, in the 1960s and 1970s, a pathologist at the University of Washington School of Medicine, Earl Benditt, talked about the monoclonal theory of the origin of atherosclerosis. Dr. Benditt proposed that if you looked at atherosclerotic lesions, they were monoclonal in origin, as if they had been induced by a single cell undergoing injury and then developing a clonal response as a dedifferentiated cell. He felt that this clonal response was a consequence of an injury to that cell, a mutagenic injury. It was not a cancer as such, but it was more like a benign tumor that we call the atheroma, which then caused alterations in vascular flow and activated the immune system, which ultimately led to infiltration of cholesterol and calcium and stage 3 atherosclerotic lesions. Dr. Benditt, along with his research group, published a number of papers about the monoclonal theory of hyperplasia. The theory was reminiscent (in part) of the Virchow model of inflammation and injury as the origin of atherosclerosis. In the years since, there have been tremendous advances in the basic understanding of atherogenesis, as well as new perspectives that open up the possibility of new therapeutic strategies. There was a wonderful series of review papers that published in Nature Medicinein 2002. This series included a discussion of the vascular smooth muscle cell (VSMC) contributing to vessel wall inflammation and lipoprotein retention and that atherogenesis was, in part, an inflammatory condition at the artery wall. Virchow and his injury model, and even Benditt and his monoclonal hyperplasia model, were not too far off from the role of the vascular smooth muscle cell alteration in atherosclerosis.1,2,3,4,5 When the vascular smooth muscle cell undergoes a proliferative response as a consequence of an inflammatory message, it leads to the development of all sorts of alterations in the vascular wall in terms of its physiology and function. This can lead to things like restenosis after stents are placed, or bypass graft occlusion, or transplant vascularopathy, which are all secondary conditions of atherosclerotic risk associated with increased inflammatory burden. This inflammatory marker became an important new component of the presumed etiology of atherosclerotic disease somewhere in the later 1970s, the 80s, and the 90s. The macrophage converts itself into the foam cell. Once it infiltrates the artery wall, it undergoes a personality change with regard to its gene expression. It becomes, then, a cell type that is incorporated within the artery wall that engulfs a lipid. It engorges itself. It has a different physiological dynamic. The artery wall shifts into an oxidative chemistry. You get LDL oxidation and you start, then, getting this free radical oxidative process of inflammation and injury. This process implies that there is an innate immune component related to atherogenesis. As a result, there may not be a complete independent separation between atherosclerotic disease and autoimmune disease. Data have been published (that we have described in previous issues of Functional Medicine Update ) that have correlated increased incidence of cardiovascular disease in patients with systemic inflammatory autoimmune disease, like systemic lupus erythematosus or rheumatoid arthritis. What is emerging is that these diseases are connected by mechanism; they are not connected by diagnosis. And inflammation plays a role as it pertains to altered vascular wall dynamics. What induces systemic inflammation? Is it just chronic infection? We know certain organisms-H. pylori and various pneumococcal organisms-have been identified as potential risk factors for cardiovascular disease. Are we then looking at atherosclerosis as an infectious disease? The answer may be, in some cases, yes. Could it be nanoparticles, like viroid particles, or cell-well-deficient forms of bacteria that induce immunological changes? And the answer might be yes to that. Could it be other factors of ischemia that induce inflammation and altered arterial wall dynamics? And the answer is yes. In other words, the etiology that could trigger inflammatory response and altered immunological function at the artery wall is multifactorial. A whole cascade of events leads to the plaque, which can be stable or unstable. An unstable plaque cap raises relative risk to a sudden coronary event. When that fibrous cap breaks off, we get all sorts of platelet activation and thrombus formation, and now we have a life-threatening coronary event. So, it is a very complex process with many players and many environmental inputs. Genes underlie risk at a certain level, but layered onto genes are all these other environmental factors that modulate and help synchronize these complex processes that pertain to immune defense, vascular smooth muscle cell function, intimal function, and endothelial cell function. It is becoming more and more recognized that this one-cell-thick lining that lines the outside surface of the artery wall (the endothelium) plays a very important role in communicating to the interior of the wall (the intima and the vascular smooth muscle cells) what is going on in the outside world. That translated message of altered endothelial function can produce altered arterial function. We now see this mechanism as much more complex than previously recognized. Therefore, looking only at lipids in a snapshot through a blood chemistry, like a cholesterol or an LDL or an HDL, is only (at best) kind of a shadow on the wall of the cave (to use Plato’s analogy). It is not really looking at the dynamic process that is occurring within the artery itself. We do know, however, as this story started to emerge, that it has implicated many lifestyle and dietary factors that can influence this synchrony and dance of the dynamic process that we associate with atherogenesis. Looking at stabilization of atherosclerotic plaque, there are a number of papers that have been published recently that demonstrate that diets that are higher in omega-3 fatty acids (the EPA-DHA) help to stabilize atherosclerotic plaque (the fibrous plaque), while saturated long-chain fatty acids destabilize plaque and increase relative risk to a thrombotic event. I am quoting from one of many papers that appeared-in this case in The Lancet -titled , “Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomized controlled trial.”6 This was a randomized controlled trial intervening with very high dose fish oils providing very high levels of EPA and DHA, in this case 16-20 grams per day of EPA-DHA, and showing stabilization of plaque. In other secondary prevention trials that have been published, the doses used are much lower-much more practical-in ranges of about 1.8 grams of combination EPA-DHA each day. That would be a dose that would be certainly achievable either by supplementation or by eating more coldwater fish. So we are starting to see that diet can modulate not only the initial lesion that is associated with atherogenesis, but also stability of the plaque once it has formed. Certainly, hypercholesterolemia is part of the story. We don’t want to throw the baby out with the bathwater. When we take our snapshot of lipids in the blood chemistry and we see elevated cholesterol (elevated LDL cholesterol) and a reduced HDL-C, those are risk factors that the Framingham and Lipid Research Center studies, as well as other intervention trials have demonstrated to be surrogate markers for risk to vascular disease. So hypercholesterolemia is a risk. But then we actually have to ask the question, how does high cholesterol connect with the dynamic process that we associate with atherogenesis? And how does that then relate to diet and lifestyle factors that can modulate cholesterol and lipids in such a way as to stabilize arterial wall physiology? Cholesterol, in and of itself, be it either high or low, is not the be all and end all in determining exactly what is going on at the arterial wall relative to atherosclerosis. It is only a marker. In a wonderful article by Daniel Steinberg (from the University of California, San Diego and credited with the discovery of LDL oxidation) he talked about how high cholesterol is associated with inflammation as “partners in crime” in the atherogenic process.7 This appeared in the Nature Medicine series. Dr. Steinberg talked about the fact that the historical perspective going back to Rudolph Virchow and the origin of atherosclerosis allows us to reflect on the hypothesis that injury caused by inflammation may ultimately result in plaque formation and, therefore, high cholesterol may be an associative factor with this process, but in and of itself, it is not the whole explanation for the origin of atherosclerosis. We need to then look at the processes that relate to cholesterol oxidation and lipid dynamics (moving in and out of the artery wall), including triglycerides as well as cholesterol, and the packaging of lipids into the various lipoproteins-lipoproteins that constitute LDL, HDL, VLDL, and the different forms within each of those because there are sub-fractions, as we now recognize, within each of those lipoproteins that are constituted by various percentages of different apolipoproteins. So we recognize there are many variables and many different messenger molecules that contribute to these concepts of vascular reactivity. Some of those relate to these lipid transport molecules that we call apolipoproteins. Let me just take a moment to give a quick summary about apolipoproteins. Apolipoproteins have names like A, B, C, D, and E. Apolipoproteins are synthesized principally in the liver after messages come to the liver cells. These are proteins, obviously, which have the principal responsibility for binding certain families of lipids and aggregating themselves into certain particles that then travel in the vascular fluid, allowing transport of lipids in a water matrix. We can think of an apolipoprotein in a very simple way: as a detergent. It basically solublizes fats so they can be transported in the blood, which is principally water. That’s a little bit overly simplistic, however, because these apolipoproteins like A, B, or E are not nonspecific detergents; they are very specific in the way they accumulate certain fats and how they assemble themselves with other proteins and other constituents (other active enzymes) to then transport that fat to specific receptor sites on the surface of the arterial wall. So they are not just kind of general and nonspecific; they have a very unique personality and therefore a lot of what we might consider the personality of atherogenesis is tied together with the personality of the apolipoproteins-how they are synthesized, and how they are transported, and how they are delivered to the cell at the surface of the arterial wall. I want to emphasize this for the following reason. When apolipoproteins, are synthesized in the liver, their synthesis is dependent upon messages that the liver cell receives. These messages are hormonal messages and neurological messages that upregulate gene expression of specific apolipoproteins. If you ask, how can stress influence atherosclerosis? How can toxic exposure influence atherosclerosis? How can dysinsulinism influence atherosclerosis? You would, in part, have to know how each of those factors is translated in the liver cell to lead to the modification of apolipoproteins, and then what does each specific apolipoprotein influence in that individual? If a high stress situation in a person results in his or her liver cell getting the message to make more apolipoprotein B, then what that will do is transport lipids in a certain way to deliver more cholesterol to the arterial wall and engage in more potential oxidized LDL, so now what we get is the potential atherogenic risk, i.e. stress connects to heart disease risk through this complex cascade of events that is related to altered cellular signaling. You’ll notice I’m setting up a very different view of atherogenesis. It is not that we’ve just got these fats floating around in the blood and they bump into the artery wall and they cause injury or they stick to the artery wall like sticky fat molecules and they produce atherogenesis. This is a simple-minded model that really is not functionally correct based upon what we are now understanding as the origin of atherosclerosis. It is a complex inter-relationship between genes, environment, and the function that they translate through via these messenger molecules that is involved with either influx or efflux of lipids (meaning influx, delivering it at the site so it goes into the cell, or efflux, pulling it out of the cell and taking it back to the liver where it can be processed and ultimately excreted in the bile as bile salts). When we start looking at the effect that various messages have on the synthesis of apolipoproteins in the liver, one of the messages that comes up very strongly and modifies apolipoprotein synthesis is insulin. When we get very high levels of insulin, like in hyperinsulinemia, it alters the synthesis of apolipoproteins-it actually increases apolipoprotein B-and that then changes vascular reactivity. It can alter cardiovascular function in a person who has metabolic syndrome or type 2 diabetes. Ultimately this cardiovascular risk is a consequence of the connection between a signaling molecule (insulin) and an apolipoprotein. I’m now quoting from one of many papers in this area. This came from the American Journal of Clinical Nutrition in 2007 that looked at the postprandial effects of increased dietary fish oils (omega-3 polyunsaturated fatty acids) and found lowered apo B-containing lipoproteins and vascular reactivity, and improved insulin stability. These changes result in lower cardiovascular risk.8 What I am saying is that this story needs a lot more exposition than just saying, “Let’s take a snapshot in the blood of the cholesterol and LDL levels and from that we know everything we need to know about a patient’s risk.” I still hear some people say cholesterol is the whole story. And then I hear other people say cholesterol is not the story at all because there are people with high cholesterol who never get heart disease, and there are people with low cholesterol who do get it, so what value is cholesterol? My position is that cholesterol is somewhere in between. Cholesterol is part of the story, but only part. It is like a snapshot or a surrogate view into a much more dynamic process that we need to take into account. If you have a high cholesterol (a low HDL and an elevated LDL), you want to take account as to why that is present as your snapshot in your blood chemistry. What are the dynamic processes that may contribute to that? Is it hyperinsulinemia? Is it related to allergy? Infection? Is it related to a toxic exposure? Many variables might influence changes in your lipid dynamics. I want to emphasize that these things are not in isolation. They are all part of the functional web of physiology, which helps us to better understand the body/mind connection and associate it with cardiovascular disease. It helps us to understand how the neuroendocrineimmune system can be connected to the vascular system, and how the heart is an organ of immune and neurologic function as well as a mechanical pump. All of these things are interconnected. I have mentioned that insulin plays a role in this process and high levels of insulin (as seen in hyperinsulinemia and insulin resistance) can be associated with altered apolipoproteins generally associated with a lowered level of apolipoprotein A-1, which is a principal lipoprotein in HDL, and increase in apolipoprotein B, which is an apolipoprotein associated with LDL. And so you might say, how does that actually work? What is the relative role that insulin plays in vascular injury? It is not only related to the apolipoproteins. It is also related to the fact that insulin influences other enzymes and proteins that are within the vascular One of those is dimethylaminohydrolase, an enzyme that is involved with the metabolism of asymmetrical dimethylarginine. Asymmetrical dimethylarginine is formed when certain proteins (proteins that are high in arginine) in our body get tagged for breakdown by being methylated at the arginine residues in these proteins to form these asymmetrical dimethylarginine components. When the protein is broken down for reassembly, it releases what is called ADMA, which is asymmetrical dimethylarginine. Asymmetrical dimethylarginine has to be metabolized or detoxified by dimethylaminohydrolase, which is an enzyme that is inhibited by high levels of insulin. In cases of hyperinsulinemia with metabolic syndrome, ADMA levels generally tend to rise. ADMA, in turn, is an inhibitor of endothelial nitric oxide synthase, and therefore it lowers nitric oxide production at the endothelium. It alters, then, the eNOS activity such that it now produces more peroxynitrite. This is a very caustic oxidizing chemical, and so now the endothelium is shifted into an oxidative chemistry with the formation of peroxynitrite, and that’s another contributor to atherogenesis. Again, I want you to recognize the web of interacting variables. We are not just on one path to enlightenment. The disruption of dimethylarginine metabolism impairs vascular homeostasis and that has really been seen now in multiple studies published over the last several years. One, which I cite, is from Nature Medicine in 2007 and talks about the fact that asymmetrical dimethylarginine (which is produced endogenously) accumulates in various disease states, including renal failure, diabetes, and pulmonary hypertension if it cannot be broken down properly by the enzyme that detoxifies it.9 Its concentration in the plasma is strongly predictive for premature cardiovascular disease and death, and therefore it also relates to lowered nitric oxide signaling in the endothelium and the vascular bed. That lowers vasoreactivity and produces higher vascular tone, which is associated with hypertension. So we see all sorts of things happening that are not so good related to the atherogenic process. One is when insulin blocks the dimethylaminohydrolase enzyme that is involved with the detoxification of the asymmetrical dimethylarginine. I think that we are seeing some very interesting multifactorial inputs into atherogenesis. The nice thing about this story is that each one of these is a factor that is modifiable by proper diet and lifestyle intervention. If we control insulin sensitivity, we control lipogenesis. Then we are going to improve dimethylarginine metabolism; we are going to improve nitric oxide output at the endothelium; we are going to improve redox potential in the artery wall by lowering oxidative stress; and we are going to help normalize some of the immune activation that is associated with inflammation. Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease even in the absence of elevated serum cholesterol levels, so it is a cholesterol-independent risk factor to cardiovascular disease. I’m now quoting from a recent paper published in Clinical Chemistryin 2007.10 How can you lower ADMA levels? First of all, improve insulin signaling. And second of all, therapeutic doses of oral arginine (L-arginine) have been used to improve the reduction of asymmetrical dimethylarginine (generally 6 to 9 grams per day or higher is used to lower ADMA levels in a person who may be at risk due to the accumulation of this arginine metabolite). So you’ll notice again there is another interesting role that diet plays because vegetable proteins are generally higher in arginine. I’m thinking of soy protein or pea proteins: high arginine, lower in lysine, as contrasted to animal proteins that are generally higher in lysine and lower in arginine. In looking at diets that contain higher vegetable proteins, what do we see epidemiologically? We see generally lowered incidence of cardiovascular disease. Most people say that is because you are getting lower amounts of animal fat when you eat more vegetable protein, and that is part of the story. Remember, we don’t eat one molecule at a time in our diet. Our diets have a specific signature that is related to the foods that we consume. That dietary signature sets up a different panel of genes that are turned on and turned off to express different functions, so it is not like pharmacology (one drug at a time). We have actually set up a pattern-a symphonic orchestration of our gene expression-that occurs in these polygenetic conditions that relate to vascular disease. By eating a diet that is high in animal protein and higher in animal fat, it sets up a different gene response profile of increased inflammatory response, decreased insulin sensitivity potentially, increased ADMA levels, decreased nitric oxide output from the endothelium, increased oxidative stress, and so forth. You’ll notice we are talking about a complex mechanism of which cholesterol is maybe only the tip of the iceberg. We know as this process occurs (as Virchow predicted over a hundred years ago) that this will induce these inflammatory responses with a change in the immune response. And so we often use the surrogate marker, high-sensitivity CRP (or C-reactive protein) to evaluate relative risk to cardiovascular disease associated with inflammation. And many clinical trials have been published. We have discussed a number of these in previous issues of Functional Medicine Update in which we have talked about values of hsCRP above 2 milligram per Liter being associated with increasing risk to coronary events. We would generally like hsCRP to be less than 1, but you get above 2 and you get into increasing relative risk. And now you’re going to say that patients who have autoimmune disease or inflammatory disease often have hsCRPs above 2; they might be 10 or 15 or 20. The answer is yes; that is another risk factor for vascular disease. Not in the moment of inflammation, but it is over time. If a person has the flu, his or her hsCRP may go up transiently, but it may only be elevated for a month. But if it is elevated for a year, or five, or ten, now the state of function of that individual is an inflammatory state with immunological imbalance and now they have a relative risk to these processes that we are talking about pertaining to oxidative stress, vascular smooth muscle cell change in the artery wall, and proliferative responses that lead to atherosclerosis. I am quoting from another interesting article about C-reactive protein and atherosclerotic risk that appeared in Clinical Chemistry in 2007.11 What do we know that can activate oxidative stress and can induce free radical pathology? One of the families of substances that do that is the transition metals. The transition metals include iron (probably the most common in our bodies; at the highest prevalence). Iron can exist in multiple oxidation states: ferrous iron (Fe+2) and ferric iron (Fe+3) are the common oxidation states. There is an Iron-Heart Hypothesis, which was actually put forth first by Sullivan in 1981, that suggests that increased body iron stores are a risk factor for coronary artery disease and thus iron depletion through phlebotomy could lower relative risk. This hypothesis was based on the markedly lower incidence of coronary heart disease in premenopausal women, who lose iron through menstruation, compared with men (and also with postmenopausal women), and seemed intuitively appealing. However, as this has been tested more over the last 25 years, the hypothesis doesn’t seem to bear out very strongly. Support for the Iron-Heart Hypothesis in humans has focused on epidemiological associations. Serum ferritin — the iron storage protein for which levels are elevated with iron overload and proportionally reduced with iron depletion — is considered the best biomarker for long-term iron stores. Recently Salonen conducted the first prospective cohort trial to suggest a positive association between serum ferritin concentration and the risk of coronary heart disease in a Finnish population.12 After adjustment for established risk factors, this small study showed a more than two-fold increased risk of acute myocardial infarction among men having serum ferritin levels of 200 ng/mL or greater compared to those having lower serum ferritin. However, these promising results have not been confirmed in a number of subsequent studies that have been published the last couple of years. There are actually polymorphisms or gene alterations that might be more susceptible to this iron story than the wild-type gene, so it is a more complicated situation than we originally thought. In a recent paper in the Journal of the American Medical Association, outcomes from a multicenter randomized controlled single-blinded trial on the effects of iron reduction through phlebotomy were reported.13 This trial was conducted from May 1999 through April 2005 at the VA and enrolled 1277 patients with symptomatic peripheral artery disease. Nearly all the patients were men. More than 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} were white. Their mean average age was 67 years. And during a mean follow-up period of approximately 4 1/2 years, there were no significant effects on either primary (meaning all-cause mortality) or secondary (death plus nonfatal myocardial infarction or stroke endpoints). Reduction of iron stores had no effect on the incidence of myocardial infarction or stroke. However, in a post hoc subgroup analysis, a significant interaction between treatment and age was found. Younger patients (43-61) randomly assigned to undergo iron reduction did have a significant decrease in primary as well as secondary endpoints, but these benefits were not significant in older patients. This kind of still leaves the iron hypothesis out there as having potential, but it raises the question, are there subtypes of individuals that are more susceptible than others? Is iron itself, without looking at its physiology in the individual, the culprit and at what age would you intervene to lower iron stores to lower cardiovascular outcome? I think, again, what seems to emerge from this is people with inflammatory situations onboard have a higher implication of iron-induced free radical pathology. Again, we should probably look at this in a multifactorial situation. Lowering inflammatory risk and lowering insulin resistance makes the iron story less a concern, so, again, I think it is weighting these factors in terms of our general understanding. With all of that as context, it leads us into the question of apolipoproteins and lipoprotein physiology and how we can regulate friendly lipoproteins to reduce atherogenic risk and reduce the unfriendly lipoproteins to accomplish the same goal. Of course, there is no better way to do that discussion than to recruit a world expert who is probably one of the few people who knows more about this topic than anyone else. A person who can tell us a little bit about why the recent CETP trials were not positive. In fact, Pfizer had to pull their drug, Torcetrapib, off of the potential approval cycle because of increase in the relative risk of cardiovascular incidence in people who had their HDLs increased by this medication, this CETP inhibitor, Torcetrapib. By the way, this was discussed in an article published the new England Journal of Medicine in 2007.14 So, we are going to go to the source and learn more about how one modulates these lipoproteins in such a way as to reduce relative risk to these complex atherogenic processes.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Roger Newton, PhD Former Senior VP and Director Esperion Therapeutics, a Pfizer Inc. Company rgrnewton@yahoo.com I think all of you who have been long-standing listeners to Functional Medicine Update or supporters of the written transcript know how much I look forward to our clinician or researcher of the month part of each month’s sequence because of the “new” news and the opportunity to learn from world leaders. We are not going to be disappointed this month. We have with us a very remarkable person who is going to talk with us about something we all need to know more about: the lipoprotein story and its connection to inflammation, vascular disorders, and now what is even emerging to be type 2 diabetes and metabolic syndrome. I’m speaking about Dr. Roger Newton. I’ve had the privilege of getting to know Roger over the last several years. He is quite a remarkable researcher in what you might consider the drug development area, but that would be a very myopic definition of the breadth of information and his contributions to the field. Just quickly-to give you a little thumbnail vignette of his background-he started off with a PhD in nutrition from the University of California at Davis, which is a very well-respected institution in the nutrition area. That followed from a Master’s in science and nutritional biochemistry from the University of Connecticut and a Bachelor’s in biology from Lafayette College. After that he went on and did a postdoc with Dan Steinberg. All of you are probably well aware of the name-having won acclaim for his work in the discovery of the oxidation of LDL at the University of California at San Diego. It was there that Roger really started to develop his interest and expertise in lipid management and in the area of regulators of cholesterol biosynthesis and I’m speaking specifically of the statin family of medications. It is interesting, however, that in the more than 60 publications that Roger has in the science literature, his first publication that I could find listed in the Library of Medicine is titled, “The Effect of Diet on Fatty Acids in the Lipoprotein Cholesterol Esters of Type 2A in Normal Individuals.”15 This appeared in 1975 in the journal, Lipids. It shows how his lineage-his academic lineage-really started in nutrition and wove its way, then, into pharmacological agents to modify cholesterol. He has been given the credit (and I think rightfully so) as a co-discoverer and product champion for what we all recognize as the most prescribed cholesterol-reducing drug in the world, which is atorvastatin, or Lipitor. He worked with the inventor of Lipitor, Bruce Roth, to really bring this product into the full amplified clinical support, and there are more clinical trials on it now than any other cholesterol-lowering agent. The mechanisms of action and all the various subtleties that underlie the support of that medication really came out of the work that was pioneered and championed by Roger. He has been the past chairman of the Great Lakes Venture Quest and a member of the Michigan Life Sciences Quarter (a steering committee). He has had numerous responsibilities: adjunct professor and professor at the University of Michigan in the area of biologics and the nature of life sciences, Department of Pharmacology at the University of Michigan. I would say that he represents, as a co-founder of the company Esperion Therapeutics, a visionary who has spanned many, many different academic disciplines. It is sometimes hard to do this because we are likely to be pigeon-holed (by our colleagues) and defined in myopic ways so that they can get a tidy little definition of who we are and what we do. Roger has really forced back that definition. He has spanned wide ranges of explorations in science and discovery. He is also known as a tremendous leader and motivator and champion of high-quality work. The people who have worked with him revere him for his leadership ability and his ability to steer clear direction in sometimes murky waters. It is a great pleasure to have the co-founder and former president/CEO of Esperion Therapeutics here. Actually, he is also quite an entrepreneur, having been successful with his colleagues to sell his business (in February of 2004) for over a billion dollars to Pfizer and then work with Pfizer Chemical. Roger, thanks for being part of our Functional Medicine Update 25-year history. RN: Jeff, it’s a pleasure to be here and thank you for the opportunity to talk about lipoproteins and atherosclerosis, something I am very happy to talk about. JB: For a lot of our listeners, it might be interesting for them to get a thumbnail sketch from you as to how your interesting journey in life took you from a PhD in nutrition and working on effect of diet on fatty acids up to and through Esperion to today. RN: Sure, I’d be happy to, Jeff. The light went off in my head about what to do in my career back when I was at the University of Connecticut. It was one night, working in the lab, and I’d been reading a book about atherosclerosis. Interestingly, a person by the name of Charlie Day had edited it, and there were both nutritional as well as pharmacologic intervention studies that were presented in that book. It came to light that wouldn’t it be interesting if I could find a way to intervene and treat the disorders that lead to atherosclerosis, which obviously included hyperlipidemia/dyslipidemias. I then went on and did my PhD (after getting my Master’s at the University of Connecticut) at the University of California at Davis, where I initially worked in metabolism with Dick Freedland and understood intermediary metabolism and the importance of lipogenesis, fatty acid synthesis, and cholesterolgenesis in liver cells. I took a pharmacology course (interestingly, pass/fail). I did pass it, and that’s the only pharmacology course I ever took during my academic career. But that opened up a whole door of the combination of pursuing nutritional and pharmacologic intervention and the interplay that metabolism has in lipoproteins, cholesterol synthesis, and its role in the production of lipoproteins and the degradation and its regulation. And then going on and working in Dan Steinberg’s group. I then began to work on another metabolic inhibitor, which was discovered by Akira Endo at Sankyo (the first statin, which never made it to the marketplace, Compactin). Using liver cells as a means of being able to evaluate the interplay of cholesterol coming in from a lipoprotein source versus that which is synthesized and the impact that has on lipoprotein synthesis as well as degradation, I began to understand a little bit more about the importance of de novo fatty acid synthesis through using Compactin as a metabolic inhibitor. That then led to finishing my postdoc after 2 1/2 years and looking at industry and academia as a potential career, and I basically read this letter on a wall that said, “Interested in working in lipoprotein metabolism at Warner-Lambert/Parke-Davis in Ann Arbor, Michigan?” I went out and interviewed, and they wanted to start up a statin program different from that that Akira Endo had done, which was looking at fermentation beers and isolating metabolites that would inhibit cholesterol synthesis. We began a medicinal chemistry approach. And so, with that, I came into a group of about five people, and basically (to make a long story short) I chaired the atherosclerosis group for 12 years. We had 11 lead compounds. Interestingly, Lipitor was the fifth lead compound in our HMG-CoA-reductase inhibitor program, so we learned a lot from those first four failures. Over about a six- or seven-year period we improved dramatically on our capabilities of making a chiral synthesis of the active inhibitor, which later because CI-981, that also became known as atorvastatin, calcium, and Lipitor. I then decided that that part of my career (working on cholesterol synthesis and LDL and reducing LDL) was over and was approached to start a biotech company called Esperion. Here we were going to be using (interestingly) a recombinant form of the major protein in HDL, apoA-1, and this variant was apo A-I Milano, which had been discovered in 1979 by Drs. Sirtori and Franceschini. And there was only a single amino acid substitution of a cysteine for an arginine at amino acid 173, and interestingly, that changed everything because it changed the efficiency of the capability of the A-1 as a monomer or a dimer to remove cholesterol from cells. Hopefully, what we wanted to prove by making synthestic HDL, to actually promote removal of cholesterol from arteries and cause regression of plaque. So I started that company in 1998, and as you said in my introduction, we then became part of Pfizer in February of 2004. So that’s kind of the long, fast way to where I am today. Interestingly enough, I’m no longer a Pfizer colleague because they closed the facilities in Michigan as part of a restructuring process. I’m looking to do new and novel things down the road. So, that’s the story. JB: Well it’s an incredible story and obviously that’s just really the superficial topline, but I think it gives all of us (the listeners) an opportunity to see the depth of your background. Let’s go back, if we can, to this apolipoprotein story and the discovery of Milano protein and how that relates to genetics, and what is HDL-why do we call that the “good” cholesterol and why do we call LDL the “bad” cholesterol? There’s probably no one who can tell that story better than you. Can you take us down that road a little bit? LDL and HDL Physiology RN: Sure, I’d be happy to. The original evaluation of LDL cholesterol and HDL cholesterol being respectively “bad” and “good” came from epidemiological studies years ago. These studies basically showed that in individuals who had risk for heart disease (and mostly through primary prevention and dietary means), that those folks who had higher HDL cholesterol seemed to be protected (most of the time), and those who had high LDL weren’t. And so this ying-yang of LDL bringing cholesterol to the periphery and laying down that cholesterol to cause the nasty plaques that caused increased heart attacks (particularly when they are unstable plaques and they rupture), that link and the antagonism of HDL trying to remove that cholesterol and other lipids from the plaque, this is where the story became much clearer from a functional point of view. In our own way, we do clinical chemistry: we take a static measurement of a dynamic process. Obviously sometimes you want to have a fasted level to have any possible involvement of VLDL due to dietary fat and chiral microns. You want to take a fasted sample to get the LDL/HDL cholesterol. That then tells you (perhaps) whether somebody is at risk. It also tells you whether your diet is having an effect of reducing the LDL and perhaps raising the HDL or whether your pharmacologic intervention is going to have that effect. But really, that doesn’t tell you about the real metabolism and physiology because as I mentioned earlier, it is a static measurement of a dynamic process. So what has happened in the field is that through a great deal and a great number of researchers doing seminal studies on understanding the interplay of cholesterol and between LDL and HDL. We now understand much better that a lot of the LDL comes from VLDL as a breakdown product. There are some people who will directly synthesize an LDL-type particle, but most of the time it comes from the degradation (and remodeling, if you will) of the VLDL particle as it loses its triglyceride due to lipoprotein lipase acting on it, and other lipases like hepatic lipase, for example. This, then, forms a lower density particle that has a larger amount of cholesterol and basically has one apoprotein called apo B. This makes LDL either the buoyant form, which is larger and has more triglyceride, or the small, dense form, which has more cholesterol ester. Really, it is a way in which we can look at the subfractions and determine whether an individual has a greater or lesser risk. The more small dense particles of LDL, the greater the possibility of having atherosclerosis and also the higher potential for the apo B to be oxidized. HDL is a very complicated series of particles because there can be an interplay of exchange and transfer of lipid and protein. There are about 17 different proteins on the HDL particle. Those that are related to apo-A (there is apoA-1, A-2, A-4). A-1 is really the one we were thinking of as a possible therapeutic opportunity with respect to A-1 Milano because we knew that in animals that had a transgenic human A-1 put into their HDL physiology, they would have a rapid effect of regressing atherosclerosis. Therefore, as a result of that, we thought, perhaps this variant form, which has a disulfide amino acid (namely, cysteine) substituted for an arginine, you may have a greater capability if it is in a dimer form with itself. And, indeed, Franceschini and Sirtori and their colleagues have done extensive and very eloquent research in evaluating how the A-1 Milano, as a potential therapeutic, actually regresses plaques in animal models. Also P.K. Shaw at Cedars Sinai in Los Angeles has been very active in looking at this under a variety of conditions, both as chronic effusions as well as doing transgenic animal studies to compare it to apo A-1 (the wild type), and showing it to be about twice as effective at reducing the amount of cholesterol in the plaques of animals such as rabbits, and also showing a significant increase in regression. The other part about HDL is it has not just A-1, but it has antioxidant enzymes such as myeloperoxidise and enzymes that affect platelet aggregation. These enzymes and proteins have effects of beneficially reducing inflammation and oxidative stress within the body, as well as (in the case of apo A-1 Milano) affecting hypertrophy and hyperplasia after injury, having effects of reducing inflammation, particularly at the endothelial level of the artery. HDL is not just having an effect of being the good cholesterol; it is also having an effect of reducing inflammation in a significant way. So these are very, very different siblings (if you will) in the same family. They are all lipoproteins, but they have very different actions and very different metabolism and physiology, both in a normal state as well as in a dysfunctional state. JB: That was the most remarkable summary of very complex clinical chemistry. I applaud that. Obviously you’ve done that a few hundred times. That was beautifully done. RN: Thank you. JB: You raised a very interesting point that I want to come back to for our listeners. I think you just provided an explanation that most of us need to reinforce in our understanding related to the connection between insulin resistance and cardiovascular disease as it pertains to these apolipoprotein dynamics. Let me just set the context of this. Most of our docs who are listening to this are familiar with, and probably use the surrogate marker for insulin resistance — the fasting triglyceride-to-HDL ratio. They would say that, as that ratio gets above 4, the higher it is, the more relative risk and prevalence of metabolic syndrome or insulin resistance. They may not understand that what they are doing (that you have just described) through the use of this ratio is to indirectly be looking at (at least the shadow of) the apo B to apo A-1 dynamics and how that then relates to lipid efflux and influx at the arterial wall. Could you help us maybe to make that connection just so people can kind of lock that down between the cardiometabolic risk of insulin resistance and how that relates to these apo B and apo A-1 dynamics? Reverse Cholesterol Transport RN: Yes, I’d be happy to Jeff. The point you make is a very valid one: there is an integral link between your triglyceride levels and your HDL cholesterol from a metabolic point of view. What happens in those individuals who are hyperglycemic and don’t have very good glucose regulation, whether it is in diabetes or a pre-diabetic state or obese state in metabolic syndrome is that the amount of triglyceride that is present in the HDL particle is quite high relative to a normal HDL composition. Normally cholesterol esters in triglycerides are found in the HDL particles as they are metabolized from the discoidal particles that are produced by the liver and intestine everyday. These discoidal particles are basically lipid-poor discoidal particles that contain phospholipids and apo A-1. They then are remodeled (if you will) and pick up more protein in the plasma compartment, as well as pick up more cholesterol ester and triglyceride through different transfer proteins and exchange proteins such as cholesterol ester transfer protein, which basically transfers cholesterol ester to LDL, and triglyceride comes into HDL. The issue that you have with folks who have too high a triglyceride, particularly if their A-1 particle number is static, is that you have too much triglyceride in the core of the HDL. Therefore, the capability of the A-1 particle to remove cholesterol is highly limited. So this process — called cholesterol efflux, and the most important (I think) metabolic pathway by which HDL functions in cholesterol metabolism — this reverse cholesterol transport, can’t take place in an efficient manner. Therefore, if you are able to put yourself into glycemic control through a variety of means, both from a nutritional point of view as well as a pharmacological point of view, you can reduce the amount of triglyceride in the HDL particles, and you can also change the composition of the particles such that they have the capability of removing more cholesterol from the arterial wall. This ratio of triglyceride-to-HDL is obviously an arbitrary measure that doesn’t tell you about the functionality of the particles. I think the point I really want get across to the listeners is that we really need to better understand the functionality of the particles that we are working with. How to do that is hopefully something that we will be able to do in a micro method down the road, which could be looked at as an additional “peeling away of the philo dough,” if you will, to better understand how this individual’s physiology or abnormal physiology for the metabolism of HDL can be more insightful into which problem they have and how to treat it: whether it is the carbohydrate side that is influencing the lipid side in a negative way; or whether it is the lipid side that is affecting the carbohydrate side. Certainly measuring triglyceride-to-HDL gives you some insight, but it is only giving you (I think) a high level (a 30,000-foot level) of what is actually going on in an individual’s metabolism. JB: Once again I want to applaud you for the opening statement you made, which I think is kind of an “aha” for all of us, and that is this these lipid measurements that we are commonly using in our clinical chemistry (the LDL, HDL, triglycerides) are these static measurements of this dynamic process. I think that gets us back to the whole functional medicine model where we are looking at the dynamic physiology. We call it the web (or however we want to define that). It is kind of your biological systems approach-looking at how things interact rather than just freeze frame, which is often what we do in medicine: to look at that moment in time that is associated with a pathology. I think that to think of these as dynamic processes where things are moving in and out of cells is a very different view than the one in which probably most of us were trained. Let me, if I could, go back to your HDL composition because I think it is a really important point. We often hear clinically about the different kinds of HDL. We have heard that certain HDLs have different atherogenicities or anti-atherogenicities, and that alcohol consumption raises certain HDLs, and exercise raises other HDLs. Could you help us to understand a little bit more about that? The different types of HDL? The Different Types of HDL RN: Yes. These are, again, ways (like I mentioned earlier with LDL) to try and better understand the particle number (the apo B relative to particle number) as well as the different composition of the particles to try to associate or better understand what the relative risks would be. It is well known that the cholesterol carrying capacity of the pre-beta HDL particles is substantial. It is more than any other HDL particle. It is the alpha particle, if you will, of HDL as it picks up more cholesterol and picks up A-1 phospholipid. And those that are phospholipid-rich HDL particles have a greater capacity for removing cholesterol. So these smaller particles are really like the tortoise versus the hare, if you will, where they are very rapidly removing cholesterol, taking it back to the liver, and then cycling back and forth to pull more cholesterol out of cells and hopefully out of the arteries. As these particles get larger-when you get from the pre-beta (the alpha particle) to the HDL 3, HDL 2, and HDL 1-they become more like the tortoise (so to speak) with respect to the capability of carrying cholesterol, the flux that these particles can go through and remove cholesterol, and they get a bit sluggish. I guess the word sluggish is probably the best way to say it. They get sluggish at removing cholesterol and promoting this process called reverse cholesterol transport. So there are associations that clinicians have made at the relative ratio of the HDL to the HDL 3 ratios and what that means, whether it is by diet or whether it is by pharmacologic intervention. And people have tried to associate a very clear line of, “Oh, the risk would increase if you have a higher ratio of HDL 2 to HDL 3.” Again, I think it depends upon the patient population. It depends on the predisposition of that patient based on the etiology of their hyperlipidemia as to whether it relates to risk-whether they are a diabetic, whether they are obese, whether they are abusing alcohol in a way that could affect the particle number and the composition. My personal point of view is that the more you understand about the apo A-1, and the more you understand of the A-1 ratio and the phospholipid composition, the more you’ll understand the efflux capabilities of those particles. Interestingly, as a segue into the whole idea of inflammation and oxidative stress, Jay Heinecke and Stan Hazen have looked at A-1 from the potential of it being oxidized by an enzyme that is very elevated in oxidative stress called myeloperoxidase. This enzyme has the capability of producing hypochlorous acid. Hypochlorous acid is bleach, basically, and it can cause pretty negative consequences on the capability of the A-1 particle to cause efflux in cells as well as hopefully in arteries. The tyrosine residues of A-1 can be chlorinated as a result of this chemical process that occurs, and it can also be nitrosylated. What we know is the tyrosine residues in apo A-1 are very, very important for the efflux capacity. If you just measure HDL cholesterol you get one indices. If you measure the amount of apoA-1, you get other indices. But unless you evaluate the functionality of those A-1-rich particles, you won’t understand whether you are having oxidation of those proteins. You may think that because someone has high apo A-1 that that person is going to be protected. Well, you really don’t know for sure unless you evaluate his capability for cholesterol efflux in cells. That is the issue that I think happened to some extent with the CETP inhibitors, where there was this belief that increasing HDL cholesterol, in any way, would then lead to a mechanism that would be protective of the artery wall and perhaps even cause regression of the size of the artery and the atherosclerotic plaque, itself. That was not the case in recent studies that used a combination of Lipitor plus a CETP inhibitor called Torcetrapib. But, it remains to be seen why that happened. Just like the situation with Compactin, which was at the first representative compound from the statin class, parous patches were found in the intestine. The results with the CEPT inhibitor, Torcetrapib, don’t necessarily mean that all of this class of new drugs will be negative. There are other companies moving forward in this area. We all learn from the knowledge that we have and the research that we do to potentially make better statins or make better CETP inhibitors, so it doesn’t mean that the whole mechanism is… let’s put it this way, will cause the end of CEPT inhibitors altogether. I think we need to learn more. And so as we uncover this information and better understand the metabolism of HDL and about these particles that the CEPT inhibitors cause to become prevalent in the blood, namely these large HDL particles, we will have a better understanding of what we want to do and what we don’t want to do. Because it may be an adverse particle that you are producing, in spite of the fact that you measure a high level of HDL cholesterol. JB: I’ve heard you use the term, “starved” HDL. I think that is a very interesting term because it gets us to think visually. It is actually the nourishment of your body that determines your function, so a starved HDL is an interesting concept. You are dropping in so many pearls right in a row here that it is hard to pick them all up. One in the lineage of the pearls that you have dropped is this relationship between myeloperoxidase and oxidized apo A-1 and the chlorination of tyrosine residues. We learned (most of us) in our immune courses back in pre-med or med school that myeloperoxidase was part of the microcidal killing reaction that white blood cells have as they try to engulf (in the innate immune system) foreign invading viruses or bacteria and kill them by bleaching them to death. It is like chemical warfare. So now you have introduced the idea that the HDL can actually have myeloperoxidase activation. This sounds like there is an immune connection — like atherosclerosis might have an autoimmune component — emerging as part of the etiology. RN: That is correct. There are actually small biotech companies right now looking at the potential of autoimmunue and immunity to atherosclerosis depending upon what effect some of these oxidative processes have on altering the primary structure of some of these very important proteins that contribute either in a positive or negative way to atherosclerosis. It is being looked at, particularly around HDL, in a pretty aggressive way. I think that, in the last three or four years, there have been two or three companies that have begun to pursue this and have venture capital in order to aggressively look at this opportunity. My thoughts are that atherosclerosis has a multifactorial etiology. Unless you have a way of being able to actually understand the immune component of atherosclerosis and what the inflammatory component or oxidative stress may have to contribute to this, and whether it is an effect on apoA-1 or whether it is an effect on a phospholipid or an epoxy fatty acid, or too much oxidation of cholesterol itself that might cause this kind of response. We have to understand much better the pathways in which this type of response would occur before we can really pursue which patients might be susceptible to this problem, and then, of course, how to treat them. JB: So now I would like to give you the luxury, if you are comfortable, to kind of-with all the years of experience and wisdom you have accrued in this field-be speculating and theorizing with me. We know that there are certain cultures that have low levels of atherosclerotic disease and in age-adjusted studies we recognize that they have certain diet and lifestyles, and we even know they have certain genes. But often when they travel from their homeland and eating their traditional diets and move to the Western world and consume the diets of our fast food nation the genes don’t protect them. They end up with high levels of atherosclerotic disease. It would suggest that there might be something in the message that triggers all these lipoprotein dynamics and this -what you have indicated-is an extraordinarily complex process of things moving in different directions. In fact, even the apolipoproteins themselves, which we might have thought of as kind of benign carriers of lipid, are really active molecules that are regulated by hormones and they are playing a role in receptor sites as well. It’s this dance of many, many different parties that are inter-related with the information that they are getting from their diets. Do you feel (from all of this) that we are starting to emerge a molecular understanding of the role that diet plays in the modulation of atherosclerotic disease? RN: Absolutely. I think that as we better understand the importance of biochemical individuality and the interplay of the environment, nutrients, lifestyle on various genes and their expression we will have a better way of changing the paradigm of how we treat people. The approach that people have taken is to look at those who are at high risk and treat them chronically with pharmacologic agents and to try and institute lifestyle and nutrition or diet therapy as a means of potentially improving their lifestyle and situation of how they live as a means of reducing their potential risk. This is not easy to do in the world in which we live, and particularly the Western civilization because we have all these temptations that the food industry has provided that are basically unhealthy and that actually have a negative effect on regulating the positive genes that we want to have a significant effect on. If we look at how we treat disease, we are going to have to look at the situation and say, “What are we going to do to change the chronic disease treatment paradigm?” As we better understand the interplay of nutrients and the really subtle changes of nutrients on nuclear receptors and transcription factors and gene expression, and particularly genes that are related (my focus would be) to lipogenesis. We may have, then, a better way in which we can treat people, and not just from a dietary point of view, but also from a pharmacologic point of view. I think that the wall of demarcation between nutraceuticals, medical foods, pharmacopeia (if you will), and the separation that exists within the industries-I think that is going to change significantly because personally I don’t think the existing healthcare paradigm is sustainable. There is going to have to be some major efforts made by the food industry to create more nutritional foods and foods that will benefit society as opposed to snack foods that won’t. And I think it is also imperative on the part of the pharmaceutical industry to begin to look at not providing&hellip;let’s put it this way, compounds and molecules from medicinal chemistry that are foreign to the body, but also look at natural products and their potential role, and particularly the fact that if we have been eating them for generations we don’t have an issue with respect to toxicity. I believe that the melting pot will be a combined nutritional-medical food-pharmacological intervention that will be harmonious. It will be an integrated process as opposed to one where what drives the business sector and the economy of pharmaceutical companies and nutraceutical companies, which are all very independent. I think that there is going to be much more of a harmonious integration. It has already started with the pharmaceutical companies and the device companies. That started about five years ago. They are having meetings now where they are talking to each other and they are realizing there is a lot more overlap and a lot more commonality to what they do. I hope this then translates into a better definition of acute and subacute medicine and how we treat people who already have a disease, and making improvements in how we treat people who are at risk or people who have chronic disease. Let’s face it, the quality of life that we want to have in our later years and how long we live is extremely important to people like me who are part of the baby boomers. I don’t want to live to 85, but by the time I am 75 years old have to deal with what would be 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of my prescription bill during that particular time and not really have a high quality of life. There needs to be, I think, a dissecting of what we are doing in the healthcare system to make it cost effective and to also make it worthwhile for all of us to follow a certain way of how we live, the environment that we live in, the nutrition that we have, and, if we need medications, not take seven medications, but take only the ones that really need. JB: That’s an incredible model and it is certainly very consistent with this whole functional medicine story that we have been evolving over the last 25 years. I am reminded of the story that you started off with about the Milano protein. I can just visualize this family in Milan that happened to have the luck of the draw in their genes that they had this cysteine substituted for the tyrosine that made their HDL apo A-1 less able to be oxidized and so they were kind of protected a little bit against the abuses that maybe other people would be susceptible to. It is not just that our genes can put us at risk, they can also protect us, and so what we are really talking about is the majority of our wild type genes, which is the majority of the population-what is the right nutritional information that washes over those genes to give rise to lowered oxidative stress, lowered immune upregulation, improved lipid dynamics, improved cholesterol efflux and influx balance effects, and how does insulin play a role-this whole symphonic orchestration of our metabolism. That’s obviously not what medicine has been focused on the last 30 or 40 years. It has been focused on dealing with each part of the system that is broken individually, compartmentally, in a silo way, so that each specialist of medicine has his or her own list of pharmacological agents that treat the body in isolation from other parts. That’s just not-as you have described the story-the way the body works. I think we are witnessing, based on what you’ve told us-the emergence of a new medicine. RN: I should hope so, Jeff, because I think the whole approach&hellip;let’s put it this way, the institution of molecular biology and then the genomics that followed and the better understanding, if you will, of the blueprint of life, to some extent fit right in to the reductionist mindset of many basic scientists, clinician scientists, and really looked at the idea that you could control the biological systems if you understand the genes. Not including what I would think is the most important and that is the environment and all these signals that come in from our day-to day existence as well as the food that we eat. I think we have to change that. We have to change that myopic kind of view to a much more integrated metabolic approach where people understand to a greater extent-and as the individual biochemistry comes forward and we are able to evaluate this in a really meaningful way-people can better then judge what they should or should not do with their bodies, as well as realize that being on 4 or 5 or 6 medications where there are drug-drug interactions that occur and where there is this polypharmacy paradigm, that’s not going to lead to optimum health. I think understanding how each individual person can reach that potential is hopefully what will happen down the road with a multidisciplinary approach to health and to treating chronic disease. I think the years of thinking that genomics is going to lead to a plethora of new pharmacologic agents&hellip;I think a lot of people have realized that that has not happened over the last 5 to 10 years, nor do I think it will happen. It is going to take a lot more understanding to really get to that point where you can then intervene. If you really look at it, 2{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of human disease actually is monogenic with respect to those diseases that really affect people in a negative way. The remainder are polygenic-or multiple genes interacting-as well as the involvement of the environment. To say that we can actually treat people by doing a single-gene therapy-that can only occur in a minor number of people in the population. And we have to be very careful that we know what their genetic predisposition is before we do that. Really what I think we need to do is look at a more integrated approach to medical treatment where you have people with different expertise contributing to the overall well-being of somebody’s lifestyle and health, as opposed to just being myopic and think that you can treat one specific receptor or one specific enzyme or one particular event in the nucleus. In the biological hierarchy, this particular target that you have is going to have a multitude of effects in improving the whole metabolic picture and the overall well being of that individual. I think those days are waning, let’s put it that way. JB: Personally, I want to thank you on behalf of all of our listeners for the years of contribution you have made. You have been a pioneer and a true seeker for a long time and it is starting to show the results of your efforts and many like you to create this new horizon for medicine to evolve to. I just want to personally thank you for the diligence that you have brought to the field and for your vision. I think if we could collect enough people like you together we would transform our medicine to become truly a healthcare system and not just a disease care system. Thanks a million and we’ll look forward to traveling down this road in your journey with you, Roger. RN: Jeff, thank you very much for the opportunity.  

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1 Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nature Med. 2002;8(11):1249-1256. 2 Li A. Glass CK. The macrophage foam cell as a target for therapeutic intervention. Nature Med. 2002;8(11):1235-1242. 3 Binder CJ, Chang MK, Shaw PX, Miller YI, Hartvigsen K, et al. Innate and acquired immunity in atherogenesis. Nature Med. 2002;8(11):1218-1226. 4 Ruggeri ZM. Platelets in atherothrombosis. Nature Med. 2002;8(11):1227-1234. 5 Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. 2002;8(11): 1257-1262. 6 Thies F, Garry JMC, Yaqoob P, Rerkasem K, Williams J, et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomized controlled trial. Lancet. 2003;361:477-485. 7 Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nature Med. 2002;8(11):1211-1217. 8 Hilpert KF, West SG, Kris-Etherton PM, Hecker KD, Simpson NM, et al. Postprandial effect of n-3 polyunsaturated fatty acids on apolipoprotein B-containing lipoproteins and vascular reactivity in type 2 diabetes. Am J Clin Nutr. 2007;85:369-376. 9 Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, et al. Disruption of methylarginine metabolism impairs vascular homeostasis. Nature Med. 2007;13(2):198-203. 10 Meinitzer A, Seelhorst U, Wellnitz B, Halwachs-Baumann H, Boehm BO, et al. Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the ludwigshafen risk and cardiovascular health study). Clin Chem. 2007;53(2):273-283. 11 Kelishadi R, Sharifi M, Khosravi A, Adeli K. Relationship between c-reative protein and atherosclerotic risk factors and oxidative stress markers among young persons 10-18 years old. Clin Chem. 2007;53(3):456-464. 12 Hu FB. The iron-heart hypothesis: search for the ironclad evidence. JAMA. 2007;297(6):639-641. 13 Zacharski LR, Chow BK, Howes PS, Shamayeva G, Baron JA, et al. Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease. JAMA. 2007;297(6):603-610. 14 Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356(13):1304-1316. 15 Newton RS, Pitas RE, Jensen RG. Effect of diet on fatty acids in the lipoprotein cholesterol esters of type IIa and normal individuals. Lipids. 1975;10(12):858-862.

Welcome to Functional Medicine Update for August 2007. The 14th Symposium on Functional Medicine in Tucson, Arizona focused on the effects from alteration of the function of the hypothalamus-pituitary-adrenal axis and the thyroid; and it was the most successful Symposium the Institute for Functional Medicine has organized to date. It was a very profound discussion of what I would call applied functional medicine across a wide rage of considerations. One of the Symposium themes that we are going to be focusing on in this month’s Functional Medicine Update is related to what we have euphemistically called (since Dr. Hans Selye gave it this label) “stress.” What does stress mean? How does it influence the activity of the hypothalamus-pituitary-adrenal-thyroid axis? What are the clinical symptomatologies? What are some of the tools that one can use to evaluate it? And then, of course, how does one intervene? What are the ways that we can actually do something about this in a clinical program? That is going to be the focus this month. We have a clinician and researcher of the month who I think will add tremendous insight to this topic and give you ‘news to use.’ She will bring this topic down to a level of user-friendliness and describe how we can apply this information to the patient. Before I get into this topic, let me first introduce the connection between stress and alteration of the hypothalamus-pituitary-adrenal-thyroid axis. This is the functional medicine perspective and what we will call “functional somatic syndromes.” It was very exciting for me to pick up my issue of Lancet magazine a few months ago and read a review paper titled “Management of Functional Somatic Syndromes.”1 This article was authored by Henningsen, Zipfel, and Herzog from the Department of Psychosomatic Medicine and Psychotherapy, University Hospital, University of Munich in Germany and the Department of Medicine at Tuegingen as well. These authors provided interesting insights that I thought gave some strong validation to the functional medicine model and its principles that we have been developing for nearly 20 years. These insights are useful tools for how we will sieve the information in this month’s Functional Medicine Update . Let me take you through a summary of this paper. The authors point out that although functional somatic syndromes show substantial overlap, research is mostly confined to looking at single syndromes. We know that in medicine there is a lack of valid and generally accepted diagnostic criteria that cross over from one medical specialty to another. The medical community likes to have conditions be seen as independent diseases that are siloed and uniquely defined within the concepts of medical specialties. Data for this article were drawn from systematic reviews and meta-analyses published since 2001, and it really demonstrates that functional somatic syndromes don’t fall nicely into single diagnostic categories with single diseases that can be identified. This article recognizes that there is a need for programs of intervention that take into account the fact that these syndromes show diverse symptomatologies and different mechanistic contributions to the signs and symptoms that a patient presents with. The authors indicate there is a need for personalized therapies and a differential approach overall (a stepped care approach is what they talk about). Conditions that May Be Considered Functional Somatic Syndromes The conditions these authors feel fulfill the concept or the definition of functional somatic syndromes include the following: irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, nonspecific chest pain, premenstrual syndrome, non-ulcer dyspepsia, repetitive strain injury, tension headache, temporomandibular joint disorder, atypical facial pain, hyperventilation syndrome, chronic pelvic pain, sick building syndrome, Globus syndrome, chronic whiplash, chronic lyme disease syndrome, silicone breast implant effects, candidiosis hypersensitivity, food allergy, Gulf War syndrome, mitral valve prolapse, hypoglycemic syndrome, chronic low back pain, dizziness, interstitial cystitits, tinnitus, insomnia or sleep disorders, and pseudoseizures. You’ll notice that the conditions on this list don’t fall within a specific diagnostic disease, but rather syndromes that defy simple explanation because there is no single etiology that has been identified as contributing to these. The authors state that pharmacological agents that have been used in the management of these conditions generally manage symptoms rather than a cause. In the case of functional somatic syndromes, a balance is required. Personalized therapy would take from biomedical, organ-oriented, and cognitive/interpersonal approaches. You’ll notice that all these functional somatic syndromes, as I have described them, might fall within the context of the kinds of presenting signs and symptoms that we often see in the patient with distress. In fact, all of the signs and symptoms that cluster around metabolic syndrome might be called functional somatic syndromes: increased weight gain of unknown origin, inflammatory conditions, altered triglyceride and HDL levels, craving for sweets, sleep disorders, sleep apnea. A Model for Managing Functional Somatic Syndromes The authors of the article say that if we are really looking at how to develop a model for the management of functional somatic syndromes, it should draw from the following: organic disease evaluation; dysfunctional peripheral stimuli, which has to do with distressful issues (or environmental agents that are received by the person and translated into altered mediators that then change their physiological function); dysfunctional early and current relationships, which has to do with what (in the functional medicine model) we call antecedents. This is really another way of restating the functional medicine model of antecedents and triggers resulting in mediators that produce signs and symptoms, leading to bodily stress, anxiety and depression, and ultimately to the experience of chronic bodily symptoms. These symptoms accumulate, leading to the loss of functioning (or altered functioning). This is, in a sense, the functional medicine model that we have described in the Textbook of Functional Medicine. It was quite interesting to see these investigators come up with (through an independent perspective) a model that is so closely allied with that which we have been talking about for 20 years. In assessing functional somatic syndromes, an organ-oriented approach is to look at those kinds of things that relate to physiological dysfunction that can be measured and analyzed by traditional methods (through biochemistry in the clinical laboratory and other kind of objective determinations). A cognitive interpersonal approach looks at body and mental symptoms over time, with a focus on dysfunction of central processing and context factors, including things like memory. Interventions are then aimed at sensations and cognitions that affect behavior and restoration of overall functioning. That might be called a stress management approach or cognitive behavioral therapy. Educating practitioners so they are better able to understand these problems and to recognize them early on is important. Practitioners can also learn how to communicate more effectively with a patient through this whole process about readiness to change, and they can also try to help patients avoid iatrogenic agents that might initiate problems (in other words, overuse of medications that might facilitate aggravation of the symptoms downstream). There must be a focus on the context, not just the treatment itself: What is the workplace of the patient? What is the patient’s cultural belief system? Does he or she have access to proper health care and counseling and education? All of these things are a part, of what the investigators in the Lancet article think is the appropriate way to both assess and then manage functional somatic syndromes. I think this is an extraordinarily useful article to highlight what we have been talking about for so many years, and it fits particularly well as we move into this discussion of psychosocial and distressful factors in our environment that translate themselves into alterations of the HPAT axis (hypothalamus-pituitary- adrenal-thyroid axis), which then gives rise over time to many signs and symptoms that can be classified as diseases in the late stage, but go through symptomatic syndrome-like changes that are very unique to each individual patient. One person who has helped us to understand the physiological mechanism by which these things occur (the so-called organ-specific component of functional somatic syndrome) is Dr. Bruce McEwen. As you probably know, Dr. McEwen is regarded as one of the top stress researchers in the world today. He is with the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller University. Dr. McEwen authored a very nice review paper that appeared in the New England Journal of Medicine in 1998 discussing the protective and damaging effects of stress mediators.2 In this article, he really sets the stage of looking at the neurophysiology of stress and how it relates to these functional somatic syndromes. Dr. McEwen’s work looks at environmental stressors, such as those found in work, home, or neighborhood, and how they get translated through the perception of threat, helplessness, and vigilance in ways that are individualized based upon each individual’s own genes, development, and experience. Once again, this is the functional medicine model: the interconnectedness between genes and environment and the perceptual translation of observations in the environment into physiological alterations of mediators. These triggering effects in life (some of which are old memories that get reinitiated by recent experiences) can be translated in the body as potential alarm reactions that then develop physiological responses and contribute to the need for the body to adapt to these changes. This is what Dr. McEwen refers to as “allostasis,” as contrasted to homeostasis. The Allostasis Model In the functional medicine model of the 1990s, we talked about “homeodynamic” change: the body does not remain constant (homeostasis); rather the body has to be dynamically changing in response to a changing environment. So, the body is “homeodynamic.” It is like a hummingbird that looks like it is stationary at a flower getting nectar, but in time-lapsed photographs, we see that its wings are moving at a very, very rapid speed in order to maintain its apparent stability at the flower. That’s how our physiology works-it’s like hummingbird wings beating at a very high speed to try to accommodate or adapt to those changing environmental conditions; that is called allostasis. As the body goes into an adaptation phase over some period of time, Dr. McEwen calls this the “allostatic load.” Over time, allostatic load charges a price to be paid from our physiological machinery, ultimately depleting functional status and reserve and what we have called “organ reserve” (taking from Dr. Fries work from many years ago about organ reserve, aging, longevity, natural death, and the compression of morbidity). Allostatic load depreciates organ reserve over time and ultimately leads to what later would be called a discrete diagnosed disease. The failure to turn off the hypothalamus-pituitary-adrenal-thyroid axis and sympathetic activity efficiently after stress is a feature of age-related functional decline in both animals and in humans. Stress-induced secretion of cortisol and other catecholamines, such as epinephrine and norepinephrine, return to baseline more slowly in aging animals with other signs of accelerated aging. This is the negative feedback effect of cortisol that becomes reduced and is seen in elderly humans, making them more susceptible to triggering events. Measuring Allostatic Load Allostatic load, as measured by McEwen and others through the MacArthur Studies on Successful Aging, was approximated by determining the number of measures for which a person had values in the highest quartile from among the following physiological variables that are all associated with this distressed response: systolic blood pressure; overnight urinary cortisol and catecholamine excretion; the waist-to-hip measurement (which is, as you know, is also a surrogate marker for metabolic syndrome related to changes in insulin resistance); glycosylated hemoglobin value (a move up from 5.5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of total hemoglobin as glycosylated hemoglobin is an indication of altered allostatic load); the ratio of serum high-density lipoprotein cholesterol (HDL-C) to triglycerides (which also is a surrogate marker for metabolic syndrome). Based upon McEwen’s definition of allostatic load, you’ll notice that a lot these things track against physiological parameters that have been given the name “metabolic syndrome.” During three years of follow up to the MacArthur Studies on Successful Aging, from 1988 to 1991, people in the higher functioning group with higher allostatic load scores at baseline were more likely to have an incident of cardiovascular disease and also were significantly more likely to have declines in cognitive and physical functioning. This suggests that one of the prices that we pay over time for these impacts of maintenance of this allostatic load is adverse effects on the neuroendocrine immune system with loss of cognitive reserves (meaning changes in memory patterns and increased incidence of depression). Repeated stress affects brain function, especially in the hippocampus, which has high concentration of cortisol receptors. The immune system, then, also responds by altering its function to pathogens and other antigens with its own form of allostasis that may include an acute-phase response as well as formation of immunological “memory” in which it becomes more intolerant to environmental substances. How many patients have we seen who become more environmentally sensitive and more allergic to things they could previously tolerate as they grow older? This is another manifestation of immunological impact of an allostatic load. You might say we are suppressing the immune system; however, not all effects are suppressive. Acute stress causes lymphocytes and macrophages to be redistributed throughout the body, such as to blood vessel walls and within certain compartments like the skin, lymph nodes, and bone marrow. This trafficking is mediated in part by glucocorticoids. When a challenge occurs, as is the case in delayed-type hypersensitivity, acute stress enhances the traffic of lymphocytes and macrophages to the site and therefore might be seen as a pro-inflammatory response. So we get these kind of unique and divergent effects of allostatic load, some of which look immunosuppressive, and others are immunoreactive (meaning increased inflammatory response). Acute stress has the effect of calling immune cells to their battle stations, and this form of allostasis enhances responses for which there is an established immunologic “memory.” So we recognize now that allostatic load has dramatic effects across a wide range of physiological parameters. It is associated with risk to heart disease, diabetes, memory loss, depression, and possibly even cellular-type effects that associate with cancer. Physicians and healthcare providers now are looking at how we can actually understand better the origin of allostatic load in the individual patient and what to do about it in individualized treatment prescription for that patient. That is the focus of what we are discussing in this issue of Functional Medicine Update: how the hypothalamus-pituitary-adrenal-thyroid axis affects the neuroendocrineimmune system, and how that ultimately translates itself into things that we try to diagnose and to put a diagnostic code on when they are really related to this altered physiological function associated with allostatic load. We recognize that physiological-activating factors alter CRH and arginine vasopressin levels in the brain, which plays an important role in then altering gonadotrophic hormone secretion during stress, and affects, then, thyrotrophic releasing factor and thyroid-stimulating secretion, so we have effects on downstream corticosteroids, catecholamines, and on thyroid hormones. In fact, high stress deactivates the conversion of T4/T3 peripherally, so we end up with a secondary-induced hypothyroidism. This doesn’t mean that the person needs thyroid hormone replacement. It means that what they need is to lower the load of catecholamines and glucocorticoids that then influence the conversion of T4 to T3 through the deaminase enzyme and thereby allow the more active T3 to be formed peripherally, which then controls cellular metabolism.3 The first step would be some kind of a program that is inducing lowered allostatic load. We recognize that the brain is, as I mentioned, significantly influenced by the allostatic load concept, with neuroplasticity of the hypothalamus-pituitary-adrenal axis altering, then, the stress-regulating brain regions and increasing neuronal apoptosis (or cell death) in certain regions of the brain.4 I have talked about the hippocampal impact of stress, so you might ask if chronic, long-term stress has any relationship to Alzheimer’s disease etiology given that the hippocampal region of the brain is one of the regions associated with Alzheimer’s disease and memory loss. We also recognize that these allostatic load concepts relate to increased inflammatory mediators that can be measured in the blood and circulating fluids, so there might be a link, then, between increased levels of tumor necrosis factor alpha or increased interleukin-6 and heart disease. This might be another example by which heart disease is connected to psychosocial stress and allostatic load. I’m now quoting from an article by John Yudkin and his colleagues at the Department of Medicine, Centre for Diabetes and Cardiovascular Risk, University College London Medical School that was published in Atherosclerosis.5 So we know that perceived stress can promote inflammation, and it also increases the release of mediators that are associated with blood coagulability, which then increases the risk of thrombus formation and sudden coronary events. This is from a study published in Psychophysiology this year that looked at plasminogen activator inhibitor (PAI-1) and other inflammatory markers such as interleukin-6 (IL-6) and soluble adhesion molecule-1 (sICAM-1) in 180 healthy individuals.6 The researchers rated stress-related effects on levels of these markers of inflammation and altered insulin sensitivity and found there was a very strong correlation between perceived stress (i.e. allostatic load) and increased stress markers and inflammation and, ultimately, coagulability or potential thrombus formation. This is a very interesting story that shows that one of the least accepted etiological factors in traditional medical training may be one of the most important factors for contributing to the outcome that we call chronic disease. During the stages of the functional somatic syndromes that I described earlier, people have broad-range symptomatologies that are hard to diagnose, and some clinicians say, “Well, they are psychosomatic.” And they use that term in a pejorative sense, indicating that there is no “organicity” with psychosomatic (it’s all in the mind). But the mind is connected to the body. It is very important to emphasize that this connection is where all the action is: how we perceive outside events and how these perceptions get translated to interior function. This is the topic that our clinician/researcher of the month will be helping us to understand. Organic Contributors to Allostatic Load Let me, if I can, shift slightly from what we have been implying through this discussion (that stress factors are totally psychosocial factors) to talk about some of the organic factors that may be perceived through the stress mechanism as contributing to allostatic load. These have to do with things like infection, toxic exposures, and even dietary factors, which are normally not on everybody’s list as potentially important stress factors, but are emerging to be so as seen from recent literature. Let’s talk first about diet because I think this is a modifiable factor that is often overlooked as an important regulator of the stress response. I’m now going to go back to a study that was published in the Journal of the American Medical Association a few years ago titled “Mediterranean Diet, Lifestyle Factors, and 10-Year Mortality in Elderly European Men and Women.”7 This is the so-called HALE project. This was published in the Journal of theAmerican Medical Association in 2004. In this study (conducted from 1988 to 2000), the investigators looked at individuals who were in the latter phases of their lives (70 to 90 years of age) from 11 European countries. It was a longitudinal study, and the participants were enrolled in the Survey in Europe on Nutrition and the Elderly: a Concerned Action (SENECA) and the Finland, Italy, the Netherlands, Elderly (FINE) nutrition intervention program. In this nutrition intervention program, they were looking at people between 70 and 90 years of age who decided to change their diets to a Mediterranean diet. The health outcomes of the participants were then evaluated in comparison to age and gender matched controls (people in the same-age cohort of 70 to 90 years who elected just to continue on as they had been eating and living prior to the study). So, basically it was not a controlled intervention trial; it was an evaluation of those individuals who elected to alter their diet and lifestyle to be more consistent with a Mediterranean diet. The investigators looked at health outcomes over this period of time. The outcome variable they chose was a pretty well-understood, non-equivocal outcome: death (all-cause mortality and cause-specific mortality). The results, when the data was worked up, were just quite remarkable. In fact, so remarkable that you wonder how this study didn’t get more media play than it did. A more than 50 percent lower all-cause and cause-specific mortality was found among the individuals aged 70 to 90 years who decided to adhere to a Mediterranean diet and healthful lifestyle, compared to those of the same age who continued on ad lib as they had been doing all their years previously. If I was to tell you that I saw a report in the Journal of the AmericanMedical Association about a pill that people could take that would lower (at the age of 70 to 90) the risk of all-cause mortality by 50 percent, how much media attention do you think that would get? I think we would be hearing about that. It would be a blockbuster drug. The drug company would suddenly be number one in its field. It would be sharing such huge profit with its shareholders. But because it was a diet and lifestyle intervention trial, it was ho-hum. It didn’t even get the Andy Warhol 15 minutes of fame. Why? That’s a very interesting question, isn’t it? Are we just so uninterested in this kind of information, which relates to having to make a change in our lifestyle as contrasted to taking a pill? Or is it that there is a suppression of the media? Or are we just kind of disillusioned about these diet studies? I don’t know the exact reason. However, the editorial that followed this particular paper was quite interesting. It was titled “Diet, Lifestyle, and Longevity-the Next Steps?”8 The authors of the accompanying editorial say that if we start really looking at the studies that have been published on dietary intervention and effects on outcome of health, we have to be very impressed because it is not just one-off evaluation. The Lyon Diet Heart Study showed that people with established coronary disease who elected to have a dietary intervention had a reduction of 79{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} in heart disease after just a few years of following the Mediterranean-style diet: that is, 79{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}! And these are people with established coronary disease. Although these results may seem to be simply too good, given the 20-fold or more differences in coronary rates across countries, the results for this dietary change are entirely plausible because it actually shows us, from other studies, that they are reproducible. For instance, look at the Dietary Approaches to Stop Hypertension Study (the DASH study). That study showed an ability to reduce blood pressure after six months into ranges that could generally only be achieved by usually 2 to 3 antihypertensive drugs. And because it was a dietary intervention, there were no potential risks to adverse effects from medication. We are starting to see more and more studies being published that are consistent with this HALE study of dramatic improvements in outcome and lowered mortality in people who elect to make these changes to a more Mediterranean-style diet. You’ll notice that this probably-in some peoples’ minds-is not very sexy. This is just another bit of diet information, so who cares? Well, we should care. Because what we are really saying is that these diets contain specific signatures from their ingredients (their nutrients) that modulate gene expression patterns in such a way as to serve as anti-stress factors. This is the so-called xenohormesis hypothesis that we have talked about before. Xenohormesis can either be inducing stress by factors that come from our diet and environment, or it can be altering the stress coping mechanism by improving stress response. There are food substances within Mediterranean diets that are minimally processed. There are complex foods that have color, and these color substances are, as you know, phytochemicals that modulate the stress response in such a way as to reduce its impact on inducing insulin resistance, dyslipidemia, inflammation, and chronic age-related diseases. Another paper in the Journal of the AmericanMedical Association titled “Mediterranean Diet: Looking at the Effects on Endothelial Dysfunction and Markers of Vascular Inflammation in Patients with Metabolic Syndrome,” confirmed the same thing.9 In this randomized trial, the people who engaged in a Mediterranean diet had lowered inflammatory mediators, improved triglycerides, improved HDL-C levels, and improved insulin levels. This indicates that there was a very powerful signaling effect on overall functional somatic syndromes to normalize function and reduce relative risk. Adaptogenic Substances You can obviously see that there must be something in these plant materials and these dietary factors that induce altered physiological function (i.e., are anti-stress). That really takes us back to looking at indigenous medicines, well before the birth of the pharmaceutical industry, going back to the dawn of Ayurvedic Medicine or Traditional Chinese Medicine. We recognize that people didn’t have access to patented drugs and that they used nature in such a way as to find the structure-function relationships between things that they could get in their natural environment and how they affected the body. They were very good observers. In the case of natural pharmacology, which is the basis of botanical medicine, we have often said that the bioactive substances from some of these complex mixtures of molecules from plants affect the body in what we call an adaptogenic way (“adaptogenic” meaning if the body is upregulated in this activity it will lower its activity; if the body is low activity-hypofunctioning-it will raise the activity toward normalization), so an adaptogen is a normalizing substance. In the past that didn’t (maybe), to a traditional pharmacologist, seem reasonable because it didn’t fall within the guise of how we normally think of drugs working, but over the last couple of decades we have come to recognize there are very good ways in which these adaptogens work. They work as a result of being agonists/antagonists, just like selective estrogen response modulators work (or SERMS). They can upregulate estrogen activity or downregulate estrogen activity depending upon the state of the function, so these are adaptogenic. They are agonist/antagonist. In the journal Phytotherapy Research in 2005, a marvelous review paper was published titled “The Effect of Adaptogens: An Overview with Particular Reference to their Efficacy Following Single Dose Administration,” which looked at the influence that a whole range of different adaptogenic substances from traditional plants used as botanical medicine have on normalizing function.10 This includes things that are derived from ginseng, Rhodiola, Withania somnifera (which is Indian ginseng), or Schizandra. These are all adaptogenic, anti-stress botanicals that have been historically used by different cultures to normalize the physiologic outcome that we associate with functional somatic syndromes that are titled “stress-related dysfunctions” and that have to do with what McEwen might call increased allostatic load. These plant adaptogens are historically a family of substances that were used prior to the onset of specific new-to-nature patented molecules that treat individual outcome parameters like elevated blood pressure, elevated insulin, elevated glucose, and elevated cholesterol. Before we had those molecules in our pharmacopoeia, we used these adaptogenic substances to normalize physiological function. We know that things like tumeric, which contains curcumin, is found to reduce the effects of chronic stress of the HPA axis. It also influences brain-derived neurotrophic factor expression and lowers brain neuronal stress and inflammation. There was a paper published recently that really looks through the whole nature of how curcumin plays a role on chronic stress on the HPA axis. This is in an issue of Brain Research in 2006.11 We know that curcumin is but one of many phytochemicals that have been found in various plant foods that have been used historically for modulating inflammatory response and stress-mediated effects. We have started seeing that there is a&hellip;I guess you would call it learning old things in new ways, or back to the future. It is regaining an understanding and appreciation for the signatures that these complex mixtures have in various plants and plant foods that modulate stress response and modulate them through activities of cell signaling-things like gene expression patterns modulated through kinases, a family of enzymes that translate outside information to inside cellular function. So I think that there is a regaining of interest in some of the traditional pharmacology that we associate with these complex mixtures found from certain plants that are of dietary origin. In pharmacology, where we look for the single molecule to treat the single outcome (i.e., the traditional kind of prescription medications of our age), these medicinal plants may have been lost along the way because they didn’t work by that mechanism; they worked by a different mechanism, which was normalizing function across these ranges of cell signaling activities that we associate with allostatic load and altered adaptation.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Sonia Lupien, PhD Director, Laboratory of Human Stress Research McGill University/Douglas Hospital Research Center 6875 Bld Lasalle Verdun, Quebec H4H 1R3 Canada sonia.lupien@mcgill.ca www.douglas.qc.ca/stress We are now at that most-looked-forward-to portion of Functional Medicine Update : our Clinician-of-the-Month section. This month we are very privileged to have both a clinician of the month and a researcher of the month in the same person. In fact, she was evaluated as the top presenter at the recent Institute for Functional Medicine Symposium. That’s not too shabby for a person who actually spoke in her second language at the Institute, English; she is actually French-speaking and Canadian. She has a tremendous background in the area that she is going to be speaking to, which is stress. Before I introduce Dr. Lupien to you I’d like to just say a couple of words about her. As you know, we have spent considerable time over the last 25 years (now moving into 26) to develop this whole concept of stress physiology. You have heard, over the years, from many of the premier investigators and clinicians in this area. Dr. Lupien has a background that I think is quite remarkable and certainly sets her up as being a world authority. Let me just summarize it for you. She started off with a BS in psychology at the University of Montreal, but then went on to get her Masters in neuropsychology, and then later her PhD in neurosciences at the physiology department, faculty and medicine, at the University of Montreal. Then she did a postdoctoral fellowship in neuroendocrinology at the University of California at San Diego with Dick Hauger, who we heard speak many years ago. And then on to do another postdoctoral bit of work in the laboratories of one of the people who is (I think) considered by many to be at the top of the game of stress physiology, Bruce McEwen at Rockefeller University. We have talked about his book, The End of Stress as We Know It, and certainly he is a very well regarded person. She was really a very important person in his laboratory and doing extraordinary work. Since then, Dr. Lupien returned to Montreal as a faculty member, first as an assistant professor in the department of psychiatry at McGill and now an associate professor there. She is director of the Laboratory of Human Stress Research at the McGill University/Douglas Hospital Research Center. I think that if you look at Dr. Lupien’s research publication record it is absolutely sterling; it’s at the head of the class. In 1998 she found that high levels of stress hormones in older adults are linked with both memory impairments and atrophy of the hippocampus (as you know, the center of memory). She has done tremendous work in understanding stress in children, which we are going to be talking about. She was named one of the 50 top young people for the year in 2000, and received Canada’s “Top 40 Under 40” award in 2002, and was named in the category “the top 20 Canadians who make a difference” by MacLean’s Magazine in 2003. So she is a pretty busy individual, plus a mother, a wife, and a student of the universe. It is with great privilege that I introduce to all of you Dr. Sonia Lupien. Sonia, good morning and thanks for being with us. SL: Good morning, Jeff. It is my pleasure. JB: Let’s, if I can, just start this discussion by going to your institution. Most of us who have come up through the understanding of stress were kind of borne first through the Hans Selye model (and, of course, we know he was at McGill), so you’re at the institution from which much of this was ultimately born. Can you tell us a little bit about how it is to be at McGill? SL: Well it is a great institution, as you know, and each time I give a conference on stress I always say (I’m not sure if it is a good or a bad thing) the concept of stress and the etiology was born in Montreal, perhaps because we are more or less stressed than everyone else. It is a great institution. Dr. Selye left his prints, I would say, here at McGill, and you have a lot of scientists actually here at the Douglas Hospital and all throughout McGill University who are working on stress and are contributing extensively on stress research. I think Canada (Montreal) is one of the best places to work on stress. JB: As you have worked your way into the position as the Director of the Laboratory of Human Stress Research, what kinds of things along your path have prepared you for this responsibility? I’ve looked at your publication record and read a number of your papers and it looks like you must have had a goal in mind throughout much of your academic history because it seems like it all lines up so beautifully. SL: Yes. A very, very simple goal, actually. I wanted people to talk to. You know, you develop a high level of expertise in a field such as stress and memory, etc., and you end up sometimes in your office because there are not a lot of people to talk about this. So I really worked hard to convince the university to recruit new scientists working on stress, and to train new scientists myself, so I could create a group of people to discuss and generate new ideas. I think that was the best thing I ever did because it is by collaborating and talking and fighting with all of these people that you come up with the best ideas. After that, what I have done is to found and create the Centre for Studies on Human Stress, which is now one step further, where all this knowledge that was generated by the lab is now translated for the public and for the health professionals in order to tell them what we learn in the lab and how they can apply it in their own lives. JB: Before we get to talking specifically about what you have done and your beautiful website and your programs, I’d like to just get your insight as to why you feel, in medicine, there still seems to be some resistance in accepting stress into curriculum in medical school and actually doing something to help docs to better know how to manage this in their patients. SL: That’s a question I have been asking for awhile. You know, at the official opening of the center I had a colleague of mine give a conference. The title was, “Can Your Doctor Diagnose Your Stress and Does He or She Care?” I’ve been thinking about this for awhile and I think the main problem comes from the word because the word “stress” is now overused. You know, we always use stress by saying, “I’m stressed. I forgot something.” etc. And anything that is overused and becomes nonspecific-so very difficult to measure or think about-is something that will die away, I would say. And it also always brings people back to this notion of mind/body, or mind over body. Kind of half of the population really gets the information from this and understands how the mind and the body can interact, and I think you have the other part of the population who see this as, you know, “soft science” or things like that, when actually when you read what has been done on stress and its impact on the mind, the brain, etc. there is a very, very good science behind this. I think that is our goal as scientists: to bring back this information and say, “Listen, there is science behind all of this and this is not just soft science.” JB: It strikes me very interesting and almost paradoxical as to why there is still some reticence to accept this at the level it should be accepted in medical school. I read a recent paper in The New York Times in which there were the results of a survey of educated individuals who were seeking out healthcare advice and they were asked to rate their most concerning health problems. Cancer and heart disease were on the list, but number one was loss of memory and loss of their minds. So this concept that somehow stress has an impact upon brain function seems like it is the number one thing people are concerned about, yet we’re not paying as much attention to it in medicine as it probably deserves. SL: Yes. And what I have realized is that we tend to be scared of what we don’t know well. As much as we think we know stress, I don’t necessarily consider that we have been informed-the public, the professionals, etc.-on what stress is. Most people-I did a survey one day with people from the public-told me they knew what stress was, and when I asked them what it was they told me it was time pressure. We know that stress is not time pressure. Now if you have the wrong definition of stress, you will use the wrong treatment. So I think that in medicine it is the same thing since you cannot diagnose this. Each time I talk to a doctor I say, “Listen, if someone breaks a leg and goes to you, it is easy. You know, there is blood, you know there is a broken bone, you can tell them you have a diagnosis, and then there is a treatment. If someone comes to you and says, ‘Listen, I’m almost burned out, I’m probably stressed, etc.’ you have nothing. There is nothing that you can do besides look at this patient crying and complaining about all of these stress-related chronic disorders that we know about, and you have nothing.” So I think that as long as we scientists aren’t able to provide tools to doctors, we will be having the same problem and that is what we are working on, actually. JB: Okay. So that’s a good segue into the next area of discussion. Much of your work has really dealt with the effects of glucocorticoids on various physiological functions and that translates, for our listeners, into how does stress/glucocorticoid production relate to things like memory. Can you tell us about some of your work in that area? Glucocorticoid Production, Stress Hormones, and Memory SL: Well, the interesting thing is all glucocorticoids and the stress hormones have been related to a lot disorders (peripheral disorders like the metabolic syndrome or cardiovascular disease, etc.). But Bruce McEwen, in 1968, found that there is the presence of glucocorticoid receptors in the brain, meaning that the steroid can access easily (it is a steroid so it can easily cross the blood/brain barrier) the brain, and when it gets in the brain, for some weird reason it has an interesting preference for the hippocampus, which is the brain structure that is heavily involved in learning and memory. So this notion, this idea, that chronic stress could lead to memory impairment because of the action of these hormones was born, I would say, in the beginning of the 1970s. Many studies have been done in animals confirming this. It has to be done in humans, so for this we have been doing a lot of studies in humans confirming, actually, the animal literature that stress does not only do something to your body, it will do something to your brain. This is very, very important. Not just because it will lead to memory impairment, decreasing your performance at work, or etc. It leads to another very important notion. It leads to the fact that it is able to explain why you lose control over your stress. When you talk to a patient who is chronically stressed, the first thing they will tell you is, “I don’t know anymore what is important.” They have kind of a big cloud over their brain (their cognitive processes). And this is what renders them more vulnerable to develop stress-related disorders because they tend to see stressors everywhere. And what we are showing now in the brain is that this “fuzziness” of the mind, if I may say so, is induced by the stress hormones. So as weird as it may sound, the same stress hormones that you produce that help you mobilize the energy you need to fight back will go back to your brain if it is produced for too long and modify the way you will interpret the next situation. And then you end up with this loss of control over your stressors. So the first thing you need to do is to decrease these stress hormones-take out a bit of the clouds out there on the minds of the people so they will be able to listen to what you have to suggest in terms of treatment. So I think this notion of the effects of stress on memory is very interesting for everyone, but clinically there is something as well that is very important that we have to keep in mind. JB: I know that Dr. McEwen introduced a concept (along with John Mason)-a kind of allostasis as contrasted to stress. Could you help us to differentiate the difference between those two terms? SL: Yes. Sterling talked about the notion of allostasis at the beginning, and it was in contrast to homeostasis. This is an important notion. We learned about homeostasis-you know, you want to keep a set range of data (in a certain range of homestasis). And when you get out of this there can be some problems. Now, in the 1970s, I would say, Sterling and Eyer came back with a notion saying that homeostasis is unable to explain most of what happens in life, meaning that the body is able to adapt. So the body, for some reason, when it is put in some types of environments, will change the range of set points and the normality range of any biological measure (will change it in order to adapt to the new situation). For us it can be called a dysregulation, but for the body it is just an adaptation. So they came up with this notion that we basically survive in life because our body is able to change the range of normality of values of any biological measure we have. Bruce McEwen came up with the notion (then worked with Sterling more on this notion) of allostatic load, meaning, what happens when you ask a body to adapt too often? You cannot always adapt. There is going to be a problem in the long run. So they came up with the notion of allostatic load. The notion is very simple. The first time you have a change in the environment, for example, you will change your range of normality of event. For example, the stress hormones are the first ones to respond to the environment. We know that there is a certain range of normality of stress hormones. However, if you measure stress hormones, for example, in poor environments, you will see that the stress hormones are always elevated compared to the norm. Now this is a change in the set point of this biological measure, and this is the body trying to adapt-mounting a stress response-because you are in an adverse environment. Makes sense: you will survive. What happens if, for a long period of time, you do this all the time? What Bruce has suggested (and we know about) is the beauty of the endocrine system is that every hormone in your body talks to each other. So they will basically try to help each other. So if you have the first stress hormones at the beginning that have been dysregulated (in our language, adapted) for too long, all the other hormones in the brain will start to change their own set points. And this is when you are going to start to see allostatic load, meaning that you are going to start to show an increase in glucose, for example; an increase in cholesterol; an increase in insulin resistance. All of these hormones will start to be dysregulated, leading to a load on your system. The allostatic load notion has been widely tested by the MacArthur Studies on Successful Aging in the US, and what they have shown is that the higher you are on an allostatic load score (so basically we are calculating the number of your biological measures that are getting very high and dysregulated), it is a good predictor that 3.5 years later it is starting to get very high allostatic load in the early 20s, and it is higher in poor people compared to rich people. Social support is a great way to decrease the allostatic load. So basically, this is where the science is. Now, if we go back to the notion of a diagnosis for the doctor, I strongly believe that the allostatic load battery, as Bruce has started to develop with us here at the center, is one of the greatest tools that we can develop in order to detect stress in humans very early in the process, meaning way before your patient will start falling from chronic stress disorders. JB: You’ve given us a lot to think about there. Let’s follow up on the allostatic battery. Where can someone find that? Is that on your website? A Useful Interactive Website for Practitioners SL: It is not on the website right now because I am really working in trying to understand the time course of how things are starting to work, but what I am trying to do, actually, is to validate further the allostatic load. I can provide a lot of information to doctors, but at the same time I think that we can create some nice collaboration all across the world. So what we are trying to do now is to work on the website, to put what I would call an allostatic load calculator, where doctors could enter a specific part of the website and enter the values that they have on a typical bloodwork for their patient (cholesterol level, etc.) and the machine (you know, the calculator) would calculate an allostatic load score. This is in association with the symptoms that the patient has, and then the next time you see the patient you re-enter the allostatic load score andthat would give you very important information. First, it would tell you if your treatment is working on the physiology of your patient. So whatever treatment you will decide to do in order to work with your patient, you will see a change in the allostatic load score. That is the first thing. The second thing, for us scientists looking at different symptoms associated with different changes in these biological markers, it could give us a very good indication of different pathways of chronic stress disease-who is going to go down first, for example. So this is exactly what we are working on. It should be available in a few months on the website, but there are many things to do before that. JB: So let’s talk a little bit about your beautiful website for the Centre for Studies on Human Stress. First of all, where can they find it, and second of all, tell us a little bit about it. SL: The website address is www.douglas.qc.ca/stress. This is my window to the public. I have a lab, that’s fine, but I was walking the dog one day and telling myself that I have two choices in my life: I am having all of this great knowledge and just keeping it for my success or I am sharing it with people, and I decided to do that. So we have created the Centre for Studies on Human Stress. I call this a safe place on the web. Because I wanted to do something with my students I said, go on the web, put stress management on Google, and give me the first 100 websites (the definition of stress they give you), and there was not one definition that was the same. So I can really understand why people have so much difficulty understanding what stress is and how to manage it because they don’t have the same information. So this is a safe place to go where you have a bunch of scientists (we have about 90 scientists all across the world who are associated with the center) providing you with scientifically validated information on stress. We have three sections. One is for the public, so if you have a patient who wants more information, it is free; it is there. Everything we know about stress is there. We have also a newsletter, which is called Mammoth Magazinev. It is written for the public. You can download it as a PDF and we have different issues (on aging, on children, etc.). This is the section for the public. It is very, very well appreciated by the public. We have these great emails that come back and this is good. We have also a section for the health professionals and education professionals which we are still working on. In there, eventually, you will find the allostatic load calculators. For the education professional, what the center is doing as well is to translate the knowledge we have. So we have programs (education programs) for children, where we go into schools or we train people so they can go themselves into schools (parents or teachers, etc.). The first one is for children between the ages of 7 and 10; it is called “My Amazing Brain.” Basically, the children in the class become the scientists and do all these great experiments to learn more about the brain. They love it and it is very fun to give. Everything is on the website: the logbook, the activities for you and for the children, the slides-everything is there. And we are finalizing another one, which is very important to me because this is based on one of my studies. I did this study awhile ago, showing that school transition (going from elementary school to high school) is where you have the largest stress response in children. This is when we start to see depression symptomatology in children, etc. Because of these results, we have created the “DeStress for Success” Program, which is a 12-session program given by school counselors (we will train them), where we will train and educate children on how to recognize stress and how to deal with it. And then you have a section for scientists. You want to know everything about the stress meetings in the world? Everything about stress questionnaires or alpha measures, stress hormones, etc.? It will eventually, as well, be in this particular section. JB: Well I can say, as a personal visitor (several times) to your site, it is brilliant. It is a tool that every clinician should have on their saved favorites so they can come back and visit on a routine basis. I really want to applaud what you have done. I know it is a work of love and a lot of tremendous effort, but it makes a huge difference in making this material accessible. We’ll make sure that the URL for the site is on the summary card and on the end of the tape so people who may not have gotten it can come back and get it later. SL: Thank you. JB: By the way, I just wanted to ask you an aside. Would you tell us why you have used the mammoth as your icon on your website? SL: If you read the second issue of the Mammoth (the first, I thought, was so wide and mammoth), and this is a very important notion and the reason is very simple: we have to make a distinction about an absolute and a relative stressor. Let me explain. What we know is that there are four characteristics of a situation (this is what science tells us) that will generate a stress response from your body. I say to people, burn-out or depression does not start in the liver; it starts in the brain. Why does it start in the brain? Because the stress hormones that you are secreting go to the brain when you are stressed (we talked about that). So, what will make you generate a stress response? Research has shown there are four characteristics of a situation that will induce a stress response. There are additives to the situation-the more you have of these characteristics the worse is your response. So in order for a situation to induce a stress response it has to be novel. It has to be unpredictable or unpredicted. It must threaten some part of your personality. We now know that there are some personality traits that make you more reactive to stress. And the most important one: you must have the feeling you don’t control the situation. So, these are the characteristics of the stress response. Let’s go back to the absolute stressor. An absolute stressor is a stressor for which it is a real threat for everyone that will not necessitate your brain to do this analysis of the four characteristics of the stress. For example, someone enters your office and says “Fire.” You will not start by saying, “This is novel and this is unpredictable.” You will start running. This is your brain telling you that you are in immediate danger, forget the analysis, run. And it will save your life. The thing is that we are not surrounded these days, in our respective countries, to a lot of absolute stressors. There are no more mammoths around. An absolute stressor was when we were chasing the mammoth in prehistoric times and you came face to face with this big thing, you would have an absolute stress response, which gave you the strength to kill the mammoth. These days we are surrounded by relative stressors, meaning situations that need to be interpreted by you as being novel, unpredictable, threatening to your ego, and without control in order for your brain to generate a stress response. We have more relative stressors today than absolute stressors, yet the World Health Organization predicts that by the year 2020, stress-related depressive disorder will be the second cause of invalidity in the world after cardiovascular disease, which is, by itself, related to stress. Yet, we don’t have anymore mammoth, and we are not in a war zone. Why are we going to die? And the reason is very simple: our body does not know we are in 2007. It doesn’t make a difference between an absolute stressor and a relative stressor. So between you and me, what it means is that your brain does not make a difference between a mammoth in prehistoric times and Sarah at work stressing you, for example. The brain will do its job (generating a stress response) because you detect a threat. What we know now (and this is all my work on the brain and memory) is that we are very good at detecting threats, like something very, very important. If you change the mind-if you change the way people interpret the situation-you will change the stress response and you will diminish the stress response. We have a lot of data now showing exactly that. So it is just to remind us that there are no more mammoths around. The NUTS Program JB: Well, you know, you also brilliantly just gave us the acronym that you have come up with, N.U.T.S. (novelty, unpredicted, threatening, and sense of loss of control). That is your N.U.T.S. program, NUTS. Maybe you just want to take another summary of that because you said it so quickly, but I think it is a tremendously useful tool. In fact, I heard doctors just this last weekend, when I was in Australia, who had been at the Symposium where you had spoken about the N.U.T.S. program, who were already repeating your concept. So it is very useful for a person to gain this tool, so maybe you could reiterate it for us. SL: I’m very happy to see that it gets there. This is a thing that I came up with. I was organizing the “DeStress for Success” program for the teenagers, and when you work with teenagers I think you have to come up with interesting stuff-that’s the first thing. And there is something else I had realized in the past. I was giving a conference, for example, in the workplace, etc. and I decided to test whether people would remember the four characteristics of a stressor, which is the most important information to remember about stress. In the first conference I had given the information (the four characteristics) twenty-three times. I’m a scientist. I said, “I’m going to test this.” I came back one month later and I said, “Can you remember the four characteristics?” I saw that the data showed that less than 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} remembered only one. So I said the message doesn’t get through, but I’m working on memory. I have to find an acronym that will stay there-stay in the brains of kids, adults, etc. I like the English acronym; I don’t like the French so far. So in English it is “Stress: Don’t go N.U.T.S.” This is to remind you that there four characteristics of a situation that will induce a stress response, whoever you are, whatever you are, whatever your age, actually. “N” stands for “Novelty.” “U” stands for “Unpredictability.” “T” is for “Threat” to your ego or your personality. And “S” is for “Sense” of control, which is diminished. So, “Stress: Don’t go N.U.T.S.” is the acronym that is really working now these days. JB: Thank you. That’s a wonderful explanation. I’m sure it is going to stick. What I find is that the people who listen to this often listen to this many times. It is amazing to me the work that they put into gaining competency in these concepts, so you are going to have people probably going nuts to learn N.U.T.S. SL: And all the N.U.T.S. information is on the website, so if they forget about it they can always read it with examples and everything you need about that to understand. We call this now (the program we are putting together) is to “deconstruct your stress.” It serves no purpose in life to say to someone, “You have to learn to manage your stress.” Because you are going to have a patient go into their car in the parking lot and say, “How am I supposed to do this now?” Managing your stress. Everyone says this. What does it mean? It is meaningless. Now if I tell you, “Deconstruct the situation.” Why is it stressful for you? Is it novel? No. Is it unpredictable? No. Is it threatening? Yes. Do you feel you have control? No.” But by now you have two of the four characteristics that are out. A well-defined problem is a problem almost solved. Now, in order to “manage” your stress, it is meaningless. If I tell you, what can you do to increase your sense of control for this particular situation? What can you do decrease the feeling that it is threatening for you? And you will come up (this is reconstructing, which comes after) with your own answer, because stress is an individualized process, but it is much easier now by reconstructing it (because you deconstructed it in the first place) to understand what you have to do in order to deal with every stressor in your life. You will realize that the method you need for one particular stressor is not the same for the other stressors because they are not stressors for the same reason. JB: So you now, I think (in the time we have remaining), led me to (I think, clinically) a very interesting question that comes up frequently. That is the question that you have already addressed, which is the correlation between a stress not regulated and (let’s call it) your relative stressor that has a long time duration and its relationship to depression. We recognize that depression is becoming almost a pandemic like essential hypertension in our society. You almost have to have it if you are a mid-life individual to be one of the norm. Depression medications are now one of the major categories of pharmaceuticals that are used, and we see its penetration of use down into younger age people. And then we witness the correlation between depression and Alzheimer’s disease and we see that the data that is now starting to emerge in the states indicate that as the baby boomers grow to be 80 and 90 the number of people with Alzheimer’s disease in our country will basically bankrupt the disease-care system. So there is kind of a theme that seems to be going along. It takes stress to depression, depression to Alzheimer’s disease and into the question of what the heck do we do because we really don’t have effective drugs in treating Alzheimer’s disease? If we were to look at this-and I guess we’d have to add to this the next confounder, which is the ever increasing use of statins to control hypercholesterolemia and the recognition now that statins have a correlation with lowering of neurosterols like allopregnenolone, which has something to do with mood and memory-people are now saying, “Well, gee whiz, is this very low cholesterol level why we see higher levels of suicide and violent death in people with very low cholesterol?” Because there is something adversely happening to their brains with too low cholesterol? There is this whole swirling story that seems to be going on right now that confuses docs about actually what to do with a patient. Could you tell us a little bit about your thinking between the depression/stress model and the depression/Alzheimer’s model and whether you see a sequence of events that we just need to start earlier in our understanding, before we get into medications? SL: Wow. That’s an interesting question. Let me just give you kind of a potpourri (as we say in French) of things that come to mind with regard to this one-million-dollar question. First, it is always a question of diagnosis. I think that we are not that good at diagnosing depression and I’m not sure that what we are diagnosing all the time is depression. No wonder we have these increasing numbers of people being diagnosed. We have this kind of pandemic now, but is it depression? We have the same problem with Alzheimer’s, by the way, and then we figure it out that they were different subtypes of Alzheimer’s disease. That’s the first thing. The second thing is that we see treatment as something that we have to change (a dysregulation in the body), and then we give medication, and then (exactly as you said) it leads to a domino effect. The body is there to help you. It is your best friend. But there is one law of the body: don’t change one thing without thinking about the rest. Because all the rest will follow and then you will end up with problems. A journalist once asked me, “Does this mean, you know, that if you could find a pill to decrease stress hormones you could cure a lot of things?” I said, “Yes, I think you can cure a lot of things with a pill or with good social policies.” Because we have shown that what increases the stress response in older people, for example, is social support. We are in an individualized society, and humans are interactive people; they love to be together. What we know from our work in stress is that the best buffer against stress is social support. We are starting to look at other variables that were not there at the time. So for sure it is going to become quite difficult. A Theory of Stress and Evolutionary Biology: Randolph Nesse The second thing I want bring up (and I have no answer, but I just want to share it with you): there is a scientist (he is a psychiatrist) named Randolph Nesse. When you talk about stress-anything related to stress-you have to think in terms of evolutionary biology. You will never understand stress or any stress-related disorder without thinking about that. Why would it be useful to still be here if stress is going to kill us? Survival of the fittest. We should all be dead in about 10 years from now. Why is it useful? Why is it that depression or depressed people survived across time? They should have been surely eliminated in terms of evolutionary biology. They have not been. So somehow this implies that depression has some importance in terms of evolution. What some people are starting to say is that depression may not be a disorder like, for example, cancer, but it may be just a manifestation of a need to others. Because when you are depressed you don’t feel good, you isolate yourself, which brings other people to come toward yourself, etc. That would send a signal to others (because animals can do this as well) to take care of you, etc. With this I just want to open up a mind and say what if this is something? Again, it is always like allostatic load: this is a system trying to adapt. By adapting, us humans, we call this a dysregulation. We try to fix it. But if we don’t understand it first we will never be able to fix it. That’s my answer to your question. What is the purpose of depression, etc. and what can we do in order to understand this? And then we will understand why things work or things don’t work. So I take a much more global approach to this. And, by the way, the evolutionary approach notion about depression would explain why you see it with so many “disorders”-with Alzheimer’s, and with many other things as well. It could be one of the first manifestations, meaning it may not be a disorder. JB: That is a beautiful thought, actually. That really sends so much of a different message rather than a defect or a disease — to talk about a social condition, in which the person is trying to find a way to be healed and looking (through their affect) for support. I think that is a much more empowering concept than a defect. SL: And I would strongly suggest if you are interested in that or the people listening to this show, to read some of the papers by Dr. Nesse. It is really worth thinking about. We’ll never have the right answer, but opening your mind to mental health disorders this way is a very interesting process. JB: Well this has been a most interesting discussion and I can’t tell you how much we appreciate your time. What you are doing is just right at the forefront of really finding solutions to these complex chronic disease processes that we ultimately treat the endpoint of but we know the origins started much earlier with the things that you’ve been describing that are part of this allostatic load and the body trying to accommodate this chronic relative stressor environment that we live in. Dr. Lupien, I can’t thank you enough. It has really been a great privilege and we’ll be checking your website frequently. SL: That’s good and it was my pleasure. I’m sure that you enjoyed Dr. Lupien’s presentation as much as I did. What a tremendous resource of information and the density of information and how rapidly it comes across to us. I hope you are going to slow your recorder down and listen again because between the two of us, probably you’re going to need to slow it down to pick up all the density of that information. That is really news to use. Heart Rate Variability Measurement One of the other things that I wanted to offer, as it relates to the wonderful comments that Dr. Lupien was providing to us in terms of stress management, has to do with another clinical tool for evaluating stress, and that is the heart rate variability measurement (HRV). I am becoming more and more convinced that heart rate variability is a very important early predictor of later-stage vascular and neuroendocrineimmune dysfunction associated with stress and other metabolic dysfunctions that we associate with chronic disease. If you have been following the literature in this area you are probably aware of the fact that there is an emerging body of very good clinical and research literature that talks about the association between various stresses (including job stress) on heart rate variability and its interrelationship with the alteration of these physiological parameters that Dr. Lupien was talking about that track against things like cardiovascular disease risk and metabolic syndrome. A paper that appeared in the Yonsei Medical Journal in 2004 was titled “Association between Job Stress on Heart Rate Variability and Metabolic Syndrome in Male Workers.”15 The finding of this study was that there is a very strong correlation between what we call loss of heart rate variability and increasing concerns of distress associated with metabolic syndrome. When I say distress I mean physiological distress, or changes in the web of the physiological interconnectedness between insulin, lipids, and inflammatory mediators. So this heart rate variability is an interesting question because as you probably recognize, when people get under stress physiologically, the line structure in their EKG or their electrocardiac rhythm starts to flatten out. As it flattens out, it loses its line structure-in fact, the simplest EKG of all is, as you know, a flat EKG in a dead person. So somewhere between the extraordinarily complex EKG patterns found in a highly fit trained athlete and a flat-line EKG is the range of functional status of the neuroendocrineimmune system as reflected through heart rate variability. We know that heart rate variability, and also alterations in heart rate variability, are associated with multiple contributors to metabolic syndrome. There are a number of interesting papers showing that heart rate variability becomes much less complex (meaning simpler) in people with metabolic syndrome, such as a study published in a recent issue of Diabetes Care.16 We know that even individuals who undergo a weight loss who have elevated body mass index and have increased ambulatory blood pressures and enhanced cardiac autonomic tone are seen to have improved heart rate variability as they control their weight and also control their metabolic syndrome. This was published recently in a very nice study that was showing the correlation between body mass index and ultimately metabolic syndrome and how the weight loss with the appropriate type of nutrition and lifestyle program, improved heart rate variability. This was in the Journal of Hypertension.17 And even toxic exposure to things like lead or cadmium or mercury has been associated with increasing incidence of lowered heart rate variability and metabolic syndrome. This was actually recently published in a Veteran’s Administration study that I think is quite interesting in Environmental Health Propectives in 2006 titled “Low-level Lead Exposure, Metabolic Syndrome, and Heart Rate Variability: The VA Normative Aging Study.”18 The findings of this study showed that heart rate variability was decreased in individuals who had been lead exposed (low background lead; this is chronic lead exposure) as was measured by looking at lead concentration in the bone and that metabolic syndrome was enhanced in these individuals. So you’ll notice there is an interconnection of a number of factors. Psychosocial stress and chemical stress associate themselves with alteration in the metabolic web and are seen as lowered heart rate variability. So, another tool that you might consider of clinical importance. Thanks for being with us in August and we look forward to continuing this theme as we move into September.

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Welcome to Functional Medicine Update for September 2007. This is going to be an interesting and unique issue of Functional MedicineUpdate. We are going to focus on a topic that at first blush you might not think is that clinically relevant, but hopefully, by the end of this issue, we’ll demonstrate how interesting it is to look at some aspects of chronic disease through the genetic expression lens. What I really want us to do throughout the course of this particular issue of Functional Medicine Update is to open our minds to the possibility that many of the conditions we see in patients who present with chronic symptoms and disease are the late-stage manifestations of altered gene expression patterns. These altered patterns modify metabolic function and ultimately become expressed as the phenotype of a particular illness or disease. I know this upstream-type of perspective is different from what we are often taught about disease (through its diagnostic specification). I think the confluence of altered metabolic function across wide ranges of cell types ultimately gives rise to the expression of what we call disease. I would like to provide a few examples of how this perspective can be of some value in evaluating patients early on and how it relates to where they are heading with the nature of the expression patterns that ultimately express health and/or disease. Processing Information through Sensing Mechanisms The information we are getting from the world at large that is picked up by our sensing mechanisms is vast. It can come as electromagnetic information. It can come as chemical information. It can come as information that we probably don’t even know yet exactly how to quantify-information that has some type of an intuitive “knowingness” that you can’t quantify in terms of a frequency or a wavelength, but you know that it is real. We hear more and more people talking about synchronicity and that there are no such things as coincidences. Events that appear to be random can occur so frequently that it is beyond random to understand how certain observations are made that are synchronous in nature. These constructs can give us pause. Maybe we are picking up information from all sorts of compartments and we are translating it into physiological, neurochemical, immunochemical, electrochemical activity in our body that ultimately gives rise to messages that are signaling to our genes how to express their response to changes in the environment. This is the molecular action (or a physiological or cell biological connection) between the mind and the body-the construct of a gene expression/gene environment relationship with our outside world and how we perceive it. We certainly know a lot about tactile sensations and how they get translated into neurological function–those that we can see with our eyes or hear with our ears. The movement of air across our tympanic membranes and the set-up of sensory perception that trigger certain changes of membrane potential that we call an action potential give rise to a neurological function that ultimately can regulate chemical functions through the release (in our hypothalamus-pituitary-adrenal axis) of a variety of different messenger molecules. These molecules ultimately control action at a distance in our body by regulating gene expression and cell biological function away from the source where we actually received that information (our eardrum). These are interesting parts of what we learn through our experience in life and through the study of anatomy and physiology, but when we translate it down into the cell level, it takes us to a different lens in evaluating, the functional changes in organisms over time. An Observation of Olfaction and Gene Expression While reading a recent issue of Science magazine, I was struck by how much we are learning concerning the very complex relationship we share with our outside environment.1 An article was published that was looking at the lowly fruit fly (Drosophilan melanogaster ). I thought this was a very interesting example of how, in an animal, information from the world can influence its gene expression. The authors of this article describe how the lifespan of the fruit fly can be influenced by the ability of the insect to smell a food that it likes-not even taste the food, but smell the food. The fruit fly likes yeast. In this case, smelling the aroma of yeast without actually having the ability to eat it influences (through olfaction) the expression of genes in such a way as to modulate what are called longevity genes (the genes that are associated with extending lifespan of the animal). It is a very interesting observation: something that didn’t even touch the nerve as a direct molecular interaction (this is a odorant), caused some kind of a receptor interaction and sent a signal at a distance through the olfaction system to regulate gene expression across the body of the animal to upregulate longevity genes (the so-called SIRT-like that are silent inducers of signal transduction). There is a lot yet to be learned about how we regulate our function in response to changing environments, even odorants. Are there certain fragrances or odors that the human picks up, beyond pheromones, that modulate gene expression? What about aromatherapy? What about the way some people feel good when they smell certain fragrances? How does that influence not only the sensory media perception, but maybe other things that relate to stress response and gene expression related longevity and stress management genes? So it is a very interesting conceptual framework that I want to build into our discussion that we’ll take from this esoteric level and bring it down into a more clinically applied level. To hang just for a moment longer on this level of esotericism so I can get the right framework built to look at the clinical implications, I’d like to talk about the translation of information by these systems to our genes to influence a process we call genetic expression. The book of life is coded in our genes, of which there are (in humans) 30,000 plus, that are not all expressed simultaneously. They aren’t all being read simultaneously; if they were we would be a mess. They are read selectively, but not one gene at a time; they are read in families that are controlled by orchestrating components, and its these components that ultimately control the expression of the functional genes. So, we get these very interesting ways that genes are organized and expressed. Some of the sites where the components that are involved with the organization of how genes are expressed are found turn out to be within what used to be called the “junk DNA” of our genome. Regulatory Sequences Control the Expression of Genes What an interesting term, right? Because we didn’t know what this did we thought it was a relic from time gone by with no real importance in terms of coding for our characteristics, so people called it junk DNA. But now we find that within that region of the genome, which in humans is one of the most significant parts of the genome, resides the regulatory sequences that control the expression of these genes. We get genetic expression differentially in different tissue types under different environmental conditions; it is not just randomly expressed. The Trilogy of ‘Omics That gives rise to what we call the proteomic message, or the production of proteins that are unique to that cell in response to that stimulus. This then translates itself into different metabolic functions, and that changes what is called the metabolomes. I have traditionally referred to this as the “trilogy of ‘omics”-the three ‘omics: the genomics, the proteomics, and the metabolomics. This trilogy regulates our phenotype and how that cell, tissue, organ, organ system, or whole organism responds, looks, acts, and feels. Metabolomics is the third of the three ‘omics and it is what we often study on wall charts and memorize for tests in our biochemistry class. It has to do with the Krebs cycle and enzymes. It has to do with glycolysis and aminolysis and all the various catabolic and anabolic pathways in intermediary metabolism. And obviously, metabolomics is tied together with the proteins that are available as enzymes and structural proteins to manifest the control of the metabolic activity. Those enzymes are regulated upstream of the actual gene. So, here we go again, the trilogy of ‘omics: genetic expression leads to active proteins, which get post-translationally modified, which then control metabolism, and ultimately, from that, resides the tens of thousands of various molecular species that are part of the metabolome. New Analytical Technologies Individuals are now starting to evaluate, using complex analytical profiling, all three of those aspects of our phenotype of our cell: the genetic expression components, using gene array technologies; the proteomics conceptualization, using proteomic chip technologies; and lastly, the metabolome. Integrating these together in an information system requires huge data management mining to try to understand the complex way that these components interact to give rise to the function of what we call the phenotype of the cell. There is an interesting paper that appeared in American Genomics/Proteomics Technologyauthored by Dr. Chris Beecher titled “Metabolomics: A New ‘Omics’ Technology.”2 It is about how these intermediary metabolites from wall charts that we studied in school but have forgotten can be measured using different types of analytical technologies and biological fluids. These would be things like GC/MS or LC/MS technologies. The data can be pumped through a complex data set analysis system that is the nearest-neighbor-type of analysis, or artificial intelligence system. This can give rise to understanding these patterns and relating the metabolic patterns (which are not linear, but are complex systems) back to that of the proteomic and the genomic expression pattern. You can ultimately start understanding at a much deeper level how a particular cell (or tissue, or organ, or organ system) is responding to its environment. This is part of the systems biology approach towards medicine that is an underpinning to functional medicine. We are starting to see nutritional proteomics develop. Animals are given specific diets, the proteins that emerge as a result of genetic expression are analyzed, and then the metabolites are analyzed. This process allows you to start getting an understanding of how various nutrients can influence the regulation of metabolic function through this trilogy of “omics” (the genomic expression, proteomics, and ultimately metabolomics). I am now quoting from a recent paper, “Nutritional Proteomics: Methods and Concepts for Research in Nutritional Science,” which appeared in Annals of Nutritional Metabolism in 2007.3 This is still in its early stages of development. The point I am trying to get you to understand is that we are starting to see tools emerge that will allow us to explore many of questions that have been around for at least 30 or 40 years about how things in our environment influence our genes and our phenotype, and modulate our health and/or disease patterns. This will no longer just be open for speculation; we’ll be able to actually start exploring this. With all of that as a background, let’s now take this discussion from the esoteric to the clinically applied. Let’s use a couple of examples that we might be more familiar with. Let’s look at hypertension, which I think is a very big problem in our culture. The major form is called essential hypertension, or idiopathic hypertension, meaning it has no known specific etiological agent that it is causing it. It is influenced by a complex shift in our metabolic function that gives rise to changes in vascular endothelial compliance, leading less to vasorelaxation and more vasoconstrictive responses, which then elevates our blood pressure. We have learned from the fundamentals of basic nutrition that cations in the diet play a role in the pathogenesis of hypertension. Certainly we have hormonal systems in the body that are there to regulate cations, such as the monovalent sodium and potassium, as well as the divalent magnesium and calcium, which all play roles in the regulation of pressure and vascular endothelial function. In a recent review that appeared in the New England Journal of Medicine titled “Sodium and Potassium and the Pathogenesis of Hypertension,” it was pointed out that high blood pressure/hypertension affects approximately 25 percent of the adult population worldwide, and its prevalence is expected to increase by 60 percent by 2025, when a total of 1.56 billion may be affected.4 It is a major risk factor for cardiovascular disease and it is responsible for the most deaths worldwide. Primary hypertension, also known (as I said) as essential or idiopathic hypertension, accounts for about 95 percent of all cases of hypertension, and therefore it is really a functional somatic syndrome (to come back to our discussion we had in September of 2007 in Functional Medicine Update where I was defining, from the article that appeared in The Lancet, what a functional somatic syndrome is). It is a condition that is psychosomatic, right? It ties the brain and the body together, and that is essential idiopathic hypertension. It has no single, organ-specific cause, but rather it is a complex, physiological dysfunction that we might say has its root origin in the alteration of the translation of messages from the environment through the HPA axis and through the gut, ultimately into-what? Altered gene expression, altered proteomics, and altered metabolomics at various tissue levels that produces what we see clinically as elevated blood pressure. I think you can get my reasoning here that the blood pressure doesn’t elevate just because it doesn’t have another thing to do. It does so because it is influenced by these altered cellular functions that occur from a change in gene expression with a changing environment. That leads us to the question of the dietary environment and hypertension. What about dietary sodium and hypertension? As you probably know, primary hypertension and age-related increases in blood pressure are virtually absent in populations in which individual consumption of sodium chloride (salt) is less than 50 mmol per day. These are the people who don’t use salt in food processing and they don’t salt their foods. In fact, in the historical record, people who lived inland from the oceans-one of the major risks they had was sodium deprivation back in the early days of human history because salt was not prevalent or common. Individuals could get into a sodium deficiency situation and it was a very significant problem. That is why salt was so highly valued as a trading commodity in early civilization. We clearly know that’s not the case today with the prevalence and plentiful nature of salt, which ends up being a food additive in our processed foods, in which now we start to see tremendous increase in the sodium intake (approximately 9.9 grams [170 mmol] of sodium chloride is excreted per day in people in the 32 countries that were recently studied). So we are starting to see much higher levels of sodium intake. Mean systolic blood pressure is about 5 mm Hg higher and diastolic pressure about 3 mm Hg higher when sodium intake was increased by 50 mmol per day. So we know there is this connection, and it is even a stronger connection between sodium and blood pressure in individuals who have a genetic propensity towards what is called salt sensitivity. These are individuals who have marked elevation of blood pressure with even modest increases in sodium intake. So we have a combination of high sodium diets and low potassium diets (potassium is the other problem because potassium is higher in vegetable foods). We have cut down vegetable foods and increased salted processed foods, so the ratio of sodium to potassium in our diet now is extraordinarily high. We have almost completely reversed the ratio of sodium-to-potassium that was found in our indigenous diets, which were low sodium/high potassium-now they are high sodium/low potassium-and that then influences the renin-angiotensin system and how it influences through the adrenal hormones the retention of salt and retention of fluid, which then ultimately causes an increase in blood pressure and altered endothelial nitric oxide output, lowered vasodilation, and increased risk to high blood pressure. So, this interesting story is starting to emerge that connects together food to gene response to cell signaling and ultimately to hormonal messages, which regulate stress response. A high-salt diet might be considered, by this definition, kind of a stress factor because it encourages a response at the renin-angiotensin-aldosterone system, that then looks like a stress response and is associated with vascular dynamic changes and increased blood pressure. With all of that in mind, you might ask what you should do to lower relative risk. One thing, of course, is to lower processed food intake (salty snacks). That seems like a very easy first step. Another step is to increase vegetable products, particularly fruits and vegetables in their whole form because they are relatively rich in potassium. Fruits are higher in sugars and vegetables are not, so generally we are talking about increasing vegetables. Vegetable juicing is very high in potassium. Through vegetable products, you can get a much higher level of potassium and a much lower level of sodium (as long as you avoid the salted, canned variety of vegetables). So that is one part of the story. Another part of the story is magnesium. We recognize that magnesium is another important vasorelaxing divalent cation. Magnesium is found in green leafy vegetables. Magnesium is associated with the chlorophyll molecule, and chlorophyll gives rise to the color green in plants, so green plants are generally high in magnesium. So the potassium and magnesium components, along with a lowered sodium intake have a salutary effect upon blood pressure. Again, I want to emphasize there are genetic uniquenesses to this sensitivity, and there are some people that are extraordinarily sodium sensitive for whom the modification of their sodium/potassium ratio in their diet has a dramatic effect on altering their blood pressure. What about substances in the natural plant food world that may have agents that regulate blood pressure? Are there things that would either increase or decrease blood pressure that are found in the plant world? I think the most interesting example of this, and one that we all learn in school but sometimes forget, is the most studied botanical medicine and flavorant that has historically been discussed in the world’s literature, going way back to the Yellow Emperor’s handbook; I’m talking about licorice. As you probably recognize, this is a very, very interesting story-the whole licorice-blood pressure connection. Glycerrhiza glabra, or licorice, has a very long history of being known as an agent that will modulate stress and will have an impact upon blood pressure and arousal. Licorice contains probably a thousand different phytochemicals, some of which have extraordinarily different effects from one another. We shouldn’t jump to a conclusion to say just licorice in and of itself. Some people call licorice by different forms, like the deglycerinized licorice. We know the glycerrhizen within the licorice plant has some blood pressure-regulating effect, so some people talk about DGLA or DGL (deglycerinized licorice) as having a different effect, obviously, on blood pressure than the full licorice plant. I want to make sure that we recognize different phytochemicals can have different effects on this trilogy of ‘omics (this translation through genetic expression into proteomics and ultimately into metabolomics and how that influences, differentially, specific cell types). Let’s go back and examine licorice as an agent that modifies HPA axis function (hypothalamus-pituitary-adrenal function) and ultimately can have an effect on blood pressure. I’ll take you back to the Journal of Clinical Endocrinologyand Metabolism in 1978-an article that was principally authored by MT Epstein from the Princess Margaret Hospital in Christchurch, New Zealand that talked about licorice raising urinary cortisol in humans.5 This was an interesting paper in which the authors discussed individuals who elected to consume 100 to 200 grams of whole licorice candy (these were 13 normal volunteers and they consumed this for 1 to 4 weeks) and had an assessment of their HPA axis function made before, during, and one-week after a cessation of licorice ingestion. Urinary cortisol excretion was found to be more than doubled in 10 of the 13 subjects when they were taking the licorice, and some excretion rates were found similar to those that had Cushing’s syndrome, which is, I think, a very interesting observation. Urine cortisol excretion remained significantly elevated above controls for at least one week after licorice was withdrawn, and despite these increases, urinary steroid metabolites were not affected (those are metabolites of cortisol). Plasma cortisol and HCTH levels were unchanged, and there was a normal diurnal variation of plasma cortisol. The direct intraadrenal infusion of the active mineralocorticoid component of licorice, which is this glycyrrhetinic acid, in two sheep who had autotransplanted adrenal glands failed to stimulate cortisol secretion acutely. It was concluded from these early studies (this is, again, I want to emphasize, back in 1978) that changes in cortisol excretion are not a result of adrenocortical stimulation, but more likely a represented change in the renal handling of cortisol, according to this article in 1978 in the Journal of Clinical Endocrinology andMetabolism. Later, in a very nice review paper that appeared in 1994 in Endocrinology and Metabolism Clinics in North America, Brian Walker and Christopher Edwards talk about licorice-induced hypertension and syndromes of apparent mineralocorticoid excess.6 It looks like these people have hyperaldosteronism who have this licorice impact upon their blood pressure. The reason I’m going through this is this specific example illustrates how agents in our world can influence-in a genetically unique way-a messaging system that translates the activity of specific molecules (in this case, licorice-the glycyrrhetinic acid) into a modification of gene expression, to a proteomic modification, and ultimately a metabolomic modification at a cell-specific level that regulates, in this case the hormones that control sodium-potassium balance, and ultimately electrolyte regulation and blood pressure. So this is a specific example of a more general theme as to how our diet and our lifestyle and things that we are exposed to can be transduced or translated into functional changes in the individual. The good news about that is if you can identify these agents that are inducing a stress response (meaning something that is causing an adverse response) by modulating or taking away that stimulus, you can have, then, an anti-stress outcome (meaning it gives you the potential for therapy). Without relying on drugs to try to neutralize that effect, what we are doing is taking away the precipitating agent that changes the function of the individual. So it is a different strategic approach; this is the functional medicine model. Looking, again, at licorice specifically in this article that was in Endocrinology and Metabolism Clinics, the authors point out that the use of licorice and its hydrolytic product, glycyrrhetinic acid, dates back to at least 1000 BC, where stores of the root were found in tombs of ancient Egyptian pharaohs, and its therapeutic activity was known for a wide variety of elements and was extolled in the writings of the Greeks, the Romans, and the Chinese. Licorice was rediscovered in Europe in the 15th century and became an established treatment for dyspepsia, and so now we recognize that as a confectionary agent (as a flavoring agent), it finds itself within a variety of different foods. A Case of Licorice Sensitivity We actually had an interesting case history a little while ago-I think it was 2 years ago-in the Functional Medicine Research Center. An individual (an older-age gentleman) was slated to have surgery for a hernia, but his surgeon was not going to perform surgery until his serum potassium and sodium ratios normalized. He was told he was a surgical risk in the absence of getting those normalized because of potential adrenal-related difficulties. He was very worried, his hernia was getting worse, and he did a consult with us. One of the questions we asked him was, “Are you consuming licorice?” And he said, “Well how do you know that? How do you know that that is my favorite before-bed snack? I take licorice every evening because it is kind of just a nice thing that makes me feel good and I sleep better?” So we encouraged him to discontinue the use of his licorice for awhile. His serum potassium ratios normalized. He went ahead and had a very successful surgery, and the outcome of this particular story was that he was one of those licorice-sensitive individuals; it had an adverse effect on his electrolytes and also had an effect on his blood pressure. When licorice is administered therapeutically it results in the chemical features of primary aldosteronism. Clinical manifestations include those of sodium retention, so you get elevated sodium with peripheral edema, breathlessness, and hypertension potentially resulting, and hypokalemia, a low potassium polyurea due to the nephrogenic effects that seem to mimic that of diabetes or proximal myopathy. Biochemical markers for the excessive activation of the minerocorticoid receptors in the distal nephron associated with excessive licorice intake include hypokalemic alkalosis and suppression of plasma renin activity. It is very interesting to see how this effect of licorice-induced minerocorticoid what-appears-to-be excess may be very individualized in its response, possibly showing genetic uniqueness, this concept of biochemical individuality that Roger Williams talked about. There seems to be a paradox of renal minerocorticoid receptor specificity associated with this particular observation. The classic model of corticosteroid action in the kidney, aldosterone is known to bind a minerocorticoid (or type I receptors) which have a restricted distribution in the distal nephron. In contrast, cortisol binds to glucocorticoid (or type II receptors) which have a ubiquitous distribution and more variable effects on tubular function. It is central to the model that there is little cross reactivity between the glucocorticoid and the minerocorticoid receptors. So your cortisol and your aldosterone receptors seem, by a traditional thought process, that they don’t interconnect or have cross-talk, so cortisol does not activate minerocorticoid receptors. However, one would predict that the specificity of minerocorticoid receptors for aldosterone would be dictated by this binding efficiency of its enzyme, but with regard to the case of licorice, it appears as if there is some cross-talk between the cortisol levels and the aldosterone receptors, so you get this kind of interesting paradox between individuals that have connection through genetic modulation of an enzyme which is 11&beta;-hydroxysteroid dehydrogenase, and polymorphisms of that enzyme apparently make individuals more sensitive to licorice-related hypertension and hypokalemia. Again, what we are seeing here through this case example is a very interesting case of uniqueness, likely related to altered genetic expression affecting proteomics, which then downstream regulates metabolomics, and, in this case, can induce, then, altered monovalent cation distribution and blood pressure. I hope that you take away a couple of things from this discussion. Number one is the connection between licorice and blood pressure and licorice and the sodium-potassium balance; secondly, the uniqueness of how that affects individuals; and third, the kind of general example/case that comes out of this specific example about how agents in our environment (even small molecules like glycyrrhetinic acid) can influence cellular function. You can actually induce this not just in humans but in animals as well. Glycyrrhiza glabra, or licorice, when administered to animals at high levels, is demonstrated to have influence on the adrenal-kidney-pituitary axis.7 We see a generalized effect of these bioactive molecules. With that in mind, what is another thing that can influence endothelial function, vasorelaxtion, and blood pressure? Of course, that is insulin. We know that high levels of insulin have an impact on endothelial nitric oxide output, on endothelial dynamics, and on the regulation of blood pressure. Certainly this is one of the hallmarks of hyperinsulinemia and insulin resistance syndrome: marginally elevated blood pressure and increased levels of plasminogen activator inhibitor 1 and how this influences, ultimately, electrolytes with increased sodium/lower potassium and what appears to be an adrenal stress, so to speak, relative to insulin resistance and metabolic syndrome. And so you might ask the question, “What about medications that are used to manage dysinsulinism, or type 2 diabetes associated with insulin resistance? Like the PPAR (or peroxisome proliferated activator receptor gamma agonist drugs) such as rosiglitazone or piaglitazone?” A Controversial Article about Rosaglitazone Use in Individuals with Type 2 Diabetes or Insulin Resistance/Hyperinsulinemia There was a recent paper published in the New EnglandJournal of Medicine-quite a controversial paper, I might add-that was a meta-analysis, authored principally by Steven Nissen and Kathy Wolski, that talked about the effect of rosaglitazone on the risk of myocardial infarction.8 This was a meta-analysis study in which it was said that there was an increased incidence of cardiac risk to sudden cardiac events as a consequence of the taking of the rosaglitazone PPAR-g agonist medication that is used for people who have type 2 diabetes and even those who might have insulin resistance/hyperinsulinemia. The article goes on to point out that one potential contributing factor may be the adverse effect that this drug has on serum lipids. It is now recognized that these PPAR-g agonists, such a rosglitazone, have very complex biological actions and effects, not just single actions, resulting from the activation or suppression of dozens of genes (so a single molecule has an effect upon multiple genes). This is not just a class effect, because it is interesting that piaglitazone appears to have a more favorable effect on lipids, particularly triglycerides, than does rosaglitazone. The use of blood glucose measurements as a surrogate endpoint for the diagnosis and treatment with these drugs is probably not warranted because glucose is not a very sensitive measure for really what is going on at the cell physiological level relative to these PPAR-g agonist drugs. We probably should be looking at things like LDLs and HDLs and even the apolipoproteins, like apolipoprotein B and apolipoprotein A, which are related to atherogenic lipoproteins, and the apolipoprotein A-1, related to HDL assembly. So, I suggest the apolipoprotein B-to-apolipoprotein A-1 ratio to be less than 0.6 to 1, and that above 7.7 to 1 (which is often seen in the insulin resistant patient) there is much significant increase in atherogenic risk and sudden coronary event risk. What has been said is that single molecule rosaglitazone may have multiple effects on genes, which influences different patients in different ways. It may regulate glucose only to alter (in an adverse way) serum lipids and endothelial dynamics and induce other kind of secondary adverse side effects. GlaxoSmithKline has characterized the article as premature and flawed as a meta-analysis study and have come back and said that there is data that actually refutes this contention.9But even if refuted, it still does raise some very interesting points, I believe, about the pleotrophic effects of many of these medications and how they don’t just influence one gene but may influence multiple genes that have downstream effects on proteomics and metabolomics that can vary from individual to individual. You might say, “What is a safer clinical way to regulate insulin, and to modulate endothelial dynamics, and to not produce dysfunctional effect upon lipids that might induce, then, dyslipidemia and relative risk to coronary events?” And, of course, we come back again to what is tried and proven, historically, from both epidemiological and intervention literature and that is things like the dietary approaches to stopping hypertension diet (or the DASH diet). Numerous papers have been published indicating the powerful benefit of the DASH diet (a more vegetable-based diet). The Mediterranean diet is a modification of the DASH diet and has been shown to have improved indices of insulin sensitivity, vascular endothelial effects, and altered lowered blood pressure and improved lipid profiles. There are many papers that have been published in this area, including one recently in the Journal of the American College of Nutrition in 2007 showing the salutary effects of the Mediterranean diet in modulating these factors that associate themselves with proper control of blood pressure.10 When you are talking about nutrient sensing and metabolic decisions, nutrients are sensing agents. They are signaling molecules and they influence these complex arrays of signals that translate into functions so our genes are waiting for these triggers-things that regulate these families of intercellular signal transduction enzymes called kinases, which are part of the proteomic profile or the proteome. These kinases pick up these nutrient signaling information molecules that are found in a whole diet-these rich array of phytochemicals that we eat in a colored, complex, minimally processed diet. It translates that into functional changes at the cellular level to alter our proteome and our metabolome. There is a marvelous article that describes nutrient sensing and metabolic decisions that appeared in Comparative Biochemistry and Physiology.11 It really shows us once again how molecular mechanisms of insulin resistance are associated with altered signal transduction that comes from “alarm” molecules that are being received by receptor sites on cells that translate themselves into altered function that we see as stress response: altered minerocorticoids, altered adrenosteroids, and ultimately altered insulin signaling as well. Many articles have been published recently on the molecular mechanisms of insulin resistance and how it contributes to inflammation. If we were to put all this together, what is the takeaway? The takeaway is without changing genes, but changing the information that comes to genes from the outside world through taste, touch, smell, feel, and maybe even extrasensory types of information, it alters our genomic expression, alters our proteome, and alters our metabolome in such a way as to alter our function. And the major events we have to change these at the clinical level are not the drugs that we prescribe to patients, but the things that the patients do everyday: the dietary information, the exercise patterns, the stress management patterns, the things that are in our environment that are foreign chemicals that may contribute to alarm signaling. These are the things that form the basis of altered genetic profiling in the individual that give rise ultimately to the risk of chronic disease. With that in mind, we are then going to move to a very interesting part of that, which is the agricultural system and our food supply system and the sanctity of these messages that come from our food that ultimately trigger these either alarm or anti-stress responses.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Jeffrey M. Smith Author, Genetic Roulette: The Documented Health Risks of Genetically Engineered Foods (Yes! Books, 2007) www.seedsofdeception.com www.responsibletechnology.org www.geneticroulette.com I’m very fortunate to have the opportunity to talk with you about a very uniquely different format than we’ve ever had in the 25 (going on 26) years of Functional Medicine Update. There is no better time, nor better person, to change our format slightly than Jeff Smith, who is going to be our discussant person on this edition of Functional Medicine Update. Jeff Smith doesn’t fulfill our normal kind of criteria for a clinician or a researcher, but yet he represents everything that we are about in Functional Medicine Update and have been about for 25 plus years. He is an advocate who is bringing to the world an understanding at a deeper level of the impact of genetically modified foods and genetically engineered foods. I think this is a very extraordinary topic that you might say (at some level, as a clinician), “How does it relate to the health of my patients?” I think after this discussion that we are going to have with Mr. Smith you’ll much better understand this. To really give Mr. Smith an introduction I want to just quickly quote from a forward by Frances Moore Lappe, who has been-for the better part of 3-plus decades-one of my heroes in the field of nutrition. This is a forward to Jeff Smith’s first book Seeds of Deception: Exposing Industry and Government Lies about the Safety of Genetically Engineered Foods. Ms. Lappe says that Jeff Smith’s book really talks about more than just nutrition. It talks about the whole nature of information, about the whole nature of truth and discovery and full disclosure. It talks about the freedom of information and access of citizens to enough information to make informed choices, which doesn’t seem to have been the case as it relates to this extraordinary topic of genetically engineered foods. Her comments really are voiced by so many others who have read this book and been deeply affected by it, including one of my good friends, Jim Turner, who is the author of The Chemical Feast and the Nader report on the Food and Drug Administration many years ago and is a well-respected lawyer in the area of food advocacy. Most recently, Jeff Smith has authored an updated and more definitive book that was just published and it is absolutely fantastic; it is called Genetic Roulette: The Documented Health Risk of Genetically Engineered Foods. It is that book that I would put on everyone’s mandatory reading list. If you are not a person that has read this book then you are really not up to date with what has been going on in this extraordinarily important area of applying molecular biology and genetic engineering to the food supply. So with that as an introduction, we are talking to Jeff in England, no less. He is on a tour and having the opportunity to speak to Parliament and at academic centers around Europe concerning this extraordinary topic. Yesterday he was discussing this with members of Parliament in Australia, and of course he has an extraordinary advocacy here in North America as well, through his advocacy expressed in Seeds of Deception and now with Genetic Roulette. Jeff, it is really a treat and a pleasure to have you as part of our history in Functional Medicine Update. Let me, if I can, just start first by introducing you to our audience and secondly asking if we can start with a definition. Could you define for us what genetically engineered foods are as contrasted to our traditional foods? Definition of Genetically Engineered Foods JS: Well, thank you. With genetically engineered foods you take single genes or combinations of genes, typically you make changes in the structure of them, and then you artificially force them into the DNA (the genome) of other organisms. So it is not natural, but it is rather a method of selecting certain traits, pulling it out of context, and transferring it into species that would never naturally contain those genes. The process itself also causes massive collateral damage in the DNA, causing mutations and changed gene expressions, etc. JB: When we look at genetically engineered foods, I think there has been a long-standing misunderstanding, even with those who are fairly well informed. I recall a conversation I had not too many years ago with a very esteemed vice president of a large food company, and his particular point of view was that we have been tampering with genes of plants in the formation of foods for centuries (or, actually, at least for decades) through selective breeding programs, so why is this any different than genetically modified foods? Maybe you could help differentiate for us what the difference is between the traditional methods of selective breeding and that of genetic engineering? JS: Well, when you want to genetically engineer a crop, typically you take genes and you add an artificial “on” switch (a promoter). You add an antibiotic-resistant marker gene to verify that the transformation has occurred. You make millions of copies and put it into a gene gun and blast it into millions of cells in the hope that some of your genes make it into the DNA of some of those cells. Then you douse the remaining cells with antibiotics, killing almost all of them. Those that survive indicate that the antibiotic-resistant marker gene is inserted correctly into the DNA and is functioning. Then you clone the resulting cell (using tissue culture) into full plant, and this is a lot of things, but it is not sex. It is not natural selection. It is nothing that has ever been done before in history. Genes are not like Legos®; you can’t just snap them into place and have them function independently, producing exactly what you want. The process can cause hundreds or thousands of mutations and changes that can, in turn, change protein expression and the expression of the plant compounds, of which there may be thousands in a particular plant. They have measured changes. For example, in the DNA they found 2{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} to 4{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} difference (due to mutation) just from the results of cloning the cell into a full plant. They also found massive changes in DNA in gene expression when a single gene was inserted into a human cell-up to 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the functioning genes changed their levels of expression when a single gene was input. So we are talking about global changes, and yet engineering was based on a reductionist model of individual genes functioning independently. JB: That was a brilliant description and differentiation. You know, it is interesting, because when you talk to proponents or members within the genetic engineering community, they will tell you things like they have protected against some of these risks that Mr. Smith is talking about because we (they) have put (as you say) the candimycin marker gene in there to tell us what is going on. And we (they) make sure that the plant can do its normal functions and it looks like the plant, tastes like it, and produces the same protein, carbohydrate, and fat, so a lot of this is theory of concern and in actual fact it doesn’t happen. How do you respond to those kinds of debate questions? Little Testing is Done Following Transgene Insertion JS: I think your example is great. It looks like, it tastes like, and we have three or four data points, so it must be the same. You know, they don’t even check to see if the transgene ends up the way they intended it to be. In fact, there were studies in Paris that found that they sequenced the transgene (the gene that was inserted into these crops) and in all five cases, what they found was different than what the company had registered. And so either it changed during insertion or was unstable and was changing over time. Likewise, the protein that is being produced from the transgene might be different, and they don’t necessarily check that either. For example, they’ll check five amino acid sequences and they will assume that the rest of the six hundred are the same. They will also assume that the transgene will produce the right protein even though the transgene can be interpreted differently. In one transgene, 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} was lopped off altogether, and the resulting protein was a combination of the inserted gene and part DNA. And they don’t actually test the food itself on animals, in many cases. What they do is they create a surrogate protein from bacteria and then test that with a single dose on a rodent to see if there has been any death occurring within 7 to 14 days and that is their animal-feeding study. So they don’t test in ways that would even evaluate these unpredicted changes in the crops themselves. They create artificial circumstances to force the conclusion that these foods are safe. JB: Well I think you used in your book Genetic Roulette, and also in Seeds of Deception, a remarkably powerful example that illustrates what you are talking about and that is the amazing work of Dr. Pusztai that maybe you could tell us a little bit about? I think that really dramatically illustrates what you are describing. Concerns in Europe about Genetically Modified Foods JS: Well he is a very pro-GM scientist, the leading leptin scientist in the world, working at one of the top nutritional research laboratories in the world in the UK. He received a grant from the UK government to create the ideal testing protocol to evaluate the safety of genetically engineered crops that was to be used EU-wide. And he created a genetically modified potato engineered to produce an insecticide (a leptin), and the insecticide turned out to be harmless to animals (he had studied it for six and a half years and characterized it quite well). But the potato that was engineered to produce the insecticide caused damage to virtually every system in the rats that were fed the potato. They had potentially precancerous cell growth in the digestive tract; smaller brains, livers, and testicles; partial atrophy of the liver; and damaged immune systems, among other things. He was alarmed because he realized it was the inherent process of creating the genetically engineered potato that was responsible for the damage. He went public with his concerns, was fired from his job after 35 years, and silenced with threats of a lawsuit. His 20-member research team was disbanded, and he was maligned by the institute he had worked for and by the established pro-GM UK scientists, among others. When he eventually was able to speak because of an act of Parliament, he got his data back and it is now published in The Lancet and it remains the most in-depth animal-feeding study yet produced on genetically engineered crops.12 , 13 What it shows is that if that same potato which proved to be so damaging had been subjected to the same superficial studies that got the GM crops on the market (soy, corn, cotton, and canola, for example), those potatoes would have also gotten onto the market. In addition, the other products were made from the same process of genetic engineering that he used to create the potatoes, so they might be creating these types of damage in human beings over the long term, but we don’t know since the studies have not been done. JB: It is really very, very fascinating, isn’t it, how things of this importance, which are discovered by very diligent people, can be held in check and the information not made available to the broader public. I guess we have to really commend what happened in Europe as a consequence of the fall out of this because it seems like it was the catalyst for putting in place regulations about genetically engineered foods that we don’t see in the United States. Why didn’t we see a translation of this from one continent to another? Many Americans Unaware of Presence of Genetically Modified Foods JS: Well, when Pusztai was able to speak on February 16, 1999, it touched off a major headline war about GMOs. One commentator said it divided the society into two warring blocks on the GM issue, and within six to eight weeks, Unilever, Britain’s largest food manufacturer, publicly committed to remove GM ingredients from their European brands. Within a week, virtually every other major food manufacturer followed suit. However, in the United States, Project Censure describes that (our Pusztai issue) as one of the most underreported events of the year. And so we don’t really have an open press right now reporting the risks, instead we have press that read like a biotech brochure. This has been the case for many years. If you ask the average American, “Have you ever eaten a GM food in your life?” Sixty percent say no, 15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} say I don’t know, and those that don’t want to eat GM don’t know how (they have labeling over here in Europe but not over there in the United States). And so the structure of the way that they have been improved and sort of slipped into our diet without notice has been responsible for the fact that Europe has rejected it and the unknowing US consumers have not. JB: So now that leads us (obviously) to the inevitable discussion about the business opportunity and how that has been a motivation for kind of circumventing (maybe) the normal process of consumer education and discussion and kind of general political support for the concept. Tell us a little bit about the Roundup Ready seed movement because it seems like it plays a pretty interesting role in this whole discussion here in the states. Roundup Ready Seed Movement JS: About 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of genetically engineered crops are designed to withstand death by a particular herbicide. So the company markets their (for example) Roundup Ready seeds or soy to withstand sprays of Roundup herbicide. And what it does over time is it increases the use of that herbicide in the city and in the fields. By 2004, for example, Round-up Ready soy fields received an estimated 86{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} more herbicide than the natural soy fields, and it allowed Monsanto to maintain a de facto domination of the glyphosate market (that’s the active ingredient in their Roundup even though the patent was expired in 2000). Now if you look at the potential impacts of Roundup, because there have only been about two dozen peer-reviewed, published, animal-feeding studies on the health aspects of GM, and only one published, peer-reviewed, human-feeding study, we have to take our information from several sources to get a big picture. Immune-System Reactions to GM Soy Reported Soon after GM soy was introduced to the UK, soy allergies skyrocketed by 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. We know that in an analysis of the composition of GM soy by Monsanto (information that had been left out of their study and found later) that among cooked soy, the trypsin inhibitor (which is a know allergen) was seven times higher than compared to one variety of non-GM soy. We know that in another study, eight individuals showed a skin-prick reaction to GM soy, but only seven of them to non-GM soy, showing that one person had a unique allergic or immune-system reaction to the GM variety. When they then did a profile of the proteins within the soy, they found a unique allergenic protein in the GM soy, one that was able to bind with IgE antibodies. We also know that the Roundup Ready protein that was intended to be created within the Roundup Ready soy has two sections of amino acid sequence that are identical to known allergens, which (according to the WHO) either should have stopped approval or forced further tests. And finally, we know that the high levels of Roundup residue might also be associated with food sensitivity or allergic-type reactions. In addition, there is a mouse study that showed the production in the pancreas of digestive enzymes was dramatically reduced in the mice that were fed the GM soy.14 Any reduction in (for example) protein enzymes could allow the protein to last longer in the system, causing it to be more likely to achieve an allergic reaction, so it potentially could increase allergic reactions not just to soy proteins, but to other proteins. When the GM soy was fed to mice and rabbits they showed changes in DNA expression and enzyme expression and metabolic activity in all the major organs that were tested.15 Also, mice that were fed GM soy had problems in the development of their young sperm cells and the embryos showed altered gene expression as well. And in the Russian National Academy of Sciences they fed rats genetically engineered soy and about over 50 percent of the offspring died within three weeks compared to about 10 percent of the offspring whose mothers were fed non-GM. The size of the offspring from the GM-fed mothers was also radically smaller, and they were not able to reproduce in subsequent studies. And they also fed soy to males and they found that the testicle structure was also considerably different among the GM-fed group. So we have a lot of information from the very few studies that have been done indicating that this thing is not just an accident waiting to happen, but might already be creating a health catastrophe in the United States if 89 percent of the soy acreage in the US is GM.16,17,18 JB: Well that was about as eloquent and complete an answer to that question as we could ever expect. Thank you very much. You know, for those who are going to read the book (Genetic Roulette-your book) which I think (as I mentioned) is mandatory reading, they might ask, “It seems so self-evident-the way that you describe it. Are your assertions documented and supported?” And if you look at the endnotes in your book (I haven’t counted up specifically how many references you have cited to support your points), but certainly it is in the thousand range. I think anyone who would like to know if you are speaking from what has been published in the authentic literature the answer is a definitive yes. JS: There are over a thousand endnotes and it is a combination of published literature and reports from the field. As I mention at the beginning of the book, if we had thousands of appropriately done studies, we wouldn’t need to look at medical reports or correlational relationships. Worldwide Consequences of Bt-Toxin Use Reported For example, Bt-toxin. Here’s an example where they took a toxin and they put it into food supply, so it was produced, for example, in every cell of corn (which means in every bite of corn) on the assumption that the toxin had a history of safe use because it is used in organic agriculture, that the protein was truly destroyed during digestion, and that there were no receptor cells in humans or mammals so it would pass right through even if it weren’t destroyed during digestion. So they didn’t have a whole hoard of scientific studies and data points to say that this toxin in our food supply would be safe. It was based on assumptions as so much of the GM approvals are. However, even among the small number of data points that were there, they had overlooked the fact that about five hundred individuals complained of allergic-type reactions when they got sprayed with the natural version of this Bt -toxin that was used for Gypsy moth infestation in the Pacific northwest.19,20 Now, they take that gene and they make the Bt-toxin at three- to five-thousand times more concentrated than the natural spray version, and farmers in India who are harvesting GM cotton (or loading it onto trucks, or working in ginning factories) are complaining of the same allergic-type reactions that the five hundred people complained about in the Pacific northwest. Then they let sheep graze in the Bt cotton plants after harvest, and within five to seven days twenty-five percent of the herds died (about 10,000 sheep in total). About two dozen farmers in the United States complained that certain Bt-toxin corn caused their pigs or cows to become sterile. There is a German farmer and others in the Philippines that claim that the Bt corn caused death among their animals (their livestock). And in the Philippines, also, people living next to the Bt corn field developed skin, respiratory, intestinal reactions, and fever during the time that the corn was pollinating.21 The following year, the same seeds were planted in four other villages and during the time of pollination when they were breathing in the pollen, they had more reactions among people living nearby. Now these are all medical reports or farming reports that are documented, yes, but not necessarily in peer-reviewed journals. For the studies that got Bt crops approved, they are typically not peer-reviewed by the companies; they are submitted only to the regulatory bodies and labeled “Confidential Business Information.” However, a lawsuit forced Monsanto’s Bt corn study for their Mon 863 into the public domain a couple of years ago. It turns out that they had an enormous amount of problems with the rats that were fed the GM corn, and some scientists recently re-evaluated the raw data based on the study and found clear signs of toxicity in the liver in kidneys that was not reported or acknowledged by Monsanto or the regulators that approved the product. So even among the company’s own studies, which I describe in great detail in part three of Genetic Roulette-how they meticulously design their studies to avoid finding problems (using the wrong samples, the wrong control group, the wrong statistics, under-reporting the details)-even with all that, they found signs of toxicity. JB: So that leads us into an interesting question. Michael Pollan, in his recent book Omnivore’s Dilemma, talks about this concept that often when farmers are feeding corn to their animals that are genetically engineered and the animals have a choice of the genetically engineered corn versus the non-genetically engineered,they will preferentially choose the non-genetically engineered, suggesting (at least from anecdote) that animals know the difference. Is there any history of that that you have seen in the way that animals respond to these foods? JS: Absolutely. There are reports from all over North America that show cows, pigs, geese, elk, deer, raccoons, mice, and rats all avoided GM feed when given a choice. In fact, the CEO of Calgene, that put out the first approved, genetically engineered food crop (the Flavr-Savr tomato) said that even if you were Chef Boyardee, these rats were not going to eat their GM tomatoes. They force fed the rats the tomatoes and several developed stomach lesions and seven of twenty died within two weeks. We know now from documents made public from a lawsuit that the FDA was willing to let that go on the market as is. Calgene voluntarily used a different line of their transformed tomato to introduce to the market.22 But it shows you that the FDA was ready to turn a blind eye to some pretty serious results. Now the FDA has no required consultation (it is all voluntary), so that was the only study in which raw feeding-study data was ever submitted to the FDA (that was basically summary conclusions and very, very superficial and flimsy reports that are voluntarily submitted). If the FDA asks for further studies and further questions, they are typically ignored. This voluntary consultation process came about because the 1992 policy of the FDA claimed that the agency was not aware of any information showing that foods created from these new methods differed in any meaningful or uniform way. On the basis of that sentence, they said that if Monsanto wants to introduce a GM crop to the market, they can determine whether it is safe and don’t even have to tell the FDA. That sentence turns out to be a deception. Documents made public from a lawsuit show that the overwhelming consensus among the FDA’s own scientists was that GM crops were inherently unsafe and could create hard-to-detect, unpredicted toxins, allergens, new diseases, and nutritional problems and had, in fact, urged their superiors to require the long-term safety studies that they chose not to require. JB: What do we do? That is the question. You have already told us that in terms of labeling there is no mandatory requirement in the United States for labeling foods that were produced by genetic engineering. In your extraordinary website and institute (the Institute for Responsible Technology) you talk a little bit about what we should do and where we are going. Maybe you can help us to kind of define a strategy. JS: Well, I think that among all the health and environmental problems in the world that we face, ending the current generation of GM crops is one of the easiest things we can do. I emphasize the words “current generation” because I’m not against the possibility that someday in the future we can safely and reliably and predictably manipulate the DNA for the benefit of human health and the environment, but the current generation is a primitive technology based on obsolete science and faulty assumptions. So how do we stop that? Grassroots Consumer Action Could Halt Use of GM Crops in US I think what we talked about earlier-the result in the European situation-when a certain number of consumers reach the tipping point of pushback against GM, who are unwilling and very unhappy about the fact that the diet was being converted to GM, when that tipping point was reached, the food industry reacted for the sake of protecting market share. And that kept GM crops out of Europe in spite of a very pro-GM European commission and a pro-GM European food safety authority. So we need to create the tipping point of enough consumers in the United States to say no to GM. Now remember, the food industry gains nothing from these GM crops, in about 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} are herbicide tolerant and about 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}produce their own pesticide. They do not have consumer benefits, so the food industry gains nothing from using GM, and if they saw a drop in market share of just a few percentage points and they perceived a trend that might grow over time, it is very easy to see how the stampede away from GM could be repeated in the United States as it was in Europe. I am predicting that with as little as 5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the US consumers avoiding GM ingredients very consciously, that 15 million people could drive the decisions for the entire food industry. So where can we get 15 million people? Well, certainly health-conscious shoppers are low-hanging fruit since there are already 28 million people who buy organic food on a regular basis, but they rarely avoid GM ingredients in their non-organic purchases. I’m working with some CEOs of major food companies in the natural food industry, and what we are doing is we are cleaning out any remaining GM ingredients from the entire natural food sector, setting up GMO information centers in all the health food stores, non-GMO shopping guides, and later on, in-store, on-shelf labeling of any products that have held out and not participated in the clean-up. We are also working with communities around the country, showing a video that I created with others called Hidden Dangers in Kids’ Meals, alerting parents and schools to the fact that children are most at risk to the health dangers of GM foods and we are establishing GM-free campaigns around the country. Likewise, we hope to approach religious leaders to explain to them the dangers. They, themselves, may believe that “GMO” means “God Move Over” and are unwilling to participate in this experiment and might choose to distribute the non-GMO shopping guide. And the fourth demographic that are really important is the health practitioners-the doctors, the nurses, the dietitians, those who evaluate science and make recommendations to their patients and clients. If the word got out to the food industry that more and more doctors are now prescribing diets to be free of GMO, then GMO will be over in the United States very quickly. And I do know many doctors who tell their patients to avoid eating GMO foods. That is why this interview is so important. What we hope to do at ResponsibleTechnology.org is to post patient education materials that doctors can download. In the meantime, they can always use Genetic Roulette in their waiting rooms. It is designed for a quick, five-minute flip-through in the way that is has executive summaries on one side and detailed text on the other side of each two-page spread. We have one doctor, an allergist, who said he used to do soy allergy tests all the time but now that soy is genetically engineered he tells his patients just don’t eat it unless it says organic. He buys in bulk this audio CD we created called, You’re Eating What? Stop Eating Genetically Engineered Foods and Please Copy this for your Friends. So he buys them for a dollar or so off our website and sells them to his patients for a dollar and has distributed over a thousand to his patients. So we have ways that we are working with the medical community so that we create this buzz that healthy eating means no GMOs, so then quickly we can reach the tipping point and the food companies will end this dangerous experiment, even if our government is unwilling to act. JB: Well, Jeff, that is an incredible advocacy. I think it was very important for our listeners to hear that you are not a Luddite by nature. You are not a person who is just anti-technology, regardless. I think your point is that if we knew enough about what we were doing that would be a very different story than doing an experiment that is early on in our understanding of the gene and how it is translated into protein and function and that that uncertainty is really the cause for great concern. I share that concern. It seems like many of the dominant-what we consider “truths”-in molecular biology when I took my first course in 1962 in molecular biology, like the “one gene, one enzyme concept” and the fact that there was all this “junk DNA” that was present in the genome has now been pretty much refuted. It is not just “one gene, one enzyme.” Genes can express themselves in different ways and this “junk” is really not junk at all; it is where a lot of the information molecules are for organizing the genetic expression patterns that ultimately control how genes are regulated. It seems like we jump prematurely with the kind of sophomoric view (the “wise fool” view) about what we knew about the gene and started inserting that knowledge prematurely into our food supply and I think that position that you have taken is a very, very scientifically supportable position. It is not a Luddite position or an anti-technology position; it is a rational thinking position. JS: You know, it is interesting. I agree with you completely, and yet the public relations spin by the biotech industry, which has been so successful around the world, wants people to believe that those of us who are demanding more science are anti-science. But there is also another very dangerous aspect. You mentioned this with respect to Arpad Pusztai, but I’ve interviewed scientists all over the world who have incredible pressure silencing them, taking away their funding from doing research, denying them access to genetically engineered seeds to do their research. Doctors have had information stolen. Even scientists in government have had documents stolen from their locked file cabinets as is the case with the scientists in HealthCanada who were evaluating Monsanto’s genetically engineered bovine growth hormone. They also said, for example, that Monsanto had offered them a bribe of one- to two-million dollars to approve their drug and that also Monsanto go fined 1.5 million dollars by the US Justice Department for bribing up to 140 Indonesian government officials to try and get their patent approved there.23 It is not just an avoidance of science, it is actually a rather sophisticated manipulation with very big goals in mind. Arthur Anderson Consulting admitted at a 1999 biotech conference that they had consulted with the executives at Monsanto by asking them to describe their ideal future in 15 to 20 years. And the executives described a world in which 100 percent of all commercial feeds were genetically engineered and patented.24 And they went backwards from that goal to create a strategy and tactics to achieve it. Imagine if they had been successful. Imagine if there hadn’t been pushback from Europe. We would be replacing the genomes-the DNA-with self-propagating genetic pollution and reducing the number of seeds around the world, because they obviously would have taken over a larger percentage of the seed supply and reduced the amount of natural seeds made available, causing a much higher level of food insecurity. If they had gone forth with their plans they would be gambling with our entire food supply on this untested, primitive technology. They are not above really risking as much as you can possibly risk. Self-propagating genetic pollution will outlast, theoretically, the effects of global warming and nuclear waste. We have never had an experience like this before in our history. Going slow, going cautious, going with plenty of consensus and thinking is the only way to proceed with such a technology, and yet we are seeing just the opposite. So I want to applaud you for taking this up as well as all of your incredible work in all the areas that you are working on, Jeff. JB: Well, thank you so much, and I think (again) the listeners can see the urgency to read Genetic Roulette and really become more knowledgeable and informed and assist their patients in making informed decisions in this area. Once again I want to cite your website because I think it is a very valuable and dense source of information; it is www.responsibletechnology.org. Jeff, I just want to thank you. I know you have taken time out of your busy schedule there in Europe to share this information with us but be assured it is being listened to by people who are very advocacy-minded and it will have a significant impact in how they counsel and discuss this with their patients. JS: Thank you and I want to add one thing. We have a geneticroulette.com site. We have 65 health risks of genetically engineered foods documented in Genetic Roulette, so we posted a page for each one of those 65 health risks and then asked the biotech industry and others to give updates, challenges, corrections, etc. in the hope that it can become the world’s forum on discussing the health risks. Not only that, but it is actually a gauntlet. We are throwing down a gauntlet to the industry, saying “You must respond to these 65 risks with rigorous scientific data showing that they are not concerns, otherwise there is no justification for allowing these foods to be on the market.” I’m traveling and speaking to parliamentarians and others, and I testified before the EPA and met with senators and congressmen, saying “We want to reframe the issue now. There is overwhelming scientific evidence that these foods are unsafe. We have parsed it out into 65 main risks. Let’s give them the checklist. If they can respond to the 65 risks, we have no further questions. If they respond with more assumptions and no data points and sweeping dismissals, then they have no justification to allow the food to be fed to humans or to animals.” JB: Very, very convincing. Once again, thank you and thanks for your tireless efforts and we will keep the fire burning here from the practitioner side. JS: Great. Thank you, Jeff. We thank Mr. Jeffrey Smith for that extraordinary discussion and interview. Certainly it was provocative and opened our minds to all sorts of questions and important issues, I’m sure. Tagging the Rice Transcriptome I want to follow-up the interview with a recent article that appeared in Nature Biotechnology, a very well-respected primary journal in the biotechnology area. This article was titled, “Tagging the Rice Transcriptome.”25 As you probably know, rice is one of the most important food crops in the world, obviously. There is a tremendous amount of work going on to find ways of modifying the genetic structure of rice to give it certain attributes that would be considered commercially more valuable. This particular article was authored by Dr. Antoni Rafalski. Dr. Rafalski is the DuPont/Pioneer Hi-Bred International Genetic Discovery Group chairperson at Experimental Station in Wilmington, Delaware. In this particular article he is talking about some of the things they are learning by tagging the rice transcriptome with 50 million express sequence tags and looking at a complex collection of the RNA species that are then derived by microarray types of analysis. I thought it was very fascinating in light of what Jeffrey Smith was just talking about to talk a little bit about Dr. Rafalski’s conclusions. He says a unique aspect of this study is cataloging the small RNAs in a crop. Small RNAs have recently emerged as critical regulators of a wide variety of developmental and physiological pathways in plants, including stress responses. Transcripts, particularly these small RNAs, were found for essentially all annotated rice transponsons and retrotransponsons. Their location corresponds to highly methylated regions of the genome, suggesting a very significant genetic complexity in the way that the rice genetic information is expressed. So now I quote, from the end of this article, which I think you’ll find very fascinating in the context of the previous discussion that we had with Mr. Smith. Mr. Rafalski says, “A significant fraction of intergenic space in the rice genome, sometimes thought of as ‘junk’ is functionally active. From a biotechnological perspective, transgenic modifications that disrupt transcription of any of these intergenic regions may have unintended consequences. Although the genic environment of transgenes is routinely surveyed in the process of governmental approval, better insight into which sequences in the rice genome are transcribed and thus presumably functionally important, will facilitate efforts to avoid transgene insertions within expressed regions.” The point I am really trying to get you to understand is not to convert you into a molecular geneticist or a molecular biologist, but rather to recognize that even from an expert in the field, we are acknowledging that there is lots yet to be learned about how insertion of genetic information can influence the expression patterns in a particular plant and ultimately the function or the phenotype that it has. We are just learning about things such as these rice transponsons and retrotransponsons, transcriptional noise, small RNAs and things that relate to the regulatory regions of genes that used to be called junk DNA (which we now recognize have very important roles in how they are epigenetically modified by methylation to be expressed or not expressed). I think you can see just from that little language I’m giving you that there is a lot yet to learn and a lot more than we thought, probably, about the complexity of the genome and how it is expressed ultimately into the phenotype. But yet, we moved ahead quite rapidly in the introduction of these genetically modified foods. So I think what we are recognizing now is that there are still many questions yet to be understood before we can totally jump on this bandwagon with security and safety as it pertains to modifying the genome of our plant foods. We thank Mr. Smith once again for his eloquent description and historic information, and urge your reading of Genetic Roulette . Thanks for being with us. We’ll look forward to seeing you in October 2007.

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1 Libert S, Zwiener J, Chu X, VanVoorhies W, Roman G, et al. Regulation of Drosophila life span by olfaction and food-derived odors. Science. 2007;315:1133-1137. 2 Beecher C. Metabolomics: a new “omics” technology. American Genomics/Proteomics Technology. May/June 2002. 3 Schweigert FJ. Nutritional proteomics: methods and concepts for research in nutrition. Ann Nutr Metab. 2007;51:99-107. 4 Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med. 2007;356(19):1966-1978. 5 Epstein MT, Espiner EA, Donald RA, Hughes H, Cowles RJ, et al. Licorice raises urinary cortisol in man. J Clin Endocrinol Metab. 1978;47(2):397-400. 6 Walker BR, Edwards CRW. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am. 1994;23(2):359-377. 7 Al-Qarawi AA, Abdel-Rahman HA, Ali BH, El Mougy SA. Liquorice (Glycyrrhiza glabra) and the adrenal-kidney-pituitary axis in rats. Food Chem Toxicol. 2002;40(12):1843-1847. 8 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-2471. 9 http://www.gsk.com/ControllerServlet?appID=4&pageID=402&newsid=1038 10 Panagiotakos DB, Tzima N, Pitsavos C, Chrysohoou C, Zampelas A, et al. The association between adherence to the Mediterranean diet and fasting indicesof glucose homeostasis: the ATTICA study. Am J Clin Nutr. 2007;26(1):32-38. 11 Lindsley JE, Rutter J. Nutrient sensing and metabolic decisions. Comp Biochem Physiol B Biochem Mol Biol. 2004;139(4):543-559. 12 Ewen SW, Pusztai A. Health risks of genetically modified foods. Lancet. 1999;354(9179):684. 13 Ewen SW, Pusztai A. Effects of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on rat small intestine. Lancet. 1999;354(9187):1353-1354. 14 Malatesta M, Caporaloni C, Rossi L, Battistelli S, Rocchi MB, et al. Ultrastructural analysis of pancreatic acinar cells from mice fed on genetically modified soybean. J Anat. 2002;201(5):409-415. 15 Tudisco R, Lombardi P, Bovera F, d’Angelo D, Cutrignelli MI, et al. Genetically modified soya bean in rabbit feeding: detection of DNA fragments and evaluation of metabolic effects by enzymatic analysis. Animal Science. 2006;82:193-199. 16 Vecchio L, et al. Ultrastructural analysis of testes from mice fed on genetically modified soybean. European Journal of Histochemistry. 2004;48(4):449-454. 17 Genetically modified soy affects posterity: results of Russian scientists’ studies. REGNUM. 2005; http://www.regnum.ru/english/526651.html 18 Ermakova I. Genetically modified soy leads to the decrease of weight and high mortality of rat pups of the first generation. Preliminary studies. Ecosinform 1. 2006:4-9. 19 Washington State Department of Health. Report of health surveillance activities: Asian gypsy moth control program. (Olympia, WA: Washington State Dept. of Health, 1993). 20 Green M, et al. Public health implications of the microbial pesticide Bacillus thuringiensis: an epidemiological study in Oregon, 1985-86. Amer J Public Health. 1990;80(7):848-852. 21 Bernstein IL, et al. Immune responses in farm workers after exposure to Bacillus thuringiensis pesticides. Environmental Health Perspectives. 1999;107(7):575-582. 22 http://www.biointegrity.org 23 Smith J. Genetic Roulette. 2007. Yes! Books. 176. 24 Smith J. Genetic Roulette. 2007. Yes! Books. 249. 25 Rafalski A. Tagging the rice transcriptome. Nat Biotech. 2007;25(4):430-431.

Welcome to Functional Medicine Update for October 2007. This is going to be an issue with an unusual focus relative to past issues. I would give this issue a working title of “Structure vs. Function Connected through Cellular Signaling.” Much of the intellectual basis for functional medicine is derived from the pioneering works of Archibald Garrod, Linus Pauling, and Roger Williams. These giants, whom we have often spoken about, gave us conceptual framework for the functional medicine approach. Dr. Linus Pauling was an extraordinary proponent of the concept of structure and function being connected to one another. He started off, obviously, with structure being molecular structure (atomic structure). He looked at the structure of the atom, then combinations of atoms to make molecules, then combinations of large molecular structures to make macromolecules, and then, ultimately, organisms made through cellular structure. One can play with the concept of structure and function at many different levels. What I believe has happened within the constructs of medicine is that we have separated structure from function and often treat them as two entities. We have physical medicine, which treats function from a structural perspective, and then we have functional physiological medicine, which treats it from a metabolic perspective. Really (as Dr. Pauling got us to understand), there is not a separate universe of structure on one side and function on the other; they are connected together very intimately. Intercellular Signal Transduction Structure can influence function at a metabolic level through the pathways that we call intercellular signal transduction. When we do things like nutritional intervention, exercise therapy, talk therapy, physical medicine, acupuncture, or bodywork, we are mobilizing this connection between the outside world (either through molecules or mechanical forces or electrical forces) into inside functional changes. These changes relate to metabolic things that we often measure with laboratory tests and other methodologies (really kind of a shadow). The image that makes the shadow is the alteration in the function of that cell, tissue, organ, or organ system that ultimately gave rise in bulk to the changes that we see using our diagnostic technologies. With that as a conceptual framework for this issue of Functional Medicine Update, let’s talk about some examples (from the molecular up to the whole organism) that show how this structure-function duality is not a duality, but is actually a continuum. We (as clinicians) are using this continuum every day; I believe it is the fundamental underpinning of what separates functional medicine from diagnostic traditional medicine, which is focused on the diagnosis and then the treatment of the dysfunction as a pathophysiological process. Let’s look at the functional medicine interpretation of this structure-function duality. The Influence of Cruciferous Vegetable Phytochemicals on Structure and Function Starting with a molecular concept first, I’m going to choose some examples that are in the news recently and exemplify this principle. Cruciferous vegetables (the broccoli-cauliflower-brussels sprouts-cabbage family) contain an interesting array of phytochemicals called glucosinolates, which we have heard much about in the past several years. We know that vegetables that contain these glucosinolates can be broken down (by secondary metabolic function in the body) into a series of other phytochemicals that have names like indole-3-carbinol, diindolylmethane, 3-hydroxy-2-butene, sulfurophane, and phenylisothiocyanate. Glucosinolates, when broken down into these secondary biochemicals (or phytochemicals), influence things like detoxification pathways. Historically, we know sauerkraut juice was used in European communities for what we would call detoxifying the body, and now we may know what mechanisms make this seem reasonable. Glucosinolates that are in fermented cabbage do, in fact, influence the balance of phase I and phase II detoxifying enzymes. Understanding how these vegetables were associated with certain health attributes occurred through observations and an evolution of thinking about mechanisms. My colleague, Dr. Deanna Minich, and I composed a review article on this topic, which appeared in Nutrition Reviews in June 2007 under the title, “A Review of the Clinical Efficacy and Safety of Cruciferous Vegetable Phytochemicals.”1 Rather than go into the specifics of how indole-3-carbinol, diindolylmethane, sulfurophane, or phenylisothiocyanate alter phase I and phase II enzyme induction and activity in terms of detoxification, I’d like to move back a step. What’s really going on with these chemicals? What are they doing? Each one of these molecules (these phytochemicals) has a specific structure. If you were a student of chemistry in your past, you probably recall that when a combination of atoms give rise to molecules, often, in nature, this happens in a geometric configuration that is so specific it can rotate plain, polarized light. In other words, it can interact with light in such a way so that it has right- and left-handed types of light twisting capability (we call this dextrotrotatory and laevorotatory). There is a tremendous amount of information, in terms of the topology of these molecules that we eat in our diets that can influence our function by their specific structural capabilities. How they do this is by binding or interacting with specific receptors, which in themselves have specific geometric structures that are very unique. So it is a lock and key, you learn. But it is really more than a lock and key because a lock and key sounds very static (like the key is always the same shape and the lock is always the same shape). In terms of these dynamic processes of the binding of a phytochemical to a receptor, these are what we might call amorphous receptor bindings in that they can be changed by the environment in which the receptor is found. The lock is not always the same geometry. Based upon the environment in which that lock is found, it might appear as different shapes, so you might have that receptor (the phytochemical called indole-3-carbinol) binding to its receptor in different ways depending upon the environment in the cell in which the receptor is found. Acid-Alkaline Balance and Cellular Physiology What do I mean by that? Let’s take an example from clinical medicine, a gross thing that we all know about: pH (acid-alkaline balance). History tells us (from diets that have been explored throughout many cultures) that the residue of acid or alkaline in a diet can have something to do with the physiological effects of that diet. There are whole dietary approaches that have been built in the schools of hygiene and nutrition for several hundred years around acid-alkaline reserve and how different diets produce different residual effects on the acid or alkaline balance of the body. What are we really talking about here? We are talking about how the constituents of that diet, in bulk, influence cellular physiology in such a way as to lead to-when the smoke clears, after the metabolism of the food, digestion, absorption, and utilization has occurred-an acid effect or an alkaline effect. We often say that the alkaline reserve foods are those that contain high levels of calcium, magnesium, potassium, and sodium. These would be things like vegetable products. Acid residue foods are those that when “burned” or metabolized in the body, lead to residual effects of more acid producing, such as sulfuric acid, phosphoric acid, or hydrochloric acid. These would generally be higher protein animal foods. States of ill health, historically, have often been associated with shifts in cellular physiology toward the acid side: metabolic acidosis, or respiratory acidosis with the build-up of organic acids, and the shift of pH to lower values (meaning, more acid shifts). The treatment for people in a state of metabolic acidosis is what? To alkalize. You give them alkaline reserve. You can either do this synthetically by giving an alkaline material like bicarbonate, or you can introduce foods that have high residual alkaline reserve to neutralize the extra acid and reestablish appropriate intercellular pH (7.37, slightly on the alkaline side). I’m sure all this is just a quick history of what you already know. Now let’s go back to the receptor story that I was talking about and how it relates to structure and function, phytochemicals in foods (say, indole-3-carbinol), and its influence on detoxification. If the physiology of a person is shifted towards an acid side, that acid environment (and when I’m talk about acid I’m not talking about the kind that can leech away stone, I’m talking about just very subtle changes in intercellular pH) it influences, then, the domain and environment of that local cellular milieu in such a way that it can alter the shape of the lock. Right? So the lock, as I said earlier, which is the receptor, is not static; it is dynamic. It has multiple configurations that it can exist in depending upon the nature of the environment. So let’s say that patient has an acid residue, or they are shifted metabolically toward the acid side, slightly. That would change the shape of the lock, which means that the same key (indole-3-carbinol) would be less able to get into the lock and would have a different influence, then, on the processes that are associated with that lock and key (receptor/ligand) interaction. Therefore, its effect on detoxification could be altered. I hope you are following my argument, here. What I am trying to say is that structure and function are intimately interrelated, even at the molecular level. But the structure is not cast in stone because the structure, in and of itself, is modified by the state of the environment. Let’s now take this and see if it really plays out, or if I’m just talking a bunch of philosophical mumbo-jumbo. Does pH, or alkaline/acid balance, have anything to do with detoxification? The answer is yes. There are many, many articles that have been published in very highly respected journals in toxicology that demonstrate that the acid/alkaline balance in a person who has been exposed to a toxin will alter their ability to eliminate that toxin (i.e. to engage in detoxification). I want to cite a recent review article that (again) Dr. Minich and I authored. This article was just recently published in Alternative Therapies, and it takes this theme and describes how it works clinically.2 Let’s take the example of a person exposed to a toxic chemical or maybe a recreational drug taken at toxic doses. He or she is in the throws of renal or hepatic failure, and so what would be, in a toxicology/poison center, the treatment that might be employed in this crisis situation? It would be to infuse this person with very high alkaline equivalents-in other words, to force his or her plasma into a more alkaline state. What is the strategy? The strategy is to improve renal excretion and detoxification because when a person is in a poison situation their physiology is shifted toward the acid, with depressed respiration so they are not oxygenating their blood correctly. They are getting more carbonic acid building up in their blood, plus they may have a whole series of organic acids that are being produced in their body as a consequence of the poisoning of their metabolism. So you shift their pH in the emergency room or the treatment clinic, forcing more alkaline reserve into their blood. That is the extreme example of toxicity, right? Now let’s back it off to a much more ambulatory, chronic state of toxicity, where a person is shifted due to the consumption of high fat/high meat, processed food diets. They are not eating a lot of fruits and vegetables. They don’t get a lot of alkaline reserve. They are exposed to-let’s say-an OTC chemical. Maybe it is ibuprofen. Maybe it is acetaminophen. They have chronic toxicity. What do you want to do? You want to move them over to a diet with higher alkaline reserve. This changes the receptor/ligand interaction. It enhances detoxification. It improves renal excretion. And the same body exposure to that toxic material leads to a lowered adverse effect on their physiological function. I hope I’m getting you to understand this interesting view of structure and function that is emerging and the plasticity of structure based upon the local environment, which is a modifiable environment. In other words, our environment is not cast in stone. We could drink more fluid. That hydrates us. That is a changing of our cellular environment. We can eat more alkaline reserve foods. That is a changing of our environment. We can think different thoughts. That is a changing of our environment. We can exercise or not exercise. That is a change of our environment. Each time we do something it changes the way the structure of these molecules influence our function. Going back, if I can, then, to the indole-3-carbinol (I3C), diindolylmethane, sulfurophane, and phenylisothiocyanate story as it relates to detoxification, what was the point Dr. Minich and I were trying to bring to the reader’s understanding as it relates to the clinical efficacy and safety of the cruciferous vegetable phytochemicals? What we were trying to point out is that the application of therapeutic doses can be beneficial (for example, I3C; there have been many clinical studies that have been published on the use of therapeutic doses of I3C-about 300 mg of indole-3-carbinol about once or twice daily against placebo and looking at the effect it has on detoxification of various substances, including the conversion of estrogens, 17-b estradiol into the 2-hydroxy estrogens versus the more cytotoxic/mitogenic 16-hydroxy estrogens). If broccoli intake (or another cruciferous vegetable) is increased, will it have a favorable effect on estrogen metabolism, even in a man? We know that men are producing estrogen to some extent in their prostate glands and that has to be metabolized. Soy products would increase 2-hydroxylation. These are phytochemical characteristics of the structure of these food ingredients that influence a function of the body, which is detoxification of an endogenous chemical called 17-b estradiol. That’s a really powerful conceptual framework as an example of a more general concept of how the myriad things in our diets can influence physiological outcome. What happens if the person who takes indole-3-carbinol, 300 mg once or twice a day, is in an acid-shifted metabolism? They are eating a diet or they are in a state where they are in an acid metabolism? Would that alter, then, the functional influence of that phytochemical on their detox? The point I am trying to make is absolutely yes. That structure, as it relates to the implication on function, would be modified by the environment. This begs the question, doesn’t it, as to how we deliver these concepts in the functional medicine treatment program? What it doesn’t mean is that just one agent is given at a time, like you might give a drug. With a drug, some practitioners might say they don’t care what a patient is doing because they are just going to lay this new pharmacological agent on top of whatever they are doing and the outcome will (hopefully) be what is desired. What I am saying is that for optimizing the functional outcome in the patient, you have to look at the full physiological status of the environment of that patient. If they are an acid-shifted physiology and they are eating a high acid, ash-type diet you need to shift them to a more alkaline-ash diet. You need to improve their respiratory quotient to lower their carbonic acid build-up, and that means you need to improve the oxygenation of their blood. What does that mean? Movement, exercise. You need to signal the appropriate signals through their cellular receptor systems, lowering inflammation (which we are going to learn more about later in this issue of Functional Medicine Update –things like bodywork, massage, acupuncture, yoga). This concept calls forth what is really the hallmark of functional medicine: not just doing one thing at a time. Functional medicine is looking at the environment and domain of the patient and adjusting it to produce the optimal conversion of the structure into appropriate function. The Effect of Soy Phytochemicals on Function I hope I didn’t lose you in that discussion. Let me try giving you one more example, beyond the cruciferous vegetable/indole-3-carbinol/estrogen connection. Let’s look at soy. Soy is another interesting food that contains a whole array of phytochemicals: such as polyphenols, and isoflavones. As you probably know, we have emerged to recognize this as a remarkable plant food. What about these substances found in soy? What influence do they have-the structure of those molecules in soy-what effect do they have on the function? We might look at things like some of the adverse results that seem to be associated with soy that people have been concerned about recently. Things like effects on testosterone in males. Phytochemicals and Neurological Function Let’s look at the influence of plant-derived phytochemicals on neurological function. There is a rich history of the use of plant substances to alter perception and cognition and produce states of altered consciousness. But we recognize that virtually thousands and thousands of phytochemicals and plants may have direct or indirect influences on cell signaling processes that could be either directly, or by feedback processes, influencing nervous system function. There is an interesting paper that was published in Neurochemistry Research that I think bears on this topic very nicely. This was in 2007 and titled “Neuroprotective Effects of Natural Products: Interaction with Intracellular Kinases, Amyloid Peptides and a Possible Role for Transthyretin.” 3 In this particular review paper, the authors discuss how things like tea catechins and polyphenols from foods-things that we consume in whole-food diets all the time-may have effects, through the structure of those molecules found on those plant-derived foods, on the cell signaling processes related to things like memory, cognition, states of arousal, and central nervous system affective behavior. Historically, we have been eating foods that influence the function of our nervous system as a consequence of this interaction of the structure of molecules in the food with the function of our nervous system through a whole series of cell signaling modulations. When I talk about cell signaling, again, I am referring to the fact that the structure of these molecules in the food interact with certain receptors that then signal through the cellular functions of the nervous system to induce (or produce) states of functional change. These would be things like enhanced alertness, or alterations of cognition or memory. These discoveries are obviously leading to new food concentrate derivatives to try to improve central nervous system function, or normalize nervous system function, or to develop neuroprotective effects (like you would get with gingko biloba, for instance). What are the individual molecules in the gingko concentrate that then influence the structure and function of the nervous system? These are the frontier-level discussions that are now ongoing. You might ask how this differs from traditional pharmacology. The difference, really, comes in the application of the concept, not in the concept itself. In traditional pharmacology as we know it, the agents within the Physician’s Desk Reference are new-to-nature molecules that have been derived by multi-phasic screening processes from synthetic chemists to have very profound effects upon specific receptors or specific enzyme-mediated functions within the body. They have been tailored (or engineered) to have dramatic effects, sometimes tying up enzymes and blocking function (like H2 blockers, HMG Co-A-reductase inhibitors, or selective serotonin reuptake inhibitors). You’ll notice it always has this “inhibitor” or “blocker” title to it. These drugs really tie up enzymes and cellular function at a very dramatic level as contrasted to the agents that are in natural products, which have a much more moderate effect upon cell signaling. You might say, “Why did nature evolve molecules that we have in our foods that have only moderate effects on cell signaling, and not evolve food that contain agents that have dramatic effects on cell signaling? I think the answer to that is obvious. If every time we ate a diet that contained drug-like effect molecules, our physiology would be whipsawed around. We have evolved this relationship with these active phytochemicals in our foods that are much more moderate in their cell-signaling effects; that normalize function. It is a similar mechanism to drugs, but a different way of playing out through these intercellular signal transduction processes. Now let’s go into another part of the body’s physiology: gut bacteria. One of the largest organ systems in our body is the enteric bacterial population that is not connected to us through our blood supply directly, but is metabolically active-a kilogram and a half of live organisms, several hundred different species, all vying for real estate in our gastrointestinal tract and all metabolizing, fermenting, and producing waste products. These waste products are, again, molecules that have specific structure that are produced by these enteric bacteria.; they have effects on different receptors within our gastrointestinal milieu (the so-called gastrointestinal lymphoid tissue, the GALT). These antennae that are sitting on the surface of our gastrointestinal epithelia, which are the receptors of the GALT or the MALT (the mucosal associated lymphoid tissue)-what they do is pick up these information molecules from bacterial activity in our intestinal tract and translate it, then, into functional changes, both locally and systemically. Here is where 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of our antibodies are produced–at the local gut level–in response to the connection between the intestinal milieu, the structure of molecules that are available to activate these receptor sites, and then how those ultimately get translated into systemic function. Gut Bacteria and Cell Signaling Processes With that as a conceptual framework of looking at structure-function (now I’ve even moved, you’ll notice, structure and function away from eukaryotic cells and I’m talking about those prokaryotes that live in our gut-those bacteria and how they interface directly and indirectly with our cell signaling processes), that leads me to an interesting article that was published recently that opens up the door to how diverse these effects of bacteria in the gut can be on influencing systemic physiology. The title of this paper is “Metabolic Endotoxemia Initiates Obesity and Insulin Resistance.” 4 That may sound like a very disparate set of topics to all put together in a single title. This article appeared in Diabetes in 2007 and says that diabetes and obesity are both known to be metabolic disorders characterized by insulin resistance and a low-grade inflammation. This is obviously something we have been talking about in Functional Medicine Update for some years. This study sought to find what inflammatory factor is causative of the onset of insulin resistance, obesity, and diabetes (in other words, the key that may unlock this whole problem). This group of investigators, from the Institute of Molecular Medicine in Toulouse, France, identified a bacterial lipopolysaccharide (LPS) as a triggering factor for this process, meaning a product of a bacteria in the gut that is released from it’s cell wall that induces, through its structure, a functional change that enhances, then, insulin resistance, inflammation, and ultimately, clinically, can contribute to the etiology of diabetes and obesity. Did you follow what I just said? I know it sounds pretty amazing, doesn’t it? This sounds like science fiction. Somehow the personality of specific gut bacteria, when they die or release these cell wall constituents called lipopolysaccharides, interact in such a way with the receptors on the MALT or GALT to induce an inflammatory response that is systemic (leading to low-grade inflammation), which then has a signaling process through these various cell types and organ systems, that we see clinically as contributing to the etiology of diabetes and obesity. Now you may have thought that diabetes comes from obesity, but this research would suggest that maybe there is a factor below that that contributes to the etiology of both diabetes and obesity that are connected clinically, but not necessarily one derived only from the other (that they come as a consequence of metabolic events that induce cell signaling associated with low-grade chronic inflammation at a systemic level). To study this, the investigators took animal models and fed them high fat diets, which in these animals induced a higher level of inflammatory markers. That increased plasma lipopolysaccharide concentrations two- to three-fold, and the investigators have identified this threshold for increased LPS from these bacteria in the gut of these animals as kind of a threshold that leads to metabolic endotoxemia, a term that we have called dysbiosis for many years in Functional Medicine Update. This dysbiosis (or metabolic endotoxemia) associated with a high fat diet increased the proportion of the LPS-containing microbiota in the gut by changing the flora to increase the relative production of this LPS, which then induced this state of chronic inflammation. Clinically, then, these animals start to develop fatty liver, with elevated triglyceride content of the liver; increased markers of inflammation including TNF-alpha, IL-1, and IL-6; and increased relative risk to and onset of type 2 diabetes and insulin resistance. In this particular case, the high fat diet induced chronic inflammation, enhanced LPS-producing bacteria in the gut and the process that relates to inflammatory signaling (systemically), which then has the effect that all roads lead to NF-kappa-B reducing insulin sensitivity and associating itself with both the onset of obesity and diabetes. This is a very interesting example of the structure-function interrelationship and how the environment can influence not only the cells that we are made of, but also these residents on board that can be commensals, or symbiotes, or parasites that we call our enteric bacteria. Let’s take this a step farther. Let’s look at a carbohydrate-restricted diet and what influence it has on gut peptides and adiposity signals. This was recently discussed in an article in the Journal of Nutrition that I thought was very fascinating.5 In this study (a human study), researchers were looking at what happens when you restrict a highly refined carbohydrate in the diet. Would this alter gut enteric peptides? The cell signaling substances that come from this interaction of food with cell receptors in the gut signal to the rest of the body things like inflammatory markers leading to adiposity or central obesity, and into insulin resistance and later into diabetes. What these researchers found is that a carbohydrate-restricted diet lowered cholecystokinin concentrations, inflammatory markers, and adiposity signals, and had a very positive effect on compensatory control mechanisms related to things like insulin signaling and inflammatory signaling. This means that highly refined carbohydrate diets may influence cellular function through the structure of those carbohydrate molecules translating, through the cell signaling process, into induction of inflammatory mediators and ultimately insulin resistance and obesity and diabetes. Is it just refined carbohydrate? Of course not. There are many, many other signals that come through the gut. Another example appeared in a recent paper published in the Scandinavian Journal of Gastroenterology. This article is titled “Prevention by a Decapeptide from Durum Wheat of In Vitro Gliadin Peptide-induced Apoptosis in Small-bowel Mucosa from Coeliac Patients.”6 In this study, what the authors suggest is that there may be substances within phytochemicals (specific kinds of structural molecules within grains) that both induce an inflammatory response (that would be your traditional gliadin-like peptides that we know respond in certain sensitive individuals by inducing inflammation, both regional and systemic, that we call celiac sprue, or hypersensitivity inflammatory reactions), but that also may contain specific decapeptides that lower inflammatory response. So it is the yin and yang. It is the upregulation and downregulation. It is the activation and inhibition. A whole-food diet contains myriad of these different messenger molecules that produce an orchestrated effect on physiology. But if we start taking specific molecules out by refining or by chemical partitioning of the diet, we get different signals that go to these receptors, producing different effects. In that case, we can produce an imbalanced effect, an aggravated effect, or an enhanced effect (like an inflammatory response not offset by an appropriate anti-inflammatory response). This begs a question: Can we find anti-inflammatory decapeptides from grain products that have a positive effect on reducing inflammation? That is ongoing research that I’m sure we are going to see more about in the future. The point I am trying to make to you is that we have eaten complexity in our diet for decades. We have lived in a complex environment-not just for decades, for millennia. And these influence, in their complex, orchestrated way the structure-function relationship of our body. Let’s take one last example, one that I think is very valuable clinically: prebiotics and stimulating appropriate bacteria (friendly, symbiotic bacteria) and proper signaling in the gut and the reduction of inflammation. What do we know about the prebiotics? We know that one of the most interesting prebiotics that has been discovered recently actually comes out of a product that originally was grown as a northern latitude vegetable, chicory. It has been found to contain very high levels of a prebiotic called inulin. Inulin has a very dramatic influence on the personality of symbiotic bacteria that are butyrate-producing and lower the levels of inflammatory lipopolysaccharide production in the gut. This enhances insulin signaling and lowers the risk to obesity through these processes that I have described (by lowering metabolic endotoxemia suggestions). The Favorable Effects of Inulin Inulin, when given in adequate levels, as well as galactooligosaccharides, are extraordinarily valuable prebiotics that influence the cell signaling process. The structure of these oligosaccharide molecules in chicory induce (as inulin molecules) an appropriate cell signaling response on the other side. How much inulin? We are talking somewhere in the range of six grams a day, probably as a threshold. Ranges could go from 6 to 10 grams, and it induces, then, these more favorable effects, and it goes along with probiotics to induce these proper gut signaling processes. I hope I have left you with thoughts of how structure and function are very closely interrelated and connected through cell signaling. It is among the fundamental processes by which functional medicine works to control the adaptive capability of physiology against a changing environment. With that in mind I think it is time to turn to our clinician-of-the-month who is going to take this concept of structure and function to the next level.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Frank Lipman, MD Eleven Eleven Wellness Center 32 West 22nd Street, 5th Floor New York, NY 10010 www.lipmanworld.com Here we are again at that portion of Functional Medicine Update that I look forward to with great anticipation every issue and I think you as a listener certainly do as well: our Clinician of the Month and what expertise they bring to us in terms of their history, background and insight. Over the years we have had the most remarkable experiences. As the person who has the pleasure of doing these interviews, I have often had epiphanies because I think I have a sense that I know how these discussions will go, and then something occurs during the interview that is just remarkable and takes it to another level. I have a suspicion that we are going to blessed with type of discussion today with our Clinician of the Month, Dr. Frank Lipman, who is the founder and director of the Eleven-Eleven Wellness Center in New York City. I want to do a quick vignette of Dr. Lipman so we can set the context of his background. Dr. Lipman is South African in his training, qualifying in medicine in 1979. He worked both in private practice as a general practitioner in the rural areas of South Africa before entering the United States. He became board certified in internal medicine, doing his residency at Lincoln Hospital in New York City, and served as the chief medical resident in his final year of the residency. As he moved his practice into focus, he was able to bring together some fairly remarkable concepts that you’ll be hearing more about from Dr. Lipman. Some of these are related to what we want to focus on in these discussions, which are related to this very interesting emerging concept of signaling through connective tissue and the extracellular matrix and how that connects to health, wellness, and also to chronic disease in terms of dysfunctional signaling. Dr. Lipman is the author of a book that I have talked about in the past on Functional Medicine Update . It was published in 2003 and titled Total Renewal, 7 Steps to Resilience, Vitality and Long-Term Health. I know that Dr. Lipman has some apprehension because he said, “Well, you know I’m not really a researcher; I’m just a clinician.” I think, for us, the word “just” is a pejorative because that is where the tire meets the road; that is what functional medicine is all about-trying to bring information to user friendliness (so-called “news to use”). So let’s just strike the word “just” and let’s introduce Dr. Frank Lipman to you. Frank, thanks so much for joining us today. I can’t tell you how much we appreciate you being available for this discussion. FL: It’s an honor to be on with you, Jeff, because you are one of my primary mentors. JB: Well, thank you. That’s very flattering for me, obviously. Could you tell us a little bit about your practice? You know, over the years I have gotten to know you I’ve been very impressed with how you have developed the personality of your practice (knowing that every practitioner has kind of a different fingerprint on their practice). FL: It started in South Africa, being trained as a regular physician and working in rural areas, in particular, and seeing results from Sangomas, the natural, traditional healers in South Africa. I already knew that belief systems and something other than Western medicine was at play because when we couldn’t help patients, I saw these Sangomas helping patients. So that started my questioning of the system. I went into general practice straight after my training, where people came to me with functional problems and I couldn’t help them. So I started exploring early and I looked into homeopathy because the homeopathic tradition is actually quite big in South Africa. But interestingly enough, when I left South Africa (I ran away from apartheid), I came to America and my mentor there (the GP I worked with) gave me a book on acupuncture ( The Barefoot Doctor’s Manual ) and he said, “Go study acupuncture.” I landed in the South Bronx in New York City without knowing that Lincoln Hospital had an acupuncture clinic. Very early on I realized I didn’t want to be a doctor here (in America) because the medicine was so different-it was all about lab tests and x-rays, it wasn’t about speaking to patients. But then I walked up to the acupuncture clinic and I started studying acupuncture and it was such a life-opening experience for me to get into the philosophy of Chinese medicine, which made so much sense to me. So it started with acupuncture in the mid-80’s and from there I discovered functional medicine through you a little bit later. And when I heard you speak, you were articulating Chinese medicine from a Western perspective, so that was the next “a-ha” experience. Here I was studying acupuncture and Chinese medicine, which was completely different from Western medicine, and then Jeff Bland comes along and he starts putting the two together. That, to me, made a huge difference. And then I started studying yoga, and yoga, to me, was another extension of functional medicine because yoga, once again as with acupuncture-I see both of them as functional medicine. I started exploring modalities that I felt were modalities that improved function. And over the years I just started using all these things together and I have developed-as you say-my own imprint, but it is focused on acupuncture. What is interesting is that no one really talks about acupuncture as functional medicine, but to me, acupuncture is your ideal functional medicine. We’ll talk about it later: how to improve cell function and how I see acupuncture which is basically a little bit different to traditional Chinese medicine which sees it in terms of energy and meridians. From the beginning I knew that Chinese medicine talks about energy and meridians, but I knew there was a Western explanation that could make sense to me from the Western perspective as you had put other parts of Western medicine into the functional medicine context. No one was talking about what was going on with the soft tissue is what I was feeling. I was feeling all these bodies and I knew there was something apart from energy and meridians and I started thinking about acupuncture (or the meridians) as the fascial system. And if you think about it, the fascia is connected all over the body, and I thought and strongly believe that acupuncture works with the fascial system. Interestingly enough there is now research by Langevin and her colleagues in Vermont which is basically saying what I have been seeing for the last 20-odd years. The Mechanism of Acupuncture: Cellular Signaling through Connective Tissue JB: You have shared a couple of her (Helene Langevin’s) wonderful articles. I think I should give a quote to support what you just said out of one of her articles that appeared in the Anatomical Record. 7 She says, and I quote, “Acupuncture meridians traditionally are believed to constitute channels connecting the surface of the body to internal organs.” However, work that they are doing hypothesizes that the network of acupuncture points and meridians can be viewed as a representation of the network formed by interstitial connective tissue. This hypothesis is supported by ultrasound imaging showing connective tissue cleavage planes and acupuncture points in normal human subjects. They mapped acupuncture points and serial gross anatomical sections through the human arm, and found an 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} correspondence between the sites of acupuncture points and the location of intermuscular or intramuscular connective tissue planes in these postmortem tissue sections. Their proposal is that there is this anatomical relationship of acupuncture points and meridians to connective tissue planes. This is very relevant to how the mechanism of acupuncture works and suggests this signaling process through connective tissue, which we have always thought of in the past-I’m now editorializing-was more dys-structural (not having a function). I think it is so superfluous and facetious of us to think that the body has only structure separated from function. It is like trying to say the mind is separated from the body. I just wanted to interject that very interesting concept from Dr. Langevin’s work. FL: Right. To me this was such a huge high experience when I found this research. There is a concept in Chinese medicine called Ashi Points. Ashi are these local points (these local areas-they’re not really points) that spontaneously become tender or painful in response to some local problem. It can be a strain, or a tear, or even drugs. I started treating these Ashi Points years ago. Even in acupuncture circles, if you treat Ashi Points, that is sort of real low-rung (or low-level) of treatment of the body. But what I have noticed from treating these Ashi Points (these local, tender fascial connective tissue points), is that people started feeling better. Not only did their ankle get better, but they started feeling better all over. So I knew something was going on, but no one was really describing it because I wasn’t using meridian points, per se; I was feeling the body and I was going into tender areas. The Concept of Integrins The easy explanation is the ankle’s swelling went down and the ankle got better, but people started experiencing other ways of feeling better, so I knew something was happening-there was some cell communication or something was happening that we weren’t aware of. Langevin and her colleagues have come up with this concept of integrins, which are a protein on the cell membrane. I think you talk about them-not about integrins, but about these cell membrane proteins–which then activate the protein kinases. I mean, I don’t know if you want to talk a little bit about the integrins or the protein kinases. JB: Can I just add, parenthetically, for people who may not be as familiar with integrins, the one that they probably have heard about in traditional internal medicine is GLP1 (glucagon-like peptide-1), which, as you know, has become Byetta (the drug, Byetta), which is the new insulin management and even weight loss drug that came out of the gila monster saliva exploration. That is an integrin signaling inhibitor. There is a whole family of these that are emerging. This is kind of the “new science” as to how outside information gets translated into inside cellular function. Excuse me for interjecting… FL: No, thank you. What I find interesting is what she is documenting here: these cells communicate via these many projections (or these integrins) which are on the cell membrane. These integrins get deformed by overuse, misuse, abuse, or disuse, and when the tissues get crowded. When you release that crowding with acupuncture or deep tissue massage, not only is that area getting better, but you are improving cellular communication. So what this research is saying-and this is what I see clinically all the time-is that acupuncture or releasing the tissue (the local tissue) is actually improving cellular function. I still can’t get over it: that we now can actually prove how manual tissue work, or releasing the fascia, is actually improving generalized function. JB: For our listeners, I again want to just put a very important benchmark here-or maybe it is even a goalpost- that has to do with what you are saying, which is highly profound. Sometimes the most profound ideas sound so simple once you have heard them, but they have very deep implications. In medicine, we often have set up these dualities, assuming that the dualities have an impermeable separation between the two of them, like light and dark, as an example. But structure and function often are taught and thought of as almost two different areas of medicine-as rehabilitative medicine, or structural, physical medicine being separate from metabolic medicine, which is the function. So we’ve got metabolism on one side, and we’ve got the structure (all the stuff that holds us upright against the force of gravity) on the other, and never the twain shall meet. The model that you are describing, which I think is very powerful, drawing from several thousand years of history, is that this duality/separation between structure and function is really incorrect-that structure interfaces with function, function interfaces with structure, and which ever way you enter into the system, you are influencing both. In this case, we are talking about a mechanism that through structure sends signals to function, which has implications on metabolism and physiology. Am I paraphrasing this correctly? FL: You have articulated that so beautifully. That is right on. Thank you for doing that. That is exactly what I am saying; you just say it so much better. I have seen that, clinically, through yoga and acupuncture; I use both of them a lot. Why do people get so much better through yoga, not only physically but emotionally? And the same with acupuncture? Thank you for articulating that so beautifully. JB: Let’s take an example. Over the years we have had conversations, and I have the benefit of drawing on those past exchanges. Let’s take fibromyalgia. Fibromyalgia is a very interesting clinical term that relates to patients who experience these very hot, tender points, which often happen to be coincident with what (historically) might be considered some of these meridian points or active energy points on the body, going way back (as you said) to Traditional Chinese Medicine. If you look at the literature on fibromyalgia, in journals such as Arthritis and Rheumatism, it has fallen within the prevue of the rheumatologist. This is an autoimmune-related family of disorders, and it has something to do with a disturbance of the hypothalamus-pituitary-adrenal axis because we can find alteration in neurochemicals and stress chemicals in patients with fibromyalgia.. These patients have a centrally mediated difficulty of the HPA axis and that, then, translates into a neuromuscular problem. Now from what you are saying (and I’m being a little presumptuous here, so I hope I’m not misleading you), it would suggest that maybe we could turn that around and say fibromyalgia is a condition that is associated with certain kinds of dysfunctions of this cellular communication process (mechanical signaling through connective tissue). Really, then, rather than coming from top-down, it comes from bottom-up, and that influences, in turn, the HPA axis function that is responding to the block in energy flow and so forth. It turns this whole concept of the etiology of fibromyalgia around on its head. Is there any validity to this model that I just stated? FL: It could be. It’s hard for me to say because when I treat fibromyalgia I use both together: I always use acupuncture and I always suggest yoga. But I will work, from a functional perspective (metabolically) as well. But, yes, it could be. I do think that the fascia, per se, is the forgotten organ system and it doesn’t get much credibility. Western doctors definitely ignore it. Even functional medicine doesn’t address it that well and hopefully that will change now. I mean the European osteopaths have developed many procedures to correct these functional problems by working closely with it. It’s the European osteopaths more than American osteopaths. That could be correct; it is hard to say. But clinically, there is no question. When I work metabolically and use the acupuncture and use some yoga (or something like that) patients respond really, really well. But it is hard to say whether it is up-down or down-up. JB: As you have gained all these years of clinical experience and become an expert in this area, have you (through your hands) learned (when you touch a person) where you can feel these kind of irregularities of the extracellular matrix? FL: Absolutely. Any body worker can tell you that when you touch a body, you can feel it. You know, you had once asked me, how I measure this. I don’t know how to measure it in terms of what tests or what blood levels are going to be off; I can just measure it by my hands. You can feel the tissue change; it is really interesting. So that has been my measurement over the years: the touching. I don’t know any other way of measuring this except the feel of the body and any body worker you speak to will talk about that. JB: When a patient comes to visit you, undoubtedly they already know something about the unique way that you approach these problems, so they are not coming in to you for kind of a traditional internal medicine blood screen, physical, history and then a prescription for a drug. How do you walk them through what is obviously (from my perspective) a very highly evolved functional approach using both the connective tissue components as well as the metabolic components coming from both directions? FL: As you say, I think I’m lucky in that most people are referred by other patients and when they come in they are already believing that I’m going to help them. I think belief, or the placebo effect, or whatever you want to call it is a really important part of the healing process. When people come in believing in you as a practitioner I think that makes a big difference. It is much easier for me. And a lot of what I’m doing is reframing the way patients see their problems. They come in with a diagnosis. My first intake is a long intake because I honestly believe you get most of what you are going to get from the history, or a lot of what you are going to get comes out in the history, even before I feel the body, so the first visit is trying to get a really good history, and at the same time I am trying to reframe the way patients see their problems. And I often put it in a functional medicine perspective. It is easier for me because I have the luxury of having that type of referral practice where people come in thinking they are going to get better. I’ll take a good history first. Because acupuncture is so intimate–patients have to take off their clothes and you are touching them-this is also an advantage. In Western medicine and Western culture, we don’t touch a lot. A nonsexual way of touching is not really part of our culture, and I think so many people need to be touched in a nonsexual way, so it becomes a very intimate experience because these patients are taking off their clothes and I’m touching them. So I have a lot of good things going for me for people to get better before I even put a needle in or before I even give them a supplement. I know it sounds crazy, but I really believe that’s part of the healing: the intimacy and the touch. I’m very functional medicine oriented-you have taught me a fortune and the way I practice is largely influenced by your philosophy and your teachings–but then I will incorporate the touch and the body work and the needles. That’s what I do. I rarely do tests. I used to, in the early days, do more functional medicine testing. Now I work clinically. Occasionally, if someone doesn’t get better, I’ll start doing tests, but I am always weary of getting lost in test results, so I’m usually working clinically. And the other luxury I have is people coming back after a week, a couple of times, for a month (for four or five treatments), so I’m seeing them every week (you know, four or five times). I’m seeing if they are getting better or not, and I have the luxury of adjusting things week by week. And that’s how I work. JB: I would like to focus for a moment on the extraordinary process of acupuncture and what is evolving to be better understood. There is this sense that I have heard from some people that you can get the same benefits that you get from acupuncture without penetrating the skin. In other words, no needles. However, the mechanistic work that is evolving around acupuncture suggests strongly that the mechanical influence on the cytoskeleton, by penetrating the skin with a needle in the right rotation and kind of mechanical forces, plays a huge role in sending these signals through these membrane-coupled cell mediators, like the kinase families, and triggering downstream metabolic as well as neurophysiological changes. So it would seem that the mechanism implies that penetration of the skin in the appropriate place at the appropriate depth with the right rotation of the needles and the techniques of acupuncture is intimately important for the outcome versus just stimulating an acupuncture point transcutaneously. FL: I would agree with that. I do think you need to penetrate the skin. My experience has been that the results are much more powerful, although there are people who don’t think you need to penetrate the skin. I think there is something to relationship beliefs working energetically, but I think that penetrating the skin is crucial to getting better results. JB: I think that for a lot of us in the clinical world, the concept of cellular biology seems very abstract and not very clinically relevant. If we think of what’s going on as you have described (your procedures and intervention using yoga and acupuncture), you are really, in those technologies, influencing (at a very fundamental level) the dynamic state of balance that relates to the function of the cytoskeleton. I think people don’t understand that cells (individually) have an internal skeleton that is made out of protein; it’s not like bone, it is made out of various types of proteins that can form in aggregate and disaggregate, so it is kind of chimeric. It can be changed, and as it changes its structure by changing the environment, all sorts of things change-electrolyte transport and intercellular voltage gates (as it relates to electromotive force), for example. In other words, you are fundamentally capable, through the changing of the cytoskeleton, of changing the metabolism of the cell. If multiple cell changes create changes in tissues, then you get demonstrable whole body changes. I think the concept you are talking about has such profound implications of using the structure of the body to speak to the function through these altered dynamic states of cellular structure function. FL: Right. This is what Langevin’s research is showing. I don’t read too much research, but that’s the way I understand her research. JB: Yes. I think, in fact, one of the papers that she and her colleagues published (this was the Department of Neurology, as you mentioned, from the University of Vermont), appeared in the FASEB journal, which is the Federation of Applied Biology and Science, and they talk about the fact that in these studies in animals with insertion of acupuncture needles, they can actually demonstrate alterations in things like extracellularly-regulated kinase, or the ERK.8 And that connects to inflammatory pathways. So from a cell biological perspective, we are now able to start delineating mechanisms that go down ultimately through things like cyclooxygenase enzymes and lipoxygenase, and can turn off or turn on fundamental things that we observe as inflammation or immunological parameters. It’s a really dramatic interface between two disciplines. It appears if they were separate in the past they are now being seen as part of a continuum. FL: Absolutely. For me to see that happening (because I’ve noticed this clinically over the years) for me to see research on this and see these changes happening–is very exciting. JB: As your patients, then, proceed along the path of recovery, do you find that there is kind of a recidivism-there’s a relapse-and they need to come back in periodically for a tune-up of this whole connective tissue/extracellular matrix, or does it last. What are the residual effects? FL: Well, it’s interesting. First of all, acupuncture is interesting because one way to see it is as irritating the nervous system. You know, acupuncture is obviously working somehow through the nervous system; you are basically irritating it.. And if you irritate it a little bit too much, like any stress, you can damage it. But if you just give it the right irritation, which is usually not much, the body heals itself. So I think the art of acupuncture is not overtreating, which some people do, and not undertreating. I think you can affect changes through acupuncture, but if a person doesn’t eat well, exercise, keep moving, maybe doing yoga or some type of body work, they are going to need to come back for acupuncture. What I tell patients is that they should have three or four treatments a year, but as we get older (and I see this in my body as well), I try to go for body work once a week, or once every two weeks, or whenever I can. I to catch problems early, so I really encourage my patients to come in whenever they feel something is off. In other words, if they sprain their ankle, don’t wait for it to heal because oftentimes it will heal but it won’t heal properly, so I would encourage them to come in straight away and then they’ll only need one treatment or maybe two treatments. So I do encourage my patients to come in every now and then for a tune up because I don’t think it lasts forever. JB: Frank, what you have given us in this discussion-I know we have just touched the surface-is just a wellspring of powerful information. You know, as I’m reading the articles by Dr. Langevin and her colleagues, she closes one of her articles with a very interesting kind of summary which I think, from a scientific perspective, is a way of describing what you have beautifully described from a clinical perspective. To paraphrase, what she says is that this acupuncture theory was based on empirical observations made over 2000 years ago, and the field of mechanical transduction is emerging to now provide scientific grounding for this ancient form of therapy. She says that acupuncture provides an important clinical application for the current explosion in basic knowledge of the diverse biological effects of mechanical signaling, as to how pressure in the right place and mechanical-electrical stimulation of tissues can signal, through these intercellular signal transduction processes, altered cellular tissue organ and organ-system function, which then produces a functional change in the organism, not just locally, but it can be systemic. I think what you have observed, which is where the reality exists, can now be explained from this emerging cell signaling perspective. What an exciting time we are in. This is just an amazing breakthrough of understanding. So where would a person start if they want to start down this road and develop some the skill that you have developed in your practice and world over the years? Acupuncture Courses FL: I think the most exciting acupuncture training that I have recently found out about is being done by a Spanish MD inCanada, Alejandro Clavalho, near Toronto. (I have never actually trained with him.) He is teaching acupuncture but calls it “functional orthopedics.” He is teaching a type of bodywork that goes with acupuncture, which I think fits right into your philosophy of functional medicine. It is really an extension of the functional medicine–this “functional orthopedics” model he has. When people call and ask for advice, I actually send people up to his training. The website is acupunturecourses.com. I know it is right near Toronto. Not to put anyone else down–I had wonderful acupuncture teachers-but in terms of the functional medicine approach, I think he comes closest to it. JB: Well, thank you. We’ll make sure we put that on the summary card for referral. To leave us with some thoughts as we close this discussion, what you have helped us to understand (or at least open the door for many of our listeners, probably) is a whole different perspective about faschia, connective tissue, extracellular matrix, how acupuncture and bodywork trigger systemic metabolic and physiological changes, and why the worlds of structure and function are not separate; they are actually part of a continuum. If we can get that concept, alone, across in this discussion we have done a big service to advancing medicine from a functional perspective. I want to thank you very, very much. This is the start of a journey, I’m sure, for many of us as we have heard you speak about your experiences and background. FL: Thank you for having me on, Jeff. JB: It has been our great pleasure. Issue Synthesis Let me do a recap of what I consider the take-home value of this month’s Functional Medicine Update . We started off talking about this duality of structure and function and then redefined it as a continuum. Structure influences function and function influences structure, and these two terms are really connected through cellular signaling. We then talked about various ways that you can influence this process by altering the environment through the alkaline/acid balance, saying that as you shift toward an acid pH it changes receptor binding and changes ligand/receptor interaction to alter cellular signaling. By using an alkaline-ash diet, you shift towards improvement in detoxification, enzyme function, and metabolic function. This is what has historically been seen clinically for many years (that an alkaline-residue diet has these positive impacts upon function). So the environment is plastic, and it alters the way that cell signaling occurs. Then we went from that to talk about specific small molecules, or phytochemicals, found in whole foods and their influence on cell signaling processes. I talked about indole-3-carbinol, and phenylisothiocyanate, and sulfurophane that are found in cruciferous vegetables. These molecules can influence detoxification and the conversion of endogenous molecules (like 17-beta estradiol) into nontoxic metabolites, which can also be used as parts of the signaling process to induce specific cellular function. And then from there we talked about soy-the small molecules that are found in soy and the influence they can have as isoflavones, or polyphenols, or lignans on the effects of function, including things like lipid synthesis, insulin sensitivity, anti-inflammation, and hormonal metabolism. From there, we talked about the fact that if you think of foods in their whole form they contain a whole rich array-a library-of substances that can influence cellular neurological function, and can have neuroprotective effects (with gingko biloba obviously being the one that is on the minds of most individuals, but there are literally hundreds of foods that have central nervous system active, neuroprotective substances that interact with intercellular kinases and alter cellular signaling). Then we moved from small molecules in food to talking about the gut. What about the gut and bacteria and the influence that they have on cell signaling and structure-function? I spoke about this extraordinary study that had looked at endotoxemia and how it initiates obesity and insulin resistance. By altering bacteria type and number and metabolism, we can alter the function of the body through altered cellular signaling. We talked about agents that would modify, in a favorable way, enteric bacteria and altered cellular signaling, like removal of highly refined carbohydrate in the diet and increasing certain probiotics, like inulin-containing substances that induce friendly bacteria, lowering LPS and lipopolysaccharide levels and inflammatory mediators and improving insulin sensitivity. We talked about agents in whole foods that can induce inflammatory response at the gut level and can have systemic implications, like gliadin (found in cereal grains), but there are other substances in those grains that might have anti-inflammatory effects. I cited the decapeptide from durum wheat that appears to have anti-inflammatory effects. Coenzyme Q10 and the Prevention of Hepatotoxicity We talked about traditional nutritionals, or biochemicals, or what might be called by Dr. Pauling “orthomoleculars” (natural molecules found in our diet, like coenzyme Q10). You might say, “How does coenzyme Q10 help to prevent hepatotoxicity?” There is a very interesting paper that was recently published, looking at the effect of coQ10 in liver cells on the protection against injury to the cells when exposed to high-dose simvastatin (obviously a statin is a HMG-CoA inhibitor drug). This article appeared in Toxicology and AppliedPharmacology in 2007 and is titled “Reduced Mitochondrial Coenzyme Q10 Levels in HepG2 Cells Treated with High-dose Simvastatin: A Possible Role in Statin-induced Hepatotoxicity?” 9 The authors of this article conclude that as coenzyme Q10 levels are depleted within hepatic cells, this insufficiency or deficiency plays an important role in statin-induced hepatopathy and that coenzyme Q10 supplementation may help protect against hepatic cell injury from this complication of statin exposure. So what we are really talking about, again, is a molecular effect (this is an endogenous chemical that is biosynthesized in the body-coenzyme Q10), and the influence it has on function of the mitochondria (in this case, an intracellular organelle), which then regulates oxidative injury and oxidative stress-related cell apoptotic events (in other words, cell suicide events) that are associated with oxidative stress. As coenzyme Q10 levels are depleted due to interruption in endogenous biosynthesis due to exposure to a statin, it enhances, then, the relative cell signaling process, shifts the balance toward oxidative injury, which then triggers in that cell (through its gene expression patterns) the potential for cellular suicide, which we call apoptosis, and that is hepatopathy. So I think this is, again, another way of taking data and observations that we have made for some time and projecting it through the lens of structure-function and looking at how, then, the appropriate environment leads to the proper structure-function relationship and outcome in that patient. It is not that statins, in and of themselves, should be avoided at all costs; it is constructing the appropriate environment in that individual to modify the functional changes that occur in these systems as a consequence of the perturbing structure of that molecule called the statin molecule. And then lastly, of course, we moved to a whole other level in this discussion in the eloquent and amazing history and description by Dr. Frank Lipman of the extracellular matrix and fascia and how that is an environmental translator of agents outside to the inside cellular function, through these same cell signaling processes I’ve been describing-through the kinases, the extracellular matrix proteins that then take information that may be things like baromechanical pressures or electrostimulation (mechanical electrostimulation) that occurs with acupuncture and translates it over into alteration in cellular signaling so that structure and function are modified. I think this plays out to produce a unified conceptual framework of how therapeutic interventions work to serve both as a preventive and therapeutic series of tools that work in concert with one another through similar mechanisms to produce outcomes. So it is not just one agent at a time. It is not the double-blind, placebo-controlled, randomized trial (hold everything constant and just change one thing and then look at the outcome). It is a pattern of changes that then alters our function through the structure of those events that then cause the genes to change their expression patterns, the signaling processes to occur, so it is work locally but act globally, as kind of the outcome from this framework. So I hope we have left you with some new thoughts and tools as it relates to how the playing field of functional medicine derives from all of those agents that modify from this very subtle and important interrelationship between structure and function. Thanks for being with us. We’ll look forward to sharing again in November.

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1 Minich DM, Bland JS. A review of the clinical efficacy and safety of cruciferous vegetable phytochemicals. Nut Rev. 2007;65(6):259-267. 2 Minich DM, Bland JS. Acid-alkaline balance: role in chronic disease and detoxification. Alt Therapies. 2007;13(4):62-65. 3 Bastianetto S, Brouillette J, Quirion R. Neuroprotective effects of natural products: interaction with intracellular kinases, amyloid peptides and a possible role for transthyretin. Neurochem Res. 2007;32(10):1720-1725. 4 Cani PA, Amar J, Iglesias MA, Poggi M, Knauf C, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761-1771. 5 Hayes MR, Miller CK, Ulbrecht JS, Mauger JL, Parker-Klees L, et al. A carbohydrate-restricted diet alters gut peptides and adiposity signals in men and women with metabolic syndrome. J Nutr. 2007;137:1944-1950. 6 Silano M, Leonardi F, Trecca A, Mancini E, Di Benedetto R. Prevention by a decapeptide from durum wheat of in vitro gliadin peptide-induced apoptosis in small-bowel mucosa from coeliac patients. Scandinavian Journal of Gastroenterology. 2007;42(6):786-787. 7 Langevin HM, Yandow JA. Relationship of acupuncture points and meridians to connective tissue planes. The Anatomical Record. 2002;269:257-265. 8 Langevin HM, Churchill DL, Cipolla MJ. Mechanical signaling through connective tissue: a mechanism for the therapeutic effect of acupuncture. FASEB. 2001;15:2275-2282. 9 Tavintharan S, Ong CN, Jeyaseelan K, Sivakumar M, Lim SC, et al. Reduced mitochondrial coenzyme Q10 levels in HepG2 cells treated with high-dose simvastatin: a possible role in statin-induced hepatotoxicity? Toxicol Appl Pharmacol. 2007;223(2):173-179.

Welcome to Functional Medicine Update for November 2007. In this issue, we are going to focus on a topic on which we have been doing quite a bit of work (because I think it deserves it): nutritional endocrinology. Our nutritional endocrinological discussions will focus on a couple of areas of topical and clinical importance; one of which has to do with the vitamin D story, which we have become more knowledgeable about over the last two years inFunctional Medicine Update. There is some new “news-to-use” in this area that I think you are going to be very excited to learn about from a world leader in this area. The other area–which we are going to start with–is the relationship of insulin signaling, insulin sensitivity, and gene expression patterns. The list of the many disorders of chronic age-related diseases related to this topic continues to grow: type 2 diabetes, coronary heart disease, autoimmune disease, bone loss, dementia. Even cancers of the colon, breast, and prostate are associated with dysfunctional insulin signaling. In some senses, this story is evolving beyond metabolic syndrome. Probably most Functional Medicine Update subscribers are aware of this, but I just want to give a quick reminder that we have recently put out a new product under the Synthesis banner: our seminar titled Beyond Metabolic Syndrome: Dementia, Diabetes, Cardiovascular Disease, Hypertension, and Autoimmune Disease. This is a product we put together in 2007, and it includes both the CD audio and the visuals that are associated with the seminar. For those of you who are not familiar with it, you can learn more about it by either going to our website, (www.jeffreybland.com ) or you can give our Synthesis office a call at 1-866-272-5789. Just ask about the education product titled Beyond Metabolic Syndrome. I think you will find it very educational and clinically valuable. Let me also say one other thing that I think you are aware of (we want to continue to fertilize the soil): We love questions. We actually thrive on being challenged. We would love you to send in your thoughts about what you want to hear on Functional Medicine Update–controversies, things you have heard about in the news, or things I have said that you don’t agree with or would like to have revisited. I think we take to challenges very well and receive them in the spirit in which they are intended, so if you have any questions or areas you want us to focus on, or concerns about something that I said that you would like to revisit, give us a call. Again, let me give you the number: 1-866-272-5789 (it’s toll free). You can also send an email through the website, www.jeffreybland.com. I’m looking forward to hearing about the interest areas that can make this FMU even more effective in meeting your needs. Let’s talk about the basic underpinning of nutritional endocrinology. I’ll just spend a moment speaking of theory. I know most of you may not be as interested in theory, and are much more interested in what this means to your patients. But, what it means to your patients often starts with a theoretical framework, so I want to share that with you quickly. The connection between genes and environment really relates to the birth of the functional medicine concept. Each person possesses their own unique genome of 23 pairs of chromosomes; but these are pluripotential, which means they are not hard-wired to give a certain expression pattern. Rather, their expression over time depends on the exposure to certain environmental signals, and we view this as the origin of chronic disease. Environmental signals include things like diet, lifestyle, thought patterns, water, air, and sunlight (which we will be speaking about in greater detail in this issue). All of these things are picked up as information units by the body and translated through intercellular signal transduction pathways (signals) into physiological actions. Those actions (what we call the phenotype) are translated through the genotype by way of the gene expression patterns. Certain genes get turned on and others get turned off. We are shaped by a combination of these hard-wired genes, which we don’t change (hopefully-they are not becoming mutated), and how they pick up information from the environment and translate it into the phenotype of the organism. This occurs over decades of living. And so we shape ourselves over time by our experiences. We shape ourselves psychologically, physiologically, spiritually, and physically as a result of our experiences, which probably occur from the moment of conception. How does that relate to nutritional endocrinology, the theme of this month’s Functional Medicine Update? “I think you can probably speculate about what direction I am going. The takeaway is that the endocrine system is connected to the immune and nervous systems, so we have this super system we call “psycho-neuro-immuno.” The Role of Intercellular Signal Transduction Pathways Endocrinology is a system that exists to translate outside information into inside physiological function, and it occurs through pathways of gene expression and intercellular signal transduction. Nutritional endocrinology would imply, then, that there are substances within our diet (macro- and micronutrients, and accessory nutrients) that, when consumed, have some impact on regulating the functional status of the endocrine system through this gene-environment interaction and intercellular signal transduction pathways (intercellular communication). That would mean if we eat a polyphenol from some food, somehow there must be a mechanism that changes androgen or estrogen levels, or has an impact upon metabolism of hormones, and that it must work through some process of regulating function at the cellular level through this transduction process (this intercellular signal transduction). I am saying this very simply-as if it’s matter of fact-but in fact, this is a pretty remarkable change in our view of how nutrients may influence physical and physiological function: through transduction pathways that modulate gene expression. To date, over 500 regulating factors for these processes have been discovered, which include cytokines, chemokines, kinase enzymes, and all sorts of interesting molecules. If you think about the future of personalized medicine, what we need to do is understand more about the interesting gene array that is in each person. What do they possess in their hard-wired book of life-their genome-and how do those unique characteristics get modified in their function, or their expression, by environmental factors? It is a combination of understanding the uniqueness of that patient, which has to do with their SNPs (single nucleotide polymorphisms)-those changes in their book of life that cause them to be a little bit different by one later substitution than someone else-and then how those uniquenesses are modified in expression by the environment to produce a functional outcome: a person’s health. I hope that is an understandable framework. This is what we are going to be contextualizing in this discussion of nutritional endocrinology. Just recently, in the American Journal of Clinical Nutrition, an interesting editorial was published titled “The End of the Beginning.” 1 Authors Shelly Cole and Anthony Comuzzie write about what gene studies are now telling us about the relative risk people might have to later stage diseases. They focus on gene uniquenesses, like the adiponectin gene. Adiponectin, which we have talked about, is an insulin-stimulating anti-inflammatory messenger molecule that is produced by adipocytes. The uniqueness of the adiponectin gene can be correlated with differing relative risk to things like type 2 diabetes and metabolic syndrome. But adiponectin genes don’t work just by themselves; they work in concert with many other genes that regulate a symphony — an orchestration — to regulate insulin. So it is not just one gene at a time; it is genes in the context of family members that create outcomes. The authors of this this editorial state that identification of well-supported candidate genes (such as adiponectin) is a necessary first step in genetic studies and understanding, say, the relative risk to things like metabolic syndrome or type 2 diabetes. In addition, we need to go on and connect those to the variation in phenotype by looking at other genes in the family. The authors actually quote Winston Churchill: “Now is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.” I think that is kind of where we are now in this whole gene expression story. We don’t know where this story is going to take us, and people who presume they know are probably being premature because this is only the first stage in our understanding of how gene diversity (the SNPs) really regulate ultimate phenotype and sensitivity to our environment. There is an interesting paper about Wilson’s disease that appeared in Clinical Chemistry just recently that I would like to mention to you.2 I have spoken about Wilson’s disease for years and years–in fact, all the way back to my start in this field with trace mineral nutriture, back to the early 1970s. There was actually a best-selling book, Mental and ElementalNutrients, by Dr. Carl Pfeiffer, that talked about trace elements and the important role they have in regulating function (zinc and chromium and copper). Wilson’s disease is a genetic disorder that is associated with higher levels of ceruloplasmin in the liver that captures copper and leads to copper toxicity, in which people end up with liver failure and dementia. I remember seeing an incredible video (actually, it was a movie-this is pre-video, back in the early 70s) of a patient at NIH Hospital in Bethesda, who had Wilson’s disorder. It was a young woman-very attractive and eloquent-and she was talking to the physician on camera, saying she was having these early-stage signs and symptoms. Then they tracked her–on film–over the course of a year. You could watch her, before your eyes on this kind of compressed time video, losing her mental function. She became totally unable to speak and unable to control her limbs. They put her on penicillamine-cuprimine-which was the treatment of choice at the time and you could watch her, then, over the last several months, come out of it and regain her function; this was all a consequence of copper toxicity associated with this genetic uniqueness called Wilson’s disease. You might recall that it has been found that counter-acting nutrient to copper excess is zinc. There were studies supported by the NIH that showed zinc is able to drive the uptake of copper down, and this has led to one approach to management of Wilson’s disease — not just with cuprimine alone, but also with oral zinc supplementation at high dose.3 Our early view of most genetic metabolism disorders was that you either had them or you didn’t; there wasn’t a variation of a theme. But now, with the availability of SNP analysis, we are finding that many people have some level of vulnerability to a genetic metabolic disorder-not just Wilson’s, but Gaucher’s, Fabray’s, Tay-Sach’s, and even phenylketoneuria-show variant forms because they are multiple gene loci. It is not just you have it or you don’t; there are variations on a theme, similar to what we know with Gilbert’s syndrome (that varying degrees of hyperbilirubinemia are associated with different penetrants of glucuronidase enzyme alteration). In a Clinical Chemistry article, the author reports that by doing SNP analysis in Wilson’s disease, you find a variegated number of SNPs that are associated with the condition. Within this condition, you might have a person with mild Wilson’s, or you might have a person with much more severe Wilson’s, meaning their ability to concentrate copper from their diet. A person with Wilson’s is not being exposed to toxic levels of copper; they are concentrating the normal level of copper found in a diet into tissues, creating the toxicity. There are four SNPs that have been identified with Wilson’s showing variation on a theme. This complicates our story a little bit, doesn’t it? We cannot just name each condition, find a gene for that condition, and then find the nutrient to modify it. It’s a variation of themes and these things work in families. Ultimately, all of this will lead us down the road towards personalized nutrition and using nutritional genomics as a tool for targeted medical nutrition therapy. But I think it’s very important for us to recognize we are still early on in this process. As Winston Churchill said, we are at the end of the beginning, not at the beginning of the end yet. There is still a lot to be learned. For those of you who want to follow the evolution of the topic of personalized nutrition through nutritional genomics, there is a nice article that appeared in Nutrition Reviews in 2007 titled “Personalized Nutrition: Nutritional Genomics as a Potential Tool for Targeted Medical Nutrition Therapy.”4 The authors of the review say that the best area we have now to apply this concept (looking at various SNPs as a family of gene uniquenesses) is in cardiovascular disease risk evaluation and coronary artery disease risk. In the August 2, 2007 issue of the New England Journal of Medicine, there was a multiple-authored paper that looked at modern genotyping and the analysis related to coronary artery disease risk.5 There are a variety of gene SNPs that cluster together (in fact, there were nine loci that were strongly associated with coronary artery disease) which had less than a 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} chance of being falsely positive. You can see that this field is starting to emerge to be pattern recognition rather than looking at single genes at a time. In this case, nine loci, when together, give rise to increasing relative risk to coronary artery disease. I want to emphasize that these genome-wide association studies are looking at risk related to families of genes that seem to encode for altered physiological function and give rise to relative increasing risk to various diseases. Cardiovascular disease is probably the one that we now know the most about. I think we will follow this very closely in FunctionalMedicine Update. Now let’s move from the abstract to the clinical reality. Where does this information take us in terms of nutritional endocrinology? What it says is that we really cannot, at this point, define specifically the genomic risk that a patient may have and the relative specificity of his or her nutrient needs based upon a genome screen to optimize endocrinological function. But we can use inferences from family and personal health history, from various types of traditional endocrinological markers, and from some endocrinological stress tests. Taken together, these elements would paint a picture-a mosaic-of that patient, and then we would use, in part, a slightly empirical diet approach by modifying the diet and following the patient’s response to that diet. I’m going to take this concept and specifically focus on metabolic syndrome, just to show you how this works. Is there the perfect diet for all patients with metabolic syndrome or hyperinsulinemia? Obviously, from what I have just said, if there is a variegated genotype for any condition, then there may not be a single diet that is optimal for all people within that family; there may be variations on a theme. I think that is part of the bane of our approach, but it is also part of the beauty because it allows us to have the diversity (or let’s call it plasticity) of clinical approaches based on the patient presentation. You may say, “How do I know what the right diet is?” Part of finding the answer is to start with what you think is as close to the center of the bull’s-eye as possible. If you don’t hit the center, then modify it slightly and use an iterative approach (working with a patient to get optimal outcome). With that as a conceptual framework, let’s get more specific. Let’s ask the question that I was asking, in part, in the audio course Beyond Metabolic Syndrome: Is there an optimal diet for metabolic syndrome? Or, what are the diet diversities that are useful for the clinical management of the patient? I’m very pleased to say that after I did this audio course, both the New England Journal of Medicine, and more recently the AmericanJournal of Clinical Nutrition, followed up with papers that supported the thesis I had presented. The title of the paper I am going to be reviewing is “Comparative Review of Diets for the Metabolic Syndrome: Implications for Nonalcoholic Fatty Liver Disease.”6 I think this is a very good article for those of you who want to dig a little deeper; it’s got an excellent bibliography. This was work that was done at the Department of Food Science and Technology at the University of California, Davis, and also the Nestle Research Center in Lausanne, Switzerland. The researchers used NASH as a marker for severe insulin resistance. People with NAH generally have triglyceride accumulation within their livers and elevated liver enzyme profiles. It used to be a very esoteric condition back when I was in my training. I recall that it was thought of as a very unusual situation. But now we are seeing it more and more, even in adolescents. It is not unusual to see modest elevations of liver enzymes that are not associated with hepatitis or cirrhosis of the traditional type. In this particular article, what the researchers are looking at is elevated liver enzymes associated with non-alcoholic fatty liver disease. This condition has been speculated to now affect (and I know this number, for those of you not familiar with it, is going to shock you) 70 million Americans. Seventy million Americans (which is 30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the adult population, by the way) have evidence of non-alcoholic steatohepatitis. Let me just let that set in for a minute. I wasn’t in school that long ago. I started in ’66 and finished in ’70 with my PhD. For maybe some of you that sounds like a lifetime ago, but for me it doesn’t seem that long. If I would have said that something like 70 million Americans in 2007 were going to have this condition back in the ’60s, I probably wouldn’t have gotten farther than being in school; I would have never graduated because I would have been considered more polemic than I actually already was. I think that this is a pretty staggering number. An estimated 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of these individuals end up having the severe form of non-alcoholic fatty liver disease, which is this NASH condition. So, 70 million total with nonalcoholic fatty liver disease, of which 20{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of these individuals have NASH, which increases relative risk to not only severe type 2 diabetes and cardiovascular disease, but also liver failure and the need for liver transplant. The question is what diet should these patients be on if this is a marker for insulin resistance and hyperinsulinemia? This question is the focus of this particular paper. There is some really interesting supporting information that follows directly from what I was speaking to in the Beyond Metabolic Syndrome audio course that I discussed earlier. The issue can be described by comparing the lipotoxicity model as contrasted to the glucotoxicity model. Lipotoxicity is the infiltration of fat (triglyceride) within tissues that normally don’t accumulate fat. We know that the adipocyte cell (the fat cell) is evolved to accumulate fat. That is where fat is normally found: the subcutaneous or visceral adipocyte. But when fat ends up spilling over out of the adipocyte, it ends up going into places where it normally shouldn’t be and in high levels, which include liver cells, muscle cells, and pancreatic beta cells. This is called lipotoxicity. Fat can also get into the cardiac endothelium and into the vasculature. These conditions that are associated with NASH are reflective of fatty spillover and triglyceride imbalances, and have been called lipotoxicity (or fat toxicity). What are the dietary treatments? First of all, you might say, “Shouldn’t we be cutting total fat down in the diet because it’s a fat problem?” Remember, the fat problem comes from an insulin-driven mechanism. It is not necessarily that a person was just consuming a huge amount of fat in their diet (although there is strong evidence that high saturated fat diets aggravate, as you might expect, the non-alcoholic steatohepatitis and non-alcoholic fatty liver disease). Certainly you want to cut down saturated fat. Of the fats that remain in the diet, however, clearly you want to increase-what do you think? Being a student of FMU, you immediately say, “Omega-3 fatty acids.” And that’s right. Omega-3 fatty acids (the eicosapentaenoic, the alpha-linolenic, and the docosahexaenoic acid family of omega-3 fatty acids) have been found to be good sources of lipids in nonalcoholic fatty liver disorders to improve insulin sensitivity and reduce (paradoxically) fatty liver infiltration, so here is a fat that lowers a fat, basically, is what the clinical evidence would suggest. What do we want to stay away from? Partially hydrogenated trans-vegetable fats, because they increase fatty liver infiltration and increase insulin resistance, says the data. How about glycemic index? Glycemic index is a very important determinant of relative severity of nonalcoholic fatty liver disease, so what do we think? Low glycemic index, right? And low glycemic load. Now, you might say, “Well that means taking carbohydrate out of the diet.” It may mean that, but it probably means preferentially taking white carbohydrate out of the diet because that seems to have the highest glycemic response. The fiber-rich flotsam-and-jetsam-containing whole grain carbohydrate generally has a much lower glycemic index than the highly refined, white, “close-to-godliness” type of carbohydrate. It is, again, increasing the fiber, decreasing the white carbohydrate (the highly refined carbohydrate). What about sucrose and fructose? That’s a very interesting question. There is still some interesting controversy about glucose, sucrose, and fructose. I think we can say, just as a general rule, too much simple carbohydrate increases lipotoxicity in a person with nonalcoholic fatty liver disease. What is too much? Does that mean take all simple carbohydrate out of the diet? No honey, no fruit? The answer is no. It really means when you get above a threshold where you are using additive amounts of white carbohydrate (meaning, simple sugars), you start to get into a problem (this is where we start getting up into the hundred pounds per person per year of added sugars). So then you might say, “Is there a difference between fructose and sucrose and glucose?” The answer is yes. The real problem may be high fructose-containing corn syrup sweeteners (soft drinks have moved from sucrose as the sweetener into high fructose corn syrup sweeteners), because it is not just fructose alone, it is fructose in combination with a variety of other partial hydrolyzed oligosaccharides and monosaccharides that come in high fructose corn syrup sweetener. You can get a lot of simple carbohydrate very conveniently in liquid sugar as high fructose corn syrup sweeteners, so I think getting soft drinks out of the diet obviously is a very, very big issue. Getting synthetic sweetener-added materials out of the diet is very important, but again, it doesn’t mean cut out fruit. There is an interesting recent report that looked at sugary drinks linked to insulin resistance (this was a component of the Framingham Offspring Study examining the effects of sugar-sweetened drinks, diet soda, and fruit juice consumption on insulin sensitivity in 2500 subjects).7 The study found that people who consume no sugar-sweetened drinks had fasting insulin of 188 pmol/L compared to 206 pmol/L for those drinking at least 2 servings of sugar- sweetened drinks per day. Sugar-sweetened drink consumption was not associated with a change in fasting glucose, and the author concluded that in these healthy adults, sugar-sweetened drink consumption appears to be unfavorably associated with surrogate markers reflecting hepatic, more than peripheral, insulin sensitivity. Of course, that’s what nonalcoholic fatty liver disorder is. It is an hepatic insulin insensitivity, right? So you may not see it, peripherally, but it is happening in the liver and that has been leading to the accumulation of fat in the liver. This study is pointing a finger towards soft drinks and bringing into question the health of kids who are going after school (or whenever) and getting these huge containers of soft drinks that they always seem to carry around; these kids are candidates for nonalcoholic fatty liver disease. Getting away from the additive sugary drinks is another part of diet modification. What about protein? It is interesting because this question is about both protein quantity (I mean, the percent calories as protein) and also protein quality. Is there a difference between, say, vegetable protein and animal protein? Is there a difference between cooked protein (like charred protein) versus baked protein or broiled protein. We have all sorts of interesting questions about dairy protein, egg protein, vegetable protein, animal protein. Is there a difference between fish and beef? This is a pretty interesting topic because each one of those sources of protein carries different information to the genomic receptor system. Did you hear what I just said? Each one of those different proteins carries different information to the genomic receptor systems. That idea is probably flying in the face of everything you learned about gastric physiology and digestive physiology. What we learned early on was that proteins are all broken down to their requisite amino acids before they are absorbed, and therefore it doesn’t matter, really, about the source of the protein because in the end they all end up in their building blocks anyway. What we have learned over the last 10 to 15 years is that this story of digestive physiology is only partially correct. There are intact, proteomic fragments that are released by partial digestion and by pepsidases in the gut. These proteomic fragments may have effects on receptor sites within the GI epithelium, which sends signals to the body and they may be immune stimulant. Or they may be perceived as foreign invaders and initiate an inflammatory response. Or they may be proteomic fragments that (by micropinocytosis and in-cell vesicle formation) get absorbed into the blood at such a level at to induce, then, action at a distance (systemic effects, because they still have information content within them). So, these different proteins are not necessarily inducing the same effects upon the enteropatic system or on the gastrointestinal associated lymphoid tissue system. I think we should not just generalize, and say “percent calorie protein” and assume that all proteins have the same impact on endocrine regulation-it’s just not true. Many papers have demonstrated that vegetable protein and beef protein, for instance, have different effects on postprandial glycemia and insulin levels. So it is a more complicated topic than just saying, “Well, let’s get the proper percent calorie/carbohydrate, fat, and protein.” Within each of those compartments of macronutrients, there are a variety of different effects on the endocrine signaling system based upon the personality of the fat, or the personality of the protein, or the personality of the carbohydrate. Is simple carbohydrate different in its information signaling than a complex carbohydrate at the same caloric amount? Yes. So is vegetable protein different in its signaling, at the same number of calories, as dairy protein (let’s say, casein)? And the answer is yes, it is. So the point I am trying to get you to understand is that when we are designing a diet to modulate nutritional endocrinology and insulin sensitivity in the patient, we must be mindful not only of the percent calories of each of the macronutrients, but the personalities that each of those components have on modifying gene expression and the phenotype of the patient. I hope this is getting through because, you might say it is in the complexity of understanding that ultimately better clinical specificity will result. Some patients don’t do well on a high protein diet because you didn’t choose the right protein. Other people don’t do well on a high carbohydrate diet because the carbohydrate that was chosen may have contained some fragment, like a glutinous grain protein, that had an adverse effect on their immune system and induced an increase in their insulin levels Whereas if you change to another vegetable protein, maybe you would have a favorable effect. So it is, again, really looking at the patient and their individual response. Going back to diets for metabolic syndrome and nonalcoholic fatty liver disease paper that I was describing, the authors say that one of the most beneficial diets for patients with nonalcoholic fatty liver disease and metabolic syndrome is the Dietary Approaches to Stopping Hypertension (or the so-called DASH diet). The DASH diet is a diet that has a high amount of fresh fruits and vegetables, whole grains, minimally processed, low-sodium foods, lean cuts of meat and fish, and increased omega-3 fatty acid intake. So this concept that carbohydrates are bad with nonalcoholic fatty liver diseases is not necessarily true if the carbohydrate is built into the context of the proper diet with the right signaling molecules present. The authors go through and discuss the Atkins diet, and the Ornish diet, and the Zone diet, as well as the Weight Watchers and the South Beach diets, and ultimately they come to a specific recommendation. I was very pleased to see that the specific recommendations they are describing are almost exactly coincident with the recommendations I derived in the Beyond Metabolic Syndrome course. It looks like we are all following the same lead. An interesting add-on to the above article is a paper titled “Low Carbohydrate Nutrition and Metabolism,” also published in the American Journal of Clinical Nutrition.8 In this article, the authors say that this persistent epidemic of obesity and type 2 diabetes suggests that nutritional strategies are needed if the epidemic is to be overcome. I think we can all agree with that. And they go on to say a promising nutritional approach is to be engaged in carbohydrate restriction. Then they go through this whole discussion of how recent studies indicate under conditions of carbohydrate restriction, fuel sources shift from glucose and fatty acids to fatty acids and ketones and that ad libitum-fed, carbohydrate-restricted diets lead to appetite reduction, weight loss, and improvement in surrogate markers of cardiovascular disease. That’s all true. There is nothing I just said that is in this thematic review that would be considered untrue. But what I found philosophically disagreeable in this article is that they never differentiate the type of carbohydrate. They never talk about all that flotsam and jetsam that comes along with a partially processed, mostly unrefined, carbohydrate-rich diet. Nor do they address the things we call phytochemicals, and accessory nutrients: flavonoids, polyphenols, and the whole rich array of things that come with a modestly refined diet. This kind of a natural diet has signals that it sends to these gene receptors beyond that which you get from a diet of white. To not differentiate in this article between a carbohydrate diet that has high information content (i.e. minimally processed, phytochemically rich diet) and a carbohydrate diet that is highly processed and sending only carbohydrate calories as white, is to me (in this day and age of nutritional genomics) irresponsible. It looks like it is speaking to something that we have gone by, passed by, the door/threshold has been crossed, and we shouldn’t be going back over it. So, this review paper, to me, on carbohydrate restriction, which does not mention anything related to phytochemicals that are found in a minimally processed, high complex carbohydrate diet, is irresponsible. I would rather champion the theme that was developed in the comparative review of diets for metabolic syndrome article that I described earlier that takes into account the full array of information molecules that modulate nutritional endocrinology in patients. In the past, we have looked at various ways of evaluating the impact of diet on the endocrine system, including using lipid markers. Of course, the most common lipid markers used in clinical practice are triglycerides (cholesterol), and if you are going to fractionate a cholesterol lipoprotein panel, you look at things like HDL and LDL. We know that as a surrogate marker for metabolic syndrome, elevated triglyceride-to-HDL ratio is associated with increasing relative indication of insulin resistance. As we get above 3-to-1 triglyceride-to-HDL ratio (so 4-to-1, 5-to-1, 6-to-1, and so forth), it indicates increasing relative risk to metabolic syndrome/insulin resistance (until you get up to 10-, 11-, and 12-to-1, and then you get in a frank type 2 diabetes-type of situation). So we have used this, clinically, as a marker. Within the last few issues of Functional Medicine Update, I have discussed other surrogate markers that may be earlier warning signs of alteration in the endocrinological pattern that leads to risk to nonalcoholic fatty liver disorders (or NASH, or even diabetes). One of those I talked about was the use of the apolipoprotein A-I-to-apolipoprotein B ratio. Remember the apolipoproteins are the protein fragments, or protein components, of these lipids that we measure in the blood that we call LDL, HDL, VLDL, IDL, or cholesterol. Cholesterol is a fat, and therefore it doesn’t circulate in the blood, which is principally water, in the absence of some transporter (something to move it along, to carry it, that is able to solublize it). We call that an emulsifying agent, or a detergent (if you want to use washing your clothes as an example). A detergent washes the oil out of your clothes by tricking it into thinking that it is like oil and getting it into the water; that is an emulsifier. The emulsifiers in our blood that help to allow cholesterol and fats to circulate are called apolipoproteins. They have names like apolipoprotein A, B, D, E. Lipoproteins are formed in the liver as a consequence of different endocrinological signals. If you have high estrogen, you get a different family of apolipoproteins formed than if you have high androgens. Or if you have high insulin, which is an endocrine hormone, you have different lipoproteins formed than if you have lower or normal insulin. Some people have said that the early precursor marker for dysfunctional nutritional endocrinology is to look at the apolipoproteins that then later get into the pathological states of altered serum lipids and altered tissue lipids. Apolipoprotein A-I-to-apolipoprotein B ratio can be analyzed by a laboratory. When this ratio is reduced (when you have a low level of apo A-I-to-apo B), there is an increasing risk to cardiovascular disease associated with metabolic syndrome; this has been called cardiometabolic syndrome. To put things in context, recently a paper appeared in the Journal of the American Medical Association titled “Clinical Utility of Different Lipid Measures for the Prediction of Coronary Heart Disease in Men and Women,” which looked at apolipoprotein A-I and apo B as predictive markers for cardiovascular disease.9 This particular study looked at all patients and did not screen for those with insulin resistance. In this large, population-based cohort (minus a propective screen), the overall performance of apo B-to-apo A-I ratio for prediction of coronary heart disease was comparable to that of traditional lipid ratios, but did not offer incremental utility over cholesterol HDL ratio. The study authors concluded that the data do not support measurement of apo B-A-I in clinical practice when total cholesterol and HDL measurements are available. I think that conclusion is correct if you look at all patients, but the question we should ask is how about if you segment for those patients with insulin resistance? Would you get higher diagnostic specificity and predictive value if you measured apo A-to-apo B-I ratios in those patients who were the subset of people at cardiovascular risk, who had lipotoxicity and metabolic syndrome? I just want you to understand that this is an area of some controversy. I believe that the combination of cholesterol HDL ratio, and triglyceride HDL, and apo B-to-apo A-I ratio gives a more composite view of the endocrinological state of the web, and allows you to titrate, then, the nutritional status of the patient to improve outcome. With that in mind, let’s take this concept of nutritional endocrinology and move into looking at vitamin D and how, as a nutritional endocrinological agent, it modifies function.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Michael Holick, MD, PhD Boston University 732 Harrison Avenue, 2nd Floor Boston, MA 02118 We’re at that portion of Functional Medicine Update again that I know you look forward to-so do I. It’s our clinician or researcher of the month and this month we are fortunate to have one in the same. He is both a researcher and a clinician. He has a PhD in biochemistry, as well as an MD. You know him because his name is in the news all the time and he has also been very kind to be a previous clinician of the month on Functional Medicine Update. He is also the recipient of the 2007 Linus Pauling Award, presented by the Institute for Functional Medicine.. I’m speaking of no one other than Dr. Michael Holick. The name, I’m sure, is very familiar to you. I want to give you a quick update without going into the really dramatic and voluminous accomplishments that Dr. Holick has had over his years of contribution, both as a scientist and as a clinician. He was educated at Seton Hall originally, with a BS in chemistry, and went on to get his PhD and MD at the University of Wisconsin, where he worked within a world-renown group in the area of vitamin D, that of Dr. Hector DeLuca. In 1970, Dr. Holick published a paper with his colleagues that would be considered a landmark paper, which he may mention because it is the start of this vitamin D story (from a publication perspective). This is the paper that appeared in Biochemistry that year titled “21,25-dihydroxycholecalciferol. A Metabolite of Vitamin D3 Preferentially Active on Bone.”10 That is probably a pretty good place for us to start. Dr. Holick is a research professor as well as a professor at BU Medical School in the area of bone. He also works in the area of dermatology. Michael, I’d like to start the discussion, if you would, talking about the evolution of this anti-ricketic vitamin (which is the way many of us learned of it in school) to become a major part of the story of nutritional endocrinology. You were really at the forefront of this. Could help us understand how that intellectual evolution occurred? MH: Well, once again, Jeff, it is a real pleasure to be on your program. I think the information that you have been getting out to physicians for so many years, you know, has just been so crucial in patient care, and I really congratulate you and your colleagues for a really outstanding job. In terms of vitamin D, you are quite right. I mean everybody had thought that vitamin D, the anti-ricketic vitamin, is for the prevention of rickets in children. We don’t see rickets in children anymore, and so we really have not thought of vitamin D deficiency as a significant health problem. But in 1970 and 1971, we began to appreciate that once you make vitamin D in your skin or you inject it in your diet, that it has to go to the liver, and it is converted to 25-hydroxyvitamin D; it’s the major circulating form. But it, too, is biologically inactive, and must go to your kidneys, where it gets activated to 1,25-dihydroxyvitamin D. It is 1,25-dihydroxyvitamin D that is the biologically active form of vitamin D, and it interacts with specific receptors in the intestine, bone, and kidney to regulate calcium, phosphorus, and bone metabolism. A Major Vitamin D Breakthrough The major breakthrough, however, came when we began to appreciate, as early as 1979, that every tissue and cell in your body has a receptor for vitamin D. And so you have to ask yourself, why would Mother Nature put receptors in your skin, brain, heart, and pancreas if they weren’t having a function? That led, then, to a very interesting observation by Dr. Suda. What he found was that pre-leukemic cells (and leukemic cells) had a vitamin D receptor, and when you incubated leukemic cells with the active form of vitamin D, not only did it inhibit their growth, but it induced them to become mature and to terminally differentiate. One clinical application for this observation was made by us in the mid-1980s when we showed that not only do skin cells have a vitamin D receptor, and that skin cells respond to active vitamin D by inhibiting proliferation and inducing maturation, but that when we topically applied 1,25-dihydroxyvitamin D to patients with psoriasis, a skin disease that afflicts probably about 1 to 2 percent of the world’s population caused by an overproliferation of skin cells, that it was effective in basically treating that disease. And so active vitamin D compounds are now used as a first-line treatment for psoriasis. The Link between Latitude and Cancer Incidence And one final comment in terms of the endocrine aspect: What has always been puzzling, and has been a remarkable observation, is that as early as 1941, it was appreciated that if you lived at a higher latitude in the United States, such as Massachusetts, New York, or Vermont, you were more likely to die of cancer than if you lived down south, like in Georgia, South Carolina, and Texas. It was speculated by Dr. Apperly in 1941 that by being exposed to sunlight, and even if you developed non-lethal (non-melanoma) skin cancer, it somehow imparted an immunity to prevent you from developing more deadly cancers. And we now know why. The other major story in the vitamin D field now is not only do your kidneys activate vitamin D, but it appears that most tissues in your body also have that capability. But it does it in a very clever way. What happens is that as you raise your blood levels of 25-hydroxyvitamin D, the molecules go to cells, and these cells can then activate it to 1,25-dihydroxyvitamin D, which will probably modulate cell growth and have a wide variety of other cellular effects. It has been estimated up to 200 different genes are controlled by 1,25-dihydroxyvitamin D. But what the body cleverly does, is that after 1,25-dihydroxyvitamin D does all of these functional activities within the cell, it then induces its own destruction, and therefore, it has no effect on calcium metabolism, nor does it have any effect on your blood levels of 1,25-dihydroxyvitamin D. So the bottom line is that we now know that not only is vitamin D critically important for bone health throughout life, but probably it is incredibly important for prevention of common cancers, has major effects on the immune system, and also has major effects on our cardiovascular system. JB: There are so many pearls that you put into that introduction. That is the most dense introduction I think we have had. It’s amazing how many ways we could go in the next question. I will start with a common theme that I’m sure is on the mind of many people. In school, we learned that vitamin D is a fat soluble vitamin like vitamin A, and if you give a little bit too much you get toxic, so we have always been very reserved about vitamin D. Tell us a little bit about the toxicity story. Vitamin D Toxicity MH: Sure. I’ll put it, again, into perspective because you are quite right. I mean, I always joke about this when I give my presentation. That is, I always tell the physicians in the audience that the one thing they probably remember from medical school more than anything else is: don’t ever make your patient vitamin D intoxicated. Now they have never seen vitamin D intoxication. They probably don’t even know what vitamin D intoxication is. But if I tell physicians to treat their patients with 50,000 units of vitamin D, they just look starry-eyed and they are concerned that they are going to cause vitamin D intoxication. And this actually comes about because in the 1950s there was an outbreak of hypercalcemia in infants in Great Britain and they related it to overfortification of milk with vitamin D (although that was never proven). And based on that observation alone, in Europe, they passed laws forbidding vitamin D fortification in most dairy products, which continues to be on the books today. But that concept has so permeated the medical community-that everybody is concerned about vitamin D intoxication-but what we now know, based on Dr. Vieth, and Dr. Heaney and our own work, is that you can give as much as 10,000 units of vitamin D a day for at least a half a year and not see any untoward toxicity. Typically, vitamin D intoxication occurs when you are taking more than 50,000 units of vitamin D daily for at least 6 months to a year. I’ll give you one example. We saw a case where a gentleman was taking a vitamin nutrient that he had purchased off the internet. The company had forgotten to dilute it. He was taking a million units of vitamin D a day. He was severely vitamin D intoxicated. JB: So if a physician is measuring in their patient that they are supplementing with D-they are measuring their serum calcium and their 25-hydroxy D levels and they are within normal range-can we assume they are not toxic? MH: Unequivocally. If fact, by definition, vitamin D intoxication is a markedly elevated level of 25-hydroxyvitamin D, and typically it is above 150 nanograms per mL. So even though the normal ranges are coming back from laboratories at 20 to, say, 100 nanograms per mL, that is only for safety reasons. But we typically don’t see vitamin D intoxication until they are above 150 to 200 nanograms per mL. So if the calcium is normal, with a level of 25-hydroxyvitamin D even of 1,25, that would not be considered to be vitamin D intoxication. JB: So let’s go back to your previous–really eloquent–point concerning this emerging understanding of how 25-dihydroxy can be converted in situ, even away from the kidney, into the 1,25 and then how that can be detoxified within the cell. That raises the question, what plasma level of 25-hydroxy do you need to get into in order to drive 25-hydroxy into these tissues that might have benefit in terms of the conversion into 1,25, or do we not know the kind of range? Optimal Range of Vitamin D MH: It is an excellent question. Most experts are now agreed that at a minimum, your patient should be above 20 nanograms per mL. But we now are considering you to be insufficient between 20 and 29 nanograms per mL. It is only when you get above about 30 nanograms per mL do we believe that all of the benefits of vitamin D can occur in the body. I’ll give you one example. There was a very nice study published by Dr. Liu, Dr. Meinken, and Dr. Adams in Science in March of last year.11 What they observed was the following. It has always been known that macrophages activate vitamin D. They convert 25-hydroxy D to 1,25-dihydroxyvitamin D, and that is the reason for the hypercalceuria and hypercalcemia seen in patients with sarcoidosis. But we have never understood why these macrophages activate vitamin D. Well, they proved why. It turns out that when a macrophage becomes infected (say, with TB, for example), what it does is it immediately upregulates the toll-like receptors, and the toll-like receptors get turned on in the macrophage. And the gene that gets turned on first is the enzyme to convert 25-hydroxy D to 1,25-dihydroxyvitamin D. Then the obvious question is, why is the macrophage making it? It turns out that 1,25-dihydroxyvitamin D tells the macrophage to increase the gene expression for cathelicidin, which is a peptide that specifically is made by the macrophage to kill infective agents, including tuberculosis. So they cleverly went ahead and did the following study. They took African-American blood, which typically runs in the range of about 8 to 10 nanograms per mL. They added monocytes and TB, and showed that the TB infected the monocytes and killed them. They then took they same African-American blood and added to it 25-hydroxy D, and raised it to the level of about 26 to 30 nanograms per mL. They showed that those monocytes made 1,25-D, increased the production of cathelicidin, and killed the TB. So this proves that indeed you need to raise your blood levels of 25-hydroxyvitamin D, at least to 30 nanograms per mL to get the full benefits of vitamin D. JB: Well that is really a fascinating observation, so here’s the connection between the endocrine and immune system as it relates to vitamin D physiology. That raises a question in my mind about periods of a person’s life where they may be more temporally at risk to vitamin D insufficiency. I’m thinking pregnancy. I know that you have recently-in May of this year, 2007-your group published a paper in the Journal of Clinical Endocrinology and Metabolism that looked at maternal vitamin D deficiency and the risk to preeclampsia.12 I think that followed on a paper that I saw in the Journal of Nutrition in February of 2007-Bodnar’s group, et al.-looking at the high prevalence of vitamin D insufficiency in black and white pregnant women residing in the United States and their neonates.13 Tell us a little bit about the pregnancy-vitamin D connection. Pregnancy and Vitamin D MH: Sure. Yes, in fact, we had published also, in January of this year. We looked at 40 mother-infant pairs at our medical center, and looked at their vitamin D status at the time that mom gave birth.14 Seventy-five percent were African-American; twenty-five percent were Caucasian. We found that 76{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of moms and 81{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of infants, at the time of birth, had a blood level of 25-hydroxyvitamin D of less than 20 nanograms per mL. Most of these women were taking a multivitamin (a prenatal vitamin) that contained 400 units of vitamin D, and drank (on average) 2.3 glasses of vitamin D-fortified milk a day, and they and their infants were still vitamin D deficient. Lisa Bodner also has confirmed this. In fact, you are right. It was, in fact, Lisa Bodner, who made the observation, and we helped her with that, in showing that when you look at the incidence of preeclampsia and relate it to the blood level of 25-hydroxyvitamin D in the mom, that the higher the 25-hydroxyvitamin D, lower was the risk of developing preeclampsia. I have recently talked with many of my OB/GYN colleagues, and they made a very interesting comment. They said, “You know, we see preeclampsia principally in the winter and early spring.” And that is at the time when the moms, of course, are not getting any vitamin D and are at the highest risk of having severe vitamin D deficiency. So there may be a very significant association with the two. And it also made one other kind of connection with the immune system, and that is that there has been this concept out there-Hope-Simpson was a physician, and in the 1980s he had suggested that it is curious that influenza occurs at the equator sporadically throughout the year, but influenza only occurs in temperate climates in the wintertime. He had suggested that there was a seasonal stimulus for this. Dr. Cannell and several other experts, including myself, wrote a recent paper to suggest the possibility, at least, that maybe indeed that seasonal stimulus is vitamin D deficiency.15 You become vitamin D insufficient and deficient around October/November because you no longer can make any vitamin D in your skin. This was followed up by a very nice study by Dr. Aloia, who looked at African-American women receiving 2000 units of vitamin D a day compared to a group receiving only 400 units of vitamin D a day, and looked at their risk of developing upper respiratory tract infections throughout the wintertime, and showed a dramatic-almost 90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}–reduced risk of developing upper respiratory tract infections in the women that were taking 2000 units of vitamin D a day.16 Vitamin D is Linked to Many Conditions JB: So that, then, leads to kind of an interesting general question. If vitamin D has this great array of impact on cellular function, then it might suggest that there would be a connection between vitamin D nutriture and physiology and overall longevity because we are talking about so many diseases. And, of course, this year in Archives of Internal Medicine we learned a little bit about that.17 Could you tell us that connection? MH: Yes, it is a very interesting study. They looked at a large number of studies and looked at the vitamin D intake and then evaluated those manuscripts for longevity. What they concluded was that there was about a 7{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} increase in longevity for those that had the highest intake of vitamin D. Turning it around another way is that there was a 7{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduced risk of dying if you increased your vitamin D intake. JB: These all sound extraordinarily positive, and, in fact, I saw a report that appeared-actually a couple of reports-since you gave your stellar performance and presentation at the Institute for Functional Medicine Symposium in May of 2007 that talked about vitamin D nutriture and type 2 diabetes risk, and even (maybe) metabolic syndrome and insulin sensitivity, so there is a whole other area of clinical implication. But then I thought I saw a report about a month ago that said that investigators found no association between vitamin D status and autoimmune disease, which I found kind of contradictory to some of the trajectory that we have been seeing in the literature before. Do you have any comments about the diabetes/vitamin D and the diabetes/autoimmune connection? MH: Sure. What we can say for sure is that there was a very interesting study that was published in 2001 by Dr. Hypponen.18 And what she did was she looked at children in Finland in the 1960s that were routinely getting 2000 units of vitamin D a day (that was what the recommendation was at that time) during the first year of life. And then she looked at their medical records for the next 31 years, and looked at their risk of developing type 1 diabetes. And she concluded that there was an 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduced risk in those children that took 2000 units of vitamin D a day during the first year of their life. The children that were vitamin D-insufficient had rickets, had a 2.4 fold increased risk of developing type 1 diabetes. We know that beta eyelet cells have a vitamin D receptor. We know that if you incubate beta eyelet cells with the active form of vitamin D it stimulates those cells to make insulin. And since it is believed that this autoimmune disease for type 1 diabetes may in fact be due to a viral infection, that being vitamin D-deficient may increase your risk of that infection, and because vitamin D plays such an important role in both T and B cell function, that, in combination, may be the explanation for why vitamin D has been protective for type 1 diabetes. Regarding type 2 diabetes, it is probably a little bit different story. Like I said, we know that 1,25-D will stimulate beta eyelet cells to make insulin. And there is some evidence that your fat cells have vitamin D receptors. We don’t exactly know why, but it may very well be that part of the insulin resistance that is seen, especially in obesity, may in part be also due to vitamin D deficiency. Obesity is associated with vitamin D deficiency because the body fat sequesters the vitamin D and doesn’t make it bioavailable to the body, and so typically obese people probably need twice as much vitamin D. So there are now several studies underway in patients with type 2 diabetes, and we are doing one of them, to see whether or not increasing their vitamin D intake to levels where we are getting the 25-hydroxy D above 30 nanograms per mL will be of any benefit. JB: And how about the autoimmune/rheumatoid arthritis/multiple sclerosis connection with vitamin D? Is that still in an area of controversy? MH: Yes, it’s a good question. Again, it is curious, but true. If you are born above about Atlanta, Georgia, and live there for the first ten years of your life, you have a 100{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} increased risk of developing multiple sclerosis for the rest of your life, no matter where you live. People have always thought that multiple sclerosis may, in fact, occur either in utero or during early childhood, and may be, in fact, due to an infectious disease. You know, we just don’t know what MS is due to. But there is a study done by a group where they looked at both men and women in the armed forces and their vitamin D intake and their relative risk of developing multiple sclerosis, and concluded that there was about a 40{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} decreased risk of developing multiple sclerosis, especially in women who were taking in more than 400 units of vitamin D a day. And then a more recent study by the same group suggested that both men and women had a lower risk of developing MS the higher their 25-hydroxyvitamin D was, so that the two were indirectly related.19 JB: I’d like to go just one step farther in your discussion about diabetes to look at the unfortunate epidemic that we are dealing with in medicine and health, which is renal failure and renal dialysis, which the centers are now growing rapidly to meet the growing need of people with renal failure. So that raises a question about the vitamin D status of people who are in renal failure. I know that Amgen has a new drug out called Sensipar® that is a calcium agonist for managing problems with hypercalcemia, renal dialysis patients, and hyperphosphatemia. What is the status on a person with kidney problems and their vitamin D physiology? MH: Yes, there are a couple of things going on. We believe that all patients with renal failure, no matter what the stage of the renal failure is, need to have a 25-hydroxyvitamin D of greater than 30 nanograms per mL. There are two reasons for it. The first is that we now know that the parathyroid glands also can activate vitamin D, and that they can make 1,25-dihydroxyvitamin D locally to suppress PTH production. And as you are well aware, patients with mild to moderate renal failure begin to develop secondary hyperparathyroidism. The second reason is that by raising your blood levels of 25-hydroxyvitamin D, it may have all these additional benefits on the body for patients who have stage 4 and 5 may be on renal dialysis and taking an active vitamin D analog or even the active form of vitamin D, calcitriol. Many physicians think that that is all that they need; that they are maintaining their vitamin D status. They are not. They are certainly satisfying the calcium and bone metabolism part of the equation, but they are not taking advantage of the local production of 1,25-dihydroxyvitamin D made in all the tissues in the body, including the parathyroid glands. Because it is likely that that production is making the concentration of 1,25-dihydroxyvitamin D within the cell much higher than it would ever be by giving it exogenously, either intravenously or orally, for preventing metabolic bone disease and secondary hyperparathyroidism. So, for example, pericalcitol, or calcitriol (given orally or intravenously), won’t raise target tissue levels to those degrees. JB: That’s fascinating. That’s very, very helpful. That’s, I think, one of the areas where there seems to be quite a bit of misunderstanding within the field of vitamin D nutriture. I have talked to a number of diabetologists and nephrologists and it seems like that is still an area of confusion. MH: Yes, and so the bottom line is that for everyone there is never a reason not to have a 25-hydroxyvitamin D above 30 nanograms per mL unless you have a chronic granulomatous disorder, such as sarcoidosis, in which case, you have to be a little bit more careful because of this extra renal production (the macrophage production) of 1,25-D that can get into your bloodstream. Plant Cognates of Vitamin D JB: One last question, and this is kind of a wild card question. A number of years ago-this is probably now 20 years ago-I recall meeting a biochemist/investigator by the name of Saul Wasserman who was doing work in animal science in hypercalcemia in animals that were grazing animals. He discovered (found) what he thought was a plant cognate of vitamin D that (if animals grazed on these plants and had this vitamin E analog) would create a condition that was hypercalcemia in those animals leading to joint calcification, soft tissue calcification, and then they would not be able to bend over and they would die of starvation. Are there, as far as you know, any plant cognates of vitamin D from certain plant foods? MH: Right. It’s a very good question. It turns out that as early as 1920, when they were starting to irradiate animals with ultraviolet light and sunlight, if you irradiate grass, if you irradiate, say, rye grass, you can, in fact, make the grass make vitamin D2 and vitamin D3. The observation by Dr. Wasserman–in fact, we made a similar observation and had published it almost simultaneously with him-is the plants called solanum, which are relatively toxic, make a 1,25-dihydroxyvitamin D that has attached to it a line of sugars.20 And it is because the cattle were ingesting such huge amounts of this compound and the sugars were removed in their gut, that they became severely hypercalcemic. But there is little evidence that most of the plant foods that we ingest have any of the active form of vitamin D, and it is really only tiny, tiny amounts of vitamin D because they have not been exposed to a lot of ultraviolet radiation. JB: Very interesting, and the solanum family is like potato, eggplant, and tomato, is that correct? MH: Exactly correct. JB: So I’d like to close with a philosophical question. This, I think, is almost like asking the obvious, but I’d like to get your very sage perspective, and that is, from all that you have said and published in your years of contribution to the field, it would seem, to the outside observer, that if there was a drug that had been developed by a pharmaceutical company that would accomplish all the things that vitamin D has been ascribed to be beneficial for that it would be a blockbuster drug and that company would be mega-successful and it would be a high investment opportunity on the stock exchange. But yet, we are still seeing reluctance to accept a lot of this information that you have shared within medicine as clinically valuable. Would you like to share your opinion as to why? Recommendations for Supplementation and Sun Exposure MH: Sure. I think that the problem is that they consider vitamin D to be a vitamin. To be a boring, fat soluble vitamin found in cod liver oil. But what we need to have a better appreciation of is that we were born, and we evolved, and we have been bathed in sunlight, and it really is sunlight production of vitamin D that has sustained vertebrate evolution and human evolution, and we have not really appreciated why. One of the major reasons is because of the photo-production of vitamin D. And because of our civilization of being indoors and the paranoia about being exposed to any direct sunlight has put the entire world’s population at risk of vitamin D deficiency, so vitamin D deficiency is really a disease of civilization and we need to appreciate the beneficial effects of the sun. If you are not getting adequate sunlight, I would encourage all of your listeners and family members-because I do it and my entire family does it-is to take a thousand units of vitamin D supplement everyday because that will help to maintain your 25-hydroxyvitamin D levels at around 30 nanograms per mL. And certainly sensible sun exposure, that is, no more than probably 5, 10, 15 minutes between the hours of 10 am and 3 pm, and that’s during the spring, summer, and fall in temperate climates, followed by good sun protection, is really more than adequate. And it is typically arms and legs, two to three times a week; you can always protect your face. JB: Well, Dr. Holick as I said in your introduction at the Institute for Functional Medicine meeting, if Nobel Prizes are given on the basis of making contributions to society that will change the course of history, I would say that your work stands tall and strong as being certainly a candidate for that kind of an award. We want to thank you for your absolute eloquence and championship/leadership in this whole area to alert the community as to the importance of this nutrient and its relationship to health. Thank you very, very much. MH: Jeff, thank you so very much. It is always a pleasure to be on your program and continue your great work. JB: You do the same. Talk to you soon.  

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Bibliography

1 Cole SA, Comuzzie AG. The end of the beginning. Am J Clin Nutr. 2007;86:274-275. 2 Schmidt HHJ. Introducing single-nucleotide polymorphism markers in the diagnosis of Wilson disease. Clin Chem. 2007;53(9):1568-1569. 3 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=304022 4 Vakili S, Caudill MA. Personalized nutrition: nutritional genomics as a potential tool for targeted medical nutrition therapy. Nutr Rev. 2007;65(7):301-315. 5 Samani NJ, Erdmann J, Hall AS, Henstenberg C, Mangino M, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357(5):443-453. 6 Zivkovic AM, German JB, Sanyal AJ. Comparative review of diets for the metabolic syndrome: implications for nonalcoholic fatty liver disease. Am J Clin Nutr. 2007;86:285-300. 7 Yoshida M, McKeown NM, Rogers G, Meigs JB, Saltzman E, et al. Surrogate markers of insulin resistance are associated with consumption of sugar-sweetened drinks and fruit juice in middle and older-aged adults. J Nutr. 2007;137(19):2121-2127. 8 Westman EC, Feinman RD, Mavropoulos JC, Vernon MC, Volek JS, et al. Low-carbohydrate nutrition and metabolism. Am J Clin Nutr. 2007;86:276-284. 9 Ingelsson E, Schaefer EJ, Contois JH, McNamara JR, Sullivan L, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298(7):776-785. 10 Suda T, DeLuca HF, Schnoes HK, Ponchon G, Tanaka Y, Holick MF. 21,25-dihydroxycholecalciferol. A metabolite of vitamin D3 preferentially active on bone. Biochemistry. 1070;9(14):2917-2922. 11 Liu, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 24 March 2006:1770-1773. 12 Bodnar LM, Catov JM, Simhan HN, Holick MF, et al. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007;92(9):3517-3522. Epub 2007 May 29. 13 Bodnar LM, Simhan HN, Powers RW, Frank MP, Cooperstein E, et al. High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates. J Nutr. 2007;137(2):447-452. 14 Lee JM, Smith JR, Philipp BL, Chen TC, Mathieu J, et al. Vitamin D deficiency in a healthy group of mothers and newborn infants. Clin Pediatr. 2007;46(1):42-44. 15 Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134(6):1129-1140. Epub 2006 Sep 7. 16 Aloia JF, Talwar SA, Pollack S, Feuerman M, Yeh JK. Optimal vitamin D status and serum parathyroid hormone concentrations in African-American women. Am J Clin Nutr. 2006;84(3):602-609. 17 Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167(16):1730-1737. 18 Hypponen E. Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358(9292):1500-1503. 19 Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838. 20 Uribe A, Holick MF, Jorgensen NA, DeLuca HF. Action of solanum malacoxylon on calcium metabolism in the rat. Biochem Biophys Res Commun. 1974;58(1):257-262. 21 Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007;370:657-665. 22 Reginster JY. Calcium and vitamin D for osteoporotic fracture risk. Lancet. 2007;370:632-633. 23 Schousboe JT, Taylor BC, Fink HA, Kane RL, Cummings SR, et al. Cost-effectiveness of bone densitometry followed by treatment of osteoporosis in older men. JAMA. 2007;298(6):629-636. 24 Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N Engl J Med. 357(9):905-914. 25 Grassi F, Tell G, Robbie-Ryan M, Gao Y, Terauchi M. Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendric cell activation. Proc Natl Acad Sci USA. 2007;104(38):15087-15092.

Welcome to Functional Medicine Update for December 2007. Can you believe we are at the end of another year? We are now going into our 27th year and I can’t believe how quickly these things go by. I think it has been a very exciting year and this issue should be a great way to finish up. I want to remind you that we now have quite a nice portfolio of audio courses that have been produced by Synthesis. These include our autoimmune course, Understanding the Origins and Applying Advanced Nutritional Strategies forAutoimmune Disease; our most recent product, Perspectives onAutism, a compilation of interviews with Jill James, Martha Herbert, Richard Deth, and Herbert Needleman, plus commentary by me; Applying Nutrigenomics in Clinical Practice to Reshape Your Patients’ Health; and then the last one is Beyond Metabolic Syndrome: Dementia, Diabetes, Cardiovascular Disease, Hypertension. These are all available through Synthesis. Our toll-free number is 866-272-5789, or you can go to the Synthesis website, which is www.jeffreybland.com. What topic are we going to be speaking to this month? A major paradigm shift in nutritional/functional medicine, and I think ultimately in standard medicine: the concept of how nutrients and other environmental factors influence genomic expression and ultimately change the phenotype of cells, tissues, organs, organ systems, and whole bodies, and how this connects the environment to our genome and ultimately to our function and our health. I recently authored a paper on this topic titled “What Role Has Nutrition Been Playing in Our Health? The Xenohormesis Connection.”1 This article appeared in Integrative Medicine in 2007, and I believe it is a nice overview of the focus we are going to have in this issue of Functional MedicineUpdate and the discussion with our extraordinary clinician/researcher of the month.. Let’s talk a little bit about this big “X” word: xenohormesis. What does it really mean? “Xeno” means “foreign” and “hormesis” is the process of small agents producing change in systems. Xenohormesis is small levels of foreign substances producing changes in biological systems. In the United States, we seem to be getting fatter even though we have introduced more and more weight loss diets, more and more calorie restriction, and more low fat foods than any culture has ever known in the history of the human species. We continue to see type 2 diabetes, certain vascular problems, renal failure, and neurological problems develop as a consequence of this pandemic of obesity. Could it be that these problems are not just solely a consequence of the direct application of the first law of thermodynamics (meaning energy in equals energy out, or there is an absence of proper calorie control)? Rather, are these problems related to a combination of calories plus the information that calories bring into the body because food is information? Food contains bioactive molecules that speak to receptors to create ligand-receptor interactions that then transmit, translate, and functionally modify the outcome of cells, tissues, organs, and organ systems, and ultimately the whole body. Maybe the things that we are eating are sending inappropriate signals. This question opens up the possibility of xenohormesis. In 2006, this topic was discussed in a provocative paper by Yun, Lee, and Doux (Palo Alto, CA) that appeared in Medical Hypotheses titled, “Are We Eating More than We Think? Illegimate Signaling in Xenohormesis as Participants in the Pathogenesis of Obesity.”2 I want to emphasize that the question “Are we eating more than we think?” is not being applied to more calories; the authors are asking if we are eating more information/disinformation-molecules that induce a stress response in the body, incite a foreign relationship with receptor sites, and trigger processes of alarm that may induce inflammation, macrophage/monocyte activation, and infiltration into adipocyte visceral fat mass. This process can produce unfriendly or hostile fat, which sends out signals (through adipocytokines) to the rest of the body with the message, “foreigner onboard/let’s do battle.” This message associates itself with a whole shift in the physiologic sands, producing, then, the dysfunction of chronic disease. Illegitimate Signaling and the Food-as-Information Concept It’s an interesting question. This is in part the question that Morgan Spurlock talked about and showed us in his marvelous film, Supersize Me. In that film, he was consuming three fast food meals a day for several weeks, which induced significant changes in his physiology. In addition, he talked about experiencing mood changes, energy changes, and sleep disturbances. It was as if he was on drugs, he said. The effects of this fast food diet were more than just elevated blood lipids and altered fasting glucose. How do remarkable multiple effects occur across organ systems through the simple concept of changing the diet? The answer may be through this illegitimate signaling (through receptor site interactions that translate information from the diet into genomic expression and ultimately into function). This is a big idea-a whole new idea about how nutrition may play roles in immunity, inflammation, appetite, blood fat levels, insulin signaling, and even cellular division and cellular apoptosis. In this “food as information” concept, nutrition regulates what we call intercellular signal transduction, or the transduction of information from the outside world (from the environment) into inside cellular function. This relay race, or passing the baton off along these various stages of transduction, involves many, many different steps, including picking up the message at the receptor and translating that into genetic or epigenetic modulation. The message has to go through the cell cytoplasm because the genome, which is the chromosomes that are bound up in their histone proteins and super-coiled through the nucleosomes into their architecture, is in the nucleus of the cell. The genome is shielded from direct exposure to the outside environment and therefore it gets indirect messages that are transduced through the cell often by kinases. Kinases are one family of transducing enzymes that relay messages from the outside world to the inside cell. Chemokines, cytokines, or other cellular regulators are also various types of cell signaling substances that influence nuclear regulatory factors and ultimately have effects on promoter regions of genes by upregulating or downregulating the expression of these genes in such a way as to induce an altered cell phenotype. I know this discussion sounds like a bunch of cell biology and biochemistry, but it really is a fundamentally different way of viewing the relationship that diet and nutrition have to our health outcome by looking at the flux of these xenohormetic molecules through the signal transduction process, ultimately modifying cellular function. The food-as-medicine concept looks beyond just calories alone, and just protein, carbohydrate, and fat. The individual personalities of the myriad molecules that we find in a complex diet, or in a highly processed diet in which we put new molecules, such as partially hydrogenated trans-fats, send signals to genes and receptor sites that cause alterations in intercellular signal transduction. These illegitimate signals may work through altered kinase pathways (these phosphorylation pathways) that occur quickly in cells. These pathways can modulate function in ways that are much more rapid than what is required by selective mutation over many years of natural selection (evolution). In this model, we are talking about things that can happen very quickly. Anti-Stress Substances in Phytochemicals Going back to the recent article I mentioned above, it begs a question: Can we get xenohormetic substances through a minimally processed whole-food, plant-rich diet? Do we have substances within the family of of phytochemicals in a minimally processed, plant-based diet that serve as anti-stress substances? The term “xenohormetic” does not necessarily mean bad. We may have xenohormetic substances that induce the stress response, or we might have xenohormetic substances that attenuate the stress response. Plants, under stress, will induce the synthesis from their own genes of compounds that are anti-stress compounds–flavonoids, polyphenols, carotenoids, etc.-that are there to help the plant respond to stress. These xenohormetic substances that the plant produces under stress are really anti-stress substances. When consumed by humans, these substances may be considered by similar shared pathways (or conserved pathways), to be anti-stress substances in the human-the so-called primordial shared metabolic or genomic pathways that we (through our plant ancestors) share in common. It may be that by distancing ourselves from a whole-food diet and foods that contain phytochemicals, that we are actually uncoupling ourselves from messages that signal anti-stress. Isn’t that a profound concept, when you think about it? A “white” diet (white sugar, flour, fat, alcohol) is devoid of all these other signaling substances I have talked about. This diet does not have the xenohormetic, anti-stress personalities or signatures that we see in a minimally processed, whole-food, or plant-rich diets. I think this is a very powerful concept that we are going to be learning much more about. It translates into what I call the systems biology approach towards looking at human pathophysiology or pathobiology. You can’t understand this by looking at one substance at a time; you can only understand this by looking at the web of interactions of a complex environment with a very diverse genome that responds in different ways in expression to differing signatures that come from the complex environment. Recently, in the journal Molecular Systems Biology, a very interesting paper appeared titled “Human Disease Classification in the Postgenomic Era: A Complex Systems Approach to Human Pathobiology.”3 The investigators, who are from the department of medicine at Brigham and Women’s Hospital, Harvard Medical School, talk about a change in thinking about disease, and, in this systems biology age that we are moving into, how we need to redefine how we classify disease and how we think about its remediation. Let me share this concept with you. The contemporary classification of human disease that we know derived from observation correlation between pathologic analysis and clinical symptoms and has resulted in the diagnostic codes that we all use in medicine (the DRGs-Diagnostic-Related Groups). These are fairly empirical and observational in their origin: you see a patient who has a certain kind of anomaly. We started off with gross pathology and moved to clinical parameters that may include biochemistry and even radiology as resonant spectroscopy. Those criteria that cluster together as a series of symptoms, signs, and pathophysiologies we call a “disease,” as if it were independent and isolated in time/space in that individual and you could disconnect it from other “diseases.” That model appears to be breaking down. We now recognize that conditions are often connected together, and there are no two people who have the exact same presentation of a disease. Even though you might diagnose a person with type 2 diabetes, the next patient that comes in with that same diagnosis may have a very different presentation and progression than the previous patient with the same diagnosis. Even within the same name of a disease we see a highly different set of parameters that relate to their expression. Characterizing disease from this concept of the correlation between pathologic analysis and clinical symptoms did establish a structure that has served clinicians well up until this time. It created convenience and a teaching algorithm that is reproducible and can be memorized, as well as a systemization of the field so that standards of practice could be codified. Yet this time-honored diagnostic strategy has significant shortcomings that reflect both a lack of sensitivity in identifying preclinical disease and a lack of specificity in defining disease unequivocally. The investigators from Harvard and Brigham and Women’s have been looking at this limitation, viewing it as a reflection both of the different clinical presentations of many diseases (meaning variable phenotypic expression, as I was describing), and the excessive reliance on Cartesian reductionism in establishing diagnosis-cause and effect (single agents producing single outcomes). This perspective is really changing to now take-as a fundamental component-this systems biology approach and classifying human dysfunction and disease utilizing a broader systems biomedicine approach, looking at interaction of systems so that the mechanism and etiology of the disease becomes more important that the disease itself. There are certain people who have been bold enough to say that we don’t have diseases, we have physiological dysfunctions that for convenience we code as a disease. Physiological dysfunction is where the action is. We should be treating the dysfunction, not the disease. You have probably heard this language before through the teachings of the Institute for Functional Medicine and the Textbook of Functional Medicine. It is the fundamental construct of the functional medicine approach. Recognizing that shift in the web of function is a consequence of the gene-environment interaction gives rise, then, to a whole array of altered potentials in the phenotype. If we were to look at pharmacology nutrition related to this obesity epidemic, we might say that we are moving into a new phenotype, which one author has called “Homo obesus.” Not Homo sapiens, but Homo obesus, which is a metabotrophin-deficient species in their phenotype as a consequence of the illegitimate signals and the translation of those signals into phenotypic change that we are seeing in our population today. I’m not making this all up (I know this sounds a little Jeff Bland-esque), This actually comes from a recent paper that appeared in Current Pharmaceutical Design in which the concept ofHomo obesus, metabotrophin-deficient species, was advanced.4 The authors of this article state that in most countries the prevalence of obesity is now exceeding 15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the population. This 15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} or greater figure was used by the World Health Organization to define the critical threshold for intervention in a nutritional epidemic, so we can actually say this is a global transition in phenotype towards this Homo obesus. Why? Is it just luxurious calories? Or is it the combination of calories that are inappropriate as illegitimate signals, which then alter secretory and/or signaling pathways that are related to this metabotrophic effect, and then are seen in all sorts of changes of insulin, adiponectin, resistin, inflammatory cytokines like TNF-alpha? Is this the new metabolic personality of the 21stcentury? Rather than just reduce the calories, we ought to be looking at reducing adverse signals and improving favorable anti-stress signals. This even leads to changing the diet to increase the intake of these exogenous metabotrophic agents that can induce proper anti-stress or adiponutrigenomic substances that can modify the expression of genes that are associated with inflammation and stress. This has to do with things like the sirtuins-the family of genes that we are going to be discussing at great length in this issue that have been dubbed “longevity genes.” They actually have effects on modulation of the outside environmental information through the epigenome into genetic expression and ultimately modulating these regulatory substances like insulin and proinflammatory cytokines and a whole array of the metabotrophic substances. Maybe we should be managing the signals more than managing the calories; that is the concept. What I have really been speaking to is defined by a term that can be found in the literature more and more: “nutritional hormesis.” Hormesis, again, as I defined, is the effect that small quantities of substances have on functional changes. Here we are talking about substances that come through the diet (nutritional substances) that modulate, at low levels, physiological function through altering the phenotype. This concept of nutritional hormesis is really gaining importance and it may explain why even small levels of new substances added to the diet through food processing or chemical transformations have resulted in more significant changes in physiology than we might have predicted. This concept of nutritional hormesis is reviewed in a very nice paper by DP Hayes, from the New York City Department of Health and Hygiene that appeared in the European Journal of Clinical Nutrition in 20076 In this paper, Dr. Hayes describes the concept of nutritional hormesis and talks about how research along the lines of understanding how hormetic effects are modulated through intercellular signal transduction through the gene expression pattern will be the forefront of the “new” nutrition and its relationship to medicine. With all that in mind, let’s take a specific example-one that we are going to be speaking to in greater detail during this issue of Functional MedicineUpdate-and that is the small molecule found in peanut skins, grape skins, in a variety of skins of fruits, and to some extent also found in whole grains. That is the molecule resveratrol. You may have heard a lot about resveratrol. You may know that it is associated somehow with the French Paradox (the French, who have historically eaten high-fat meals that include foods we might even think of as cardiotoxic, historically have had very low incidences of cardiovascular disease relative to people who ate a lower fat diet-this is paradoxical if the diet-fat hypothesis is correct). People have been exploring the French Paradox for some time. There have been suggestions that it might be alcohol that reduces cardiovascular risk in these individuals (through the consumption of wine at meals). Red wine contains polyphenols and phytochemicals such as resveratrol, which have been said to be “antioxidants and cardioprotective.” What is the story that has emerged around resveratrol recently? It is much more than just the story of antioxidation. Animal Studies and Resveratrol Recently, a paper was published in Nature, a very well-known scientific journal, titled “Resveratrol Improves Health and Survival of Mice on a High-calorie Diet.”7 I think this is a pretty profound study. In this particular study, mice were intentionally fed a high-fat diet, similar to a diet that might be consumed by those eating a lot of processed fast foods. Some of the animals received a supplement with 3,5,4′-trihydroxystilbene, which we know as resveratrol, one of the principals from red wine (coming from the skins) and peanut skins. Resveratrol was of interest because it had previously been shown to extend the lifespan of diverse species, including the yeast, Saccharomyces cerevisiae, the flatworm, Caenorhabditis elegans, and also the fruit fly, Drosophila melanogaster. All, when given supplemental resveratrol, were found to have an extended lifespan, as if somehow it had an effect similar to that of calorie restriction, which is the only reproducible way of extending lifespan in animals (restricting calories by thirty percent without restricting micronutrients). In looking at how resveratrol could influence the lifespan of yeast, flatworms, and fruit flies it was found that it had an effect upon a gene called Sir2 in these species, a conserved deacetylase, which is a gene that is very important for regulating the expression of other genes that are associated with such diverse things as insulin sensitivity, inflammation, cell cycling, apoptosis, and oxidative redox potential. Even things like insulin-like growth factor 1 levels, adenosylmonophosphate-activated kinase (or APK), and PPAR-gamma (the peroxisome proliferated activated receptor associated with insulin sensitivity) all have interrelationships with the Sir2 gene. In looking at the effect of a resveratrol supplement in animals with a high fat and calorie intake,that the study authors found they could-by supplementing with resveratrol-neutralize some of the adverse effects of the higher fat-higher calorie diet to modulate gene expression of the SIRT gene and decrease some of the incidences of shifting phenotype that are associated with diseases of aging. This is a pretty remarkable study, I would say. Not only did the authors show improved AMPK activities, improved PPAR activated receptor 1 co-activator activity, increased mitochondrial number, and improved motor function, but they also showed that some of these parameters associated with the high-calorie diet had a modifying effect on 144 out of 153 genes that were associated with the adverse effects of the high-calorie diet. Somehow resveratrol is speaking to the genes-multiple genes-through the effects that it has on this deacetylase enzyme (the SIRT enzyme) and how that translates, then, that message to all sorts of other patterns of genes (families of genes) that regulate factors that are associated with biological aging. What about the sirtuin family of genes? There are pretty interesting new observations that you are going to hear much more about from one of the leaders in the field. I’m just setting the stage by this introductory comment because this ties back to our hormesis concept, xenohormesis, and nutritional epigenomics (in other words, how nutrients influence the effects that then regulate the promoter regions of genes to create altered gene expression in response to dietary and environmental signals). If this sounds like new information to you and the whole landscape is changing around us, that is what’s happening in the field right now. We are undergoing a paradigm shift that is second to none since Atwater made his first calorie discovery, Casimir Funk made his first discoveries on B vitamins deficiency and beriberi, the Goldbergers made their discoveries on pellagra with niacin, and Szent-Gyorgyi and his discoveries on vitamin C and scurvy. I think we are seeing the same magnitude of change in our thinking as at the dawn of what we might consider modern nutrition, back at the turn of the last century. The idea that signals from our environment and diet, through receptor-site interactions and kinase signaling, modify epigenetic gene expression and the phenotype of cells is generating more interest in the interface between molecular genetics, molecular biology, nutritional medicine, and histopathology and disease (sometimes seen years downstream). Needless to say, the genetics of the individual plays a very significant role in the way this whole orchestration plays out. We can’t divorce ourselves from the genes of the person. These modifying factors in the environment are going to play differently through different orchestras. The orchestras-and the assembly of each musician’s chair in each orchestra-is determined by the genes. How individual instruments play a suite will depend on the environment in which it is played, but the obvious orchestra will be determined genetically. To continue this analogy, what if you just happen to get a bunch of first-year musicians in your orchestra by your genetic lot? Let’s say that your string section, your woodwind section, and your percussion section are all world-class performers, but somehow you have a high school brass section. If you wanted to play one of the orchestrated suites that had a lot of brass in it, you’re not going to play it as effectively as you would if you had a world-class brass section. That’s our genes. Our genes will determine the potential quality of each of the individual instruments in our orchestra. But how those instruments are played, and the way that they ultimately make individual music, will be dependent upon the environment in which the orchestra is playing. That’s the basic concept of this xenohormesis construct: nutritional epigenomics and nutrigenomics and how that translates, ultimately, into the changing of the outcome of the health of the person.It is the construct of a person’s genes in the matrix of their environment. Now let’s go back to sirtuins. The sirtuins are the so-called longevity genes. In sirtuins, “SIR” stands for silent information regulator. These related enzymes have originally been identified or defined as a family of nicotinamide adenine dinucleotide-dependent enzymes (NAD, for those of you who remember your biochemistry). Remember where NAD comes from. The precursor of NAD is from niacin, which is a vitamin B3 derivative, so that starts already telling us there is some nutritional connection to the way these particular enzymes in genes interact. So the sirtuins are NAD-dependent enzymes that deacetylate lysine residues on various proteins. These enzymes are controlled by genes that have this deacetylase role and therefore control how other genes are going to be expressed and how the enzymes and proteins within the cell work. This is a fundamental and important part of setting the stage for how the orchestra will play the suite. The sirtuins are remarkably conserved throughout the evolutionary system, all the way from very primitive organisms (going back to primitive bacteria), through yeast, and ultimately into eukaryotes, or nucleated cells.8 I believe there is something very ancient and important about the sirtuin enzymes and genes in that they are a very, very important conserved part of all life. They have a variety of cellular functions, ranging from gene silencing and the control of cell cycles and apoptosis, to energy homeostasis through the way they influence mitochondrial oxidative phosphorylation. On a whole-body level, the wide range of cellular activities of the sirtuins suggest that they could constitute potential therapeutic targets that would allow us to possibly combat the dysfunction associated with metabolic neurodegenerative and proliferative diseases. It is this important role that sirtuins have that make them really important candidates for therapeutic intervention. And because there is a nutrition link to their expression patterns and their activity, it has opened up a new and important door for understanding how nutrients may modulate sirtuin function and may ultimately mimic some of the effects that we see with calorie restriction (i.e. the French Paradox). This concept, I know, is very complex. I think as you hear our clinician/researcher of the month you are going to be able to understand this at a much deeper level. Lastly, before we hear from him, I want you to recognize what I mean by NAD-dependent deacetylase. These deacetylation enzymes that take an acetyl group off a lysine and allow a protein to change its confirmation or unmask a genome so that it can be read by deacetylation of a histone protein. These particular effects that occur at the epigenome are such that they require adequate levels and delivery of NAD. As I illustrated earlier, the precursor for NAD is a niacin molecule (a nicotinic acid) that interconverts to niacinamide, and ultimately into NAD. Where do a lot of these B-complex vitamin derivatives have their function? They have their function not only in intermediary metabolism, but also at the mitochondrial level that helps to control some of the oxidoreductive processes that are involved in mitochondrial oxidative phosphorylation. A major cause of cell death is this genotoxic stress that is thought to be due to the depletion of NAD from the nucleus in the cytoplasm. NAD depletion from the mitochondria can also be very damaging because it is actively involved in support of cellular physiology associated with energy production. In a recent paper that appeared in the journal Cell, a highly regarded cell biology journal, a group of investigators showed that NAD levels in mitochondria remain at physiologic levels when nuclear and cytoplasmic pools are depleted.9 Rodents fasted for 48 hours will show increased levels of the NAD biosynthetic enzyme, Nampt, which makes more NAD from niacin, and a concomitant increase in mitochondrial NAD, which may, in part, account for some of the benefits that calorie restriction has on cellular bioenergetics. Increased Nampt provides protection against cell death and requires (as this article goes on to say) intact mitochondrial NAD salvage pathway. This is all, then, dependent on the deacetylase activity of SIRT and may help us to understand something of the relationship that the SIRT genes and enzymes have to prolongation of healthy function, relationship to the healthspan, and how that interconnects to nutrient signaling and xenohormesis. If we were to tie together the resveratrol studies with the NAD observation, what it illustrates is that there may be a variety of different nutrients that play important roles in setting up the signals of orchestration of these “longevity genes” through these epigenetic modulations. What I mean by epigenetics is that every cell in our body has a message for every other cell. Our 23 pairs of chromosomes contain all the information needed to make every cell at every age in every tissue, so how is it that they are making only those things that they are supposed to be making (eg, the heart is not making the stuff needed in the liver)? That is controlled by masking of the genes with methyl groups and with acetyl groups that prevent genes from being read. Deacetylation, opens up the genes to be read in specific regions, which then can turn on the promoter regions of other genes and you can have a cascading effect. Similarly, methylation silences genes, particularly when methylating the promoter, and that then downregulates gene expression. It is these processes at the epigenome that can be modulated by diet, lifestyle, and environment that open or close down the genes to be read. You don’t want to read oncogenes; you want to keep them silent. You do want to read your defense genes and your anti-stress genes, and these are the things that we are learning can be modulated with a specific nutrient. It is a very fascinating chapter in our evolving understanding of how to engage in improving the health span. I think we are ready to move to our discussion with our clinician/researcher of the month, who is someone of the type that we’ve never had in our 25 years of previous interviews. He is Dr. Christoph Westphal, from Sirtris, and I think you’ll find his discussion to be very important and of high relevance to this topic.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Christoph Westphal, MD, PhD Sirtris Pharmaceuticals, Inc. 790 Memorial Drive Cambridge, MA 02139 (617) 252-6920 www.sirtrispharma.com Once again we are at that place in Functional Medicine Update that I think all of us look forward to: our clinician and/or researcher of the month. We are very privileged this month to have someone who represents what I think is the cutting edge-where the action is-right now in the advancing frontier of nutrition and that is Dr. Christoph Westphal, MD, PhD who is the CEO and Vice Chairman of Sirtris Pharmaceuticals.. Fortune magazine featured a cover and article on the company in the February 12, 2007 issue under the title of “Drink Wine and Live Longer.” We are going to be talking, in a moment, about the Sirt gene, the French Paradox, resveratrol, and all sorts of things that I’m sure you have heard something about. Dr. Westphal is not only really exploring and moving towards commercialization of these concepts as CEO of Sirtris, but he is also a medical doctor from Harvard Medical School, and he has a PhD in genetics from Harvard. He graduated with his BA, summa cum laude and Phi Beta Kappa, from Columbia University and was formerly a consultant with McKinsey. Sirtris, it is a very interesting biopharmaceutical company that is focused on discovering and developing proprietary, orally available, small molecule drugs to treat chronic-related diseases associated with aging such as type 2 diabetes. You are going to hear more about that and how that interrelates with diet and lifestyle and, I think, a new paradigm for the pharmaceutical industry. With great pleasure, Dr. Westphal, we welcome you to Functional MedicineUpdate. Maybe you could tell us a little bit about your background and how you-through this interesting road we all travel in our lives-got to Sirtris. CW: Thank you very much, Dr. Bland, for inviting myself and Sirtris to join you on your program. As you mentioned, I have a technical background, having done an MD and a PhD at Harvard. Previously, I had started with Phil Sharp, who is the founder of Biogen, a company called Alnylam, which publicly traded on NASDAQ, and also (with Bob Langer and Paul Schimmel) a company called Momenta (again, a publicly traded company). About four years ago, I became very interested in resveratrol and in the sirtuins, based on a set of papers that were published in Nature, Science, and Cell (those are very well-known publications in the academic research world). A young researcher named David Sinclair at Harvard Medical School had published what I thought were quite extraordinary findings which indicated, first of all, that SIRT1 was a gene that appeared to govern the aging process. It has been known for a long time that calorie restriction, or the reduction in calorie intake by about 30-40 percent, extends healthy lifespan in a wide variety of organisms including yeast, worms, flies, mice, and rats. It was shown in 1999 and 2000 by David Sinclair and Lenny Guarente at MIT that SIRT1 governed the beneficial effects of calorie restriction. By that I mean if you deleted the SIRT1 homolog in these various organisms, they no longer lived longer under calorie restriction, and conversely, if you overexpressed SIRT1 in these various organisms, even in the absence of calorie restriction you were able to extend healthy lifespan. Research by Dr. David Sinclair And so about four years ago, David Sinclair published a paper in Nature showing that resveratrol, which is a component of red wine (and many of you have heard of the red wine French Paradox), was able to activate SIRT1, and on its own, extend lifespan in yeast.10 When I saw those findings I thought, “Well, it’s not that far from yeast to worms, to flies, and on to mammals.” In fact, the data for calorie restriction was very strong all the way into humans (that it would increase healthy lifespan), and so we decided to start a pharmaceutical company to develop FDA-approved drugs seeking to target the aging genes, such as SIRT1, to treat chronic disorders such as type 2 diabetes. So that was really the origin of Sirtris. JB: When we look at the SIRT1 gene, it is a member of the family called the NAD-dependent deacetylases, which has something to do with the epigenetic structure of the genome (the nucleosome structure). Could you help us understand that connection? I think that is a very interesting evolving frontier (this whole epigenetic connection to environment and diet). CW: Yes, absolutely. What we are very excited about at Sirtris, and what I think our SAB (our Scientific Advisory Board-which has about six National Academy of Science members/Nobel Prize winners) are excited about is that a lot of what we are doing seems to be mimicking a natural process, and specifically addressing your question regarding NAD (of course your listeners will be aware that NAD is an intermediate in metabolism). It was very interesting to David Sinclair and then to Sirtris that NAD controls the activity of the sirtuins, specifically of SIRT1, and provides really a compelling link between this long-standing observation that your nutritional status (your level of calorie intake or calorie overload on the one hand, your glucose levels/insulin on the other hand) and your NAD levels ultimately in your cells control the activity of the genes that appear to control the aging process. When we started Sirtris about three-and-a-half years ago, we started from a very simple precept that the sirtuins seemed to be beneficial enzymes, they seemed to control the response to calorie restriction, and they seemed to control, really, a downstream signaling cascade of proteins that ultimately would appear to be a great way to treat type 2 diabetes. So that was really the origin of the company. JB: When we look and think of NAD, obviously we think of redox and its connection with NADH and NADPH and how that is related to the reduction oxidation quotient of a cell, which then takes us back to mitochondria, so there is this whole interesting story of connecting the energy powerhouse of the cell somehow to signaling to the epigenome. Could you help us to understand that a little bit? Sirtuins and Mitochondrial Biogenesis CW: Yes, it’s a great question, Dr. Bland. It’s just such a fascinating science story and we have begun (with our SAB member, Eric Ravussin) human studies. We have really shown this natural pathway, which is reduction of calorie intake, increasing SIRT1 activity (SIRT1 being the founding member of the sirtuin family which is dependent on NAD), apparently controlling the mitochondrial activity. So when you turn on SIRT1, you increase the activity of the key regulator of mitochondrial biogenesis, a gene called PGC-1a. When you turn that on, you seem to increase the number and function of mitochondria by about 30 percent. We published a paper in Cell in November of last year-the senior author is Auwerx-where we showed that when you treated mice on a high fat diet with resveratrol, which activates SIRT1, you increased the activity of PGC-1&alpha; and you turned on mitochondria such that those animals then had lower glucose, lower insulin, and in fact they ended up having higher performance as measured by a treadmill.11Then, thinking therapeutically (since we are a drug discovery and development company), we moved those compounds into human clinical trials. We have now dosed more than 200 volunteers and type 2 diabetics with our formulation of resveratrol. I probably need to add here a cautionary note that the general media did pick up on early on, which is that nutritional supplements containing resveratrol, or, in fact, resveratrol from food stuffs, has been published in the literature to not reach therapeutic blood levels in man. We have now, in the last several months, reported at scientific meetings and will publish in the academic literature our findings with our formulation of resveratrol, which basically has a smaller particle size and excipients that stabilize resveratrol, and we’ve shown that we can reach therapeutic blood levels in man with our formulation and linear pharmacokinetics. The next step, of course, is to look at effects on diabetics and, in fact, we have several phase 1-B and a phase 2-A study currently enrolling and expect to begin reporting data in early 2008, so it is really a very exciting time for Sirtris right now. JB: I would say so. I’d like to go back, if I could, to how Dr. Sinclair made the discovery of resveratrol in the sea of different interesting phytochemicals that might have been chosen. I’m sure that his discovery process was very interesting. Could you give us an insight into that? CW: Well it is one of these fascinating science stories. I always like to think that if it is a natural process and if you are right about your science, you happen to end up being fortunate when you look under the lamppost. And so the original discovery, which in itself is just a really exciting and fascinating discovery, was that single genes could control the aging process. Until the late 90s, it was frankly heresy for researchers like David Sinclair and Lenny Guarente when they said, “We believe there will be single genes that control aging.” Most people thought aging would be too complex a process. They then went into model organisms such as yeast, which are tractable, genetically, and showed in screens that you could find specific genes where you (if you increase their activity) were able to increase lifespan in yeast-those were the sirtuins. And then they went on to show that downstream of calorie restriction you found the sirtuins were turned on and could, in fact, substitute for calorie restriction (so bringing the world of physiology together with the sirtuins in a way that no one had expected but one might have been able to predict, given the findings). The next step, then, was finding that the sirtuins were dependent on NAD, the intermediate in metabolism, which again made an enormous amount of sense: that the metabolic state of humans (or any organism) really does correlate in a great way with the aging of that organism. And then that next step, which you questioned and was really quite exciting, was when David said, “Well let me take an unbiased approach and screen the Harvard library of small molecules and see which small molecules could, on their own, activate SIRT1.” So he took an unbiased approach and went into screening mode, found resveratrol, and then we at Sirtris have found molecules that are about a thousand times more potent than resveratrol, completely distinct in terms of their structure, and are moving into human clinical trials in the first half of this coming year, so arguing that we should be able to have lower dose levels needed for these synthetic resveratrol equivalents. JB: That’s really, really an exciting process. I mean, just the whole method of getting to an answer is a whole new model for the pharmaceutical industry. Dr. Sinclair talked about-kind of on a more philosophical plane-how these interesting events might occur. It seems (probably to the first-time listener) that the connection between calorie restriction and small molecules (in this case, in food, which share a similar pathway) sounds very-probably-unusual, but he advanced the concept of xenohormesis, which I think is a very interesting concept as it relates to our whole evolutionary history coming up through lower animals and then ultimately to humans/mammals. Could you describe a little bit this xenohormesis concept? I think it is very interesting. CW: Yes, it goes again to this idea that we think we are mimicking a natural process, and so the belief is when we face periods of adversity or lack of food stuff, it should be evolutionarily preferred, and conserved, and, in fact, favored if we would be able to respond to signaling molecules in our environment. The theory is that over evolutionary time, billions of years ago when the sirtuins evolved, they evolved to be able to sense periods of adversity and periods of lack of food. When our forebearers (or, perhaps, yeast, which, of course, are a couple of billion years older than humans) evolved, they evolved to be able to overcome a period of lack of food by being able to sense in the environment signaling molecules such as resveratrol, which is actually expressed at higher levels in stressed plants. To make it even more clear (hopefully), for example, resveratrol found in the skin of grapes is actually increased in content when those grapes find a harsh climate (a climate without enough water or nutrients). The thought would be that the organisms that depend on food stuffs, such as us or yeast, when they are exposed to stressed plants, would then turn on a system that would allow them to overcome that period of lack of food. That being evolutionarily conserved, once you survive that period you could still have offspring. So it is very complicated and it’s a pretty big idea, but when you think it through it does actually make sense. JB: Well, we’re on the horns of big ideas. Obviously there is another very big idea implied in your work that I think is very fascinating because it relates to medicine as a whole, and the whole concept of the primacy of diagnosis: the concept that a substance (let’s use resveratrol as an example) could modulate processes that cut across so many ICD-9 codes (diabetes, cancer, neurodegenerative diseases), and this kind of flies in the face of the way that many of us learn differential diagnosis and histopathology and the fundamental underpinning of medicine. Could you give us your insight as to where you think this work is taking us in terms of our medical paradigm? CW: Yes, Dr. Bland, it’s a great question and it is really something that we think about everyday at Sirtris because it has pretty profound implications, not only for our small company, but if we are right about this idea, it may have pretty interesting and far-reaching implications for medical care. Perhaps the best way to answer that is with a question I will ask you-a rhetorical question-and then I’ll answer your question. When folks ask me, “Well, if you are right, this might apply to many diseases,” I say to them, “Could you name to me the diseases that, strictly speaking, are not associated with aging?” In fact, when we think about it, diabetes is, of course, associated with aging; it used to be called “age-associated” diabetes for type 2 diabetes, Alzheimer’s, Huntington’s, ALS, inflammation, cancer. And really it makes sense, when you take a step back, to think if we are targeting the genes that control the aging process, not to stop aging, but to modulate aging and to perhaps slow aging, it would make a lot of sense that we should be able to develop therapeutics based on that approach for a variety of very important chronic diseases of aging. That is why at Sirtris Pharmaceuticals we actually believe our drugs should have applications not only for type 2 diabetes, which has an age association, but also for severe neurological illnesses, for inflammation, for cancer, for many of the mitochondrial illnesses. When you ponder that, of course, it is an enormous opportunity. We need, as a small company, to focus on the straightest shot from animal models into human studies, but certainly our hope, ultimately, is to be able to affect many of the major killers of Western society. JB: That was really beautifully stated. It sounds to me, as I just listened to you, that you are really painting a wonderful verbal picture of what might be called a systems biology approach to medicine, which is a very different way than most of us learned about anatomy and physiology and ultimate translation into disease. CW: That’s very kind. Yes, it is a very exciting time for Sirtris. I do always want to make sure when we talk to the media we do always want to emphasize that this is, of course, several years from approval by the FDA, and as you understand there are, of course, enormous risks still ahead of us on the clinical development path. JB: So one of the things that you have alluded to, which I find really fascinating, is this redox connection to the SIRT1 gene and its control of all these various interesting functions. When we think of redox, in the parlance of Helmut Sies (his concepts from a number of years ago of oxidative stress), we often think of the oxidative stress relationship to redox gone array. And then that leads us to think about DNA strand breaks and repair of DNA and ties into things like polyadenyl ribosomal polymerase, or PARP and I know that there is a connection here between SIRT1 and PARP. So, it seems like we are also talking about protection of DNA, as well, against oxidative injury. CW: Yes, the way we agglomerate and sort of interpret our data, which has mainly been published in the academic literature and we continue to do so, it’s a reasonably parsimonious (we think) explanation. When you have type 2 diabetes you go to your doctor and your doctor, of course, suggests, first of all, calorie restriction (in other words, reduce your calorie intake) or exercise. When you are doing those two things, as far as we can tell, and consistent with the field that you are alluding to, you drive mitochondrial biogenesis. In fact, you appear to be increasing the coupling of mitochondria, such that the mitochondria are more efficient, with less oxidative damage. When we turn on the sirtuins, via resveratrol or our much more potent and novel small molecules that do the same, even in the absence of exercise and calorie restriction, in our animal models we increase the number and function and affect the coupling of the mitochondria such that there is less leakage (proton leakage) through the mitochondria and less oxidative damage. I think that’s how you can really bring these different fields of insight together such that we understand what people have always been telling us (reduce your calorie intake and try and exercise) and put that together with the other insight, which has always been to try and prevent oxidative damage to your DNA. The way we think that is happening is really via SIRT1 turning on PGC-1a, increasing the number and coupling and functioning of mitochondria in a way that is intuitively obvious, the same way that you do with exercise or calorie restriction. JB: So from that I take away that we are moving into an era to redefine the term “antioxidant.” It has always kind of been problematic for me that “antioxidants” is like a generic term-it is like the term “love”-in that has many meanings to different people in different concepts, whether it’s agape or amore, and by a similar token, “antioxidants” is a fairly broad-based term that doesn’t have much specificity related to tissues, or organelles, or even function. It sounds like what we are starting to say is that these processes that you are describing have very specific influence on cellular redox within certain tissues and how that influences ultimate outcome in the phenotype of that tissue, which is much more specific than just the broad-based concept of antioxidants. CW: Yes, our perspective-and, of course, it continues to evolve and it is certainly not 100 percent confidence at this time-but our perspective is if you can reduce the number and amount of oxidative units by having your mitochondria be more coupled, that may be a better way to treat diseases, or to prevent diseases, versus trying to soak up the oxidants that are already there. Our view is we appear-as with calorie restriction or exercise-to be reducing the damage to end organs and reducing disease by preventing the disease from taking place in the first place. JB: That’s beautiful. That’s very, very interesting. I’m going to ask you-if it is not too uncomfortable for you-you know food is a very complex matrix that has, literally (now, we are learning), tens of thousands of different potentially bioactive molecules in it, some of which were not considered very interesting until recently. Do you think that there are other things in the complex matrix of foods that have influence on sirtuins other than just resveratrol, itself? CW: We’ve found, of course, much more potent and totally unrelated molecules to resveratrol that also turn on the sirtuins and we think are probably even better suited to be drugs for diabetes. We believe that there will be multiple molecules in foodstuffs, not only resveratrol, that have a similar effect. I do need to emphasize, however, that ultimately our point of view is that you either need to turn on the sirtuins with a small molecule such as resveratrol or our new chemical entities, or you need to turn on the sirtuins by reduction of calorie intake. So I would caution the view that significant calorie intake plus some good food additives, that being very good for your health, I don’t know that I’d support that. JB: Yes, I think we would completely support that concept as well. Lastly-I know you’ve got to run-I just have two quick questions, one of which is these effects that you are describing have a different influence, mechanistically, than the way that often people have learned about nutrients. They have learned about nutrients having an effect more on the metabolome, directly, by vitamins activating a cofactor which then controls a metabolic pathway, or (as you discussed earlier) an antioxidant such as ascorbate or tocopherol trapping a free radical at a certain cellular site. What you are describing is the influence of substance (in this case resveratrol) way upstream of that at the initiation of cellular signaling, which really occurs epigenetically. I think this concept of response to our environment due to epigenetic, kind of histone-related effects is a pretty dramatic change from the way that we have traditionally thought about nutrition and its effect on cellular physiology. Could you just quickly summarize your view of this epigenetic-nutrient connection? CW: Yes. At this point I will move into pure speculation and hypothesis versus very strong data. Our point of view is that either exercise or calorie restriction probably has very broad and very pleotrophic effects on your gene expression and the status of your chromatin. I think you have alluded to probably having a similar view. We think that there are a couple of switches that the body flips from off to on in that setting. We know in humans, of course, that calorie restriction or exercise turns on SIRT1 and we can mimic that with small molecule activators quite dramatically. So we think you are absolutely right. We think this is going to be a whole host of changes-a wide-ranging beneficial change that is really sort of triggered by a few key cellular switches such as the sirtuins. JB: I can’t tell you how much we have enjoyed this discussion and just watching your work evolve. It is really reframing so many of the fundamental things that we thought were facts that now have to be modified. One last quick question, just from a commercial perspective as the CEO of Sirtris Pharmaceuticals: How do you protect these amazing discoveries in IP that come out of the natural world? CW: At Sirtris, (the ticker on that is S-I-R-T), we’ve raised about 170 million dollars to date. Most of that we continue to have on our balance sheet so that we can invest very significantly in our intellectual property. We have over 120 patent applications, and several of those patents have been issued. There is a very broad set of claims related to activating SIRT1 to treat diseases of aging which we believe covers any molecule that will do so. We also, of course, have the specific formulation of resveratrol that we believe is able to reach therapeutic blood levels in man. And, finally, we have composition of matter for our completely novel synthetic molecules. We are very focused (if we are really right about this area) to try and get these medicines to man as quickly as we can, and we believe that the earliest that that can be is probably about 2012 in terms of FDA approval. We are also very actively speaking with a broad set of companies. Really our goal is to enable the field because if we are right we really think it could be quite important for human health and there is no reason for us to want to stand in the way of that. JB: Well, Dr. Westphal, this has been very inspiring and I want to compliment you and your colleagues and obviously also Dr. Sinclair for this pioneering work. I think it is going to reset a lot of our views and premises about the way that discovery is made in the field of pharmaceuticals and also the role that natural products may play in human health. CW: Thank you so much, Dr. Bland. I really appreciate the great work you do as well. The discussion that we have had with Dr. Westphal also raises another very interesting question: what are the number of environmental factors that could influence these important gene response elements that ultimately regulate cellular function and modulate stress response and various functions that go downstream to induce insulin resistance, dyslipidemia, alarm, inflammation, and associate with accelerated cytological aging? Of course, one of those factors is what we consider physiological stress. This takes me back to an interesting observation. You probably know that more than a century ago Robert Koch established that infectious diseases were caused by microbes-it won him, actually the Nobel Prize in physiology and medicine in 1905-which was a major, kind of fundamental discovery in medicine. About that same time Dr. Elie Metchnikoff, who was (I think, at that point) the actual chairman of the Pasteur Institute in France and was one of the pioneers of cellular immunology and also won a Nobel Prize in medicine and physiology, was the first to recognize that microbes might also have beneficial effects on human health. The concept of lactic-acid-producing bacteria prolonging life was actually part of his book that was a best-seller, first in French and then later translated into English, called Prolongation, and that particular book advanced the concept that the consumption and even the use of enemas containing Lactobacillus acidophilus would be valuable for improving health and improving immune function. This raises a question whether our enteric bacteria might also influence our stress response in gene regulation, and of course that then leads to a more recent discovery. When I say “more recent,” it is really more recent but is built on some initial discoveries made by William James back in the 1800s, who was a psychologist at Harvard given some of the early credit for developing psychological theory. He had published a provocative theory of emotion: that the perception of emotions follows from the perception of our physical responses to cognitive apprehension of external threats or even pleasant stimuli. That is, I guess we could say, the experience of emotion is integrated with the somato- and viscero-sensory signals that result from cognitively driven motor, neuroendocrine, and autonomic responses (in kind of this brain-body-brain loop of communication/integration), which is really one of the fundamental themes that functional medicine talks about. It is more of a systems biology approach to looking at how we respond to our environment and how the stress response can be modulated. Dr. James further proposed that when emotions are mapped in the brain, rather than existing in separate centers (like an anxiety center or a happiness center) that the neural substrates of emotion would be integrated with the somato/ viscerosensory representation and that we would see this kind of integrated holograph of how the immune system, the endocrine system, and the nervous system interrelated with one another. So we would have neuro-endocrine-immunology connection. This goes way back to the 1800s, and, of course, one of the agents that could trigger this function (we have discovered since) could be the enteric bacteria and their functional effects on the gut-associated lymphoid tissue or the gut-immune system. So that leads into this host-microbe interaction, and is there any relationship between bacterial activity and viscerosensory signals from the gut that enhance anxiety? What are the implications of such for the field of psycho-neuro-immunology? These are kind of interesting modulators of gene expression and the stress response that may not be on top of mind for most people who are thinking about immune modulation. Infection-induced Viscerosensory Signals Recently a paper was published by a group of researchers out of the Department of Psychology, University of Virginia, Charlottesburg and the School of Pharmacy at Texas Tech, Hill Sciences Center. This appeared in Brain Behavior andImmunity in 2007, in the November issue.12 In this particular paper the researchers looked at the effect of infection-induced viscerosensory signals that came from gut bacterial activation (these would be considered parasitic bacteria, or what we have often called “dysbiosis”). What they found is that the signals from these bacteria in the gut (the molecules they produce and the interaction they have with the gut-associated immune system) actually induced or enhanced responses through the immune system of anxiety in these animal studies. It goes through the vagal sensory neurons and occurs as a consequence of the response to various chemical mediators that are produced as a consequence of these bacterium. At the clinical level we could say that gut infection or dysbiosis may have impact upon brain chemical function and induce stress response, but it occurs through a very interesting web of interaction of the immune and nervous systems that then induces changes in behavior. When we talk about events that trigger different gene response elements inducing different phenotypic changes in the individual, we have to look at the whole organism. We have to look at the interaction of that stimuli with the whole of the body, and it takes us back, actually, to the early days of trying to look at the origin of disease (as I said, going back to Robert Koch and infectious disease, or Elie Metchnikoff and the role that bacteria have [friendly bacteria-symbiotes] on improving the immune system function, or even the psychological theory of William James that really talks about these viscerosensory signals that then translate into mood and behavior changes). So it certainly redefines psychology in a different way. I believe it is part of this whole emerging model that we are starting to see that Dr. Westphal alluded to of agents in our environment and the case of small molecules in our food like resveratrol, but also psychological or chemical events that occur from the result of bacterial enteric activity can all influence, similarly, the stress response. Vitamin D Takeaways Well I know that you enjoyed listening to Dr. Holick’s extraordinary presentation as much as I did. There is so much news-to-use as a takeaway from his words and his wisdom and experience in the field. And of course it begs a very important question, doesn’t it? That is, are you supplementing every one of your patients with 1000-2000 IUs of vitamin D a day? If you are not used to giving supplements of nutrients to patients you might still have some reservation about the potential toxicity of vitamin D. Should you do testing prior to the supplementation by measuring the 25-hydroxy and the serum calcium as Dr. Holick was speaking to? The answer I think we can takeaway from his presentation is that if you are dealing with a patient who doesn’t have sarcoidosis and doing this enhanced conversion of 25-hydroxy to 1,25 through their macrophage conversion, then you have a patient who, at worst, is going to do no harm, and at best is going to be of great benefit in raising their 25-hydroxy at or above 30 nanograms per mL, which is the level of serum 25-hydroxy that he was speaking to where you get this threshold effect. As he has indicated, levels in the serum up above 100 nanograms per mL have not been associated with vitamin D toxicity. I think the takeaway that I have-and I believe Dr. Holick’s book actually speaks to this-is 1000 IUs of vitamin D supplementation a day would be considered safe and valuable. In people of northern latitude, or people who have reduced sun exposure, or people using high SPF sun-blocking formulas, the level might even be as high as 2000 IUs a day. But certainly a1000 IU a day supplement for all people would be considered safe and effective except for that outlier that he spoke to (the person with enhanced macrophage conversion of 25 to the 1,25 which is the sarcoidosis patient). This also begs a question about bone loss and goes back and asks the question: is vitamin D really important beyond that of calcium supplementation and estrogen replacement therapy for women, and maybe even men, related to bone loss? In the August 25-31 issue (2007) of The Lancet, the cover featured a breakout that said calcium supplementation alone or in combination with vitamin D is effective in the prevention of osteoporotic fracture.21 There has been a long-standing debate as to whether calcium and vitamin D are, in fact, truly preventive agents in patients at risk to osteoporotic fracture. This was a study looking at people 50 years of age and older, a meta-analysis actually of many studies (29 randomized clinical trials) with total number of patients 63,897. The trials were evaluated based upon quality. Of those, 17 trials of the 29 were found to be of high quality and that constituted 52,625 patients. What the authors found was that by vitamin D and calcium supplementation at 1000-1200 milligrams of calcium a day and 800 IUs daily of vitamin D supplementation there was approximately a 12{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} risk reduction in fractures of all types across these trials with a p value of less than .004 (a highly significant reduction over those who did not supplement with calcium and vitamin D). This represents the largest meta-analysis of calcium/vitamin D intervention trials that has been published and certainly suggests strongly that vitamin D and calcium are beneficial at the level of 1000-1200 milligrams of calcium a day and 800-1000 of vitamin D daily. Following this article, there is an editorial titled “Calcium and Vitamin D for Osteoporotic Fracture Risk” that says that osteoporotic fracture represents, indirectly, about the 12thleading cause of death in America, which is kind of hard to believe because we don’t normally think of bone fracture as being a fatal event.22 But for an older age person, if they have a hip fracture and they go to hospital, many of them don’t leave the hospital-they get opportunistic infection, they get other metabolic problems, and it becomes a lethal event. By reducing bone fracture in the elderly, we have a significant reduction in mortality as well as morbidity. This also pertains to males as well. We often focus our interest only on females, but older and older age men, 65 years of age or older, are also at significant risk to increased fracture as a consequence of osteoporosis. In the Journal of the American Medical Association just recently, there was a report on cost effectiveness of bone densitometry followed by calcium and vitamin E treatment with various types drugs to reduce osteoporotic fracture in men.23They showed it was cost effective and that increased quality of life years, as well as overall longevity, and that osteoporosis and osteoporotic fracture in males is clinically significant as well. Of course, that begs the question, is it just calcium and vitamin D? And the answer is no. There are obviously anabolic therapies that are also used to build the protein in bone as well as the matrix of calcium and vitamin D. There is a nice paper that just appeared in the New England Journal of Medicine titled “Mechanisms of Anabolic Therapies of Osteoporosis.”24This paper tries to get us to recognize that morphogenic-proteins are very important for forming the matrix upon which calcification can occur, and that this is stimulated by agents that activate protein synthesis (growth hormones and anabolic factors). It is also recognized that agents that increase oxidative stress and agents that increase autoimmune reactions have untoward effects on the formation of the bone matrix and become risk factors. There is an interesting paper that appeared in the Proceedings of the National Academy of Science in the September 18 issue talking about oxidative stress causing bone loss in estrogen-deficient animals as a consequence of enhanced bone marrow dendritic activation, and it almost sounds like activation of an autoimmune process that is associated with this bone loss.25 Estrogen loss in female animals causes an imbalance of Th1 and Th2 macrophages (monocytes) and so what we get ultimately is a change in the immune vigilance leading to higher levels of inflammatory cytokines and more oxidative stress and this contributes also to lowered protein synthesis. So when you are dealing with a patient with bone loss, certainly calcium and vitamin D is important but we ought to be looking at the anabolic factors, the insulin sensitivity, and we ought to be looking at the autoimmune profile as well to see if there is any evidence of inflammatory disorders. I hope this gave you some news-to-use as it relates to this extraordinary evolving story of vitamin D. We’ll talk to you next month.

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Bibliography

1 Bland J. What role has nutrition been playing in our health? The xenohormesis connection. Integrative Medicine. 2007;6(3):22-24. 2 Yun AJ, Lee PY, Doux JD. Are we eating more than we think? Illegitimate signaling and xenohormesis as participants in the pathogenesis of obesity. Med Hypotheses. 2006;67(1):36-40. 3 Loscalzo J, Kohane I, Barabasi AL. Human disease classification in the postgenomic era: A complex systems approach to human pathobiology. Mol Syst Biol. 2007;3:124. Epub 2007 Jul 10. 4 Chaldakov GN, Fiore M, Tonchev AB, Dimitrov D, Pancheva R. Homo obesus: a metabotrophin-deficient species, pharmacology and nutrition insight. Curr Pharm Des. 2007;13(21):2176-2179. 5 Yun AJ, Doux JD. Unhappy meal: How our need to detect stress may have shaped our preferences for taste. Med Hypotheses. 2007;69:746-751. 6 Hayes DP. Nutritional hormesis. Eur J Clin Nutr. 2007;61(2):147-159. 7 Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337-342. 8 Yamamoto H, Schoonjans K, Auwerx J. Sirtuin functions in health and disease. Mol Endocrinol. 2007;21(8):1745-1755. 9 Yang H, Yang T, Baur JA, Perez E, Matsui T, et al. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell. 2007;130:1095-1107. 10 Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425:191-196. 11 Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PCG-1a. Cell. 2006;127:1109-1122. 12 Goehler LE, Park SM, Opitz N, Lyte M, Gaykema RP. Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain Behav Immun. 2007 Oct 4; [Epub ahead of print]

Welcome to Functional Medicine Update for January 2006. It is the beginning of a new year. In fact, we are now at the quarter-century mark of continued service with FMU. As my colleague, Jay Johnson and I look at one another, we wonder what happened to those years. It is a pleasure, once again, to be with you at the start of our 25th year. This publication began as Metabolic Update, evolved to Preventive Medicine Update, and finally, to Functional Medicine Update. 13th International Symposium on Functional Medicine I want to remind those of you who may have just joined us this year, of our upcoming 13thInternational Symposium on Functional Medicine, which will be held on April 19–22, 2006 at the Tampa Marriott Waterside Hotel & Marina in Tampa, Florida. The symposium will focus on Managing Biotransformation: The Metabolic, Genomic and Detoxification Balance Points. I am very excited about the plenary lecturers and the concurrent sessions we have put together. We are going to take a contemporary approach to this complex topic to make it clinically useful, and we will cut through a lot of misunderstanding and confusion to deliver news to use to all of the attendees. The symposium is usually held in May, but please note that it is being held earlier this year. On April 19th, we will conduct the preconference course, which deals with the basic biochemistry and physiology of detoxification and biotransformation. We have put together a detailed session that will set the tone for the three-day conference from April 20 – 22, and we will apply the preconference information to a variety of clinical areas. I encourage you to attend the preconference course. In preparation for the symposium, I thought it would be worthwhile to start the January 2006 issue of FMU by focusing on what we know about nutrient modulation of physiological function. What are the emerging areas of understanding that are making this topic less subject to controversy and differences of opinion, and moving it toward consensus? The topic is a moving target that is constantly open to reinterpretation. Over the last ten years, I have continually questioned what nutrients have become more accepted as participating agents in pharmacological and physiological actions that help remediate different disease processes, particularly in individuals with specific need. This goes back to arguments about specific types of nutrigenetic underpinnings requiring specific nutrigenomic interventions. I thought we would stay focused on the question of science-based micronutrient intake and what it relates to in terms of understanding the physiology. This would go beyond deficiency and move us into the area of nutrient pharmacology. It is interesting to note that nearly 25 years ago, Dr. Gene Spiller edited what I consider a very pioneering book, titled Nutritional Pharmacology1 He went out on a limb to even coin that term, if you think about what the climate was like 20 years ago regarding nutrition in the medical and scientific community. The book would have been considered quite ambitious at that time. In his book, Dr. Spiller talked about various areas that were emerging indicating that specific nutrients could be used for pharmacological purposes. The topic has evolved quite remarkably since then. In previous issues of FMU, we have talked about Dr. Bruce Ames’ wonderful review paper that discusses genetic polymorphisms and the need for specific nutrients to push through different steps and intermediary biochemistry to activate the conversion of substrate to product, and how those nutrients serve as coenzyme activators, or how they might participate in gene expression modulators, and work through the trilogy of “omics”-the genomics, proteomics, and metabolomics that give rise to phenomics2 We have talked about the nutritional phenotype, which is what you see in your patients. They express the complex interrelationship of their genetic predispositions with their environmental exposures since the time of conception. Those interactions give rise to who they are, how they think, act, feel, and look. Their health patterns are a complex interaction of genetic uniquenesses with environmental exposures. Nutrition is a shared common environmental experience. The nutrients we consume in our diets are now recognized as information molecules. They participate in the regulation of receptor site activities and intracellular signaling transduction processes through what are called the kinase pathways, to give rise to alterations in DNA function, which create different physiological outcomes in cells that have received different messages from the outside environment. The genes remain the same, but their expression and how they are translated into active proteins, as well as how they are modified epigenetically, including glycation, oxidation, and phosphorylation, are controlled and modified by environmental choices. Diet selection plays a principal role in getting the most from our genes and achieving our full potential for good health. The questions are, which nutrients do we need, how much do we need, and how do we know? Let’s go back to some studies that have been done under the aegis of the Federal Government, such as the National Nutritional Health and Examination Surveys, or NHANES, as it is abbreviated. These large population surveys represent the most extensive documentation on how various nutrients are related to various health patterns. They have been done over a 20-year period, looking at nutritional status and shifts in health patterns. Certain alignment of nutrients and health outcomes can be gleaned from that data. Folic Acid One of the nutrients that has received a tremendous amount of attention over the last five years is folic acid. As we have talked about in previous issues of FMU, this goes back to a report that appeared in the Lancet in the early 1970s by Dr. John Smithels. He observed that women who give birth to sequential children with neural tube defects (NTDs), or the anencephaly seen with spina bifida cystica, had to do with the folate status of the mother, and are often the most common birth defects found in our population. He postulated that increasing folate and other B vitamins during the periconceptual period could be useful to lower the risk and incidence of NTDs. It took nearly 30 years for this concept to work its way through the body politic and ultimately be seen as not only a reasonable observation, but a justifiable physiological concern. It took a long time to identify the difference between a frank folate deficiency seen as pernicious anemia, versus a chronic folate deficiency (a long latency disorder), that results in NTDs in offspring. It is easier to identify an acute deficiency syndrome, such as vitamin C deficiency in scurvy, than it is to identify a long-term, marginal deficiency that produces increased risk of a complex disorder like NTDs in children. The NHANES studies demonstrated that the average intake of folate in the population may be in the gray zone for individuals who carry certain types of genetic uniqueness, particularly related to folate processing and metabolism. Aspects of folate processing are locked into genetic uniqueness through single nucleotide polymorphisms (SNPs). One very frequent SNP is the cytosine-to-thymidine 677 polymorphism of the gene that controls the production of the enzyme, methylenetetrahydrofolate reductase (MTHFR). About 5 to 10 percent of the population is homozygous for this polymorphism, and at least 15 percent of the population is heterozygous for this SNP. It is a very common polymorphism that may penetrate the population at large and result in perhaps 1 in 12 individuals, or 1 in 15 individuals, being highly susceptible to marginal folate insufficiency at a dose intake in the diet that would be adequate for other individuals. That raises the question in the public health milieu as to whether we should administer folate in the diet by fortifying our grains to cover individuals that represent 5 to 10 percent of the population with this polymorphism. This is a very different discussion than that which was discussed when the Food Nutrition Board met and decided on what were originally the Recommended Dietary Allowances (RDAs), later to become the Dietary Reference Intakes (RDIs). These RDA and RDI associations were not built upon the principles of polymorphisms that evolved from the Human Genome Project. We are looking at a very new “aha” or discovery that, when reflecting back on the standards we have used to judge nutritional adequacy, make some of those assessments questionable. That is why there are many people who feel there will be no further modification of the RDIs or RDAs, because they have run their useful lifetime. We now recognize that we need to individualize nutritional recommendations based upon genetic and health status uniqueness. This is a new development in the field of nutrition, as we move into the area of genomics and start to attach nutrition and health to genomic principles. Science-Based Micronutrient Fortification-Which Nutrients, How Much, and How to Know? When we apply this concept to folate, it is an interesting example of how the field has evolved. I am now looking at an interesting recent editorial that appeared in the American Journal of Clinical Nutrition. The author talks about the synthesis of folic acid, which was first accomplished by scientists at Lederle Labs back in 1947, and considered one of the milestones achieved during the era when vitamins were discovered.3 This was to manage a particular medical need related almost entirely to folate deficiency, which was seen as different hematological aberrations, particularly certain types of anemia associated with an altered shape of the red blood cell. It was later found that high levels of folic acid could mask the signs of vitamin B12 deficiency and that over time this deficiency could impair the neurological system. In defining the upper limit of tolerability for folic acid, continued emphasis should be placed on establishing levels that will not mask vitamin B12 deficiency symptoms. When most people think of higher doses of folic acid, they see it as a potentially toxic nutrient because the government has so closely regulated the dosage in a single preparation at 800 mcg in a pregnancy formula, and generally about 400 mcg in a non-pregnancy formula. This suggests that doses above those ranges would be considered toxic. This whole story is being reevaluated based upon understanding the MTHFR polymorphisms and that individuals may need higher levels of folic acid to promote certain positive physiological functions. There may be effects of folic acid on physiology that go beyond the traditional MTHFR effects of producing 5-methyltetrahydrofolate and reducing homocysteine. We also need to consider the effect that folic acid conjugers have on the activation of biopterin synthesis. That has to do with things like nitric oxide production in the vascular endothelium, and central nervous system production of dopamine, which has to do with neurotransmitters and the prevention of depression. S-adenosylmethionine (SAM), which is the product of folic acid metabolism, has been used for the treatment of depression. There may be people with specific defects in folate pathways that require higher doses of folate in order to increase SAM levels in the brain and lower the risk to biochemical, neurological insufficiencies seen as clinical depression. There may be people with hypertension who require higher doses of folic acid to similarly activate the formation of biopterin, the central coenzyme responsible for activating endothelial nitric oxide synthase, or eNOS, which converts arginine into nitric oxide in the vascular endothelium and produces vasorelaxation effects upon vascular smooth muscle and lowers blood pressure. I am talking about a different view that is emerging about how a nutrient can be used and how it influences physiology based upon different genetic uniquenesses. We have just introduced the concept of individualized folate nutriture and its effects on methylenetetrahydrofolate reductase polymorphisms and tetrahydrobiopterin synthesis for optimal biochemical function. Going back to the question of science-based micronutrients, which nutrients, how much, and how to know, we get into functional assessments that go beyond deficiency assessment. Almost all of the standard laboratory methods that have been developed to evaluate micronutrient status were established around deficiency levels. What is the level below which that nutrient is considered to be deficient? We generally measure nutrients in biological fluids-plasma, serum, or urine. These measurements are not intracellular functional analyses of how a nutrient may be influencing a specific tissue or organ system function, such as the vascular endothelium with hypertension, or the neuron as it relates to dopamine synthesis and mood and memory. We are witnessing a remarkable transition from looking at low levels of a nutrient associated with a deficiency in the general population, to specific functional assays of a nutrient in an individual that lead to a functional outcome-in this case, folic acid. Nutrients are not just related to homocysteine and methylmalonic acid; they can also be related to hypertension and neurological function. Using that example as a measuring stick for determining what nutrients have passed scrutiny tests for being potentially valuable in doses considered greater than the normal dietary intake for promotion of improved physiological function, there are nutrients that fall within the vitamin category, the essential trace mineral category, and what might be called the accessory nutrient category, or conditionally essential nutrients, all of which fulfill those criteria. I would like to talk about a few of those to illustrate how far we have come over the last 10 years. Chromium Chromium is a very interesting essential trace mineral. In 1978, I had the pleasure of being on sabbatical and I spent the year at Evergreen State College in Olympia, Washington overseeing a course in nutritional biochemistry. I had the privilege of working with the same 59 students all year. It was an unusual curriculum, and a very intensive, year-long learning program. During that time, a number of guest lecturers visited our class. One of them was Dr. Walter Mertz from the United States Department of Agriculture (USDA), who talked about chromium, the essential trace mineral responsible for what he called the glucose tolerance factor. Dr. Mertz was one of the primary investigators involved with trace mineral research at the Beltsville, Maryland Research Laboratories under the aegis of the USDA. He was a very articulate spokesperson and a good scientist. He presented compelling data from animal studies showing how chromium deficiency related to glucose intolerance in what appeared to be conditions like diabetes. He went on to show that the chromium level in the standard American diet had gone down considerably, and that the USDA Handbook No. 8 Food Tables were not even reporting chromium levels. Chromium levels in foods had decreased as a consequence of a change in agricultural patterns and, therefore, there was significant concern about the adequacy of chromium in the standard American diet, and how it might relate to blood sugar abnormalities and diabetes. That concept was not well received in the 1970s. It was considered antithetical to thought. I recall speaking about chromium at a number of symposia and meetings during the late 1970s and early 1980s, and unless I was addressing what you might call an “enlightened group, that concept fell on unreceptive ears. Over the last 20 years, the concept of chromium and its relationship to glucose tolerance factor has gained much more credibility and support. Dr. Kursheed Jeejeebhoy (a Clinician of the Month on FMU in August 2001), is a world expert in parenteral nutrition. He conducted a considerable number of studies examining parenteral nutritional formulas that were not replete in chromium, and their relationship to glucose tolerance. He showed that in humans, a chromium functional deficiency occurred over a certain period of time in those on intravenous feeding formulas that were low in chromium, often resulting in insulin resistance and glucose intolerance. It is now recognized that trivalent chromium is an essential nutrient that plays a role in a number of metabolic systems. Research indicates that chromium is implicated in insulin function, diabetes mellitus, metabolic syndrome, polycystic ovary syndrome, gestational and steroid-induced diabetes, and depression.4 In fact, the FDA has approved health claims related to chromium, which is quite remarkable, considering the 30-year controversy that has been going on about it.5 As we look at more recent work by Dr. Richard Anderson, a respected investigator in the chromium research area, we see that chromium plays an important role as one of myriad substances needed in trace quantities for improvement of physiological function. We cannot ascribe a chromium deficiency disease, but we look at its relationship to function in the range of somewhere between 400 and 1000 mcg a day. This illustrates a remarkable change in the importance of trace minerals from years ago. This is an indication of what is occurring as we move from focusing on deficiency conditions to looking at functional disorders and the role various nutrients play in conditions like glucose intolerance. By the way, chromium is stored as a glucose tolerance factor bound form in a trivalent state in the liver. It is released during an oral glucose load. It is involved with insulin sensitivity and plays a very important role in the glucose transport process. The nutritional need for chromium in physiology is now quite well recognized. Our highly processed diets are often depleted of many important trace minerals. Vitamin E Let me move to another example-the fat-soluble vitamins and vitamin E, which is a mixed story. We are familiar with the work of the Shute brothers from London, Ontario in the 1950s. They told us about the important role of the vegetable oil concentrate called tocopherol (from the Greek word “to give birth”), that was found to be absolutely necessary in the birthing of animals. (It has never been identified in humans to have that effect.) The vitamin E family is a series of different molecules. The alpha, beta, gamma, and delta tocopherols, plus the tocotrienols, are extracted at low levels out of oils from soy beans and wheat germ (to name just two) that give rise to vitamin E antioxidant activity potential. The Shutes suggested that vitamin E is very important for the prevention of heart disease. The Nurses’ Health Study, conducted many years later, found that individuals in the highest quintile of dietary vitamin E intake had a nearly 50 percent lower incidence of heart attack. This tended to confirm the Shutes’ epidemiological association between vitamin E and cardioprotection. Many other subsequent small studies were done that implicated, or at least suggested, that vitamin E was cardioprotective. More recently, larger clinical intervention controlled trials have been done, using a-tocopherol, both the synthetic DL-a- and the natural source RR-tocopherol as the acetate or succinate form. These studies were equivocal, and led to much negative press surrounding vitamin E’s role as either cardioprotective or cancer preventive. For example, one research group published studies indicating that vitamin E, when given along with statins and/or niacin, was not beneficial and they suggested its use should be questioned. That put a stigma on the vitamin E story. Where are we right now as it relates to single nutrient intervention studies-the double-blind, placebo-controlled trials from which we try to ascribe a value or a risk? There is a good article in the Journal of the National Cancer Institute that examines that question6 The author talks about randomized trials of aspirin and vitamin E as potential agents for cancer prevention that draw support from epidemiological and observational evidence. Both aspirin and vitamin E have plausible biological mechanisms as antioxidants. It appears that natural vitamin E has the ability to protect people from cancer and that various aspirin-like derivatives (non-steroidal, anti-inflammatory drugs [NSAIDs]), as well as a proven ability to protect against heart disease and stroke. Could benefit be achieved in reducing the risk to cancer by using aspirin and vitamin E together? A variety of papers have been published recently that examine that question. As reviewed in the Journal of the National Cancer Institute articles, the Journal of the American Medical Association published two papers in the summer of 2005 written by Buring and his colleagues that looked at the interrelationship between aspirin, vitamin E, and cancer.7,8 These were large, randomized control trials as part of the Women’s Health Study protocol. Forty thousand healthy women were randomly assigned to take aspirin, vitamin E, and/or a placebo for ten years in the hope of clarifying what clinical associations might exist between aspirin, vitamin E, and cancer risk. According to the results, no association was found, and the findings raised questions about where to go with these kinds of chemoprevention trials using purified nutrients and/or pharmacological agents. The Buring studies raised all sorts of questions. Many researchers do not think these studies are the final word. For instance, Dr. Nancy Cook of Brigham and Women’s Hospital, and lead author of one of the two JAMA papers, believes that further aspirin studies may still yield positive results for specific types of cancer. Taking single nutrients out of complex dietary convention and using them in an intervention trial as if they are drugs, may be the wrong way to address the question as to whether nutrients influence disease. Single-Agent Intervention Trials Single-agent studies on beta carotene or vitamin E may not mimic what is going on when we consume these substances in higher doses in the diet as a complex mixture, along with the myriad of other physiologically active agents in foods and food concentrates. Is there a different mechanism of action for a drug versus a nutrient? Perhaps nutrients work in combination with one another as part of a natural selection process of how they were found in the diet and how they evolved a relationship in human physiology that is different than a drug designed specifically as a new-to-nature molecule to modulate one enzymatic step or one physiological function. As a consequence of a major action for which it was selected, it has a reproducible effect as a single agent, whereas that single nutrient may have evolved as a complex part of the diet over many years to work in combination with other signaling-active substances in the genomic pathways. These are complex issues, but they seem to be emerging out of the data coming from these clinical trials. How can we rationalize the strong association of nutritional epidemiological data with the lack of support we see in single-agent intervention trials? It appears that single intervention trials are not duplicating what is really going on in human physiology when we eat a single substance or agent in a complex diet, which interacts with multiple other agents. We get into more complex study designs that may not be as amenable to the double-blind, placebo-controlled, one-agent-for-one-outcome variable type of philosophy upon which drug efficacy studies were built. We have to be cautious not to get painted into a corner in this field, assuming that because data derived from a single agent against a single endpoint outcome study was not positive, and that it means nutrients do not play a role in improving physiological function-in this case, chemoprevention or heart disease prevention when used in the context of a natural selection process that evolved over time in a complex diet. Are we using the right substances when we do these particular intervention trials? In our attempt to reduce the complexity, we take a complex mixture (in this case, vitamin E as a natural source, containing a mixture of alpha, beta, gamma, and delta forms), and we may purify it down to a single form in order to make it a simpler trial. For example, we may use an alpha-tocopherol derivative alone, rather than the mixture found in the natural source. In the case of vitamin E, that means we would eliminate g-tocopherol, which has been identified as an important part of the story. Maybe we have just taken out one of the components of the vitamin E mixture that is critically important for modifying the endpoint we are trying to evaluate. Several lines of evidence support a role for oxidative stress and inflammation in many conditions. Epidemiological studies on heart disease are very clear, and there are literally hundreds of animal and in vitro studies that suggest a correlation between antioxidants and cardioprotection. Mechanisms are starting to emerge that make a connection between reactive oxygen species and antioxidant protection, and protection against atherolsclerotic physiology. Vitamin E is one of those antioxidants (at least in the lipid-soluble realm), that has been extensively discussed in the literature. Vitamin E exists in a series of different forms-the alpha, beta, gamma, and delta forms-and it also exists as synthetic alpha (called DL-alpha), which is a racemic mixture of eight different stereo-isomers. It can also exist as the natural source RRR vitamin E a-tocopherol, which is a single enantiomer, just one of the eight made by nature. In some supplementation studies using a-tocopherol, the major form of vitamin E has been found to reduce biomarkers of oxidative stress. The prospective vitamin E trials almost always use a-tocopherol exclusively. Is a-tocopherol the only form of vitamin E that is useful in the prevention of vascular disease? To answer that question, we need to ask why a-tocopherol was chosen to begin with as the principal form of vitamin E sold in supplements. It is historical, because in the early research, a-tocopherol was found to have the highest potency. What was the potency built upon? It was built upon the ability of that substance to prevent rat fetal resorption, which was the bioassay, meaning the amount of vitamin E required to prevent a rat from resorbing its fetus. People do not take vitamin E to prevent fetal resorption. Does that bioassay map very well against the physiological effect in humans? Maybe using a-tocopherol because it has the highest potency is the wrong way of assessing potency in humans. Gamma-tocopherol is the most prevalent form of vitamin E in plant seeds. Vegetable oils such as corn, soybean, sesame, and nut oils, including oils from walnuts, pecans, and peanuts, are rich sources of g-tocopherol. They represent 70 percent of the vitamin E consumed in the typical US diet from a food form. If we look at the epidemiological studies on vitamin E intake and heart disease, we see g- tocopherol analysis, not a-tocopherol analysis. Yet, these intervention trials were done with a-tocopherol, looking at cardioprotection. Gamma-tocopherol is a powerful antioxidant. It is somewhat less potent as an electron donator than a-tocopherol. We might say that it is slightly less powerful as an antioxidant. However, g-tocopherol’s unsubstituted C5 position on the chromanol ring appears to make it better able to trap lipophilic electrophiles, such as reactive nitrogen species. In pioneering studies, Cooney et al. found that gamma-tocopherol is superior to a-tocopherol in detoxifying nitrogen dioxide.9 Gamma-tocopherol has been shown to inhibit smooth muscle cell proliferation by inhibiting protein kinase C activity, while b-tocopherol had no effect, indicating that its effect is independent of its antioxidant activity.10 We are concerned with more than antioxidant effects when we look at tocopherols and the difference between g- and a-tocopherol effects may go beyond that of its antioxidant effects. Animal studies (rat studies in particular), have shown that there is a significant difference between the physiological effects of a-tocopherol and g-tocopherol, particularly when focused on platelet aggregation and delay of arterial thrombogenesis.11 Gamma-tocopherol supplementation results in a stronger inhibition of superoxide generation and lipid peroxidation. Therefore, we could say that possibly, the epidemiological work looking at the dietary association between vitamin E intake and lowered cardiovascular risk was a surrogate measure of g-tocopherol intake, but the clinical intervention studies used a-tocopherol, so it may have been the wrong nutrient for the outcome variable that we were looking at. The point I am trying to make is that we are evolving a much more sophisticated understanding of how to measure, what to measure, and when to measure. We know that vitamin E increases the production of vasodilator prostanoids in human aortic endothelial cells and has an effect on lowering cyclooxygenase-2 and phospholipase A2 arachidonic acid.12 We also know that vitamin E influences the glutathione redox pathway and therefore has something to do with the maintenance of proper intercellular redox buffering-the glutathione-to-glutathione disulfide ratio. In fact, we know that mixed antioxidant-enriched diets in animals improve glutathione redox status and mitochondrial function, and lower the rate of senescence in animals predisposed to it, or increased biological aging. This is discussed in some nice work by Drs. Sohal and Packer, two well-known investigators in the molecular gerontology area at the University of Southern California School of Medicine13 We are starting to witness different associations between vitamin E and vascular function, immune function, inflammatory function, and cardiovascular and metastatic function that take us beyond the synthetic or single isomer a-tocopherol into the mixed tocopherols, which is more a food-based form that delivers different nutrigenomic messages. An Overview of DHA from Cognitive and Behavioral Tests in Humans and Animals What I am talking about is the evolution of a model. Sometimes, we would like clear answers and no ambiguity. Unfortunately, because of the rapid evolution of this field over the last ten years, we are still in a state of hypotheses more than facts and proof, but we are moving to knowing what we should know. For instance, we now know that docosahexaenoic acid (DHA), a long-chain, omega-3 polyunsaturated fatty acid, is very important for brain, ocular, and immune development. An association between cognitive and behavioral effects and brain DHA can be seen in animal studies, and suggests negative consequences for children who do not get adequate levels of DHA in utero and post utero.14 This is a new “aha” that we did not know about ten or 15 years ago when it was not considered important. How many children have been fed infant formula devoid of DHA, resulting in some adverse neurological effects in their development? Who knows the answer to that question, as we move from breast feeding to infant formula to the new recognition of the role that DHA has in brain development? These are the questions that are framing a new form of functional medicine and a new form of nutrient pharmacology. This is a good time to segue into our discussion with our Clinician of the Month, who will talk about the pharmacological relationship to health patterns.

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INTERVIEW TRANSCRIPT

Farid Wassef, RPh, CCN Guardian Houston’s Pharmacy 6316 Main Street, Box 817 Stouffville, ON, Canada L4A 1G8 JB: It’s time for our Clinician/Researcher of the Month. This month, we are privileged to have someone who has had a voice in functional medicine for more than a decade. Farid Wassef received his Bachelor of Science Degree from the Massachusetts College of Pharmacy. He has extensively diversified his expertise through post-graduate training at the International and American Association of Clinical Nutritionists, and now works at the Guardian Houston Pharmacy store and at Memphis Star Health Services in Stouffville, Ontario. He is a leader in the Canadian functional medicine movement, and has been a member of the Institute for Functional Medicine Advisory Board. He has a perfect record of attendance at all our international symposia. More than that, he is a leader in thought, and he understands what the future might look like as we move toward a distributive healthcare system. Farid, it’s a great pleasure to have you on FMU. Let me begin by asking how you made the transition to nutritionist, focusing so much of your energy on patient counseling and therapy, as well as becoming a best-selling author with your book, Breaking the Age Barrier: (Strategies for Optimal Health, Energy and Longevity)?15 That’s a big departure from the traditional role of a pharmacist. It sounds like you had an epiphany along the way. FW: Absolutely. Thank you, Jeff, for that lovely introduction, and it’s my pleasure to be with you. The greatest influence on my career came from my father. We have operated our pharmacy here in Stouffville, Ontario for the last 35 years, and this is where I got first-hand exposure to some of the shortcomings of pharmaceutical care. When I graduated from pharmacy school in the late 1980s, I was ready to make a difference in people’s lives. Like many other healthcare professionals, I became discouraged and disillusioned with the system. One of the things I wanted to do was find solutions for people. I wanted to help them age better. I didn’t want to just stand by, watch their medication lists grow longer, and assume the role of insuring compliance. I didn’t want to just get people to take eight to ten drugs and somehow try to manage side effects and adverse events. It was an extremely frustrating situation. Counseling Patients I decided that people deserve more care than just two or three minutes at a prescription counter. In 1993, as bold and unheard of as it was, I opened an office adjacent to my pharmacy and began to counsel patients about what was going on with their prescription care. Had the right medication been selected? Was the diagnosis accurate? What other factors were driving the pathology? I came across some basic principles that have served me well. One is that the nature of chronic disease is multi-factorial and that intervention needs to be multi-dimensional. In the process of reviewing all of this, I stumbled upon nutrition, and it has been a wonderful journey for me over the last 15 years learning how to improve people’s diets. We now know that diet has a tremendous influence on health. These are the things that I examined and researched as I started to write my book, Breaking the Age Barrier: (Strategies for Optimal Health, Energy, and Longevity). There are 6000 diseases with genetic components, and we are still counting. These diseases are decreasing the quality of people’s lives, and result in people dying early or ending up on eight to ten medications. Many of the chronic, age-related diseases result from poor lifestyles and diets. That is what led me to learn more. I think this will be my 10th year in a row attending the functional medicine symposia, and all of them have served to build a good foundation for me. I learn all the cutting-edge information and bring it back to my practice. It helps me make sense of what I see every day. These are the kinds of things I encourage pharmacists to do. People are interested in self care. They want more from their pharmacists, and are willing to pay for it. I encourage pharmacists to get involved with functional medicine to see how they can enhance the lives of their patients. When I started out 17 or 18 years ago, I didn’t feel I was making a difference. Now, I do, and it’s been very rewarding for me. I’m glad I made the change and I haven’t looked back. JB: You have said some things I would like to follow up on, because I believe they touch every one of our listeners, no matter what their backgrounds or disciplines. First, let me deal with the phrase you used-“self care.” Dr. Jim Gordon, the director of the Center for Mind/Body Medicine in Washington, DC, has suggested from data accumulated from consumer surveys that the transition in health care we’re undergoing right now is going to be driven by consumer interest in self care. Dr. David Eisenberg, a professor of medicine at Harvard Medical School, is the principal author of a study that examined the use of unconventional medicine in the United States and which found that it was much more broadly used than previously thought. It constitutes several billion dollars of expenditures, and it rivals out-of-pocket expenses for hospitalization. There are more patients seeing unconventional providers than those seeing family doctors. That all relates to the term, “self care.” It seems that when a person wants to get diagnosed and treated for a disease, he or she goes to a doctor. When patients want to deal with something related to what is referred to as the “walking wounded,” they often look at self care. It is difficult to identify good professionals who can provide quality information about self care. They don’t generally get the information from their doctors who are trained in pathophysiology. As a result, patients go to the health food store or to an exercise facility to seek out someone who might have that capability. Here is where an educated pharmacist or other ancillary healthcare professional can provide a significant contribution. There may be more people looking for self care than are going to hospitals. Self-Care Movement FW: You’re absolutely right. You mentioned two researchers, but several prognosticators in our own profession were sounding the alarm back in the mid-1990s, letting pharmacists know that the self-care movement is huge and that the over-the-counter category is growing tremendously. People are spending money out-of-pocket with very little guidance, without being matched up with a qualified healthcare practitioner, and some of them are going about it blindly. As pharmacists, we’ve heard about this over and over again for the last 10 years, and that this is an area where we can evolve and become experts in self care. In fact, patients are demanding it. It’s much more than a trend; it’s here to stay. The baby boomer generation wants health and wellness-more integrative care-and they want to understand all of it. Because of the amount of information in the media about nutrition and various fad diets, pharmacies are becoming inundated with vitamin and mineral preparations, herbal remedies, and so forth. We can no longer say that there’s no data to back this up or that this is just a passing trend. We need to examine this. Integrating Information into Pharmaceutical Care Beyond becoming a self-care expert, it’s a great opportunity to engage patients and understand how we can help them integrate the information into their pharmaceutical care. We also need to be able to critically appraise information. Pharmacists, as well as doctors and other healthcare professionals, need to understand about evidence-based medicine. We need to collaborate with one another. We need to understand patient-centered care. We need to understand about health promotion and preventive care. These are the four pillars that have been proposed by every single province in Canada and every state in the United States. These are the kinds of things we need to instill in health care that are going to solve a lot of problems and help us to move forward. That’s what I’ve done. I’ve known about this forecast for a decade and a half and I’ve taken it upon myself to collaborate with physicians and to get involved with patients by sitting down with them for a half hour to an hour at a time. It’s really not that difficult. That time spent with patients often results in some good answers as to what’s going on with them. We can no longer practice assembly-line medicine where we give people two or three minutes of time and expect to solve all their complex, chronic problems. That’s just not working. The self-care movement is well entrenched and people are interested in it. Pharmacists can seize this opportunity. It’s something I certainly have recognized. JB: Let’s move to some of the realities you deal with every day. Clearly, most pharmacists spend their professional lives on the other side of a counter, during which they are providing a product to an individual with a little bit of information that could be encoded in less than a minute in a sound byte. There’s a barrier between the customer and the pharmacist in the form of that counter. When you cross that counter and become a counselor, a therapist in part, that’s establishing a whole different relationship with a customer. Now, they are more likely to be seen as real people with complex lives. How does that transition occur? The Transition from Pharmacist to Counselor FW: First, pharmacists in North America are recognized as primary healthcare practitioners. We are the first point of entry into the healthcare system in a number of instances. During a busy day dispensing medication, we need to decide when a patient approaches us if that particular situation warrants a three-to-five-minute discussion, or whether it warrants more assessment and requires more probing questions. I’m able to decipher that need very quickly and I invite people to make an appointment. Twelve or 13 years ago, I wondered who would sit down with a pharmacist and pay them for between a half hour and perhaps even two hours of their time. Much to my surprise, people are willing to do that. The public trusts us. They are tremendously loyal to us, and we have never really parlayed that into an office-based practice where we charge for our time. We mistakenly associated ourselves primarily with pharmaceutical medicine when we really needed to align ourselves with clinical services. In speaking to some of my colleagues here in Canada and in the US, I’ve discovered they are getting into things like diabetic care, asthma care, cardiovascular disease care, and looking at what is the best medicine to select in each situation. What is the best dietary approach to take? What kind of nutraceutical approaches can be integrated into a multi-dimensional approach to get the patients well? We have to rely upon many interventions. We can’t just fixate on any one thing. I think the biggest factor in making this transition is that each pharmacist needs to conduct a self-evaluation and realize that the time is ripe to begin to make sense of what they see every day. Why is cardiovascular disease so prevalent? Why has cancer moved into the number two disease spot, when it didn’t even crack the top ten 50 years ago? Why is there such an epidemic of obesity? Why is diabetes now the fastest-growing illness? Asking some of these questions will lead to some very profound answers. We now know that stress has a lot to do with some of the chronic, age-related diseases. We also know how chronic inflammation links diseases. We know about oxidative stress in the body. We know about how dietary factors, such as macro- and micronutrient balance, fatty acid balance, glycemic load, dietary fiber content, and even things like the pH of the diet to sodium/potassium balance, all have a tremendous influence on a person’s functional health. We have pharmacology and pathophysiology, but we need to look at functional biochemistry and functional physiology to figure out how we can influence the other end of the spectrum to improve care. It can be done. Every day, we see people getting off medication, or finding a minimum dose on which we can manage their diseases, free of side effects and adverse events with other interventions, and motivating people to make changes in their lives. I can’t tell you how rewarding it is. People want this type of care. JB: When you are counseling a customer (now a patient), do you have difficulty bridging the two worlds of pharmacology and nutrition? Are they in conflict, or is there a way to harmonize what might appear as two disparate philosophies? Bridging the Worlds of Pharmacology and Nutrition FW: It’s a matter of perspective. For instance, we might look at someone with high cholesterol and recognize that he or she is at risk for cardiovascular disease, or heart attack and stroke, so we might put that person on statin therapy. They may come back to the pharmacy and tell us that the doctor wants to increase the dose because they haven’t yet reached “target,” and they still don’t know why the cholesterol keeps soaring. Here is an opportunity where, instead of just filling a prescription for increased dosage of a drug, the patient may want to talk about side effects, muscle pain and fatigue, or abdominal cramping. Patients are very educated. They will challenge us. They’re reluctant to take more medicine. They’re reluctant to expose themselves to side effects; they’re very cautious. They want to get help, but at the same time they don’t want to surrender to high-dose, pharmaceutical polypharmacy approaches. It was acceptable a generation ago, but it’s not acceptable now. As a pharmacist, along with my understanding of functional medicine, I can look at dietary cholesterol. We can lower it, but that may only influence serum cholesterol by about 20 percent. We now know that the bulk of cholesterol is produced in the liver, and that excessive insulin is a potent molecule that will signal the liver to wrap up cholesterol production, for several reasons. Is the person in a state of chronic inflammation? We know cholesterol can be a reparative molecule. Or, is the person locked into a state of biochemical stress? We know that cholesterol is a precursor to cortisol and perhaps the patient needs more stress hormones. If we understand physiology and biochemistry, we can begin to peel off the layers and look at why this is happening, and where in the web of biochemistry to push and tug. What other interventions can we suggest to go along with statins to bring the cholesterol down? It may mean a number of other interventions, and it needs to be done on an individualized basis. That’s really what I do. I look at why the medicine isn’t working from a pharmacological perspective. Why is the problem getting away from us? What are the drivers of these problems? This is where functional medicine points to many of the answers. It points to multi-factorial causes and gives one the ability to come up with a systematic approach using various interventions to address the problems. The problem in pharmacology is that, while we know a lot about all the different pathways, and we know a lot about many of the players, we don’t know how all the mediators are connected. We don’t bother to identify the triggers, and we don’t bother to take each patient’s uniqueness into consideration. If 10 people visit a doctor for depression, they all walk out with a prescription for an SSRI. In some cases it helps, in some cases it hurts, and in some cases it has no effect. We can’t continue to practice protocol medicine. We need to understand why pharmacological approaches fail. This is why I have benefited so much from learning about functional medicine. It helps me to make sense of the aberrant biochemistry I see and to determine what action to take. It takes some time and patience to sort it all out, but it is very fruitful when you understand how to bring the patient along. JB: How about the dialectic with the doctor of record for that particular customer or patient? Does this establish an opportunity for a dialogue, or do you find that it ends up in a dialectic confrontation? Developing a Relationship with Physicians in the Community FW: Thirteen or 14 years ago, it was a tough go between physicians and myself. But in that time, I recognized what I needed to do to establish myself as a credible source of information, and practice pharmaceutical care and self care in a responsible manner. In 1996, I touched base with 150 physicians in my area who refer patients to me, and I began to send them periodic newsletters. The newsletters were based on clinical information the doctors see in their journals. I helped review the information and crystallize it for them. I gave them some clinical pearls and let them know that I was on top of the information. Little by little, this helped me to become established as a credible person in the community. It helped me to facilitate when I would phone a physician and thank them for referring Mrs. So and So. I would say that I had assessed the situation and instead of, in this case, raising the dosage of a statin, I would tell the doctor what I would recommend. Then I would ask what he or she thought about my recommendation. They would respond by saying that I made a lot of sense, and if I felt that strongly about it, they would be open to my approach because they didn’t want to run the risk of side effects and just arbitrarily raising medication dosage, but that they were at their wit’s end as to what to do with this patient. We need to engage physicians in this manner, but we first need to distinguish ourselves in the community. I go out into the community and give lectures. I speak to doctors and send them letters. I publish articles in various magazines and journals, and send information to the doctors. All of that goes a long way in distinguishing one’s self as a primary healthcare practitioner. This is what pharmacists need to do. Surveys have told us that. Five or 10 years ago (unfortunately, I can’t remember the citation), 2600 physicians were surveyed and asked what they thought about pharmacists getting involved in self care, pharmaceutical care, and practicing integrative medicine. New physicians appeared to hold pharmacists in high regard and they had high expectations of them, but as they moved on in their careers, they lost confidence in pharmacists. However, when a pharmacist expanded clinical services and gave them a call, they were open and receptive to reasonable approaches to health and wellness, and that needed to be substantiated by significant data. We back things up with data and, little by little, physicians today are much more open minded and much more experienced in working collaboratively. Today, a family physician knows he or she can’t go it alone. They’re busy; they’re swamped, and if somebody steps up to the table, such as a pharmacist, and tells them he or she can help, they’re open to it. The time is ripe for us to collaborate with physicians to do this type of care. JB: That leads me to the last question. When you engage in a discussion with a patient, there are many ways that you can make your presentation. You can lead with the diet relationship to that condition, such as a lipid-lowering diet with statins, for instance, or you can lead with the concept of nutritional pharmacology. Or, you could take a drug/nutrient position and tell the patient the drugs he or she is taking may have adverse effects on nutrients and therefore, suggest that those nutrients be augmented. Is one of those approaches a principal route, or do you assess the patient and then make your decision about the primary route? Multiple Effects of Medications FW: We are getting more and more data all the time. Some of the common medications do indeed deplete nutrients to deficient and sometimes insufficient levels. I don’t think you can take a simplistic approach to functional medicine. It’s very linear just to look at six to eight medications a patient is on, open up a textbook and see what nutrients are likely to be depleted, and that it’s just a matter of getting them on, for instance, coenzyme Q10 because they’re taking a statin, or a little more zinc because they’re on an ace inhibitor, and then perhaps throw in a multi-vitamin. That approach is unlikely to work. What we really need to do, and it goes back to what I said earlier, is to go beyond and really understand the multiple effects that drug is having on the individual. For instance, in the case of statins, we need to look beyond coenzyme Q10 depletion, and look at whether the statin is being properly metabolized. Is phase 1 and phase 2 detoxification working in the liver, the gut, and the kidneys? Why are they continuing to have muscle pain? I’ve given them coenzyme Q10 because I’ve looked up the research that says coenzyme Q10 is likely to be depleted, but they continue to complain of muscle pain. Here is where you have to look at the possibility that the drug isn’t being properly metabolized. This is one of the things I’m anxious to learn more about at the upcoming symposium in April. I love the topic of biotransformation because as pharmacists, that is our domain. We need to learn more about drug metabolism and detoxification and then look at the multiple effects way beyond simple drug/nutrient depletion. I go beyond that to assess how well the drug is working, how well it is being tolerated, and whether we are reaching target in this particular situation. If the answer is no in all those situations, then we need to go beyond the simple repletion of nutrients. JB: That’s very helpful. Do you feel that it’s imperative for a pharmacist doing your kind of work to become a compounding pharmacist? Is that not a critical component of this focus? The Compounding Pharmacist FW: There is a huge need for compounding as we move toward personalized medicine, individualized care, and patient-centered care, and away from protocol medicine and a doctor-centered healthcare system. A lot of my colleagues have decided to go into compounding and have found it to be very rewarding. I chose not to do that because I’m thrilled about the counseling I’m doing. I would suggest selecting one thing that you are really excited about. What do you see in your practice? Do you have a lot of cardiovascular disease patients in your practice, or diabetics? Do you want to help patients with smoking cessation? Do you like working with obese patients? Pick something you see in your practice that you’re excited about and want to get involved with. That’s the main thing. It’s easy for me to say that all pharmacists should get into compounding, but if you’re not interested in that, and you’re not excited about it, you’re not likely to be successful with it. That’s the secret to growing and evolving into a primary healthcare practitioner. You need to focus on a particular area of interest. JB: Your philosophy and mission are very motivating. It creates a sense of imperative about the quality of a distributive healthcare system that provides health information, not just disease-care information. Your book, Breaking the Age Barrier (Strategies for Optimal Health, Energy and Longevity) which can be found on amazon.com, is a very good manifesto of everything you’ve talked about. I certainly would recommend it for people who want to follow up on the insightful comments you’ve shared. I also want to recognize you as a leader. Being a visionary in any profession carries with it an associated risk. You’ve been willing to step out and be counted as a member of the front-edge group of healthcare providers who are going beyond what might be considered their comfort level, to introduce your services and knowledge to your customers in a way that opens up the opportunity for discovery. That’s tremendously unique. Many people feel apprehensive and wonder if they really have the stuff to open up a dialogue with customers in such a way that they’ll share their private lives and collaborate with them on finding a path to better health. I think you’ve spoken both from an implementation perspective, and from a philosophical and humanistic perspective about a different kind of health care, one that is, as you said, more patient-centered, more humanistically oriented, and one that deals with information as the key tool for motivating people to change. Thank you so much for your advocacy, your hard work, and for sharing it with us. FW: Thank you. JB: We wish you the best and will check back with you at a later date. I can be assured, just on the strength of your information, you’re going to set a lot of people’s minds to thinking about what they can do better. FW: We certainly hope so. Statins and Coenzyme Q10 Mr. Wassef raised a very interesting question-what effect do statins have on CoQ10 status, and is supplementation a nutritional pharmacological antidote to the depletion caused by statins? This was the topic of an interesting mini-symposium published in Current Topics in Nutraceutical Research that I would like to summarize. There is a broad recognition that statins block the synthesis of the isoprenoid family of compounds. The biosynthesis of coenzyme Q10 in cells comes through the isoprenoidpolymerization pathway, the isoprenyl pyrophosphate pathway. Therefore, it is known that CoQ10 levels could be lowered by blocking prenylation and isoprene synthesis. Dr. Chandan Prasad, associate editor of the Department of Medicine in Current Topics in Nutraceutical Research at the LSU Health Sciences Center in New Orleans, speaks about whether statin users should take supplemental CoQ10 as a way of balancing out the functional depletion that might occur from taking statins.16 This concept is really born out of a wonderful review paper by Dr. Ronald Lieberman of the Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, titled “Statins and coenzyme Q10 intersection of established medical therapeutics, clinical pharmacology and the emerging evidence-based science of complementary and alternative medicine for protecting cardiovascular health.”17 In this review paper, Dr. Lieberman advocates that monitoring of CoQ10 status should be considered during use of statin therapy. It may be necessary to provide for a conditionally essential nutrient that might be low due to the inhibition of its synthesis as a consequence of taking statins. He recommends more controlled research on the supplementation of CoQ10 in the range of 200 to 400 mg a day while people are on statins. The clinical observation that people have had in using CoQ10 supplementation during statin therapy has been mixed. There is no definitive clinical intervention trial that has really developed a statistical analysis of the value of supplementation with CoQ10. Theoretically, or at least conceptually, it would seem like a good idea because of the potential blocking in CoQ10. In fact, a series of investigators from the East Texas Medical Center and Trinity Mother Francis Health System in Tyler, Texas, who have looked at the potential role of concomitant CoQ10 with statins for patients with hyperlipidemia, came to the conclusion, once again, that 200-400 mg per day of supplementation with CoQ10 during statin therapy was, in fact, valuable, and they support this level of supplementation to prevent CoQ10 depletion and lowering some of the adverse side effects that appear with statin therapy, including neuromuscular complaints.18 The other side of the coin, just to give a balanced comment, is that of Dr. Barry Bleske from the College of Pharmacy, University of Michigan, who says: “This is a wonderful hypothesis and certainly worthy of our attention, but quite honestly, no clinical intervention trials have ever been done, and there is not even evidence that intercellular CoQ10 is actually depleted during statin therapy. This is suspected, or a hypothesized depletion in the absence of proof of hypothesis. In the absence of really having available intervention trials that would look at intercellular CoQ10 before and after statin and whether you could remediate that with oral CoQ10 therapy, that it is premature to recommend CoQ10 therapy.” The time is not now to recommend CoQ10 therapy to patients receiving statin. Before this recommendation can be put forth, we must validate this hypothesis with outcome data.”19 Again, as is the case in this emerging nutritional pharmacology area, every white has a black; every discussion has a shade of gray, and we are just emerging a fundamental platform upon which these decisions can even be made, and some of these questions are related to methodology as much as association. How do you actually study these associations? What are the ways that the studies can be properly designed to lead to outcome-based understanding and to evidence that is actually directing you to the right conclusion, rather than just misdirecting you. You have a number, but you are not sure what that number is associated with. Again, clinically and empirically, many patients report improvement of their outcome with statin therapy when they are taking concomitant CoQ10 supplements, but I want to put in context that there is no definitive clinical intervention trial that has been done evaluating that hypothesis. Vitamin D What about vitamin D? That is another interesting, emerging supplement that seems to be lower than optimal in the American diet because we see low blood levels below 25 ng/mL of 25-hydroxyvitamin D very commonly in people that have a variety of immunological problems-type 2 diabetes, fibromyalgia, depression, dysphoria, and difficulties with multiple sclerosis-like symptoms. Increasing risks also of colon, some breast, and prostate cancers are also associated with low 25-hydroxy D3. Recently, in the journal Carcinogenesis, the authors of an article talk about colon-specific regulation of vitamin D conversion to its active hormonal form, and this might be a very important thing for reducing the risk of colon cancer.20 Vitamin D can be converted into the 1, 25-dihydroxy vitamin D, the active hormonal form, in the intestinal mucosa. Diets that contain higher calcium and vitamin D appear to be chemopreventive against colorectal tumor pathogenesis. Here again is a very interesting complication of a simple question. Does vitamin D prevent colon cancer? The answer may be yes, when it is in the appropriate GI mucosal environment and has proper levels of activation of vitamin D to its 1,25-dihydroxy form, because cytochrome P450s found in the gut mucosa hydroxylate vitamin D into the active hormonal form that regulates cell cycling and the potential carcinogenesis associated with other exposures. These things are not always easy to understand, in part because our gut is a bioreactor that can convert one substance to another by the presence of certain flora. Not everybody has the same flora. We get the proximal nutrient converted into the ultimate nutrient that influences function. Silencing of Genes by Promoter Hypermethylation What about the relationship of genes and cancer-the genes that control cell cycling? These are the genes that are sometimes associated with tumor promoters. A factor in keeping these genes in check, or silenced, is by methylation. Methylation is controlled, in part, by things like folate status and SAM through the methylation pathway. If you can silence tumor prompter genes by methylation, can genes that are protective also be silenced by methylation? The answer is yes, and the questions being asked now are: How is methylation of DNA controlled? Can specific non-tumor promoting areas be demethylated, while keeping the tumor promoter genes silenced? What role does folate have? What happens when we give too much folate? Would that cause a problem? Some studies show that hypermethylation of genes, or too many methyl groups stuck on the histones of genes and nucleic acids, creates its own problem associated with tumorogenesis, but how this hypermethylation is regulated is not well understood.21 A recent study in Carcinogenesis looked at the effect of differing folate levels in the development and progression of mammary tumors in animals. It was found that giving very high levels of folic acid (8mg per kg of the diet in animals, a very high dose) did not lead to any increased level of breast cancer after the exposure to a known breast carcinogen, N-methyl-N-nitrosourea.22 The investigators came to the conclusion that you cannot over-methylate by increasing folic acid. What you want to make sure of is that you have adequate folic acid to properly methylate. That is an interesting dose/response relationship. Does the body have some kind of control mechanism upon which it will not allow excessive amounts of function to occur with excessive nutrient intake? Benefits of Soybean Foods hat leads us to the last question about various macronutrients that carry all sorts of phytochemicals in the diet that can regulate function. How do we study them? For instance, let’s take soy. The soy controversy is really raging these days. Does soy cause harm? Does it cause or prevent dementia? Does it cause pancreas problems and digestive difficulties? Does it cause allergy? Does it cause or prevent cancer? The answers to those questions are often related to arguments based upon removing something from soy and trying to analyze it in very high doses in animals versus looking at the whole food. If you look at the whole food and the data that has been published, you find that soy as a whole food with its natural constituents, has tremendous benefit in regulating physiological function.23 We have to look at it in the context of how and at what levels it has been consumed. I hope I’ve set in context for you some of the things that are in the news related to nutrient pharmacology, where we are going, and how this relates to biotransformation and detoxification, in preparation for our April 2006 symposium. Thanks for being with us at the start of this New Year.

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Welcome to Functional Medicine Update for February 2006. This is going to be an exciting issue. We are going to focus on an area of functional medicine that has great opportunity for both general learning and for specific application to a major clinical condition-autism and autistic spectrum disorder, a rapidly advancing area of concern, interest, and clinical opportunity. It is also very telling, because it represents a condition that has multiphasic inputs. It is not a single condition; it does not have a single cause; it does not have just one etiological agent. Therefore, it lends itself nicely to the functional medicine model as a general teaching tool, as well as a clinical evaluation tool. 13th International Symposium on Functional Medicine This topic fits nicely into our preparation for the 13th International Symposium on Functional Medicine, to be held at the Tampa Marriot Waterside Hotel & Marina in Tampa, Florida on April 19-22. Please note that the symposium is being held earlier than usual this year. It has been held in May in previous years. The focus of the symposium is Managing Biotransformation: The Metabolic, Genomic and Detoxification Balance Points. This is nicely amplified and discussed in our Applying Functional Medicine in Clinical Practice training program and in our new Textbook of Functional Medicine. We could not be happier to see the textbook hit the desks of our clinicians, practitioners, and Institute for Functional Medicine members. I hope you are as excited about it as I am. It is a culmination of a couple of years of very diligent work on the part of the IFM staff, particularly Sheila Quinn, our Senior Editor, working with David Jones, president of IFM. The quality of the work that has gone into this book on the part of the authors, the editors, the reviewers, and the graphic layout people is a tremendous representation of what we have been trying to achieve over the past 20 plus years we have been talking about functional medicine. If you have not yet seen a copy of the Textbook of Functional Medicine, it certainly should be on your list of things to read. Reading the chapters on biotransformation and detoxification would be a good way to prepare for the 13th International Symposium on Functional Medicine. This issue is going to focus on one of the most significant debates in medicine, which has been ongoing since 1998. That is saying a lot, with all the things going on in the field of medicine, but in terms of the functional medicine model, the autistic spectrum disorder debate is at the forefront of medical controversy, medical interest, media attention, and parent activism. It has all the trappings of one of the great social issues and historical medical movements of our time. In 20, 30 or 40 years, I am sure that medical historians will write about this period with interesting color. Like all times of great paradigm changes, it is full of energy (and sometimes volatility), a lot of preconceptions and strong statements, as well as strong personalities, which makes it interesting from a humanistic perspective. It also makes it very confusing at times when trying to sort out the wheat from the chaff. Start of the Debate–1998 Study by Andrew J. Wakefield, et al. We are going to do our best during the course of this month’s issue of FMU to go through the debate that started with a seminal paper in 1998 that resulted in a rising tide of international controversy and interest in this area. I am talking about the paper by Andrew J. Wakefield, SH Murch, and their colleagues that came out of the Inflammatory Bowel Disease Study Group, University Department of Medicine, Royal Free Hospital & School of Medicine in London. We reviewed this article almost eight years ago in FMU. It is titled “Ileal-lymphoid-nodular hyperplasia, non-specific colitis and pervasive developmental disorder in children”1 This report has generated continuous debate, as well as inquiry, discussion, invectives, and every possible kind of adjective that could be used to define human emotion. For eight years, there has been an ongoing debate about this paper and its implications to the etiology and potential treatment of autism and autistic spectrum disorder. For those of you who may not remember the nature of this particular paper, it was a report on 12 children (mean age of six years) who were referred to a pediatric gastroenterology unit with a history of normal development, followed by a loss of acquired skills, including language, together with diarrhea and abdominal pain. This was conducted in a gastroenterology clinic setting; therefore, the principal reason for referral was digestive problems. The children underwent gastroenterological, neurological, and developmental assessment. Ileocolonoscopy, biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were also done (under sedation). Barium follow-through radiography was done where possible, and biochemical, hematological, and immunological profiles were examined. Based upon information from the parents, it was reported that the onset of behavioral symptoms was associated with measles, mumps, and rubella vaccination in eight of the 12 children, with measles infection in one child, and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in seven, but no granulomas. Behavioral disorders included autism (nine), disintegrative psychosis (one), and possible post-viral or vaccinal encephalitis (two). There were no focal neurological abnormalities, and MRI and EEG tests were normal. Noted abnormal laboratory results included a significantly raised urinary methylmalonic acid, as compared with age-matched controls (p=0.003), low hemoglobin (4 children), and a low serum IgA (4 children). The researchers concluded that the gastrointestinal disease and developmental regression in this group of previously normal children was generally associated in time with a possible environmental trigger-the MMR vaccination. Groundswell of Controversy When this article was published, it created a groundswell of controversy. Those in support of a multifocal environmental connection to neurologic disease jumped on the bandwagon, whereas those who felt this was presumptuous and not supported by hard facts considered it an exaggeration of findings and an extrapolation beyond reason. There is something interesting about this study that I have not heard discussed much-the biochemical recognition that these children had a significant increase in urinary methylmalonic acid excretion as compared to age-matched controls. What that means to me as a clinical biochemist, and probably to all of you who are students of functional medicine, is that it may have been an indication of a functional vitamin B12 deficiency. A raised methylmalonic secretion is often coupled with elevated homocysteine-the metabolic abnormalities associated with functional B12, folate, and/or B6 deficiency. Elevated urinary methylmalonic acid could represent a functional B12 deficiency, which may track back to certain biochemical genetic markers. In other words, do these children have some form of subclinical genetic susceptibility for altered vitamin B12-dependent metabolism? Or, do they have a malabsorption problem, such as a parietal cell insufficiency of intrinsic factor secretion? Vitamin B12 is a very large nutrient that needs to be absorbed in the absence of a “helper,” which is called intrinsic factor. This raises all sorts of questions about gastrointestinal (GI) physiology, vitamin B12 absorption, and the effect B12 has on the neurological system beyond the frank immunological influence between ileal nodular hyperplasia and autistic spectrum disorder. This is an interesting interpretation of the story: Could there be some kind of immunological event in susceptible children that modifies their gut-associated lymphoid tissue (GALT) activity that, in turn, influences inflammatory processes, lowers absorption of critical nutrients such as B12 (required for neurological function), and translates into not only elevated urinary methylmalonic acid excretion, but also the problems we see associated with autistic spectrum disorder? That is just a question, a hypothesis. If the folate connection to neurology goes through the pathway of the folate cycle and through 5-methyltetrahydrofolate, homocysteine and, ultimately, to S-adenosylmethionine (SAM), it is possible that the combination of B12 and folate metabolism polymorphisms, coupled with immunological triggers in a child, gives rise to an overlapping series of events that could trigger certain types of neurological dysfunction. These are all interesting speculations, but as we move forward from the initial observation of ileal nodular hyperplasia (like mumps of the intestinal tract), ultimately being found with pervasive developmental disorder in children labeled as autism, it raises questions about what autism really is. Is it a brain disease, or is it a disseminated disorder associated with immunological imbalances that have neurological sequelae? And that leads to a further question. Could one of the potential environmental triggers in a genetically or immunologically susceptible child be something like mumps, measles, and rubella vaccination? In public health, this question strikes terror in the hearts of people, because we have, with hard-won success, been able to immunize children and lower many of the very serious diseases that have threatened children’s lives and created huge epidemics of infant mortality, such as rubella, small pox, and diphtheria. These conditions caused serious epidemics and have resulted in the death of many tens of thousands of children. The ability to immunize against these disorders and make them virtually non-existent has been a very successful medical breakthrough. To suggest that immunization is contributing to something as severe as an autistic spectrum disorder, even in a small group of children, raises the question as to whether parents will continue to immunize their children. That has resulted in much debate and controversy. What is the risk versus the benefit? What can we say about the connection between an MMR-precipitating trigger and the ultimate expression of something called autistic spectrum disorder? Wakefield’s 1998 paper triggered many Letters to the Editor that appeared in various journals, particularly the Lancet. In 1998, there was a plethora of letters 2 arguing that a study of only 12 children is too small to draw any kind of strong conclusions, and indicating that other studies have not corroborated these findings. And, there is evidence from epidemiological records in the UK that there was no increase in the prevalence of autism with immunization. If autism is triggered by the MMR vaccine, one should be able to track back to the 1950s when this vaccination was first routinely required in children. If there is a connection, it should be seen in an increase of autism, but that does not seem to hold true when looking at the epidemiological record.3 In the May 1998 issue of the Lancet, there was an article that talked about autism, inflammatory bowel disease, and MMR vaccination.4 Again, the discussion was about the risk/benefit and how much we can make of the Wakefield data. On behalf of the authors, Wakefield replied, saying that: yes, there are all sorts of reasons to be concerned about the methodology, whether the selection of patients was biased, whether it was a large enough sample size, and whether the data was reported correctly, but that the authors stand by the findings. Furthermore, he stated: “We recommend that pediatric gastroenterologists investigate this problem further, since it is our belief that there is both a large unmet need in the community and a possible window-of-opportunity for some children with autism.”5 We start to see a swirl of debate developing among different factions. Is the data adequate? Is it accurate? Was the study done properly? Did the investigators have a preconceived bias and pounded the data into that bias, or was it a real effect? Many Letters to the Editor in the Lancet over a period of several months debated this topic. We begin to look at how autism and the GI tract may be interrelated. Another review of Wakefield’s work generated an interesting, critical editorial that came to the conclusion that this paper is a wakeup call. “Wakefield, et al. are to be congratulated in opening yet another window onto the ever-broadening spectrum of gut-brain interactions. Their findings raise many challenging questions that should provoke further, much-needed research in this area, research that may provide true grounds for optimism for affected patients and their families.”6 This editorial, in response to the Wakefield work, was written by Drs. Eamonn Quigley and David Hurley from the Department of Medicine, National University of Ireland and appeared in the American Journal of Gastroenterology. Wakefield and his colleagues continued their studies and have published more papers on this concept, with a recent (2000) report in the American Journal of Gastroenterology (a very highly respected journal), titled “Enterocolitis in children with developmental disorders.”7 The authors describe some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) associated with behavioral regression and bowel symptoms, and compares them with pediatric controls. This study extended the size of the previous sample to 60 affected children and 37 developmentally normal controls. Ileal nodular hyperplasia was present in 54 of 58 (93 percent) affected children, and 5 of the 35 control children (14 percent), with a statistical significant difference of p<0.001. Colonic LNH was present in 18 of 60 affected children (30{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}) and in 2 of 37 controls (5.4{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}). Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}) ileal biopsies from affected children and in 4 of 14 (29{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}) with ulcerative colitis, but not in non-inflammatory bowel disease controls (p<0.01). By extending the sample size to larger groups of children, they were able to support what they had first reported in the Lancet in 1998. They concluded that a new variant of IBD was present in the group of children with developmental disorders. That “raised the ante,” so to speak, relative to the critics who said there could be no such connection. If it were not for the MMR vaccination connection, this would probably not be so controversial. Had Wakefield’s report just contained a discussion of ileal nodular hyperplasia and the gut/brain connection, he would have presented a striking, new view of the etiology of autistic spectrum disorder. The addition of the vaccination issue resulted in a bite that was too big for many to swallow. Wakefield’s 2000 paper resulted in another series of commentaries in the Lancet, including one that appeared in the June 15, 2002 issue, titled “MMR vaccination, ileal lymphoid nodular hyperplasia and pervasive developmental disorder.”8 The authors of this editorial (Barbara Hendrickson and Jerry Turner from the Section of Pediatric Infectious Diseases, University of Chicago, Chicago IL) state that perhaps we are starting to develop more understanding of this issue and we should not be rejecting it out of hand. They went on to say: “Thus, the idea of pervasive developmental disorder-associated inflammatory bowel disease deserves further consideration. In support of this hypothesis, Torrente and colleagues (again with Wakefield) have now reported that IgG and complement C1q were found deposited on the basolateral epithelium in duodenal biopsy specimens from 23 of 25 autistic children, but not in specimens in control cases.”9 The model starts to grow. There was a paper that put a negative twist on this There was a study published in The New England Journal of Medicine, titled “A population-based study of measles, mumps, and rubella vaccination and autism.”10 It was concluded that there was no correlation between the initiation of MMR and frequency changes in autism. The authors conducted a retrospective cohort study of all children born in Denmark from January 1991 through December of 1998. The cohort was selected on the basis of data from the Danish Civil Registration System, which assigns a unique identification number to every live-born infant and new resident in Denmark. MMR-vaccination status was obtained from the National Board of Health. Information on the children’s autism status was obtained from the Danish Psychiatric Central Register, which contains information on all diagnoses received by patients in psychiatric hospitals and outpatient clinics in Denmark. They obtained information on potential confounders from the Danish Medical Birth Registry, the National Hospital Registry, and Statistics Denmark. They looked at 537,303 children in the cohort; 440,655 had received the MMR vaccine. They identified 316 children with a diagnosis of autistic disorder and 422 with a diagnosis of other autistic-spectrum disorders. After adjustment for potential confounders, the relative risk of autistic disorder in the group of vaccinated children, as compared with the unvaccinated group, was 0.92, or slightly lower, and the relative risk of another autistic spectrum disorder was 0.83. The investigators concluded that there was no association between the age at the time of vaccination, the time since vaccination, or the date of vaccination and the development of autistic disorder. This study provides strong evidence against the hypothesis that MMR vaccination causes autism. In 2002, in the journal, Alimentary Pharmacology and Therapeutics, there was another paper published by Wakefield and his group. Now, he is under tremendous pressure, as you might imagine, from all sorts of groups for his outspoken position on the correlation between MMR and autism. This paper was titled “Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands.”11 In this paper, Wakefield states: “There is growing awareness that primary gastrointestinal pathology may play an important role in the inception and clinical expression of some childhood developmental disorders, including autism. In addition to frequent gastrointestinal symptoms, children with autism often manifest complex biochemical and immunological abnormalities. The gut-brain axis is central to certain encephalopathies of extra-cranial origin, hepatic encephalopathy being the best characterized. Commonalities in the clinical characteristics of hepatic encephalopathy and a form of autism associated with developmental regression in an apparently previously normal child, accompanied by immune-mediated gastrointestinal pathology, have led to the proposal that there may be analogous mechanisms of toxic encephalopathy in patients with liver failure and some children with autism. Aberrations in opioid biochemistry are common to these two conditions, and there is evidence that opioid peptides may mediate certain aspects of the respective syndromes. The generation of plausible and testable hypotheses in this area may help to identify new treatment options in encephalopathies of extra-cranial origin.” Again, this suggests that autism is not just in the brain, and that it has etiological factors produced elsewhere in the body that contribute to what we see as autistic spectrum disorders and functional brain changes. Wakefield goes on to say: “Therapeutic targets for this autistic phenotype may include: modification of diet and entero-colonic microbial milieu in order to reduce toxin substrates, improve nutritional status and modify mucosal immunity; anti-inflammatory/immunomodulatory therapy; and specific treatment of dysmotility, focusing, for example, on the pharmacology of local opioid activity in the gut.” In the functional medicine model, we call this the 4R Program-remove, replace, reinnoculate, and repair. This GI restoration program adds back friendly biota and prebiotics, nourishing the GI mucosa, eliminating toxic or parasitic organisms, reducing food allergies, and other immune-activating substances from the diet. The first therapeutic target based on this model would be what, in functional medicine parlance, we call the 4R Program. The second thing Wakefield talks about is anti-inflammatory and immunomodulatory therapies. These would be things that can reduce the activity of an upregulated GALT (the gut immune system) and lower immunological activity, systemic and hepatic, as well as neurologic microglial and immune inflammatory activity. The next thing he talks about is a specific treatment of dysmotility, focusing, for example, on the pharmacology of local opioid activity in the gut and trying to lower the production of some of the endogenous opioid mimetics. Some of these may come from certain food families by partial hydrolysis. One family that has been implicated is dairy proteins, from which release of certain fragments may take place after partial hydrolysis of the milk proteins that have neurologic activity. Or, there may be secondary byproducts of bacterial fermentation in the gut by specific types of bacteria. Similarly, gluten has been suggested to be potentially neuroactive. This raises some questions about food types, diet types, the GI milieu, and inflammatory/anti-inflammatory balance. Perhaps these would constitute different approaches one might take toward the management of autism and autistic spectrum disorder. Small Intestinal Enteropathy with Epithelial IgG and Complement Deposition in Children with Regressive Autism Following up, Torrente et al. published a marvelous paper in Molecular Psychiatry.10 This was the paper referred to in the Lancet article that appears to demonstrate that IgG deposition was seen in the basal lateral epithelial surface in 23 of 25 autistic children, co-localizing with complement C1q. This was not seen in other conditions. These findings seem to demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The findings are suggestive of an autoimmune lesion. There is some kind of activity that results in the body producing an antibody to itself-to the GI and possibly to brain tissue. We have now put the autistic spectrum disorder into the family of potential autoimmune disorders. In another issue of Molecular Psychiatry, there was a very interesting editorial by Dr. Wakefield, titled “Enterocolitis, autism and measles virus,” in which he states that, in some children, measles infection that attacks the gut mucosal immune system can induce an upregulated immunological vigilance associated with the appearance of autistic spectrum disorder12 Sometimes, we lose the sense of this story because it is so tightly tied to MMR vaccination, but actually, there may be many different triggering factors that precipitate immunological changes that are ultimately seen as autistic spectrum disorder, suggesting there is more than one cause. Yes, the MMR vaccination component is certainly worth attention, but in and of itself, it is not the whole story. Dr. Wakefield speaks to this beautifully in another article he wrote for the Journal of Pediatric Gastroenterology and Nutrition, titled “The gut-brain axis in childhood developmental disorders.”13 In this article, he proposes that there may be multiple molecules produced through immunological activation in the intestinal lumen that can mediate what we call autism, as noted in this quote:. “Neuroactive compounds derived from the intestinal lumen can permeate the mucosa; cross the blood-brain barrier; and cause psychiatric, cognitive, and behavioral disturbances. Indeed, this axis is critical in oral medication of psychopathology. Awareness is growing, particularly within the field of childhood developmental disorders, that in a substantial proportion of affected children, gut-brain interactions may be central to abnormal neural development and the subsequent expression of aberrant behaviors. Difficulties in accepting the biological plausibility of such a model, particularly among those whose interests have focused on primary pathogenic mechanisms operating within the central nervous system, may reflect, in part, a perceived lack of an analogous gut-brain interaction in either human or experimental models of encephalopathy. Among gastroenterologists and hepatologists, however, the evidence for such a mechanism is readily apparent. Seeking an analogy with circumstances in which clear evidence shows an influence of the gut on the normal brain, may help advance this argument. ” “Untreated celiac disease-a aberrant immune response to dietary gliadin, is associated with intestinal mucosal inflammation, increased intestinal permeability, increased absorption and urinary excretion of neuroactive dietary peptides, autistic and psychotic behaviors, and neurological complications. The precise mechanism(s) of central nervous system sequelae has not been established, although toxicity from the gut and autoimmunity are pathogenetic forerunners.” There is a precedent here. We can even talk about hepatic encephalopathy-a variable impairment of cerebral functioning in patients with acute or chronic liver disease-being the result of multiple biochemical influences on central neural transmitter systems. In addition to the neurotoxic effects of ammonia, we now recognize that derangements of what are called middle-molecular-weight nitrogenous molecules, such as gamma aminobutyric products, or serotonergic products, are evident with regard to hepatic encephalopathy. It should really be called gastrointestinal hepatic encephalopathy-the gut connected to the liver connected to the brain. I am saying that there is some circumstantial evidence from other fields of medicine that indicates these mechanisms exist in human physiology. They track against specific types of neuropsychiatric disorders, and the connection with children appears to make good sense and be worthy of attention. During the course of the clinical assessment and management of children with autistic spectrum disorders, Wakefield and his group have been impressed by the improvement in symptoms and general improvement in well being after bioclearance before colonoscopy with simply the purging of gut contents. Treatment of intestinal inflammation with 5-amino-salicylate-based compounds or a polymeric diet resulted not only in the relief of chronic constipation, but significantly improved overall function in these children. There was an elimination of certain potential reactive proteins, like casein and gluten. There was improvement in the microbial function of their gut. In seeking to test this hypothesis (a role for intestinal Clostridial dysbiosis in autism, specifically through neurotoxic encephalopathy), Sandler et al. noted objective cognitive improvement in autistic children in an open-label study of oral vancomycin, an antibiotic that exhibits minimal systemic absorption. “Children regressed after cessation of therapy, suggesting that any colonic dysbiosis and associated toxic sequelae probably were secondary to underlying intestinal disease, rather than the primary problem.” It is interesting that an antibiotic that works principally in the gut could have such an effect on brain chemistry. Again, from a functional medicine model, we see the interconnectedness of the gut to the immune system to the liver to the systemic circulation to the brain and the brain’s immune system through the microglia. The failure of vancomycin to eliminate clostridial spores is also a possibility, although less likely, given the efficacy of the drug in treating Clostridia difficile. This is one approach that has been used as part of the 4R Program (ie., the remove step). By removing specific organisms through antibiotic or antimicrobial therapy, the load of potential secondary metabolites is lowered, which alters immunological function and improves neurological function. Wakefield goes on to say: “In summary, within the autistic spectrum, a substantial group of children have what may be primary intestinal pathology. The constellation of developmental disorder and gastrointestinal pathology (provisionally termed ‘autistic enterocolitis,’ combines the paradoxic elements of a motility disorder-esophageal reflux and constipation with spurious diarrhea-and enterocolonic mucosal inflammation, a feature more commonly associated with frank diarrhea.” Understanding the neurochemical basis of the gut-brain interaction in autistic enterocolitis may be very important in resolving this paradox and helping to develop rational therapeutic approaches. Wakefield has continued this work. One of his papers appeared in the Journal of Clinical Immunology, titled “Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology.”14 Again, he has extended his research to more detailed work on immunity. Allegations of Research Misconduct An amazing thing happened in 2004. The Lancet went after Dr. Wakefield and set up an independent investigation board to examine his protocols, his methodology, his research, and his lab notebooks, to see if, in fact, they stood the test of scrutiny. Ultimately, this led to a series of statements in the Lancet, one by Dr. Wakefield in the March 6, 2004 issue, in which he expresses his rancor at such allegations of research misconduct.15 Ultimately, through several debates, that led to a position statement on the allegations published by the editors of the Lancet.16 “The evidence we have seen indicates that ethics committee approval was given for data collection from clinically indicated investigations in the children with an initially undiagnosed illness and who were described in the 1998 Lancet paper. “As described under Allegation 1, detailed clinically appropriate investigations led to a re-evaluation of the initial diagnosis of these children, as set out in protocol 172-96. “We do not judge that there was any intention to conceal information or deceive editors, reviewers, or readers about the ethical justification for this work and the nature of patient referral. We are pleased to have had the opportunity to clarify the scientific record over the matters raised by these serious allegations.” In all the years I have followed this publication on a weekly basis, I consider some of these statements to be quite remarkable. Lessons of the Research on Autism and MMR What are the lessons of MMR and of this work, the most remarkable probable evolution of a functionally-based view of chronic disease that we have seen over the last 10 years? Ultimately, this controversy led to Dr. Wakefield’s change of professional residence. He left the Royal Free and University College Medical School in London and moved to the United States to set up his own private research institute. He continues to publish extensively. He published a paper in the Journal of Clinical Immunology, in 2004, titled “Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10.”17 Most recently, Dr. Wakefield published a paper in the European Journal of Gastroenterology and Hepatology, in which he continues to reinforce his original theme. The title of this paper is “The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder.”18 He concludes: “Ileo-colonic LNH is a characteristic pathological finding in children with ASD and gastrointestinal symptoms, and is associated with mucosal inflammation. Differences in age at colonoscopy and diet do not account for these changes. The data support the hypothesis that LNH is a significant pathological finding in ASD children.” We are at an interesting juncture in the evolution of this hypothesis. People have challenged that the work was not extensive enough. Dr. Wakefield responded by continuing the work and publishing it in top-flight journals. It has opened up more debate in the field. It has challenged our views, in the sense that disease of the brain is beginning to look more like a functional disorder. It is consistent with a different paradigm of medicine than that of the differential diagnosis-one of the organ-specific pathology model of disease, where multiple organ involvement across many different systems is examined. This is functional medicine, and I honor Dr. Wakefield for being such a vigilant warrior, despite the extraordinary abuse and criticism he has sustained in developing this hypothesis, and his scholarly work and commitment to excellence in getting this message better understood. It is time for our Clinician/Researcher of the Month, who will do a good job of carrying this discussion forward

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INTERVIEW TRANSCRIPT

CLINICIAN/RESEARCHER OF THE MONTH Martha R. Herbert, MD, PhD Center for Morphometric Analysis/Pediatric Neurology Massachusetts General Hospital-East Bldg. 149, 13th Street; Room 6012 Charlestown, MA 02129 JB: I’ve been looking forward to this month’s interview for a long time. We are going to be talking with Dr. Martha Herbert, who is an assistant professor of neurology at Harvard Medical School and a pediatric neurologist at Massachusetts General Hospital in Boston. She is a member of the Harvard/MIT Massachusetts General Hospital Martinos Center for Biomedical Imaging. That is all very interesting, but there is something well beyond that we are going to learn about Dr. Herbert. Jay Johnson and I have been recording FMU for almost 27 years. During that time, I can honestly say I have never read a more interesting, rich, and robust C.V. than that of Dr. Herbert. It stands alone as being the most unique C.V. I have seen over the years. She started off with a Bachelor’s in Fine Arts from the California Institute of Arts in Los Angeles. She went on to pursue a PhD in the history of consciousness, which is pretty remarkable. It gave her some very fundamental knowledge in, as Humphrey Osmond said, “understanding understanding.” Dr. Herbert received her MD from the Columbia University College of Physicians and Surgeons. Here is a person with a Bachelor’s Degree in Fine Arts, a PhD, and after that an MD, who ends up as an intern in pediatrics, a resident in pediatrics and neurology, a pediatric neurology Fellow and ultimately, a clinical associate in neurology at Massachusetts General Hospital and Harvard Medical School. With that background comes a tremendous range of understanding, from the standpoint of philosophy, psychology, and the history of science, as well as the medical and biomedical sciences. You might have heard Dr. Herbert give one of her many lectures. Autism is one of the areas on which she is focusing a lot of attention. Her work is ongoing at the Martinos Center for Biomedical Imaging, and her Harvard Medical School/Massachusetts General Hospital connection is focused on research devoted to the structural and functional connectivity in neurobehavioral disorders, particularly autism. She is an active member of the Defeat Autism Now (DAN) group. I have had the privilege of reviewing a manuscript that Dr. Herbert allowed me to look at that has just been accepted for publication. Before we get into the topic at hand, I’d like to read the abstract portion of this paper. I think it defines the spectrum of discussion we will have in this month’s issue of FMU. “Autism is defined behaviorally, as a syndrome of abnormalities involving language, social reciprocity and hyperfocus or reduced behavioral flexibility. It is clearly heterogeneous and it can be accompanied by unusual talents, as well as by impairments, but its underlying biologic and genetic basis is unknown. Autism has been modeled as a brain-based, strongly genetic disorder, but a series of emerging findings and hypotheses support a broader model of the condition as genetically influenced and systemic. These include imaging, neuropathology, and psychological evidence of pervasive (and not just specific) brain and phenotypic features; postnatal evolution and chronic persistence of brain, behavior, and tissue changes (e.g., inflammation) and physical illness symptomatology (e.g., gastrointestinal, immune, and recurring infection); overlap with other disorders; and reports of rate increases in improvement or recovery that support a role for modulation of the condition by environmental factors (e.g., exacerbation or triggering by toxins, infectious agents, or other stressors, or improvement by treatment). Modeling autism more broadly encompasses previous work, but also encourages the expansion of research and treatment to include intermediary domains of molecular and cellular mechanisms, as well as chronic tissue, metabolic and somatic changes previously addressed only to a limited degree.”19 (This paper is available from herbertbrainstudies@partners.org.) This is probably the longest introduction I’ve ever made on FMU, Dr. Herbert, but it’s well deserved. Your background, experience, and focus on this very complex disorder all fit together. Welcome to FMU. The first question I want to ask is: How did your travels take you to this point? Your journey sounds very remarkable. MH: Thank you. First of all, I didn’t start out as an artist. I started out as a biochemistry major in college. I went to the Bronx High School of Science and I was a “geek.” I come from a family that was very interested in social and political theory, as well as science, so I was imbued with a range of concerns. I took a journey away from science and, while I was doing that, a few things happened. When I was still in college, I got involved with some peer counseling work and became very interested in the biology of emotional catharsis. That’s what eventually led me to neurology. The other thing that happened was spending some time in Mexico working with Ivan Illich before he wrote Medical Nemesis. I stayed in touch with him and went to his medical school to work with him on the history of the body. I also studied with a variety of complex systems thinkers. The most prominent of them was Richard Levins at the Harvard School of Public Health. I also studied with Gregory Bateson and a variety of other people. I was exposed to integrative thinking for decades and, between graduate school and medical school, I worked with a group of very reflective developmental and evolutionary biologists for a number of years doing seminars. When I got into medicine and neurology, I thought I was going to look at the biology of emotion, but I got handed autism data. The autism data was initially frustrating and kind of dull. I was trying to do brain behavior correlations, such as which region of the brain is a different size and how that correlates with behavior. We pulled out a few things like language area asymmetry alterations. But what we found really interesting was that the brains were big and they reflected widespread, non-uniform changes. It wasn’t just in one place. You couldn’t reduce the kind of things we were coming up with to any known neuropsychological model. Parallel to that clinically, I began seeing more children. These children didn’t just have behavioral problems; they were sick. I went to a conference in Rome in 1999 to deliver my brain behavior correlations, and there was someone there by the name of Paul Shattock. He put up a slide about abnormal urinary peptides in autism. As a pediatric neurologist, I knew something about peptides-urinary peptides reflect a metabolic abnormality. That was not what I had been told about autism. If we’re finding measures that are abnormal at that level, the thing we are looking at is a very different animal than what I had previously thought I was looking at. I had a complex biology systems background and then, I walked into a situation where I began to question something I’ve heard Sid Baker say. Do you see what you believe or do you believe what you see? I started seeing things that were different than what I had been told to believe, and I had to deal with it. That’s how I got to where I am. JB: Through imaging, you see certain things, but what you see is obviously sifted through your belief system. Tell us what you’ve seen through your imaging studies with the autistic spectrum disorders. Brain Volume Increase in Autism MH: The first thing we saw was that these brains are bigger. We saw an overall volume increase, and this is the most replicated finding in autism research. I have a review of this in the October 2005 issue of Neuroscience, titled “Large brain in autism: the challenge of pervasive abnormalities.”20 We have been oriented toward looking for modular changes to explain modular behaviors, but here, we have a widespread change. We found that the largest brains existed in high-functioning autism (first identified by Pauline Filipek, who is now at the University of California Irvine), compared to controls. Low-functioning autistic brains in our sample weren’t as big as the high-functioning brains were, but they were still bigger than the brains of children with comparable mental retardation but without autism. We also found that developmental language disorder (DLD) brains were larger than normal. Nobody had ever measured the whole brain in DLD; everybody had been looking at the language areas, presuming that a language disorder is specific to language parts of the brain. We’re now finding out that even developmental language disorder is systemic. These children have a lot of non-language-related neurological problems-clumsiness, and EEG/ERP abnormalities in a variety of things, as well as a possible association with autoimmune abnormalities, in the children or their close relatives in some cases. We found that there was a tendency for the brains to be bigger, and a seemingly countervailing tendency for mental retardation to bring them down a little bit. That was the first thing. Significance of Brain White Matter In trying to find out what was making the brain bigger, we found that the predominant thing was the white matter. White matter makes up 30 percent of the total brain volume (cerebral white matter), but it makes up 65 percent of the volume increase. That’s interesting, because most people don’t think of white matter; they’re into neurons, and white matter is just supposed to be there to get neuron signals from one neuron to the next one. Actually, it’s not looking that way anymore. White matter has become interesting in a variety of neurodegenerative disorders, as well as in children’s disorders. The thing about the white matter was, is it all of the white matter, or is it just some of the white matter? White Matter Parcellation We have a technique in our laboratory called white matter parcellation. We divide the white matter into zones related to the tract architecture. This was developed for scans where you can’t see the fiber tracts, as new diffusion imaging allows you to do. We found that the white matter that was contributing to the enlargement was what we call the radiate-the outer white matter (including the “corona radiata”) tucked under the gyral folds. This predominantly includes short connections between parts of the cortex that are both close to each other and within the same hemisphere-not the longer tracts, not the corpus collosum that connects the two hemispheres, not the long tracts that go down to the body, but predominantly, the shorter corticocortical tracts. This is also the area that myelinates latest-myelination starts deeper in the brain. We also found that the later an area myelinated, or the longer it took to myelinate, the more it tended to be larger than in the brains of the controls. We felt that we had found some sort of “archaeological footprint” of something that happens in time, which changes and becomes more intense over time. The last thing we found was a rather large-scale shift, not away from leftward asymmetry, which was the same in comparing autism, developmental language disorder and controls; but instead an addition of a lot more areas that were rightwardly asymmetric, particularly in the higher order association areas-that is, the areas that are most highly connected up with other multiple parts of the brain. That is interesting, because other people are finding a lot of right hemisphere problems in autism. Those are the main things that we found.21 Where I’m going now is to study these findings on some other levels. JB: The general suspicion is that the frequency of autism is increasing in our population. Is this factually correct? Increased Incidence of Autism Linked to Geographical Toxicity MH: I’ve been showing some slides I got from Ray Palmer, who is at the University of Texas has a paper on autism rates in Texas. They are visual slides-maps of Texas by school district. The interval from 1990 to 1993 is shown on the first map. The interval from 1998 to 2000 is reflected on the second map. There are a lot more districts in the 1998-2000 interval that show a high rate of autism. These images are very visually powerful. Then, Palmer showed the slide of the later time interval with the higher rates next to the Federal Toxic Release Inventory, followed by another map showing the distribution of total toxicity by district. The overlay was remarkable. Every time I show this slide, it’s a complete show-stopper, because you can see powerfully that the increases have occurred more frequently in the areas where there’s more toxicity. Interestingly, there was one district in southwestern Texas that had a very high rate of autism but did not overlap with any indications of high toxicity. It turns out that the oldest mercury mine in the country is located there. The last thing this paper showed was that for every 1000 pounds of airborne-released mercury (I’m talking about environmental pollution here), there was a 43 percent increase in special education rates, and a 61 increase in autism rates. This paper and these images are a potent piece of data consolidation. My feeling is that if you look at the epidemiological studies, there are differences in methodology from one to the next, which some people use as grounds to say we “cannot be sure” what is happening. But knowing what we know from this Texas study, and what we know is going on environmentally on the planet, my position on this is that the null hypothesis cannot any longer be that nothing is happening. We can’t wait around until we’ve definitively proved there’s an epidemic and exactly what agent is causing it. We need to be incorporating hypotheses right now that address potential mechanisms that could be driving an increase like this, particularly when you see it overlaid with toxics, as was done in Palmer’s paper. JB: What is this new term, “autistic spectrum disorder,” which seems to broaden the diagnostic criteria, and how did it arise? Autistic Spectrum Disorder MH: There’s been a history of trying to refine the behavioral criteria clustered together that we call autism, but even though it’s defined in relation to three behavioral domains, it’s a continuously distributed set of features. Each of the three defining domains of behavioral deficits-language, socialization, and repetitive behaviors-is continuously distributed. Autism spectrum includes conditions called pervasive developmental disorders NOS (not otherwise specified), which are basically the same thing, only milder. To be PDD-NOS rather than autistic, either you don’t meet all the criteria, or you don’t meet them by the age of three. It’s something less severe. In Asperger’s syndrome, there isn’t the language abnormality and the same language delay or impairment, although there may be unusual language. The continuous distribution of the features is a real issue. People involved in the world of genetics are trying to develop measures that deal more with continuous rather than dichotomous variables, because the dichotomous variable approach wasn’t resulting in genetic findings of significance, and it wasn’t helping with studying milder features in relatives. Geneticists are hoping that maybe they’ll get further with the continuous variables. My problem is that if we define this autism syndrome behaviorally where you’re talking about a biological disorder-we don’t know what the biology is that is driving it, but we do know there’s a set of symptomatologies that tend to travel with it-then maybe the way we’re defining it doesn’t point to the right level at which to look at what’s going on. If these children have GI and immune problems, maybe some of the genetics are GI or immune genetics, or maybe it’s environmental vulnerability genetics-not just brain or behavior. Autism Environmental Genomics Project I did an autism environmental genomics project, which I’m just writing up, where I overlaid the genes from the environmental genome project from an inflammatory database (Seattle SNPs) and from the comparative toxicogenomic database, onto autism genome linkage regions. I found 135 genes with mutations in areas that change coding, and 67 of these have never been thought about before in relation to autism. Most people are looking for genes that will directly hit the central nervous system (CNS). Well, maybe the CNS is downstream. Maybe it’s systemic where lots of things are hit in parallel, or maybe cytokines in the gut go to the brain. There are a lot of possibilities, but we need to begin to collect more data that would relate to the range of possibilities that could be going on, given the clinical and epidemiological pictures, and not just assume it’s a brain disorder. That’s what I have tried to convey in my paper, “Autism: A brain disorder or a disorder that affects the brain?” the abstract of which you read at the start of this interview. JB: Obviously, you’ve gotten everyone inspired with that last discussion. If that doesn’t raise questions and open our minds to new opportunities, nothing will. I recently heard an interview featuring Nobel Prize-winning Laureate, James Watson (the arguable dean of molecular biology). He was talking about the exciting breakthrough in discovering the gene that controls autism. As I listened to him, I asked myself how someone so astute, so erudite, and so knowledgeable, could talk about the gene for autism, but yet that’s what he was saying. I presume from your discussion that you would argue there is not a single loci, but that we’re looking at a polygenomic type of disorder? Autism Genetics MH: Yes. We’re looking at multiple high-frequency, low-penetrance genes. I was with Susan Santangelo last night, who has recently written quite a good review of autism genetics. She has been saying that if there were high-penetrance genes that strongly influenced autism, we would have found them by now. It doesn’t look like that’s the type of genetic abnormality going on. And today I just finished listening to Vamsi Mootha who gave Grand Rounds in my department. He received a MacArthur Foundation Award in 2004. He was talking about mitochondrial genetics, and they’re looking at diabetes type 2 as a chronic disorder. They’re looking at patterns of interactions of large numbers of genes and not individual gene changes, as you might see in a minority of disorders. Many of us think that’s the kind of thing going on in autism. You can have multiple polymorphisms in a pathway that give you vulnerability. The vulnerability would come out looking very similar. Let’s say you mess up your glutathione pathways (there’s evidence that this is going on in autism). But you wouldn’t have to do it in the same way each time. What are the methodologies? That’s one of my problems with studying these network analyses of genomic function. I’m not sure they take into account specific environmental vulnerabilities that we know something about. That’s something I’m actively thinking about. But in one way or another, it’s not going to be one gene/one disease, and unfortunately, James Watson has said oversimplified and reductionist things like that before. I don’t think he’s oriented toward thinking about gene-environment complexity. JB: That takes me back to your previous discussion (another blockbuster concept) about the amount of white matter in the brains of autistic children. I am reminded of one of the many articles I’ve recently seen that appeared in the Annals of Neurology in 2005, titled “Neuroglial activation and neuroinflammation in the brain of patients with autism.”22 This is work by Diana Vargas and Carlos Pardo at Johns Hopkins. They were talking about the fact that there is a hypothesis that autism is associated with a neuroinflammatory condition. Of course, the white matter of the brain has the glial cells, which is like the brain’s immune system. It puts structure and function together. Is there something you see to this connection of neuroinflammation with autism? Neuroinflammation and Autism MH: For those of us who were already aware of the recurrent infections in these children-the eczema, IBD, and the multiple (not always consistent, but definitely multiple) measures of inflammatory dysfunction-this paper was pivotal, because to see microglial and astroglial activation in the brains of those from five years to 44 years old, and inflammatory cytokine and chemokine profiles in both brain and CSF, says that we’re dealing with a chronic disease. The Vargas-Zimmerman-Pardo paper was a breakthrough in identifying these things in the brain and not just “peripherally.” There’s another abstract by Perry and Salomon that reports finding carboxyethylpyrrole, which is a lipid peroxidation marker, in every autistic brain they’ve cut.23 This means that what we’re looking at in autism is something different than what had been thought before, and it’s consistent with what functional medicine is about. Pardo and Vargus say that this is an innate immune reaction in the brain, whereas it’s been pointed out that there’s both innate and adaptive immune reactivity in the gut. It raises the question of interaction among multiple systems of the body. First of all, it’s a chronic disease. Second, it could be environmentally mediated. Third, it’s multi-system. JB: That segues into what may be one of the greatest controversies in medicine, at least if you’ve followed medicine in the Lancet for the last several years. I’m talking about Andrew Wakefield’s discovery about ileal nodular hyperplasia and MMR vaccination. Do you see this emerging in the field to create some space for discussion, or has it just been rejected as being too preposterous to warrant serious evaluation? The Vaccination Controversy MH: I’m going to put on my sociologist’s hat here, if you don’t mind. What I see going on needs a sociological dimension to analyze it, because it’s not just about science. People who are deeply committed from a public health perspective are very concerned about reducing the proportion of the population that gets vaccinations. It’s very difficult to have a discourse in that setting about anything that may appear to undermine the legitimacy of the vaccine program. On the other hand, people involved with immunology and immunotoxicology seem to be more intrigued by the mechanisms that might interact among certain kinds of vaccine exposures and issues in other systems, such as the GI tract. There are other considerations having to do with economics. I think one of the reasons immunology in autism isn’t further advanced is that people have been staying away from it because they don’t want to be tainted by the vaccine controversy. But now, a lot of people are finding that the immune system is an important thing to deal with in autism. In a way, the levy is down, and we have to start grappling with immune studies in autism. It’s becoming more and more acceptable to do that. Let’s go back to our previous discussion. I’ve been hearing more and more geneticists talking about the rising rates of autism. I think there’s a kind of evolution to get space to deal with these things, but it isn’t happening in a direct, head-on way. It isn’t about getting the people who have been saying it’s really dangerous territory to do such an abrupt 180 about-face. It’s more that there’s a whole lot of circumstantial information coming out about this, showing that we need to be thinking about immune exposures in certain contexts as being the basis for chronic problems. Once you get that general framework, the vaccine issue could be a special case. As far as people got with it early on, the epidemiological data had not been sufficiently powered to exclude this kind of impact in small numbers of people, but it excludes it as a cause of the overall epidemic. Now, people are starting to get more involved in studying the level of mechanism. If we’re going to treat these children, we have to understand mechanisms. My focus has been toward getting people to gain an appreciation for the multiple types of mechanisms that could be involved in mediating these sorts of changes. JB: You and David Ziegler, from the Brain and Cognitive Sciences, Mass Institute of Technology, published an interesting paper in NeuroToxicology on volumetric neuroimaging and low-dose early-life exposures related to these conditions, and how there may be a coupling of this pathogenesis of exposure.24 Would you tell us a little bit about that paper, because I think it bears on some of the things you’re talking about. Autism and Rate of Toxic Exposure MH: Most toxicological studies have been done with high-dose exposures. When you have a high-dose cytotoxic exposure, enough to directly knock off a cell, you’re going to get a hole in the brain. A few years ago, when I would discuss these things with my colleagues, they would say that autism couldn’t have anything to do with toxins, because if it did, the brains would be smaller. The brains in autism are bigger, so it’s got to be something else. But there is so much research going on now having to do with low-dose and multiple toxic exposures. Let’s talk about low-dose exposures. At low doses, chemicals can have biomimetic effects. They can act like other signaling molecules and confuse things. If that happens during development, one could experience changes, not like a hole in the brain, but rather widely distributed, involving changes in scale and proportion. That’s the kind of thing I’ve been measuring. These changes are not hugely dramatic because, first of all, there’s not a whole lot of tolerance in the brain. You can’t wildly change the size of something in the brain without causing an enormous problem. We need to understand that when we measure volume changes in the brain, they can be subtle. I think the issue is that people have been very much involved in looking at brain behavior relationships, and they’ve assumed there’s some kind of different genetically determined developmental trajectory and that the brain tissue is basically healthy-they’ve assumed that the brain is just wired differently, or it has different neurotransmitters. If we’re now looking at chronic tissue changes, we could have altered developmental trajectories or subtle tissue changes, such as chronic mild inflammation, that could also change things at a subtle level, but wouldn’t necessarily be confined to the neural systems that govern any particular behavior. They would just be an overlap between the tissue-based pathology of inflammation or oxidative stress and the behaviorally related neural systems that happen to be in the same territory. I don’t know whether inflammation would specifically target a certain visual or cognitive pathway. I don’t think people have looked at it that much, because for the most part, people who do neurobehavioral research haven’t been thinking about chronic brain tissue pathology. JB: You’ve raised an interesting question. If, in fact, autism, or a variant thereof, has some neuroinflammation component, the easiest assumption might be to give these children non-steroidal antiinflammatories to treat their disease. But I don’t think the results are quite that simple. Treating Autism with Steroids MH: There is a history of treating autism with steroids, going back to the 1970s. Actually, there’s a reporter who’s been on a tear about autism, and he actually googled and found the first person ever diagnosed with autism by Leo Kanner at Johns Hopkins. (Kanner developed the diagnostic category.) This individual was 71 years old. The reporter showed up on his doorstep, but he wasn’t home. When he was diagnosed back in the early 1940s, Leo Kanner told the family that autism was hopeless, and advised them to place the child with a nice family somewhere to be taken care of, and to get on with their lives, which they did. The child came back six years later at death’s door. He was taken back to Hopkins, but couldn’t be diagnosed, so he was sent home to die. Back home, a local doctor said he had juvenile rheumatoid arthritis, and advised treating it with gold salts, which they did. The juvenile rheumatoid arthritis was resolved-and at the same time, so was the autism! Therefore, the very first child ever diagnosed with autism actually turned out to have an inflammatory condition that seemed to be associated with the autistic symptomatology, in that the autism went away when the inflammatory condition went away. Of note, in a follow-up paper, Kanner noted the improvement in this patient, but attributed it to the kind care of his foster family and made no mention of the inflammatory disease or the medical intervention. When that investigative news story came out a few months ago, there was a flurry in the community about giving our children gold salts. One of the issues (Carlos Pardo has been very concerned about this and posted cautions on his website), is what kind of inflammation is this, what is it doing, and how do you best treat it? Steroids are radical and they have side effects, but there are people who are thinking about other approaches to treating inflammation, more along functional medicine lines. In a way, the DAN group, a major proponent of such interventions, is like a sister organization to functional medicine. They do a lot of more gentle functional medicine-like interventions with these children, with a fair amount of good results. JB: That leads us to the end of this extraordinary journey. What does the clinician do, considering the complex state of understanding on this topic? Things seem to be changing. What is the logical thing to do? Are there evaluating methodologies for managing these children? Assessment and Treatment of Autism MH: It’s basically a functional medicine type of assessment, but in a pediatric setting. To zoom in from 50,000 feet, you’d want to take care of predominant biomedical imbalances in inflammatory oxidative stress and other pathways, and you need to do behavioral intervention with these children, because they need a lot of reinforcement and systems remapping to function. That’s the outermost level. In order to figure out which kind of problem is predominant, you need to do further studies and history-taking. On any clinic day, I’ll have some children with diarrhea and other children with no diarrhea; some with regression, some with no regression; some who had 30 ear infections, and others who had none. You need to go through that with some kind of cultivation of biochemistry and immunology, and sort out what the most likely initial target would be that would give you leverage. Also, you can’t just do one thing at a time. There are a lot of things going on that are mutually co-modulating and mutually reinforcing. If they were mutually reinforcing in a bad way, you’d want your treatments to be mutually reinforcing in a good way. Beyond that, there’s a lot of material on line for the functional medicine approach at the Autism Research Institute. Hopefully, there will be more and more material coming along that will reflect some kind of integration of behavioral and biomedical approaches. There’s a textbook, published by the Organization for Autism Research (OAR) on evolutionary approaches to neurodevelopmental disorders, which does some integration of behavioral and biomedical approaches (Neurobehavioral Disorders of Childhood: An Evolutionary Perspective.25) Hopefully, we’ll see more of that. JB: That was a brilliant answer. Just last week, I saw an interesting paper that speaks to what you’re talking about with regard to a broad-based approach that’s individualized to the patient. It was a discussion about methylene tetrahydrofolate polymorphisms and their relationship to autism, again, perhaps implicating folic acid in some of these conditions as another thing to be considered.26 Then, of course, there’s Mary Megson’s work on the cod liver oil/vitamin A connection to autism. It seems as if this is an ever-advancing opportunity for developing integrative therapies that are personalized to the individual patient. Dr. Herbert, I can’t tell you how much we appreciate this interview. It has been an extraordinary journey in sharing your wisdom. We wish you the very best as you continue your work, and we hope we can check back in with you. This clearly is one of the great stories in 21st century medicine. MH: Thank you for all your help. I’ve learned a lot from you and your work in functional medicine. Microcurrent Therapy I would like to conclude this month’s FMU with one other topic. This comes as a consequence of a follow-up with a previous FMU Clinician of the Month, Dr. Carolyn McMakin, and the work she has done on microcurrent therapy. She has been developing this approach and using it to treat low-back myofascial pain, as well as a variety of other pain-related and immunological-related dysfunctions. A very novel study of her work has been published, which is quite exciting.27 It ties into what we were just talking about-cytokines and immunological imbalance, and how they ultimately end up influencing function. Dr. McMakin was able to demonstrate that microcurrent therapy had a very dramatic effect on cytokine production, and that this production showed a reduction in proinflammatory cytokines within just a few minutes after therapy. This was work done by measuring cytokines and blood spots taken by finger-stick from patients before and after intervention with microcurrent therapy. It indicated that the immunological system, the regulator of inflammation, is actually changed by this energy-medicine concept. Therefore, it opens up multiple ways that we might approach inflammatory conditions resulting from sequelae related to organ-specific pathologies. I find this a very interesting contribution to our understanding. We are starting to see that the immunologically imbalanced individual may present with many different disease forms. We have been speaking principally in this issue of FMU about the conditions of autism and autistic spectrum disorder, but it is not too far a reach to say that there are many other conditions, such as fibromyalgia syndrome and chronic fatigue syndrome, that also have immune, endocrine, and neurological components associated with inflammation. We might cluster all of these under the category of autoimmune-like disorders-the body becoming allergic to itself. That would be the gross way of describing it, but perhaps it is not allergic to itself; perhaps it is responding in a way that is designed to be there for molecules in the body that have been modified by oxidative injury, glycation, or by some kind of post-translational effect that makes them into foreign molecules to which the body’s immune system responds. It may be that many of the chronic age-related diseases have their roots in the immune response of the body, which collects injury along the road of life. In children with autism or autistic spectrum disorder, it is possible that these injuries occur very early, perhaps even in utero. At the molecular level, these injuries may activate, modulate, or modify the function of the immune system in individuals with unique genetic characteristics. Post-natal environmental exposures may serve as triggers that lead to the alteration of these mediators that are ultimately immune-modulating and inflammatory-initiating substances with specific tissue focus. The report by Dr. McMakin-that that the modulation of inflammatory mediators, like cytokines, neurotransmitters, or endorphins, can occur as a consequence of long-wave length, low-energy radiation-indicates that there may be specific patterns, frequencies, or energy pathways that regulate many immunological functions, opening up new doors for potential therapy beyond just that of biochemical or medical interventions. We are at the threshold of a very extraordinary revolution in thinking about the etiology of chronic disease, how the environment is translated through the immune system into inflammation, and what the therapeutic tools are that may modulate gene expression, post-translational effects, and ultimately immune regulation. I believe that sometime in the future, we will look back on these past 20 years and say that the techniques used for immunological regulation were very primitive. As we move forward, we will use things like gut signaling and modulation of environment input that will lead to both the prevention and treatment of many problematic disorders of today, such as autistic spectrum disorder. Thanks for being with us. We will see you in March.

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1 Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998;351(9103):637-641. 2 Chen RT, DeStefano F. Vaccine adverse events: causal or coincidental? Lancet. 1998;351:611-612. 3 Sabra A, Bellanti JA, Colon AR. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive development disorder in children.. Lancet. 1998;352:234-235. 4 Fombonne E. Inflammatory bowel disease and autism. Lancet. 1998;351(9107):955. 5 Wakefield AJ. Author’s reply. Lancet. 1998;351:1356. 6 Quigley EM, Hurley D. Autism and the gastrointestinal tract. AJG. 2000;95(9):2154-2155. 7 Wakefield AJ, Anthony A, Murch SH, et al. Entercolitis in children with developmental disorders. Am J Gastroenterol. 2000;95(9):2285-2295. 8 Hendrickson BA, Turner JR. MMR vaccination, ileal lymphoid nodular hyperplasia, and pervasive developmental disorder. Lancet. 2002;359(9323):2051-2052. 9 Torrente F, Ashwood P, Day R, et al. Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry. 2002;7(4):375-382. 10 Madsen KM, Hviid A, Vestergaard M, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002;347(19):1477-1482. 11 Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O’Leary JJ, Murch SH. Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Aliment Pharmacol Ther. 2002;16(4):663-674. 12 Wakefield AJ. Enterocolitis, autism and measles virus. Mol Psychiatry. 2002;7(Suppl 2):S44-S46. 13 Wakefield AJ. The gut-brain axis in childhood developmental disorders. J Pediatr Gastroenterol Nutr. 2002;34(Suppl 1):S14-S17. 14 Ashwood P, Anthony A, Pellicer AA, Torrente F, Walker-Smith JA, Wakefield AJ. Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin Immunol. 2003;23(6):504-517. 15 A statement by Dr. Andrew Wakefield. Lancet; 2004;363:823. 16 A statement by the editors of The Lancet. Lancet. 2004;363:820-821. 17 Ashwood P. Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004;24(6):664-673. 18 Wakefield AJ, Ashwood P, Limb K, Anthony A. The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder. Eur J Gastroenterol Hepatol. 2005;17(8):827-836. 19 Herbert MR. Autism: a brain disorder, or a disorder that affects the brain? Clin Neuropsychiatry. 2005;2:354-379. 20 Herbert MR. Large brains in autism: the challenge of pervasive abnormality. Neuroscientist. 2005;11(5):417-440. 21 Herbert MR, Ziegler DA, Makris N, et al. Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol. 2004;55:530-540. 22 Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57:67-81. 23 Perry G, Nunomuria A, Harris P, Siedlak S, Smith M, Salomon R. 2005. Is autism disease of oxidative stress? Oxidative Stress in Autism Symoposium New York State Institute for Basic Research in Developmental Disabilities, Staten Island NY, pg 15. 24 Herbert MR, Ziegler DA. Volumetric neuroimaging and low-dose early-life exposures: loose coupling of pathogenesis-brain-behavior links. NeuroToxicol. 2005; 26(4):565-572. 25 Melillo R, Leisman G. Neurobehavioral Disorders of Childhood: An Evolutionary Perspective. New York, NY; Springer Science & Business Media: 2004. 26 James SJ, Cutler P, Melnyk S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80:1611-1617. 27 McMakin CR. Microcurrent therapy: a novel treatment method for chronic low back myofascial pain. J Bodywork Movement Therapies. 2004;8:143-153.

Textbook of Functional Medicine Welcome to Functional Medicine Update for March 2006. When we developed the concept of functional medicine nearly 20 years ago, as with any emerging concept, we had little idea how it would evolve. Now, in the year 2006, we are all very excited about how it has caught on. Clinicians and researchers have embraced the concept and have added their own texture and flavor to it, creating what I call “personalized preventive medicine,” using functional medicine to personalize therapy to the individual’s needs. The concept is very well described in the Textbook of Functional Medicine, published by the Institute for Functional Medicine. I am holding a copy of it in my hands as I speak. It is a remarkable outgrowth of the work of literally hundreds of researchers, clinicians, and multiple authors who have given tirelessly of their time in putting together a true textbook on functional medicine. It is some 800 pages in length, has well in excess of 20,000 references, and has multiple authors, multiple editors, and multiple referees. It presents the best of 20 years in the evolution of functional medicine. This issue of FMU will keep the flame alive and burning, and prepare us in charting the course over the next ten years. 13th International Symposium on Functional Medicine The 13th International Symposium on Functional Medicine will be held April 19-22, 2006 at the Tampa Marriot Waterside Hotel & Marina in Tampa, Florida. The focus of the symposium is Managing Biotransformation: The Metabolic, Genomic and Detoxification Balance Points, one of the core principles of the functional medicine concept. The time we have spent during the last few issues of FMU in becoming familiar with this concept will pay dividends in both preparation for the 13th symposium, and also to better understand how to properly use what we call the functional medicine matrix, the algorithm that provides patterns from the interconnections between different functions that give rise to personalized therapy. Over my years as a clinical chemist and laboratory director, I have received periodicals and journals from the American Association of Clinical Chemistry (AACC), including a weekly newsletter magazine, titled Clinical Laboratory News. It illustrates how the medical technology of today is emerging, and includes many articles that relate to the functional medicine concept. In the last issue of 2005, the lead article in this journal was titled “The challenges of pharmacogenomic tests: Has personalized medicine arrived?” 1 I found this to be an interesting and different perspective on how we see the functional medicine concept becoming one that provides therapeutic opportunities for doctors and ultimately, for their patients. Cytochrome P450 Genotyping Test Let me tell you how the AACC presents the arrival of personalized medicine. They talk about the fact that in January 2005, the Food and Drug Administration (FDA) cleared the Roche Molecular Systems’ AmpliChip® cytochrome P450 (CYP) genotyping test and comment that many experts hailed the approval of this test as the birth of a new era in personalized medicine. “The first pharmacogenomic microarray designed for clinical applications, the AmpliChip detects specific genetic variations in the cytochrome P450 gene that can provide information on how well an individual will metabolize certain classes of drugs, thereby allowing clinicians to tailor drug therapies to the individual’s genetic makeup.” This is a huge breakthrough in the way we view medicine and prescriptions. Rather than just giving a dose of a drug based upon body surface area, we can tailor drug therapy based upon pharmacogenomics and pharmacogenetics-the dynamics of specific drugs and how they pass through phase 1 of the detoxification system. This is what we might call managing biotransformation through detoxification at a very fundamental level-the genomic level. Roche released the chip for sale in the US in June 2005, and labs have now started to use the technology for evaluating specific CYP450 polymorphisms in individual patients. I recall reading a number of case-precedent examples in the courts over the last two years of patients who brought suits against physicians because of adverse responses to various medications. The patients complained that they had not been tested for specific detoxification abnormalities before the medications were prescribed, and that their unique genetic polymorphisms had prevented them from properly metabolizing the drugs. They ended up having adverse events, which they claimed were the responsibility of the physicians for not having properly evaluated their genetic uniqueness before the medications were prescribed. The AmpliChip may greatly influence prescribing patterns. It can greatly change the way medicine is practiced. Rather than assuming that all people are within certain acceptable standards of deviation relative to the way they metabolize drugs, a personalization perspective is emerging, indicating that patients need to be evaluated individually because polymorphisms in their detoxification enzymes may result in different outcomes. In a sense, this is another way of going through the door into the room of functional medicine. This new chip is a tool to evaluate patient genetic uniqueness-or biochemical individuality-that ultimately leads to molecular medicine-based forms of intervention, which is the focus of functional medicine. I find this an interesting way that some physicians will ultimately be led to looking at functional medicine concepts. Obviously, most physicians already recognize that not all patients respond similarly to certain drug therapies, but the label “pharmacogenomic test” may scare some doctors, as well as some patients who might be worried about a test that examines their genetic makeup. We have talked about pharmacogenomics for over 10 years. It is not a new concept; however, when we start talking about its specific application through the use of gene testing chip technologies, like the AmpliChip, it leads to a new, potential generalization of the concept. Pharmacogenomics gets more attention now because it has matured to the point where it can be used in a very practical sense to help ensure that safe and effective drugs are brought to the market. “Personalized medicine” is somewhat of a catch phrase for the practice of clinical medicine that relies upon the ever-advancing science of pharmacogenomics and pharmacogenetics. Let me emphasize how I am using these terms: pharmacogenetics relates to the individual characteristics of a patient, whereas pharmacogenomics is the study of how different polymorphisms influence different metabolic outcomes. One is a general theme of the science of biotransformation and detoxification (pharmacogenomics), and the other is evaluation individualized to the patient with his or her own single nucleotide polymorphisms (SNPs). Pharmacogenetics is the study of the role of inheritance in inter-individual variation in drug response. A primary inspiration for this type of research has been the promise of individualized drug therapy. Adverse Drug Reactions We are starting to look at this because it has been recognized that there are a lot more adverse drug reactions (ADRs) than perhaps have previously been accounted for. This comes out of the study published in the Journal of the American Medical Association in 1998 that reported there are 2.2 million hospital events and up to 100,000 deaths per year annually in the US as a consequence of hospital-based ADRs.2 If there are that many in hospital environments where medications are administered to patients by professionals at the “right dose,” what could be the implication of ADRs in non-hospitalized patients? “The labs that are bringing the AmpliChip in-house believe that its potential to bolster patient safety will ultimately make it a very marketable test. The AmpliChip uses microarray technology and polymerase chain reaction (PCR) technology to detect variations in the CYP450 2D6 and 2C19 genes.” These are constitutively expressed genes (not genes with highly inducible characteristics) that are very important in the metabolism in a number of different drug families. We now know that there are over 33 unique alleles, or different potential variations on a theme, for the CYP2D6 gene. The enzyme encoded by the 2D6 gene plays a primary role in the metabolism of drugs used to treat depression, schizophrenia, bipolar disorder, cardiovascular disease treated with beta-blockers, and attention deficit/hyperactivity disorders. This may have a relationship to how some children respond to various medications. The enzyme produced from the CYP2C19 gene metabolizes many proton pump inhibitors used to treat esophageal reflux disorder, anti-malarials, and anticonvulsants. The AmpliChip CYP450 test ultimately provides a predictive phenotype for patients, which ranks them into four categories-poor metabolizers, intermediary metabolizers, extensive metabolizers, or ultra-rapid metabolizers. Obviously, in slow or poor metabolizers, a certain drug dose may build a higher tissue or plasma level and produce toxicity, whereas in ultra-rapid metabolizers, the same dose may be rapidly cleared from the body and have no therapeutic outcome of importance. We need to be looking at how these agents might be transiting through the CYP450 systems of patients. This is an exact application of what we will be speaking to at the 13th International Symposium on Functional Medicine-managing biotransformation-because of the wide range of genetic characteristics associated with detoxification. We are looking at the development of an effective means of therapeutic drug monitoring and individualizing patient therapies. That leads to predictive testing, as contrasted to pathology testing. For years, we have talked about the use of the laboratory for evaluating patient status. Tests that have traditionally been used for multiphasic screening are designed to evaluate pathology, and include such tests as SGOTs (aspartate aminotransferase) and PTs (prothrombin time) to evaluate liver enzyme profiles, glucose tolerance tests to evaluate the presence of diabetes, cholesterol and/or triglyceride levels to evaluate lipid disorders, or blood urea nitrogen and creatinine levels to evaluate kidney disorders. In these cases, we are talking about the use of the laboratory for identifying the presence of an existing disorder. To some extent, cholesterol testing is a predictive analyte, because it focuses on understanding the prognostic potential for later-stage vascular events. This may be considered the first predictive analyte that arrived on the multiphasic screening profile, having more preventive, rather than disease diagnostic capabilities. CYP450 genetic polymorphism testing would not necessarily be called prognostic, but would certainly be considered predictive, because these tests tell us a little bit about how that individual, based upon his or her genetic uniqueness, will respond to certain exogenous and endogenous agents that require detoxification through specific enzyme pathways. This is the birthing of a new concept that goes beyond psychiatry and clinical pharmacology into looking at how people respond to their environment in general. The same detoxification enzyme systems used for the metabolism of specific drugs are also those used for the detoxification and clearance of environmental toxins, as well as some endogenous substances. It will be exciting to see the emergence of a new science developed around pharmacogenomics, which is part of the functional medicine model. The Question of Insurance Reimbursement for Pharmacogenomic Testing There are a few hurdles that will challenge the rapid spread of pharmacogenomic testing. Not unexpectedly, one is the reimbursement issue, because there has been a question as to whether there should be insurance reimbursement allowed for the evaluation of CYP450 polymorphisms. It is interesting that we are very quick to reimburse for pathology-based tests, but very resistant in reimbursing for a predictive test, even when that test may allow for the prevention of a disorder that would result in very expensive evaluations, treatments, and potential high hospital costs. These are philosophical questions that need to be addressed so that functional medicine and predictive and personalized medicine will ultimately find their places as important parts of the healthcare delivery system. Obviously, we have a highly evolved disease-care delivery system. Almost all the incentives and motivations are to financially and physically support the disease-care delivery system. We have a much more primitive predictive, prevention-oriented healthcare delivery system. We have discussed that in previous issues of FMU, when we talked about chronic disease and the need for new clinical education and assessment technologies for evaluating individuals who are on a trajectory toward later-stage, more acute disease. There is certainly no lack of excitement among those who design and perform these pharmacogenomic evaluations. As the testing expands and focuses on more application-specific panels that include genes beyond metabolism-like genes associated with drug transport-enthusiasm will likely rise outside of the larger labs that do most of the current testing. I believe that, ultimately, pharmacogenomics will be a big driver for converting medicine into a predictive, personalized form. Ironically, that will be one of the ways that biochemical individuality and the concepts of functional medicine will become incorporated into a more traditionally-based, pathology-focused medical practice. There will always be syndromes that do not fit nicely into a tidy diagnostic category, and may be relegated to the borders between various disease diagnostic criterions. Three of those are chronic fatigue syndrome (CFS), fibromyalgia syndrome (FM), and multiple chemical sensitivity syndrome (MCS). The reason we add the word “syndrome” rather than disease to these conditions is that they do not fall into a nice, clean fit with the diagnostic criterion of an ICD9 diagnostic code. Does that mean they do not really exist? Are they not real clinical entities just because we cannot get our arms around them and cleanly define them based upon pathophysiological assessment? If we cannot define it, we cannot name it, so we think it does not really exist. Patients with CFS, FM, or MCS would say that these syndromes certainly do exist. Physicians who have seen patients with these syndromes are aware of the fact that they are real clinical entities. It does not mean that we understand their origin. In fact, these disorders may be models for 20th century dysfunctions of a chronic nature, because they are multifactorial in origin. They do not have one specific etiology. They are related to imbalances in the neuroendocrineimmune system, as are many of the immunological problems we see today that ultimately may be called autoimmune diseases of various types, such as thyroiditis, inflammatory bowel disease (IBD), colitis, and systemic lupus erythematosis. There is a complex milieu of dysfunctions related to the nervous, immune, and endocrine systems that have inflammatory relationships, and we are not exactly sure what to call them because they do not fit into clean, tidy diagnostic criterion. Let’s look at CFS, FM, and MCS. You may recall that we interviewed Dr. Martin Pall on FMU in March 1999. Dr. Pall is a professor of biochemistry and basic medical science at Washington State University in Pullman, Washington. He described the work he had been doing in trying to put together a comprehensive understanding of the etiology of MCS, FM, and CFS, knowing that they share much in common (as was reported by Dr. Debra Buchwald in an article that she and one of her colleagues published in the Archives of Internal Medicinein 1994).3 We also interviewed one of Dr. Buchwald’s colleagues, Niloofar Afari, in the August 2003 issue of FMU, and she described patients with CFS who present with an overlap of both FM and MCS symptoms, suggesting that there is a common etiology among these syndromes. Dr. Pall brought this to our attention in 1999 and now, some seven years later, we are starting to gain a better understanding of how things like Gulf War Syndrome, MCS, CFS, and FM are interrelated through a common paradigm-a feed-forward cycle.4 This feed-forward cycle has to do with activation of the nitric oxide (NO)/peroxynitrite/oxidative stress pathway. Activation of the immune system produces inflammatory mediators, including interleukin-1 beta (IL-1b;), IL-6, tumor necrosis factor alpha (TNFa), and interferon gamma, that interrelate (like a dog chasing its tail) with the stimulation of the production of NFkB as a transcription factor, and the controlled gene expression patterns associated with upregulation of these inflammatory mediators. All of those feed onto themselves to keep perpetuating the problem. It is different than an infectious disorder where, when a person gets over the infection, the body’s immune system has successfully won the battle with that organism and he or she gets well. In the case of CFS, FM, or MCS, there is a re-initiation and a re-stimulation of the condition through the feed-forward cycles that occur through oxidative stress-related mediation and upregulation of the immune system. Diagnosing FM, CFS, and MCS When we look at how to diagnose and treat FM, CFS, and MCS, it leads to the concept of neuroendocrineimmune functional medicine web-like balancing. It requires a complex approach that deals with the hypothalamus/pituitary/adrenal axis. It deals with detoxification, gut function, oxidative stress, and immune stabilization of thymus dependent-1 (Th1) and thymus dependent-2 (Th2) activities. It is a classic example of personalized medicine, focusing on the web, which is the algorithm that is taught as the central teaching and therapeutic clinical tool in functional medicine by the Institute for Functional Medicine. There are various receptors that have been identified as being associated with activation of these complex immune, endocrine, and neurological conditions. These receptors become activated by their ligands under conditions associated with chronic inflammation and oxidative shifts in physiology. In a recent paper in Free Radical Biology & Medicine, investigators from the Vascular Diseases Research Unit at Ninewells Hospital and Medical School in Dundee, Scotland, reported that the etiology of CFS, although unknown, is emerging as being related to oxidative stress kinds of phenomenon, because one sees fairly high levels of 8-iso-prostaglandin a-isoprostanes in these patients.5 These isoprostanes are related to the free radical oxidative injury that occurs to unsaturated lipids, and is a measure of real-time oxidative stress. CFS patients had very high levels of these isoprostanes. In fact, the degree of CFS symptoms correlated with the level of isoprostanes. This is the first time a strong clinical association between in vivo oxidative stress and CFS symptoms has been seen. What is the origin of CFS symptoms and oxidative stress? They come from the feed-forward cycle that Dr. Pall spoke about, as it relates to the activation of the immune and neurological systems through various receptor-ligand interactions. Some of these reactions are precipitated by the production of various types of secondary metabolites through inappropriate detoxification. One of those is activation of the vanilloid receptor as a putative target of the first chemicals in MCS. As reported by Dr. Pall and his colleague, Julius Anderson, in the Archives of Environmental Health, we are starting to see that activation of specific receptors can, in fact, induce some of these reactions that lead to feed-forward cycles of oxidative stress, immune upregulation, inflammation, and perpetuation of the symptoms of MCS.6 The vanilloid receptor can be activated by things like mycotoxins, for instance, which may account for the sick building syndrome associated with MCS, and various other types of volatile organic solvents and chemicals. Endogenous chemicals can also activate the neurological system through NMDA receptor activation. This may be why we see such diffuse symptoms in CFS, such as neurological symptoms, immunological symptoms, cutaneous symptoms, and endocrine symptoms. These are all interrelated to the alteration of physiology that occurs by teasing the web, pulling the web into states of chronic inflammation, oxidative stress, immunological imbalance, and endocrine disturbances. Now, we start to see that it does not look like a disease; it looks more like a syndrome. It presents in multiple ways in multiple forms in different patients. Treatment of CFS, FM, and MCS What is the treatment of choice? That is a good question. Obviously, because there are multiple etiological components, a single drug is probably not going to be the answer. In fact, what we would think about from a functional medicine perspective is personalizing therapy to the individual’s need based upon the perturbation of their own individual web by looking at the matrix, a teaching tool in functional medicine. We would look at gut-related immune function, oxidative stress, neuroendocrine function, immunological function, and how the body/mind relationship was influencing the neuroendocrine immune system. Ultimately, from this, a personalized treatment, based upon both the genetic uniqueness of the patient and his or her antecedents and personal past history, would be developed to manage their CFS, FM, or MCS. This leads us to recognizing that the functional medicine approach for the management of CFS, FM, MCS, and what has euphemistically been called Gulf War Syndrome, would be specifically focused on the algorithm that derives out of their web, out of their matrix. We would focus on GI function, and immune function as it arises out of GI disturbances. We would look at the effects on oxidative stress, effects on neuroendocrine function, effects of the body/mind factor, and how stress may play a role in the symptoms of the individual patient. We would recognize that there are common themes that would emerge by asking the right questions about the patient’s story to design a personalized program for intervention. It does not fit into a specific singular intervention. When a person asks to be given thealgorithm for the treatment of CFS, there is not a treatment. There is a general principle, and it relates to the etiology and the mechanisms of action in these feed-forward cycles, for which a specific treatment plan would be designed for the individual patient, based upon evaluation of their matrix. These are the tools of the functional medicine model. These are the outcomes described in the Textbook of Functional Medicine. It is a very different model than that which results in a tidy diagnosis of a disease using a singular treatment algorithm for that diagnosis. It requires a more thoughtful approach toward patient management. We need to listen to the patient’s story and develop a response to it. The outcome of these complex symptom-related clusters called syndromes, may be much more profound in positive outcome than just trying to pound a round peg in a square hole and get a singular diagnosis. Let me use one more example that I believe illustrates the matrix in the functional medicine model. It is related to the auditory system and hearing loss. We are an aging population, and hearing loss is becoming more prevalent in our society. Also, in younger people we are starting to see hearing loss as a consequence of sensory trauma to the auditory system through things like listening to very loud music with head phones, and continued over-stimulation of auditory tracts. What is emerging through a basic understanding of the mechanism of hearing loss is that there is a functional medicine connection. Some drugs are now available to ameliorate predictable damaging effects of excessive noise and ototoxic substances, but the real question is: where does hearing loss come from? What is the actual physiological source of hearing loss? These are interesting questions, because what has emerged is that part of the problem is related to the activation of the oxidative stress machinery in the very sensitive organs of the auditory neurological system. Noise-Induced Hearing Loss (NIHL) Let me review some of the recent findings. Noise is the greatest environmental causative factor among the defined etiology of hearing loss.7 Traditionally, prevention of noise-induced hearing loss (NIHL) has been addressed by providing wearable hearing protection and reducing noise emissions. According to the National Institutes for Deafness and Communication Disorders (NIDCD), the American Speech, Language and Hearing Association (ASHA), and the Occupational Safety and Health Administration (OSHA), >30-40 million Americans are exposed to hazardous sound or noise levels on a regular basis. NIHL affects ~10-15 million people, of all age groups in the USA. There are many noisy occupations, including construction, manufacturing, mining, forestry, farming, aviation, trucking, military, and recreational exposure to high noise levels through music and other types of auditory stimuli.8 The prevalence of this problem-which is very high-can be thought of as a functional condition. What is its pathogenesis? “In response to sound waves traveling through the cochlea, the auditory hairs in the organ of the Corti depolarize following the opening of the mechanotransduction channels caused by the physical deflection of the stereocilia on their apical surface. The organ of Corti contains two types of auditory hair cell: inner and outer hair cells (IHC and OHC, respectively). These cells are organized into three rows and are usually the first hair cells affected. Healthy hairs contract in response to acoustic stimulation, resulting in an increase in sensitivity at about 40-50 decibels.” Here is where we get into some interesting functional medicine physiology. “Mitochondria are some of the first and most affected intracellular organelles in models of NIHL. IHCs are predominantly sensory in nature and are heavily innervated by the eighth cranial (auditory) nerve. The constitutive array of IHCs and OHCs is dramatic given our noisy environments. The amount and type of hair cell damage depends on the frequency, intensity and duration of the noise exposure. Above a specific intensity level, OHCs show signs of metabolic exhaustion with the accumulation of reactive oxygen species and reactive nitrogen species (ROS and RNS, respectively).” Over a long period of time, this results in an oxidative stress situation that leads to apoptosis, and death of the cell neuronal reserve associated with proper reserve for hearing. “Over the past decade, much progress has been made in our understanding of the cellular and biochemical basis of NIHL.” We now recognize how these are associated with the formation of free radicals, particularly the reactive oxygen and nitrogen species that ultimately overwhelm resident detoxification and antioxidant mechanisms, showing that even in hearing, antioxidation and detoxification become very important as control points for resistance against environmental pressure, in this case, noise. “A major intracellular antioxidant pathway that can detoxify free radicals and attenuate ROS and/or RNS involves the tripeptide glutathione (GSH). Loud noise can reduce GSH and increase the level of oxidized glutathione in the inner ear, leaving it prone to ROS- and/or RNS-mediated cell damage. GSH interacts with glutathione peroxidase, which catalyzes the ability of GSH to act as an antioxidant. …The additive effect of increased ROS and/or RNS and depleted antioxidant capacity can lead to cell injury or death.”9 The buildup of peroxynitrite is seen, which is the same chemical I described earlier when I was discussing CFS, FM, MCS-a toxic byproduct of activation of the immune system and oxidative stress. “These free radicals degrade lipids and damage membrane-bound organelles such as mitochondria and nuclei. …Excess ROS and/or RNS generated by elevated hair cell metabolic activity during intense noise exposure could overwhelm the antioxidant buffering capacity of the cell, leading to permanent loss or injury of hair cells.”9 That leads to the question of otoprotection. What would be a functional medicine approach, other than just removing the noise, which is obviously a part of the reduction of the antecedents? What may also be some of the other things that could lower injury? “Recent studies with antioxidants, N-methyl-D-aspartate (NMDA) antagonists, caspase or cell death inhibitors, and growth factors have some significant design limitations that restrict their direct clinical application.”9 However, the part of this research that seems most interesting is about the compounds that influence GSH, such as the GSH precursors-N-acetyl cysteine (NAC) and methionine (MET). “NAC is a GSH prodrug that, upon de-acetylation to L-cysteine by the liver and local tissues, enhances GSH production. High-dose oral NAC is FDA-approved as a mucolytic agent for respiratory diseases and can reverse acute hepatoxicity following acetaminophen overdose. It is given orally or intravenously (i.v.) at 70 mg/kg for 24-48 h.”9 This can enhance GSH levels, and is under investigation for ability to attenuate NIHL. There are compounds that accentuate NAC activity, including N-acetyl carnitine, magnesium, and methionine-oral agents for helping to protect against NIHL. In a double-blind, placebo-controlled study, 300 young, healthy military recruits were supplemented with 4 grams of oral magnesium per day and showed significantly less noise-induced injury than those who were exposed to the same noise who received placebo.9 I have already talked about the NAC relationship. Similarly, CoQ10 has been shown in a few studies to have some potential protective effects from hearing loss. We are starting to see that the functional medicine model, at the cellular physiological level, comes to what we might consider a strict environmental problem-NIHL-and that we have to go back to fundamental mechanisms and understand physiology and cellular activity. There is a further review in the journal DDT, of a number of approaches toward reduction of ototoxicity, with a principle focus on lowering oxidative stress and increasing detoxification of free radicals.10 I hope you can see from this discussion that our topic at the 13th International Symposium on Functional Medicine is not singular in its focus. When we talk about managing biotransformation and the detoxification balance points, we are looking across many different clinical conditions. We are tying together genomics with environmental exposures and trying to design a personalized program for individuals who may not even understand that they have symptoms related to alteration, biotransformation, and detoxification. That is a nice lead-in to our Clinician/Researcher of the Month and I think you are going to find the interview very exciting. Our guest has a broad range of over 30 years experience in medicine that speaks to this specific topic

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INTERVIEW TRANSCRIPT

Jacob Kornberg, MD Center for Health Awareness 1215 Regents Tacoma, WA 98466 JB: It’s time for our Clinician/Researcher of the Month. I look forward to these interviews each month, because I learn so much from the experiences of these experts in applying the concepts of functional medicine. Our guest this month is Dr. Jacob “Jack” Kornberg. Jack has been a good friend and colleague for the last several years through interactions at functional medicine events and trainings. He has an extraordinarily interesting background, both personally and professionally. Dr. Kornberg received his undergraduate degree from the University of California at Los Angeles and his medical degree from the University of California, Irvine College of Medicine, in 1969. After completing an internship at Los Angeles County Medical Center, he returned to the University of California, Irvine College of Medicine, and finished his four-year surgical residency in 1974. He served two years in the United States Navy as a surgeon at the Naval Hospital in Corpus Christi, Texas. Along with their two children, Jack and his wife, Peggy, moved to Puyallup, Washington in 1976, where he established a successful general surgery practice and became highly respected in the local medical community. He was certified by the American Board of Surgery in 1975 and was elected a Fellow of the American College of Surgeons in 1979. During his years of surgical practice at Good Samaritan Hospital in Puyallup, he served many years as chairman of the Quality Assurance Committee and the Surgical Committee. He was also president of the medical staff for two years. He is a graduate of the IFM’s Applying Functional Medicine in Clinical Practice (AFMCP) training program, which led to the incorporation of functional medicine into his surgical practice. I am going to ask him how a surgeon evolves into becoming a functional medicine practitioner. That may seem like an anachronism to some of our listeners. In 2003, Dr. Kornberg decided to give up his surgical practice, and he created the Center for Health Awareness, an integrated holistic medical clinic, in Tacoma, Washington. This was a big step for a highly respected general surgeon. He has lectured internationally on health and wellness. Since July 2005, he has been seeing patients one day a week as a consultant at the Metagenics Functional Medicine Research Center (FMRC). JB: Jack, there’s much more to you than just those few words, and we welcome you to FMU. My first question is: What led you to make such an extraordinary transition in your career-from highly successful general surgeon to functional medicine physician? Transition from Surgeon to Functional Medicine Physician JK: Good morning, Jeff, and thank you. The transition was interesting, because being a surgeon, and especially the “older surgeon” in our community, I used to see a lot of patients who experienced abdominal pain. They were sent to me with a diagnosis of “adhesions.” The concept was that they needed another surgery to help them with their abdominal discomfort. As I listened to their stories, it became very obvious to me that this was not a surgical problem; it was a functional problem. However, at that time, I didn’t have any kind of framework in which to work them up or to put things into perspective. One time, when I was at the operating table, I was complaining about how all these patients were being sent back for multiple surgeries. One of our anesthesiologists used to be a student of yours. He told me I had to find you, listen to you talk, and that you would probably be able to give me some insight into what’s going on with these patients. That led to my attendance at a couple of your lectures. Once I started to understand the concept of functional medicine and that these patients did not have an anatomical defect that required surgery, but a functional problem with their gastrointestinal tract, I was able to start incorporating that into my practice. Toward the last year of my practice, I was sending more patients away who didn’t need surgery than those who did. That’s not very appropriate for a surgeon. Finally, Peggy and I decided that I couldn’t straddle the fence-I couldn’t be a functional medicine physician and do surgery. Things had changed in the 30 years I had been a surgeon, and it was no longer much fun. I’m sure a lot of the physicians who have been in standard medicine know things have changed, especially in terms of paperwork and litigation. So, we made the jump and I decided to give up surgery and practice functional medicine. Of course, I had to take lots of classes and courses. I took the AFMCP course twice and now, I love what I do. I didn’t want to give up medicine, but it was time to move from surgery into something new and exciting, and it really has been. This practice has grown and the impact we’ve had is just amazing. We’ve been able to help guide people back to health in a system that is not geared to do so. Even though we call it a health system, it’s not geared to health. The transition has been very rewarding. JB: That’s an exciting story, and the kind we love to hear because it’s the raison d’etre for IFM’s attempts to provide opportunities for, as David Jones says, “becoming re-enchanted with medicine.” Congratulations to both you and Peggy for taking the plunge and thanks, too, on behalf of your patients. Working a day a week at the FMRC has created an opportunity for you to see patients with what are euphemistically called “autoimmune disorders.” That is an interesting stretch for a traditionally trained surgeon-working in the area of autoimmune disorders. Tell us a little bit about the experiences you’ve had over the last year seeing patients with complex immunological imbalances, and what your perspective is as it has emerged about a category of conditions called “autoimmune disease.” Aspects of Autoimmune Disease JK: A lot of practitioners are probably overwhelmed by some of the patients’ stories and the physical findings of those with autoimmune disease. It encompasses over a hundred different types of diagnoses. When I thought about it, I realized that we learn about a lot of tools in functional medicine that can help us approach autoimmune disease differently than those using the traditional approach. One of the problems with the traditional approach is that autoimmune disease is systemic, yet it has been chopped up into little pieces by the various specialties. The GI practitioner deals with inflammatory bowel disease (IBD); the neurologist deals with multiple sclerosis, myasthenia gravis, and so forth; the orthopedist deals with bone issues, and the rheumatologist deals with lupus. Yet, we’ve seen that these conditions are all one disease. I love the story of the blind Chinese man trying to figure out what an elephant is by just feeling one little part. From the traditional perspective, I don’t think you get a 10,000-foot view of what autoimmune disease is. But from a functional medicine point of view, you can. We make the assumption that autoimmune disease is a systemic and multifactorial disease. From the functional medicine point of view, we look at chronic disease differently. We look at it from the perspective of what the predisposing factors are, and what things the patient brings from his or her past that create susceptibility to a certain disease. We look at the triggers and mediators going on that keep the disease going. For example, some of these people will have three other people in their family that have had viral infections, yet that patient might be the only one in the group who never got better. They’ll tell you that since they expressed that “something,” they’ve never been the same. They appear to have some type of susceptibility that singles them out to become susceptible to autoimmune disease. The Multifactorial Concept The multifactorial concept is very appropriate for a functional medicine approach because from our training, we know about the web of connectivity. We believe that all the balances and functions in the body are interconnected. When I approach autoimmune disease, I have that picture in my mind. I try to take the story of the patient and translate it into physiology, biology and what’s really happening. I use the tools of functional medicine I learned about to frame what’s going on so I can make sense of it. I’ve found that these diseases don’t begin when the patient is diagnosed. Most of the time, the patients we see at the FMRC have had a long history of what I call an “inflammatory process.” Their history reflects other family members with different types of (or perhaps even the same) autoimmune disease. But it’s interesting that, most of the time, it’s not the same autoimmune disease. A relative, for example a sister, might have lupus, and this patient might have rheumatoid arthritis. Or, a family member might have Hashimoto’s thyroiditis, and this patient will have some type of IBD. Most of these patients have some type of genetic susceptibility that can be picked up from their history. The Role of Stress in Autoimmune Disease Stress seems to play a large role in autoimmune disease, so I place it at the top of the list. The mind/body connection appears to be really important. In our stressful lives, we are not smart enough to stop behaviors that are destroying us, but the body is smart enough. A lot of times, the body will stop the patient from engaging in an activity that is extremely stressful. It might be work; it might be being a “super Mom,” and so forth. When patients come to the clinic, we have to recognize that. If we don’t change the environmental inputs, we probably will not have an impact on changing the disease. Examining the Antecedents, Triggers, and Mediators We look at the antecedents, things the patient has in his or her past. Then, we look at the triggering episodes, and they can be anything. The same autoimmune disease can have multiple triggers. A lot of people will swear their problem started after a viral infection. Some people say the problem started after some kind of trauma, such as an automobile accident, or even a mental trauma, such as a divorce or a death in the family. Onset could occur after taking a certain medication. The stories are just as varied as the number of people. As a functional medicine physician, that doesn’t bother you. You put the pieces together. You “peel the onion” down to the core thing that’s going on. Eventually, you get to the mediators, or the processes that are going on in the body that maintain the disease. Autoimmune disease is very complex. You can get into CD4 versus CD8 ratios, and Th1 and Th2 ratios. I love that quote about the patient saying he doesn’t really care about the science; he just wants to know if he can be cured. From a functional medicine point of view, the intricacies of all the various processes going on are interesting, but the key is, what can we do to impact the disease? JB: That’s a great segue, because you’ve defined a different playing field and a different domain from the functional medicine perspective. What would you call the perimeter goal post? From a clinical perspective, what types of things became part of your tool kit? The Functional Medicine Practitioner’s Tool Kit JK: It’s as varied as the web. All of the areas we look at can have an impact on autoimmune disease. We know a few of them. As a surgeon, I always go to the gut. We’ve been taught that the gut is responsible for a large percentage of the body’s immune function. One of the things that I immediately evaluate is GI function and balance. In a study of 20 patients we’ve done at the FMRC, four of the patients had celiac disease and didn’t even know they had it. They had no symptoms, but they had some of the highest antibody numbers to gliadin and transglutaminase that we’ve seen. The gut is a very important place, and it’s where I start my evaluation. I use the stool analysis, food, antibody panels, and now, we’re doing a celiac panel on almost every patient because it has cropped up so many times. It’s kind of hit us from the side, because there were no GI symptoms leading us to believe the patient had celiac disease. But all these things upregulate the patient’s immune system. Estrogen Metabolism In the FMRC study, I believe we only had one male with Crohn’s disease. All the other patients were females. That brought up the concept of where estrogen metabolism fits into autoimmune disease. I use some of the tools we have to look at the ratio of metabolism of the 2- and 16-hydroxyestrone as an indicator of whether there’s something on the estrogen side that’s stimulating the disease process. Studies have shown that patients with autoimmune disease tend to have higher 16-hydroxyestrone, and patients that do not seem to have these diseases have a higher 2-hydroxyestone. Therefore, the concept of estrogen metabolism is very important, and I use these tools in my office to measure this. Most of my patients have a problem. About 75 of the patients appear to have a high 16-hydroxyestrone level and we needed to address that and modulate their metabolism. JB: That relates to the concept of altered detoxification because estrogen is metabolized principally through the cytochrome P450s in the liver. I’m wondering if you see any correlations with other types of imbalances of detoxification capability? Imbalances in Detoxification JK: Yes, we have seen that, especially from the perspective of the gut being one of the largest containers of toxic material. We look at bowel function, constipation, and methylation. We look at a lot of the parameters in our workup and use the data to try to tailor specific things to each patient’s needs. I usually do these things after the initial evaluation. In the research center, it’s really neat, because we have a fairly nice budget. We have a long list of tests that we can do that would usually end up costing the patient several thousand dollars. In real practice, you have to pay attention to where you’re going to get the biggest “bang for your buck.” The framework of functional medicine allows you to go through the patient’s history and figure out where you think you’re going to achieve the most influence on this complex physiological system. Using that approach, which I learned in the AFMCP course, sometimes makes it very obvious that the problem is in the GI tract. In other patients, it will be obvious that they’re toxic. I’ve had several patients who became toxic from exposure to heavy metals. In my practice, it hasn’t been a common thing, but you have to be aware of it. Vitamin D Deficiency It’s interesting. Most of these patients have a vitamin D deficiency problem. There is literature discussing that vitamin D is a very pivotal, important component in modulating and slowing down the autoimmune response. We’re finding that most of our patients have vitamin D levels in the 20s, with some even in the teens. That’s another important tool that is part of the picture. JB: I want to comment for the listeners that when you’re talking about vitamin D levels, I presume you’re talking about 25-hydroxy vitamin D3, just so people will know what to order to assess vitamin D status. JK: I’m even using that in my private practice. It’s almost like a standard test now. It’s a little pricy, but it’s amazing how many times it’s abnormal. I’ve used it as almost a base test for people with autoimmune disease. JB: I know that you’ve had extraordinary experiences with some of your patients. Perhaps you could tell us about one or two of them. An Extraordinary Case History JK: I’d love to. It’s amazing how all these things come together. For instance, there was an article that appeared in the Tacoma newspaper about a rare disease called erythromyalgia. It’s a disease that’s exactly opposite from Raynaud’s syndrome, in which you get constriction of the blood vessels resulting in cold hands and the fingertips turning white. In erythromyalgia, there is dilatation of the microvasculature resulting in very hot and painful hands and/or feet. The newspaper article on erythromyalgia was published during the same week that a patient came to me suffering with that condition. In the article, the disease was described as one that caused the kind of pain that nobody can really deal with, and there was a picture of a lady and the 20 or 30 pills she took to try to alleviate the pain, the constancy of which continued despite all the medications. When the patient came to see me with this disease, I liked the idea of being challenged. (If somebody says you can’t do it, of course you have to try.) I decided to take her on because the disease is rare. You wonder why I would want to treat a rare disease, and it was because this lady was in constant pain. She had not been able to wear tennis shoes or other shoes for five years; she had not really been able to walk for two or three years. It had taken five years to come up with her diagnosis. She was positive for ANA (anti-nuclear antibodies) in her workup and there were several other interesting things of note. She was on Neurontin®, Celexa®, and lots of other medications to relieve the pain. Essentially, her physical examination was negative, except for the fact that when she was not experiencing extremely hot fingers and feet, they were actually cool to the touch. It appeared that the entire thermal regulatory system was reversed. She also had a very low vitamin D level. We conducted genetic testing and she had a polymorphism in tumor necrosis factor alpha (TNFa), which meant she probably had upregulation of her immune system. She also had an interleukin-10 polymorphism, which meant there was a probable downregulation in its dampening effect. She’s had different problems with allergies all her life-problems with eczema and problems with one type of inflammatory process after another, because she had carried these polymorphisms since birth. It was interesting to put this all together. She had personal or family histories of multiple surgeries and allergies and she had these genetic polymorphisms. She had an abusive childhood and had a lot of emotional baggage. She had repeated antibiotic use in the past. She did not eat well, so she had nutritional deficiencies. She had some back and neck trauma. What could have been the triggers? Well, she obviously had problems with the antibiotics and gut microbes. She had endogenous toxins. The temperature of the environment was a trigger for her. Then, there are the mediators, of course. You could list all the interleukins, and the signaling molecules and cytokines. What did we do with this lady? We put her on an antiinflammatory medical food and added a product that had things that we knew help to modulate the immune system-selenium, zinc, and an extract from hops of reduced iso-alpha acids. That’s all we did in the beginning. During the first couple of weeks, she reported a 50 percent improvement in her symptoms. She had less fatigue, and she noticed that other pain, for instance in her shoulder, had decreased. We got her lab work back, which reflected that she was low in vitamin D, so we added that, as well as some omega 3 fatty acids. She had an elevated homocysteine and we thought she might have some problems with methylation, so we added some B12 and folate to her regimen. We put her on an elimination diet. By the fifth week, she had a 100 percent reduction in the pain in her feet and hands. For the first time in three years, she was able to open a jar. Her migraines were gone. She was able to sleep, and she had resolution of her intestinal gas. By the fifth week, we got back her stool analysis that reflected very, very high calprotectin and very, very high eosinophil proteins. That’s when we did the celiac panel, which showed some of the highest scores: she didn’t know she was celiac, but she was. She was already on an elimination diet. We put her on celiac diet. Her eosinophil proteins were over 31 and her calprotectin was over 250. She had no growth of lactobacillus or bifidobacterium. She had 4+ proteus. We put her on the 4R Program to try to rebuild, to reinoculate, remove pathogens, and replace digestive function. She continued to experience great improvement and, by about the eighth week, she had taken herself off almost all her medications. She was down to only three tablets of Neurontin® per day, rather than nine, and she said: “I feel like I’m 20 years younger.” That was really cool, because her disease was the same disease that the article in the paper described as one that nobody could help. Using the simple tools of functional medicine, we were able to make a major impact in this lady’s life. By the 12th week, she was off all her medications. She was able to stand for the first time in a long time, and started to wear shoes. When I saw her recently, she told me I wouldn’t believe what she’d done. She went to the mall in tennis shoes, which she hadn’t done for six or seven years. She didn’t realize how much of the abdominal symptomatology-the bloating and stuff-had been resolved. By the 12th week, her lab work showed that her eosinophil proteins had come down to almost 18; her calprotectin was down to 35 from 250; she had bifidobacteria growing; she had lactobacillus growing; and her intestinal permeability was actually coming back toward normal. Her homocysteine had come down from 9 to 4. Her vitamin D was still a little low, so we increased that. But, here’s a lady who was being told by her physician to be prepared for a long life of pain; of not being able to wear shoes; and of not being able to do the things she loved to do. Now, she’s a functioning person. She said she knew it was wintertime, but she went out and did some gardening. She hadn’t worked in her garden for five years. When she came in, her MSQ scores were way up around 30; they went down to 5. Here’s a lady who feels as if we gave her 20 years of her life back. That’s very rewarding, and it’s done with just the simple tools of functional medicine, approaching the problem from a multifaceted viewpoint and listening to the patient’s story. Piece by piece, we separated the environmental influences on her susceptible genes so that we changed how her body responded. To me, this is where it’s at. JB: Jack, that was so compelling. I’m sure anyone listening to this for the first time who has not had any experience with functional medicine is sitting there simply amazed at your story. Of course, those who have been in functional medicine probably have similar case histories to report. It raises a question that may be unanswerable, but I’d like to get your opinion as a practitioner with more than 30 years of experience. Why do you think there’s resistance in traditional medicine to this concept? It seems non-toxic; it doesn’t necessarily prohibit the application of other intervention modalities, so why the resistance? Resistance to the Functional Medicine Concept in Conventional Medicine JK: I think it has to do with perspective. That was one of the biggest things I had to change when I went from surgeon to functional medicine physician. It isn’t a matter of changing the science; it’s a matter of how you change your perspective and your interpretation of the science. We’ve all seen that picture that has two faces looking at each other. It’s either an old lady or a young lady, depending on how you look at the picture. It flips back and forth from one picture to the other. Yet, the data in the picture didn’t change. What changed is how we look at it, how we perceive the data. That’s the problem. People who are doing functional medicine perceive the data with a much broader interpretation. Unfortunately, I think that traditional medicine perceives data from a very narrow point of view, especially within a specialty. Specialists have a hard time adjusting their binoculars for a wider view so they can see outside the box. The funny thing is, this information is in the literature, but traditional medicine is 20 years behind what is coming out in its own literature. I think that’s where the problem is. And, not to get into politics, but my own personal opinion is that medicine is now being funded by pharmaceutical groups. That’s where the money comes from to run medical schools and to do the research, and it’s biased. The approaches we use are simple. One of our patients is taking the intravenous medication, Remicaid® and I think that’s about $3000 per dose. It’s a change of perspective. We’re giving folic acid, which is about 25 cents a dose. It’s amazing. When I talk to physicians about it, they respond with statements like, “Huh! I never thought of that.” They’ve never considered another scenario outside of their little boxes. That’s one of the things I’ve noticed. JB: This has been one of the most enchanting discussions I’ve had the privilege to experience on FMU. You’ve brought clinical insight to our listeners “from the trenches,” so to speak. Sometimes we get caught up (I certainly do) in the esoterism of this mechanism and that mechanism, and great technology breakthroughs in our understanding of how the body works. But it all eventually distills down to how that patient behaves in the world in which they live and how they present themselves. I think you’ve done a magnificent job of making this complex story sensible and understandable. If someone was thinking about functional medicine and they listened to this interview, I have a suspicion they would take the time to gain some mastery of this area, because it’s pretty motivating. Long Latency Period in Autoimmune Disease? JK: Another thing I want to share is that there’s a huge latency period between when patients start having symptoms on the slippery slope to autoimmune disease. This is very similar to what we found with diabetes, and now with syndrome X/metabolic syndrome. There is a syndrome, (I’ve called it the inflammatory immune syndrome) that begins years and years before they actually get the four criterion of the condition; for example, with lupus. When telling their stories, these patients have gone from doctor to doctor and sometimes they’re given Paxil® because they are seen as depressed. As functional medicine practitioners, we have a golden opportunity to intervene in a potentially devastating disease years before there is physiological damage, in a way that actually stops the process. This is a whole new field about how we can get in early, before the patient actually comes in with gnarled up hands or, for example, in patients with sclera derma, with skin that looks like leather. How do we get to these patients early and prevent this whole process from ever happening? That’s where the future is going to be exciting. JB: I can’t thank you enough for spending time with us today. This has been very motivational. We’ll take the lead and continue to try and inform people about this emerging inflammatory syndrome that you’ve described. Thank you, Jack, for being part of the functional medicine family. We appreciate it. JK: Thank you. The Functional Medicine Assessment It struck me, in thinking about Dr. Kornberg’s extraordinary comments, that when we start looking at the functional medicine model from 30,000 feet in a kind of broad-brush evaluation, the approach is very different from that of the traditional differential diagnosis, which is to try to know more and more about less and less, so that you can ultimately get a specific diagnosis. The functional medicine assessment, so eloquently described by Dr. Kornberg, is to keep moving up to higher levels of organizational perspectives to look at where the interconnections occur, and then to drill down into the individual mechanisms of action related to each of the nodes on the matrix. There is a sense that we are moving back and forth between a telescope and a microscope with the functional medicine model. There is a broader-based perspective and then a very small perspective, and a personalized approach for the patient is developed, based upon the interrelationship between the connection of the whole and focusing therapeutic energies into implementation to the individual components. Oxygen as a Therapeutic Agent What is one of the most important elements that all air-breathing organisms need to be concerned with, as it relates to dysfunction? That, of course, is oxygen, which is about 20 percent of the air we breathe. Often, we forget about air and water as being very important parts of therapy. Every traditional form of healing, from the dawn of medicine, had something to do with delivering air or oxygen to tissues. It could be deep breathing, yoga, exercise, various types of physical medicine, or dance-any number of things up through aerobic exercise and later, into mechanical intubation. I am talking about making sure that oxygen delivery and respiratory gases are properly controlled. Low levels of oxygen in tissues produce oxidative stress, which is associated with inflammation and tissue injury. We want to make sure that tissues are properly oxygenated, and that a person is delivering oxygen to things like the monooxygenase enzymes, which are the cytochrome P450s, the various detoxification enzymes we have talked about that require oxygen for their activity and for proper function to detoxify endogenous and exogenous toxins. Water as a Therapeutic Agent Water is also a very important therapeutic agent, because hydration is critically important for establishing appropriate environmental conditions within cells, tissues, and organs for their function. Dehydration increases the solute concentration and changes enzyme function, cellular activity, and membrane transport. Proper hydration becomes an extraordinarily important part of any therapy in making sure that there is proper balance of intra- and extracellular fluids. The nature of the medications many patients take may alter their intra- and extracellular fluid balance and can lead to intracellular dehydration. Anyone who has overdone alcohol sometime in his or her history recalls the effect that it has on intracellular hydration. It produces a dehydration effect and makes one very thirsty because the cells become dehydrated and, as a consequence, there are toxic symptoms. I want to make sure we recognize that sometimes the simplest things become the most important for proper breathing, delivery of oxygen, and proper fluid intake for intracellular hydration. Again, that obviously ties into the topics that Dr. Kornberg was speaking about as part of the matrix-concepts of GI function, immunological function, hepatic detoxification function, oxidant balance, redox balance, neuroendocrine balance, and body/mind balance. These all interrelate as components of the web in the matrix to things as simple as proper delivery of oxygen and proper fluid intake. What we have outlined in the course of this issue of FMU is a model that has sprung out of nearly 20 years of the emergence and evolution of functional medicine. It paves the way for increased application of this model to a variety of different complex, chronic disorders that do not necessarily fit into a tidy diagnostic profile. I am holding the Textbook of Functional Medicine, which relates to the themes and concepts described in this issue of FMU. This is an 800-page embodiment of the spirit of what we have been talking about for nearly 20 years. I hope you will have a chance to read the textbook and spend some time getting the kind of mastery of these techniques that will allow you to help your patients more effectively. Thanks for being with us. We will see you in April.

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Bibliography

1 Pizzi R. The challenges of pharmacogenomic tests. Has personalized medicine arrived? Clin Lab News. Dec 2005. 2 Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279(15):1200-1205. 3 Buchwald D, Garrity D. Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Arch Internt Med. 1994;154(18):2049-2053. 4 Pall ML. Multiple chemical sensitivity: towards the end of controversy. Townsend Letter. Aug/Sept 2005:52-56. 5 Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ. Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Rad Biol Med. 2005;39:584-589. 6 Pall ML, Anderson JH. The vanilloid receptor as a putative target of diverse chemicals in multiple chemical sensitivity. Archives Environmental Health. 2004;59(7):363-375. 7 Holley MC. The auditory system, hearing loss and potential targets for drug development. DDT. 2005;10:1269-1282. 8 Lynch ED, Kil J. Compounds for the prevention and treatment of noise-induced hearing loss. DDT. 2005;10(19):1291-1298. 9 Attias J, Weisz G, Almog S,et al. Oral magnesium intake reduces permanent hearing loss induced by noise exposure. Am J Otolaryngol. 1994;15:26-32. 10 Rybak LP, Whitworth CA. Ototoxicity: therapeutic opportunities. DDT. 2005;10(19):1313-1321.

Welcome to Functional Medicine Update for April 2006. The focus of this month’s FMU will be on estrogen-estrogen-related dysfunction and estrogen-related functional capabilities in physiology. I think you will be pleased to hear from our Researcher of the Month, who is coming back for a second time after a two-and-a-half-year absence-Dr. Eleanor Rogan from the Eppley Institute at the University of Nebraska Medical Center. She will talk about her extraordinary pioneering work on estrogen metabolism. The Women’s Health Initiative (WHI) Before we get to that, let me speak briefly about the WHI. You probably recall that the WHI was an extraordinary study of over 160,000 women, age 50 through 79 years. This multi-million dollar, 15-year project was focused on trying to understand the relative impact of diet, lifestyle, and other factors on post-menopausal women’s health. In this study, hormone therapy, calcium and vitamin D supplementation, and dietary and lifestyle patterns were all examined in association with heart disease, cancer, and osteoporosis, respectively. We owe Dr. Bernadette Healy, the previous director of the National Institutes of Health, a debt of gratitude for her advocacy to do this extraordinary bit of work to try to better understand the gender-specific relationships between risk factors and age-related disease in women. In particular, this project focused on the peri- and postmenopausal times in women’s lives that are associated with increasing incidence of breast cancer, heart disease, bone loss, bone fractures, and osteoporosis. Low-Fat Diets and Weight Loss This extraordinary work is now starting to be analyzed and the data, which is massive, is being examined from multiple perspectives. We have seen things like the relationship between low-fat diets and weight change, which is one of the more recently published parts of the WHI. The outcome of that part of the study is quite fascinating. There has been a trend over the last several years in thinking that carbohydrate somehow increases weight gain, and is the scourge of our population. As a consequence of too much carbohydrate intake, we are seeing insulin resistance, type 2 diabetes, cardiovascular disease, and rampant obesity. This speaks in opposition to the previous concept that a high complex carbohydrate, high-fiber, lower-fat diet actually achieved weight loss, lowered insulin, and promoted better glycemic control and lipid patterns. It seems paradoxical that we have swung from the high-carbohydrate to the low-carbohydrate regime as being a favorable diet. The low-fat diet connection to heart disease in postmenopausal women, therefore, is part of trying to understand the dietary connection to disease risk. Low-fat Dietary Pattern and Weight Change A paper was published earlier this year in the Journal of the American Medical Association, titled “Low-fat pattern and weight change over 7 years: the Women’s Health Initiative Dietary Modification Trial.“1 Initially, the investigators had targeted trying to get the total fat calorie percent in the intervention group down to 20 or lower. In actual fact, this was not achieved. The women did not comply with the extent of the low-fat diet. They were able to lower the average fat intake by about 8 calorie percent over the standard American diet for the control group, so it was a modestly restricted carbohydrate diet. Therefore, the results of the study would probably be considered intermediary, or somewhat compromised, because the fat restriction was not achieved with all that was proposed. The outcome of the trial, even with that limitation, indicated that there was a marginal weight loss, but it was a loss and not a weight gain in the individuals on the lower-fat, higher-carbohydrate diet. The concept that a carbohydrate-rich diet increases body fat does not appear to be true, based on this study. Types of Fat, Carbohydrates, and Protein There are a number of variables that should be taken into account when examining this topic. One of the most important, which we often forget, is what type of fat, what type of carbohydrate, and what type of protein is involved? It is becoming more apparent that, although we have spent much of our time focusing on the calorie percent of each of these macronutrients, the actual composition of those families is as important, or more important, than the number of calorie percent they represent. If we talk about carbohydrate as refined (sugars and starches)-the highly white type of diet-they will have a different physiological effect than a diet with the same number of calorie percent carbohydrates that come as minimally processed grains, rich in fiber, rather than rich in bleached starch. As a consequence, the glucose molecules from carbohydrate are digested and absorbed differently, but there is also the association in the minimally-processed diet with literally hundreds (probably thousands) of different phytochemicals that influence physiology through their individual signaling properties to gene expression patterns. When one looks at carbohydrate in the Pridikin or Ornish approaches, it is a different kind than what we are talking about-increased white carbohydrate (starch and flour products) in a refined state. We often get caught up in the carbohydrate/fat/protein argument, and we are missing the focus, which should be on the composition of the diet in its total nature. Many other nutrients-soluble fibers, insoluble fibers, lignans, isoflavones, polyphenols, carotenoids, xanthophylls-as well as all the other bioactive molecules in a minimally processed diet, influence function. That was not controlled for in the WHI dietary intervention trial. We saw that by decreasing fat by about nine calorie percent (meaning an increase in percent carbohydrate calories), there was no increase in body weight. Actually, there was a statistically significant, though marginal, lowering of body weight. It comes down to how we can arrest the epidemic of obesity. The individuals who wrote the editorial on the JAMA article discussing the WHI low-fat diet hit upon some very important information.2 It was written by Michael Dansinger and Ernst Schaefer, the co-authors of a previous study published in JAMA about a year ago that we reviewed in FMU, comparing the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction. 3 These authors, who also wrote the editorial to the 2006 paper, ask: “Is it time to admit defeat? Is US society doomed to be one in which few individuals maintain body weight and one third of the adults are obese?” The recent low-fat diet in the WHI does little to reassure skeptics, and some see no hope on the horizon. “Many believe humankind does not have the self-control to counterbalance the forces that create a predictable wave of obesity in technologically advancing societies. Some believe national governments will never enact the bold policy changes that could make a dent in the obesity rates, such as substantially altering food advertising practices and creating economic incentives for vigorous adherence to lifestyle recommendations. Even modest steps, such as limiting advertising of unhealthy food during children’s television programming, or placing small taxes on unhealthy foods are met with seemingly insurmountable resistance from the food industry and others. With a government and society that seemingly reject the pursuit of economic and other reforms that could make a real difference, the burden of obesity treatment and prevention continues to rest on the shoulders of ‘individual responsibility’” That is an interesting perspective, and one certainly worthy of our attention. If we are constantly feeding our children and adults molecules that create a different message that translates into storage rather than metabolic utilization, we are going to see a continued increase in the obesity epidemic, with what might be considered very severe consequences as our children grow into adulthood, with regard to coronary artery disease, stroke, and perhaps even certain cancers associated with hyperinsulinemia. We have to start asking questions that are different from those that have been asked in the past about just restricting calories and changing protein/carbohydrate ratios in diets. We need to look at the complex nature of the diet that creates the signaling in cells that regulates appetite, physiology, and metabolism, so that usable energy is available for physiology, and storage is less likely to occur-storage for the rainy day that never comes called adipocyte hypertrophy, where we start storing lipids in our fat cells, producing central adiposity, insulin resistance, and adipocytokines that induce inflammation. We need to come up with a better model. The concept of calorie restriction, weight-loss diets, and eating less of the same foods we have available in commerce, which send the wrong messages to our genes and produce an outcome called dysfunction and inflammation, is a model that is not working. We need to find something different than the first law of thermodynamics to try to address this problem of obesity. That is my takeaway from the article on the WHI. Yes, there was a minor weight loss seen in these individuals by restricting some degree of fat in their diet, but it was not significant enough to deal with the major nature of the sea change that is occurring in obesity. We need to find a different model, one that relates to finding out how to promote proper nutrigenomic signaling to the cells, producing an outcome related to proper physiology and appetite regulation through the gut, the liver, the pancreas, the muscles, the adipocyte cells, and the brain, all working cooperatively to regulate what has evolutionarily been built into our genes. We have overridden it. We know how to eat. Our genes know how to control these aspects of physiology, but we have been sending toxic molecular signals to the cells through toxic diets that create outcomes of gluttony and lack of self-control. People do not elect to eat gluttonously. It is the number of things that we are signaling to this regulatory system that create the outcome. It is not as simple as simply cutting calories. If we cut calories, and we are still delivering these false and toxic messages to that person, it is likely we are going to have the same outcome. That is my takeaway from the WHI weight management, lower-fat diet study. There was a paper that appeared in the 2006 issue of JAMA on page 58 that is another interesting example of how a nutrient component can have an effect on cellular signaling in physiology.4 I am talking about an amino acid found in protein-L-arginine, which has been frequently discussed in the news over the last nearly 15 years. In the mid 1990s, nitric oxide (NO) was chosen as “Molecule of the Year” by the editors of the journal, Science. NO is formed in the body by the conversion of arginine into citrulline. The identification of NO and the work identifying its synthesis pathway won the Nobel Prize in Physiology and Medicine for three researchers in 1998. One of those researchers was Dr. Louis Ignarro, a distinguished professor of pharmacology at the University of California at Los Angeles. It has been suggested that L-arginine could be useful for increasing endothelial NO, which would lead to improved vascular compliance, lowered blood pressure, and an overall improved vascular endothelial outcome and function in individuals with damaged endothelia. This was a model we were fortunate to have discussed with Dr. John Cooke on FMU in November 2002. Dr. Cooke is a cardiology researcher from Stanford University, and he talked about his clinical intervention trials using oral arginine supplements in individuals (first in primates, and later in humans) with either hypercholesterolemia or vascular endothelial injury. He found that supplemental L-arginine appeared to improve vascular and endothelial functions. The paper in JAMA that I am now discussing is titled “L-Arginine therapy in acute myocardial infarction,” and contains a description of the randomized clinical trial called “The Vascular Interaction With Age in Myocardial Infarction,” the so-called VINTAGE MI trial. In this intervention trial study, which was performed from February 2002 to June 2004 at Johns Hopkins by Steven Schulman and his colleagues, the amino acid, L-arginine was used as a supplement in a single-centered, randomized, double-blind, placebo-controlled trial. The trial involved 153 patients following a first ST-segment elevation myocardial infarction; 77 patients were 60 years or older. These were post-infarction patients who were all quite sick. In this trial, patients were randomized to receive either L-arginine (the goal was to get them to take 3 grams of arginine three times a day, or 9 grams total) or matching placebo for six months. The investigators examined change in gated blood pool-derived ejection fraction over six months. The results showed that baseline characteristics, vascular stiffness measurements, and left ventricular function were similar between participants randomized to receive placebo or L-arginine. At the end of the trial, it was found that there was no significant change from baseline to six months in the vascular stiffness measurements or left ventricular ejection fraction between the two groups, including those 60 years or older. It was pointed out that in the L-arginine group, six participants, or 8.6{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, died during the first six months of the study versus no deaths in the placebo group. The researchers go on to suggest that L-arginine may be contraindicated in this patient population. Although not directly assessed in the study, this raises questions about what happens if you put a person on a high vegetable-based diet, which is rich in L-arginine, and they have vascular defects. Might you induce some injury? Recall that arginine is found in high quantities in proteins, particularly in some vegetable-based proteins, and might this imply that dietary proteins high in L-arginine, given to people with post-infarction injury could pose a risk to more serious outcomes? That does not appear to play out with the data that has been previously published, in which it has been suggested that vegetable-based diets decrease the relative risk to secondary heart attacks. This suggests that one would want to recommend diets in which proteins were probably richer by nature in arginine. Some of these things just do not seem to line up. Is there a difference between L-arginine given as a supplement to post-MI patients versus arginine in the diet? Again, there are many questions, because we would again assume that L-arginine from dietary protein would be delivered into the blood. Once the protein had been digested, the amino acid would be absorbed into the blood and produce a postprandial elevation of L-arginine, similar to what one would get when supplementing with equivalent amounts of purified or isolated L-arginine. This is a swirling debate. I asked Dr. Louis J. Ignarro, the Distinguished Professor of Molecular & Medical Pharmacology at UCLA, if he would like to offer his opinion about this particular trial. Work in pharmacology has shown us that all substances are toxic at some level, even air and water. The question is: What is the level of potential toxicity and relative risk of L-arginine, if at all, in individuals with specific types of cardiovascular defects? With this in mind, Dr. Ignarro pointed out the following concerns he has about the study published in JAMA:” 1. Patient Selection– This clinical study was performed with very sick patients (dying patients) suffering from advanced cardiovascular disease. They were receiving several different types of potent drugs to treat their condition. We know that these individuals have very brittle physiological function that is very sensitive to interaction with any additional bioactive agent. L-arginine is not a drug, but rather an amino acid nutrient, which when administered therapeutically to patients with serious cardiovascular disease might have numerous influences on vascular biology just as any dramatic dietary change could have. Generally, in order to test the potential therapeutic benefit of any dietary supplement or functional food in humans, it seems prudent to design the clinical study carefully and to use as a measurable endpoint a parameter that is known to have the potential to respond to the given treatment.” 2. Study Design and Endpoints of the Study– The VINTAGE MI clinical trial was designed to test whether the addition of L-arginine to standard post infarction therapy in patients following a first STEMI over a 6-month period “would decrease vascular stiffness and improve left ventricular function.” There is a serious flaw in this design and the expected therapeutic response to L-arginine. That is, the nitric oxide generated from L-arginine is a vascular smooth muscle relaxant and inhibitor of platelet function. There is no evidence, however, that nitric oxide decreases vascular stiffness. &hellip;Increasing the production of nitric oxide would NOT be expected to alter vascular stiffness. Therefore, the design and rationale for the clinical study are ill conceived.” 3. Sample Size and Outcome– The patient sample size was small and the statistical evaluation was marginally significant. It is clear that the control patient group itself (not receiving L-arginine) experienced a mortality rate of greater than 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} as would be expected in a group of patients this ill. The percentage of patients taking L-arginine who died during the study was well less than 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. This means that the deaths of the patients taking L-arginine were likely attributed to chance. Indeed, the authors themselves indicate this as a likely possibility. Therefore, a second and larger clinical study might reveal no significant response to L-arginine in a similar subset of patients. Accordingly, it is premature, unscientific, and unethical to conclude that the patient deaths in this study were attributed to the ingestion of L-arginine.” 4. Lack of Proof of a Cause and Effect Relationship- This small clinical trial does not provide any evidence for a cause and effect relationship between L-arginine administration and death in sick patients with cardiovascular disease. There is no evidence that L-arginine was responsible for the patient deaths. Moreover, there is no scientific or statistical evidence for any association between L-arginine administration and patient death.” 5. Flaw with Proposed Mechanism of Action- When a beneficial or detrimental response to a substance ingested by humans is reported in the literature, the authors are obliged to provide a clear rationale for the study and a viable hypothesis to explain the response. Neither was done in this study. The hypothesis forwarded to explain the potentially harmful action of L-arginine in this patient population is flawed and scientifically unsound. The authors concluded that tetrahydrobioterin (BH4) levels were deficient in these sick patients, and that this condition resulted in more superoxide anion production than normal, and at the expense of nitric oxide. That is, L-arginine is normally converted by NO synthase to nitric oxide plus L-citrulline in the presence of adequate amounts of BH4. But when the BH4 is deficient, more superoxide anion than nitric oxide is formed. Since superoxide anion is an oxygen radical, the thinking is that this excessive production of superoxide anion can cause local tissue injury. There are many flaws in the application of this hypothesis to the current findings. First, no measurements of tissue levels of BH4 were made. Second, the quantity of NO synthase in the affected tissues in these patients was not determined and there would have to be very high levels of NO synthase to make enough superoxide anion to be of any concern. Third, it seems that the authors were not familiar with the biochemistry of nitric oxide. It is well known that when NO synthase is saturated with L-arginine substrate, the enzyme produces exclusively nitric oxide and no superoxide anion. This can be demonstrated clearly in vitro. As L-arginine concentration increases, no superoxide anion production occurs. The cell would have to be deficient in L-arginine for the production of any appreciable quantities of superoxide anion to occur. As these patients were given relatively large doses of L-arginine, it is highly likely from many past studies that their cells were NOT deficient in L-arginine. Indeed, the likely presence of saturating concentrations of L-arginine around NO synthase would assure only little or no production of superoxide anion. Therefore, the authors incorrectly conclude that tissue BH4 deficiency might have caused increased production of superoxide anion, which in turn might have contributed to the death in the patients.” 6. The inappropriate mechanistic connection of arginine to atherosclerosis–The authors claim that an increase in inducible NO synthase (iNOS) can increase in patients with atherosclerosis. There is a well recognized relationship between inflammatory markers and atherosclerosis. However, iNOS is a marker of inflammation rather than a cause of it. Indeed, the iNOS goes up in order to produce more nitric oxide to act as an anti-atherogenic agent in the body. The authors claim that the increased nitric oxide can react with the superoxide anion that might be formed to produce peroxynitrite, a potentially dangerous substance that can cause tissue injury. This is theoretically possible but there has been no evidence for this in vivo. The current belief is that insufficient peroxynitrite would likely be produced to elicit any deleterious effect in tissues. Moreover, the nitric oxide and the superoxide anion would have to be generated very rapidly in precisely the same spot in order to allow the two to react chemically to form peroxynitrite. As discussed above, the presence of such a large concentration of L-arginine in these patients who ingested L-arginine would make it highly unlikely that any superoxide anion was being generated.” 7. The inappropriate connection of arginine to homocysteine–The authors make a statement that L-arginine administration causes an increase in plasma homocysteine levels in humans and that this could increase the risk of heart failure. Again, this statement is incorrect as it is well known that one of the most important physiological roles for nitric oxide in the body is to function as an antioxidant to lower the levels of homocysteine and, thereby, protect against atherogenesis and atherosclerosis.” 8. The lack of balance in describing the influence of L-arginine on vascular function– The authors have chosen to ignore the extensive literature documenting that L-arginine administration to animals and humans with atherosclerosis causes a provocative reversal of inflammation and disease state. L-arginine administration in animals also increases the expression of endothelial NO synthase, which serves to allow the production of more nitric oxide in the blood vessels, thereby slowing the progression of atherosclerosis.” 5 Editorial Bias and Philosophy in the Literature With regard to Dr. Ignarro’s comments on this paper, one might ask how it ever got published in JAMA, when there are so many papers that vie for publication in this primary, distinguished, peer-review journal. It begs the question as to why the editors decided to accept it for publication, and why it did not end up in a secondary or tertiary journal instead, where it could be seen as an “n of one” type study requiring a fuller evaluation to demonstrate proof of the model. These are interesting questions that come up in this field. It is my observation that a number of published studies related to nutrient impact on physiology that have a negative spin end up in primary journals, whether or not the methodologies are flawed or the trials of limited size. Therefore, they fall prey to the same criticism that is often levied against nutrition studies that show a positive effect. That is, they are not done with a large enough study group. They do not have a high enough statistical significance. They deal with mechanisms that are not completely understood. When that criticism is levied against something that comes out positive, it often will not appear in the journal; it will be rejected. When the criticism is levied against something that shows a negative outcome, it seems to somehow end up being published. It raises some interesting questions about editorial philosophy and bias that we need to take into account as we evaluate the published literature. That leads into a discussion of the estrogen connection to autoimmune disease. Almost 90 percent of autoimmune disease disorders of the most common forms-rheumatoid arthritis and systemic lupus-are primarily found in females. In March 2005, there was a remarkable report published by the U.S. Department of Health & Human Services through the National Institutes of Health (NIH), titled “Progress in autoimmune disease research” (this can be found on the Internet).6 It is the summary of a report to Congress on the progress on autoimmune disease, and it contains some remarkable statistics. Autoimmune disease is much more prevalent than previously recognized because historically, it has been broken up into 80 or more clinical conditions that have never been grouped as an aggregate so as to examine the total number of people affected. For reasons we are still trying to understand, approximately 23.5 million people in this country have autoimmune disease, and the prevalence is rising. In fact, the number of people affected rivals that of other major disease indicators, including dyslipidemia, insulin resistance, and hypertension. The autoimmune family of disorders, which is on the rise, is certainly a significant problem. Another thing that is pointed out in this report, which I think is very interesting, is that the conditions-although they have been segmented as independent diseases under respective diagnostic categories-are now being found to be associated with changes in various immunological mechanisms. Our concept of this disease category is that the individual diseases are distinctly different from each other. For example, we try to completely segregate myasthenia gravis from systemic lupus erythematosus, multiple sclerosis, and ulcerated colitis. This concept of differentiation is starting to change; we are starting to look at similar mechanisms of immunological imbalance and dysregulation of the thymus dependent 1(Th1) and thymus dependent 2 (Th2) lymphocyte system to help us better understand the etiology and the potential origin of these diseases. That leads to what I would call a functional medicine approach-one that is focused more on the underlying mechanisms and less on the medical taxonomy of a disease. Medical taxonomy is no longer the “sine quo non” for understanding these diseases. As we begin to examine the mechanisms that connect these diseases one to the other, estrogen metabolism seems to be one of the metabolic variables associated with these conditions that may help us to better understand why they are more common in women than men. In fact, in this nicely written and lengthy report published by the NIH, the authors discuss the metabolic, environmental, and genetic factors associated with autoimmune disease. The first thing the authors point out is that there is no single gene allele connected to individual autoimmune diseases. No one has “a gene” for thyroiditis or multiple sclerosis, but rather there are families of genes that interrelate immunological susceptibility, or sensitivity, to environmental triggers that can weave together to give rise to the outcome we call autoimmunity, or immunological imbalance. Genetic Relationship to Autoimmune Disease It is now being said that about one third of these autoimmune disorders has a genetic relationship, which implies that two thirds of the disorders are related to environmental factors, both internal and external, that weave together to give rise to the expression of the disease in the phenotype. When we talk about something that is two thirds related to the environment (67 percent), it strongly addresses the hypothesis that we should be spending more time trying to understand environmental relationships, rather than trying to focus on genetic propensity. Part of prognostic screening would be to understand genes of risk, but beyond that, we would want to look at the environmental modifiers that give rise to the potential outcome of expression of the immune system that we diagnose as “immune disease,” or “autoimmunity.” This is an interesting part of the emerging story-beginning to look at key factors that can modulate the expression of autoimmune susceptibility. These are reducible, or modifiable factors, and we now understand that they have potential for being altered by modifying the environment. In the NIH report, it is stated that although approximately one third of the risk of developing an autoimmune disease can be attributed to hereditable factors, the remainder of risk is thought to be associated with non-inherited events. These include things like mercury in the environment, and other toxic heavy metals now being seen as potential immune-activating substances in sensitive individuals. It also includes exposure to certain chemicals and xenobiotics, such as halogenated hydrocarbons, polynuclear aromatic hydrocarbons, and polychlorinated biphenyls. All of these have potential xenobiotic risk to the immunological system in susceptible individuals. We know about drug-induced systemic lupus erythematosus. This is a variant form associated with increased levels of single-stranded DNA auto-antibodies. As a consequence, these individuals may have a unique reaction to exposure to specific chemicals that can induce an autoantibody against their tissues. Now, we start to piece together that this could be a “total load” effect. Layer upon layer is added to the immunological system until auto-antibodies are expressed (depending on the individual’s genetic uniqueness). This is the immune system reacting with itself, but perhaps it is reacting with things that have come as a consequence of injury to self. Infectious Agents and Autoimmune Disease Infectious agents are the most often-cited environmental factors implicated as triggers of autoimmune disease. We know about the classic example-the Group A beta-hemolytic streptococcus in the development of rheumatic heart disease. Acute Guillian Barre syndrome has been associated with a number of bacterial and viral infections. Even reactive arthritis has been linked to a variety of intestinal infections. We begin to see focal infections, which could be a root canal, dysbiosis of the gut, or sinusitis, any of which may result in continued leakage of bacterial and viral products that initiate immune imbalance. Lifestyle and Dietary Factors in Autoimmune Disease Lifestyle and dietary factors are now being seen as much more important issues in autoimmune disease. Diets very high in total calories and fat calories induce injury to DNA and produce “funny” DNA. The immune system may recognize these as “foreigners” and begin to form antibodies against DNA called “anti-DNA autoantibodies.” It is actually against a foreign DNA that has resulted as a consequence of oxidative injury to native DNA. Diet is beginning to be seen as a potential additional modifying factor in the expression of autoimmune disease. Food Allergy and Autoimmune Disease We know that food allergy and food sensitivity may modify function via the immunological changes that occur. Gluten sensitivity stands out in conditions such as thyroiditis, ulcerative colitis, and Crohn’s disease. We are beginning to understand how the food of one may be the poison of another, as it relates to the immune system. When I read through this NIH document, I recognized that we are entering into a dramatic period of change related to how we view the origin of autoimmune disease. Estrogen and Autoimmunity Estrogen is another factor in autoimmunity. It used to be thought that 17-beta-estradiol was strongly correlated with autoimmune disease. Now, there is more and more evidence indicating that estrogen metabolites, possibly the 16-hydroxyestrogens, and perhaps the 4-hydroxylated estrogens, may be precipitating metabolites for immunological imbalance, inducing immunological activation of inflammation. We will talk more about estrogen metabolites with our Researcher of the Month, Dr. Eleanor Rogan. Autoimmune Disease in Females Compared to Males I want to mention the prevalence of autoimmune disease in females as compared to males and how that may relate to androgen/estrogen balance and estrogen metabolism. Some therapies for arthritis have to do with increasing androgen, such as administering DHEA at high levels with systemic lupus erythematosus patients, or giving an aromatase inhibitor, which has shown to be of some benefit. Taking women off birth control pills to lower estrogen exposure, or giving Tamoxifen to block estrogen signaling have been found to decrease some of the signs and symptoms observed in autoimmune disease. Clearly, there is an estrogen metabolism component in autoimmunity. What is interesting is that the exacerbation of signs and symptoms in autoimmunity does not appear to be directly correlated with the plasma levels of 17-beta-estradiol, but more related to estrogen metabolites, the 16-hydroxyestrogens in particular. This was discussed in an article published in the journal Lupus in 2002, which examined the relationship between 16-hydroxyestrogen and the appearance of signs, symptoms, and severity in systemic lupus erythematosus patients. There is a correlation between a variety of environmental factors and dysregulation of the immune system. Modulation of estrogen metabolism is certainly on the list of factors we need to keep in mind that may help in autoimmune disease. Stress and Autoimmunity Stress also plays a large role in autoimmunity, as well. I want to thank Dr. Peter Madill for calling an interesting paper to my attention. He is one of our long-standing supporters and a physician in Sebastopol, CA. In a paper published in The Journal of Neuroscience in 2005, the authors discuss maternal programming of stress responses, and how activation of the hypothalamus/pituitary/adrenal axis can initiate various types of messenger molecule changes, including inflammatory cytokines and other cell regulating substances that have to do with growth hormone and gene expression patterns. This interaction can create a feed-forward cycle that can facilitate and activate stress responses that we see as inflammation, and encourage and feed into the inflammatory pathway.7 This paper is also remarkable because it demonstrates (in animals) that one epigenetic response can be epigenetically reversed. That is, the epigenetic programming thought to be static after birth was reversed with respect to stress-related marker genes. This reversal was accomplished by infusion of methyl donor nutrients in these adult animals’ brains, and demonstrated a lowering of some of the stress responses. These are epigenetic types of phenomena that occur, not from modifying the genetic code directly, but the environment in which the genes are expressed, leading to changes in the messenger RNA and subsequent proteins. This is a huge, new advancing concept in medicine. We used to think that everything was linked to our genes and there was little we could do about it. Now, we recognize that the environment actually influences not only how our genes are expressed, but how biomolecules are expressed from the genes finally evolve into the phenotype and alter metabolism, cell signaling, and what we call the phenotypic component of the cell. People with many inflammatory conditions have a lot of dysregulation in their immune systems. Things can be done posttranslationally, such as improving methylation patterns with folate, B6, and B12, as well as reducing stress. With that in mind, let us move to our Clinician/Researcher of the Month interview.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Eleanor Groniger Rogan Eppley Institute 8210 Bowie Drive Omaha, Nebraska 68114 JB: It’s time for our Clinician/Researcher of the Month. Those of you who attended the 13th International Symposium on Functional Medicine were privileged, as I was, to hear Dr. Eleanor Rogan, one of our premier plenary lecturers, talk about the extraordinary work she has done over the years on estrogen metabolism. This is such an important area, and one that we previously introduced on FMU during our first interview with Dr. Rogan in November 2003. We thought it would be important to update our listeners on the significance of Dr. Rogan’s work. Just to review her background, Dr. Rogan works at the Eppley Institute at the University of Nebraska Medical Center. She is an elegant researcher, developer, and discoverer of both the mechanisms and influences of estrogen metabolites-a very sophisticated area of chemistry. We’re not talking about things that are produced at very high levels. Therefore, methodologies have to be developed to analyze them, as well as their reaction products. Many of these products have high reactivity so they don’t remain in biological specimens very long after the sample has been taken. Analytical ways of demonstrating their presence have to be found, either by surrogate markers or direct chemistry analysis. This is a very complicated portion of the “cellular soup” we see in animals. Dr. Rogan and her colleagues have been able to sort out these complex puzzles with great precision. We’re very fortunate to have her with us again to update us on the latest information in this emerging area, which has tremendous clinical implications for breast cancer, as well as prostate cancer. Once again, Dr. Rogan, welcome to FMU and thank you for being willing to share your extraordinary work, which has led to publishing more than 160 papers over the years. You’re certainly the person in the field. ER: Thank you, Dr. Bland. JB: For our listeners who may not have heard our first interview in 2003, and for those who did not attend the 13th symposium, would you tell us how you got into the area of estrogen metabolism that led to your discoveries on the 2- and 4-hydroxyestrogens? Aromatic Hydrocarbons Lead to Estrogens ER: We’ve always been interested in the estrogens, but I began 30 some years ago studying another class of carcinogens called aromatic hydrocarbons that are involved in pollutants in any kind of smoke. I studied them for 20 some years, understanding the kinds of DNA adducts that they form. When they react in cells, it initiates the process leading to cancer. In the early 1990s, we were able to move from the hydrocarbons over into the estrogens. We were able to apply what we’d learned from the hydrocarbons to estrogens very quickly. What we already knew from the hydrocarbons was that the reactive forms that attack DNA and attach themselves on the purine bases-the adenines and guanines-cause those bases to fall out with the carcinogen attached, leaving behind gaps in the DNA message called apurinic sites. These are the important adducts that relate to cancer-causing mutations. We also knew, from other people’s work that there are two catecholestrogens, depending on whether the second or third OH group is on the 2 position or the 4 position. We knew that the 2 catecholestrogens, with the OH on the 2 position, were, at best, very weak carcinogens, whereas the 4- catecholestrogens are stronger. We immediately discovered that it’s the reactive form of the 4-catecholestrogens, the so-called catecholestrogen quinones, that formed the so-called depurinating adducts that fall out of DNA, leaving behind the apurinic sites, whereas the 2-catecholestrogens quinones form the so-called stable adducts that are in a different position in DNA, and they stay in the DNA unless removed during normal repair. They actually form the depurinating adducts, but at a much, much lower number than the 4-catecholestrogens. We were able to apply all that. We also found that the mutations that come from these depurinating adducts come from the 4-catecholestrogens. All of this fit together. Now, we are applying that to humans. JB: This is a very exciting evolution of the story. I recall from reading your work and discussing it with you in 2003, that you talked about the different isoforms of cytochrome P450 (CYP) that were involved in the formation of these different hydroxylated products, the difference between CYP 1A1/2, CYP 1B1, and CYP 3A4 (each one of those being inducible), and that there may be inducers that would drive each one differently. Am I summarizing it correctly? Isoforms of CYP Involved in Hydroxylated Products ER: Yes, that’s correct. None of it is an absolute, but certainly some of the inducers will induce more of, let’s say, the 1A family. For example, TCDD, particularly dioxin, induces the CYP 1B1, which predominantly forms the 4-catecholestrogens, whereas the 1A1 or 1A2 predominantly form the 2-catecholestrogens. These two forms are the ones that are primarily present in extra-hepatic tissues. The 3A4 is highly concentrated in the liver. JB: Let’s move from the point you made about the inducing properties of CYP 1A1 and 1B1. You made the very important point that CYP 1B1 and A1 are in extra-hepatic tissues at high levels, where 3A4 is primarily in hepatic tissues. That obviously directs us toward the breast or the prostate. Are there any data that have come out of those tissues related to the activities of these transforming enzymes? EG: They’re certainly present. The 1B1 and 1A1 are both present in the breast. We haven’t published that, but 1A1 is present. We’ve also seen them in the prostates of animals. I would say that these enzymes are clearly present in breast tissue, both 1A1 and 1B1. JB: What you’ve said would suggest that in tissues where there is high potential activity of 1B1, one might have higher risk to these apurinic bases adducts that come as a consequence of the 3-4 quinone estrogens from 4-hydroxylation. Presence of CYP 1B1 in Women With and Without Breast Cancer ER: That’s exactly correct. When you have higher levels of 1B1, you are more likely to get formation of the 4-catecholestrogens, and you get higher levels of the DNA adducts formed. We have begun analyzing that in breast fluid from women with and without breast cancer, but I don’t have any results to share yet. We think we see differences, but the work is too preliminary to share. I can tell you that we have published a very small preliminary study, comparing breast tissue from women with breast cancer (non-tumor tissue) and women without breast cancer (excess tissue from reduction mammoplasty). What we find is that the level of P450 1B1 is significantly higher in the breast tissue from women with breast cancer than in the women without breast cancer. We looked at four different enzymes, and found that the two we consider estrogen-activating are higher in the women with breast cancer and lower in the women who don’t have breast cancer. On the other hand, two enzymes that we consider protective against activation of estrogen are higher in women with healthy breasts compared to women who have breast cancer. JB: That’s fascinating. ER: That fits right in with what we had hoped to find. Impact of Bioactives from Cruciferous Vegetables on Estrogen Transforming Enzymes JB: We’ve talked about the fact that these are inducible enzymes, so the inducers of some of them may be different, one from the other. We talk about the cruciferous vegetable family and its relationship to purported epidemiological breast cancer risk reduction. Would you help tell us a little bit about the bioactives in crucifers and the impact they have on these estrogen transforming enzymes? ER: I think they have a variety of effects, one of which is that they have some compounds that will scavenge the reactive estrogen metabolites so that they’re not reacting with DNA. That’s one of several effects they have. One of the most important effects of cruciferous vegetables is that they contain compounds that induce a very important enzyme called quinone reductase. That takes the reactive form of estrogen back to catecholestrogens, which are not reactive. We’re trying to collect data to support the idea that induction of quinone reductase is a very important component of what the cruciferous vegetables do. I know that they also affect a variety of other anti-tumor cell processes. In addition to inducing the metabolic enzymes, I think they also have some effects on the repair of DNA damage and on some signaling pathways. JB: That leads to looking at some of the individual glucosinolate bioactive secondary metabolites, such as indole-3-carbinol (I3C) and some of its acid polymers like 33 prime indolymethane, or what has been called diindolymethane (DIM). As you know, in our field, there is a fairly large controversy going on right now as to whether there is preference for one of those bioactives over the other in favorably affecting estrogen metabolism. Would you tell us a little bit about the 4-hydroxylation and the aromatic hydrocarbon receptor activation of I3C versus DIM, as you’ve reviewed the literature? ER: I certainly have reviewed the literature to try to sort out these differences. One of the confounding effects is that when you look, for example, in animals, or even in people (because the I3C is metabolized to the so-called DIM), it’s hard to sort out what’s doing what. You treat with I3C, but you don’t know what the active component is. That confuses the whole issue. However, when I reviewed this literature, I didn’t see a great difference between what I3C was doing and what DIM was doing. There were a few differences in the effects of these two compounds, but it didn’t seem to me that people had demonstrated that there are significant differences. JB: We were told at a recent meeting that there was a very significant difference in 4-hydroxylation patterns between the I3C and DIM. Does that seem to be true from what you’ve seen in the published literature? ER: I have seen that opinion stated, and I’ve seen it purported in citations, but when I read the papers in the literature, I don’t see that that’s been demonstrated. I see that people have made some assumptions (for example, on P450 1B1), but I have not seen anybody actually demonstrate that. I’ve also read that administration of I3C significantly increases the amount of P450 1B1 and consequently the 4-catecholestrogens, but again, the only data I find in the literature shows a small increase that is far from being statistically significant. JB: In looking at some of the purported adverse effects of either I3C or DIM, people have talked about cross reactivity with the aromatic hydrocarbon receptor, or the formation of 6-alpha-hydroxyestrogens (which you probably know a lot more about than I do), and implied that perhaps there’s some difference that could be seen in either hormone receptor or in 6-alpha-hydroxyestrogens. Have you seen anything relating to that? JB: I have seen a study in women where DIM was administered, and the 2-hydroxylation to form the 2-catecholestrogens increased significantly. That increased the ratio of the 2-catecholestrogens to the 16-alpha-hydroxyestrogens, which would be a good thing. Again, that difference was not quite statistically significant by general standards. It seemed to be going in the right direction, but it was not a conclusive study. Unfortunately, since that study, there hasn’t been anything published specifically on the effects of I3C or DIM on 4-hydroxylation of estrogens in humans. JB: How about the effects in humans of I3C with formation of the 2-hydroxy versus the 16-hydroxy? Has that been adequately demonstrated? ER: Yes. That improves the ratio of the 2-catecholestrogens to the 16-alpha-hydroxyestrogens. Whether that is important has not been demonstrated. In my view of the world on this whole subject, this is not a significant difference, but I don’t really want to pretend to be an expert in terms of human medical issues. The data are pretty marginal. JB: Let’s talk about the intermediates, which I know you’ve done quite a bit of work on-the 2,3 and the 3,4 catechols (the quinines)-and their roles in physiology. I am now alluding to the methoxylation pathways. Would you tell us a little bit about where these intermediates travel and what happens to them? Action of Quinones in Physiology ER: These are pretty reactive compounds and so they’re going to react with something in the cell. (They won’t travel very far in a cell.) They don’t just react with water in the cell; they react with glutathione, which is a scavenger for many kinds of oxidized products. That’s a good thing, because that takes them to being excreted. They can also react with DNA (a bad thing) to form these DNA adducts that can lead to the apurinic sites that seem to the source of the initiation of cancer. The catecholestrogen 3,4 quinones are much more reactive than the catecholestrogen 2,3 quinones, just because of their chemistry. The formation of these DNA adducts by the 2,3 quinones is very small compared to the 3,4 quinones, and I think the major danger comes from the catecholestrogen 3,4 quinones. That’s what seems to happen with them. They either react with DNA or they react with glutathione. They probably react with proteins, too, although I don’t think anyone has shown that particularly. But I don’t think that would be a damaging thing; it would just get rid of them. In the worst possible case, if one molecule of an enzyme gets screwed up, that’s not a big deal JB: One of the things you point out in the excellent review paper that was published in the journal In Vivo last month, titled “The natural chemopreventive compound indole-3-carbinol: state of the science,” 8 is that the 2-hydroxylation patterns, facilitated by upregulating the enzymes associated with I3C, go on to principally form the methoxylated derivatives, which can be trapped, versus the 16-hydroxy compounds that don’t get methylated, so they may be more promiscuous types of molecules. I think that’s a very interesting concept-that there’s an exit opportunity for the 4- and the 2-, but that doesn’t seem to be the case with the 16-. ER: Right. The 16s can continue to have effects on various cellular processes-biochemical processes, signaling processes, and things like that. JB: Do you feel that the ratio of 2- to 16-hydroxylated estrogens measured by laboratories is more of a surrogate marker for relative risk, and that what we really should be measuring is the 4-hydroxylation pattern, or do you feel that there is something of concern relative to the increased 16-hydroxylation? ER: I think the 4-catecholestrogens are the important ones to be measuring. I don’t think it’s been significantly shown that the ratio of the 2- to the 16-alpha is a particularly useful characteristic to measure. It’s the 4-catecholestrogens that are going to do the damage and start the cell down the road to being cancerous, and that’s what we should be measuring. JB: If I interpret your review paper correctly, you are suggesting that to date, there is no statistically significant data that show that either DIM or I3C significantly elevate 4-hydroxyestrogens. ER: Correct. The only paper I have seen that dealt with the 4-catecholestrogens was published in 1997. There, the difference, for example, the 4-hydroxyestrone, the so-called P value, which normally you would want to be at 5 percent or less, was only 16 percent. That’s not statistically significant and you can’t rely on that. Normally, you would feel comfortable if the statistics indicate that the difference you’re seeing occurs 95 percent of the time, let’s say in terms of the 4- catecholestrogens being induced. At 95 percent of the time, at least you’d almost always see that result. In the case of the P values indicating a 16 percent significance, you would only see the difference perhaps 85 percent of the time, which is not really good enough to consider it a reliable difference. JB: It sounds as if there’s still room for a lot of additional work in this area, and that there are other variables influencing this, You mentioned methylation patterns and other things that participate, perhaps away from the 2- to 16 ratio, that have to do with how crucifers modulate cancer risk. ER: I think that’s very true. I also think that maybe next year, we’ll probably publish a lot of data from humans that will put to rest a lot of these different controversies, because the technologies for doing these analyses have improved by orders of magnitude. The sophisticated kinds of analyses that you can do now, you couldn’t do even five years ago, with the same level of sensitivity and the ability to separate all of the very similar compounds chemically or chromatographically. JB: Being a researcher, a woman, a mother, and a person of the universe, based on what you’ve seen, would you recommend women not eat crucifers or foods containing either I3C or those that would be converted to DIM? Is there any evidence at this point that those foods could be hazardous? ER: Oh, absolutely not. Everything I have seen has indicated that eating crucifers is an excellent thing to do. That food group, to me, is the most likely one to help prevent cancer. JB: It sounds like we are at the threshold of some very exciting abilities, using the methodologies that you’re developing. Also, from what you just said, I interpret that some of the past published data probably is somewhat questionable, just on methodological grounds, because we didn’t have the sensitivity to address some of these questions about 4-hydroxylation patterns that we’re now asking. It seems that we’re on the threshold of being able to answer some very important questions about how the fractionated components of crucifers-phenyl isothiacyanates, I3C, DIM, or sulfurofane-influence these individual pathways. ER: That’s absolutely true. We are looking at the levels in urine, serum, and different body fluids in tissues, but I think that other laboratories that have access to much of this same improved analytical technology are going to be doing studies to see what happens when people ingest crucifer components. For example, there was a paper published about six months ago from a lab at the University of Kansas and analytically, it was the nicest and most advanced paper I’ve seen. Unfortunately, they didn’t look at the 4-catecholestrogens, but they were already using much better technology than was available six, eight, or 10 years ago. JB: As we look at where we are today, do you feel that we are seeing the emergence of a new field of chemoprevention that is going to be focused on personalized diets based upon metabolic characteristics of estrogen metabolism? ER: I absolutely do. For me, and for our research group, this is really the goal-to use dietary supplements from natural chemicals, tailored to different people’s basic metabolic profiles to contain the estrogens so that these reactive metabolites either aren’t formed or are scavenged, so they are much less likely to damage DNA and start the process leading to cancer. I think this whole field is going to make tremendous strides forward in the next few years. JB: At press and in the literature, have you seen a greater prevalence of human clinical work with I3C versus DIM, or is there about the same ratio between the work on these two chemicals? ER: There’s more on I3C. JB: The next couple of years in this field will be quite extraordinary for you, your colleagues, and your associates, in helping us to piece this all together and move us toward personalized medicine. ER: I think so. I’m very confident about that. JB: Thank you very much for all your diligent work. We’re going to save a lot of unnecessary misery and suffering as a consequence of the application of your discoveries. ER: I hope so. That is certainly the goal. JB: Thank you again, Dr. Rogan. Our best to you, and we’ll talk with you as the data start coming out. Modification of Estrogen with Nutrient Management I would like to spend the last few minutes of this issue of FMU reviewing the takeaways of what we have been talking about. We talked about estrogen and dietary intervention, and the relationship of low-fat diets to women’s health. What I did not mention, which I think is clearly apparent to most of you who have been in this field for some time, is that moving to a more vegetable-based, minimally-processed diet modifies estrogen production and metabolism quite dramatically. It has an effect on the outcome from estrogen states of modified function. In women on vegetarian diets, there is altered estrogen level, improved androgen/estrogen balance, and increased metabolism and alteration in sex hormone globulin levels so that what we ultimately end up with is a better regulated endocrine system. I am talking about the work published by Joanna Dwyer and others over the years. We also recognize from what I discussed earlier concerning the reversal of stress responses in maternal programming, that the immediate environment of the individual can influence aspects of hormone balance. We talked about the neuroendocrine, or the psychoneuroendocrine environment playing an important role in modulating some of these factors. We also talked about dietary factors that influence estrogen metabolism directly by hydroxylation (the wonderful work of Dr. Rogan), and how these intermediary metabolites that come through the regulation of the cytochrome P450s that metabolize estradiol and estrone into their various hydroxylated derivatives, can be encouraged to eliminate these estrogens in a non-toxic form through methylation and enzymes that go through S-adenosylmethionine (SAM). These are the catecholmethyltransferase enzymes, and they can be facilitated with proper levels of substrates of the SAMs by proper B6, folate, B12, and betaine nutriture. Many women who are on marginal diets relative to these methylating nutrients could benefit significantly by increasing those four nutrients in their diets, so as to promote proper methylation of their hydroxyestrogens. We also talked about the use of the crucifers and their glucosinolate breakdown products-indole-3-carbinol (I3C) and diindolymethane (DIM)-to facilitate improved formation of the 2-hydroxylated estrogens at the expense of the 16.9 I said that both the 2- and 4-hydroxyestrogens can be trapped as the methylated derivatives, whereas the 16-hydroxy cannot. We talk about one to two portion sizes of cruciferous vegetables a day, or somewhere in the range of 200 to 300 mg of I3C equivalent that comes from the crucifer glucosinolates, as the level that has been demonstrated in clinical trials to have positive effects on function in women. These are hormone-driven functions, such as papillomas, that have been demonstrated to improve with I3C supplementation. What I am starting to see emerge is the recognition that many of these women’s health issues that occur postmenopausally are more than just modifying protein, carbohydrate, and fat levels in the diet. There is a rich library of phytochemicals that are present in a minimally processed diet with color that have influence on function. I also reviewed some of the more recent studies that have been published about bone loss in postmenopausal women that did not seem to be effectively managed by calcium and vitamin D supplements. This was a big “aha” coming out of the WHI that you heard about recently. Calcium and vitamin D supplements did not seem to reduce fracture incidence in these women. I believe this is because osteoporosis and bone fracture is more than just a calcium and vitamin D problem. It is also an inflammatory signaling problem. The osteoclasts-the bone resorbing units-are stimulated into resorption as a consequence of inflammatory signaling. Therefore, if one eats a diet of low inflammation content that has rich gene programmed nutrients that lower inflammatory potential, that will have a better effect on reducing risk to osteoporosis than simply focusing on calcium and vitamin D alone supplemented into a “white” diet. I keep coming back to how estrogens and androgens travel properly in a woman’s body. We have to look at historical and evolutionary perspectives to better understand that, because historically, women have eaten complex diets rich in an array of all these signaling molecules in foods that have impact upon estrogen balance production and metabolism. Last, we talked about things in the diet that may precipitate an alarm, or allergic reaction. That obviously has to do with things that in one person’s diet may appear to be a very good food, but in another’s diet, not such a good food, because it alerts the immune system to do battle. I am talking about things like gluten or alpha-gliadin found in some cereal grains, and things like beta-casein, a milk protein, which may initiate immunological reactions in certain individuals. There is an ever-increasing understanding of the changing patterns of food allergy. A very nice review paper written by Dr. John Walker-Smith appeared in the journal European Journal of Gastroenterology and Hepatology. He talked about food allergy affecting many more people than we previously thought, and that this food allergy may really be considered food sensitivity, because some of these are not traditional allergies, but may have other types of effects by influencing things like enteric flora.10 Certain foods may then alter flora, which secondarily may have an influence on GI mucosal immune function, causing inflammation. It is both a direct effect of the food constituent and possibly an indirect effect. The management of these types of food reactions, what we call allergies, is, in part, related to the full composition of the diet-things like components of the diet that support proper bacterial flora, flora that would be “anti-inflammatory” versus “proinflammatory.” There has been some very nice work done showing that oral supplementation with probiotics can help to lower food reactions and food sensitivity. One good article was published in the European Journal of Gastroenterology and Hepatology last year.11 Certain species of probiotic organisms, when administered orally, may have a salutary effect on food reactions and lower gut inflammatory conditions. I am talking about both localized gut inflammation seen in conditions like Crohn’s disease or IBD, and perhaps systemic inflammatory conditions, as well, with arthritis-like symptoms. As breakdown of the gut mucosal barrier occurs and the gut becomes permeable, it increases the relative risk, and one is now exposed to these antigens to the gut mucosal immune system, which can signal this inflammatory process to the rest of the body. Gut barrier immune function is very important. In fact, breakdown of gut mucosal integrity is often a hallmark of long-term, food-related allergy at the gut level. Antigens can then penetrate the mucosa and induce allergic inflammation. There is another good article that describes this process in the European Journal of Gastroenteroly and Hepatology. 12 Clinically, the way one often goes about understanding this is by measuring the level of calprotectin in a stool sample. Fecal calprotection is an inflammatory response protein that is produced and shed by neutrophils in the gut. High levels of calprotectin in the stool are markers of gut inflammation. They are also tightly correlated with increased intestinal permeability that could be measured by things like the oral lactulose/mannitol challenge test, which you are probably familiar with. We have found much more clinical utility recently in using the fecal calprotectin test. We have seen patients with fecal calprotectin at a level of 200 mcg/g in stool (the normal range is less than 30 mcg/g) who have very serious breakdown of gut mucosal integrity, a lot of gut inflammation, and systemic inflammatory conditions that can be precipitated or aggravated by this immune response. The whole system is interrelated-gut connected to immune system connected to liver connected to all the circulating white cells-and all of those influence physiological health. In this case, I am talking about estrogen, estrogen metabolites, and ultimately, female-related health problems associated with different cycles in a woman’s development, including perimenopause and menopause. Postpartum Seizures Last, when you have increasing inflammatory signals, there is also increasing risk to mitochondrial dysfunction. One of the things that is interesting in women is a condition involving postpartum seizures. Postpartum seizures are pathophysiological and they are associated with alteration in neuroendocrine signaling, particularly allopregnenolone, pregnenolone, progesterone, and estrogen. Wide swings in the neuroactive hormones can lead to depolarization, mitochondrial uncoupling, and seizure disorders. Mitochondrial dysfunction is implicated as a contributing factor in a diverse range of acute and chronic neurological disorders, but I think it is interesting to consider how estrogen may be related to this postpartum seizure condition seen in some women. This may come as a consequence of very rapid alterations in androgen/estrogen ratio levels, leading to alteration in membrane polarization, which (I am hypothesizing here) could lead to changes in mitochondrial function That leads us to ask what alters these things. Certainly, the stability of estrogen and progesterone signaling plays a very important role in normalizing the nervous system. I have used an extraordinary example talking about postpartum seizures, but we might think about chronic neurological dysfunctions associated with endocrine ratio changes in menstruating women as they go through the estrogenic and androgenic phases of their cycle. How does this interrelate with mitochondrial function, energy to polarization, and eventually, alterations in central nervous system and peripheral nervous system function? There is some significant work now going on looking at the connection between the nervous, immune, and endocrine systems in women, to try to understand what the modifying or balancing factors are. The only way we can understand this is to look at the system as a web. You cannot look at any one single agent. You need to look at it as a web of interacting variables. The nervous, immune, and endocrine systems are intimately tied together through receptors and signaling molecules. As we develop the functional medicine model, we recognize the importance in the connection of the gut and the liver, which is connected to the immune system, which is connected to the inflammation system, which is connected to the cardiovascular system, which is connected to the nervous system. The approach we have been describing in this month’s issue of FMU is to look at estrogen more as a surrogate signaling molecule, how it interrelates with different cycles and functions, how that is connected to the neuroendocrine immune system, and how it ultimately connects to metabolism and excretion through hydroxylation and methylation patterns. When you get to that level, you start understanding why it is that autoimmune disease is possibly heavily centered in women, why it is that postmenopausal women have cardiovascular disease, neurological disease, and bone loss as principal features of their health histories, and why the environment plays such an important role through proper dietary and lifestyle manipulation as “the best medicine.” I hope this issue of FMU has been of some interest and help to you. We look forward to sharing with you again in May.  

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Bibliography

1 Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years: the Women’s Health Initiative Dietary Modification Trial. JAMA. 2006;295(1):39-49. 2 Dansinger ML, Schaefer EJ. Low-fat diets and weight change. JAMA. 2006;295(1):94-95. 3 Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA. 2005;293(1):43-53. 4 Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction. JAMA. 2005;293(1):58-64. 5 Ignarro LJ. Evaluation of the article published in JAMA (295:58-64, 2006) by Schulman et al. Review of Arginine and Vascular Health Study. As communicated to Jeffrey Bland, PhD, Chairman, Institute for Functional Medicine and Chief Science Officer of Metagenics. 6 http://www.niaid.nih.gov/dait/pdf/ADCC_Final.pdf 7 Weaver IC, Champaagne FA, Brown SE, et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci. 2005;25(47):11045-11054. 8 Rogan EG. The natural chemopreventive compound indole-3-carbinol: state of the science. In vivo. 2006:20;xxx-xxx. 9 Lizotte L, Rush C. Why choose DIM over I3C? Designs for Health. Science first. 10 Walker-Smith J. An eye witness perspective of the changing patterns of food allergy. Eur J Gastroenterol Hepatol. 2005;17:1313-1316. 11 Laitinen K, Isolauri E. Mangement of food allergy: vitamins, fatty acids or probiotics?. Eur J Gastroenterol Hepatol. 2005;17:1305-1311. 12 Heyman M. Gut barrier dysfunction in food allergy. Eur J Gastroenterol Hepatol. 2005;17:1279-1285.

Welcome to Functional Medicine Update for May 2006. This is going to be an exciting month following on the heels of the 13th International Symposium on Functional Medicine in Tampa, Florida, which always lifts my energy and enthusiasm as to functional medicine beginning to “have its day.” And the Textbook of Functional Medicine has certainly helped to put functional medicine on the marquis. DNA Diet: Bogus or Breakthrough? This month, we are going to focus on nutrigenomics and the clinical application of that concept. What is nutrigenomics? What is the future of nutrigenomics? What can it do to improve patient outcome? Some of you probably saw the segment on ABC’s Good Morning America recently, in which the topic, “DNA Diets, Bogus or Breakthrough?” was discussed.1The commentators talked about the use of genetic testing to evaluate nutritional needs. Dr. David Heber, a colleague and friend, and a professor of medicine at the UCLA Center for Human Nutrition, described this revolutionary new change in nutrition-the nutrigenomics evolution. This is probably the most remarkable thing that has happened in the interface between nutrition and medicine in decades. Nutrigenomic Testing There are now a number of commercial laboratories offering nutrigenomic tests that evaluate some of the genetic uniquenesses that may require specific types of nutrients or diets to be personalized to an individual’s need. This becomes the birthing of a personalized medicine that is the culmination of what Dr. Roger Williams talked about in 1949 in his article in the Lancet on genetotrophic disease, and Dr. Linus Pauling’s concept of orthomolecular medicine. As Dr. Heber said, this genetic evaluation testing will allow for individuals to better understand how lifestyle and diet changes could influence their functioning, improve outcome, and reduce their risks to disease. Some experts say it is too soon to apply nutrigenomics in a clinical setting, and that we still have a lot more research to do. That is certainly true. There is no question that we are only on the front edge of this particular revolution. However, the early information that is starting to come in is giving us significant potential for starting to look at patterns of nutritional needs related to genetic uniqueness that we did not have access to before. That is a consequence of the revolution in molecular biology and molecular genetics. With that in mind, we are going to focus our attention on the revolution in nutrigenomics, and how this information can be clinically applied. We are fortunate to have a world-renowned expert on this topic as our Clinician/Researcher of the Month-Dr. Ruth DeBusk. She has a PhD in nutrition with research experience in biology and molecular nutrition and genetics, and she is also a Registered Dietitian (a very unique background). Looking at the big picture for a moment, we are trying to find ways of preventing premature cell death that results as a consequence of declining function in cells, tissues, organs, organ systems, and ultimately, the whole body. This is what Dr. James Fries has talked about since around 1980-improving organ reserve, compressing morbidity, and extending the health span of the individual. When we look at the clinician’s strategic objective in trying to improve health outcome by compressing morbidity and increasing organ reserve, it would be to maintain cellular and tissue function. Cellular Processes If we were to go inside a cell with microscopic molecular eyes, we would see thousands of processes occurring simultaneously in a time-dependent fashion and with rhythm, like the tides, that create different pulses of activity in all the different organelles. These would be generating all sorts of intermediary metabolites. Those processes would be influenced by external and internal factors in the so-called “environment.” Mixtures of molecules float around, as they are conducted on a tour of the cell and hopefully, they will leave the cell as non-toxic waste products, such as carbon dioxide, water, urea, sulfate, and phosphate. That gives rise to biochemical energy leading to the organization of the cell, the tissue, and the organ to create, sustain, and direct their function. If, however, there is a buildup of non-endproduct metabolites, or debris (molecules that were not supposed to be the endpoints, but only transient in concentration and number), and they start to increase in number, a “toxic response” might occur from the non-toxic series of molecules that ultimately overcome the control mechanisms of that cell. What once was considered non-toxic becomes toxic. As Tolman’s principle in pharmacology tells us, everything is toxic at some level, even air and water. It is possible to over-hydrate a person when infusing them with water. Or, a person can be hyperoxygenated as a consequence of not controlling blood gases. What is the threshold when a toxic or adverse response to a substance occurs in a cell, leading to dysfunction? That is going to be individualized to the person’s uniqueness, and this is where nutrigenomics or nutrigenetics comes into play. The signaling molecules that trigger cell death go through cellular dysfunction before apoptosis takes place. I am weaving the term “function” into my conversation. The early stages that precede cell death and cellular pathology are altered cellular function by altered metabolic processes, and altered genomic, proteomic, kinomic, and lipomic expression into the metabolome, which ultimately influences the phenomics, or function of the cell. The process of dysfunction at a cellular, biochemical, or organ-specific level ultimately gives rise to apoptosis or necrosis through adverse effects, which causes loss of organ reserve and ultimate disease. Roles of Molecules in Promoting Apoptosis What roles do various molecules play in promoting cell death? There is an interesting article in the Journal of the American Medical Association, titled “Messenger molecules and cell death: Therapeutic implications.”2 It opens the door for what we are going to be speaking about, in part, in this issue of FMU, and how it interrelates with the topic of the 13thInternational Symposium on Functional Medicine-biotransformation and detoxification. Programmed cell death, called apoptosis, participates not only in normal physiological processes, such as the development of the immune system, when immune cells come and go, as needed. We do not constantly build increasing numbers of immune cells over the course of life. They increase in number when we need an immune response, and they die off by apoptosis when we do not need them. It has also been found that premature, accelerated apoptosis, or cell death, is associated with many diseases-neurodegenerative disease, cardiovascular disease, and diseases associated with muscle wasting. These are conditions that accelerate apoptosis, particularly in the so-called post-mitotic tissues. These posttranslational tissues-the brain, the heart, and the muscles-do not replicate very quickly. As a consequence of injury to these tissues (as contrasted to the liver or the skin that can regenerate), accelerated loss of cells can lead to loss of organ reserve and increased risk to dysfunction. It has been implicated that increased risk to accelerated cell death in certain tissues is a consequence of exposure to various messenger molecules that produce a death message to the cell. Bilirubin What are those molecules? Bilirubin, often thought to be a toxic endproduct of heme metabolism, serves as a physiological cytoprotectant that may attenuate multiple forms of morbidity. It helps to protect against some of the things associated with increasing apoptosis, which are triggered as a consequence of increasing concentrations of reactive oxygen species. Apoptosis and reactive oxygen species, or what has been called oxidative stress, are very tightly tied together. Bilirubin is often a compensating mechanism for the increase in oxidant toxic molecules. As a cytoprotectant, bilirubin is not the effect, but perhaps the response to these processes. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Secondly, the enzyme glyceraldehyde-3-phosphate dehydrogenase mediates a novel death cascade. This is triggered as a consequence of hyperglycemia, or poor glucose transport. In a diabetic-like situation, glucose becomes a potentially toxic molecule through the activation of the cascade of events that induces cell apoptosis. Excess free fatty acids and excess glucose in cells can induce cytotoxicity and initiate apoptosis and loss of organ reserve. Both dysinsulinism and dyslipidemia have a nutrient-toxic relationship to the accelerated cell death phenomena. That is tied together with diabetes, coronary heart disease, and even certain forms of cancer that appear to have a dysglycemic and dyslipidemic component. Third is cytochrome C, which is released from mitochondria in early apoptosis and interacts with the inositol-1,4,5-triphosphate (IP3) pathway to elicit a large uptake of calcium across cell membranes. Calcium influx into cells is tantamount to triggering apoptosis. All the calciphylaxic processes associated with chronic stress, infection, and trauma (the conditions Hans Selye talked about in the 1960s) lead to the rush of calcium from outside the cell to inside the cell. These triggering events are associated with increased apoptosis and loss of cellular reserve. There are many different cellular processes associated with accelerated cell death, or toxic events in the cell, such as excess glucose, excess free fatty acids, excess reactive oxygen species, excess inflammatory mediators, and excess relationships to trauma that induce calcium influx into the cell and trigger apoptosis. In people with high coronary artery calcium scores, each of the little focal calcifications are indicative of a site where inflammation has occurred in the artery wall and calcium moved from outside the cell to inside the tissue, leading to calciphylaxis. That is the point when cells died, and where there is debris. The cytoskeletons were calcified, to use an archaeological or paleological model. I want to talk about one of the precipitating events, or triggers (to use the nomenclature of patient-centered assessment in functional medicine) of toxic events. This is discussed in a paper by Dr. Paul Ridker, whom most of you know as the father of high-sensitivity C-reactive protein (hsCRP). He is located at the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Harvard Medical School, and has been actively involved over the last decade in advancing the concept that inflammation is associated with atherogenesis and ultimately, heart disease and cerebrovascular disease. Low-Grade Chronic Infection, Inflammation, and Oxidative Stress In Dr. Ridker’s paper, published in the journal, Circulation, he talks about the triggering of the oxidative inflammatory response by focal infection, leading to cell death in the arterial system.3 We often forget about the importance of the effects of low-grade chronic infection on triggering aspects of inflammation and oxidative stress. Where can focal infection reside? There are many places in the body containing warm, nutrient-rich media where bugs like to hang out-the sinuses of the nose, the GI tract, the gingiva around the teeth, and periodontal ligaments. Bugs can harbor focal infection in all of these places. People with gingivitis or periodontitis have been found to have higher incidence of autoimmune disease and coronary artery disease (CAD). The process is similar in chronic sinus infection or chronic GI dysbiosis. Dr. Ridker talks about the fact that if we look at inflammation and infection in the causes of atherosclerosis, there is an interesting correlation, and these are further fed by dietary variables, such as diets that cause insulin resistance and hyperinsulinemia. When there is inflammation from an infection, coupled with hyperinsulinemia, it is like a dog chasing its tail. Increased amplification of adipocytokine production, with more and more inflammatory mediators, more reactive oxidative species, and more tissue redness (rubor, color, and dolor), produces more injury to the arterial wall and the arterial intima, increasing the risk to CAD. The point I am trying to make is that there are potential multiple environmental factors, multiple genotypes with differing susceptibilities, and multiple outcomes of pathogenesis, depending upon the organ or tissue in the individual that is most likely influenced by this process. It is a much more complicated process than that rendered by the differential diagnosis, suggesting that each disease is independent of the other. What we are really looking at is the connection of multiple diseases to the process of inflammation that is a consequence of the interaction of genes with the environment. It is the clinician’s responsibility to understanding something about genetic susceptibility and the unique environment of the patient that allows for personalization of therapy to reduce the risk of inflammation-related dysfunctions. Obviously, atherosclerotic disease is only one in the family of inflammatory-connected diseases. Others fall into the same category-dementia, metastatic disorders, type 2 diabetes, and autoimmune disease. It cuts across many different areas. How does the body regulate its response to these triggers and precipitating events? We are exposed to them all the time. No one lives in a perfect environment. Many things might trigger these events. It seems almost impossible that we could even live to the age of 60, based upon all these factors. The body has had to evolve protective pathways over millennia to regulate these insults, or exposures, so that it does not amplify the toxic response and lead to whole-body free radical pathology, or toxicity events that lead to cellular apoptosis and serious loss of function. One system that offers protection is the body’s antioxidant system, which includes enzymes like superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. These enzymes help to defend us against the processes associated with inflammation, oxidative stress, calcium uptake across cell membranes, and ultimately, mitochondrial depolarization, energy loss, and cell suicide (apoptosis). This process also involves specific phytochemicals that act as antioxidants and are known to regulate the detoxification of environmental compounds. Many of these phytochemicals bind to the antioxidant response element in target detoxification and antioxidant enzyme genes, resulting in upregulation of these enzymes. It is pretty interesting that these processes have a coincidental convergence. Toxicity reactions produce greater output of oxidants in the body; greater output of oxidants, in order to be quenched, requires not only detoxification of the toxic substances of the process, but also attenuation of the oxidant stress, so that the fire does not run uncontrolled (using free radical oxidative stress as a metaphor to a fire). By this interesting duplicity of effects, the substances in our food communicate chemically with the antioxidant response element, resulting in an ultimate reduction in the amount of fire. This is described beautifully in a review paper, titled “Antioxidants in photosynthesis and human nutrition,” published in Science magazine.4 In this article, the authors talk about an interesting observation: how plants have evolved such a rich array of phytochemicals that are consumed by humans in minimally processed plant foods, and that gives rise to the support for both detoxification and antioxidant protection against cellular oxidative injury, damage from reactive oxygen species, and ultimately, excess apoptosis. There is an interesting figure in this paper (Figure 5), a scheme showing how key redox-modulated pathways of signal transductions are related to human diseases and disorders, including such things as attention-deficit hyperactivity disorder (ADHD) and other types of neurological problems that are modulated through phytochemicals- including omega 3 fatty acids, as well as bioflavonoids. From basic science, applied medical science, clinical research, and animal and epidemiological research, there is a convergence of data that leads us to recognize that these nutrigenomic connections to environmental modulation are extraordinarily important in finding the trajectory that ultimately gives rise to health or disease in later age. I have gone through this to try and make a point. Recently, I had a conversation with a well-informed, intelligent professional in our field. He is not directly in the functional medicine field, but he is in the general health field. He and I got into a vigorous discussion. To summarize what he said, his criticism was that I was promoting a plasticity of health that was not justified, and that people got sick as they got older as a consequence of bad genes, and there is little you can do about it. Basically, medicine is there to save people when they are injured, and he felt that I was unjustifiably promoting the concept that you could do something about this by trying to personalize one’s diet and lifestyle, suggesting that our genes have a lot more plasticity and could be expressed in different ways. According to him, there was no science that would justify that. I was just speculating and leading to false expectations of outcome, and giving people a heightened sense of control when it really did not exist. He suggested that we should try to live our lives, eat the foods of commerce, do what everybody else does, and medicine would be there to save us, because there is really no other way out. That was the model-a kind of medical determinism. Obviously, I do not believe that. At the core of everything we have been trying to do in functional medicine for 30 years, I think that is wrong. I do not think the data supports that view. I do not believe that the basic science, clinical science, or even the rules of reasonableness support that model. However, that model still resides in the minds of well-informed, trained professionals in our field. Somehow, they feel that to try to get involved in modulation of the environment of the patient is ill-served, a waste of resources, and it takes us away from doing good medicine, which means treating sick people, because we cannot do anything about it anyway. That model, which still remains resident in the minds of many professionals practicing medicine today, is a self-fulfilling prophecy. Believing that there is nothing we can do about our genes leads to believing that there is nothing we can do about our health. People believing this generally have outcomes that are determined without modification; their genes are likely expressed in probably the most deleterious way. If we take a different set of presumptions, however, based upon the nutrigenomic argument, and all the literature that is coming out that we have been discussing in FMU for the better part of more than 20 years, we see that there is a different understanding that is emerging that speaks against the model of “treat it when it’s broken.” It starts speaking to the fact that cellular dysfunction, which we later call pathology, and its association with things like apoptosis and loss of organ reserve, did not result as a “bump in the night.” It occurred over a period of time as a consequence of the collective injury resulting in large part from the inappropriate interaction of our environment with our cellular physiology. This is not to say that all problems could be entirely alleviated or prevented if we could optimally adjust the environment. That would suggest that what I am arguing for is pro-longevity-that people would live forever in an optimal environment. There is no evidence from animal studies to indicate that is true. There is, however, strong evidence indicating that the survival curve can be rectangularized, compressing morbidity and increasing health span when, through a better understanding of genetic uniqueness, we modify the environment appropriate to a person’s needs, thus producing a better outcome. That is the model encoded as a core concept in functional medicine. We are now seeing that nutrition and food science are going genomic. The reason is because we are finally developing the tools to start looking at genetic uniquenesses in the laboratory, outside the range of a few specialists. The new genomic tools-the gene chip models and the molecular biology assays-are becoming accessible, so that students in undergraduate curricula in universities are now doing these tests as standard routine in their studies. It is not esoteric. These technologies are being commonly used in crime labs all over the US, which can be seen by the number of TV shows now referencing molecular genetics. This is becoming rote technology, routinely done using dependable technologies, which have allowed it to develop from esoterism to the bench. Nutrition is the recipient of this technology. The wealth of genomic information and high throughput profiling technologies are now being explored in the disciplines of food science and nutrition. Diet and food components are prime environmental factors that affect the genome, transcriptome, proteome, and metabolome, and therefore influence the life-long interaction between our diet and our bodies, such that health and disease states are the results of that interaction. For the first time, the interaction of foods and individual food constituents (so-called phytochemicals), and the relationship they have to biological system control is being defined on a molecular basis. Profiling technologies are being used in basic-science applications for identifying the mode of action of foods or particular nutrients, and we are similarly taken into the science-driven development of foods with a defined biofunctionality. We are not just moving toward foods that are “tasty,” “attractive,” and “stable,” in the consumer world of shelf-stable foods, but we are looking at things with biofunctionality-functional foods and medical foods-the nutraceutical market that connects with specific genetic uniquenesses. Biomarker profiles and patterns derived from genomic applications in humans should guide nutrition and food science in developing evidence-based dietary recommendations and health-promoting foods. We are seeing the emergence of a personalized nutrition that was talked about by Williams, Pauling, and many others, that will deliver on biochemical individuality. If we look at where we are heading in the application trends of biotechnology to food science, it is happening in real time. It is not just something that is still in the planning phase that is talked about by only a few early adopters and futurists; it is happening right now. I would urge you to look at a recent article, titled “Nutrition and food science go genomic,” published inTRENDS in Biotechnology.5 We are witnessing the evolution of this concept in real time, and it is changing every view of nutrition and how it impacts health and disease. The textbooks that students are studying from today are already out of date, before schooling is even finished. We have gone across a one-way threshold, one that does not allow people to go back the other way. We are in the age of molecular nutrition and, in real-time, we are learning how nutrition interfaces with genomics. Effects of a Vegan Diet Free of Gluten Improves Signs and Symptoms of Rheumatoid Arthritis Let me give you an example of how this plays out clinically. Let’s look at the effect of diet on rheumatoid arthritis. This is a very interesting connection that includes many sub-topics on which we could spend many issues of FMU, have many discussions, and undoubtedly, we will, over the years to come. I want to focus on an article that appeared in the journal, Rheumatology, that presented information about a vegan diet free of gluten improving the signs and symptoms of rheumatoid arthritis, and that the effects on arthritis correlate with a reduction in antibodies to food antigens.6 The food of one may be the poison of another. It may initiate an immunological response as a consequence of the constitution of that food, which triggers a unique immune response, principally mediated through the gut-associated lymphoid tissue (GALT), the immune system of the gut, which produces reactive substances to constituents of the diet that are perceived by that individual’s own unique genes as being “foreign.” As such, the body initiates an antibody response to those antigens. In this study, 66 patients with active rheumatoid arthritis were randomized to either a vegan diet free of gluten, or a well balanced, non-vegan diet, which was maintained for one year. At the end of the year, very strong evidence was found that the low-gluten dietary modification resulted in significant improvement in arthritis symptoms. In fact, about 40 percent of patients in the vegan group fulfilled the ACR20 improvement criteria, compared with only 4 percent in the non-vegan group. This is strong evidence that a gluten-free diet with a minimally processed vegan base modulates inflammation, both by reduction of the inflammatory trigger, and by probably improving the control over oxidative stress and inflammation due to the range of phytochemicals in a vegan diet. When the diet is “white,” which means white flour, white sugar, and white fat, we have few of those phytochemicals that I talked about earlier that have evolved over time to help balance the gene expression patterns; that regulate cell signaling and intercellular signal transduction; and that control inflammation and how the body responds to the environment as a “friend” or a “foe.” There are many variables at play when dietary changes are made. It is not just gluten; it is the absence of gluten in the presence of many other phytochemicals that, in a minimally-processed, vegetable-based diet, help to regulate gene expression patterns. As we review these types of papers that have appeared in traditional medical journals, we begin to have a different perspective. We see that this dietary treatment is not just the result of a gluten-free diet alone. It has multiple variables, gluten-free in the presence of increased phytochemical intake, which are antioxidants and xenobiotic response element activators that improve detoxification, lower intracellular toxicity, alter the immunological effects, and reduce cellular apoptosis. Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction Let’s look at another example-coffee and its relationship to cardiovascular disease. There has been a long-standing debate about whether high intake of coffee has any adverse effects upon heart function. A recent paper appeared in the Journal of the American Medical Association, titled “Coffee, CYP1A2, genotype, and risk of myocardial infarction.”7 In this study, the researchers showed that individuals with a genetic polymorphism in the cytochrome P4501A2 (CYP1A2) gene-one of the phase 1 detoxifying CYP 450 isoforms-that resulted in their being “slow metabolizers” who consumed relatively high levels of coffee, were more at increased risk of MI. People who consumed five or more cups of coffee per day who were CYP1A2 slow metabolizers had a much higher incidence of sudden coronary events. There was no statistical relationship between coffee consumption and heart problems in those who had the common or rapid metabolism CYP1A2 genotypes. Again, here is an example of a connection between a genetic uniqueness and a dietary variable-i.e., CYP1A2 slow metabolizer phenotype and caffeine consumption (nutrigenomics). We are starting to witness some very interesting ways of stratifying clinical studies to look at variant responses based upon genetic uniqueness, instead of the past method of putting everybody in one big data set, regressing to the average, and trying to come up with a mythical conclusion about the average person that did not exist in the study. No one is “average;” everyone is unique in his or her own response. Let me mention one more example. What about metabolic syndrome? Metabolic syndrome’s connection to heart disease is, in part, related to increased inflammatory mediation and increased oxidative stress, with the build-up of reactive oxygen species in the arterial wall, therefore increasing oxidation of LDL cholesterol, which is associated with the indications of metabolic syndrome-elevated triglyceride-to-HDL cholesterol ratios and increased waist-to-hip circumference ratios. These particular characteristics of increased oxidative processes leading to LDL oxidation through activation of the immune system, connect metabolic syndrome and hyperinsulinemia with heart disease risk. I am now quoting from a 2006 paper in the American Journal of Clinical Nutrition, in which it is suggested that this is the key to understanding the metabolic syndrome-the connection between oxidized LDL cholesterol and abdominal obesity.8,9 There is a clustering of metabolic abnormalities, not only in adults, but also in adolescents with hypertriglyceridemic waist phenomena.10 In my evaluation, elevated triglycerides and elevated postprandial fatty acids are very toxic because they induce increased production of oxidant free radicals through the activation of the enzyme that I talked about earlier that is associated with cellular apoptosis-GAPDH. The upregulation of that enzyme is associated with the problems of metabolic syndrome, oxidative stress, diabetes, and ultimately, CVD. There is a companion paper to those I just mentioned, titled “Whole-grain intake is inversely associated with the metabolic syndrome and mortality in older adults.”11 What do the authors of this article say? Let me stop for a moment. Recall that we have just gone through an interesting period in which carbohydrate was suddenly considered toxic, and protein and fat were good. This is interesting, because it came out of the previous period (the 1980s), when high carbohydrate diets (the Pritikin approach) were desirable, and high-protein, high-fat diets were toxic. The pendulum swung very quickly. What actually is going on? I believe it is much more than we are hearing about. The changes in macronutrients levels, going from high protein to high carbohydrate, may be secondary to other factors that are not being discussed in these studies. What happens when you take a lot of minimally-processes carbohydrate out of the diet? The type of carbohydrate that Nathan Pritikin and Dean Ornish talked about in their studies was minimally processed-high complex carbohydrate and high fiber foods-the kind of diets Richard Anderson from the University of Kentucky School of Medicine talks about. These are particularly nutrient-rich forms of carbohydrate because they carry the phytochemicals initially made in plants, not only vitamins in the incorporation of minerals, but also flavonoids, polyphenols, carotinoids that get converted to retinoids, and the tocopherols (vitamin E). These myriad phytochemicals have impact upon function, as well. We often forget about that in clinical studies. We just look at the macronutrients overall. In this study, showing whole-grain intake inversely associated with metabolic syndrome, we are not just looking at increasing carbohydrate with whole grain, we are looking at the effects the fibers, lignans, plant sterols like beta sistosterol, and the flavonoids have on gene expression, intercellular signal transduction, and the relationship of that specific dietary signature as “food information” to the genes to produce a different outcome-lowered inflammation and improved function through regulation of insulin sensitivity. If we take that argument and extend it to other phytochemicals, we come out with a similar theme. For instance, a very interesting paper was published in Cancer Research that showed we could help protect against aflatoxin-induced tumorigenesis by giving a synthetic substance (a new anti-inflammatory) based on a natural product found in a variety of foods that has a tremendous effect on upregulating glutathione-S-transferase and the antioxidant response element, as well as helping to protect against oxidative injury. This is a triterpenoid found in many plant foods, particularly in spicy, Indian foods, that is a natural antiinflammatory, downregulating the potential production of a toxic reaction. What about the flavonoid, quercetin? We now know that it has a direct effect on gene expression signaling. It inhibits proinflammatory cytokine effects through reduction of tumor necrosis factor-alpha (TNF&alpha;) gene expression in peripheral blood in individuals who have been administered high oral doses of quercetin.13 Quercetin is the aglycone of rutin; it is found in whole grains. We are starting to witness the emergence of the connection of the genes with the nutritional environment to give rise to different outcomes, personalizing the effect of outcome and designing nutrigenomically-tailored diets that will ultimately allow people to be properly managed based upon their individual needs-the dream and objective of both Drs. Roger Williams and Linus Pauling. With that in mind, let us move to our Clinician/Research of the Month, Dr. Ruth DeBusk.

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INTERVIEW TRANSCRIPT

Clinician of the Month Ruth DeBusk, PhD, RD Mahan Center 2625 Mitcham Drive Tallahassee, FL 32308-5404 JB: It’s time for our Clinician/Researcher of the month. We have been waiting for a couple of years to interview this month’s guest on FMU. She is very busy, and has been making significant contributions to the field of nutrigenetics and the interaction between genes and diet. I’m talking about Dr. Ruth DeBusk, who has a remarkable background that will lend itself nicely to a lot of questions that have come up over the last several years on the interaction between genes and diet. Dr. DeBusk has a PhD in genetics and molecular biology, but she’s also a Registered Dietitian. She has been very actively involved in the American Dietetics Association (ADA) in trying to establish a different thrust for dietetics and nutrition in that organization, moving away from traditional food-based programs to individualized nutrition, nutritional counseling, and clinical nutrition, which has not been the major thrust of the ADA. Ruth has been a leader in that organization and in changing the entire field of nutrition. She has recently published what I think is the premier book in the area of nutrigenomics and personalized approaches to nutrition. It is a dynamite, must-have book for any of you who want to see where the future is going to be taking us in the field of nutrition. (DeBusk R, Joffe Y. It’s Not Just Your Genes! BKDR, Inc., 2006.) It is with tremendous pleasure, both on a personal and professional level, that I welcome you to Functional Medicine Update, Dr. DeBusk. My first question is, was it dietetics first, followed by molecular biology, or was it molecular biology, followed by dietetics? How has the thrust of your career led you to your current, unique status? RD: Thats a great question. I started out being absolutely fascinated by the chemistry aspects of food and nutrition. I never thought of nutrition as applied biochemistry. I came into it from a food and nutrition training base. After doing the Master’s/PhD Program in Food and Nutrition, I realized that what I really loved was molecular biology and the genetics base. I pursued training in that area, and was fortunate enough to land a faculty position in genetics. I focused my research on putting nutrition and genetics together, looking at the genetic regulation of nutrient absorption, and always planning, ultimately, to be able to bring those two disciplines together in practice. It seemed like it was going to take forever, so I’m thrilled that it’s all of a sudden here, barreling along, with lots of good studies in progress. I think we’re going to see quite an impact before too long. JB: As I look at your background, I see that our chronologies match up very closely. Your undergraduate degree was just a year after mine. Your PhD was a year after mine. Your post-doctoral work, which you did in genetics and molecular biology, and nutrition and food science at Florida State, was an interesting dual specialization. Then, you moved into physiological chemistry at the University of Wisconsin, Madison and became a Registered Dietitian. All along the road, I imagine you had people asking you what you were trying to do. You must have had a very clear vision as to where you wanted to take your career. RD: I felt like Joan of Arc many times-a voice in the wilderness. Most people saw one discipline or the other. They couldn’t see what one had to do with the other. That’s frustrating, because genetics is absolutely fundamental; it under girds everything we visibly see and can now measure biochemically. Genes make the proteins that control an organism’s structure, its metabolism and ultimately, its function. That has to have profound effects on any aspect of health care that I can think of. Nutrition is so much more than cold food; it’s the bioactive, dietary components in the food and the way they communicate, not only to the genes within the cell, but as signals from the environment into the genetic material and ultimately, turn gene expression on and off. That’s such a powerful connection, and something that organisms have had from the very beginning. It’s a very fundamental, biological process. JB: It’s interesting. I notice that early on, you did quite a bit of work in an organism that I talked about, which is Neurospora crassa, the red bread mold. In medicine, people often ask why we would think it’s interesting to do research in yeast, bacteria, mold, and fungi. That seems so simplistic, but a lot of the genetic pathways we are describing are conserved up through time immemorial. Perhaps you can tell us a little about what you learned about Neurospora crassa that can be applied to humans. Research with Neurospora crassa RD: It’s amazing, but most eukaryotic cells are very good model organisms for much more complex organisms. The beauty of Neurospora crassa was it’s haploid, so you could introduce a mutation and directly look at its effect. And, you could define the environment it was in, manipulate that environment, and look at the impact on the gene. You could look nutrigenetic-wise at what the effect was of changing the genes on the organisms that they will need to function, and then you could do the reverse, which is more in the area of nutrigenomics, looking at the impact of change in the environment on the organism’s function. Then, you have a system you can manipulate and try to take apart in very systematic ways, compared to a very complex organism like the human. I think what we may not appreciate is just how similar these organisms are. We like to think we’re a lot more complex than single-cell yeast or Neurospora crassa (even the bacterium), but it’s amazing how many things are conserved. Even now, the organism of choice seems to be the mouse, which has a great deal of homology with the human. Thank Heaven we have these model systems, because we can’t just do selective breathing in humans like you can do with model systems, and really look at the impact of changing the genes or changing the environment. JB: I’d like to go back and build up this discussion for the person who is not as familiar with the topic as we are and first, talk about the difference between nutrigenomics and nutrigenetics. Maybe even before that, I should ask you, is it “nutra” with an “a,” or “nutri,” with an “i,” genomics? Nutrigenetics versus Nutrigenomics RD: It’s nutri. As you know, in any emerging field, the terminology evolves. It’s still in a state of confusion, but I think it’s starting to sort out. I think of nutrigenomics as short for nutritional genomics. What is the interaction between dietary components and our genetic makeup? Within that, there are sub-disciplines. Nutrigenetics looks at the effect of an individual’s unique genetic makeup on their nutrient requirements. Your genes and my genes are, obviously, basically the same, because they’re both of the same species, but there are some three million base pairs that are different between us. All of the characteristics that make us unique come from those genes. In addition to our hair color, eye color, intellectual capacity, etc., there’s a difference in how we are going to be able to use particular nutrients, as a result of structural differences in the enzymes that are coded for in these genes. That’s nutrigenetics. It has an impact on us in terms of how much of a particular nutrient or bioactive food component we need in order to function optimally. That’s going to be slightly different for each person. Nutrigenomics, in addition to being a whole broad field, also refers to looking at how food molecules from the environment impact the genetic material itself, turning expression on and off, or modulating it up and down. I look at nutrigenetics as “inside out”-what’s in the individual and how they respond to various nutrients in terms of levels required, and metabolites required. Nutrigenomics is sort of “outside-in,” looking at the impact of the environment on the particular expression of the genes that individual has. JB: That’s a great definition. Let me see if I have this right. Let’s take apo E4 as a genetic polymorphism. That would be a nutrigenetic characteristic that might make that person more susceptible to certain kinds of diets or environmentally-related disorders. Would that be correct? RD: Correct. JB: Whereas a glucosinolate in a cruciferous vegetable, such as indole-3 carbinol (I3C) and how it impacts detoxification of estrogen, would be more of a nutrigenomic relationship. RD: Yes. That’s a good way of thinking about it. I’ve told people not to get hung up on definitions. When nutrition and genetics come together, however they relate, I call all of that nutrigenomics. I think at this point in time, if people got that, it would be great. JB: Let’s go from there to what is becoming another part of the emerging story. The community of molecular geneticists and biologists almost expressed surprise when Celera and the NIH mutually disclosed the structure of our chromosomes and the sequence of DNA nucleic acids. It turned out there are only about 30,000 genes, which was very surprising. People thought there would be so many more than that. Then, they said genes are not expressed one at a time; they’re expressed as specific families of genes connected to non-coding regions we used to call “junk DNA.” Maybe the principal difference between humans and other organisms is in the non-coding regions, and we better throw away the term “junk,” because it’s not junk. RD: Exactly. JB: Would you tell us a little bit about that-how genes get turned on through the other loci? Understanding Single Genes RD: That whole story is fascinating, and it’s very much in its infancy in terms of unraveling it. There’s so much to consider and, from a scientific basis, we always tend to start with the simplest part, try to understand that, and then look for more complex explanations. Most of the current focus is on trying to isolate one gene and understand it. What is its protein product? What’s the function of that protein, and how do various environmental factors impact that function and the expression of that gene? We’ve got quite a bit of work to do in that area. Overlaid on that is the growing understanding of just how complex it is. Not only do you have a single gene able to make multiple proteins and protein interaction, but potentially gene/gene interaction. I think most people are probably ignoring that as much as possible, because it’s so complex. Thankfully, there are some great researchers who are working hard to understand those dynamics. I’m not sure that I know all of the intricacies of that. JB: Let’s move to what has been a term in our literature for some time that is now gaining some better understanding as a consequence of the work you’re describing. That term is “conditionally essential nutrient.” We can put on that list things like coenzyme Q10, lipoic acid, taurine, and carnitine. These are substances that our body makes, but perhaps under certain conditions, can’t make enough to meet the needs of an individual, so they become conditionally essential. I would presume the concept of conditionality relates, in part, to the nutrigenetic relationship, individualized to the person. Is that correct? Conditionally Essential Nutrients RD: Absolutely. I believe that a lot of our terms are going to fall away because they were descriptive back in a time when that’s the best we could do. We could just describe what we observed. I’m thinking of terms like “penetrance” and “homozygous.” Our vista is changing as we learn more at the molecular level, and the idea of conditional essentiality was geared toward the “average person.” As we come to understand that there’s no such thing as an “average person,” and that we have to deal with the genetic uniqueness of each individual, I think we’re going to find those sorts of terms falling away. We were compelled to define an “average” so you’d have a starting point, and here is the amount of nutrients that an “average” person needs, without taking into account all of the variations on either side of that. If we had just understood and kept a more open mind about how different everybody is, I don’t think we would have gotten so lost into “this is the level everybody needs.” Clearly, it’s not conditionally essential for that individual. That is what they need, but it’s conditionally essential from the standpoint that we define some arbitrary average for “the population.” But even “the population” makes no sense, because there are all these sub-populations, and there may be an average for a particular related genotype, but I have a real problem with “average.” I agree with you in that a nutrient may be essential for an individual and they may need 100 mg a day. Somebody else may need 300 mg a day. It depends on what the particular gene variations are and the protein variations that result. JB: That’s a very nice explanation. Let me use an example, and perhaps you can walk us through it. One of the polymorphisms that has been very heavily studied and discussed in the literature is the methylenetetrahydrofolate reductase polymorphism, C-677®T, that leads to changing folate requirements. I’ve had a lot of doctors tell me over the last few years that they understand this polymorphism, but if you have the heterozygous type (let’s say your mother had the allele for the sluggish MTHFR, and your father gave you the one that was the common form, or the wild type), why do you worry about it, because won’t the father’s common one take over from the mother’s slow one, or vice versa? I think there’s a misunderstanding going back to the Mendelian concept of dominant recessive genes. Would you tell us a little bit about that? The Methylenetetrahydrofolate Reductase C-677®T Polymorphism RD: That’s exactly the kind of terminology that is not going to make any sense. For the longest time, we thought that if you had anything except two impaired genes you were normal. If you had the common form, or had at least one of the normal alleles-a heterozygote (a carrier)-that it was the same as being totally normal. That made sense at the observation level, and as we began to develop chemical measures and ultimately, molecular measures, it started not to make sense because we realized that there is co-dominance. Both of those copies, or alleles-one from the mother and one from the father-were both contributing some sort of function, either no function at all, or maximum function, or something in between. We started to see that the carrier individual has not quite fully impaired, not quite fully wild type or normal, but something in between. Particularly, if you stress the organism and put it under conditions where it absolutely must have a robust supply of folate, you’re going to see the inability of that carrier to supply enough methylated folate cofactor for the needs of that individual. It looks like there’s a pretty generous amount of enzymes produced in the normal individual. We may find there are control mechanisms that read the level of enzyme activity that exists, and see that we need to regulate the normal allele more to compensate for the lack of production by the variant alleles. Those sorts of questions certainly still remain to be answered. I have a real worry about the carrier individual that we’ve just lumped over into normal, because at the clinical level, they don’t seem to be quite as robust as the normal person. JB: That’s a very important takeaway for our listeners. Two conditions come to mind that I learned about in school that I thought were like on/off switches. One was phenylketonuria (PKU), and you either had it or you didn’t; the other was Gilbert’s syndrome, which is a glucuronosyl transferase polymorphism. I learned that these were point gene mutations and you either had them, or you didn’t. If you didn’t have PKU, you were fine. Now, as you say, we’re learning that there are variant forms of both of those conditions-Gilbert’s and PKU. You might not end up with the dementia of infancy and the mental retardation that’s seen with frank PKU, but you may have a latent form of a milder PKU that expresses itself with dopaminergic neuron changes and affective changes in mid-life. Varient Forms of Polymorphisms RD: You might be further stressed if, for some reason, your environment puts particular pressure on you. Maybe you’re in an environment with a high phenylalanine content. Maybe you didn’t realize that one of the artificial sugars was also in the diet drinks that you just love, which are high in phenylalanine. That’s going to further stress that carrier individual who thought he or she was fine. I have a real worry, and I’m always looking for red flags within the GI area for things like celiac disease-gluten-sensitive enteropathy, or hemochromatosis. Even individuals who are not stressed in their environment with excess gluten or excess iron seem to function just fine. We’ve been thinking that these are not very common diseases. Again, it’s a misnomer-the thought of a genetic disease. In my mind, there’s no such thing as a genetic disease. It’s virtually all genetic. We need to be thinking about how a person is functioning. Someone who has one normal and one impaired gene typically doesn’t process some of these trigger molecules as well as the wild type might. What we’re seeing clinically is an enormous rise in the amount of gluten sensitivity. The carrier rate for both of those disorders is something like 1 in 8 to 10. That’s very much an undetected problem. JB: That is a superb clinical example, because many of our clinicians have heard people say that the frequency of gluten sensitivity in our population is 1 in 1000. They see a lot more than that in their practices. What we’re dealing with are people who have gene characteristics that are only expressed in the phenotype when they’re under environmental stress, and we start to see all sorts of different things appear. RD: And look at our diet. I think the diet is probably a major environmental stress, because it’s so wheat-based. JB: That’s a very interesting point. This years symposium was on biotransformation and detoxification. One of the themes that came out of that whole area was whether diet can influence detoxification. Certainly, what we’re speaking to has some relevance to the inducible detoxification enzymes. Would you tell us where you see the diet/detoxification connection as it relates to the nutrigenomics concept? The Diet/Detoxification Connection to the Concept of Nutrigenomics RD: It’s a really critical area, and one that I encourage nutrition professionals to get a handle on. They get all excited, and there’s so much to learn, so everybody’s on a learning curve right now. They want to know what they can do right now, and staring us in the face is the whole detoxification process, which is an area where diet meets genes head on. It’s an area that’s not addressed and understood in terms of how much nutritional demand detoxification places on an individual, particularly in today’s environment-for instance, anyone who is on any kind of prescription drug, over-the-counter medications, or dietary supplements. A lot of the toxins are contained in our food, beverages, or the air we breathe. It’s seems like our poor liver is under constant demand and both the phase I and the phase II reactions are very dependent on nutrients that we supply in order to optimize those reactions. Any number of those enzymes-certainly the cytochrome P450s-come in a number of isozymes which hark back to particular gene variants. That determines how well people do or don’t do from the phase I reaction, and the ability to move that highly reactive intermediate on through phase II. Again, you’ve got the glutathione S-transferases, which are genetically variable. If there was just one area we could test for and have information about, I’d be happy if we’d focus on detoxification. What is this patient’s phase I activity for the key cytochrome P450s? What are their phase II gene variants? What can we know about particular nutrients that upregulate or downregulate, depending on what’s needed, with the particular variants that patient has? How can we manipulate those, diet-wise? For example, if you have a sluggish phase II and you need more of it, then certainly the cruciferous vegetables with their glucosinolates are directly in order. If you’re a nutrition professional, you’ve got to figure out how to get people to eat cruciferous vegetables (it might not be their favorite thing to do), but there are lots of ways around that. JB: You’ve raised a clinical “tire-meets-the-road” question. That is, are we ready for prime time in nutrigenetic testing? There have been many different articles written on that recently. Some have said we are absolutely not ready. But there are commercial companies offering tests that can evaluate some of the more commonly understood genes associated with nutritional regulation. What’s your thought, as it relates to 2006? Nutrigenetic Testing RD: That’s a hard question for me. The academic in me says, oh, no; we need 20 more years of work before we can possibly do those. The clinician in me says that people need it now. I’ve more of a mind to take what we have, however limited it might be, and use it to the betterment of the patient if it’s not going to be harmful. I think there are some good tests that are soundly developed and validated that are really helpful. It’s very helpful to know what a patient is feeling. Typically, if you’re not doing functional testing, you’re not seeing a lot of the characteristics beneath the surface in that individual. You can really get a good feel for what’s going on if you can add in not only functional testing, but nutrigenetic testing, as well. I’m thinking of things like the cardiovascular-related genes. We have these conventional things that we do that we wouldn’t do if we had genetic information. You put people on a low-fat diet, or on a salt-restricted diet. Does that make any sense if this person has the apoE1 variant that’s going to give them high HDL levels? Do they really need to be on a low-fat diet? Maybe they are an apoE2 genotype that doesn’t respond particularly well to a low-fat diet. They may have a particular variant in apoE1 that requires their polyunsaturated fats to be above an 8{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} level. All of that factors into nutritional intervention, and there’s no way you can get that kind of information, certainly from conventional clinical assessments or, for the most part, even from functional testing. I see that as being enormously helpful to the clinician in terms of getting underneath what’s really going on with a patient. JB: For people who are listening who want to fill in the gap, your book, It’s Not Just Your Genes! would be a very good place to start. Where can people find the book? It was published this year. RD: It’s readily available from amazon.com, which is probably the easiest way to get it. JB: Great. I know that also, just a couple of years ago, you were a principal author on the book, Genetics: The Nutrition Connection, for the ADA (The American Dietetic Association; 2003). Is that book beginning to have an impact on teaching dieticians and the practice of dietetics? RD: Yes. It’s gotten to the point where people are excited about it, but they don’t know what to do about it. What we’re trying to do now is forge a career path. This is so fundamental to nutrition, to virtually any aspect of food or nutrition practice that a dietician would get into. It’s going to be absolutely essential that they get a solid background in genetics, but I would like to see a particular career path analogous to the nurse practitioner that develops a very well-educated, very competent practitioner in nutrigenomics; a nutrigenomics practitioner that can take charge of this area, do the genetic counseling, do the testing, and do the therapeutic interventions and prevention that ultimately will be developed, and just be responsible for that area so they’re a valuable contributing member of the healthcare team. And it’s one less thing the physician has to worry about. From my perspective, its so much easier to teach genetics to someone who has a very broad base of food and nutrition, than to try to teach that base to somebody that has competency in genetics. I see a real niche at a high credentialed level-very skilled, but very unique, and very much needed within the healthcare team. JB: That’s a tremendous model. I never thought about the nurse practitioner model. It makes very good sense. Let me close with one last question. You’ve been very kind to give us this amount of time. You’ve been actively involved in the chapter of the ADA called “Nutrition and Complementary Care” which, by virtue of its definition, may be an anachronism when they think of the stereotype of the ADA. Would you tell us a little bit about this sub-group and its activities, and whether you feel it’s having an impact? Nutrition and Complementary Care Sub-Group of the ADA RD: ADA is much more progressive than they get credit for. It’s so hard in a large, very old organization to turn things around. I just spent last night with the incoming president, Dr. Judy Gilbride, who is very much a proponent of nutrigenomics, and who has worked hard to get that on the table, to the extent that it’s now one of the top priorities for ADA. Again, we’re moving into a whole new area. We’re talking about a whole different type of credentialing, so how do we get all these details together? The Nutrition and Complementary Care group came about five or six years ago to deal with all of the unconventional aspects of nutrition and food. At the time, probably a major emphasis there was dietary supplements, which is clearly applied biochemistry and nutrition, but it was not something that conventional dietitians had embraced. That group has been very progressive, I think. Their whole mission is to educate members about what this is all about. What is the science behind it? They’re trying to keep it as solidly financed a base as possible. They want to know what different modalities are out there. It’s not all snake oil and hocus-pocus. Here’s the science and heres the effects that practitioners are having. I think it’s moved us away from a very conventional, conservative stance. As you know, change takes time. JB: Absolutely. As we bring this interview to a close, I’d like to give you the opportunity to speak to our listeners (who are principally clinicians) about anything you feel they should keep their eyes and ears open to, or that they might want to consider as they start to integrate these concepts into their practices. Recommendations for Clinicians RD: I think it can be totally overwhelming. We’re dealing with a whole new language. I can make the analogy of trying to learn immunology. It has its own language and its own alphabet. Once you’ve finally mastered that, it starts to make sense. Understand that genes underlie all of function. Ultimately, virtually everything that’s going on with your patients harks back to their genes. It’s going to become more important to look into the genes and figure out what particular variants they have and what the impacts are. Personal health is a continuum between wellness and illness. Where we function on that spectrum is directly related to our lifestyle choices. That’s very empowering to a patient. With education, you can learn to make the best choices that will optimize health and total function. For a clinician who is just getting into this, I would try to remember the tremendous impact this will have and how fundamental it is to the health of patients. In order to feel comfortable with it, I would pick some area that’s of interest to you, whether it’s your practice, perhaps a chronic disease that runs in your family, or something you’re really concerned about, start at one corner, and build a base of knowledge around that. Start to read the literature that deals with particular genes. Look at the impact of a gene or two and how dietary manipulation can enhance or improve the function of that gene. Just try it out. I find patients are very receptive if you just lay it out. We don’t have all the answers we’d like to have, but this is what we know, and this is what I think will be helpful for you. Let’s try it. JB: That’s a marvelous message. I can’t tell you how much we appreciate your time. Again, your book, It’s Not Just Your Genes, is a very good place to start for a person who is moving down this path. Thanks a million, Ruth. You are truly a pioneer and a leader. I think well look back at this interview ten years from now and say that this was where it all started in the early 20th century, and that Dr. DeBusk was right at the head of the class. Thank you so much. Effect of a Low Glycemic Index Diet with Soy Protein and Phytosterols on CVD Risk Factors in Postmenopausal Women It might seem presumptuous to add anything to Dr. DeBusk’s eloquent discussion, but I thought it might be useful to complete this month’s visit together with a review of a paper we just published out of our own research group, which is quite germane to the topic. This paper appeared in the journal, Nutrition.14 It is the work of Lukaczer, Liska, Lerman, Darland, Schiltz, Tripp, and myself, titled “Effect of a low glycemic index diet with soy protein and phytosterols on CVD risk factors in postmenopausal women.” Let me summarize the results of the study and how it relates to what Dr. DeBusk was talking about. In this study, we recruited a group of 59 postmenopausal women who were experiencing increasing lipids and body weight. They were not morbidly obese; they were not diabetic; and they did not have cardiovascular disease. They were in the “increased risk “category. The average age of the subjects was about 55. We randomized them into two groups, one on a low- glycemic index diet that included 30 grams of soy protein and 4 grams of phytosterols per day (LGID), and one on the American Heart Association Diet (AHAD). Both groups were isocalorically managed and they received approximately the same calorie amounts. Both received the same exercise regimen-a regular walking program. Both groups received the same consultation with a trained nutritionist/dietitian, and both groups had approximately the same fat calorie percentage and similar protein calorie percentage, although the AHAD diet resulted in increased carbohydrate calorie percentage to that of the LGID (54{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} to 43{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, respectively). Clearly, even though there were no major differences in the total amount of calories, there was a difference in the kinds of foods that were consumed by the two groups, one receiving the AHAD, the other the LGID. The point I want to make here is, there is a theme that still resides in our culture that calories are the name of the game, and that as long as you adjust the calories with the right protein, carbohydrate, and fat percentages, there will be a favorable outcome. For years, many of us have been saying that is not the whole story. For the story to be more complete, it needs to include what those calories deliver in the form of information. Morgan Sperlock, in his classic video, “Supersize Me,” had more than just supersizing of calories. He had supersizing of bad information from toxic food that was inducing different gene expression patterns. It was not just the calories, in and of themselves, that created the multiple effects he saw in his body over the weeks that he ate “fast food.” By the same token, we wanted to ask, if you hold the calories comparable, and you hold the percent of calories as protein, carbohydrate, and fat comparable, would you change the information coming from the food between the two groups? Would there be a difference in outcome between the two groups? The result was absolutely unbelievable. I’ve been involved in these types of clinical studies for the better part of 20 years and for me, this was the most remarkable outcome I have witnessed. The results were so dramatically different that you could not help to recognize the power of nutrigenomics. The AHAD group did experience improved outcome: they lost about the same amount of weight as those in the LGID group: their total cholesterol was improved; their triglycerides were improved; and their body composition was improved. But, these changes paled in comparison to the members of the LGID group, who had the same calorie intake and the same exercise, but had a different level of phytochemical intake and a different diet persuasion. These individuals had a 46 percent reduction in their triglyceride-to-HDL cholesterol ratio, a significant reduction in total and LDL cholesterol; a significant reduction in high-sensitivity C-reactive protein (hsCRP), a significant reduction in fasting insulin, and a significant reduction in glycosylated hemoglobin. Every one of those variables was extraordinarily better after intervention with the LGID diet. This demonstrates the power of nutrigenomic tailoring and getting the right information to send to the genes to produce the right outcome. I cannot tell you how impressed the whole clinical staff was in seeing the difference between these two groups. In fact, I went to the literature and asked what drugs these patients would have to be on to produce these same effects. The answer was that if you put people on statins, metformin, and ACE inhibitors, you would still be able to get the same dramatic effects seen across the full range of parameters studied found in these dietary interventions (based on the published literature). Therefore, the LGID diet group had results that represent the best medicine-not alternative medicine, not complementary medicine, not integrative medicine, but the best medicine. The best approach with this group relative to risk factors to the major cause of heart disease in postmenopausal women (not drugs), based upon evidence of comparison, was a personalized, nutrigenomically-tailored diet focused on improving insulin signaling, lipid management, intracellular signal transduction, and lowered inflammation. Both the AHAD and the LGID groups lost about the same amount of weight. Therefore, it is not solely a weight-loss argument; it is not solely a calorie-restriction argument; and it is not solely a protein/carbohydrate/fat percentage argument. It is an argument related to what information is sent to the genes. I have recently heard people talk about the toxic effects of soy. I find this ironic, because there are hundreds of clinical trials in humans published in the literature that demonstrate the beneficial effects of moderate amounts of soy in the diet. Our study is one of many showing that with appropriate intake of something like 30 mg of soy isoflavones (part of the soy protein isolate found in the beverage), and in the context of an overall, well-balanced, low glycemic-index diet rich in plant foods, there are no toxic effects. There is a highly desirable effect on every lipid, glucose, insulin inflammation connection that was studied. We are witnessing the emergence of a new form of nutrition, as Dr. DeBusk discussed-personalized nutrition based on the interaction between nutrigenetics and nutrigenomics. This is an exciting new chapter in the story of the evolution of medicine, and it will result in the bestmedicine in the future-that which derives from old concepts in new ways by personalization of the diet. Thanks for being with us. We look forward to our next visit in June.

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Bibliography

1 http://abcnews.go.com/GMA/Atio/story?id=1718017 2 Sedlak TW, Snyder SH. Messenger molecules and cell death. Therapeutic implications. JAMA. 2006;295(1):81-89. 3 Ridker PM. On evolutionary biology, inflammation, infection, and the causes of atherosclerosis. Circulation. 2002;105:2-4. 4 Demmig-Adams B, Adams WW. Antioxidants in photosynthesis and human nutrition. Science. 2002;298:2149-2153. 5 Rist MJ, Wenzel U, Daniel H. Nutrition and food science go genomic. TRENDS Biotechnol. 2006: In Press. : 6 Hafstrom I, Ringertz B, Spangberg A, et al. A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatol. 2001;40:1175-1179. 7 Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006;295(10):1135-1141. 8 Knopp RH, Paramsothy P. Oxidized LDL and abdominal obesity: a key to understanding the metabolic syndrome. Am J Clin Nutr. 2006;83:1-2. 9 Weinbrenner T, Schroder H, Escurriol V, et al. Circulating oxidized LDL is associated with increased waist circumference independent of body mass index in men and women. Am J Clin Nutr. 2006;83:30-35. 10 Esmaillzadeh A, Mirmiran P, Azizi F. Clustering of metabolic abnormalities in adolescents with the hypertriglyceridemic waist phenotype. Am J Clin Nutr. 2006;83:36-46. 11 Sahyoun NR, Jacques PF, Zhang XL, Juan W, McKeown NM. Whole-grain intake is inversely associated with the metabolic syndrome and mortality in older adults. Am J Clin Nutr. 2006;83:124-131. 12 Yates MS, Kwak MK, Egner PA, et al. Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res. 2006;66(4):2488-2494. 13 Nair MP, Mahajan S, Reynolds JL, et al. The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulating of the NF-kb<&beta; system.>Clin Vaccine Immunol. 2006;13(3):319-328 14 Lukaczer D, Liska DJ, Lerman RH, et al. Effect of a low glycemic index diet with soy protein and phytosterols on CVD risk factors in postmenopausal women. Nutr. 2006;22:104-113.

Welcome to Functional Medicine Update for June 2006. When your patients sit before you, do you ever wonder how much of their conditions are related to their genes and their family history, as compared to the influence of the environment to which their genes have been exposed? That question is a fairly important one because, obviously, we believe that we cannot change genes, but we can change the environment. Genes vs. Environment: The Debate Continues You might think that a patient’s condition is solely the consequence of his or her family history, and there is virtually nothing you can do, other than try to manage symptoms. Whereas, if the condition is principally the result of environmental exposures, you can hopefully help your patient to modify the environment to both prevent and treat the condition. The old model we used to use, in which there is a clean separation between genes and environment, has started to lose some of its distinguishing points of differentiation. The field of epigenetic, or post-translational medicine is starting to show us that Lysenko wasn’t totally wrong. The debate between Darwin (natural selection) and Lysenko (adaptation), which won Darwin the battle and lost Lysenko his reputation, is being resurrected into a new perspective, because it is now recognized that our environment can modify the way our genes are expressed. Though we may not change the genes in and of themselves, we may change the way our book of life, locked into our genome, is read. This post-translational effect-through methylation, phosphorylation, glycation, and oxidation of proteins, can lock different physiological function into the cell that can modify function even without modifying the genes. Even in the case of methylation gene patterns, this translational effect can even post-genomically modify what is passed on to the offspring. I’ve just said something fairly revolutionary, haven’t I, because it flies in the face of everything we have learned about the traditional concept of genetics. We inherit these dominant and recessive characteristics from our mothers and fathers, and they can get passed down as “hard-wired” tabulae rasae, from which we ultimately derive our phenotype. The environment in which the egg was nurtured during fetal development ultimately can alter, post-genomically, the way that the book of life can be expressed, closing certain chapters and opening others to being read into the phenotype, and this can be transmitted to the next generation. This indicates that the smoothing of genetic natural selection over millennia does still occur, but there is a much more rapid response potential for changing characteristics in populations through post-genomic-epigenetic or post-translational-modifications. This might explain why, as I recall hearing many years ago, Lucille Hurley at the University of California at Davis, in the Department of Nutrition, found offspring from animals given a marginal zinc-sufficient diet (meaning zinc was really lower than what would be optimal for proper development of the fetus) during pregnancy were immune-compromised. It took three generations of subsequent nutrition with higher levels of zinc to get back the original immunological function of the of-zero generation, which means that the characteristic of poor immune function was passed down post-translationally, or epigenetically as a consequence of a mother, three generations before, having been pregnant with a low zinc status. This sounds very much like the Pottenger studies on cats that were done many years ago, showing that suboptimal nutrition of cats led to the first asthmatic cats, which could be passed down to subsequent generations. Again, ironically, it took three generations of proper nourishment, as observed by Dr. Pottenger, before the cats arrived back to the original immune competency of the first-generation parents (that is, the health level before being on the suboptimal diet). This is raising some very interesting questions. For example: Is a patient affected more by his or her genes or by the environment? These influences are really closely interrelated, though, and we are enough steps down the road in the postindustrial civilization to have had all sorts of post-translational epigenetic influence on gene expression in the absence of actually changing our genes. People say that we are really Paleolithic humans. Our genes have not changed since Paleolithic times. The actual homology, or the structure of the nucleotide chains, the polynucleotide chains, has not changed; what has changed is the methylation patterns and the histone acetylation patterns that coat the genes and render them available for being read into the phenotype. These are modified much more quickly than is the mutational natural selection processes, smoothing our characteristics over millennia. Darwin talked about that. We are not really Paleolithic humans. The underlying code in our book of life may be that of a Paleolith, but the way it is expressed into the function of the organism is modified in temporal ways by our environmental exposures: changing stress patterns, changing exposures to toxic chemicals, and changing nutritional status. That opens up many interesting questions about the emergence of various chronic, age-related, degenerative diseases. One might say that the only reason we’re seeing increasing chronic disease is because we are getting older and you have to get something as you get older, don’t you? But if we start looking at the penetration and prevalence of certain chronic conditions, like asthma, atopy, eczema, and systemic lupus erythematosus in menstruating women, these conditions are increasing in absolute frequency in younger age populations, demonstrating that somehow, without our genes changing, the response we have to our environment is creating a different outcome. We do not have to wait for the process of natural selection and Mendelian genetics to change underlying structural gene patterns in order to see those effects. This month, we are going to be talking with one of the most remarkable people I have had the fortune of learning from for over 30 years, Dr. Herbert Needleman, at the University of Pittsburgh School of Medicine, who is going to talk to us about his pioneering work in the development of behavioral toxicology. We will look at functional medicine from a functional neurological perspective and ask: What are the things, epigenetically, that modify function in such a way as to create diagnoses that seem to be increasing in frequency, for which we can find no known neuropathology that leads to diagnoses like language processing problems, delinquency, attention deficit disorder, and hyperactivity disorders? Where do these things come from if they are not necessarily a consequence of changing our genes? This is a very profound concept that relates more to a functional medicine perspective than that of a histopathology-based perspective, into which most of us were intellectually born. With that in mind, you’ll notice that I am speaking to a theme that has been a recurrent one in Functional Medicine Update for some time-the nutrigenomics/proteomics/metabolomics concept of how our environment and factors that wash over our genes ultimately influence their expression into functional changes within cells, tissues, organs, or in systems and, eventually, the whole organism. I’ve been very interested in watching the emergence of the concept of nutrigenomics over the past two or three years because we are starting to see more and more research demonstrating how nutrients serve as signaling substances for modulation of genomic expression, proteomic activity and, ultimately, controlling metabolism through metabolomics. As Dr. John Milner and his colleagues have recently pointed out in an excellent review article that appeared in the Journal of the American Dietetic Association, we now recognize that the human genome is estimated to encode over 30,000 genes, and to be responsible for generating more than 100,000 functionally distinct proteins.1 One wonders how it is that 30,000 genes can make 100,000 proteins if it is a one-gene/one-protein concept that we learned in our molecular biology classes in the 1970’s. Now, we recognize that genes can be expressed in different ways, depending upon such things as which specific exons, the modular sections of a genes, are included in the final transcript and, ultimately, how these are seen as distinctive families of genes that are turned on and off under different environmental circumstances. In many cases, then, it is not just one gene at a time; it is a family of genes. We learned this very beautifully recently from the extraordinary interview we had on nutrigenomics with Ruth DeBusk in the May issue of FMU. Dr. DeBusk helped us considerably in our understanding of this complex topic. Understanding the relationship among genes, gene products, and dietary habits is fundamental to identifying those who will ultimately benefit most from being placed at risk by specific intervention strategies. Unraveling the multitude of nutrigenomic, proteomic, and metabolomic patterns that arise from ingestion of foods or the exposure to substances in the environment that modulate these processes of genomic expression will not be a simple task, but is likely to provide insights into a tailored approach to health, diet, and environment that will, be matched to an individual’s needs. This is what Roger Williams talked about in the late 1940’s as genetotrophic disease and biochemical individuality. It is what Dr. Linus Pauling talked about as molecular medicine and, later, orthomolecular medicine. We are starting to witness this very interesting emergence of a concept that is theoretic at first, but becomes more clinically applicable as we start to evaluate these single-nucleotide polymorphisms and families of genes that are expressed as differing variants. An example is the methylenetetrahydrofolate reductase polymorphism associated with folic acid metabolism, which is one of the more well-recognized examples of polymorphisms that are influenced by nutritional status, or nutritional status and function that is influenced by polymorphisms, depending on how you want to look at it. When we take this theme and map it against the patient sitting there before you, who expresses these complex symptomatologies, you may think that you have just been intellectually stimulated by listening to Functional Medicine Update, but now you are really confused because you don’t know exactly what to do with all this information. Let me go back to basics, because actually you do know quite a bit about what to do with this information, if we simplify it into one or two steps. The questions that bear on that individual patient are: What are the environmental factors unique to his or her life? What does he or she do? What is he or she exposed to? And how does the patient respond to those exposures in such a way that it demonstrates a phenotype of dysfunction?” Now, why do I suggest dysfunction? Because it is highly unlikely that this patient came to see you because he or she feels good and wants to find out why. It is more likely that the patient is seeing you because he or she wants to find out what is wrong. The patient has some level of dysfunction, which means the alignment between genes and environment is somehow not optimal. We go first to diet. Diet is a shared, common human experience. Everybody has eaten at some time. The bioactive components of our diet influence the whole array of genomic expression-proteomics, kinomics, metabolomics, lipomics-and can ultimately create different phenomics (the outcome in the phenotype of the individual). We eat bulk ingredients. Over the course of living, we may eat 20 or more tons of food, which are potential bioactive-molecules, many of which differ from those from which we are made. Our body has a very complex process for separating out friends from foes in our diet and hopefully delivering neutral information from which our energy-processing systems can be powered up, as well as our cell-signaling systems, ultimately leading to homeostasis, or control. When the patient is sitting with you in the exam room with a rash, headache, sore throat, sore joints, chronic irritable bowel syndrome, upper respiratory problem, or a chronic obstructive pulmonary disorder, you need to ask what is going on unique to that individual that gives rise to these complex symptomatologies. You need to address how the environment may be seen by the receptor systems in this patient’s body; for example, as “foe,” as an alarm agent which, in another patient (in fact, in the majority of people) might be seen as a “friend.” We talk about diet because it presents a bulk series of ingredients, or substances, for which our receptor systems have evolved over millennia of living, to give rise to signaling messages. This is a whole different way of looking at eating, isn’t it? In the past, we thought eating was for hedonic gratification, gustatory satisfaction, and satiety, and for preventing scurvy, beriberi, pellagra, xeropthalmia, rickets, kwashiorkor, marasmus; for preventing anemias; and for keeping our blood albumin levels adequate-all those kind of traditional clinical nutrition relationships between diet and function. But now we see that, within our foods, are literally thousands of differing phytochemicals and other substances that influence cellular signaling processes and ultimately, the genomic/proteomic/metabolic triad. Over historical periods of time, we may have removed things from the diet that had evolved to set up signals to our genes and control function. Why am I saying that? Let’s look at the Mediterranean diet. How does that diet differ from a diet of fast food? Obviously, one of the differences involves the amount of fat, sugar, and processed white starch. There is also the absence of the substances that were taken out to make those things white, which are all the things found in a colorful, Mediterranean diet. If we look at the scientific evidence of interventions using the Mediterranean Diet, what do we find? There is a wonderful review that appeared just recently in Nutrition Reviews. 2 The Mediterranean diet has been associated with greater longevity and quality of life in many epidemiological studies. The application of this evidence-based medicine to the area of public health nutrition involves, by necessity, the development of clinical trials in order to understand how this epidemiological association is related mechanistically to the reduction in risk or incidence of disease. The authors of this paper reviewed, in a meta-analysis, experimental studies on the Mediterranean diet and disease prevention. They examined a total of 43 articles corresponding to 35 different experimental studies. The results of these studies were analyzed for the effects of the Mediterranean diet on lipoproteins, endothelial resistance, diabetes, antioxidative capacity, cardiovascular disease risk, arthritis, cancer, body composition, and even psychological function. Through this meta-analysis, the Mediterranean diet was found to have favorable effects on lipoproteins, endothelial vasodilatation, diabetes and antioxidative capacity, improved insulin resistance, reduced metabolic syndrome, and increased antioxidant capacity. Myocardial and cardiovascular mortality was reduced, and cancer incidence in people with previous myocardial infarction and obese people was also lower. Is this just because we modified the levels of protein, carbohydrate, and fat in the Mediterranean diet? The alteration of the bulk macronutrients may play some role, but it’s much more than that. The results of the Mediterranean diet in health outcomes is related to the complex array of colored, secondary metabolites in plants called phytochemicals, that modulate function in very unique ways not found in a phytochemical-poor diet. It is a consequence of taking a lot of things out and adding some things back that gives rise to the dietary association with a changed environment on an epigenetic modification of function of the individual. When that patient sitting there in front of you is suffering with a chronic illness (sinusitis, rhinitis, headaches, eczema, or chronic irritable bowel syndrome), you suspect that, something related to the way their environment is being picked up by their receptor sites is translated into dysfunction of alarm (immunological imbalance). Therefore, you should be reviewing what in their bulk exposures, first, might be triggering factors. Then you go to the secondary factors. Then you go to the tertiary factors. But start with the big variables first. And diet is a big variable because, as I said, most of us eat three meals a day, and those bulk molecules have a relationship with modifying our function. In looking at the Mediterranean diet studies, the results disclose mechanisms of how the Mediterranean diet is involved with disease prevention, particularly in secondary prevention of cardiovascular disease. We see that these genomic/metabolomic/proteomic effects as a result of modifying dietary signaling molecules, have a significant influence on function, well before the onset of pathology. There have been many studies published in the literature involving diet intervention trials in which the concept of controlling for phytochemicals in the diet was not considered as a variable. This means we may have a huge amount of inappropriate conclusions about a diet-health connection because we did not control for a very important variable-the presence or absence of certain phytochemicals in the diet. Maybe what we assumed were results of changing the carbohydrate, fat, and protein ratios, were also modified by taking out or adding specific phytochemicals, based This is a very important issue because we often discount these factors as playing important roles in any kind of physiological outcome. But, as we have learned much more about nutrigenomics, we recognize the important role the various phytochemicals play. For instance, let’s look at the effect of different types of millet versus a control of corn starch on oxidative stress and glycemic status in a controlled animal study involving alloxan-induced diabetic rats. This study compared corn starch versus a complex starch mixture that has lots of phytochemicals. What was the outcome? I’m speaking now to a very interesting paper that appeared in Nutrition Research, in which the authors showed that by not changing the protein, carbohydrate, or fat level in the animal diet, but just changing the presence of different phytochemicals, they had a tremendous change in oxidative stress and diabetes-related risks in the animals.3 I conclude that this is because these phytochemicals were participating in signaling processes that modulated insulin sensitivity, mitochondrial oxidative phosphorylation, and the influence it has on a whole array of metabolomic influences that can result in dyslipidemias, dysglycemia, and oxidative stress. It is not just the starch carbohydrate; it’s not just the protein; it’s not just the fat. It is the presence of these other factors, some of which are not even considered essential nutrients. Let’s use another example. What about soy? Soy has been in the news heavily recently. The pendulum seems to swing back and forth very quickly with the changing in public opinion about nutrition and health. One moment, we hear fiber is very important and valuable; the next moment, we hear that fiber is bad, and then fiber comes back on the radar screen as being good. We have seen the same thing with carbohydrate: High-carbohydrate diets with Pritikin and Ornish were considered good, then they became poison, and now they are coming back into favor once again. There is a difference between the unrefined high-complex carbohydrate diet and the high-glycemic-index diet of refined sugar and white starch. These trends tend to swing back and forth as well, and we have to be very cautious not to jump on bandwagons or we will be whip-sawed around with the changing of opinion. There is some truth that we need to keep in mind related to the trajectory of clinical and experimental research in these various areas. Such is certainly the case with soy. Right now, the pendulum seems to be swinging back to soy being an unfavorable component of the diet. This flies in the face of literally thousands of epidemiological, animal and human intervention studies, as well as clinical-controlled trials that have shown the benefit of soy or its components in a whole array of physiological, functional outcomes. Beneficial soy components include whole soy in the diet, with its lignans, fibers, isoflavones and proteins, and essential fatty acids. Looking at soy isoflavone-enriched diets and markers of lipid and glucose metabolism in postmenopausal women, do we find any favorable association in Caucasian women by including soy foods on a regular basis as it relates to their serum lipids and glucose? This issue has been examined in many studies, but one that I thought was quite interesting was recently published in the American Journal of Clinical Nutrition. The authors show that the isoflavones found in soy, like genistein and daidzein, are substances that modulate function in a favorable way.4 In fact, they found that isoflavone supplementation could increase HDL cholesterol in a specific estrogen-receptor-polymorphic subgroup. Therefore, there may be women with certain types of gene patterns who have a much more enhanced benefit from a soy-based diet than others. We too often tend to regress our conclusions to the mean. We say that the “average” person would respond in the following way. Maybe what we should be doing is recognizing that the person sitting in our office for consultation responds in her own unique way, and the diet is to be modulated to her needs. In fact, with soy isoflavones and lignans it has been found that the lignans are converted by certain enteric bacteria into a secondary metabolite called equol. Equol is a hormone modulator and a very important chemopreventive substance for estrogen-modulated dysfunction. Only about 50 percent of women convert their lignans into substantial amounts of equol as a consequence of the GI metabolism from their enteric bacteria. You might want to have more women convert these soy constituents into equol because that’s a favorable outcome, and it is associated with a reduced risk to breast, endometrial, and ovarian cancer. The way you might do that is to modify the GI enteric environment by changing the bacterial flora I am introducing another complicating factor. Not only is it just the diet that the person eats and his or her unique response to it, it is also the secondary metabolism of some of these phytochemicals by these living organisms-two-and-a-half to three pounds of these several hundred species of living organisms in our gut. This makes our gut a bioreactor, resulting in the production of secondary metabolites that our body sometimes may see as toxins, and other times may find as favorable immune-activating or -stimulating substances, or cell-physiological normalizing substances. This introduces another variable. Now, you may want to try a modified diet with your patient, doing it in a step-wise fashion, getting away from a diet of white to a diet with more diversity of information in the form of phytochemical-rich foods. We need to recognize that maybe some of the benefits of these are occurring as a consequence of secondary metabolism by gut bacteria, so we have to be very cautious and conscious of gut physiology and think of the gut as a bioreactor. This is a very important thing when doing what we call the 4R Program, which is the gastrointestinal restoration program-Remove, Replace, Reinoculate, and Repair. The third “R,” which is Reinoculate, is to add back to the GI milieu the friendly bacteria, bifido bacteria and certain strains of acidophilus, with prebiotics, the selective foods like arabinogalactans and beta-glucans that are fermented by the friendly bacteria into secondary metabolites that would serve as gut fuels and, as appropriate, selective substrates upon which the friendly bacteria can grow. I’m introducing some complexity in this discussion because this nutrigenomic concept goes beyond just the specific substances you add; it is also how they get processed and the biochemical result of that processing. This also relates to things like food allergy and food hypersensitivity because it may turn out that the patient is not allergic to the food you have given him, in and of itself, but rather to a secondary metabolic compound that is formed from the food. On a skin test, you may not see a positive, but in terms of the biotransformation of that substance through the gut reactor system, it produces a reactive substance that the gut-associated-lymphoid-tissue, the immune system of the gut, picks up as a foreigner. You will notice that we are trying to layer on different levels of understanding and sophistication as to how the nutritional environment can influence function unique to individuals and their specific genes and metabolism. We learned about this in the Functional Medicine Research Center, in a clinical trial that we have recently published. This appeared in the journal Nutrition. 5 The title of this paper is “Effect of a low glycemic index diet with soy protein and phytosterols on CVD risk factors in postmenopausal women.” This was work was overseen by Dr. Daniel Lukaczer and Dr. Robert Lerman. It’s a very interesting study because it recruited a group of postmenopausal women who were not diabetic, had no cardiovascular disease, were modestly overweight (meaning elevated body mass indices), had some evidence of dyslipidemia and insulin resistance (as measured by elevated-fasting-triglycerides-to-HDL ratios). These women were randomized into two study groups: both groups were isocaloric and got the same exercise program, which was a regular walking program. They also spent the same amount of time with a professional nutritionist/dietitian, who counseled them on their dietary programs. The two programs they were randomized to were: (1) the American Heart Association (AHA) Program, which is a standard of identity for nutritional intervention studies for reducing cardiovascular disease markers; (2) a low-glycemic index diet with a soy protein based phytosterol beverage. Therefore, there were two groups with the same calories with the main differences the glycemic index of the programs and the phytochemical and micronutrient compositions. For those who still believe in The Zone, as if there is some magic number of protein, carbohydrate, and fat that will lead to optimal physiological function, it appears, from the results of this study, that these may be secondary to the signaling molecules that are present within a diet. Why am I saying that? Because after 12 weeks, the differences between these two groups were absolutely remarkable, with many variables showing statistically significant differences at the P < 0.001 to 0.005, meaning highly significant differences. Triglycerides are an example. The fasting triglyceride levels in the low-glycemic index diet group went down 57{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} over baseline versus only 12{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} over baseline in the American Heart Association diet group. The HDL levels remained constant in the AHA diet group, but were elevated in the low-glycemic index diet group, meaning the triglyceride-to-HDL ratio (a surrogate marker for metabolic syndrome) was extraordinarily improved and, as a result, the ratio of triglyceride-to-HDL went down by almost one-and-a-half points in the low-glycemic index diet group versus the American Heart Association diet group. In fact, in reviewing the literature, there seems to be no pharmacological product that one could prescribe that would produce the same benefits as seen in the low-glycemic index with phytosterol and soy beverage group that were achieved in these women. You could not use a combination of metformin with statins and ACE inhibitors to produce the same favorable outcome across all these parameters. When it is said that it is all about the ratio of protein, carbohydrate, and fat, and it is all about the number of calories alone, that is very short-sighted. There are many other signaling molecules present in a complex diet that give rise to modified function that we should be paying attention to when we are doing biochemically tailored, or individualized diet planning. Let’s move to another microingredient found in our diet that is being seen as a very important modulator of function, one that we have spoken to in previous issues of FMU. I want to bring you up to date with some more recent information on vitamin D3. There are significant barriers for optimizing vitamin D3 intake, particularly for older-age individuals. Available data on metabolic utilization of vitamin D3 indicates a total daily equivalent of about 4000 IU, or twice the current tolerable upper level in certain individuals necessary to maintain health.6 In young individuals, most of this comes from the skin. However, cutaneous vitamin D3 synthesis declines with age, creating a need for increasing oral intake to maintain optimal serum 25-hydroxyvitamin D, and that is what we should be measuring in patients to evaluate sufficiency. Now, the levels we are trying to shoot for are 50 nanograms per mL, or greater. Estimates of the population distribution of serum 25-hydroxy D3 levels coupled with available dose-response data indicate that it would require input of an additional 2600 IUs per day of oral vitamin D3. That is about 65 micrograms to give an equivalency to ensure that ninety-seven-and-a-half percent of older women have 25-hydroxy D3 values at or above desirable levels. This has been recently published in the Journal of Nutrition. 7 In this article, the author (Robert Heaney) states that the age-related decline in cutaneous input, taken together with the low published upper limit, creates a substantial barrier to the deployment of public health strategies to optimize vitamin D status. When we establish the clinical level for vitamin D3 for a patient, we should be looking clinically at two important variables. One is the calcium-phosphorus ratio in the blood (to make sure it’s not elevated), and the second is the level of 25-hydroxy D3 in the blood. If you do not see an elevated 25-hydroxy D3, and you do not see an elevated serum calcium-phosphorus ratio, then, in fact, that patient is not toxic with vitamin D. There is very high concern for vitamin D toxicity because of hypercalcemia, but we should be measuring these parameters and then titrate to the patients need using the serum calcium-phosphorus ratio and the 25-hydroxy D3 serum level to determine the sufficiency of the person and comparing it with their clinical symptomatologies. Again, the kind of things that I have often had reported to me (seen in patient’s that have come through our Functional Medicine Center) are those who have eczema or psoriasis, or hair loss of unknown origin, looking like autoimmune alopecia areata, thyroiditis, or arthritis-like symptoms. When placed on a vitamin D supplement to raise their 25-hydroxy D3 into the proper level, they have clinical remediation of many of these symptomatologies. It is quite a remarkable part of our biochemically tailored nutrition story that is starting to emerge. We recognize that even the human mammary epithelial cells express a CYP 27B1 with vitamin D metabolism, which is being investigated as a surrogate marker for risk to breast cancer.8 25-hydroxyvitamin D3, as determined by Dr. Colleen Hayes at the University of Wisconsin, is also utilized a substrate by the macrophage to produce 1,25 dihydroxy D3, which attenuates the inflammatory process activated through interferon gamma released by T-helper cells. In the immune system, and in the neuroimmune system-the glia-vitamin D plays a very important role through its 25-hydroxy metabolite in controlling immunological activation and inflammation. Vitamin D has been recently found, at least in the animal model, to help prevent colonic cancer, and there is relevance for human colon malignancy. I’m now quoting from a paper that appeared in the Journal of Nutrition, in which results show that colonic vitamin D synthesis is not only under stringent control by nutritional calcium, but also of folate, which suggests that there is epigenetic control of vitamin D hydroxylases, which then may regulate the immunological potential in the gut mucosa and in the colon.9 There is a complex interrelationship between methylation, through folate chemistry, vitamin D hydroxylation, and ultimately, the regulation of immune function. This takes us to the role that is emerging for vitamin D and autoimmune diseases, and implications for the practice from multiple sclerosis literature. I’m now back to an article in the Journal of the American Dietetic Association that reviews studies that link vitamin D with several autoimmune diseases, not only multiple sclerosis, but also SLE and maybe even rheumatoid arthritis. 10 Animal studies are suggesting a strong connection, and the limited human data are showing possible benefit from vitamin D supplementation as well. We are starting to recognize the development of an epigenetically-based medicine that is taking us beyond the genes-environment separation into this continuum, and we are going to hear about this from a different perspective-environmental-behavioral toxicology, and how small, toxic molecules in the environment can regulate function, from our Clinician/Researcher of the month, Dr. Herbert Needleman.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Herbert L. Needleman, MD School of Medicine University of Pittsburgh Western Psychiatric Institute and Clinic 3811 O’Hara Street Pittsburgh, PA 15213 JB: It’s time for our Clinician/Researcher of the Month. This month’s guest has been a seminal figure in my education and intellectual development over the last 30 or more years-Dr. Herbert Needleman, who is at the School of Medicine, University of Pittsburgh at the Western Psychiatric Institute and Clinic. Dr. Needleman is a medical doctor, and board-certified in both psychiatry and pediatrics, which gives him a very interesting perspective of the field in which he has been such a pioneer-behavioral toxicology. His contribution was first made evident by publication of a series of studies, on which he was principal author, in the early 1970’s. These studies looked at the effect of low-level lead exposure on cognition performance and intelligence in children. In the past 30-plus years, he has expanded this model to look at the effect of lead on cognitive performance in delinquents, as well as in post-menopausal, aging women and many other individuals. He has focused specifically on lead, but his work has general implications to the whole developing field of behavioral toxicology and the sometimes very vigorous debates about the effect of the environment on behavior. Dr. Needleman, we welcome you to Functional Medicine Update and thank you so much for being with us. HN: Happy to be here. JB: I’d like to go back to 1971 or thereabouts. Please tell us the fascinating story about how you got into this field and about the time you were at Harvard, when you made some extraordinary observations. Early Work with Lead Poisoning HN: Well, I was a practicing pediatrician and I made house calls. In my training at the Children’s Hospital of Philadelphia, I treated my first case of lead poisoning-a very sick little Hispanic girl-and I just followed the recipe. She got better, and I felt very exalted. I told the mother what I had been trained to say, and that is, if the little girl was re-exposed, she was essentially doomed. I told her she had to move out of that house. She asked me: Where will I move to? She said that any house she could afford would be no different from the house she now lived in. And that shocked me and smartened me up. I realized that lead poisoning and the approach to it wasn’t simply making a diagnosis and giving a drug. It had to do with how children lived. I was sensitized to the fact that there probably was more lead poisoning around than was being recognized. At Children’s in Philadelphia, the year I was a resident, we admitted 12 cases, which was much more than any other hospital in the city. But the year I was the chief resident and insisted on certain standards for drawing blood lead, we doubled the rate just by making the residents do a blood test on any kid who had a behavior change, anemia, or a stomach ache. That showed me that there was much more lead out there doing its damage, and that stayed with me when I went into psychiatry. I began to wonder about the children in north Philadelphia where I trained at Temple. How many of these kids were, in fact, behavior disordered or were doing badly in school because they were lead poisoned? My office was across the street from a public school and I’d watch these kids go to school. I wanted to go in to the first grade classroom, measure their lead burden, and then do IQ tests, but lead in the blood has a short-term half-life-28 days. So, if a child was exposed at two- or three-years of age, the blood lead might well be normal by the time they are six or seven and in the first grade. I began to think about what I could do to look back in the child’s history. Now, lead goes to the bone and most of the lead in our bodies is in our bones and it stays there a much longer time, but you can’t do bone biopsies. It occurred to me that there was a spontaneous, painless bone biopsy, if you were there to catch it, and that’s the deciduous tooth. I collected a lot of deciduous teeth from children in the Philadelphia school system. I went back to the records at Children’s Hospital and found children who had been discharged as lead poisoned and was able to get teeth from five of them. We showed that tooth lead levels in inner-city kids was 5 or 10 times what it was in suburban kids, and that 20 percent of the ostensibly undamaged, unexposed inner-city kids had blood leads higher than lead-poisoned kids. Measuring Lead Levels in Teeth The rate of severe exposure was extremely high: one child out of five had evidence of severe lead exposure. The next thing was to see if that exposure had any impact on their brain function. At that time I had gotten an invitation to Harvard and the Boston Children’s Hospital where I had the good fortune to have an office across the hall from a superb epidemiologist, Al Leviton. With his guidance, I designed a study in which we collected about 2500 deciduous teeth from about 2000 children in the Sommerville and Chelsea school systems, measured their tooth lead levels, and brought the children in the highest tenth percentile and the lowest tenth percentile of lead levels in for a clinic visit-none of whom had ever been recognized as having a problem with lead. We found that in that group of children who had high lead in their teeth had a significantly lower IQ score and poorer performance on a number of attentional measures. We followed them and, when they were 18 years old, they were doing worse than they were when we first examined them. The news was that lead exposure effects are permanent and they are expressed in life success measures, like how far you go in school. There was much higher failure to graduate, lower IQ measurements, and a decreased ability to attend to stimuli in the high-lead group. The message was that lead exposure has long-term serious consequences for child success. JB: I originally read your article in The New England Journal of Medicine in 1974. HN: The first tooth study was in 1974. The lead and IQ study was in the Journal in ’79. JB:. You had a cute way of measuring attention. Didn’t you use the game, Simon, or something like that to evaluate the children? Measuring Attention Span HN: It was very simple. I actually stole it from a very prominent psychologist at the NIH who used it to study schizophrenia and whose name escapes me at the moment. A child has a telegraph key, and they’re instructed to hold the key down, and when they hear a musical note, take their finger off as quickly as they can. That’s hooked up to electronic clocks and we measure the response latency. Then we tell them that when we say “Ready,” that means the note is coming, so get ready. By varying the time between the “Ready” signal, Ready…beep and Ready…six seconds…beep, and measuring the reaction time, we see how long they can maintain their cognitive set, which is one of the functions that describes attention. We showed very clearly that children with higher lead in their teeth had longer response latencies than children with low lead, and that was duplicated in England by Bill Ewell, in South Africa, and a couple other places. JB: From our perspective in the field of Functional Medicine, we would probably call that functional neurology. It’s really a functional stress test, a neurological stress test, in some ways. HL: Yes, it is. It’s so simple, but it’s so informative. JB: I want to compliment you. Your ability to publish your work and keep it out in front of us so that we can understand what’s going on has been superlative. Just tracing through your record of over 100 publications, it gives us a wonderful record of the whole development of this concept. It seemed to me early on that there was an attempt to trivialize some of the observations you had made because they were only seen in children of low socioeconomic background who are deprived in some way, who are perhaps eating the lead in the paint on their cribs or in their homes. The sound byte was to downplay it. Was that your experience? Environmental Health and Conflict with Vested Interests HN: Oh, yes. If you’re going to do environmental health, you’re going to get into conflict with vested interests. When I first described the tooth analysis, that got me a trip to the Netherlands to an international meeting. EPA paid my way, and there was a huge audience, most of whom were people working for the fuel companies. Any time somebody got up and said they thought that lead is dangerous, a whole crew of people would attack them. A very well-prepared group of people would challenge them. That same thing happened to me. I presented my tooth data, and I realized that this was not just a scientific meeting: this was a war. Thereafter, any time I published something, the lead additive industry and the lead paint industry would challenge my statements of association between lead and brain damage by saying, as you said, it’s really confounded by poverty, by race, and by other issues, which we controlled for in our analyses as carefully as we could. JB: As I remember, in your Boston study in The New England Journal of Medicine, there wasn’t a connection between socioeconomic status and level of lead in the dentin of the deciduous teeth. Is that correct? Umbilical Cord Blood Lead Levels HN: After we did the lead in deciduous teeth study, in which we did put socioeconomic status in the model, we did a study of lead beginning at birth, looking at umbilical cord blood leads, and following children until they were ten years of age. The strongest lead effect in that group was in the children of the middle class, and that was because of an unusual distribution. We went back and looked at that, and the children who had the highest lead levels lived in Beacon Hill and they were children of professors at Harvard, etc. They were middle class children and had the biggest effect, so that emphatically challenged the issue of social class as a confounder. JB: I would credit you and your group’s work with the impetus for this. Eventually, the mounting pressure was to remove lead from gasoline, assuming that that was going to solve this problem. What politics and communication was going on related to your papers in that period around removing lead from gas? Removing Lead from Gas HN:. When we published that paper in ’79, that was a critical time, because William Ruckelshaus, at the administrative EPA, was making a decision about banning lead in gasoline. Up until that time, they had a regulation that every gas station had to have one lead-free pump, but the next step was to-in step-wise fashion-take lead out of gasoline. And he was considering that at the time that we published that paper and it was very influential in his decision. And then, a real battle occurred over getting lead taken out of gasoline. The industry spent an enormous amount of money trying to convince people that this was a frivolous thing. I remember them saying repeatedly that nobody ever got sick from lead in the air, and that if you take it out of gasoline, nothing will happen. Well, what happened was, when lead was taken out of gasoline, beginning in the late 70’s, the blood lead levels in this country went from a mean of 15 to where they are now, below 2. Millions of children and adults have been spared nasty lead exposure because of that one step. JB: There was also some pressure brought to bear from the lead acid battery industry, as well, because they had some vested interest in the whole lead issue. HN: Oh, yes. JB: How did that manifest for you as a scientist? You were just trying to dig into the truth and find an answer about why some kids may have less performance than they’re capable of. HN: They challenged me and a couple of psychologists who were consultants to the lead industry accused me of scientific misconduct. They came to my office and I allowed them access to my data files and they submitted to the NIH a charge that I had manipulated the data, which effectively took three years out of my work life defending myself. At the end of that, there was no evidence of misconduct. The NIH ran the regressions, and the university ran the regressions based on my data and got exactly the same result. It did serve to muddy the waters for a considerable period of time. JB: For those of us who have never had the prominence of making the discovery you have, how does one handle this level of inquiry? It sounds like it’s almost one of those guilty-until-proven-innocent type situations. You get into a confounder in which the front end of negative press may never be buttressed by the truth that comes out later that you were exonerated. HN: Yes, that’s true. The answer is, you fight as much as you can, I guess. It was a very difficult time. We didn’t get a lot of work done because I was too busy writing responses to inquiries, but in the long run, it worked out. JB: Did it adversely affect your ability to get funding for your research? HN: No, I have had almost continuous support from the federal government since the 1970’s. JB: Well, that’s very encouraging. Let’s move from there to the question of international issues of lead. We often think very provincially about our own domestic problems, but it appears to be a global problem. What about the developing countries? I’m familiar with a little bit of work in Latin America. Global Issues with Lead HN: In Africa, there are still enormous amounts of lead in gasoline. What happened was when the Ethyl Corporation was barred from distributing it in this country, they exported it to some countries in Europe and to Africa. Africa has enormous amounts of lead in gasoline, in the air, and in the children. I don’t have the numbers at my fingertips-but the blood leads are very high. And that’s true in some South American countries. Venezuela makes a lot of gasoline. They export lead-free gasoline, but the gasoline for home consumption has lead in it. JB: In 1998, you authored a paper published in the American Journal of Public Health, titled “Childhood Lead Poisoning: The Promise and Abandonment of Primary Prevention.” It’s a very powerful discussion of how things get twisted in the process. Can you tell us a little bit about that? Testing for Blood Lead Levels in Young Children HN: Yes, I can. I had been the chairman of the advisory committee to the Centers for Disease Control in the 70’s, and then was a member of the committee, and then a consultant. I think it was in 1991, we recommended that every child in this country have a blood lead test at one and two years of age. Blood lead tests now cost somewhere between six and ten dollars, and that would have been a very powerful public health maneuver. In 1993, the CDC began to retreat from that. In ’94, when the election put the Congress in the hands of the Republicans, there was a great move to cut back on public health policy, and CDC knuckled under to that. I wrote a piece which described the forces that led to this retreat from universal screening, which I still think is an enormous bargain and would be an incredibly powerful pay off for our country. Instead of universal screening, they developed a very complex system for deciding where you should do blood lead tests in children. As soon as you do that, the people who need it the most fall through the screen. I wrote that and made a lot of enemies and a few friends out of it. JB: In the 1990s, I recall going to a meeting and having a kind of off-the-meeting-floor discussion with some people in the field in which they said that one of the problems of doing serial blood analysis, or looking in screening, is that it will pick up a lot of children that possibly have excess blood lead. Then, the question is, do we have enough money in the public health service to afford to give them therapy, so maybe not asking is the right approach. Did you hear anything like that? Variability of Toxic Blood Lead Levels HN: Yes, I’ve heard that at frequent intervals. When I started in the field of lead toxicology, we thought that 60 micrograms (mcg) per deciliter (dL), 60 millionths of a gram per milliliter, was the threshold for toxicity. Because of developing data over time, it went down to 25 to 20, and now it’s at 10, and there’s very good evidence that there are health effects below 10 micrograms (mcg) per deciliter (dL). There seems to be no threshold for lead effects. Because of that, the CDC and the NIH sponsored a study about the efficacy of treatment of children who had no symptoms, but who had elevated blood leads. These were children who had blood leads over 25 and under 45. They found that using the current drug Succimer, dropped the blood lead levels, but the control group, over a slightly longer period of time, came down to the same level, and there was no difference in the IQ of the control group versus the treated group. There’s no efficacy in using a pharmacologic treatment in children whose blood leads are below 45. It seems quite clear. What does that mean? Well it means that the only response to that is primary prevention, which means getting lead out of the environment and that’s a very expensive task, but the monetized payoff for that is much higher than the expenses. There was a CDC study done a few years ago, I think in 2002, which looked at the payoff to a one-year cohort of children in the United States, the 4 million children born in, I think, 1998, whose blood lead (if we hadn’t taken lead out of gasoline), would have been 15, and instead it was 2. And the payoff for that one-year cohort was between 100 and 300 billion dollars. There’s an enormous profit to be made from doing good. Now that the major source of lead for children has been found to be lead in old housing paint, we need to develop a unified strategy to attack the worst houses first, get the lead out, sequester it in safe places, and move on to the next group of houses which are not in as bad repair. That poison will stay there for as long as that house is up, and the only answer is removing it. Now, in removing it, you create jobs where they are most badly needed. So the money spent on de-leading a house would have many multiples. It would put people back to work. Our worst problems in the inner-city right now are lead paint, no jobs, and bad housing. The multiplier for doing the right thing is enormous. JB: Some of your publications have also extended this into cognitive function of older women (language processing in adults), and adjudicated delinquents, suggesting, as you indicated, that this has a trajectory that doesn’t stop in infancy or childhood. Can you tell us a little bit about what happens-you’ve alluded to it-as you grow older and you have a higher body burden of lead? Lead Body Burden in Postmenopausal Women HN: I think the effect of lead exposure on the aging is a very important issue. Susan Muldoon, who was a graduate student here at Pitt a few years ago,(we have a study of healthy aging in women in the area) looked at postmenopausal women, and compared the cognitive ability of those whose blood lead was over 8 to those who were under 4. There was a significant difference. I think what that means is that when people get older, their bones demineralize, and that huge store of lead in the bone has to go someplace. Some of it gets into the brain. Susan’s paper quite nicely showed that. Now, there’s another issue. I’ve often wondered about whether lead has any association with dementia. This lead recirculates. Some of it gets back into the brain, and how much of the disordered thinking of aging is due to that? Fetal Exposure to Lead A very clever neuroscientist at the University of Rhode Island, Nasser Zawia, gave minute amounts of lead to one-day-old mice, and their APP (amyloid precursor protein which is associated with Alzheimer’s), went up, and then came down to normal. At 21 months, which is old age for a mouse, he looked at their APP and it was up again. This may be one of the examples of fetal exposure and disease late in life, which is one of the hottest new subjects in neuroscientific research. We are pursuing the question, as to whether there is some association between early exposure to lead and later dementia. You asked me about another issue? JB: It was about language processing and the adjudicated delinquent problem. Association of Bone Lead Levels with Delinquency and Arrest Rates HN: I did a study of children in the Pittsburgh school system who were not considered lead poisoned and who were not considered delinquent. I measured their bone lead levels with a relatively new device, actually fluorescence, and then measured the association between bone lead and scores on the child behavior check list, which is a well validated inventory of behaviors. We showed, after controlling for other factors, such as race and socioeconomic status, that bone lead levels were associated with increased aggression, increased delinquency, and poor attentional function. We published that in the Journal of the American Medical Association, I think in 1992. The next step was to see if it had anything to do with arrest rates. With the cooperation of the court here in Pittsburgh (the Allegheny County Juvenile Court), we looked at 195 male youths who were adjudicated as delinquent (arrested and adjudicated) and we compared their bone leads to controls from the same high schools that were not delinquent. The bone lead levels in the delinquents were 7 times what they were in the controls. By doing a statistical procedure called logistic regression, we measured the strength of the association between lead and delinquency after adjusting for the possible confounding factors. We found that the odds ratio for delinquency, if you had high lead in your bone, was 4. In other words, you were 4 times as likely to be delinquent if you had elevated bone lead levels. If you have the odds ratio, and if you know what the exposure was when they were children, you can make an estimate of what’s called the population attributable risk: how much of the delinquency in the population is attributable to lead exposure? We did that, and for Allegheny County, the population attributable risk was between 11 and 38 percent. We estimate that between 11 and 38 percent of the delinquency in Allegheny County is attributable to lead exposure. That is a lot of children. JB: I’ve heard some discussion in which people have said that there is a very good correlation between this lead burden and these behavioral changes, however, it may be a surrogate marker rather than a causal agent, and there may be other things that are the primary causal agents. Do you have any thoughts about that? Lead Burden at Birth and Behavioral Changes in Later Life HN: First of all, we showed in our prenatal study that the blood lead level at birth was associated with IQ and attention later in life, so there is no question about which came first. And the criteria for making a causal inference are priority in time (that the cause comes before the effect), dose-response relationship (the more of the culprit you have, the more the response you have), non-spuriousness (that is, you’ve adjusted for the other factors), and that it makes biologic sense. And lead subscribes to all of those criteria. JB: One of the things that we’ve seen, obviously, is an increasing public awareness of what has been labeled attention-deficit hyperactivity disorder (ADHD). Do we see a difference in the prevalence of ADHD in lead-exposed environments versus in those that may be less lead exposed, or can you not make those correlations? Lead Exposure and ADHD HN: Right now I’m analyzing the data on a study we’ve done that examined that question. I can’t answer it yet, but there are a number of reports that lead is associated with poor attention, as I described earlier with that test of response time and parents’ reports that a child will not sit still. So, I think it’s a plausible association. We have looked at bone lead levels in, I think it’s 190 children with attention deficit disorder (clinically diagnosed), and controls. JB: We’ll stay tuned for that. That sounds like its going to be a very interesting additional part of the story. HN: Yes. JB: There’s so much, obviously, that we could talk about, but I don’t want to take too much of your time. This is just a fascinating development of something that probably, for most people, in the absence of your work, would still be considered a mystery. This is a tremendous addition to our understanding of where certain disease patterns might originate. As you’ve been in this field for the better part of more than three decades, how important do you feel the environment is in our disease patterns, and the inter-relationship between stuff out there and stuff that goes on inside the human being? Mercury, Pesticides, and Phthalides HN: There are so many xenobiotics-chemical substances that are not natural that we haven’t had a million years to adapt to. Most of them, at some dose, could produce harm. Lead is the best study, but not the only toxin we should be looking at. There is mercury, and then the many endocrine disruptors. We don’t know how smart our children could be, or how healthy our lives could be if we were separated from these unnecessary exposures. We just need to get careful data to document these things, and it’s beginning to come in. Mercury is a real risk factor. The pesticides are an important risk factor. Phthalides, which are in plastics, are endocrine disruptors. I think these are things are just coming into attention. I think it’s very informative to look at the history of lead, in that at the end of the 19th century, people believed that children were not at risk for lead toxicity; it was a disease of workers. Then it was accepted that children could become lead poisoned, but it was thought that (look at the pediatric literature in the 30’s)- if the child survives the acute episode and is separated from lead, they’re untouched by the disease. Then, in the 1940’s, it was shown that lead exposure produces long-term effects, but they were only supposed to occur in children who had obvious symptoms, such as lead encephalopathy. And then it was shown, beginning in the 70’s and conclusively now, that lead exposure in the absence of any symptoms, interferes with cognition, attention, and social adjustment. And, it’s not just my studies. There are at least 30 studies of lead in children around the world, almost all of which converge on the same thing. JB: I saw a paper-I think was in 2005-in an environmental health prospectus, which is a collaborative group of investigators from the Cincinnati Children’s Hospital and others, including yourself, looking at low-level environmental lead in children’s intellectual function in international pool analysis that certainly supports exactly what you are saying. HN: Bruce Lanphear pulled everybody together and he did a remarkable job. There are seven very good studies, and they all converge on the fact that lead effects exist down to 10, and probably below, and that most of the damage occurs even below 10. JB: In closing, I’d like to give you an opportunity, in the strength of the wisdom of experience that you’ve had, to talk to the clinicians who are listening. What message would you like them to take away from three plus decades of very diligent work? HN: My instruction to clinicians would be, I think every child in your practice should have a blood lead test at one and two years of age. If they don’t have an elevated blood lead at two, they’re going to be okay, probably. I mean, the risk goes way down. The only effective response to the national problem, or the international problem, of lead exposure is getting at it at the source. JB: Did you say above 2 micrograms per dL is considered something of concern? HN: The slope of the regression curve between 0 and 5 is steeper than it is between 5 and 10, so it looks like the lower the blood lead you can get, the better off you are. I don’t know if there is any nontoxic level. JB: On behalf of all of our listeners, and on behalf of myself, personally, over the 30 plus years I’ve had the pleasure of reading your work and listening to you a couple of times at different conferences, I want to thank you. Sometimes, it’s a lonely world when you come up with something new that’s not agreed upon by everybody, and it takes a very special person to stay on task, fight those battles, and come out on the other side. You certainly fought a very important battle for the health of millions of children and we want to thank you. HN: Thank you. I’ve enjoyed very much talking with you. JB: Likewise. The best to you. Final Thoughts It’s probably unfair of me to add anything to the brilliant thoughts and comments of Dr. Needleman, but I feel obliged to say a couple of things because he is so self-effacing and understated. His work has been unbelievably important for all of us, not only specific to the lead issue, but to raise the question of behavioral toxicology to a higher level of science and inquiry, and at the highest levels of epidemiology, behavioral science, toxicology, immune function, and neurology. This has crossed-disciplines and is truly what we would embody as a functional medicine concept because he’s really discussing neurological function as it relates to these low levels, well before neurotoxicity. The functional medicine concept is trying to define the space in-between optimal physiological function and pathophysiology. In that intervening gap, there is a tremendous range of differing functional abilities of the organism. In the case of the nervous system in children, which is a very sensitive biomarker group for toxicity, we can start demonstrating using these extraordinarily interesting neurological stress tests that Dr. Needleman has employed in his studies. We can look at the functional changes in the neurological system that make our understanding of the impact of the environment on our function much more scientifically understandable and definable than waiting for the endpoint of neuropathology. Most of the conditions of concern that we were describing-IQ, learning, language processing, behavior, delinquency, and attention disorder-are not pathologies as much as they are functional changes in the organism. And yet, in medicine, we are still in search of the Holy Grail of the diagnosis as if, through it, we will understand its treatment, when the functional changes that precede diagnosis are the places where we can most likely intervene at lower technology, lower expense, and lower risk, with higher outcome in performance. Dr. Needleman’s work symbolically identifies the juxtaposition between the pathophysiologically based medicine that most of us learn, the medical taxonomy of learning by memorization, and lists of histopathological identification of specific named diseases. What people really walk around the world with is compromised function as a consequence of an imbalance between cellular capabilities and environmental exposures. And this gene-environment interaction gives rise to these functional decriments that precede the onset of pathophysiology and demonstrate, in a society, whether it’s healthy or sick. I read articles about ten years ago, discussing that one of the reasons the USSR fell apart as a country was because the workplace environment was so polluted, and such high levels of body burden were placed on young men and women, that absenteeism, work productivity, and illness (particularly respiratory illnesses) became so frequent that their overall productivity was compromised to the point that they could no longer manufacture and produce enough for the large size of the country. As a consequence, they could not even mount an effective military because so many young men had health problems that were not allowing them to pass muster as candidates for the military. These are not pathophysiological effects; they are subtle effects that undermine the patency, or capability, of a society, and are seen as the outliers and yellow canaries of health effects. And then we wait in the wings of medicine, with our remedies, trying to treat those conditions at the endstage, knowing that, at best, we may be marginally successful. Dr. Needleman expressed it very well when he was talking about what kind of therapy would be used in individuals with excess lead body burden. He pointed out that in studies that had been done with intervention on marginally lead-impaired individuals that intervention with chelating agents did not result in significant improvement. You have to catch it earlier. Prevention, primary prevention, was better than trying to catch it after the fact. This work of Dr. Needleman’s is paramount. It is significant. It is like the work that we saw with Kilmer McCully with homocysteine. It is revolutionizing our view of the interaction between our environment and our function, ultimately giving rise to what we see as a decreased health pattern with increasing healthcare expenditures. It is why we need a functional medicine. Thanks so much. I look forward to being with you next month.  

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Bibliography

1 Trujillo, E, Davis C, Milner J. Nutrigenomics, proteomics, metabolomics, and the practice of dietetics. J Am Diet Assn. 2006;106(3):403-413. 2 Serra-Majem L, Roman B, Estruch R. Scientific evidence of interventions using the Mediterranean diet: a systematic review. Nutr Rev. 2006;64(2):S27-S47. 3 Hegde P, Rajasekaran N, Chandra T. Effects of the antioxidant properties of millet species on oxidative stress and glycemic status in alloxan-induced rats. Nutr Res. 2005;25:1109-1120. 4 Hall W, Vafeiadou K, Hallund J, et al. Soy-isoflavone-enriched foods and markers of lipid and glucose metabolism in postmenopausal women: interactions with genotype and equol production.Am J Clin Nutr. 2006;83:592-600 5 Lukaczer D, Liska DJ, Lerman RH, et al. Effect of a low glycemic index diet with soy protein and phytosterols on CVD risk factors in postmenopausal women. Nutrition. 2006;22:104-113. 6 Vieth R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. Am Soc Nutr. 2006:1117-1122. 7 Heaney R. Barriers to optimizing vitamin D3 intake for the elderly. Am Soc Nutr. 2006:1123-1125. 8 Kemmis C, Salvador S, Smith K, et al. Human mammary epithelial cells express CYP27B1 and are growth inhibited by 25-hydroxyvitamin D-3, the major circulating form of vitamin D-3. Am Soc Nutr. 2006:887-892. 9 Cross H, Lipkin M, Kállay E. Nutrients regulate the colonic vitamin D system in mice: relevance for human colon malignancy. Am Soc Nutr. 2006: 561-564. 10 Mark B, Carson J. Vitamin D and autoimmune disease-implications for practice from the multiple sclerosis literature. J Am Diet Assn. 2006;106:418-424.

Welcome to the July issue of Functional Medicine Update. Thank you for being with us. I think this will be an epic issue, focused on a topic that is long overdue: healing environments. Over the last 25 years of Functional Medicine Update, we have talked about topics related to therapy, intervention, diagnosis, and assessment, and also how one looks, early on, at altering function. But we have never focused a whole issue on the nature of the healing environment: the context surrounding patients and their conditions, and how this ultimately relates to the ability to recover, repair, and restore function. This month, we are privileged to have Dr. Wayne Jonas as our clinician/researcher of the month who, as many of you know, is a very important member of our community. He is the former director of the National Institutes of Health Center on Complementary and Alternative Medicine, and now is the director of the Samueli Institute of Information Biology. You will hear more from Dr. Jonas later in this issue about the work they are doing on establishing the context of the optimal healing environment. Before we get to his eloquent discussion, I thought it might be useful to set the tone and provide an overview of this topic. The concept of the optimal healing environment is so timely; it is an important part of the algorithm that is incorporated within the context of functional medicine and the functional medicine matrix. Functional medicine attempts to understand the interactions of the complex processes that connect the individual to the environment. This gene interaction and epigenetic connection to function is what ultimately gives rise to health and disease patterns. The trajectory of living arrives at an outcome called our health or our disease. Understanding these interactions ultimately supports our ability to use the functional medicine model effectively in clinical practice. The concept that underlies functional medicine is the assessment of antecedents, triggers, mediators, signs, and symptoms; this concept contrasts with the sine qua non of traditional medicine, which is a differential diagnosis. Rather than just provide a description (in the way of a diagnosis for the outcome), functional medicine attempts to understand processes that underlie dysfunction. The Environment of the 21st Century What is the environment into which we are interjecting this model? The environment is one that is fraught with conflicts about what we say compared to what we do. This cognitive dissonance can set up challenges in the exam room with a patient because what a patient may believe and what he or she is doing can translate into dysfunction that ultimately may lead to disease. A part of what we would define as an optimal healing environment is helping to make the perspective of what a patient believes the same-or as close to the same-as what he or she does. Hopefully, as functional medicine providers, we can guide the patient into a functional congruence between the beliefs he or she has and what he or she is actually doing. The Traditional Office Visit Let’s do a quick review of the domain that defines the way patients are traditionally treated today. The patient arrives with signs and symptoms that are evaluated, often using a SOAP (Subjective, Objective, Analysis, Plan) process. Ultimately, through some kind of diagnostic criteria or classification, a diagnosis is generated with an ICD descriptor code. This sets in motion a specific therapy designed for that specific diagnosis. Although the patient may present with multiple signs and symptoms that cut across many diagnoses, they are codified into very specific, independent classifications that we call disease classifications. Different disease codes and classifications are ‘owned’ by different medical specialties. The presentation of a patient with symptoms that reflect multiple symptomatologies across multiple organ systems (therefore transgressing across multiple subspecialties of medical areas of expertise) begs the question: Who is the shop boss who will oversees the whole organism rather than just the individual management of piece parts, as if each of the diagnoses were independent each other? Without this coordination, the patient may end up with appropriate medical therapy for each of their diagnoses by different practitioners, each treating him or her independently, ultimately arriving at polyintervention. None of these therapies is evaluated with respect to how they interact with each other, or how the multiple signs and symptoms with which the patient presented may point toward a common theme in a mechanistic (or functional) disability. Pharmacotherapy The treatments generally employed (for both efficiency and presumed effectiveness) are pharmacotherapy and surgery. Pharmacotherapy is a convenient way of introducing therapy because of its speed. Once the diagnosis has been made, a simple annotation on a prescription pad can lead the patient out of the exam room, out of the office, and into remedial care. The prescription becomes a psychological and socially acceptable way of terminating the relationship patients in the exam room, allowing them to move on with their life, presumably with a more positive outcome. The prescription pad provides a mechanism for high-throughput efficiency (the six-minute office visit; the turnover of tens of patients in a day). In six minutes, the trained and skilled provider can ask a few salient questions, check vital signs, review some laboratory analysis, come to a conclusion as to what the most appropriate diagnosis is, write the prescription; and the patient can be on his or her way. When medicine is structured with an assembly line-type of efficiency, it is more cost effective. Over the last ten years, various scholars have written about the difficulties with this approach. The concept of differential diagnosis leading to independent disease diagnoses-separated one from the other-is a fallacious concept. Patients generally do not present with one independent, isolated disease. They have multiple signs and symptoms that relate to different levels of dysfunction. There may be an Occam’s Razor-a connector-that relates their apparently different dysfunctions through a root mechanism. It is this construct that frames the foundation of functional medicine: looking at the underlying mechanism(s) that connect genes and environment together in a patient to result in either function or dysfunction, either health or disease. The pharmacotherapy generally employed today is a recipe designed to manage independent symptoms. If a patient has a specific type of dysfunction-for example, hypertension-there is a family of medications that work by different mechanisms to produce the desired effect, which is to lower blood pressure. You could consider using a diuretic; you could consider using a beta-blocker; you could consider using an angiotensin receptor inhibitor or an angiotensin receptor blocker. You could use a number of different types of calcium channel blockers. For the management of the endpoint called high blood pressure, all of these prescription options would be at the disposal of the practitioner. These medications-these new-to-nature molecules-will have different impacts in different individuals; the functional change within a person’s vasculature may be dramatically different from one patient to the next, requiring a very different intervention for the improvement of function. The drugs may be treating the signs and the endpoint of the symptoms downstream rather than managing a mechanism (or ultimate cause) of a condition that was initiated upstream. This leads into some very interesting difficulties relative to the safety and effectiveness of pharmacotherapy. The actual functional disability of the patient is not understood, but an empirical approach based upon a presumed mechanism for managing his or her problem is employed. The interesting part of this empirical approach to pharmacotherapy is that it can result in unexpected adverse effects. Potential Adverse Effects of Pharmacotherapy Practitioners who are experts in pharmacotherapy understand early-stage adverse effects and monitor their patients closely for signs. They modulate the patient’s dose and their scheduling of administration, and even the class of drugs that are being used to try to avoid adverse effects. Even so, practitioners do not know on the front-end how a patient will respond to a particular drug; they can only look at the back-end and how the patient responded post hoc. Often, we are told that this form of medicine-this pharmacotherapy-is based on scientific principles, and people who use it are doing scientific medicine. If you really listened to what I just said, though, about an empirical approach toward the application of pharmacotherapy, it is ironic, because we are doing a kind of medi-science (or proto-science). It is not predictive in its nature; it is post hoc (evaluative on the outcome side). We have presumed mechanisms, but we do not know if the mechanism of a particular drug applies to an individual patient. After the drug is applied to the patient, we try to monitor and manage any potential less-than-desirable outcome, which can be either ineffectiveness or adverse drug reactions. Chronic pain from inflammation is a specific example of a need for pharmacotherapy. There are many drugs that can be applied to this particular concern. You can look at the nonsteroidal anti-inflammatory drugs (NSAIDs). You can look at agents that are steroidal in nature. You can look at the new class of selective cyclooxygenase-2 type of inhibitor drugs like the celecoxibs. Each one of these drugs works by a different mechanism, has a different pharmacodynamics and pharmacokinetics, and influences the inflammatory process indifferent ways. Yet, they are often all viewed in a similar vein, and administered to a patient on the basis of some body- surface-area argument or body-size argument, as if the metabolism of different patients is going to be similar, and the mode of action of the drug is going to be similar. After marketing, a clinical trial on rofecoxib (Vioxx) showed that after 18 months of treatment, some individuals have unexpected serious adverse outcomes from the drug, which included cerebral vascular accident or a cardiovascular accident leading to death. How could this happen with a medication that had gone through rigorous front-end testing and had been proven scientifically valuable, in addition to being validated by the Food and Drug Administration (FDA) and approved for insurance reimbursement for the management of pain? It can happen because the patient’s uniqueness is not understood when that particular drug is administered. For drugs that are used chronically-possibly for many years-the adverse effects may not be fully seen until after many months or more of post-marketing experience, when the full effects on physiological function get to a point of dramatic enough intensity (or severity) that they can be recognized. Sudden cardiac death is a pretty dramatic outcome, and there may be many other subtle functional changes that occur well before that that are not easily picked up as post-market drug surveillance data. Ultimately, it requires (as in the case of rofecoxib) 18 or more months before these outcomes become assembled in a large enough data set that the company voluntarily removes the product from the market. Pharmacotherapy and Chronic Disease When pharmacotherapy is applied to the management of chronic disease, there are a number of potential challenges that should be considered. The management of chronic disease entails the application of pharmacotherapies for extended periods of time, but medications are only being studied for a fairly short period of time in clinical trials prior to approval by the FDA. The first group of study subjects to understand how a newly-approved drug of that type works long-term in the management of chronic disease is the first group of patients who take it for a long period of time. This understanding is not going to come out of the clinical trial because clinical trials don’t go on for years with a large and diverse patient population. Pre-market clinical trials generally don’t go on for 3, 5, or 10 years. As more and more products to manage chronic illness (the dominant form of healthcare challenge that we have today, constituting 78 percent of healthcare expenditures) come onto the market, we start asking questions. Eventually, we can examine stratified data sets and look at unique genotypes in individuals and how these different risk factors exist in different people. We may become wiser downstream, but only after individuals may have been injured on the front end due to the lack of understanding. The pronounced inhibition of cyclooxygenase-2 (COX-2) seen with the COX-2-specific inhibitors can have effects on blood pressure, reduction of heart rate, increased vascular endothelial injury, and increased platelet adhesiveness causing thrombi formation. These effects can differ from person to person. This has been well documented in the literature, including in a recent paper in the journal Arthritis & Rheumatism that talked about the differences among the different classes of these drugs and how they interact with the vasculature in different ways in different people.1 It is much more complex than we may have been led to believe by the simple statement that these are new, specific drugs selected for COX-2 isozyme that have a significant advantage over the nonspecific NSAIDs. Multiple Medications What happens if you use multiple medications, all taken at the same time? I am often asked about why I talk about areas in Functional Medicine Update that have not been totally subjected to double-blind, randomized, placebo-controlled trials (like diet and lifestyle intervention), and suggest that these things should be used in clinical practice, even in the absence of large clinical intervention trials. My response to this question comes out of the type of thinking that was described in a recent paper in Nature Genetics, which talks about a recipe for looking at drug interaction networks.2 It is hard just to prove how one drug works at a time in a patient over a long period of administration in terms of efficacy and safety, and when you start looking at two drugs at a time, three drugs at a time, or more, the problem becomes exponentially more challenging. In fact, there are very few (if any) combinations of medications that have been studied in randomized, clinically controlled trials. Therefore, my response to people who ask me the question about discussing, in Functional Medicine Update, things that have not been subjected to randomized, clinical controlled trials, is a query: Do you, as a physician, ever prescribe more than one drug at a time to a patient? If you do, you are not doing science; you are not using randomized, clinically controlled, placebo-crossover trial data to understand how those multiple medications work in that patient over time. You are using suggestive evidence, along with your belief that it is going to be successful based upon commentaries or editorials. That is not true science; that is proto-science. The point I am trying to make is that clinical decisions about how to manage patients are often made from imperfect data. I’m not casting aspersions at the use of polypharmacy in the absence of randomized, double-blind, placebo-controlled trials because I understand the complexity and challenge. What I am trying to point out is that medicine derives its origin from clinical decision-making using the best information that we can find for management of the complex problems that patients present with. One of the differences, however, in our discussions in Functional Medicine Update is that often the molecules we suggest are those derived from nature. These often have a long history of safe use and have arrived, through natural selection and evolution, as having some biological compatibility with our function. This is in contrast to the new-to-nature molecules that may have only been on the scene since bench chemists synthesized them within the last 30 or so years; we don’t have that same kind of history with these molecules and how they incorporate into our physiology. I want to make sure we are all operating from the same theme when we are talking about a healing environment. As we use new-to-nature molecules and pharmacological therapy that is not individualized or personalized, and on the back-end we examine adverse signs and symptoms, we are not always setting up a healing environment. We have not yet talked about the context of the administration of medication. If medication isn’t administered-as we’ll learn from Dr. Jonas later-in an environment that is actually conducive to healing, the efficacy of the medication may be limited just by the nature of the belief of efficacy. We get into a whole interesting conundrum here relative to how to establish, within a functional medicine context, the healing environment. Adverse Drug Effects: Gatifloxacin and Glycemic Control I have talked a lot about medications, but let me say something about adverse drug reactions (ADRs) because these are becoming even more concerning. The medical community and the public have seen a steady stream of reports linking the use of widely prescribed medications to serious health risks. An article appeared in the Journal of the American Medical Association in the 90’s that talked about over 1 million adverse responses in hospitals and 100,000-plus deaths due to adverse drug reaction to the appropriate drug, administered by trained health professionals in the hospital under proper monitoring.3 That was a wake-up call, and many people started to look more intensively at the risk-benefit relationship of some of these medications. I found a recent article in The New England Journal of Medicine that presents one such story. This article, authored by Jerry H. Gurwitz, MD, was titled, ‘Serious adverse drug effects: seeing the trees through the forest.’4 The author discussed a paper in the same issue of The New England Journal of Medicine about an antibiotic-gatifloxacin. This was Park-Wyllie’s work, titled ‘Outpatient gatifloxacin therapy and dysglycemia in older adults.’5 This paper was very interesting because this drug has been on the market for six years and is used commonly as a third-generation antibiotic. In studying the drug over several years, adverse effects on glycemic control that included severe hypoglycemia in some patients and hyperglycemia in others were found. This is a 180-degree different response in different patients to the same molecule. Once again, this indicates that an extraordinarily different response can occur in different individuals, leading to very different types of patient outcome. In this case, both outcomes can be potentially life-threatening. The analysis of risk of hypoglycemia in the patients associated with the use of gatifloxacin was higher than similar molecules within its class, so there is something very interesting about this particular molecule. The relative risk of hyperglycemia (as contrasted to hypo) was 16 times as high (compared against other macrolide antibiotics). Use of gatifloxacin is now linked to both an increased risk to hypoglycemia in some patients (leading to emergency room medicine), and hyperglycemia in others (leading, again, to emergency room medicine). According to Gurwitz, gatifloxacin was first marketed in 1999, and reports of dysglycemic effects appeared soon after the drug was approved. Health Canada, the Canadian FDA, published a report about the drug that was very critical in 2003. Gurwitz poses the question: is six years too long to wait for a high-quality, controlled, epidemiological study quantifying such important drug related risks? In other words, how long does it take before we start to understand these potentially adverse side effects that occur from these new molecules? The author says that gatifloxacin now takes its place among an ever-growing list of medications that have been associated with very serious adverse effects. The Changing Face of Teenage Drug Abuse If you couple this example together with another interesting and important trend-the changing face of teenage drug abuse-it raises a bigger question about what our medical world is becoming. There is a trend (as you may be aware) in teenage drug abuse, toward the use of prescription drugs. One of the most commonly prescribed drugs in America is hydrocodone-acetaminophen (trade name: Vicodin). Where does some end up being used? Some is being used illicitly, particularly in teenage drug abuse situations. For some teenagers, street drugs have been replaced by prescription drugs, and it is a very interesting trend. The number of high school students who are abusing prescription pain relievers, such as hydrocodone or oxycodone, is on the rise as we see a decline in some of the traditional street drugs. A total of 7.2 percent of high school seniors reported non-medical uses of sedatives in 2005, up from 2.8 percent in 1992. The similar reported use of oxycodone in this group increased from 4 percent in 2002 to 5.5 percent just three years later in 2005. These findings are reported in The New England Journal of Medicine in an article by Dr. Richard Friedman titled, ‘The changing face of teenage drug abuse-the trend toward prescription drugs.’6 This is a dramatic trend. Why is this happening? It is happening because some teenagers see prescription drugs as being safer than illicit street drugs, but yet the prescription drugs produce the desired pharmacological effect: to medicate them to be able to manage their lives. This is in a culture where our watchword, a few years ago, was ‘just say no.’ It seems paradoxical that the medications that have been used to manage disease are now starting to be used for the management of chronic complaints of maladjustment to living. In the article by Friedman, some teenagers who were abusing prescription drugs were interviewed. One of them wrote, in an email message, ‘We’re living in a time that seems decidedly more apocalyptic. Maybe we need something to slow us down.’ He or she is apparently referring to medications that will make life more manageable. These are dangerous trends that speak against the whole concept of functionality and a healing environment. The Perception that Prescription Drugs Are Safe We know that kids can get prescription drugs from parents, friends, or even on the internet. A 2004 survey of physicians (also mentioned in Dr. Friedman’s article) found that 43 percent of physicians did not ask about prescription drug abuse when taking a patient history, and one-third of these physicians did not regularly call or obtain records from patients’ previous physicians before prescribing potentially addictive drugs. Even those medications that we might consider to be some of the more dangerous drugs are now becoming available to our youth as ways of managing life. This is driven, to some extent, by the facetious belief that these medications are safe because of direct-to-consumer advertising. Dollars spent on direct-to-consumer drug advertising rose from 1.8 billion dollars in 1999 to 4.2 billion dollars just five years later, in 2004. The author of The New England Journal of Medicine article says, and I quote, ‘physicians play an important role in this problem, given their apparent laxness in prescribing controlled drugs. Physicians should routinely assess their patients for substance abuse and psychiatric illness before they put pen on a prescription pad’ The perception that prescription drugs are largely safe seems to justify, in the minds of our teenagers, the attitude that occasional use poses little risk.’ These are very dramatic trends that are painting a picture of relative risk. Black-box Warning on ADHD Drugs If we look at the drugs used to treat attention deficit hyperactivity disorder (ADHD), it is a very interesting constellation. On February 9, 2006, the Drug Safety and Risk Management Advisory Committee of the FDA voted, by a narrow margin (8 votes to 7), to recommend a black-box warning description (for cardiovascular risk) be placed on stimulant drugs used to treat ADHD.7 This decision came more than a decade and a half after these drugs were first prescribed for our youth. The drugs under review were primarily amphetamines (Adderall and other brands) and methylphenidate. (Ritalin, Concerta, and other brands). These drugs are broadly classified as sympathomimetic amines and have very active effects, not only on the central nervous system, but also the cardiovascular system. They substantially increase heart rate and blood pressure, and in placebo-controlled trials (when administered to adults) they increase systolic blood pressure by 5 mmHg. Similar effects were found across all the drugs in these families. The FDA advisory committee heard testimony indicating that 2.5 million children now take these stimulant drugs for ADHD, including nearly 10 percent (or 1 out of every 10) of ten-year-old boys in the United States. Did you hear what I just said? One out of every ten 10-year-old boys in the United States is on a stimulant drug for the management of ADHD. Do you remember the quote from the eighteen-year-old mentioned above? ‘We’re living in a time that seems decidedly more apocalyptic. Maybe we need something to slow down.’ These drugs for ADHD are the opposite of ‘slow down;’ these are ‘speed up’ drugs. The Connection between ADHD, Insulin Resistance, Hyperinsulinemia, and Obesity What are the alternatives? What is the functional medicine approach? What would lead to a healing environment for these concerns? Those are big questions. There is a strong connection between the mechanism associated with ADHD and obesity, metabolic syndrome, and insulin resistance. In a recent paper in Medical Hypotheses, the authors talked about the model for revealing mechanistic overlap among cognitive metabolic and inflammatory disorders that connect ADHD to insulin resistance, hyperinsulinemia, and obesity.8 These are not unconnected problems; the central nervous system (CNS) is connected to the liver, which is connected to the pancreas, which is connected to the adipocyte, which is connected to the muscle, which is connected to the gut signaling process. We have fed disinformation to our children and put them in a very complex environment, thereby creating less optimal network signaling and producing dysfunction for which the empirical clinical intervention is to use sympathomimetic stimulant drugs to manage what appears to be a hyperactivity disorder. When one considers it from a rational perspective, it appears crazy, as well as antithetical to the context of a healing environment. Years ago, we learned, from the work of investigators at the University of Colorado School of Pediatrics, that low-quality diets in children can alter brain chemical function, change learning abilities and the ability to thrive, and alter immune function. Zinc is one of the many nutrients implicated in this effect. We know that zinc is an important nutrient for cognitive performance, immune function, muscular development, and growth and development in children. Zinc is obtained in the diet; it is not fortified, like iron. Snack or convenience foods (highly processed, shelf-stable foods) generally contain low amounts of zinc. Furthermore, low serum zinc levels have been linked to major depression, and zinc treatment has been shown to have an anti-depressive effect. Therefore, it is possible that we should be looking at trace minerals like zinc in situations involving neurocognitive performance problems. The concept of zinc as a nutrient important for mood is discussed in a review paper that recently appeared in Nutrition Reviews.9 Zinc is found in high-quality, muscle-made foods and whole grains (such as organically grown). Zinc is also very important for taste and olfaction. People with a poor sense of taste (often the case with children who have poor-quality diets), may have impaired discrimination for sweetness and saltiness, and require high stimulation with salty and sweet foods in order to get the same level of sensation as a person who is not impaired. We often use the zinc tally test to measure this. Some of you may be familiar with this. A dilute oral zinc sulfate solution is put on the tongue, and if a person has a very bitter feeling from that-an astringent effect-then they are presumed to have high zinc status. If, however, they can’t taste the zinc sulfate solution (even if quite a bit of the liquid is administered), this is presumptive evidence for zinc insufficiency. Supplementation with zinc to help restore their taste and olfaction may be desirable. This is seen not only in children, but also in older-age individuals. Mercury is an environmental substance that can modify neurocognitive performance. Last month on Functional Medicine Update, we were privileged to have Dr. Herbert Needleman tell us about the pioneering work he has been doing with lead and intelligence quotient in children over the past 30 years. Mercury is a problematic neurotoxicant. Recently, in the Journal of the American Medical Association, there were two papers published on neuropsychological and renal effects of dental amalgam in children.10,11 The first of these papers was principally authored by Dr. David Bellinger, who was a presenter at the 13thInternational Symposium on Functional Medicine (on biotransformation and detoxification) in Tampa. The same week Dr. Bellinger presented at the Tampa Symposium, the article he authored appeared in the Journal of the American Medical Association, and it was very fortuitous for the attendees to have the principal author of this work there to discuss the implications. He pointed out that although statistically the studies did not indicate that amalgams had any adverse effect on neuropsychological performance in children, there were children within the study group that seemed to have adverse effects. Therefore, one might ask: Are there some genotypes that are more at risk than others? This gets into the bigger issue of how we look at averages; sometimes we wash out any specificity for individuals who have unique genotypes and susceptibility factors. In Bellinger’s study, an increased urinary output of mercury was seen in the children who had dental amalgams. If you believe that mercury is not really a desirable element to have in the body, then the appearance of mercury in the urine at least suggests that there is some kind of a release into body fluids and tissues, and this could potentially have adverse effects in some children. Certainly this is the same type of battle that Dr. Needleman has been fighting with the lead question over many years. These are difficult issues to resolve and relate to how to establish a personalized, optimal healing environment for an individual. Before the development of insulin, (at least from 1914 to 1922) diabetes was managed with diet. There were extraordinarily effective diets for the management of diabetes that were reminiscent of what we are relearning today: low-glycemic-load diets that were low in sugar, high in unrefined carbohydrate (such as fiber), modest lean-animal protein, and essential fatty acids. Many different dietary variables had been used during this period, well before insulin was developed. What is interesting is that the drug eventually made it so seemingly easy to manage diabetes that people no longer had to worry about their diet or lifestyle. Now, however, we are recognizing that type 2 diabetes (the predominant form of diabetes in our culture), is associated with an altered lifestyle gene-environment interaction, and is probably best managed not by drugs, such as metformin or peroxisome proliferator activated receptor (PPAR) agonists, but rather by diet and lifestyle intervention. We are going back to the future, learning about what worked for many people prior to the development of medications. For those of you who are interested in reading about the history of the dietary treatment of diabetes in the pre-insulin era, you might want to look at the winter 2006 issue ofPerspectives in Biology and Medicine.12 The context has been set for the question: what is a healing environment? Is there something about the relationship between the provider and the patient-and the patient’s condition-that can lead to differing types of outcomes? With these questions t in mind, we are fortunate to have the most interesting person to bring this topic to our perspective and help guide us in integrating it more effectively within our functional medicine model-Dr. Wayne Jonas.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Wayne Jonas, MD Director, Samueli Institute for Information Biology 1700 Diagonal Road, Suite 400 Alexandria, VA 22314 (703) 299-4800 www.siib.org JB: Once again we are at that place in Functional Medicine Update that we all look forward to-our clinician or researcher of the month. This month’s discussion has been 20 years in the making. Dr. Wayne Jonas and I have known one another for more than 20 years. I have watched, with great admiration and respect, what Wayne has done in the field that we have shared over the past two decades. It has been quite remarkable. Many of you are familiar with Dr. Wayne Jonas because he has made a tremendous contribution and is one of the leaders in our field. Dr. Jonas is a medical doctor who, after training at Wake Forest University School of Medicine, went into service in the Army and had a family medicine internship at Dewitt Hospital in Fort Belvoir in Virginia. Through many different theaters of activity and places to gain greater skill and experience, his seeking mind and his background (both in humanities and biomedicine), brought him to a position in which he was looking at ways to improve the efficacy and safety of therapies. He opened his mind to things that work across wide ranges. He expanded his universe for thinking and a lot of other peoples’ universes for thinking in the process. Eventually, he became the director of the office of the Alternative Medicine/National Center for Complementary and Alternative Medicine. The center had an annual research budget of 50 million dollars and, during the time he was there, established 13 major research centers around the country, supported over 50 other research projects and four multi-center clinical trials, and started to codify the nature of research methods applied to complementary and alternative medicine. Dr Jonas asked the ‘get real’ questions about what works and what doesn’t and how we can define what works and what doesn’t. From there, Dr. Jonas went into the Uniformed Services University of Health Sciences in Bethesda as an Associate Professor and Brigade Surgeon. A major transition occurred in his career in 2001, which has had a very strong, positive impact on our field. Dr. Jonas helped found the Samueli Institute for Information Biology in Alexandria, Virginia and Corona del Mar, California, and now serves as its director. Over the past five years, Wayne has brought this Institute to a place of international prominence, and we are going to hear much more about it. Wayne, I want to welcome you to Functional Medicine Update and thank you for being available for us today. It is a real pleasure to finally have you as one of our clinicians after two decades. WJ: Thank you, Jeff. It’s an honor to be on Functional Medicine Update. You know, the first tapes that came out when you started doing this many, many years ago had a profound influence on me as a resident, because I was looking for ways to connect my training in biochemistry in medical school with actual practical application and nutrition. When I came across some of your educational tapes and seminars, I thought, ‘Here is somebody who is finally doing it.’ I’ve really enjoyed learning from you and being inspired by you over the years, so it’s a great pleasure to be on FMU now. JB: Thank you. It’s a mutual admiration society that I share with you and what you have helped me to understand. Let’s talk a little bit about the Samueli Institute. Many of our listeners are probably well aware of it, but it might be useful (in that this goes out to people around the world) for you to tell us a little about the Institute and its origin. The Samueli Institute WJ: The Samueli Institute was started in 2001. It was founded by a couple out in California by the name of Susan and Henry Samueli. Henry Samueli was a UCLA engineer who invented some very useful electronic information that allowed broadband communication. He started a company right at the age of broadband communication, and it is now one of the leading companies in that area. Susan is a trained mathematician. She practiced the use of a variety of natural medicines, first for her family and friends, and then her community. She looked at homeopathy and herbal medicine and these types of things. They were both interested in science and they were interested in healing and complementary and alternative medicine’s role in facilitating healing. In 2001, we got together and discussed what was needed in the field. We decided a nonprofit independent organization was needed that could ask fundamental questions and then develop partnerships with groups and individuals to help answer those questions about how to move medicine forward in the direction of healing approaches. And so the Samueli Institute was founded as a nonprofit research institute in 2001. We are now coming up on our five-year anniversary, and the goal of the Institute is really to transform medicine through science. Our research is especially focused on learning how to better apply the science of healing: how do we recover, how do we repair, how do we restore? We focus on that, and then look at the relationship between that and disease treatment and how they can best be integrated. JB: I have followed the work you have been doing at the Institute very closely with regard to the definition and codification of the optimal healing environment. I think this is such a tremendous concept because no matter what a person’s background is in the health sciences, I believe their objective would be to try to assist in the development of an optimal healing environment for a patient. Whether it be a surgeon, an oncologist, a natural medicine specialist, or a body work practitioner or psychologist, all of these people would be trying to define an optimal healing environment. Your group has done the best job of any I’ve seen in codifying what that kind of environment might look like. Can you take us through its evolution and what you’ve learned? I think it’s transferable, in principle, to many of our listeners. The Healing Environment: A Concept in Evolution WJ: Yes, I’ll be happy to talk a little bit about where we are, and let me just say that this is a concept in evolution. By no means have we come up with definitive definitions or measurements or understanding about the components that go into an optimal healing environment, but the goal of our optimal healing environments program is to try to look at the processes of healing and the components that support and stimulate healing processes from a scientific point of view, so that we can begin to develop a science that allows us to maximize those components in any environment. I think the thing that originally inspired us in this area was my exposure to healing practices in different places in the world. I was stationed in Germany, for example. I lived in Asia for a number of years. It dawned on me that there were a variety of healing approaches that were quite diverse, both in their assumptions and in their practices, and yet most of them claim that they were getting good effects, especially in the management of chronic disease and mind/body areas (pain, and that type of thing). If you look back through the history of medicine, even in the west, there are two main philosophical thrusts that have paralleled each other in medicine. One is the idea that if you facilitate healing processes that are innate, this brings about recovery and is a useful approach to the treatment of illness, suffering, and disease. The other is what I call the disease-specific approach, in which you try to identify an isolated cause for a disease and then you interfere with, or somehow break, that causal chain. Both of these concepts, obviously, are very useful at different times, and in recent times (meaning the last 100 years), with the explosion of science and technology, and detailed understanding of specific causal change around particular diseases, modern biomedicine has really revolutionized health care by focusing on isolating those particular chains of cause and effect around disease and then developing treatments (drugs, surgery, etc.) to interfere with those. But along with this (and in parallel), science has also revealed the complex web of interactions that facilitate healing. There is an emerging understanding that the healing approach can be understood on a scientific basis, and that by doing so we can facilitate healing. It provides us with a whole new perspective and a whole new set of approaches in these areas. What we have been attempting to do at the Samueli Institute over the last few years is, first of all, try to start with a description of the broad domains of components that facilitate and stimulate healing, and then begin to understand how they are being delivered in healthcare systems: how we can define them, how we can measure them, how we can begin to then (from that) investigate the optimal way in which they may be applied in health care. That is really the perspective of why we have gone about trying to formulate the idea of an optimal healing environment. JB: I know you have put together a very nice model-a grid-that describes some of these domains of healing and the interface among them. Could you describe that for our listeners? The Five Domains WJ: Sure. This process has come out of several years of bringing together experts from diverse areas in health care, getting their input, synthesizing it, providing feedback, and then getting into larger groups. We started with a series of small meetings of clinicians, patients, and scientists who are interested in this area, and then developed a grid. We have had a series of meetings since then with larger groups, getting their input and attempting to refine these ideas. What has emerged is that there are basically five main areas if you look at healing systems from around the world, including those that are being developed in hospitals and in clinics in conventional medicine. There are five areas that we think-and our consultants feel-need to be addressed if we are going to optimize the process. When we talk about healing environments, we have a broader concept than just the physical environment; we are talking about both the internal and the external environment. Some of the components in the internal environment involve the proper management of our own mind/body aspects (the inner aspect of our intention, our belief, and what we pay attention to). We know, for example, that belief, expectation, and the control of our stress is really an inner management issue; it’s management/control of the mind and the mind/body. The whole area of intention is one domain. A second domain involves the concept of holism, and this is the idea that the mind and the body are, in fact, a unit. The mind/body spirit is a unit, and so experiencing that connectivity and that holism, and engaging in activities that help to complete that sense and experience of holism, then brings the mental aspects into the body in a functional way. There are a variety of ways of doing this: mind/body practices, bioenergy practices, psychological/psychotherapy types of practices, and even things like yoga and acupuncture (which are really mind/body practices). Within standard psychotherapy there is also the concept of healing the past and healing the future. So, for example, being able to address past traumas appears to be an important aspect of attaining a sense of wellness and well-being. Having a sense of meaning and purpose in the future is also an important aspect of survival and of improved function. This area of experiencing wholeness and practices that do that is the second domain. The third domain, which is really at the center of much of this, is the social relationships that we are involved in. There is now extensive research showing that social support, social interaction, altruistic behavior, and social service have a significant impact on our health. They are salutogenic; they are health protective, and preventive. And so, the proper engagement in healing relationships then becomes the third domain. The last two domains are things that are more well known in medicine because they focus on some of the behavioral and external environmental components. For example, lifestyle and proper behavior-behavioral medicine and lifestyle medicine-are key aspects to both maintaining health and recovering health once it’s lost. This includes appropriate nutrition, exercise, stress management, life balance, and addiction management, which is a major issue in our culture. Smoking, alcohol, and other types of addictions are part of lifestyle approaches, and many of your listeners, I know, have developed effective ways of delivering lifestyle medicine and behavioral medicine within their own practices. Finally, the fifth domain is something we call collaborative medicine, and this is the idea that one individualizes, or personalizes, the therapies for individual patients, from the perspective of, first of all, supporting and stimulating healing processes and then moving on, when necessary, to remove or interfere with the disease. Each of these can be delivered in conjunction with each other. They need to be properly integrated. They need to use good evidence-based aspects when that information is available, but it also has to be individualized to the particular patient-to their cultural background, the use of complementary medicine, as well as conventional medicine when necessary. These five components have to be nurtured, they have to be planted in a garden that is supportive, and so the leadership-the culture, if you will-has to support that. The organization in which one works, be it at a hospitable or a clinic, needs to explicitly say, ‘We are about healing;’ needs to outline that, needs to provide the structure and the support to do that, and then, of course, we know that the physical environment, itself, can either detract or enhance all of these processes. Proper air, proper light, proper clean water, and organization of the work sites so that one can facilitate communication-these types of things are important. Those are the primary domains this group has come up with that we think are elements of an optimal healing environment. The Institute is now in the process of working with partners, both in hospitals and clinics, and at work sites and elsewhere, in order to try to begin to understand how these kinds of domains are being applied in medicine. There are many programs that are already applying these, and I know a number of your listeners have been focused on these areas for a long time. They themselves have probably developed some ideal healing environments for the interaction with their own patients and clients. JB: Wayne, thank you. That was a very eloquent description/summary of what I know has been thousands of hours of collaborative work on your part and your group’s part. It strikes me, when I hear you go through those domains, that the majority of the first part (intention, holism, relationships) could be categorized as a state of being, but often in western medicine all of our training is a state of doing, and so there seems to be a juxtaposition between this being and doing duality. How have you rationalized, resolved, or communicated this dialectic in the field of medicine, in which the training that docs undergo seems to be all about doing, intervening, fighting a battle, and winning the war-all of this versus this sense of being that you just described? WJ: The first two components I described are bringing in one of the unique aspects that I think the Institute can bring to this field, which is a focus on the crucial role of the inner environment. We are always being and doing; you can’t separate them. Even when you are doing, you exist in some way, and so it is a matter of focus, intention, and training in those areas. If you look at other traditional healing systems-Ayurveda, Chinese medicine, or even many practice swithin western medicine that are not necessarily focused on new technologies or techniques in their application-the idea of the role of being and the healing presence is predominant. For example, in nursing practice, there is extensive discussion, literature, and theoretical models that have been developed around the idea of caring, and the role of being and caring in the facilitation of healing. Within Ayurvedic medicine, consciousness is a core aspect of how you maximize being. Actually, physicians have also discussed this extensively-maybe not extensively enough-but they’ve discussed it over the years when they talk about the therapeutic alliance and the healing presence. You see this in the literature, and-everybody’s probably experienced this-where you go into a medical encounter, and in some cases you come out and you feel like whatever you needed in there you didn’t get. There was no connection. And there may be other medical encounters where you go in and you immediately feel a sense of connection and you feel, essentially, a healing presence. We have all known individuals who are natural healers, and no matter what their background, training, technology, and what they’re actually doing, they do it in a way in which you get a sense of increased wholeness, of focus, of presence, that facilitates your own sense of well being, and then facilitates healing. What are these components? How does this get maximized? There are training programs. We know now, for example, that skills in empathy, communication, and compassion are things that can be learned and are an important part of healing. We also know from the placebo literature that the manner in which you deliver a therapy, and the context in which you deliver the therapy, can have profound effects on the outcomes. For example, there have been studies showing that simply changing the tone of voice and delivering a placebo in a warm, caring, and confident manner can almost double the rate of recovery, compared to providing things in a neutral or negative way. This is especially true in functional illnesses where there is no major organic problem, which actually comprises the majority of things dealt with in the average family doc’s office, We know that the culture and the context in which a therapy is delivered (the belief of that culture in a particular therapy) is important. For example, in the west, we believe a lot in technology, and so lasers and surgery and those types of procedures have a very powerful cultural therapeutic expectation attached to them. There have been studies showing that that expectation-that environment, that relationship, and communication issues that develop along with delivery of the technology-in many cases is the major contributor to the outcomes, even more so than what is actually done in the technology itself. These components have been undervalued in recent times, and certainly underevaluated when it comes to doing rigorous science to try to understand the mechanisms and understand how they can be applied. The Institute is focused on those areas (realizing that the areas of nutrition, for example, are extremely important), and we support and do some of that research, but there are actually a number of groups already doing research in those areas, and we hope what we are doing will both help facilitate that and complement that kind of research. JB: That obviously leads to a very interesting question. You have 135 or more publications that I could find on PubMed that have pioneered this field of interfacing science with these healing environments and healing methods. How do you use research to study complementary and alternative medical concepts? I know one of the many areas you have been looking at is the area of homeopathy, which is certainly a very historically interesting area that has been difficult for people to get their hands on from a research basis. Can you give us a structure as to how you start down this road of evidenced-based science underpinning these concepts? Is Homeopathy Evidence-Based? WJ: Yes. First of all, I am often asked this question ( at NIH and other places, it was one of the main questions that came up). Can you use standard, reductionistic, conventional, scientific approaches to investigate complementary medicine, which tend to be more holistic and multi-component in their application? The answer I give, that I’ve come to over the years, is that you have to use good scientific methods in these areas. If there is anything we’ve learned over the last 100 years in the application of science, it is that without science we can easily get led astray. We can easily begin to believe (or provide attribution to) areas that turn out not to be beneficial or, in some cases, may be harmful. So you have to apply high quality research methods in these areas. That being said, the question comes up: if there is a whole system-one that has evolved out of a culture involving these complex interactions of the dynamics of the delivery, as well as the components-how do you understand that? To understand that using scientific methods, we need a multi-modal approach; we need a multi-methodology approach. There is no one single research design that is going to answer these questions. I have written extensively on this area and propose that we need to look at evidence as building an evidence house, rather than a hierarchy. There are various types of evidence, all of which provide us with important information to understand what’s going on in the areas of medicine and healing, and this includes randomized controlled trials, observational research, quantitative biological biomarker data (laboratory-type of research), and qualitative interviews to look at what is relevant to patients. Each of these things has its own set of methodologies, but has to be applied in an expert and high-quality way. To do qualitative research well is a very complex process. Within each of those methodologies-building this evidence house-good quality methods need to be used. In some cases, we have to look at whole systems, and the goal there is to ask pragmatic questions. How useful are these systems? The answer comes from observational and health services types of research. In some cases, we want to identify and isolate a component: does this contribute on its own and, if so, how much does it contribute? When you do that, of course, you always risk pulling out the component that is not the most crucial one, or, if by disentangling them, you undermine the synergistic components, then that also can lead you astray. A multi-modal/multi-method approach is needed in these areas. The area of homeopathy illustrates this. Homeopathy, if you look at how it was developed classically by Samuel Hahnemann and how it is applied in its original classical form, involves a detailed interview (hour to an hour-and-a-half) with a patient in which small aspects of their general health and their mental health, as well as the modalities and the pros and cons of their illness, are taken. There is a deep relationship-or interaction-that is developed. All of the symptoms the individual has are valued; they aren’t discounted, so there is a context in which it is delivered. If you look at it from the mind/body and the healing relationship perspective, it is expected to have a profound effect. If you then want to ask the question of whether the pills, themselves, have an additional effect on that, you have to look at it within the context of that delivery system. You have to look at not only the traditional aspects of quality research (internal validity and external validity), but you have to look at model validity, that is, has this been applied in an appropriate way? We need research that looks at the entire practice, as well as the individual components, to see what contributes to this. I’m not saying anything new in terms of research methodology. In conventional medicine, we do research on whole systems all the time. For example, studies that compare medical treatment to surgical treatment of coronary artery disease, two systems that couldn’t be more different; going in and getting bypass surgery versus maximizing medical therapy are completely different systems of therapy. One can’t set up double-blind designs in those areas, but one can do (and there have been) good, pragmatic, randomized, comparison studies to see what the relative contribution of each of those is. Those are the kinds of whole-system methodologies that I think need to be looked at. The other thing that is arising now on the cutting edge of mainstream medicine and science that needs to be applied in the area of healing, is the area of the cellular and systems functions. This, of course, Jeff, is an area that you’ve been working on, talking about, and demonstrating for decades, and I think finally the time has come where your cutting edge work and the mainstream science are going to merge in the area of functional medicine. What used to be identified as isolated and individual diseases, we are now realizing are contributions of multiple functional components, and they may be different for different individuals. By looking at the functional components, there is a new way emerging of approaching health and disease that is not based on simply the medical diagnosis (as was developed over the last 200 years). Those kinds of categories are eventually going to disappear as we look more and more at the fundamental functional aspects of how our bodies work. JB: You’ve said, obviously, some tremendously important things with a high degree of insight. I know in the minds of many of our listeners for whom this may be a new thought process, they are probably trying to connect together your description of placebo and also the concepts of homeopathy. Can we say from the research methods that homeopathy is more than placebo, at this point? Is there data to support that? WJ: I don’t think we can say that for sure. There was a recent meta-analysis published in the Lancet in which the authors looked at clinical trials in homeopathy, and then did a whole series of selections based on quality issues to try to see if there was evidence from the clinical research within homeopathy as to whether it worked better than placebo. The findings of that article, which was published, I think, last year by Shang and Egger, reported that there was no evidence that it worked any better than placebo. The curious thing is that about eight years ago, a colleague of mine, Klaus Linde, and I, used almost identical methods to look at almost the same data set in these areas and, in fact, the recent article in the Lancet used our data set as a basis for doing their research. They went through almost the same methodologies, and yet we came out with different conclusions. We found that we could not eliminate the effect of homeopathy greater than placebo in the clinical research. The problem with both of these studies is that clinical research is a messy business. If you look at the details of these studies, they are all set up differently. The quality is quite different. The outcome measures are different. The remedies are different. Even the systems of applications of homeopathy are different. Some of them are small studies. Some of them are large studies. Some of them are properly managed and some of them are not. You get a real heterogeneous group, and you end up easily coming to a conclusion of, ‘yes, it works,’ or ‘no, it doesn’t work,’ based on which set of studies you think are good or which set of studies you think are not good. And even with that, it is very difficult to use clinical research to ask this question. For example, we probably wouldn’t ask the question, ‘Does surgery work-‘ as a general question. We would want to know, does surgery work for what? In the homeopathic studies-the ones that we did and the ones that were recently published-they aren’t asking that question; they are just asking, does homeopathy work in general? That doesn’t make a lot of sense. What should be asked is if there is an effect from the specific remedies, and if there is a different effect from the remedy versus the social interaction (or the history) that I described before. Then you would expect, in certain types of conditions, that you would be able to see more of an effect or less of an effect. And yet, there is not enough research, not enough independent, replicated, clinical research in the area of homeopathy to answer that question. I published a critical overview of homeopathy in the Annals of Internal Medicine a couple of years ago, in which we took the standard approaches that are currently used within groups like the Cochran Collaboration, which is an international group that does high quality, randomized, controlled trial analyses of clinical research. I looked at whether there were independent replicated studies on individual conditions within homeopathy. In other words, is there evidence that some areas (clinical conditions) work better with homeopathy, and some that do not work? And we found a handful on each side. For your readers-if they are more interested in the details of how you go about this and what the conclusions of that are-I’d be happy to put the reference on your disk for them to look up; it was in the Annals of Internal Medicine last year. It also talked about whether we can use basic science research to help understand some of these fundamental questions. Part of what the Institute is doing is trying to support and conduct high-quality research in these and other areas and try to disentangle these questions. Useful References JB: Yes. For our listeners, your article in Annals of Internal Medicine in 2003 was titled, ‘A critical overview of homeopathy.’13 And, for our listeners, you also wrote a very nice article titled, ‘Research on homeopathy: state of the art,’ that appeared in the Journal of Alternative and Complementary Medicine in 2005.14 And then, this article that you were referring to in the Lancet-this meta-analysis-that appeared in volume 366 in 2005.15 And then you and Dr. Linde wrote a very nice response that appeared in the Lancet in 2005 in the December issue,16 and that was replying on your original Lancet article that appeared in 1999 in which they chose to use some of your data.17 Obviously, there is a very nice lineage of intellectual contribution here for people interested in homeopathy, and also the inter-relationship that it has to the work you have published over the years on the placebo effect. I think it is a very good study of both of these areas of extraordinary importance, and I think we both agree that placebo has been stigmatized negatively, but it is an extraordinarily important tool in medicine. Your work has really helped us to understand that as well. WJ: Thank you, Jeff. And thank you, as usual, for, having all the literature at your fingertips, even some of the stuff that I’ve published. I think we’ve got a problem with the term ‘placebo’ because it is being used in different ways, but we use the same term. It has been given a negative connotation over the years. Part of the problem is that we use the term ‘placebo’ for two completely different things. In some cases, we use ‘placebo’ to mean the use of an inert substance in medicine, which, of course, you wouldn’t want to do in medicine; if you knew it was inert, you wouldn’t intentionally use it. On the other hand, people use the term placebo to indicate that it is all in your mind, and we know that a lot of things occur because of expectation, belief, and tension-things that are in the mind-and those things we want to enhance; we want to maximize our relationship, our communication, our expectation with our patients in a therapeutic encounter within the culture because we want to support our treatment interventions as much as possible. Those are completely different things, one we want to avoid and one we want to encourage. Several years ago, Dan Moerman and I wrote a piece-also published in the Annals of Internal Medicine-on placebo, titled ‘Deconstructing placebo and finding the meaning response.’18 It was our suggestion that we start using the term ‘context and meaning effects’ rather than ‘placebo effects’ because ‘placebo effects’ is a confusing term. What we really want to know is how you can use communication, the context, and the facilitation of meaning-these components that also go into the optimal healing environment-in a way to facilitate healing. I should add, not to detract from it, the so-called ‘nocebo’ effect. Negative communication, for example, can have profound negative effects on individuals and individual outcomes, especially when it is delivered within a context of great authority, like many physicians hold. These are things that produce very real effects in actual practice. We need to train, attend, and pay attention to those, as well as investigate them, so that we understand how they work and how to best use them for our patients’ benefit. JB: Well, Dr. Jonas, I want to thank you. This has been a very important missing link, I think, in our 25 years of Functional Medicine Update, to really dig deeper into this question of what healing is and what the variables are that connect an individual to their healing process. I think you have done an eloquent job in a very short period of time in helping to guide us. I know that people can go to the Samueli Institute website. You’ve got an extraordinary amount of in-depth information and content there that they can follow-up on. Your work will continue, I think, in the publications that you are instrumental in getting into our literature and guiding us. Wayne, thanks a million. It has been a pleasure, sharing this field over the last 20 years . I look forward to the years to come. I think we are going to see some interesting things in synthesizing a better healing environment in the western medical model. WJ: Thank you, Jeff. It’s been a pleasure and an honor to be on Functional Medicine Update.  

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Bibliography

1 Hinz B, Dormann H, Brune K. More pronounced inhibition of cyclooxygenase 2, increase in blood pressure, and reduction of heart rate by treatment with diclofenac compared with celecoxib and rofecoxib. Arth Rheum. 2006;54(1):282-291. 2 Schmatz D, Friend S. A simple recipe for drug interaction networks earns its stars. Nat Gen. 2006;38(4):405-406. 3 Lazarou J. Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta- analysis of prospective studies. JAMA. 1998;279(15):1200-1205. 4 Gurwitz J. Serious adverse drug effects-seeing the trees through the forest. N Engl J Med. 2006;354(13):1413-1415. 5 Park-Wyllie LY, Juurlink DN, Kopp A, et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med. 2006;354:1352-1361. 6 Friedman R. The changing face of teenage drug abuse-the trend toward prescription drugs. N Engl J Med. 2006;354(14):1448-1450. 7 Nissen S. ADHD Drugs and cardiovascular Risk. N Engl J Med. 2006;354(14):1445-1447. 8 Bazar K, Yun A, Lee P, Daniel S, Doux J. Obesity and ADHD may represent different manifestations of a common environmental oversampling syndrome: a model for revealing mechanistic overlap among cognitive, metabolic, and inflammatory disorders. Med Hypotheses. 2006;66:263-269. 9 Levenson C. Zinc: the new antidepressant? Nutr Rev. 2006;64(1):39-42. 10 Bellinger D, Trachtenberg F, Barregard L, Tavares M, Cernichiari E, et al. Neuropsychological and renal effects of dental amalgam in children. JAMA. 2006;295(15):1775-1783. 11 DeRouen T, Martin M, Leroux B, , et al. Neurobehavioral effects of dental amalgam in children. JAMA. 2006;295(15):1784-1792. 12 Westman E, Yancy W, Humphreys M. Dietary treatment of diabetes mellitus in the pre-insulin era (1914-1922). Perspect Biol Med. 2006;49(1):77-83. 13 Jonas WB, Kaptchuk TJ, Linde K. A critical overview of homeopathy. Ann Intern Med. 2003;138(5):393-399. 14 Walach H, Jonas WB, Ives J, van Wijk R, Weingartner O. Research on homeopathy: state of the art. J Altern Complement Med. 2005;11(5):813-829. 15 Walach H, Jonas W, Lewith G. Are the clinical effects of homeopathy placebo effects? Lancet. 2005;366(9503):726-732. 16 Linde K, Jonas W. Are the clinical effects of homeopathy placebo effects? Lancet. 2005;366(9503):2081-2082. 17 Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Lancet.1999;354(9193):1896-1900. 18 Moerman DE, Jonas WB. Deconstructing the placebo effect and finding the meaning response. Ann Intern Med. 2002;136(6):471-476.

Welcome to Functional Medicine Update for August of 2006. In the July issue, we had an extraordinary visit with Dr. Wayne Jonas, director of the Samueli Institute for Information Biology. He talked about the work they are doing on optimal healing environments. This research is important and can improve the effectiveness functional medicine programs. This month, we are going to be speaking about two areas that I think have some direct implication on the healing environment. One of these is something we have spoken of extensively over the last 25 years of Functional Medicine Update, and that is how the nutrition and psychosocial environments translate (through the genes) into messages that ultimately influence an individual’s function. The second area is new to Functional Medicine Update. We will be discussing the concept of humor and laughter in medicine, which is emerging to be important in this world of seriousness and time compression in which we live. This month, let me start with a little poem that comes from 18th century English literature. The author is unknown, but this poem has been repeated over the last couple of hundred years. It goes something like this: The best six doctors anywhere And no one can deny it Are sunshine, water, rest, and air Exercise and diet These six will gladly you attend If only you are willing Your mind they will ease Your will they will mend And charge you not a shilling. This poem is insightful; it has to do with concepts we can modulate: sunshine, water, rest, air, exercise, and diet. These can be six friends to the gene-environment interaction, or they can be six enemies (depending on how the message gets translated). How do we treat disease? We often treat disease by battling it (‘winning the war’ against it), or by treating it with a therapeutic agent. Possibly what we really need to do is construct an environment for a patient that is in harmony with the patient’s genetic pluripotentiality, so that what emerges in the phenotype of the individual-or their outcome-are the characteristics we associate with good health. Some of those variables that are often not considered strongly in medicine as important tools (such as sunshine, water, rest, air, exercise, and diet) may represent some of the most important gene modulators of expression that can translate into improved function. When planning an optimal healing environment, one should look at these six variables and consider how they might be modified to improve outcome. Part of the outcome depends upon the response of the patient to environmental messages, as well as how the patient see him or her self as worthy or unworthy of getting better. Compliance Relationships are Examined Following a Clinical Study on Candesartan Last month, we talked at length with Dr. Jonas about the so-called placebo effect. I read a recent paper in the Lancet that reported on a double-blind, placebo-controlled trial of the drug candesartan cilexetil (which is approved for the treatment of chronic heart failure) that found that placebo adherence was therapeutically more valuable than the overall statistical treatment difference between the placebo and the active drug.1 This study indicated that reduced mortality was similar among individuals who maintained good adherence to the program, whether on placebo or active. How is this result rationalized in the face of what we know about pharmacology? A potential explanation is that those who complied were also more likely to comply with other drugs they may have been taking simultaneously, and the cornucopia effect of all drugs led to better management of their condition. The data inspection, however, does not seem to support this as the primary reason for the difference in outcome between compliers and non-compliers. Rather, the authors of the study propose that adherence may result in lower mortality, even if the treatment is placebo, and it might relate to expectations and beliefs that the therapy will work. It may also be that compliance defines a particular personality type that is more likely to demonstrate positive health habits-activities such as weight management, diet control, and exercise. Such habits can confer a positive outcome benefit regardless of whether a person is taking a placebo or drugs. The results of this study suggest that whatever these associated factors with compliance are, compliance may be more important than the specific drug in determining efficacy. That is a powerful concept. Maximizing the Therapeutic Value of Patient Compliance If we were to look at an assembly of published studies, we might theorize that the context of healing-the belief that a person is going to get better and the patient’s willingness to comply with treatment-may be powerful therapeutic tools regardless of the specific agents that are being administered. The most important information with regard to clinical decision making may be related to how committed the patient is to getting well and what investment he or she is willing to make in the healing process. How do we maximize the therapeutic value that resides in what we loosely term ‘complianc?’ A true understanding Some of you probably recognize I am speaking with some degree of controversy because I am flying in the face of what most of us think with regard to pharmacology. We know that pharmaceutical products do work; the drugs that have been developed to specifically impact certain steps and physiological processes are well designed. But, although they certainly do the job of blocking, inhibiting, or modifying/modulating specific physiological processes, due to genetic polymorphisms and unique differences, drugs do not work the same on all people. The dark side of pharmacology has been the rejection of other things that are considered low-impact modifiers, such as dietary factors, lifestyle factors, environmental factors, and psychosocial factors-which are not considered to be the bailiwick of mainstream medicine. These things have not been thought to constitute an important part of the recovery or therapeutic process, as they are not part of treating a condition and winning the battle against a disease. One topic that has been in the backwater of conversation for some time is the concept of dietary fats. We have had modified dietary fats, the partially hydrogenated vegetable oils, in our food supply system for the last 30 years. By partial hydrogenation, vegetable oils have been intentionally isomerized to form trans that are more stable to heat and oxygen. For many years, even in peer-reviewed medical and nutritional publications, individuals who raised concerns about trans fats in our diet were considered renegades who sensationalized something that had no clinical relevance. In The New England Journal of Medicine (2006), an article appeared titled ‘Trans fatty acids and cardiovascular disease.’2 This article reminds us to not always believe what we read; that knowledge is an evolutionary process and there are new things to learn if we keep our mind open. In this particular article, the authors talk about trans fats being a very important part of an emerging understanding of cardiovascular disease risk and that they probably have greater relative risk contribution to cardiovascular disease than saturated fat themselves. This article (from Walter Willett and Meir Stampfer, et al. at Harvard) goes on to say that the average consumption of industrially produced trans fatty acids in the United States is about 2 to 3 percent of total calories consumed. Major sources of trans fats include deep-fried fast foods, bakery products, packaged snack foods, margarines, and crackers. These are shelf-stable foods that can sit around for months without going stale because they contain retardants to spoilage and these modified fatty acids are more stable from oxidative damage than the natural cis form of fats. These authors discuss the potential molecular mechanisms by which trans fatty acids can directly or indirectly modulate metabolic and inflammatory responses of the vascular endothelium, which include altering the secretion, lipid composition, and size of apolipoprotein B-100 (apoB-100) particles produced by hepatic cells. This alteration is paralleled in studies in humans by decreased rates of LDL apoB-100 catabolism, reductions in the size of LDL cholesterol particles to the atherogenic-dense LDLs, and increased rates of apoA-I catabolism, lowering the effects of HDL as a lipoprotein that causes cholesterol efflux from the artery wall. These are not good things; these are risk factors. I lay this on top of the backdrop of 20 years of information suggesting that trans fats were benign and had no adverse effects on physiological function; this information came from good science and respectable investigators who were opinion leaders from whom we derived our clinical decision-making. We must be cautious about what we contextualize as facts, because as we learn more, ask different questions, and have the tools to examine those questions, new and important observations may emerge. I encourage you to read this article on trans fats and cardiovascular disease because it goes through the effects that trans fats have on hepatocyte lipid clearance and on endothelial cell dynamics at the vascular endothelium; their influence on the adipocyte cellular signaling and how trans fatty acids may encourage lipogenesis and lipodystrophy; and also the effects on the immunological system. All of these mechanisms increase the risk of atherosclerosis, sudden death from cardiac causes, plaque rupture, and diabetes. Trans fatty acids are far from benign. This article argues very strongly that consuming trans fatty acids increases relative risk. When you eat a diet that is very high in refined carbohydrate, trans fats, and overall fats, and low in omega-3 fatty acids and polyphenolic substances that come from fruits and vegetables, you have a much higher incidence of increased inflammatory markers. This was pointed out in an article authored by Dr. Jialal and his colleagues at the University of Texas Southwestern and the University of California at Davis, Division of Endocrinology3 In this particular work, the authors showed that humans have a very dramatic response to a diet that is high in processed carbohydrates and high in trans fats, in that it increases inflammatory markers, as measured by such markers as high sensitivity C-reactive protein and serum amyloid A protein. This is consistent with what Dr. Willett and Dr. Stampfer were talking about in their review article on trans fatty acids in The New England Journal of Medicine. The Jialal article is in the American Journal of Clinical Nutrition, and indicates that it is not just trans fats in and of themselves, but rather it is the complex way these are delivered in the diet that results in an amplified inflammatory influence. When we talk about dietary signatures, and information coming from food that modifies function, the diet that we consume of shelf-stable, processed, convenience food is a diet that has shifted these inflammatory signals over into the state of alarm. The problem is not just too many calories; it is too many of the wrong types of calories that create information expressed by our genes through inflammation, which can induce physiological changes associated with an increased risk of cardiovascular disease, cancer, diabetes, and arthritis. We now know that these inflammatory responses to altered diet and physical inactivity associate themselves with many chronic diseases, including autoimmune disease. Early-stage Autoimmune Disease of Unknown Etiology An article by Dr. M.C. Gracia appeared recently in Medical Hypotheses that talks about how the immune system can be shifted in its balance between the thymus-dependent-1 and thymus-dependent-2 regulatory lymphocytes into a state of autoimmunity.4 Self-regulatory T-cells start to lose discrimination and start forming antibodies toward host tissue resulting in autoimmune disease. The endocrine organs appear to be particularly vulnerable to this. If we look at what happens in these inflammatory-mediating situations, it may lead us to recognize subclinical and early-stage autoimmune disease in the clinic. This early recognition may explain why we are seeing more systemic lupus erythematosus and more autoimmune thyroiditis, and why more and more men and women are being placed on medications to manage these inflammatory conditions. In the Functional Medicine Clinical Research Center, we recently had a very dramatic example of this. It was so dramatic that it just stopped us in our tracks. This case is from Dr. Jacob Kornberg and Dr. Robert Lerman. A patient who came to the clinic had not worn shoes in some time. She was a woman who had young children and was basically incapacitated; she could not stand for long, and she could not walk due to a very serious and unusual type of autoimmune disease called erythromelalgia. This condition is characterized as being the opposite of Raynaud’s syndrome. Raynaud’s is a vasoconstrictive disorder; erythromelalgia is a vasodilation-related disorder, with the extremities becoming very hot and looking seriously sunburned. There is also a lot of pain with this condition. This particular patient was on Neurontin three times a day-an extraordinarily high dose-and still was in very serious pain. She was receiving standard of care from a very well-respected center of rheumatology, and certainly was getting what we might consider the best medicine. But she was still very seriously disabled. Erythromelalgia: Understanding the Molecular Basis of a Pain Syndrome Recently, in the journal, TRENDS in Molecular Medicine, there was an interesting article on the molecular basis for this pain syndrome.5 The authors of the article give a very detailed discussion of erythromelalgia: how the sympathetic ganglion neurons are influenced, what nociceptive dorsal root ganglions are influenced, how this relates to specific single nucleotide polymorphisms and genetic risks, why this tends to run in families, and why this results in inherited painful neuropathy. This is a complex genetic disease and a dramatic example of the exquisite uniqueness of a person’s immune and neurological systems. The authors also point out, however, that this condition has sporadic onset and a dramatic phenotypic variability, so it is not a hard-wired, one-size-fits-all type of disease. They go on to say that there may be things that modulate the appearance of these particular processes. I quote, from this article, ‘This suggests the involvement of other molecules in the form of the disease, possibly with modulation by other genetic and/or environmental factors that can trigger the appearance of disease symptoms.’ That is obviously an entrée to our functional medicine thinking, because once you start saying gene-environment interactions, then you start seeing the situation as part of a web? How would we use the matrix in functional medicine to actually define the triggering points in a patient that might mediate what is ultimately seen as the cause of erythromelalgia and manage the symptoms associated with this condition?. A Simple Approach to a Complex Syndrome? With that in mind, let’s go back to the patient that came to the Functional Medicine Research Center. She had a complex disease, but the treatment approach for the patient was actually quite simple. She was placed on a gluten-free diet to lower any potential immune stimulation. She was given a variety of low-antigen foods that were minimally processed. She was administered a mixture of EPA-DHA at about 6 grams per day, which provided about one-and-a-half grams of EPA. She was administered an anti-inflammatory medical food that has specific anti-inflammatory and immune-modulating phytochemicals/phytonutrients. Lastly, she was given a natural anti-inflammatory nutraceutical that contained selenium, zinc, and vitamin D. You might think this particular treatment approach is too simple and too benign to really have an impact on such a very severe type of autoimmune disorder. The outcome of this story is very positive. Over the course of three to four months on this ‘very simple’ program, without any additional medications, the woman was able to lower, and ultimately reduce to zero the majority of the polypharmacy that she was taking, while improving her function throughout the whole treatment regime. At the end of three months, she was wearing shoes, walking through the mall, and standing up with little pain; the redness in her extremities was absent. Here was a case of a complex disease and yet the treatment program was very simple. In this case, modifying the environment-the context of healing that was unique to the needs of this patient. We felt that gluten in this patient’s diet was one of the precipitating factors of her illness. Prior to coming to the Functional Medicine Research Center, no one had ever asked this patient about her diet or her gut function. By appropriately balancing her environment through these dietary modifications and augmentation of nutrients, the outcome was dramatic: lowering the signals that are associated with activation of inflammatory autoimmune responses and increasing immune regulation. We have talked about gut function so many times in Functional Medicine Update, but we can really never say too much about this area. We know that the gut microbiota is a very important factor in energy regulation in the body. The gut is the second brain (as was described by Dr. Gershon in his remarkable book of that name) and signals through various trophic factors and hormones, through both the immune system and through systemic circulation. The gut influences activities in the rest of the body related to appetite, oxidative chemistry, anti-inflammation and/or proinflammatory cytokines, and trophic molecules that can enhance immune function. Recently, Dr. George Wolf, from the University of California at Berkeley, authored a very interesting critical review on gut microbiota.6 In the article, Dr. Wolf says that if we really want to look at the role that intestinal bacteria play in immune function and in overall energy regulation, i.e. fat deposition, we only need to look at germ-free mice because they have no bacteria. These gnotobiotic animals have a very different response to diet in terms of increased body fat deposition. If we start modifying our gut flora, we can have a very dramatic change in the way our energy economy is managed by the body. It is hard to believe that gut bacteria can influence our appetite and our energy economy and regulation, but that is what is emerging from this work. If we look at studies with Lactobacillus acidophilus and bifidobacteria supplementation we find a variety of interesting reports. One study looked at the role of oral pretreatment with lactobacilli and bifidobacteria to improve the efficacy of quadruple therapy in eradicating residual Helicobacter pylori infection. This study was performed with patients who had failed triple therapy alone. By administering triple therapy with probiotic supplementation, researchers found a significant decrease in H. pylori loads despite antimicrobial resistance, thus improving the efficacy of quadruple therapy in eradicating the residual H. pylori infection. This was work that was done at the Department of Internal Medicine at the Institute for Public Health at the Imperial Medical College in Taiwan and was published in the American Journal of Clinical Nutrition.7 We know that probiotics have a very powerful immuno-modulating effect, and they can be very useful for balancing TH1 and TH2 immunological systems. In a Nutrition Reviews article titled ‘Probiotics: immunomodulation and evaluation of safety and efficacy,’ authors Janine Ezendam and Henk van Loveren say that if a person has an imbalanced immunological system-autoimmunity or atopic disorders-the use of specific probiotic supplements can help to modulate immune system function by using the gut as a signaling agent to the rest of the body’s immune system.8 These immunomodulatory effects of friendly bacteria may play an important role in helping to regulate immune function. Again, this leads to the concept of specific types of probiotic supplementation to regulate specific types of immune function, and that is certainly a theme that is starting to emerge in nutritional therapeutics. We know that bifidogenic factors show promise for treatment of active ulcerative colitis. There are a number of clinical trials that have been published recently on this, one of which is found in the journal Nutrition in 2006.9 We are starting to witness dramatic opportunities for improved outcomes in patients with ulcerative colitis using probiotic supplementation. It is also recognized that the use of probiotics is often amplified in clinical effectiveness when administered simultaneously with prebiotic substances. These are substrates that preferentially support symbiotic bacteria at the expense of starving the parasitic bacteria. These prebiotics then are substrates that are selectively fermented (or used as food) by the friendly bacteria. A recent paper that appeared in Nutrition Reviews is titled, ‘A Prebiotic Substance Persistently Enhances Intestinal Calcium Absorption and Increases Bone Mineralization in Young Adolescents.’10 This article described the use of substances that are fermented by friendly bacteria and also improve calcium absorption and bone mineralization. I have talked about gut-immune function associated with enteric bacteria, and the effects this has on systemic immunity. I have talked about calcium mobilization. I have talked about vitamin D chemistry that goes on within the gut mucosal system that is activated by specific bacteria. These are all very important therapeutic tools in setting up the context of healing. If the gut bacterial flora are not appropriately composed to modulate immune system function, then the individual may have an ongoing immunological imbalance that triggers systemic effects. We are starting to recognize that gut function is one important arm of the therapeutic opportunity in managing these inflammatory processes. This is why in functional medicine we constantly emphasize the 4R Program, which is our gut restoration algorithm. The first ‘R’ is remove the offending agents-the toxins, the allergens, etc.; the second ‘R’ is replace (where necessary) stomach acid through betaine hydrochloride or hydrochloric acid or pancreatic enzymes (if the person is pancreatic enzyme insufficient); the third ‘R’ is the reinoculate phase, which is the use of the prebiotics and probiotics to stimulate proper enteric bacterial species and to normalize gut immune function; and the fourth ‘R’ is the repair phase, which is to add nutrients that are needed for proper gut mucosal repair (L-glutamine, arginine, zinc in a non-irritating form, pantothenic acid, vitamin E-these are all agents that support gut tissue and repair). The Reappearance of ß-Glucans in Grains When I talk about prebiotics, I want to emphasize that this concept of nondigestible carbohydrates that are substrates for the fermentation of friendly bacteria is a very important part of getting the most out of the third ‘R,’ the reinoculate phase. An interesting article that just appeared in Science magazine talks about ß-glucans-a ‘dietician’s delight.’11 In this paper, the authors point out that ß-glucans in grains have been historically considered to be the bane of brewers because they do not allow proper fermentation of beer. They have often been selected out by plant breeding, resulting in lower ß-glucan content in certain grain products. We know that barley grain has historically contained ß-glucans, but it has been genetically selected to lower the ß-glucan content. Now people are beginning to recognize the importance of ß-glucans as prebiotics, and so there is a trend toward going back to genetically hybridized grains to form specific types of high-glucan-containing grains for therapeutic application, such as improving gut fermentation and proper bacterial proliferation. Inducing Higher Levels of Equol Production When you have the proper bacteria in your gut, it helps in the secondary metabolism of various types of phytochemicals in food, such as soy isoflavones, which are converted by favorable bacteria into secondary substances like equol. Equol, we know, is very important as a hormone modulator-as an estrogen regulator in women-and is associated with lowered incidence of breast cancer and other estrogen-related cancers. In a recent interesting paper that was published in the journal Nutrition, a group of investigators from Ghent University, headed by Dr. Willy Verstraete (head of the department in the medical microbiology area), found a mixture of bacteria that can convert isoflavones into equol.12 We are starting to see that it might be possible to stimulate proper gastrointestinal microbial ecology to induce higher formation of these secondary metabolites from phytochemicals, which then may have a favorable effect on hormone modulation. This has been a long-standing question, and I think that Dr. Verstraete’s work will help us to actually start to develop a specific microbial culture that can induce higher levels of equol formation in women and/or men who are low-equol producers. This may help us to understand more about the interrelationship between soy intake and breast cancer. A Meta-analysis of Soy Intake and Breast Cancer Risk Women may have differing effects to a soy-based diet depending upon their individual gut flora and how it converts the isoflavones into estrogen-modulating substances. In reviewing soy intake and breast cancer risk a paper in the Journal of the National Cancer Institutereports results from a meta-analysis that used many studies performed from 1978 to 2004, including 18 epidemiological studies, 12 case-controlled studies, and 6 cohort (or nested case-controlled) studies.13 The authors came to the conclusion that soy intake is associated with a modest reduction in breast cancer risk. We now come back to where I started this whole discussion-the little poem talking about the best six doctors anywhere (sunshine, water, rest, air, exercise, and diet). From that, let’s talk about the concept of humor and laughter in medicine, another contextual aspect that is associated with the optimal healing environment. In this issue of Functional Medicine Update we want to talk about a concept that does not receive much attention in medicine (and certainly not in traditional medical education). But this concept can be a powerful tool. It was first brought to my attention by the book, Anatomy of an Illness, written by Norman Cousins. Many years ago, back in the late 70’s or early 80’s, Dr. Cousins, at UCLA, got us thinking about his own personal experience with healing from a very serious, chronic, life-threatening illness. He rented versions of The Three Stooges and Laurel and Hardy, and watched these laugh-filled comedies of a slapstick nature while he was in the throws of a very serious crisis situation (life-threatening). He recovered (he had a ‘spontaneous remission’), and he later talked about how important humor and laughter is as a therapeutic tool in medicine. Humor Can Reduce Tension and Create Connections Since then, many investigators have been looking at humor as a tool or a technique that enhances the healing experience. Rachel Sobel, who is a fourth-year medical student, just recently authored an article in The New England Journal of Medicine titled, ‘Does laughter make good medicine-‘14 In the article, she discusses her experience as a UCSF medical student, working at the Moffit-Long Hospital in the bay area of California, and talks about how humor breaks pressure, stress, and tension, and creates the space for clarity and for improving the connection between the doctor and the patient at times when things are ‘very serious.’ The doctor may be sleep-deprived and working under multiple demands; there is a sense of overload. By bringing in humor as a clear beacon, there is suddenly a space to reconnect to the purpose, and to be involved in a process of reestablishing the context of healing for the patient and for the doctor ‘Why in those few seconds of juvenile hilarity did I not feel an ounce of guilt-‘ she questions in this article. ‘Perhaps it was simply that being with a group of other medical ‘professionals’ made it seem okay. Or maybe it was justified because laughing brought us together as a team in an important bonding moment, which would ultimately benefit our patients. Or perhaps laughing was less about making fun of patients and more about coping, finding humor in a day filled with suffering.’ You need to find those oases to create the context for the healing experience. Humor is a very important part of the process of developing a style by which one can find a path of enlightenment, and maybe even the opportunity for a learning experience that opens the door to healing and recovery. Healing may be-in the broadest sense of the term-more than just getting over the disease; maybe it is feeling good about where that person is. The Science of Laughter: A Variety of Clinical Studies and Articles When we go back and look at the history of the science of laughter and its relationship to medicine, we are reminded that there are many very interesting studies that have been published. In the journal, Oncologist, in 2005, an article was published titled, ‘Laughter: the best medicine-‘ which talked about the application of laughter, even in the field of oncology.15We might think that in cancer treatment (being one of the most serious and moribund types of disciplines, with gravity of the situation being present at all times) humor can build the connection between the caregiver, patient, and family. However, as they point out in this article, insensitive joking is offensive and distressing, and therefore you have to find the right way to use humor in the context of healing-one that allows for it to be a positive rather than a negative force. There are other review articles on this subject. ‘Laughter really is the best medicine: the use of humour in therapy,’ was published in the journal, Perspectives in the spring of 2005.16There is a series of articles that go back to 2000, 2001, and 2002 on laughter and medicine and how humor can help the patient heal, including publications in the Mayo Clinic Womens Healthsource in 1999.17 I was very interested to find an article in the Nursing Journal of Indiain 2003 that is titled, ‘Laughter is the best medicine: the value of humour in current nursing practice.’18 And in the Journal of Oncology in 2005, ‘Humor and oncology,’ and how, again, cancer therapy, being this very serious business, may be contextualized in a different way by bringing humor appropriately into the relationship of the clinic.19 It is interesting to note that the Tennessee Medical Journal actually has had articles on the use of humor and laughter in medicine going back almost 25 years.20 Nursing, oncology, cardiology, internal medicine-there are articles in all of these areas. There is even an interesting article in Australian Family Physician from 2001 titled, ‘Happiness and humour: a medical perspective,’ in which the author, at the Monash Institute of Public Health, Faculty of Medicine at Monash University in Victoria, talks about how the medical profession’s focus on dealing with negative mental states has led to the suggestion of classifying happiness as a major affective disorder.21 Maybe what we need to do is recast this to demonstrate that happiness and laughter during conditions of illness is a desirable attribute to bring into the healing process and even into the therapeutic encounter with the patient. The author goes on to say that epidemiological data suggests that happiness is related to personality factors such as high self esteem, feelings of personal control, and is a very important part of mounting an appropriate immune response. Recapturing the optimistic enchantment with life that is part of our childhood may be a key to happiness and health, even in patients who have disease. These are very interesting concepts that I think fit into trying to define the status of an optimal healing environment. As we go through this discussion, we are very touched with the fact that there are some individuals in the field who have been the standard bearers for bringing laughter and humor into medicine. One is Dr. Patch Adams at the Gesundheit! Institute, and also the extraordinary work of Dr. Neil Shulman, who is our clinician of the month. Dr. Shulman, a medical school professor at Emory University School of Medicine, has been involved in finding ways to bring humor and laughter into health care in a positive way to contextualize the healing process. I think when you hear from Dr. Shulman about his experiences, you will find that this is another tool, another technique, another skill that we can actually learn. Many of us don’t think of ourselves as comedians, but yet we might have that sense of knowing when the comedic moment is present. It can help to break down barriers and reconnect the patient to their healing process. Is Humor Applied Biochemistry at the Whole-organism Level? Those who have been listening to Functional Medicine Update for many years may wonder why we are talking about humor when we have so heavily focused on biochemistry, but the affective influence of disease on behavior, which ultimately then influences immune-system function and the healing process, is, in some way, applied biochemistry at the whole-organism level. I think we are dealing with things that really can make differences. I think it is appropriate to talk about laughter and humor and how we contextualize it, how we integrate it within medical practice, and how it can become part of the skill-building bag of tools that we have to help in patient management. With that in mind, let’s move to the interview with our clinician of the month.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Neil Shulman, MD 2272 Vistamont Drive Decatur, GA 30033 JB: Once again we are here at that portion of Functional Medicine Update that I am always excited to engage in because we have the privilege of talking with some of the most remarkable creative thinkers-people who are really creating change in health care. That is the case in this issue with our guest, Dr. Neil Shulman. Dr. Shulman-on the pedigree, you might say-sounds like a very diligent professional in the medical research area: associate professor of medicine at Emory University School of Medicine, 20-plus years of experience in the cardiovascular/hypertension area of research, and multiple publications (over 50 of them in this area). He was co-investigator of an eight-million-dollar study in NIH-funded cardiovascular clinical research. But when you go a little bit deeper, you find that Dr. Shulman is a remarkable person to have developed a concept from his own experiences (that he will discuss), which is to bring humor into medicine. Dr. Shulman is a comedian, par excellence; he is an author, and has written extensively in the area of medical humor. I have had the privilege of reading a couple of his books. Dr. Shulman was principally responsible for writing the movie, Doc Hollywood, which starred Michael J. Fox. You may recall that this humorous movie was about a doctor who was going to go seek his fame and fortune as a cosmetic surgeon in California, but got waylaid along the way in rural America, and decided maybe that was where he wanted to stay. It was a very humorous-but also very poignant-story that came from the ideas and pen of Dr. Shulman. In the context of what we are discussing in this issue of Functional Medicine Update, which is the optimal healing environment as it relates to humor, I can think of no one better than Dr. Shulman to represent this concept. Dr. Shulman, we welcome you to Functional Medicine Update. I guess the first question that everyone probably asks you is, how did a medical researcher/academic clinician get to where you are today? NS: I was giving a lecture on blood pressure some place in the world, and I heard somebody snoring, and it was me. I decided I should change my course a little bit. Seriously, I was always blessed to have a lot of humor around me as I was growing up. My parents both had a great sense of humor. My grandmother was very funny. She was a matchmaker; she had come over from Belarus in 1905. So, it was being around a lot of humor, and I think the other thing was that I was a klutz growing up. I couldn’t throw a baseball very well, and kids would laugh at me when I was five-, six-, seven-, eight-years old, and it made me very self-conscious. And then one day it just dawned on me: whether they are laughing at me or with me makes no difference-I’m making them happy. When I went on stage and did comedy, I was still the same klutz, but people actually paid to laugh at me. JB: I have that same thing except mine isn’t considered humor. It is considered seriousness, but I still get that laughter, so I can appreciate this. NS: There’s nothing like exploiting your own disabilities. I’ve got plenty to exploit. Humor as a Teaching Mechanism JB: I read one of your recent books, 101 Ways to Know if You’re a Medical Services Professional. I thought it contained some great insights. You have used humor as a remarkable tool for introspection and for self-evaluation in a non-threatening way. Can you tell us a little bit about how humor comes to be a teaching mechanism and how you contextualize it? I think you do it in a very interesting way. NS: In the teaching arena, you’ve got one person who is supposed to be sort of the know-it-all and the other person who is supposed to be learning from the know-it-all. That can be pretty intimidating. No matter what the topic, whoever you are talking to might have unique or interesting insights that can be valuable, that you haven’t thought about. I think when we’re talking about humor and using it in that process of teaching, it makes that person who is learning more comfortable (particularly if it is the appropriate type of humor), and more receptive to what you are saying and not putting you on a pedestal, but seeing you as another human being. Then they open up more, and you can learn from them. I think, for instance, any time you create something, you don’t know what you create until you get responses from people. It is the same in teaching-you don’t know what you’re teaching until you hear back, and you want to make the other person comfortable. JB: I notice that in your book-I think it may be your most recent book-Your Body, Your Health, Jane Fonda wrote a very glowing forward. I worked with Jane, myself, a number of years ago and I have a great admiration and respect for her. She obviously was touched by the way that you are contextualizing your information and motivating people to change. What was the nature of the relationship you had with her? NS: I first met Jane Fonda when I was performing for a comedic fundraiser. It had to do with eating disorders, actually-a fundraiser for an organization dealing with that issue. She was the co-host with me and we hit it off. After that, we got together for a number of other activities that had a humorous slant. I did a comedy performance called ‘What’s in a Doctor’s Bag-‘ with the instruments in a doctor’s bag-Otis the otoscope, Lubb and Dubba, Ms. Kneeknocker-for her grandson at a birthday party. Then we went and did a bunch of other similar types of activities. Dr. Patch Adams and the Gesundheit! Institute JB: When you originally met Patch Adams-I know you have had some engagement with the Gesundheit! Institute and I’ve also known Patch for probably 20 years, as well-you two must have hit it off very quickly, sharing a common view of how humor can be brought into healing. NS: Yes. Patch actually called me when he had just spent time with Robin Williams doing clowning at a hospital. It was before they shot the movie, Patch Adams, but Robin was getting a flavor of Patch, and then Patch called me and said this movie was going to be coming out and he was wondering what my experience was because I had a movie come out and I was a doctor involved in humor. I gave him some insight and then I said, ‘Patch, why don’t you come down to Atlanta and let’s do a fundraiser for Gesundheit!, your nonprofit, on the coattails of the promotion of the movie when it’s about to come out?’ He agreed to do that, and we had about 1500 people at Symphony Hall in Atlanta, and we did the real Doc Hollywood and the real Patch Adams. We then did a number of other events in Atlanta, and we were able to write him a check for seventy-five or eighty thousand dollars for his nonprofit and he called back and asked if I would be on his Board. I ended up getting on his Board of Directors and now I’m President of the Gesundheit! Institute. I think Patch has a really good message and we’ve connected a lot, and we’ve done other humorous performances around the country, as well as workshops on humor and health. Doc Hollywood JB: Tell us a little bit about the Doc Hollywood experience. That sounds like a fascinating chapter. It is one of-I think-the great medical comedies. It really has, as I said, a very poignant underlying message. How was it working with Michael J. Fox and what response did you get to the movie, not just from an entertainment value, but also from kind of an ‘aha’ experience? NS: The experience was great. I got some great help and collaboration from somebody who is recognized in the book, Carl Hiaasen (Carl has a movie coming out on a book of his own called Hoot in the next couple of weeks). That book, which was originally called, What Dead…Again?, became Doc Hollywood ten years after it was published. Michael J. Fox was absolutely delightful to work with on that project. I was associate producer, so I worked with the screenwriters. There were lots of different screenwriters until Michael agreed to the final script. When we were shooting in Okeechobee, Florida, it was Thanksgiving time and there were a bunch of homeless people around. Michael just took money out of his pocket and threw a big party for Thanksgiving for the homeless people there. He is a really wonderful caring individual; unfortunately that iswhen he found out he had Parkinson’s. Saluting Healthcare Providers in Underserved Areas One of my hopes with the movie, Doc Hollywood, is that it had impact on drawing attention to the issue of shortages of doctors and saluting the doctors who do work in underserved areas. There is actually a ‘Doc Hollywood Day’ that is starting. You can go to www.dochollywoodday.com. The president of the Indiana Rural Healthcare Association is starting this and hopefully there will be a national day that doctors and nurses and other healthcare providers in underserved areas can be saluted for their work-maybe put apple pies at their front doors and have parades and put them on floats and tell them we’re glad they are practicing where they are needed. As for the experience of actually making the movie, Hollywood is a really interesting place; there are a lot of interesting characters who I became friends with. I got a lot of experience which then led to me independently co-directing a movie that I actually acted in that we’ve just finished called Who Nose- It is sort of a reality comedy about a desperate man looking for a life, and I play that desperate man. JB: Well, we can hardly wait to see the ‘desperatism;’ it sounds exciting. It is a legacy of our lives, right, that we don’t often know-in fact maybe we never know-exactly where the journey will take us. We may have a premonition, but then it unfolds. Through this remarkable history-this journey-how have you seen humor (in the way that you have described it through your medical allegories and metaphors) integrating itself into healthcare? Do you have any sense that people are starting to see this as a tool and that there are places where it can be introduced, contextually, within medicine in an appropriate way? Or in health care? Helping People Through Laughter NS: Absolutely. There is a guy who has dedicated his life to that very issue named Steve Wilson. He went over to India and met a doctor who used to get together every week with his patients and tell jokes. And then eventually they ran out of jokes, so they just started laughing. Steve Wilson came back to the US and started this laughter club, and he goes all over the country certifying people in becoming laughter leaders. They do all sorts of laughter-with people who are disabled, people in nursing homes, Alzheimer’s patients, and then just everyday people to help them. I wrote a paper-sort of a review article-with Zoe Haugo, on the area of the science and practice of humor, and there is a lot that has been published: studies looking at the immune system, looking at improvement of the cardiovascular system, the psychologically positive impact of humor. Incorporating Humor into Curriculum Unfortunately, the resources to get humor taught in medical schools as a serious topic is very difficult and that is because medical education is very much driven by money, sometimes money that is tied to patented products. If you have a patented product, you can sell it at a premium price and use that extra money to give grants to medical schools and get professors to do additional research on that particular product, whether it be a pharmaceutical drug or some device. You can have a tremendous number of detail reps going and knocking on the doors of doctors, giving out brochures and having dinners and events and so forth. If you don’t have a patented product and you are just trying to promote the humor, you are not going to have anything-anything-like those resources. So, even though it may be very helpful-and free, you can laugh for free-it is going to be very hard to get an established curriculum. The only place I know of was Washington University in St. Louis where they had month-long rotation in pediatrics in humor and clowning for the residents. I lecture a lot on humor, in a hopefully humorous way; I was just at the University of South Florida for the Dean’s Lecture Series and I just did it at Emory for the Department of Internal Medicine residents, medical students, and faculty. Intermittently, I have even gone to medical school graduations where I addressed the issue of humor, but I do it in a humorous way so it is sort of like a stand-up comedy act. I got up at Oklahoma, at the medical school there, a couple of years ago, and I said, ‘This is going to be the longest graduation speech known to mankind.’ There were 3000 people in the audience and they started booing and hissing. And then I said, ‘I’m just fooling. It’s the shortest.’ I sat down and got a standing ovation. I did get back up. Humor is something I think should be incorporated not only into medical school education, but into the education all health providers, nurses, and physicians’ assistants. It should be incorporated into primary and secondary school. I think that humor is a serious enough matter, and just like reading, writing, and arithmetic, it should be part of education. It is very, very important. In my opinion, life is the dash between two numbers on a tombstone. You should enjoy your dash and help others enjoy it. We all won the lottery-it takes 250 million sperm to fertilize an egg and we are all winning sperm. If you are a winning sperm, you get a dash-why not enjoy it? And why shouldn’t enjoying it be considered an integrated part of the processes of education? We are the only animal creatures I know of that laugh. We have this wonderful ability to laugh, and I think we have to exploit it. Kids, up to the age of puberty, laugh maybe 20, 30, 40 times a day. But adults only laugh maybe 5 or 6 times a day. I think before puberty the whole human race enjoys laughter and spontaneity. It does seem to come back around after menopause. I think before puberty you have a good time because you don’t know any better and after menopause you have a good time because you don’t care anymore. Engaging Laughter in Alzheimer’s Patients JB: You said something that I want to pick up on that I thought was quite insightful. I know you do a lot of work with older-age segments in various types of environments like nursing homes and care centers. You mentioned that in Alzheimer’s patients you can engage laughter, and often we have this stereotype that humor and laughter are high-cerebral functions and that people who may have some cognitive dysfunction can’t laugh. I’d like to come back and revisit that with you. Do you have experience with Alzheimer’s patients who can see humor and can engage in laughter? NS: Yes. I was medical director of a nursing home for about 23 years, but I really didn’t understand Alzheimer’s until my mother got it. I remember in the early stages I brought her this big bouquet of flowers. She lived in Washington, DC and I lived in Atlanta, and I’d go home and visit intermittently and I brought her this big bouquet of flowers. She got all excited and gave me all these kisses. I came back two minutes later with the same flowers, did the whole thing again, and she was really excited. And I said, ‘Mom, I only have to buy these flowers once, but I get credit five times.’ She laughed, and we laughed about it. That was in the early stages, but in the latter part of her life, when the disease was really difficult and she was very agitated and wasn’t communicating much at all, if you got really close to her and just started laughing, it was like everything disappeared and she would just start laughing and it was magic. There are other things with Alzheimer’s patients-hugging them, for example. I did go and do humorous performances for Alzheimer’s patients and also for some fundraisers for Alzheimer’s. With the Alzheimer’s patients, I found that they responded very well, but more to the slapstick sort of thing. There are all kinds of humor, and slapstick humor was one that they could enjoy and appreciate more, and that is also the type of humor that little kids seem to enjoy the most-2-, 3-, 4-, 5-year-olds. When I perform with them I am Dr. Neil, the banana peel; they like that much more than the real Doc Hollywood. JB: Can you actually engage humor into healing by projecting humor to patients so that it becomes infectious in their own response? In other words, do you have to be more assertive about getting humor into the relationship so they’ll imprint that or can you subtlety encourage humor and laughter in that individual? NS: The safest humor for me is self-deprecating-when you make fun of yourself-because you’re not making fun of somebody else, and then they laugh and then they see you as not being this person on a pedestal, but somebody who is connecting with them as a friend. With patients I find that is the case. I had a doctor once who said he did not want to just walk in a room and have the patient be intimidated by his white coat and stethoscope, but he didn’t feel he was a funny person. So what he did was he started telling his patients that he was giving them a homework assignment: every time they were to seem him they were to bring a joke. He did this so he could set up some humorous rapport. But he said that people started canceling their appointments because they didn’t have jokes… JB: So he needed to have some jokes in the waiting room that he could give them in case of an emergency… Laughing at Yourself NS: That’s right! I have found that some of the best humor comes from real life experiences and, particularly, when you have had embarrassing moments. I was once in front of 250 cardiologists and I was trying to get them to loosen up and I said, ‘I’d like one cardiologist to come up and tell me the most embarrassing thing that ever happened to you.’ So they were sort of an uptight group and this guy comes up and he says, ‘Well, I was examining a woman who had a lump in her breast and I thought it was totally benign, but I wanted to explain to her husband what was going on. So I went out to the waiting room, got this gentleman, brought him into the examining room, where the woman was lying on the examining table. I took his hand and put it on the woman’s normal breast. I moved it around and said, ‘This is a normal breast.’ Then I took his hand and put it on the other breast and moved it around and said, ‘This is the lump, do you understand now-‘ And the gentleman said, ‘Yes, I do, but this is not my wife.” He had gotten the wrong man. The woman thought it was another doctor. She did calm him down and the doctor did make it through the visit. I find that in times of stress, if you can rewire your brain by throwing in some humor, either for yourself or if you are in an argument with somebody, just throw in some humor and get things rerouted. Humor and Professionalism: Finding the Right Balance JB: Let me ask one last question because your experiences are remarkable. I think a lot of doctors feel that if they brought humor into their practice it might lower their professionalism and create a lack of confidence in their patients. Could you speak to that? I think that is one of the reservations that many docs have about showing their personalities. They have been trained to have this austere demeanor that connotes-supposedly-professionalism. NS: You want people, obviously, to have confidence in you. But I haven’t found that confidence is associated with somebody feeling as though you are on a pedestal. Frequently you are thought to be egocentric if you are standoffish. Obviously, you want to be honest with patients about what you know and what you don’t know. I think you want them to see you as a human being who has flaws, but you are self-critical about those flaws. I think most of the population is smart enough to realize nobody is perfect. I was once on a plane, sitting next to a pilot, and he said, ‘Doctors are just like pilots. If we make mistakes, we can lose a lot of lives.’ I said, ‘There’s a big difference. A doctor is not on a plane.’ I think the patients know that. I will say, by the way, we have a website, which is www.neilshulman.com, and on that website there are links to other websites that have humorous things, like the spots we’re doing on public TV now. There is a program called ‘Second Wind Dreams’ to give wishes to people in nursing homes. And there are also some serious things, like warning signs of disease for consumers. There is a lot of stuff there to demystify medicine that might be useful or helpful for people in this area who have interest in that. JB: Dr. Shulman, I want to thank you. I think you’ve given us some really important messages about the optimal healing environment and bringing humor and laughter into that environment and making it joyful. As you said, this experience we have is fairly short. All of us will ultimately encounter health challenges, sometime throughout this process, and somehow finding the levity that is associated with this unknown experience called life puts it in the proper context, and, as you said, can activate that immune system in a very positive way. In terms of contextual healing, this is a pretty good therapy. I really thank you for helping us to understand that. NS: I really enjoyed this conversation a lot. I will say that I think life does have three phases. The first part of life, you follow grades so you will do well; the second part of life, you follow money so you will make a living; and the third you follow doctors, so you can stay alive. JB: And hopefully you can have some laughter with them through the process and create a good outcome. Thanks a million and we wish you the best and keep spreading the message. NS: Thanks a lot. This was really fun.

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Bibliography

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Welcome to Functional Medicine Update for September 2006. We are in for a real treat this month with our clinician of the month, who will discuss bariatric surgery-a topic that we have never talked about in the 25 years of Functional Medicine Update, but I think is timely at this juncture in the evolution of medical technology and social history. We are witnessing an epidemic rise in the prevalence of obesity in our society. Morbid obesity has a very dramatic relationship to chronic health problems, metabolic disturbances, and virtually every chronic, age-related disease: coronary artery disease, stroke, hypertensive-related disorders, renal failure, diabetes, cancer, osteoporosis, arthritis, and spinal compression fractures. Many Variables Can Contribute to Obesity Why are we seeing this rise in obesity? Is it just because of a luxurious diet that is rich in calories? Or is it a combination of the calories, plus the way calories are constructed in processed food that is sending signals to our genes and creating a different energy economy? What about psychosocial-related issues, such as post-traumatic stress syndrome and the neuroendocrine impact of our lifestyle on our appetite and eating behaviors? Just about every field is related somehow to this problem of epidemic obesity and its subsequent health problems. In 2005, a landmark paper was published in The New England Journal of Medicine from a group of collaborative investigators, all of whom are leaders in their field.1 This paper suggested that, based upon morbidity and mortality trends that are occurring in our society right now, children born today may be the first in the history of the United States to have mean average life expectancy lower than that of their parents. We have never seen this happen before. This appears to be a consequence of the rapidly rising prevalence of obesity, not just in the older-age portion of society, but also in our youth. These are dramatic social changes that are creating pressure on the healthcare system; a tremendous amount of human potential could be lost. Who has looked inside the body and understands the technical consequences of these particular trends at a metabolic and physiological and anatomic level? A bariatric surgeon sees-firsthand-the physiological outcomes of these conditions. Our clinician of the month this month-Dr. Lee Trotter, is a bariatric surgeon and a person who has a remarkable collection of different skills and perspectives, including a background in nutrition. To many of you, bariatric surgery may appear to be fairly esoteric and outside the range of your clinical experience. Because of the rapid rise in the frequency of this surgical procedure, I think it will become a more important topic for everyone in health care. Bariatric surgery is the most dramatically increasing surgical procedure performed in the western world, and is included in more and more training programs for surgeons, particularly the new microsurgery technologies. The Impact of Bariatric Surgery on Nutritional Status and Metabolism Nutritional status can create the need for a bariatric procedure, but the procedure itself can also have an impact on nutritional status and metabolism. Some of the recent publications on nutritional management of patients after bariatric surgery are based on observations of professionals who have performed this procedure and have studied the outcome in their patients. One such article is ‘Nutritional Management of Patients after Bariatric Surgery,’ from the American Journal of Medical Science.2 Bariatric procedures are surgical procedures that change gastric physiology and absorptive surface areas. Malabsorption syndrome associated with deficiencies of iron, folate, vitamin B12, and even the fat-soluble vitamins (particularly vitamins A, K, and E) is being seen in these patients. Essential fatty acid malabsorption is suggested as well. Wernicke-Korsakoff Syndrome has also appeared in some bariatric surgery patients; this is a thiamin deficiency associated with hepatic encephalopathy and often connected with alcoholism. Some of these consequences are the exact conditions that a practitioner may be trying to treat by doing gastric bypass surgery on a morbidly obese patient. Currently, there are nutritional guidelines for the management of bariatric surgical patients after surgery, but in most surgical centers these guidelines are not rigorously adhered to. Nutritional intervention is simplistic at best. A number of patients develop problems with hair loss, muscle wasting, skin problems, digestive difficulties (nausea and vomiting), and generally altered immunological status as a consequence of nutrient insufficiencies. These insufficiencies may be related to protein/calorie malnutrition (particularly protein), but also the micronutrient problems that I have been describing. It is really necessary to look at the results of bariatric surgery and learn from them. Postoperative nutritional status is a very big area of concern; we know there is an impact of varying levels of protein intake on muscle mass accrual after bariatric surgery. In an article that appeared in Obesity and Surgery, the authors discuss how protein has a very important role to play in modulating body composition after surgery.3 With bariatric surgery patients, it is not adequate to measure just the weight loss-you must also measure where that weight is being lost from. If weight loss is from the muscle mass compartment via the loss of body protein, this may result in the patient being in a less helpful situation postoperatively. We know from other studies that both the quality and quantity of protein in the diet can greatly influence the type of tissue that is maintained during weight loss; that is, whether or not lean mass is conserved compared to fat mass. In ambulatory weight management programs, the goal is to improve body composition utilizing dietary and lifestyle intervention, and to retain muscle mass while losing body fat selectively. This is one of the reasons why things like bioimpedance analysis (BIA) of body composition is so important, because the scale alone may be misleading. If you just measure body mass index (a measurement of the weight-to-height ratio), it may not tell you where that weight is being lost. Is it being lost as water and muscle, or is it being lost as fat? The healthy outcome from a weight loss program (be it through bariatric surgery or diet and lifestyle intervention) is to lose body fat, particularly visceral adipose tissue fat, while maintaining body muscle stores. Are there recommendations regarding obesity surgery in terms of nutritional follow-up? I would say these guidelines are still in a state of evolution. There are some enlightened surgeons who seem to have a better understanding of these nutritional variables, and then there are others who are fairly naïve about how to evaluate nutritional status properly and understand the trajectory that a patient has after surgery relative to his or her health. In a 2005 article in Current Gastroenterological Reports, the authors state that 16 million Americans are currently candidates for weight loss surgery.4 This could be more people than all of the surgical centers, surgeons, and surgical teams in the United States could handle. What are we going to do? We are going to have to utilize lifestyle, diet, and other technologies (maybe even pharmacology) to try to gain control over this epidemic. The problem may start early in life, as alterations in our lifestyle and eating habits. This includes the types of foods we eat, the information that food provides as signals to our genes (that create differences in insulin signaling), and this complex network of neuroendocrine hormones that regulate things like appetite, thermogenesis, metabolic function, and adipogenesis. We are going to have to take a very different view of this whole problem-a view that looks beyond just calorie restriction and what I call the application of the first law of thermodynamics, which means you balance your calories in with your calories out. This concept has value, but what is forgotten is that in between calories in and calories out is what we call metabolism, and metabolism in the individual is controlled by many variables that are related to environmental and genetic factors. I think we need to address not only the calorie content, which is the energy/heat potential of food, but we also need to look at the metabolic implications and this neuroendocrineimmune signaling that controls and regulates things like appetite metabolism and cell signaling. Endocrinological Improvements and Changes in Metabolism Following Surgery Many of the problems that patients have as a consequence of morbid obesity may dramatically and rapidly improve after gastric bypass surgery. Ironically, those improvements often occur much more quickly than you would expect based upon the amount of weight that is lost. Why would that be? As I see it, bypass surgeries, such as the Roux-en-Y procedure, change the absorptive surface area and the size of the stomach. After surgery, the flux of information molecules from the diet is greatly reduced. This cools off (or calms down or quiets) the neuroendocrine arousal that has come from the loud voice-maybe even chaotic voice-that has come from excessive calories that contain the wrong information. By cooling that voice down-quieting it-the effect on gene expression that results in the stress responses that we see as insulin resistance and hyperlipidemia and inflammatory markers seem to all be remarkably improved. This implies that these metabolic consequences of obesity are not solely a consequence of the fat itself, but a consequence of what occurs metabolically from signaling that is associated with fat accumulation. How much weight does a patient have to lose to get a dramatic and favorable impact on his or her metabolism? Could it be that just small amounts of weight loss (but improvements in physiological function), could then dramatically reduce some of the metabolic disturbances that associate themselves with diabetes and heart disease and cancer and so forth? It is an interesting question because for years it was felt that this was all a problem of excessive calories and extra body fat; there was a presumed direct relationship between incremental increase in body fat and decrease in metabolic performance. What we are talking about now is another variable beyond that of just fat itself. It has to do with the impact of diet and lifestyle on our gene expression patterns, which ultimately can regulate the metabolic outcomes that are associated with disease. There was an article in The New England Journal of Medicine that focused on lifestyle, diabetes, and cardiovascular risk factors ten years after bariatric surgery.5 This was a multi-center review, and the news was quite encouraging. After two years, weight had increased by 0.1 percent in the control group and had decreased 23.4 percent in the surgery group. There were also significant improvements in insulin sensitivity, serum lipids, and uric acid levels in the group that underwent bariatric surgery. In this particular study, the authors concluded that, compared with conventional therapy, bariatric surgery appeared to be a viable option for the treatment of severe morbid obesity, resulting in long-term weight-loss, improved lifestyle, and amelioration of the risk factors that were elevated at baseline. The one thing bariatric surgery does not appear to significantly improve over standard approaches is elevated serum cholesterol, which suggests that there are other factors associated with triggering the cholesterologenic process (seen as elevated LDL cholesterol). I have talked about the nutrient deficiencies that are secondary to bariatric surgery. I have talked about the problems that are often seen with patients who have morbid obesity in which tissue integrity and the immune system are compromised. By having surgery, weight loss will improve some of these functions, but patients may then have new problems that are associated with macronutrient (for example, protein deficiencies) and micronutrient deficiencies. I have added the additional insight that after gastric bypass surgery, even before a significant amount of weight is lost, there has been demonstrated a dramatic improvement in metabolic function with reduction of risk to diabetes and heart disease and stroke. This implies that metabolism can be changed by reducing the stress on the body from extra calories containing the wrong information. A number of publications have included articles on this subject; one that I think is very interesting appeared in Current Opinions in Clinical Nutrition and Metabolic Care in 2004.6 A consequence of malabsorption syndrome relates to the fat-soluble vitamins, specifically vitamin D, which is necessary for bone health. We often see patients who, after bariatric surgery, end up with bone loss and increased parathyroid hormone levels-a nutritionally-induced secondary hyperparathyroidism-resulting in increased risk to osteoporosis. I think we can say that for virtually all nutrients that are malabsorbed, appropriate supplementation in a form that does not produce hyperosmolarity is a very desirable feature of postoperative nutrition care. We have been discussing vitamin D at some length in Functional Medicine Update over the last several issues, but let me just give you a few additional insights that I think are interesting. We have talked about the role vitamin D has on the immune system and the fact that it can lower some of the pro-inflammatory cytokines that are produced in the neurological system-these are the discoveries of Dr. Colleen Hayes at the University of Wisconsin, Department of Biochemistry. She has demonstrated that in animal models of multiple sclerosis, you can lower some of the inflammatory mediators in the nervous system if you supplement the animals with vitamin D, particularly the 25-hydroxy derivative or the 1,25-dihydroxyvitamin D3. Vitamin D as a Potential Anti-Inflammatory Agent in the Future Treatment of Congestive Heart Failure A study that was recently published in The American Journal of Clinical Nutrition supports another important role for vitamin D.7 This was a study done on 123 human subjects, randomly receiving either 50 mg of vitamin D plus 500 mg of calcium per day or a placebo (that would be a placebo vitamin D plus 500 mg of calcium) for 9 months. Ninety-three of the 123 patients completed the study, and there was a significant treatment effect observed on the logarithmic-transformed serum concentrations of 25-hydroxyvitamin D. The supplemented group had a significantly increased level of the 25-hydroxyvitamin D3, which is the biomarker for vitamin D status. There was also a decrease in parathyroid hormone, tumor necrosis factor a , and interleukin 10, suggesting that supplementation with vitamin D in humans has a dramatic positive effect on balancing the TH1/TH2 immune system and lowering inflammatory effects. The authors of this study concluded that vitamin D3 reduces the inflammatory milieu in congestive heart failure (CHF), and might serve as a new anti-inflammatory agent for the future treatment for CHF. In that same issue, in the editorial titled ‘Vitamin D and Congestive Heart Failure,’ the authors state that this is another thing that can probably be added to the list of positive benefits of vitamin D.8 People with CHF may have adverse physiology/biochemistry of vitamin D metabolism and end up with secondary hyperparathyroidism, alterations in calcium physiology, and other effects on the immune system related to lowered vitamin D status. With vitamin D supplementation (about 2000 IUs per day; that is 50 mg), there can be amelioration of inflammatory mediators and improvement in parathyroid hormone and calcium levels. Vitamin D and Metastatic Disease The hormonal form of vitamin D (1a; ,25-dihydroxyvitamin D3), in cell culture work, inhibits prostate cancer cell invasion and modulates the specific kinase pathways that are involved with cellular replication (and possibly metastases). These findings support the idea that vitamin D-based therapies might be beneficial in the management of advanced prostate cancer by improving immunological function and lowering metalloproteinase and cathepsin activities that are associated with metastatic disease. An article on this subject was published in the journal Carcinogenesis in 2006.9 Vitamin D is manufactured by photobiology in the skin. People are advised to stay out of the sun to prevent skin cancers, but doing so may increase risk to other cancers due to poor vitamin D status. This has been discussed at some length in various issues of The Journal of the National Cancer Institute. A recent editorial authored by Gary Schwartz and William Blot was titled ‘Vitamin D Status and Cancer Incidence and Mortality: Something New Under the Sun.’10 This piece discusses a number of studies (including the Health Professionals Follow-Up Study) that have found there is a correlation between sun exposure and lowered cancer incidence (overall cancer incidence, not just skin cancers). There is probably a bell-shaped curve between proper exposure to the sun and benefit in keeping vitamin D levels adequate, and too much sun exposure increasing risk to skin cancer. Supplementation with vitamin D may be an alternative. The authors state that sunlight, although generally an effective means of generating large amounts of vitamin D, may not be safe for all people. For many individuals, including those who are darkly pigmented and who live at northern latitudes, sunlight exposure may be insufficient to generate adequate vitamin D. Most of us have carried a view that vitamin D is very toxic as a consequence of being a fat soluble vitamin that is stored. We know it is toxic when you have elevated levels of 25-hydroxy in an altered serum calcium-phosphorus ratio. In supplemental doses, vitamin D is now considered safer than it was previously. In the above-mentioned article, Drs. Schwartz and Blot point out that the present recommended allowance for vitamin D at 400 IUs for individuals 50-70 years of age is inadequate to maintain skeletal health and is probably too low for meaningful anti-cancer levels of 25-hydroxy-D3. The world is changing, isn’t it? Things that we thought were rules of nutrition that we learned and memorized to get good grades now appear to be the wrong answers. There is new information that has caused us to reconsider the RDA and its adequacy. The full paper that relates to the editorial by Drs. Schwartz and Blot is titled ‘Perspective Study and Predictors of Vitamin D Status and Cancer Incidence and Mortality in Men.’11 The authors of this study state that low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestive-system cancers, and a vitamin D supplementation program may be necessary to achieve adequate levels of 25-hydroxyvitamin D in the range of 30 or more nmol/L. Trying to establish the tolerable upper intake for vitamin D and safety is another part of our review. There is a discussion of this subject in the Journal of Nutrition that has suggests that if we really want to understand the upper tolerable level of vitamin D we should be measuring the 25-hydroxyvitamin D3 level and the serum calcium-phosphorus ratio.12 We do not want to get above 500 or so nmol/L for 25-hydroxyvitamin D3, and we certainly do not want to cause hypercalcemia (as evidenced in the blood). What are the barriers for optimizing vitamin D intake, particularly in older age individuals? This is the subject of an article by Dr. Robert Heaney that appeared in the Journal ofNutrition.13 I think it is the fear that older-age people may have about sun exposure; they may be using high SPF formulas to block the risk to skin cancer. Also, they may have diets that are compromised relative to vitamin D, and so a supplementation program is probably desirable. We recognize now that vitamin D as a hormonal form (the 25-hydroxy and then later the 1,25-dihydroxyvitamin D3) can actually be formed in situ in certain tissues. The human mammary epithelial cells have been found to express CYP27B1, which converts 25-hydroxyvitamin D3 to it active form. These studies (discussed in a recent issue of the Journal of Nutrition) demonstrate that nontransformed human mammary cells express as CYP27B1, that they are growth inhibited by physiologically relevant concentrations of 25-hydroxyvitamin D3, and this provides a biological mechanism linking vitamin D status to breast cancer.14 Vitamin D and Male Osteoporosis Osteoporosis is not just seen in females; it is also seen in older-age males. This is related to vitamin D status, so physicians ought to be measuring 25-hydroxyvitamin D3 levels in males (relative to skeletal integrity) and coupling that together with bone mineral density and amyloid peptide studies for bone demineralization. This is discussed at some length in an article titled ‘Assessment of Vitamin D Status in Male Osteoporosis’ that appeared in Clinical Chemistry.15 Much of what we have witnessed with bariatric surgery and malabsorption syndrome could be related to vitamin D. A lot of other potential adverse downstream outcomes that I have just described (heart, endocrine, and skeletal problems) may be effects from some of the things that we are trying to use to treat problems. Life is always more confusing than it seems, but I think we are going to learn much more about how to make this complex topic understandable from our clinician of the month, Dr. Lee Trotter.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Lee Trotter, DO 410 Fleischman Way Carson City, NV 89703 (775) 887-8885 JB: Those of you who are long-time Functional Medicine Update subscribers know how fortunate we are to have remarkable clinicians and researchers of the month that continue to stimulate us and point us to the future of where medicine might be going. We are fortunate this month to have such a personality who will, I think, help us understand a major trend that is happening in medicine. I am speaking about bariatric surgery. We have not done a lot on the subject of surgery on Functional Medicine Update over the last 25 years, but we are very fortunate to have a world leader in the area of bariatric surgery, Dr. Lee Trotter. Dr. Trotter has a dramatic and remarkable background, not just in the bariatric area, but also thoracic surgery, trauma-related surgery, cosmetic and reconstructive surgery, and endoscopy-related work. He had a tremendous reputation while serving as a surgeon in the military. Following his military service, he was medical director of the Black Hills Bariatric Center in Rapid City, SD. More recently, he is medical director of the Carson/Tahoe Hospital Medical Surgical Weight Loss Center (American Society of Bariatric Surgeons, Center of Excellence, provisional status approved). Dr. Trotter is a board-certified surgeon, and a member of the American Society of Bariatric Surgery. He has been a diplomat in the American College of Surgery since 1994. Beyond that, he is a dramatic broad thinker, and quite an interesting human being with a broad range of interests and you will hear about those as we have a chance to visit with him. Dr. Trotter, it is wonderful to welcome you to Functional Medicine Update. My first question is, can you give us a little bit of your history in surgery over the last 15-20 years? LT: It goes back to my early high school and college years. I always wanted to be a plastic surgeon, looking at reconstruction. You see the pictures on TV of some of these children with facial deformities, and that is kind of what got me moving toward the surgery area. My father was a chiropractor, and so my upbringing was perhaps a little bit different than traditional-or allopathic-medicine. I ended up going to an osteopathic medical school. I believed it would give me a little broader aspect of teaching. A little-if you want to use the word-‘holistic’ approach to medicine, and not just strictly western medicine. It was at that point that I joined the Air Force, and ultimately went through residency training with the Air Force at Keesler Medical Center. It was toward the latter part of my training that laproscopic surgery, as we know it today, came into being. For whatever reasons, I was given a gift for what people might term ‘Nintendo’ surgery, or the laproscopic techniques. Early on, I was able to perform surgeries that my professors were doing traditionally open. That is basically how I started on my surgical career, and ultimately got into the bariatric arena. That’s me in a nutshell. The Future of Surgery: Laproscopic Technology JB: Having only observed laproscopic surgery a few times, it seems like it is a remarkable breakthrough in technology, relative to the field and the trauma of the patient, but it also seems like it selects for certain hand-eye coordination skills in the surgeon. It seems like maybe not everybody is capable of doing it as effectively as you. I would imagine, as we start to see this technique be used more and more in surgery, that it is going to select for certain skill sets within individuals who are in the surgical field. Has that been your observation? LT: Without a question. In fact, if I might be so bold to say so, I think in the next decade you are going to see that traditional surgery through large incisions, as has been done in the past, will be a thing of the past. Just about every surgery that we have done historically is now being done laproscopically, which, for the patient, is a tremendous benefit. It is a lot less invasive. The recovery times are significantly less. And in multiple studies it has been shown to have less of a complication rate and better overall success rate for the patient. JB: With that, the other feature that you just alluded to briefly that paints a unique picture of you, is the interest that you have had in nutrition and how that ultimately will weave into this discussion that we are going to have around bariatric surgery, both pre- and post-recovery experiences. What was the connection you had to nutrition? The History of Weight-Loss Surgery LT: That started with my father (a chiropractor). I was raised to believe that nutrition was a very important aspect of overall health and well-being. I think this was solidified for me in my early surgery years, when we were reversing jejunoileal bypasses that were done in the early 50’s as a weight-loss procedure. Historically, it was in the early 50’s when we started doing surgery specifically for weight loss. At that point, we had a very rudimentary understanding of the whole disease process. It was felt that if we could essentially bypass all the absorptive capabilities of the small bowel, the patients could continue to eat what they desired and they would be unable to absorb the nutrients, and therefore, they would lose weight. It was in my early surgical years that we would see the end result of decades of malabsorption in these patients. They would come in with kidney and hepatic failure. They would have all kinds of metabolic disturbances that they were unable to manage. And so, I saw the end result of severe protein malnutrition, if you will. We were then reversing these procedures, and it came to my attention at that point (and this is what I was taught), that obesity was not a surgical disease. I really had a bad taste in my mouth about surgery for obesity, just from my early years and seeing the end result of malnutrition. That brings us up to about eight years ago, when I was looking into obesity surgery and thinking about going into it. I had the laproscopic skills to do it, and it was actually the industry that came to me, asking me to perform these procedures laproscopically. When I started reviewing literature, I questioned what we are going to do differently now that we did not do in the 50’s. What will make a difference in these people so we don’t just repeat history? Of course, the biggest part of that was the nutrition aspect. That is where my nutrition focus kind of diverged from the surgical procedures. JB: For the sake of some of our listeners who may not be familiar with what is happening in the field of bariatric surgery, can you tell us a little bit about what you see-as a surgeon-happening in the field of surgery and how it relates to bariatric surgery and what are the different procedures that people are using because often maybe we think there is just one procedure? The Three Categories of Weight-Loss Surgery LT: You bet. We can simplify the types of surgical procedures into basically three categories. One of them would be the malabsorptive category: bypass all of the intestines so that you can’t absorb the amount of calories that you would otherwise absorb. The second category would be one of restriction: let’s just make the stomach so small that one cannot put very much food in there, and so you get full very quickly and the calorie limitation is based on gastric size. And then the third category would be kind of a combination of both, where we take elements of the malabsorptive procedures and elements of the restrictive procedures and put them together. Today, the gold standard is what we term the Roux-en-Y gastric bypass. This is in honor of Dr. Roux, who came up with this intestinal rearrangement that physically looks like the shape of a ‘Y.’ If I could draw it out for you, basically you would have this ‘Y’ of intestines, with one of the limbs going to a very small stomach pouch. There are benefits and downsides to all of these procedures. The malabsorptive procedures are typically very high maintenance procedures, and as such (at least in the United States), we don’t really do those routinely. However, they are the most effective for weight loss. If we had a patient with BMIs in the 60 to 70 range, that may be a nice alternative for them. The restrictive procedures come in various flavors. Through the 70’s and 80’s, these were most notably known by the words, ‘I had my stomach stapled.’ For every surgeon there was a different version of how this might be performed, so it was very inconsistent. Perhaps one of the more common restrictive procedures is called the vertical banded gastroplasty. Basically, a staple line is made across the stomach, and then a small band is placed adjacent to that (at a 90 degree angle) to limit the opening of that small pouch. The point that needs to be made with this procedure is that the pylorus remains intact; the food goes first into a little ‘staging’ stomach, if you will (or the small stomach), and then drops in to the native larger stomach, and then goes through the pylorus as it normally would. This prevents what we term ‘dumping syndrome.’ That was the main benefit of that procedure, but patients would develop a maladaptive eating disorder and could eat high-calorie liquids. Therefore, the weight loss (long term) was very poor. Today, we have a variation of this vertical banded gastroplasty, which we term the ‘LAP-Band.’ This is a device that is a plastic ring, and on the inside of this ring is a balloon that is attached to a tube and then a port that is placed in the subcutaneous tissue. A physician can inject saline into the balloon to inflate it, consequently making the opening of that stomach narrower because this ring is placed right up at the top of the stomach. If the patient has trouble swallowing, they can then deflate that balloon in a reverse manner so the patient can eat more effectively. Today, that has become a very popular device because it can be placed laproscopically in about a half-hour, and there is no dividing of any intestines, so therefore (it would seem) the complication rate overall may be less. However, that ring can be become displaced; it can erode into the stomach, and it can also cause difficulties with reflux (heartburn, esophagitis); the device is not without its problems. The gold standard, of course, is the Roux-en-Y, which is probably performed laproscopically by most bariatric surgeons today. The benefit of that procedure is that there is a very small gastric pouch, about the size of a golf ball. The remainder of the stomach is left in place; there is no stomach resection. For purposes of understanding, should this procedure need to be reversed, all the pieces of the puzzle are still there. It could be reversed, although we don’t do that routinely. So we’ve got the small stomach pouch, then there is that Y-that Roux-en-Y-that I made reference to earlier. One of the limbs of that Y is pulled up to that small stomach pouch and attached, so that now the food that is eaten will go into the small, golf-ball-sized stomach pouch, then go through the anastomosis, which is a fixed diameter connection, into the jejunum. The problem with this is that it sets up what we call a ‘dumping physiology,’ where the small bowel will receive (without control) whatever foods are eaten. Should they be high in sugar content, this is usually not tolerated; the small bowel wants to eliminate it as fast as possible. Patients will experience cramping, flushing, nausea, and ultimately diarrhea, hence the name ‘dumping syndrome.’ This whole process takes place perhaps 15 to 20 minutes after they eat, and can last for several hours. One of the benefits is that this is a forced behavior modification. Those foods that these patients should not be eating typically are not eaten because of the dramatic penalty that occurs immediately after eating. The main portion of the stomach-the pylorus, the duodenum-have all been bypassed. That is important for later discussion when we start talking about malabsorptive issues and problems with vitamin and mineral absorption. Basically, these are the three types of procedures. To summarize, we’ve got the LAP-Band, representing the restrictive type of procedures. We have the Roux-en-Y gastric bypass that represents a combination of both restrictive and malabsorptive procedures. And then, on the fringes and not used much in our country, but in other countries is used a little more frequently, is the pure malabsorptive (or duodenal switch); it is also referred to as biliopancreatic bypass. JB: Lee, that was just a magnificent summary. Thank you. I know there is a tremendous amount of other stuff underneath that, but that really helps us to get a perspective. What are the thresholds that you as a surgeon use when you evaluate a patient for the Roux-en-Y? In terms of BMI or metabolic status, what are the criteria you would generally use? Evaluating Patients for Bariatric Surgery LT: We use the criteria that has been established by the National Institutes of Health (NIH), as well as through the World Health Organization (WHO) to evaluate patients for surgery. Back in 1991, a consensus panel for the NIH comprised of multiple disciplines ranging from internists to surgeons to endocrinologists-various organizations that had any type of interest in weight loss- published a consensus, and so I will make reference to that. This is the criteria we use even today in our offices. The first thing is that patients must have tried a non-surgical approach to weight management. This may or may not necessarily include medication. We are all familiar with the phen-fen issue of years’ past. Medicines do have their downsides and they may be contraindicated in some patients, for example, perhaps those with hypertension. So, they don’t necessarily have to have taken medication, but they needed to have been overseen by a physician who has experience in weight loss. That is the entry gate-they have to have tried non-operative management and failed that. Statistics show that for people who are in the 80- to 100-pound overweight category, upwards of 95 percent of these patients will fail medical weight loss. That is looking at (roughly) the 3- to 5-year mark after making these attempts. The second criteria that we look at would be that of their actual weight. We found that the more accurate way of assessing somebody’s weight was with a Body Mass Index (BMI). That is a relationship between the patient’s height versus their weight. We use a table to look it up and there is a formula that one could run things through. It is quite a bit better than the Metropolitan Life Insurance table that we are all familiar with, where we have the male/female chart, and then you decide if you are light-, medium-, or heavy-boned. I think that data has been long since put to rest, and we now rely primarily on Body Mass Index. Those who have a BMI greater than 40 will be surgical candidates based purely on their weight. That is with stratifying the complications of surgery against the complications of non-surgical management. We find-in several studies-that those who have a BMI greater than 40 can have upwards of 10 times the mortality rate with non-operative management. This is why we would qualify those patients. Let’s say a particular patient already has comorbid conditions of their weight, such as obstructive sleep apnea, diabetes, or hypertension. If these types of problems are already present, we will reduce the weight requirement to a Body Mass Index of 35. Since these folks already have complications of their disease, we find they would benefit. Patients also must go through a very comprehensive preoperative evaluation to stratify their surgical risk. This would include a psychiatric evaluation to determine if there are any eating disorders present. Why are they heavy? Do they use food to cope with stress? These types of issues do come up quite frequently. If we remove the ability to eat larger quantities of food, what is a patient going to replace that coping mechanism with? It is very important from a psychology standpoint that we figure out these patients. They need to undergo standard blood work to make sure there is no obvious hormonal problem, perhaps with hypothyroidism. We need to check their lung functions and obtain EKG chest x-rays. And any other particular problems that they may have need to also be evaluated and controlled. For instance, with a lot of patients I see, we will be discussing various issues of their life, and I’ll hear that they pull up to a stop sign and fall asleep. This is an indicator, perhaps, of sleep apnea. We will obtain a sleep study preoperatively and initiate treatment for that prior to surgery. Those are some of the basics of what we look at in a patient. The patient also needs to be extensively educated on the types of procedures that are available. What are the life-long ramifications that are going to take place, not only from a nutritional standpoint, but from a physical activity standpoint? A lot of these people have disabilities from their weight; they have knee, ankle, and hip difficulties that don’t permit them to do routine activities. This is vital to success, postoperatively, so we need to get them with an exercise physiologist and into physical therapy to help them with that preoperatively. A lot of people think these heavy folks just sit around and eat, eat, eat all day long and (from a protein/nutritional standpoint) that these folks would be very robust and very healthy, but it is quite the opposite. These folks are typically severely malnourished. When you look at their body composition, they may have additional muscle mass for their size, but when you look at the composition with regard to lean mass versus fatty tissue mass, it is severely abnormal. I recognize this in surgery; the quality of their tissue is very poor. Oftentimes you can put a stitch in a healthy person’s tissue and it holds very nicely. With these folks you’ll put a stitch in and it will be like trying to stitch wet tissue paper together; it is very difficult. I can’t really measure that, per se, but I can tell you that their body tissues are not healthy at all. So we start with a nutritional program preoperatively, trying to reverse some of these malnutrition issues so the patient will be able to tolerate the stress of the surgical procedure much better. That is kind of a long answer for criteria. JB: That was very helpful. This is obviously a series of procedures that are being used more frequently in the United States and elsewhere in the developed world. How many procedures a year, approximately, are we talking about today? LT: The statistics for 2005 put this procedure at about 140,000 to 150,000 just in our country alone. Every year it seems to be going up, geometrically. At one of our bariatric meetings (I’m sorry, I don’t remember the speaker), a comment was made that we have seen an explosion of surgeries, and the speaker said that we have not seen the explosion yet, we have just lit the fuse. This begs multiple questions as far as why, in our country, are we seeing the preponderance of obesity that we are. What is different now than, say, 20 years ago, when there was just a fraction of what we are seeing, weight-wise? But it is not just limited to the United States. There is this fallacy that Americans are basically gluttonous-type people, but if you look at the weight of other (even third-world) countries, they are also seeing geometric rises in the weight of their own populations. It is not just the United States, it is a worldwide problem. JB: I know that you have had extraordinary experience, yourself, in this procedure. How many patients have you operated on? LT: I, personally, have operated (primary procedures, laproscopically) on about 600 people. JB: Are there surgeons who have done thousands of these procedures? LT: Absolutely. I am not going to profess to have a tremendous case load, but I can tell you that after the first 100 patients, you really get a good feel for what these patients’ problems are and what their needs are. This is what got me into the nutrition arena. Surgeons, in general (and I am not trying to defend or talk down about a profession), go through our medical and our surgery residency training, and there really is very little emphasis placed on the nutritional aspects of our patients. We have become very talented and gifted-the laproscopic developments over the last decade have been extraordinary. I am awed-in just my short career in surgery-by the dramatic changes that have taken place. I could probably tell you that when I look back at when I first started surgery about 18 years ago, and I look at what I do today, the practice is 100 percent different. The things that I learned and the techniques I used 18 years ago are completely different (although I use the same principles). And that is just in one guy’s short lifespan. It is exciting to think about what the future holds. Although we have come so far on the technical side, the physiological side of surgery (and particularly the nutritional side of surgery) has kind of been left in the background and I think there is so much work that needs to be done. The understanding that could help our patients have better outcomes and more fuller lives-I think there is a lot there that can be offered. This is where I started with bariatric surgery. As I mentioned, my earlier experience was that of a severe malnutrition issue in these weight-loss patients. I started doing the Roux-en-Y gastric bypass laproscopically on my patients, and technically I did really well. I can tell you that to date I have never had a leak, which is the most feared complication of these procedures. But I noticed that postoperatively in my patients, although I did what I would term a ‘perfect surgery,’ I was not obtaining perfect outcomes. I had patients with excessive hair loss, excessive fatigue, and-with the very things I was trying to remedy-I didn’t seem to be making much headway. Postoperative Challenge: Maintaining Lean Muscle Mass Then I started looking into nutritional aspects because of my prior experiences. One of the interesting things I found, and I was very skeptical at first, was that of bioelectrical impedance analysis (BIA). That is a whole topic in and amongst itself, but suffice it to say that this body composition analysis for trending was helpful (and, I found, accurate) and reflective of how patients were eating, how they were exercising, and how (overall) they were doing. Were they doing well? Were they utilizing that tool that I had given them properly or not? I am not trying to product name drop or degrade any of these, but I used Carnation Instant Breakfast. I used Flinstones Vitamins. And I found, when I looked at body composition analysis, that they were losing weight, yes, but they were not losing the proper weight. I saw excessive lean muscle mass loss, to the tune of upwards of about 25 percent. With my trauma background I knew that when you are talking about 25 percent lean mass loss it is extraordinary and unacceptable. But in the bariatric circles, as long as the scale showed that we had weight loss, that was our measurement of success, and I thought it was a very inaccurate measurement. I started looking at various products and was disappointed in that going through a whole array of different products available on the market, I could not be successful in maintaining lean mass. You need to remember that these patients are limited in what they can eat. They have a golf-ball-sized stomach pouch and they would come back saying, ‘Dr. Trotter, I cannot physically put another drop of liquid anything in me. I am full up to my eyeballs. There is just no way I can do any more of this.’ And so I started thinking that perhaps it wasn’t necessarily an intake problem, but perhaps rather an absorption problem. Since I wasn’t really able to alter the patient’s anatomy, I needed to look at the quality of what patients were taking. That is what got me looking into the nutritional aspects, and I had a lot to learn. The learning did not come from medical sources, and I was a little disappointed. In talking to some very knowledgeable people throughout the country, I slowly picked up that not all food and not all supplements are created equal. There are benefits from specially ‘engineered’-type products that were much more specific for these patients so that their tool (that I had given them surgically) could be used much more efficiently, and that we could meet the goals not only of weight loss, but improved health. For me, that is where the nutrition and the surgery now come together. We have great surgical skills, and I do believe we have great knowledge today about some of the nutritional dynamics in how to truly fool Mother Nature in a way that we can lose the weight, but do it responsibly while maintaining health. I do believe it is possible, and, in fact, over the last seven or eight years or so, I have demonstrated that we can minimize lean muscle mass loss. That reflects in the patient’s well-being, not only in the biological markers that I can measure through blood draws, but also in sitting and talking to a patient. How do you feel? How is your life now, quality-wise, compared to before? There is a marked difference. JB: That is an extraordinary story. Using engineered foods both pre- and post-op to improve nutritional status would imply both macronutrients (things that are protein, carbohydrate, or fat) as well as micronutrients. What kind of biomarkers and outcome do you look at? For instance, you mentioned hair loss. Are there other kinds of biomarkers that you use as indicators of the nutritional status of the patient? Biomarkers of Nutritional Status LT: In our office, what we use routinely, as I made reference to, is a body composition analysis. That gives us kind of an overall picture. Remember, these are trends that we follow. On our first visit with these patients, I obtain a baseline study. From that study, we compare subsequent studies, pre- and post-op. That gives us an overall look. There are several labs that I believe are very important. I have found that following albumin and pre-albumin levels has not been as helpful to me in determining how well a patient is doing as the body composition analysis, although we do follow those. Some of the other markers that we look at are vitamin B12 levels, thiamin, vitamin A, 25-hydroxyvitamin D, parathyroid levels, serum iron, folate, and then just a comprehensive metabolic panel that would comprise electrolytes, glucose, kidney function, and hepatic function. For diabetics, we will obtain hemoglobin A1Cs, and for those who have prior history of hyperlipidemias, we will obtain a lipid profile as well. So, that would be kind of a standard blood profile that we would look at. All of these are important. There are a lot of potential long-term complications, even with the Roux-en-Y gastric bypass. We don’t see these things as frequently with the restrictive procedures, such as the LAP-Band, because patients are able to eat essentially everything they would like without consequence, as far as dumping syndrome goes. With the Roux-en-Y, though, the duodenum has been bypassed (your listeners may recall that the duodenum is an important area for iron absorption and for the B-complex vitamin absorption). Also, more distally, you can have B12 malabsorption. There is not really an intrinsic factor-bound B12 complex because that portion of the stomach has been bypassed, so B12 can become an issue. Vitamin A can become an issue. It is, of course, one of the fat soluble vitamins. If you have a patient who has had a malabsorptive procedure, you really have to watch the fat soluble vitamins (A, D, E, and K) because I can guarantee you will have malabsorption of these, and then vitamin deficiencies that go along with them. With the Roux-en-Y, osteoporosis and anemia, as well as thiamin deficiencies, have been quite prevalent. In even the surgical literature, these problems are being brought up more frequently. For osteoporosis, instead of waiting until you can actually, on study, identify bone mineralization problems, I follow parathyroid hormone levels, and find that they will be slightly elevated. When I encounter this, typically the vitamin D levels may actually be low-normal, but I find that if you push those low-normal levels up into a mid- or upper-normal range with added calcium, parathyroid hormone level will drop down into the normal range. I think this will go a long way in preventing the osteoporosis that we have been seeing in these patients. JB: I am going to have to break in because I know you have a busy schedule and we are coming to the end of our time. I think that what you have brought to us is an absolutely fascinating example of how functional thinking in medicine can create a different and more improved patient outcome. The coupling of extraordinary skills in surgery with the kind of mindset you have about patient outcome and looking at metabolic and nutritional parameters produces an outcome that probably has not been seen by most of your colleagues who are doing the surgery. It sounds to me like your patients remarkably benefit from this kind of thinking and I bet you get tremendous patient satisfaction and referral based on the way you are approaching this. I want to thank you. I think this is a conversation that we need to continue to explore because it has so many interesting implications relative to why we are getting obese: what are the nutritional problems, why do people who look like they have too much nutrition because they are so ponderous actually have undernutrition, and what are the metabolic consequences of this? If you wouldn’t mind, I’d like to come back and revisit with you at another time for a continuation of this discussion because I believe it has an implication not just solely on the morbid obesity-related problem, but this whole epidemic that we are seeing of metabolic transitions in our society. LT: Absolutely. Right now, obesity and the problems associated with it has surpassed tobacco-related deaths. We have over 300,000 deaths directly related to obesity in our country every year. This is a problem that is not going away; it is being amplified every year. We’ve got, as you referenced, metabolic syndrome issues, and this is all part of this big picture. There are so many areas to explore that are very exciting and I’d be happy to discuss some of these things. For physicians, if they do not have bariatric patients now, they will in the future, and knowing some of the anatomy and some of the pathophysiologic conditions that can occur as a result of the altered anatomy will go a long way in helping patients. In closing, for every one patient I’ve operated on, I probably see ten patients that have had procedures elsewhere that were done very well; it is not a procedure-related issue. JB: I can’t thank you enough. What an extraordinary course you have given us here in really a very short period of time. I am going to take you up on your willingness to revisit this topic at a future time. I wish you and your patients the very best. I think those people who go to the Carson-Tahoe Hospital Medical-Surgical Weight Loss Center and are seen by you and your staff are getting a tremendous benefit. Thank you very much and we’ll be in touch soon. What a marvelous job Dr. Trotter did in describing a very complex topic in a very short period of time. I think you are probably as amazed as I am at how well he could cover this expansive amount of material in such a clear and understandable way. We are not experts in the field of bariatric surgery and how nutrition relates to it at the end of this discussion, but certainly we know a lot more now than we did before we had the pleasure of listening to Dr. Trotter. One of the things I would like to follow up with in close this month is how this all relates to some of the more garden-variety problems that we are experiencing in populations that are not morbidly obese. That is, what role does the flux of molecules that come from our highly processed, shelf stable, convenience diet have on things like longevity and health and disease patterns? These are questions that obviously will be debated, discussed, defined, and massaged for years to come, but I think it is important for us to at least continue to put stakes in the ground as we learn more about this-trying to understand the complex issues and then how to translate this into individualized, personalized patient management through our functional medicine approach A Clinical Study on Calorie Restriction With that in mind, I was very impressed when I saw a paper published in The Journal of the American Medical Association titled ‘Effect of 6-Month Calorie Restriction on Biomarkers of Longevity, Metabolic Adaptation, and Oxidative Stress in Overweight Individuals.’16 For those of you who are not familiar with this particular study, let me just give you give you a couple of quick insights into it. This was a randomized, controlled trial of healthy (or presumed healthy), sedentary men and women (about 48 of them) conducted between 2002 and 2004 at the Pennington Center in Baton Rouge, Louisiana. The participants were randomized into four groups for six months: controls; calorie restriction; calorie restriction with exercise; and very low-calorie diet (this was an 890 calorie-per-day diet until 15 percent weight reduction was achieved). It is a very interesting study. What did they find? They found that the mean weight change at six months in the four groups was as follows: the control group had a loss of weight of about 1 percent on average; the calorie restriction group without exercise had about a 10.5 percent weight reduction; the calorie restriction with exercise had about a 10 percent reduction (so it was about the same); and the very low calorie diet had about a 14 percent weight reduction. The very low calorie diet group had the greatest amount of weight reduction. At six months, however, the metabolic principals were as follows: fasting insulin levels were significantly reduced from baseline in the intervention groups (all were P<.01), whereas DHEAS and glucose levels were unchanged; core body temperature was reduced in the calorie restriction and the calorie restriction with exercise groups, but not the very low-calorie group or the control group. After adjusting for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction group, the calorie restriction with exercise group, and the very low-calorie diet group. The authors point out that these ‘metabolic adaptations,’ (based upon loss of metabolic mass) were statistically different from controls. This is where the study gets kind of interesting. Protein carbonyl concentrations were not changed from baseline to month six in any group, whereas DNA damage was reduced from baseline in all intervention groups. The findings suggest that two biomarkers of longevity (fasting insulin levels and body temperature) were found to decrease by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. What I take away from this is that if you look at a 12.5 percent calorie restriction with a 12.5 percent increase in calorie use by modest exercise, that that is an achievable value for most individuals by dietary and lifestyle modification; it does not put them at high risk and does not make them feel like they are starving and moving to some kind of a deprivation lifestyle. And yet the effects that it had on the flux of molecules over the genes that created excessive mitochondrial oxidative fire and oxidative injury and glucose intolerance was dramatic. I think what we are learning about bariatric surgery in the extreme can be applied in ambulatory care centers by diet and lifestyle modification that is very modest-a 12 percent reduction in calories, a 12 percent increase in energy expenditure by regular exercise. Food for thought, as we move to next month’s October Functional Medicine Update. Thanks so much.

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Bibliography

1 Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century. N Eng J Med. 2005;352(11):1138-1145. 2 Parkes E. Nutritional management of patients after bariatric surgery. Am J Med Sci. 2006;331(4):207-213. 3 Schinkel R, Pettine SM, Adams E, Harris M. Impact of varying levels of protein intake on protein status indicators after gastric bypass in patients with multiple complications requiring nutritional support. Obes Surg. 2006;16(1):24-30. 4 Khaitan L, Smith CD. Obesity in the United States: is there a quick fix? Pros and cons of bariatric surgery from the adult perspective. Curr Gastroenterol Rep. 2005;7(6):451-454. 5 Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351(26):2683-2693. 6 Alvarez-Leite JI. Nutrient deficiencies secondary to bariatric surgery. Curr Opin Clin Nutr Metab Care. 2004;7(5):569-575. 7 Schleithoff S, Zittermann A, Tenderich G, Berthold H, Stehle P, et al. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006;83:754-759. 8 Vieth R, Kimball S. Vitamin D in congestive heart failure. Am J Clin Nutr. 2006;83:731-732. 9 Bao B, Yeh S, Lee Y. 1&alpha;,25-dihydroxyvitamin D3 inhibits prostate cancer cell invasion via modulation of selective proteases. Carcinogenesis. 2006;27(1):32-42. 10 Schwartz G, Blot W. Vitamin D status and cancer incidence and mortality: something new under the sun. J Natl Cancer Inst. 2006;98(7):428-430. 11 Giovannucci E, Liu Y, Rimm E, Hollis B, Fuchs C. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst. 2006;98(7):451-459. 12 Vieth R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J Nutr. 2006;136(4):1117-1122. 13 Heaney R. Barriers to optimizing vitamin D3 intake for the elderly. J Nutr. 2006;136:1123-1125. 14 Kemmis C, Salvador S, Smith K, Welsh J. Human mammary epithelial cells express CYP27B1 and are growth inhibited by 25-hydroxyvitamin D-3, the major circulating form of vitamin D-3. J Nutr. 2006;136:887-892. 15 Al-Oanzi Z, Tuck S, Raj N, Harrop J, Summers G, et al. Assessment of vitamin D status in male osteoporosis. Clin Chem. 2006;52(2):248-254. 16 Heilbronn L, de Jonge L, Frisard M, DeLany J, Larson-Meyer D, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals. JAMA. 2006;295(13):1539-1578.

Welcome to Functional Medicine Update for October 2006. Functional medicine often deals with the underlying mechanisms that inter-connect different diagnostic codes to try to provide an explanation of common cause for what later is seen as differing pathologies. It is that detective-type of story that really highlights (and gives a specific personality to) functional medicine. It is like putting together a puzzle: taking different pieces of information from clinical presentation, history, antecedents (such as in the genes), and environmental factors (often called “triggers”) that then lead to the modification of mediators, which results in the signs and symptoms of a disease. The emerging concepts that underpin functional medicine are codified very nicely in the Textbook of Functional Medicine. True functional medicine, however, requires some pretty detailed detective finding and some searching by the clinician. Some people are much more suited to this than others, as can often be seen in how a person approaches his or her life. For individuals who like a detective story and like putting together different bits of information to create an outcome of understanding, functional medicine provides a formalism to achieve that objective. One of the most interesting examples related to how this model can be applied is in the area of neurosciences and neurological conditions (what is sometimes termed as “behavioral neurology,” the interface between psychiatry and neurology). There are a variety of diagnostic codes-things like attention disorders and hyperactivity disorders; various forms of schizophrenoform disorders; cognitive deficit disorders; and also autistic spectrum disorders. All of these have very complex etiologies and interrelationships of environment, genes, and basic neurochemistry. In this issue of Functional Medicine Update, we are going to take a new look at a story that we have heard about before in Functional Medicine Update over the years: the homocysteine story. You may recall that we interviewed Kilmer McCully-the father of the theory connecting homocysteine to cardiovascular disease-talk about his 1969 discovery connecting elevated homocysteine and vascular disorders. Since then, there have been a lot of controversial papers on both sides of the table on this-some saying that vitamin supplements with folic acid and B12 will lower the risk to homocysteine-induced cardiovascular injuries; some saying the say the opposite (most recently, apaper in The New England Journal of Medicine titled “Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease” in which it was concluded that there is no benefit from B vitamin supplementation 1 ). In this issue of Functional Medicine Update, we will be discussing the concept of behavior neurology. We will start with our interview with a clinician of the month who I think has a tremendous concept to share with us, Dr. Richard Deth.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Richard Deth, PhD Northeastern University Department of Pharmaceutical Sciences 312 Mugar Hall 360 Huntington Avenue Boston, MA 02115 JB: Once again we are at that part of Functional Medicine Update when we have the privilege of speaking to someone who is doing something that I think represents where the field of functional medicine is going-the trajectory of change. Our interview this month is with Dr. Richard Carlton Deth, who is a professor of pharmacology at Northeastern University in Boston, Massachusetts. He has been there for a number of years as a full professor; he is also a past chairman of the department of pharmacology. He has been involved with pharmaceutical sciences now for more than 25 years. His research publications are many, and you are going to hear much more from him about the areas that he has focused on for the last 10 years or so. These have to do with molecular mechanisms that underlie autistic spectrum disorder and biobehavioral changes (cognition changes). I think Dr. Deth brings a unique and incredibly insightful perspective to these topics, which translates to real clinical benefit. We will even have the chance to talk with him in this interview about his congressional testimony. There are many parts to the series of discoveries that Dr. Deth has made that I think you will find fascinating. Dr. Deth, welcome to Functional Medicine Update. For our listeners, I think that the way we might start into this is to have you tell us a little bit about the D4 dopamine receptor activity and its connection to cognition; I know that is going to lead us down a path to discussing some of the discoveries you have made over the past several years. An Introduction to the D4 Dopamine Receptor RD: Thank you, Jeff. It is my pleasure to be here; I appreciate the invitation. Let me try to introduce the D4 dopamine receptor. In doing so, you’ll recognize that the neurotransmitter dopamine, of course, has a family of receptors-that it exerts effect times 5, to be exact. The D4 dopamine receptor, which is our focus here, is the only one that carries out this process that we discovered, in which it is able to transfer methyl groups (that it receives from the folate pathway). It transfers them one at a time, but very rapidly, and places them on the phospholipids that surround the receptor, in the membrane of nerve cells. The D4 receptor is typical of G protein-coupled receptors (a big family), but it is the only one that can do this job because it is the only one that has methionine residue. That is the critical chemical location necessary in order to be able to carry out this process. Just by way of personal recollection, how we got started on this was because we were doing molecular modeling studies using the technology of computer graphics and studying these G protein coupled receptors, and then we particularly focused on the location that happens to be where this methionine is. We were studying other receptors, and the process we were interested in had to do with why they had spontaneous activity, and it turns out that this methionine location is involved in that; it regulates the spontaneous activity of these receptors. The D4 Dopamine Receptor and Cognition The D4 dopamine receptor is very interesting in humans and primates, in particular. After we noticed this methionine, which is-again-a unique feature, we started to look at the general literature of the D4 receptor. In about 1995, I guess it was, there was a study (the first one) linking it to ADHD, obviously a problem related to the role of dopamine and attention that involved the D4 receptor. The link that was brought out at that time was that a particular feature called a “repeat” (a structural feature on the cytoplasmic side of this receptor that was variable in humans as a one-to-the-other) was found to be a risk factor, if you will, for ADHD. This broke down to if you had 7 of these repeats, then your risk of ADHD was estimated at 3- to 5-fold higher than if you didn’t have the 7-repeat form. So this was intriguing and it gave the first clue to us that that receptor might have a unique role to play in attention since variations in its structure apparently were related to variations in attention. The number of repeats is one feature of the D4 receptor, but at the same time there are 35 different sequences (or probably more by now) that are possible for each of those repeats. So there is a fantastic variety from human to human in terms of the D4 receptors makeup and its structure. The function of these repeats is to hold other molecules-other proteins and channels and transporters-to the receptor; it’s a binding site where they can be held by the D4 receptor. We think that this feature goes hand-in-hand with the methylation of the membrane by the receptor (as dopamine stimulates it) because these other proteins that are bound to it become targets-they become things in the neighborhood (or the microenvironment) that can be modulated or affected by the methylation of the membrane that we discovered. All of these things, together, make for a very interesting signaling complex involving dopamine and attention. Really, that is how we got started and it sort of led us to all the other features, like autism. JB: That is a really interesting background. For the sake of our listeners-often we have people with a variety of different strengths in the area of biochemistry and molecular genetics-I just want to summarize it. What you are referring to, obviously, are these receptors that are protein in nature. They are coded for by our genes, so we have unique polymorphisms that are possible, and in this particular receptor there are possibilities for a repeat of certain amino acid sequences that then change the structure function of that receptor and can alter, as you said, its ability to transfer methyl groups to the phospholipid core of the membrane, which then, in turn, changes receptivity of the membrane and its fluidity. It sounds like a very dynamic dance that has a lot of genetic underpinning, and-you are going to tell us, I know-also some environmental factors that can influence this. RD: You did a very good job of summarizing that. JB: Thank you. One of the things that you said in your papers, which I found fascinating-I never had recognized this-is that all mammals have this DR4 (dopamine receptor 4), but there is a very interesting relationship between cognition in the animal and this repeat frequency, and so you can actually kind of do a map of cognition or attention in the animal’s own DR4 genetics. Could you tell us a little about that? Mapping Cognition RD: Well, this is an area that is still sort of being worked out. I mentioned that these particular repeats were restricted to primates, that is, the nature of them turns out to be 16 amino acids involved in each of the repeats, 48 nucleic acid bases at the level of the gene, and that’s what primates have. You have to have at least 2 of these repeats which aren’t present in other species to be a primate, if you want to think of it that way. But, there are similar kinds of repeats, not exactly the same as the human primate type, but there are similar signs that other species also have modifications (or repeats) within their D4 receptor structure. These other species include dogs, whales, and animals to which we tend to attribute the ability to think in certain intelligent ways. While that is really an area that is early in its clarification, it might mean (and I think it does, at least) that whatever process this dopamine receptor facilitates might be very important for the function of the mind as a whole. So, we will have to wait and see, but we think that (and we have proposed) it is involved in synchronizing parts of the brain to be able to work together, more or less, as a whole (sort of integrating parts of the brain). JB: That leads us, then, into a question as to what is the proposed relationship between DR4 activity and polymorphisms and ultimately conditions like ADHD or autism? The Relationship between DR4 Activity and ADHD and Autism RD: Well, I mentioned that the 7-repeat form was linked to ADHD and we were measuring this methylation activity, also, in different receptors with different repeats, and we found that the 7-repeat form was weak in carrying out methylation in response to dopamine. This caused us to think that the weakness of methylation might end up being a weakness in attention, and if that was true, it could sort of join up with that genetic risk-factor idea. Reasonably, we know that there are really two activities of dopamine that help support this overall process. One has to do with changing the shape or the confirmation of the receptor. The second has to do with stimulating the supply of methyl groups to the receptor. It looks like the 7-repeat stimulates the supply of the methyl groups to the enzyme methionine synthase very well. Some factor associated with the receptor’s shape, or other features of the physical properties of the receptor are sort of less favorable, and so there is a balance of things, but it appears as though the 7-repeat form is associated with a risk of ADHD. What I think goes on (just to be more precise about it) is that the process by which the dopamine D4 receptor normally makes its own methyl supply better (or adequate) involves the activation of the enzyme methionine synthase. This is the enzyme-the B12 and folate-dependent enzyme-that brings methyl groups to the receptor and, therefore, has to get a new methyl group every time a previous one is donated. It looks like D4 receptors stimulate that enzyme, and they do it by helping the enzyme to create methyl B12, or methylcobalamin, in a glutathione-dependent manner. This is an area of work that really gets started from an observation made by Dr. Jim Neubrander, which you may have heard about (many people now have). He observed that methyl B12 (or methylcobalamin) was having unique therapeutic effects in a significant number of autistic kids, and so it was a challenge to us to relate that to our D4 receptor work. JB: What you are describing is absolutely an example of functional medicine. You are crossing what were considered separate channels in traditional science and medicine. We know Dr. Neubrander very well-he has been a functional medicine supporter for many years-and to move from the clinical world to the genetics world, back to the clinical-biochemical world, and then to the neurological sciences world-and to do it with such ease-is, to me, the embodiment of what functional medicine is all about. I want to applaud your willingness to do this because I know that often in the field of scientific research we are not supported for doing that; we are often criticized because we’ve cut across somebody else’s domain. RD: You’re right. With the way both medicine and research are practiced and explored, there are these boundaries, which are not fixed, but are quite real, nonetheless. In our case, it is pieces of molecular puzzles. In some cases, puzzles of the disease, such as autism or ADHD, but in other cases, a puzzle of how nature accomplishes something. Those boundaries disappear, really, when you approach problems from a practical standpoint of trying to figure out the puzzles. More or less, we have gone step by step and discovered, and actually taken on, new areas of understanding and learning-whatever is necessary for the next challenge, or the next step in the process that has presented itself. JB: Let’s get back to your story; it is very exciting. We have now said that the DR4 receptor biochemistry has some genetic polymorphisms. That means that there are things which can vary its ability to transfer methyl groups up to the membrane, and that methionine synthase is involved through the methylation transfer reactions. This also means an interrelationship to the folate cycle and the B12 connection exists, which leads to the questions: What are the natural methionine synthase agonists that generally turn on this methylation pathway? And how do these vary from individual to individual? Methionine Synthase and Homocysteine RD: The methionine synthase is an enzyme, rather than an agonist like turning on a neurotransmitter receptor, we are thinking here of an enzyme, which carries out a reaction and which needs certain cofactors and conditions to function effectively. Of course, its reaction is to take homocysteine (formed through the methionine cycle, as it’s called) and convert the homocysteine back to methionine by attaching a methyl group from methyl folate (tetrahydrofolate). It does that by temporarily taking the folate-derived methyl group and attaching it to cobalamin (or to, actually, the cobalt atom in the B12 or cobalamin), and then the methylcobalamin sits in the active side of the enzyme and waits for the homocysteine to be brought close in. When homocysteine is close enough, the methyl group is transferred to the homocysteine, and becomes methionine. With all of that having been done, the cobalt of the B12 is now bare again; it just needs to be refilled from the folate to carry out that cycle again. In the case of the D4 receptor, the ability to carry out this cycle is directed toward the methionine that is attached to the receptor, the one that is passing the methyl group along to the membrane phospholipids. What we proposed, and what we have now certainly very clearly shown, is that the anti-methionine synthase had two substrates. On the one hand it has the homocysteine, which is what it is certainly best known for. Elevations of homocysteine in various diseases-cardiovascular, atherosclerosis-related diseases, but also now in both schizophrenia and Alzheimer’s-probably also reflect problems with methionine synthase activity, but in addition to the homocysteine itself (as a substrate), we have the D4 receptor in its homocysteine state. The efficiency of this dopamine-stimulated phospholipid methylation depends critically on this enzyme. Anything that alters its activity-or its ability to deliver methyl groups to the receptor-is going to result in a loss of something like attention, or whatever role the D4 receptor plays in attention. JB: Is homocysteine elevation a plasma biomarker for this condition, or are they not really closely correlated? Elevated Homocysteine as a Biomarker RD: To my knowledge, there has been no description of an elevated homocysteine level in ADHD, for example, and certainly it is not elevated in autism, but I was referring to some conditions in which it is elevated. It is elevated, as I said, in schizophrenia, especially in first-episode males; it is very clear and one almost could consider it a biomarker there. And then in Alzheimer’s it is very commonly measured and has certainly been widely confirmed. But it is not specific for those conditions, of course. Elevations of homocysteine are associated with different conditions involving different organ systems and different tissue types because it is such a general metabolic process in all cells. JB: Do anti-folate medications have any adverse effects, clinically, on autism or attention deficit disorders? RD: That’s an interesting question and I’m thinking of methotrexate, widely used for leukemia. I’m well aware of neurological syndromes precipitated by methotrexate-but, again, it is in vulnerable individuals. Methotrexate, in and of itself in the broad population, does not typically produce neurological problems. But, if there is a background of vulnerability (typically genetic) that impinges also on these same pathways, and with the addition of methotrexate (for example), the lack of supply of methylfolate is brought about, then in conjunction with those other risk factors, a syndrome can develop. This is an interesting parallel to autism, more generally, where we think that people (kids) would have done fine in their lives and would not have suffered autism if it weren’t for some precipitating factor, not methotrexate, commonly, but certainly other environmental factors-heavy metals certainly being near the top of that list. JB: I want to move to that and take a little sidebar summary. What we have said so far is that those things that support proper methyl transfer from the DR4, which would be things like the folate cycle nutrients (B12, 5-methyltetrahydrofolate, B6, betaine [as a methyl transfer component]) seem to be helpful. Then we go to the other side of what are things that might actually inhibit methionine synthase and cause problems (in the susceptible individual) in the transfer of methyl groups to the phospholipids. That leads us to one of your great additional discoveries around the heavy metal connection, so I would like to ask you about the lead and mercury part of the story, which I know has been a major advance that you’ve brought to our attention. The D4 Receptor and Heavy Metals RD: As we pursued the factors that are important for the D4 receptor (the methionine synthase activity), we recognized that there is a role here for glutathione and for the redox state of cells. In particular, in neuronal cells and neurons and in the brain and in the cortex (just to be quite specific about that), the methionine synthase exhibits a specific and an absolute requirement for methyl B12 (or methylcobalamin), and the methyl B12 has to be synthesized by a glutathione-dependent pathway. Even if we consider the pharmaceutical forms of B12 like cyanocobalamin, that must be converted first to glutathionylcobalamin, as an intermediate, and then the glutathionylcobalamin gets converted to the methyl B12, and the methyl B12 is essential for methionine synthase activity in the cortex and in the neuronal tissues. It is not essential in the liver and in other organs because the enzyme is configured differently in those other organs. In the brain and neuronal tissues, the ability of methionine synthase to be reactivated when the cobalamin gets oxidized requires this exogenously supplied methyl B12 (or synthesized methyl B12). The way that heavy metals come in is because heavy metals are a prime example of agents that cause a decrease in glutathione levels. We showed that mercury, lead, and thimerosal are all very potent inhibitors of methionine synthase, and that the inhibition occurs because these metals cause about 40 percent decrease in glutathione levels in the cells. As a result, the methyl B12 availability is blocked, and accordingly methionine synthase activity decreases to an undetectably low level. It was a very critical effect that the heavy metals had via their effects on the glutathione. Now that is important because, as Dr. Jill James’ work has shown a second time in her recently released paper, autistic kids have decreases in glutathione of about 40 percent in their peripheral blood. That kind of a decrease certainly suggests that these kids don’t have the capacity to make methyl B12, and therefore will have a deficit in methionine synthase activity and a deficit in the dopamine-stimulated methylation process. JB: This is really fascinating. Again, we are looking at genetically unique individuals who, as a consequence of the way that their tandem repeats are seen in their DR4, may have differing relative susceptibilities to ineffective methylation of phospholipids and membrane transport phenomena, and that due to genetic uniquenesses certain individuals may be much more sensitive to these environmental agents-like heavy metals. And then you introduced the substance-which I want to come back to-“thimerosal,” which I know has been a hugely controversial topic in medicine. Thimerosal is a preservative that is used in various types of products, particularly immunizations. In one of your papers, or maybe it was in a couple of your papers, you had a very interesting bit of data that I was unfamiliar with that relates to the effect thimerosal has in cell culture. And then, you reported actual levels in the blood in children after they get an immunization. Could you tell us a little bit about that? That was news to me. Thimerosal Data RD: Yes. As we tested these environmental agents (and by that I mean lead and mercury, but also arsenic and cadmium had similar effects), we found that they were very potent. By that I mean the concentrations that could be described as “sub-nanomol,” or really low concentrations (concentrations that were known to be associated with lower IQ). For example, in the case of lead, these concentrations detected in the blood have been very clearly linked to lead poisoning and neurological consequences. As we did response-type of experiments, we could gauge the potency of these agents. In the case of thimerosal, the relationship was such that at the concentration of 10 to the minus 9 (one nanomolar, as it is called scientifically) we had a good 50 percent inhibition of this process. There have been papers published (by Pichichero, in particular-the one I am thinking of was in The Lancet) where they measured the levels of mercury that were produced in the bloodstream (the peripheral blood of children that were vaccinated). 2 Their studies showed about a 10 nanomolar concentration in circulation as a result of vaccination, and that was even 10 days or so after the vaccination. Clearly, that concentration was enough in our system-the cultured cells, which is considered artificial. Still, we have to be kind of circumspect about these concentrations-the effects that we were seeing (the inhibitory effects on the enzyme methionine synthase) were occurring at physiologically relevant concentrations. That is important because mercury and ethylmercury and thimerosal can inhibit many (if not all) cellular processes at some concentration. I mean, if you have enough of it, you can kill anything; that is why it is used as a preservative. To implicate it in something that might be related to, let’s say, mercury vaccines, you certainly had to show that it [the activity in question] is exquisitely sensitive to very low concentrations of the thimerosal, and in effect that is what we found. Congressional Testimony on Thimerosal JB: I was able to pull up a record of your testimony that you gave to the US House of Representatives Committee on Government Reform and Rights and Wellness, and I think you also gave a similar testimony to the Committee on Appropriations, on the link between thimerosal and autism back in 2004. How did that go and how was it received? RD: The political realm is certainly different from the scientific realm. The first testimony was basically Dan Burton’s subcommittee, and of course he has been a champion of the anti-mercury cause (if you can say it that way) for a number of years and still is because of his grandson’s autism and his conviction that is has something to do with mercury. Just to be frank, it was a subcommittee called for the purpose of bringing this to light and there were persons like myself offering testimony. I gave testimony and it became part of the congressional record and so you are able to access it. It serves that kind of a purpose, but it really wasn’t involved in, let’s say, a legislative process; it was like a hearing about something that a congressman was interested in. The other hearing was actually a little more dynamic and a little more central. There was actually quite a bit of interest in that hearing. The basis for that appropriations hearing was to question the thimerosal in vaccines because of the flu vaccine (purchase of flu vaccines could be thimerosal-free vaccines or thimerosal-containing vaccines); this was really the basis for that. There were (if I can say it this way) some “big-shots” or important people besides myself on that committee. Julie Gerberding from the head of the CDC, for example, and Tony Fauci from the NIH were there talking about the value of vaccination, generally (they didn’t necessarily advocate mercury). In any case, the setting for that was a little more electric. There was coverage by CSPAN and there were reporters; it had the makings of a bit of a media event. What was interesting was that part way through that very hearing about thimerosal safety it was announced that there was a flu vaccine shortage. We all recall that there was this rush to get vaccines because of a problem in their manufacture, and there indeed was a flu vaccine shortage for a little while and then it went away within a few weeks and there wasn’t a flu vaccine shortage. But it was just kind of interesting. There was a confluence of issues, and what the world heard about certainly had nothing to do with thimerosal and vaccination; it had to do with a shortage of flu vaccines and rushing out to get one would be a good idea. JB: We have had the opportunity to speak with Dr. Herbert Needleman. Undoubtedly you know about his work with lead and IQ in children. I am just wondering if there is a connection between your discoveries that lead (as one of the heavy metals) could have an adverse effect on DR4 activity and its methylation and IQ? DR4 Activity and Lead RD: That is such a great question. I just heard the answer this last week. I just came back from a meeting in Little Rock, Arkansas where a speaker (unbeknownst to me) who was speaking about lead (Dr. Ken Dietrich, I believe, from Cincinnati) was presenting. He had shown that different concentrations of lead produced deficits in function (neurological deficits), and then he went back to look at the D4 receptor genotype in those individuals in the different lead concentration groups. What he showed (and presented here) was that if you had that 7-repeat form of the D4 receptor (the risk-introducing form), then indeed you had more severe effects of lead. He, therefore, was presenting this in the context of a gene-environment interaction-that is to say, that genetic feature made individuals more sensitive to the environmental presence of lead. It was very remarkable for me to be sitting in the audience, not knowing this investigator, and hearing that relationship. It really answered the question that you just asked in a very clear way. JB: That’s fascinating. Obviously we have gotten to what for many of the listeners is probably the payoff question. That has to do with what are, in your estimation, the potential implications of this work, specifically for clinicians who are treating autism? Are there some “pearls” that we can take away? You have talked a little bit about the cobalamin, methylcobalamin, and the 5-methyltetrahydrofolate, the glutathione…can you guide clinicians as to what you feel is coming out of this as it relates to its implications? The Clinical Applications of D4R Research RD: Those things, in fact, are clearly coming out of this. In our most recent work, I just want to emphasize (it’s very exciting) that the cortex requires methyl B12, and it requires glutathione to make it. Supportive treatments, which of course are very well known to functional medicine, that could raise glutathione levels (and by that I am referring largely to N-acetylcysteine, for example) would be very complementary to the administration of methyl B12, along with methyl folate or folinic acid (either one of which raises the levels of 5-methyltetrahydrofolate. That combination of three things would seem to be best targeted to support this process in the cortex (critical for that, as a matter of fact). In addition, there are other modalities that we hear about that are interrelated to this. What this brings up is the importance of normalizing redox state in the cortex. To do that, those things that I mentioned certainly go in that direction, but so do a lot of the other things that are already being used (to name some: omega-3 fatty acids, by virtue of their nature, influence oxidative stress and reduce oxidative stress by a different pathway; and antioxidants of all different forms can be helpful here). To look ahead, hyperbaric oxygen is another thing that seems to be helpful in this regard. Lowering the levels of adenosine, which is a player that is also a part of this process, would be a useful therapeutic goal, and I believe that the HBOT (hyberbaric oxygen therapy) may be acting through that means when it produces benefit. Then there is the interest in drugs that address inflammatory state (beyond NSAIDs and things like that). I’m thinking here of the so-called PPAR-gamma agonists, things like Actos and other glitazone drugs used commonly for type 2 diabetes, but also now being tested for use in Alzheimer’s, for example. They also seem to be effective in autistic children. So there are a number of those things, some of which are clearer than others, and the methyl B12 issue now of concern is what dose should we be using and should we be delivering it through nasal, transdermal, or subcutaneous injection methods? Clinical trials and comparative studies are necessary to sort that out. So there is benefit, but then one needs to figure out how to optimize the benefit. JB: I can’t tell you how much we appreciate what you have done in this very short period of time. You have raised the level of our understanding an order or two of magnitude. Your work is pioneering and you communicated it so very well. It is a very complex topic, but you brought it to a level that we can understand. Dr. Deth, I really want to thank you. I know this is a sacrifice of your time, but it will spread widely and I think many people will value from what you shared today. We wish you the best in your continued work and hope we can check back with you in the future. RD: I look forward to that, Jeff, and thanks for having me on. JB: It’s my great pleasure. Thanks so much. For many of you, you may have just had your mind expanded with the concepts that Dr. Deth was sharing with us concerning the methionine synthase connection to the DR4 genotype and how that relates to membrane methylation, how that connects to neurotransmission and to arousal and attention, and how that may then inter-relate with environmental factors, such as nutritional status and toxic environmental exposures to things like mercury or lead.

Dr. Roger Williams: The Relationship between Early Research and Current Findings

As I was listening to Dr. Deth and reading his papers, I flashed on a reflection of a conversation I had many years ago with one of the founding fathers of nutritional medicine. He is a paragon (as we have viewed his work in the development of this field) and that is Dr. R.J. Williams (Dr. Roger Williams from the University of Texas), the father of the concept we call “biochemical individuality.” Many years ago, when I was attending a seminar he was presenting, Dr. Williams said, “Nutrition is for real people. Statistical humans are of little interest.” In light of the postgenomic era that we are now living in, and in the context of Dr. Deth’s presentation, we are starting to look at this as a nutrigenomic question, aren’t we? That is, the interrelationship with specific genotypes and environmental modifiers of function, both genetic and epigenetic. The Concept of Genetotrophic Disease It struck me that I should review and share with you what Dr. Williams was talking about in the 1940s. Nineteen forties-I want you to recall the context of this discovery. He was helping us to understand, early on, the nature of biochemical individuality and what he later termed “genetotrophic disease.” This is a concept that seems as prescient and as current today (in light of Dr. Deth’s comment) as it was ahead of its time in the 1940s. The Discovery of Pantothenic Acid For those of you not familiar with Dr. Williams (and I would be surprised if you listen to Functional Medicine Update and are unfamiliar with him), he was a prolific scientist, and he cultivated many extraordinary students and co-investigators. For example, Dr. Don Davis, a colleague of mine and a friend, was one of his postdoctoral (and later) research colleagues in the field, and he has continued to do extraordinary work. There were hundreds of young investigators coming through Dr Williams’ laboratories. He was known as the father of pantothenic acid, having discovered it as one of the B-complex nutrients, and so he had earned his stripes as a very competent scientist and, in fact, at one time was the president of the American Chemical Society, one of the largest professional organizations for chemists. He was highly respected. If you want to read a classic, read the review of Dr. Williams’ work on pantothenic acid, which was published in Nutrition Reviews in 1979. 3 Evaluating Nutritional Adequac Dr. Williams and his colleagues (including Dr. Davis) looked at all sorts of different ways of evaluating nutritional adequacy. What they went on to say is that there are ways of looking at nutrition adequacy from a pathologic perspective (like you would see with anemias or protein wasting, hypoalbuminemia, scurvy, beri beri, or pellagra), or you could use functional criteria for establishing nutritional adequacy. They published a paper back in the middle 1970s in the American Journal of Clinical Nutrition titled “Potentially Useful Criteria for Judging Nutritional Adequacy.” 4 They looked at things like voluntary consumption of food, sleeping time after anesthesia, weight gain after surgery, healing time after surgery, hair growth after clipping, voluntary sugar consumption, and recovery time after cyanide poisoning. They varied the nutritional status of the animals and then they looked at those functional criteria and showed that there was very marked difference in functional response to each of those parameters that would be early warning indications of undernutrition, well before you saw frank malnutrition (the pathological signs of scurvy, beri beri, pellagra, or whatever it might be). They then asked the question: how can the climate of medical education change to incorporate some of these concepts into teaching so that doctors are more attuned to these early warning markers for later-stage, more serious problems? That, of course, was all built upon the belief that each individual patient was different from any other patient and had genetic uniqueness. This was first discussed by Dr. Williams in The Lancet, in a classic paper published in 1950 (three years before Watson and Crick talked about the structure of the gene and the double-helix). This was all discussing biochemical individuality. Dr. Williams ultimately derived the term “genetotrophic disease.” In this landmark paper in The Lancet, where Dr. Willimas describes and defines genetotrophic disease (later reviewed in Nutrition Reviews in 1950), he talks about how genetotrophic disease describes a condition that a patient has that is of a complex origin and that came about because of long-term nutritional inadequacies (individualized to the patient). 5 This is seen in such things as increased risk to diabetes, heart disease, arthritis, and a variety of conditions, including complex disorders like alcoholism. This work was received with great resistance and tremendous push back from the medical and scientific community when it was published. In fact, the genetotrophic concept of nutrition (when reviewed in the Journal of the American Dietetic Association in 1954) was criticized because it “did not have adequate clinical support.” 6 Over the years, however, we have seen this concept of genetotrophic disease become accepted due to a better understanding of the underlying clinical and laboratory science. In 1953 in Science magazine, an article was titled “Genetotrophic Disease,” authored by Loeffer and Mefferd, in which they said that the concept of genetotrophic disease offers a totally new paradigm potential in the origin and explanation for complex chronic disease. 7 In fact, Dr. Williams, himself, in the classic article, “The Concept of Genetotrophic Disease,” which was published in 1950 in The Lancet, said that individual metabolic patterns could result from genetic uniqueness that is modified by environmental factors, of which the major one is nutrition leading to expressions of different patterns of function. 8 In a Proceedings of the National Academy of Sciences paper in 1949, Dr. Williams and his colleagues wrote about individual metabolic patterns, genetotrophic disease, and alcoholism. Alcoholism: Connections to Genetotrophic Disease and the Dopamine Receptor What we have just heard from Dr. Deth causes me to go back and rethink alcoholism, arousal, attention, and the dopamine receptor. Those of you who are following this in the area of neurology and behavioral psychology are undoubtedly well ahead of me, because you know that there is an ever-increasing body of literature to indicate that dopamine receptor polymorphisms are associated with the risk to various substance abuse problems. People who may have depressive tendencies and/or low arousal tendencies often have dopamine receptor polymorphisms. From what we have learned from Dr. Deth, these individuals may be less able to transfer methyl groups to membrane phospholipids and to respond to messages of arousal and attention and mood. This is a very interesting concept. I want you to recall that in 1949 Dr. Williams had the clarity of understanding to propose the concept of genetic uniqueness, although he had no idea of DR4 and he had no idea of molecular genetics post Watson and Crick and he had no idea of the birthing of nutrigenomics that would occur around the turn of the 21st century. He gained this understanding from animal work and the extraordinary studies he had done with nutrition, noting that the modification by environmental factors in the diet were extraordinarily important in determining outcome (phenotype and trajectory of response). Even such things as sugar craving and alcohol craving in animals could be modified by dietary variables that were unique to the individual. Think about this in the context of what we are seeing in our society today, such as the “Supersize Me” fad or the high sugar-high fat diets. Receptors are pleasure centers that can give constant loud messages of joy and of pleasure going to our neurochemical system, and they are varied in they way they are responded to on the basis of the person’s own unique biochemistry. But in the end-just like turning up the volume at a rock concert to the point that it causes ear damage-eventually the receptor system goes quiet; it loses its sensitivity. It accommodates for this excessive noise by turning down the sensitivity so you have to go louder and louder with more and more messages of excitement to ultimately get the arousal to be perceived. What Dr. Williams was talking about with genetotrophic disease is genetic uniqueness not being met by the nutritional intake of the individual and the resulting effect on expression over time-not in a day, maybe not in a week, maybe even not in a month-but over months to years (maybe even over decades). Consumption of a suboptimal diet ultimately leads to suboptimal performance that culminates as a disease. With alcoholism, his principle was that there is something unique in the genes that if not properly modulated in the diet, can express itself as an increasing hunger for alcohol. Recent Literature about the DR4 Receptor The literature on the DR4 receptor and alcoholism connection is very fascinating. We know that cortical dopamine receptors genetically seem to be different in alcoholics versus controls, which can be seen in whole-hemisphere autoradiography and cortical function tests in the individual. This was published in Psychopharmacology in 2005.10 We know that if you knockout different types of message signaling systems in the brains of mice it influences dopamine receptor activity. These mice will display reduced ethanol-induced rewarding effects, which alters their hunger for alcohol; this was shown in Neuropsychopharmacology in 2005.11 We know there is strong evidence that dopamine receptors are interrelated to the addictive properties of alcohol, and that different polymorphisms appear to be more susceptible to alcohol intoxication and other substance abuse dependencies. These relate, again, to the uniqueness of the individual with regard to their own genes. The long-term effects of maternal separation on ethanol intake and brain opioid and dopamine receptors was studied in rats. Alteration in dopamine receptor activity and function and alteration in dopamine levels stimulating arousal translated into differing intakes of ethanol (increasing intakes with lower dopamine activation) were associated with time away from mothers.12 Dopamine receptors and transporters in alcoholics were measured by whole-hemisphere autoradiography in humans, and differences were found between the Cloninger type 1 and type 2 alcoholics.13 Some studies have also suggested that novelty-seeking or extraversion behaviors are associated with alcoholism, but the relationship with Dopamine receptor polymorphisms is not well established.14 The Relationship between Alcoholism and Nutrition The concept is that there may be genetotrophic uniquenesses to alcoholism. The question is how does that relate to nutrition? I am, again, going back to Dr. Roger Williams. Remember that his first papers on alcoholism as a genetotrophic disease go back to 1949, well before any of the information in the discussion that we had shared with us by Dr. Deth was even the glimmer of understanding or a hypothesis. Is there any relationship between those nutrients that we have talked about with regard to methylation properties through the DR4 receptor and alcoholism? This would have to do with methionine-homocysteine transference and those nutrients like B12, B6, folic acid, or 5-methyltetrahydrofolate and betaine. If you do a quick little research review of the literature on homocysteine and alcoholism, you find some very interesting things. Recently in Epilepsia in 2006, a paper was published titled “An Assessment of the Potential Value of Elevated Homocysteine in Predicting Alcohol-withdrawal Seizures.” This study investigated the observation that alcoholics with elevated homocysteine levels have more difficult withdrawal symptoms.15 Alcoholism and Plasma Homocysteine Levels We recognize there are short-term cognitive deficits during early alcohol withdrawal that are associated with elevated plasma homocysteine levels in patients who have alcoholism. This was the Journal of Neural Transmission in 2006.16 We know there is a very high presence of homocysteinemia in chronic alcoholics. One could ask, is that a cause or an effect? Is it an associated variable as a consequence of the alcoholism or does it precede the alcoholism as a co-variable due to alterations in the genetics of methyl transfer reactions? These are all very interesting questions that I think bear back on what Dr. Roger Williams talked about in the genetotrophic theory of disease and alcoholism being an example of one of those diseases. I have just cited a paper on the prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics that was reviewed in Alcohol Clinical and Experimental Research in 2005.17 What I would like to leave as a concept for us to consider is that maybe there is more than autism and maybe there is more than ADHD that is associated with what Dr. Deth has been proposing to us: that these are examples of genetotrophic complex situations; that a variety of different chronic conditions that present themselves as not related, one to the other, all may have some connection to this methylation pathway and to unique concepts of genetic transference of methyl groups or methionine synthase and this whole other family of enzymes that are involved in the tetrahydrofolate cycle and methylation as a pathway. Depression: Connections to Genetotrophic Disease and the Dopamine Receptor In many individuals, depression is a condition treatable with intramuscular B12 injections and oral, high dose tetrahydrofolate supplementation. A paper in the Journal ofPsychopharmacology in 2005 talks about the prevalence of low B12 status and low folate status in depressive patients and the use of diets and/or supplements that are high in folate and B12. 18 This is seen more frequently in individuals having the MTHFR C677T polymorphism that impairs homocysteine metabolism and this is over-represented among depressive patients. The authors talk about oral doses of over the RDA for folic acid (around 800 mcg daily) and B12 (1 mg per day) should be tried to improve clinical outcome in patients with depression. Again, Dr. Williams in his genetotrophic concept of disease, talked about this as being an example (depression and alcoholism as genetotrophic diseases). Now, some 60 years later, we are revisiting this in light of new mechanisms in the work that Dr. Deth shared with us (methyl transfer reactions and the DR4 receptor and how this relates to possible propensity or sensitivity to melancholia and to lowered arousal and lowered attention). I think these are quite dramatic examples of where this field of functional medicine is going: to interconnect different pieces of information to try to piece together a detective puzzle that leads to different clinical approaches beyond just treating the individual symptoms, or, what some people call, “chemical incarceration” (giving a drug that will suppress a certain symptom but then makes the individual less than fully functional. Betaine: An Important Cofactor in the Tetrahydrofolate Cycle One of the things about this homocysteine connection and methylation that I wanted to add to the story (because we often forget its importance) is the additional methyl donation nutrient called betaine. Betaine is an essential cofactor in a portion of the tetrahydrofolate cycle. As I mentioned, there are a number of different enzymes involved in the tetrahydrofolate cycle (methionine synthase only being one) that all have the potential for polymorphisms. That is one of the reasons that this is a very complex problem to treat because you can have a multiple series of uniquenesses in this pathway that present as the same thing (elevated homocysteine) but have come from differing contributions. Betaine (or so-called trimethylglycine) is a very important cofactor in one of these steps involved with the tetrahydrofolate cycle. It was shown a number of years ago by the Wilkins husband-and-wife-MD team in Australia that people who are non-responsive to B6/B12 and folic acid but have elevated homocysteine may respond to supplemental doses of betaine. The Effect of Betaine on Plasma Homocysteine In a paper that was published in the Journal of Nutrition in 2006, investigators evaluated orally administered betaine and its effect on both serum betaine and plasma homocysteine concentrations in apparently healthy humans.19 In this particular study they used graded doses: 1, 3, and 6 grams per day of betaine. The doses were mixed with orange juice and ingested after a 12-hour overnight fast. The volunteers were all randomized into different treatment groups. They found that orally administered betaine had an immediate and dose-dependent effect on serum betaine, so it was well absorbed and could be measured in plasma. Single doses of 3 and 6 grams lowered homocysteine significantly, whereas the 1 gram dose did not. So, it appears as if you need at least 3 grams in order to have a homocysteine-lowering effect if a bolus dose is given. The change in plasma homocysteine was linearly associated with the betaine dose and also serum betaine concentration. Urinary excretion of betaine seemed to increase with an increasing dose. I think we should keep in mind that that is another component in our clinical bag of tools for managing homocysteine and promoting support for methylation reactions. This, again, is trimethylglycine and the single dose threshold in the healthy human population was around 3 grams. Are Specific Genotypes More Likely to Respond to Vitamin B Supplements? When we go back to where I started this discussion at the beginning of this month’s Functional Medicine Update, I talked about the homocysteine-lowering studies with folic acid and B vitamins in vascular disease (the so-called HOPE trials-the Heart Outcomes Prevention Evaluation Trials), published in The New England Journal of Medicine and which were negative about the value that B vitamin supplements for cardiovascular benefit. One has to ask the question now, are there specific variant genotypes that are more likely to respond? Are we over generalizing to say that all people with homocysteinemia will have the effects of lowering the homocysteine from B12 and folic acid or B6 alone, or are there variants that are more highly sensitive to this interrelationship and by stratifying the data to those genotypes we might see much more significant interrelationships between vascular disease, homocysteine, and the lowering of homocysteine with folic acid and B vitamins? I don’t have the answer to that question, but I am just trying to raise in our minds some observations that are coming from how this literature and these studies are proceeding over time, but always going back, really, to Dr. Kilmer McCully’s observations and (preceding that) to Dr. Roger Williams with his genetotrophic disease concepts. I think often we tend to want to throw the baby out with the bath water. We find, from one study, that something did not work as we thought and therefore we go back and throw out in our minds the whole conceptual framework without understanding the specificity of that study relative to the framework. The framework of the genetotrophic disease concept is as viable and strong today as it ever was and it continues to get stronger with more information that is accumulating related to nutrigenomics and to chronic disease etiology. I think the homocysteine trials are very important and I I think we have a lot to learn about individualization and genotypes that pertain to individual response. L-Arginine Supplementation: Discussion of a Response to a Study Published in JAMA I would not have done a complete discussion on this subject if I did not also talk a little bit about the study by Schulman, et al, in the Journal of the American Medical Association in 2006, surrounding the role of L-arginine supplementation in vascular disease. You know L-arginine also plays a role (through its influence on endothelial nitric oxide generation) on the homocysteine-mediated effects on the vascular endothelium. You might recall that the Schulmann paper, which describes studies of intervention using oral arginine supplementation failed to show any positive benefit on endothelial function or on cardiovascular risk from arginine supplementation. This article was titled “L-Arginine Therapy in Acute Myocardial Infarction: The Vascular Interaction with Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial” and it appeared in the January 4, 2006 JAMA.20 The clinical study enrolled patients who were at least 30 years of age and within 3 to 21 days of their first ST-segment elevation myocardial infarction (or STEMI). Cardiac catheterization was performed and patients were documented with Q-wave MI, present cardiogenic shock, active acute coronary syndrome, and severe underlying non-cardiac disease limiting predicted life span to less than one year. If we were took those individuals who were excluded from the study, and also excluded people who had poorly controlled diabetes or renal disease or hepatic disease, and then we looked at the effects that L-arginine had in that inclusion population, it didn’t look as if there was any positive influence on vascular function from L-arginine supplementation. However, as you probably recognize, there were a number of questions raised about the study and its conclusions. Published Comments of Dr. Louis Ignarro I think the most insightful of these comments were from Dr. Louis Ignarro, distinguished professor of molecular and medical pharmacology and also the Nobel Prize recipient in Medicine and Physiology for the discovery of nitric oxide at the Department of Pharmacology at the University of California, Los Angeles. His response was recently published in the Journal of the American Nutraceutical Association in 2006.21 In this particular response Dr. Ignarro raised a number of questions about the study and the conclusions derived from it. He says that L-arginine is one of the most abundant amino acids in the diet and adult humans consume 3 to 6 grams of L-arginine daily depending on their dietary protein habits (it is higher in vegetable protein than it is in animal protein). Administering L-arginine is something we do everyday when we eat a normal diet. He goes on to say, however, that therapeutic L-arginine given as a single amino acid can have a very significant positive role in increasing endothelial nitric oxide activity and reducing asymmetrical dimethyarginine levels, all of which have been shown by other studies to have positive benefit (long-term) in the prevention of vascular dysfunction. His question is: Does the absence of an effect with an acute administration of L-arginine post MI negate the potential benefit of L-arginine taken prophylactically to improve endothelial function with individuals who have marginal endothelial dysfunction (as measured by vascular elasticity studies or modest hypertension)? Many studies, as Dr. Ignarro goes on to point out, have demonstrated that L-arginine in humans has a salutary and beneficial effect on those vascular functional parameters, well before acute therapeutic effects as a drug are talked about. I think this raises some interesting questions about the role these nutrients play in medicine. We are really talking more about functional interventions when we are talking about things like ADHD, or alcoholism, or vascular/arterial stiffness; these are functional parameters (well before acute pathology) that relate to fundamental underlying translations of genetic uniqueness into phenotypic outcome (into the function of the individual). I believe this model is perfectly compatible with a pathology-based model because there will always be need for managing a patient who has a demonstrable pathology using acute intervention strategies. These may be new-to-nature molecules that are derived from the wonders of pharmaceutical science or surgery or many other new technologies that are being developed, including biotechnology. But in the same breath, there is also the need for ways of intervening early through functional improvement using those indicators of suboptimal translation of genes into phenotype. That is where the story that Dr. Deth has been sharing with us on this issue may play such an important role in the framing of this new medicine. Thanks for being with us. We are going to have some questions and answers to talk about in this particular issue. Questions and Answers I would like to finish up this month’s Functional Medicine Update with a few questions that have been raised by our listeners that I think are clinically pertinent and probably of general interest. The first relates to magnesium status and how we evaluate it and what some clinical signs and symptoms are. Dr. Sidney Baker talks about “zips” and “zaps” that are associated with magnesium deficiency. These are funny little pains-like short circuits in your neurological system-and you get spontaneous muscle cramping. These things are not as obvious as pathophysiologies, but they are early-warning clinical markers of magnesium insufficiency. A more clinically relevant issue, mitral valve prolapse, has a very interesting (and not obvious) connection to magnesium insufficiency. Idiopathic mitral valve prolapse refers to the systolic displacement of one or both mitral leaflets into the left atrium, with or without mitral regurgitation. It is not uncommon, it is seen more frequently in women than in men, and it usually appears to be a benign condition and even capable of recovery. In a minority of cases, mitral valve prolapse may predispose to complications. Some evidence has accumulated suggesting genetic heterogeneity, and possibly some SNPs (Single Nucleotide Polymorphisms), that are related to susceptibility to this condition. It appears as if there is a magnesium connection to this condition and it may be connected through specific SNPs that make this condition more prevalent in certain genotypes. This has to do with what might sometimes be called “latent tetany” (tetany being an example of an acute magnesium deficiency). There was a review paper on this subject published in Magnesium Research in 2005 that titled “The Importance of Magnesium Status in the Pathophysiology of Mitral Valve Prolapse.”22 In this article, the authors write about the fact that there are now a variety of both epidemiological and intervention trials that seem to indicate that hypomagnesaemia is associated with increasing incidence of mitral valve prolapse. This question of hypomagnesaemia is an interesting question in its own right. Are we talking about low serum levels of magnesium (the most standard clinical evaluation that is used for detecting magnesium insufficiency), or are we talking about intracellular magnesium insufficiency (which deals with something like red cell magnesium, if the test was done right and the red cells didn’t leak and lead to partial hemolysis that causes alteration in the test values), or are we talking about a functional test for magnesium (which is to do a magnesium loading test where you administer oral or intravenous magnesium and then you look at the level spilled in the urine in 24 hours? Generally if a person is saturated with magnesium, the loading test will show significant excretion in the urine of that magnesium load (over 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} will be excreted in 24 hours). If a person is magnesium depleted, then obviously their cells will pick up and incorporate that magnesium and so their urinary spill may be very nominal over the next 24 hours (10-15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} spill). The loading test has been considered by many to be a better functional test for magnesium status as it pertains to cellular levels. The intracellular erythrocyte magnesium is kind of considered the second-level test for detecting magnesium status. Lastly, is the serum magnesium test (which has limited value because you are not sure exactly what you are measuring in that magnesium is historically an intracellular element as contrasted to, say, sodium and calcium, which are extracellular). The assessment tool that best clinically correlates with mitral valve prolapse is to use either red cell magnesium or the magnesium loading test; it doesn’t seem to correlate too closely with the serum magnesium level (that may be more related to frank magnesium deficiency, when you are getting into tetany and more severe magnesium deficiency symptoms). If you look at this magnesium connection, we are really talking about lymphocytic magnesium being very important. Lymphocytic magnesium is indirectly related to erythrocyte magnesium, which is then correlated with the relative function of cardiac activity and the mitral valve function. There is a published paper that discusses magnesium deficit in lymphocytes as part of the mitral valve prolapse syndrome. This paper appeared in Magnesium Research in 2004.23 There is ever-increasing evidence to suggest that hypomagnesaemia, as measured by these cellular functional tests (either erythrocyte magnesium or the magnesium challenge excretion test) are very good correlates with the relative risk to mitral valve prolapse. If you are examining a patient and, when doing your cardiac evaluation, it turns out you have a sticky valve or something that is going on that suggests mitral valve prolapse, you might consider doing a magnesium status evaluation either with the red cell magnesium or the magnesium loading test. The other question that has been raised, and I think for very good reason, is the question concerning what appears to be the complex (and maybe counterintuitive) results of the studies that have been recently published on homocysteine and the role that vitamin supplementation with folic acid and vitamin B12 have in altering cardiac risk in patients with hyperhomocysteinemia. As we will discuss in more detail in this issue of Functional Medicine Update, the HOPE 2 Trial results were recently published in The New England Journal of Medicine. This trial focused on homocysteine as a biomarker for cardiac risk and the role that vitamin B12 and folic acid supplementation has in modifying that relative risk through the lowering of that biomarker. The conclusions of the study were very disappointing for those of us who felt that folic acid and B12 do play salutary and beneficial effects in hyperhomecysteinemia and lowering cardiac risk because the data did not demonstrate that; it did not say that there was any real advantage. So, what about these studies? I have been in conversation with my colleague, Dr. Dan Lukaczer, about this and I want to share our joint view on this topic because we have had a chance to exchange some thinking. If you look at the HOPE 2 Trial results published in The New England Journal of Medicine, there are a number of things about these studies that raise some questions. I want to be cautious about not always being critical of a study that is negative to our belief because sometimes a negative means a belief was wrong, it does not mean the study is wrong. There are, however, some questions about the design of this study. The patients who were recruited for the study had initial homocysteine levels that averaged around 12 ng per milliliter, which many investigators might think is not high enough to really demonstrate the pathophysiology of homocysteine (more around 15 or higher). Maybe the average levels were lower than desirable. Second, the reduction in homocysteine after intervention was not really down to the level that most of us would like to see homocysteine reduced to (Dr. Kilmer McCully talked about this and it was somewhere around 7 ng per milliliter). The average lowering in these subjects in the HOPE 2 Trial was between 9.6 and 9.7, which we might consider not low enough. Maybe they did not start high enough, and maybe at the end of the study they did not end up low enough on the intervention trial. This may have been because they didn’t use high enough doses or the prolongation of the therapy was not extensive enough, or maybe they had a collection of different genotypes, some of which were more responsive and some less and so they actually averaged out (all questions yet to be answered). Another (and probably more interesting) part of this story is that this study used people who had already-existing cardiac disease. These certainly were not healthy people and this was not a prevention trial (not to the extent of primary prevention, this was secondary prevention). The study was 2 to 3 years in duration. If a person has already had an MI and they have a lot of pathophysiology going on, is it realistic to expect that in 2 to 3 years of intervention (when they only lower their homocysteine down to a modest level) that they are going to get marked improvement when they have already had injury to their arterial endothelium and their vascular function? That is a question for which I don’t have an answer. I think raises some questions about the extrapolation (or conclusions) of this data to apparently healthy people in an earlier stage of cardiac dysfunction or endothelial dysfunction, and what role intervention with folic acid and B12 might have in them. I think we still have not really answered the question about prevention versus treatment. I would consider secondary prevention to really be treatment because we have ongoing pathophysiology. If we are really dealing with an intervention based upon a sick population, the question is what level of intervention is required for promotion of function (in that their dysfunction may be multi-phasic in origin because one thing begets two begets three begets more than that when systems start to fall apart to pathology)? Maybe you cannot just put one block in the dam and have it all focus on health because you’ve still got other things going on in the pathophysiology of the arterial wall. I think we need to keep in mind the HOPE 2 Trial as we start looking at how therapy designed to lower homocysteine is applied. In the course of this month’s FMU we are going to be talking about some other additional elements (beyond folic acid and B12) that you, as a clinician, should be aware of. These elements include trimethylglycine or betaine intervention, because we recognize that this is another important nutrient for the lowering of homocysteine and the improvement of vascular function (this is work that we cite). We will also address pyridoxine (vitamin B6). We are starting to look at variables that relate to this complex array of polymorphisms associated with the folate cycle, to modify homocysteine metabolism and to produce improved arterial function. I think you will find that there is an “aha” beyond that which the HOPE 2 Trial talked about, and that is what role do these methylation functions have (in which the surrogate marker for their evaluation is homocysteine elevation) on cellular function across many diseases, independent of ICD-9s? It may be that homocysteine is a phantom surrogate marker. It may be that it is only part of the story or the tip of the iceberg for broader implications of the methylation story.

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Bibliography

1 The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1-11. 2 Pichichero M, Cernichiari E, Lopreiato J, Treanor J. Mercury concentrations and metabolism in infants receiving vaccines containingthiomersal: a descriptive study. Lancet. 2002;360:1737-1741. 3 Williams RJ, Truesdail JH, Weinstock HH Jr, Rohrmann E, Lyman CM, et al. Nutrition classics: journal of American Chemical Society volume 60, 1939 pages 2719-2723 pantothenic acid. II. Its concentration and purification from liver. Nutr Rev. 1979;37(1):15-18. 4 Davis DR, Williams RJ. Potentially useful criteria for judging nutritional adequacy. Am J Clin Nutr. 1976;29(7):710-715. 5 Williams RJ. Concept of genetotrophic disease. Nutr Rev. 1950;8(9):257-260. 6 Elbert EM. Genetotrophic concept in nutrition. J Am Diet Assoc. 1954;30(9):900-902. 7 Mefferd RB Jr, Loeffer JB. Genetotrophic Disease. Science. 1953;117(3044):3. 8 Williams RJ, Beerstecher E Jr, Berry LJ. The concept of genetotrophic disease. Lancet. 1950;1(7):287-289. 9 Williams RJ, Berry LJ, Beerstecher E. Individual metabolic patterns, alcoholism, genetotrophic diseases. Proc Natl Acad Sci USA. 1949;35(6):265-271. 10 Tupala E, Hall H, Tiihonen J. Visualisation of the cortical dopamine D3 receptors in alcoholics and controls with human whole-hemisphere autoradiography. Psychopharmacology (Berl). 2005;181(2):412-413. 11 Houchi H, Babovic D, Pierrefiche O, Ledent C, Daoust M, et al. CB1 receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors. Neuropsychopharmacology. 2005;30(2):339-349. 12 Ploj K, Roman E, Nylander I. Long-term effects of maternal separation on ethanol intake and brain opioid and dopamine receptors in male Wistar rats.Neuroscience. 2003;121(3):787-799. 13 Tupala E, Hall H, Bergstrom K, Mantere T, Rasanen P, et al. Dopamine D2 receptors and transporters in type 1 and 2 alcoholics measured with human whole hemisphere autoradiography. Hum Brain Mapp. 2003;20(2):91-102. 14 Soyka M, Preuss UW, Koller G, Zill P, Bondy B. Dopamine D4 receptor gene polymorphism and extraversion revisited: results from the Munich gene bank project for alcoholism. J Psychiatr Res. 2002;36(6):429-435. 15 Bleich S, Bayerlein K, Hillemacher T, Degner D, Kornhuber J, et al. An assessment of the potential value of elevated homocysteine in predicting alcohol-withdrawal seizures. Epilepsia. 2006;47(5):934-938. 16 Wilhelm J, Bayerlein K, Hillemacher T, Reulbach U, Frieling H, et al. Short-term cognition deficits during early alcohol withdrawal are associated with elevated plasma homocysteine levels in patients with alcoholism. J Neural Transm. 2006;113(3):357-363. 17 Blasco C, Caballeria J, Deulofeu R, Lligona A, Pares A, et al. Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics. Alcohol Clin Exp Res. 2005;29(6):1044-1048. 18 Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol. 2005;10(1):59-65. 19 Schwab U, Torronen A, Meririnne E, Saarinen M, Alfthan G, et al. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans. Nutrition. 2005;136:34-38. 20 Schulman SP, Becker LC, Kass DA, Champion HC, Terrin ML. L-arginine therapy in acute myocardial infarction: the vascular interaction with age in myocardial infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006;295(1):58-64. 21 Ignarro L. Bland J. Evaluation of the article published in JAMA (295:58-64, 2006) by Schulman et al. Review of arginine and vascular health study. JANA. 2006;9(2):1-3. 22 Bobkowski W, Nowak A, Durlach J. The importance of magnesium status in the pathophysiology of mitral valve prolapse. Magnes Res. 2005;18(1):35-52. 23 Kitlinski M, Stepniewski M, Nessler J, Konduracka E, Solarska K, et al. Is magnesium deficit in lymphocytes a part of the mitral valve prolapse syndrome? Magnes Res. 2004;17(1):39-45.

Welcome to Functional Medicine Update for November 2006. I am frequently asked questions about some of the topics I discuss and how these topics may relate clinically. One question that has come up recently from a number of listeners has to do with the connection among vitamin D-calcium-magnesium, gut function, and risk to colorectal cancer: How does this work? Is this clinically relevant? And how much calcium, magnesium, and/or vitamin D might be useful? To introduce my response, I’d like to go to an article that appeared in 2005 in the Journal of Steroid Biochemistry and Molecular Biology titled (and this sounds like a functional medicine title), “The Vitamin D Endocrine System of the Gut-It’s Possible Role in Colorectal Cancer Prevention.”1 I think we all know that the gut represents the seat of the immune system. Over 50 percent of the immune system is clustered around the gut (the gut-associated lymphoid tissue), and 70 percent of antibodies are produced by the gut-associated lymphoid tissue (GALT). It is a very rich site of immune function. A lot of receptors are on the surface of the gut mucosal cells, and these receptors pick up messages that they then translate to the rest of the body through cell signaling processes-such as with cytokines and chemokines and other regulatory molecules. The Role of Vitamin D in Gut Signaling We know vitamin D plays a role in signaling at the gut level because there are receptors for vitamin D, and because of the ability of the colon cells (the mucosal cells) themselves to convert vitamin D into 1,25-dihydroxy D3 (the active hormonal metabolite of vitamin D). If you take colonocytes in the laboratory and grow them, you can show they possess vitamin D-synthesizing CYP27B1, which produces 1,25-dihydroxy D3, and also they have the activity of CYP24 hydroxylases, which are the catabolic enzymes that break down 1,25-dihydroxy D3. It is a dynamic equilibrium between production in the gut and breakdown in the gut. A low calcium diet upregulates the expression in the gut mucosa of the CYP24 hydroxylases, which are the catabolic enzymes that break down 1,25-dihydroxy D3. This tends to lower the activity of the hormonal form. The hormonal form of vitamin D is a very important agonist for a number of cell signaling processes that relate to the regulation of insulin signaling, the regulation of inflammation signaling, and the regulation of cell proliferation and cell cycling. If you increase the breakdown of 1,25-dihydroxy D3 signaling, it increases cellular proliferation, decreases differentiation, and decreases some of these cell regulatory processes that occur under proper immune balance. That occurs when your diet is shifted toward low vitamin D and low calcium. As people take away dietary calcium and/or vitamin D (through either the absence of sunlight exposure or vitamin D in their foods), it tends to shift these cell signaling processes toward altered gut-immune function and increased cellular proliferation, both locally and systemically. This raises a question, doesn’t it? What about the oriental diet? It is not a dairy-product consuming diet and historically very low in calcium. How is it that there is such a low incidence of colorectal cancer in Asian communities, where they don’t eat a lot of calcium in their diet and they don’t take a lot of vitamin D? It is a northern latitude population, so you might not expect that they are getting a lot of sunlight exposure. Recently, it has been reported in a number of interesting papers that the soy isoflavones are activators of the hydroxylases (the CYP27B1), and therefore promote (in the gut mucosa) the formation of 1,25-dihydroxy D3. You can get-through the combination of calcium and isoflavones-a very beneficial effect on this synthesis and the prevention of accelerated break down of the hormonal form of vitamin D locally/regionally in the gut mucosa. Now, we start looking at epidemiological cultural variations in the diet and the influence that has on cell signaling. Is this an example of co-evolution? Did we evolve, by natural selection over millions of years, the ability to accommodate and use different signaling molecules to produce salutary beneficial effects on regulating the immune system? Obviously I don’t have a crystal ball, but it sounds like a reasonable explanation. What we do know (epidemiologically), is that diets that are higher in isoflavones and lower in calcium seem to have a similar beneficial effect on regulating epithelial differentiation in the colonocyte, as does a diet that is higher in calcium and vitamin D. This might account for differences in dairy-product-consuming individuals with higher calcium intake versus low-dairy-product-consuming individuals who have higher isoflavone intake. If you take soy out of the diet (or other isoflavone-rich foods) and you take calcium out of the diet, now you have a double-barrel problem because you are not upregulating the synthesis of 1,25 at the colonic level, and you are increasing the breakdown, so you can shift this toward proliferation, dedifferentiation, and poor regulation. That is the story that is starting to emerge from these observations. The Relationship between Nutrients and Cell Signaling There is a very interesting take-away concerning the relationship of nutrients (bioactive compounds in our food) and cell signaling, and how this regulates gene expression patterns. We are not talking about changing the genes. We are talking about changing the expression of those genes (polymorphic genes) that then regulates the phenotype of cells. A person is not born hard-wired to get colon cancer, but there may be people who are more susceptible based upon their polymorphisms. An environmental modulator can be seen as a variable that penetrates through all the genotypes and is a modifier with different levels of sensitivity. An interesting paper has been published recently in Nutrition Cancer titled “Vitamin D Receptor Gene Polymorphisms, Dietary Promotion of Insulin Resistance, and Colon and Rectal Cancer.”2 The authors of this article investigated an interrelationship between insulin resistance, downregulation of the signaling of vitamin D active hormonal metabolite formation, and the dedifferentiation of colonocyte cells (increasing oncogenic risk). You are going to hear more about this as we move into the discussion in this month’s Functional Medicine Update. We should not leave other conditions out of this. This is a complex web-insulin resistance plays a role, genetic polymorphisms play a role, dietary calcium plays a role, and sunlight exposure plays a role. There are many different variables, including exposure to environmental in situ carcinogens (produced either by gut fermentation or direct intake). It is an example of the complexity of gene-environment interaction. Vitamin D Hydroxylase Expression and Tumor Prevention and Therapy Nutritional regulation of vitamin D hydroxylase expression has potential applications in both tumor prevention and therapy. There was a very interesting paper published in Future Oncology in 2005 that discusses this whole mechanism that I have been describing to you.3This is an emerging story about calcium and vitamin D, and we should add magnesium to that story because magnesium is a critically important agonist for the calcium dynamics of the cellular membrane, and may have some of the effects on the enzyme activity of these hydroxylase enzymes forming 1,25-dihydroxy D3. I encourage you to reflect back on our October issue, when I discussed the role of magnesium in these processes. Calcium, magnesium, vitamin D-do we need supplementation? The answer really comes from a diet evaluation. Is the patient consuming adequate levels of these nutrients, or exposed to sunlight in an adequate way (for vitamin D)? If not, then we might start talking about vitamin D supplementation (1000 IU) to support of function. We might talk about soy isoflavones or a soy-enhanced diet (1 or 2 portion sizes a day of soy with isoflavones; 20 to 30 mg a day soy isoflavones). We might talk about calcium in the range of 1000-1200 mg. Lastly, 400 to 500 mg elemental magnesium in a non-GI-irritant form. That is the range of therapeutic intervention that you might consider if a patient really has evidence of compromised status (relative to those nutrients that help regulate gut-immune function) and has evidence of GI imbalance in terms of immunological regulation through these cell signaling pathways (the cytokines, chemokines, and intercellular communication agents). Because we are on the subject of the gut, let me take a little sidebar related to one of the most significant gut-inflammatory conditions that we are seeing with high prevalence in our population. In fact, it is one of the most common afflictions in western countries; I am talking about diverticulosis. Diverticulosis is so common that its presence is more normal than its absence among older Americans. Is diverticulosis normal? I don’t think we consider it optimal, but it is the way people are as a consequence, primarily, of what is acknowledged as a low-fiber diet. Fiber, by the way, has more than just a physio-mechanical effect upon the gut mucosa (like a scouring pad that wipes the villi clean). It is able to be fermented by various types of microbiota that live in the colon, which produce secondary trophic factors that can have favorable influence on the physiology of the colon. One of these factors is butyrate (a colonocyte fuel). We should think of fiber (or the appropriate types of fiber) as a precursor to support proper formation and function of gut anatomy and physiology. Many gastrointestinal symptoms (such as hiatal hernia) are attributed (rightly or wrongly) to diverticulosis. We know there are two very real complications of diverticulosis that can carry serious consequences-diverticulitis and diverticular hemorrhage. Diverticular diseases (diverticulitis, in particular) are problematic because they can exist as abscesses of the colon and can create chronic sites of focal infection. Obviously, this can lead to perforation and very serious problems of sepsis. Even under the best of care I think there is about 7 to 11 percent mortality in people who have abscess and perforation as a consequence of diverticulitis. This is not to be taken lightly; these are serious considerations. Generally, the medical treatment for diverticulitis is bowel rest and total parenteral nutrition (TPN), followed by probiotics and prebiotics to improve gut flora. Specifically, patients are put on a high antibiotic regime, which is a combination of antifungal, antibiotic, and antibacterial agents (broad spectrum). They are on bowel rest (TPN) for 2 to 3 weeks, or sometimes as much as 2 months (depending upon the degree of inflammation of the gut). Following rest and the recovery, the GI specialist and/or surgeon will evaluate whether the patient is a candidate for surgery. Hopefully, there is a resolution of the problem without the need for surgery, because if surgery occurs it is generally a two-step surgery: first a colostomy (to allow cleaning up of the environment and “cooling off”) and then a reconnection of the GI tract afterwards. It is a pretty invasive process. The attempt, conservatively, is to first allow the bowel to heal by intervention with bowel rest and antibiotics, and then a diet that hopefully will renourish the colon with high fiber and friendly bacteria. Use of Probiotics in Patients with Diverticular Disease You might ask about using probiotics when you’ve got potential abscess (maybe even a perforating abscess) of the colon-is it really a good idea? What happens if you add bacteria to the gut-aren’t you running the risk of potential sepsis and infection? This question was recently addressed in a review article titled, “Probiotic Use in Clinical Practice: What are the Risks?”4 This appeared in the American Journal of Clinical Nutrition in 2006. I would encourage those of you who are probiotic users to take a look at this article because I think it does a very nice job of reviewing the literature; I’ll give you a quick appraisal of it. The authors of the article review papers that have been published about different strains of Lactobacillus acidophilus, Bifidobacterium supplementation, Lactobacillus reuteri, and even Saccaromyces boulardii (all of these various types of probiotic organisms). They look at cases of bacterial sepsis temporally related to probiotic use in humans. They cite 6 different studies that have been published that go back over the last 10 years that are case reports of potential septic disorders that were associated with the administration of probiotics. This includes liver abscess, endocarditis, and bacteremia (most common). These were using various kinds of LGG and Bacillus subtilis. The most common one is LGG (associated with 4 of these 6 reports). I need to emphasize (as the authors emphasize in the review) that these problems are not proven to be necessarily a consequence of the probiotics. These were sick patients who had perforated bowels and they had all sorts of other things going on, but because they were also supplemented with bacteria and they were able to culture their blood and find these probiotic organisms in their blood, there is some suggestion that it was a contributor. The authors’ take away is that if a person has serious gut inflammation with perforation, be somewhat cautious about the use of probiotics. The authors then go on to look at cases of fungal sepsis temporally related to probiotic use. The number of case histories is longer and principally associated with Saccharomyses boulardii. There are over 20 case reports with S. boulardii being associated with fungemia and fungemic shock. Again, the authors point out that we consider these safe organisms used for reinoculation of the bowel, but in cases where the individual is immune compromised (many of these case reports were people with perforation of the bowel in combination with HIV infection, so these were immune-compromised patients or very much older patients-patients that might have might have been in the intensive care unit) there may be sensitivity. These are extreme examples, maybe, of immune compromise and sensitivity to any kind of burden of foreign organisms that are not normal. Without raising too big of a red flag I want to put this out, just as food for thought. We recognize that probiotics often have a very beneficial effect on gut micorflora and they may (as has been suggest by a number of studies) lower gut inflammation when used appropriately. There are many more studies published in the literature showing favorable effects of probiotic supplementation with chronic gut inflammation than there are that describe an association with sepsis (or bacteremia or fungemia). I think the concept here is that nothing is completely safe. When we get up in the morning, we don’t have assurance that the day will be 100{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} safe; we just get up and move around our world. There is always some risk just to living, to breathing, to drinking. In a relative risk-benefit, it appears as if probiotics (certainly in the earlier stages of nonperforating diverticulitis) is beneficial in the remission of the disease. There are many good reports about this, including a recent paper that appeared in the World Journal of Gastroenterology in 2006 titled “Management of Diverticular Disease is Changing.”5 The authors of this article advocate the use of probiotics after bowel rest and antibiotics as part of the therapy for the management of diverticulitis. Everything in balance, I guess, is always the watchword. We should keep in the back of our minds the issue of what the state of the dysfunction or the pathology is of the patient when we use probiotic supplements. What we are really speaking to here is an interesting connection to inflammatory disorders, and that is going to be the theme throughout the rest of this month’s Functional Medicine Update, with specific focus on modulation of autoimmune disease. I am very intrigued with the story that you will hear because part of the clinical concern we have relates to the biomarkers that we use to identify whether a patient has early insipient inflammatory disorders (prior to joint disfigurement, renal failure, carditis, and some of the more acute symptomatologies that develop with autoimmune tissue-specific reactions and inflammation). It doesn’t take a very high level of diagnostic acumen to recognize an arthritide when it is deforming. But, well before that occurs, there is a sequence of events at the cellular level that occur from imbalances of the immune system. These events can be occurring over, maybe, decades before resulting in deformation and the serious pathophysiology associated with autoimmunity. Biomarker Development for the Early-stage Recognition of Inflammatory Disorders What are the earlier-stage markers that we might clinically evaluate? That is a question that I wish I could give you a definitive answer for because it is a question in flux. What we are really talking about is biomarker development for early-stage recognition of inflammatory disorders. Paul Ridker certainly helped us to understand some of this in greater detail when he and his colleagues at Harvard got us to think about high sensitivity C-reactive protein. That is an example of a biomarker that is used for earlier warning recognition of potential insipient (or smoldering) inflammation. As we learn more about inflammation, we recognize that it is much more than just a marker called CRP. There are literally hundreds of differing signaling molecules that give rise to an alteration of immune function, which may express as an inflammatory disorder. Downstream from that, ultimately, is the production of C-reactive protein by the liver. Let me speak briefly about biomarkers because this is a term that we are going to be talking much more about in the years to come. The development of good, accurate, and respected biomarkers will really be the lynchpin upon which the future of functional medicine rests. In the absence of good biomarkers, we can speak philosophically all we want about early stages of disorders ,and antecedents and triggers and mediators, but the clinician doesn’t really know what to do. It just sounds like an interesting philosophical exercise: What do I look for in my patient? Exactly how to I know if they have an early precursor marker? How do I know if their genotype is expressing itself as an inflammatory phenotype that later will be a disease if I don’t have something that I can measure and evaluate and track? Biomarkers are very important. The sensitivity, precision, and accuracy of a biomarker with clinical specificity to a condition provides reliability in the way to assess, intervene, and then track the success of therapy. Serum Cholesterol as a Biomarker Serum cholesterol would be considered a biomarker. It is really not a measurement of pathology for any disease. If you are asked what disease is diagnosed with elevated cholesterol, the answer is really none. Elevated cholesterol is a prognostic marker-a physiological function marking a trajectory toward a disease (cerebrovascular disease, cardiovascular disease, and so forth). We have started down the biomarker road by including cholesterol in the standard SMAC test (the multiphasic screening laboratory analysis), but clearly cholesterol represents a pretty broadbrush-type of biomarker and there must be other individualized biomarkers in the sea of new genomic markers that are being discovered that would give better specificity and ability to identify personalized needs of the patient. Biomarkers are really part and parcel part of the development of personalized medicine. Recently, in the journal Genome Technology, there was a review paper about biomarkers on the horizon. The title of this article is “Betting on Biomarkers: Researchers Aim for the Clinic.”6 This is where clinical laboratories are starting to focus-to endorse and incorporate some of these new biomarkers. Biomarkers are central to personalized medicine, but they are only slowly trickling into clinical trials and there is some concern that although research is discovering potential new biomarkers, they are not being put to clinical tests. Although it may not appear that they are getting out into clinical evaluation adequately to help spur the development of personalized medicine, there is a great impetus to develop biomarkers. Pharmaceutical companies need better biomarkers for tracking some of their new individualized drugs, such as inhibitors for cancer treatment (which are based upon the individual tumor type of the patient). Categories of Biomarkers We can really break down biomarkers into a few categories. First would be the diagnostic biomarkers, which differentiate healthy from a specific disease state. Second, which for functional medicine devotees is probably the most important family of biomarkers, are what we call prognostic biomarkers. Prognostic biomarkers are those that predict the likely course of disease; here we look at expression analysis, epidemiological studies, and mechanism of disease, which is really what functional medicine has tried to focus on. How do genes get expressed? What environments alter gene expression? How does that track against epidemiological studies, where we can see some real effects in human populations? And, what are the underlying mechanisms that may cut across the ICD-9 codes? This really speaks to the origin of the disease. The biomarkers that understand the disease prognosis, help with the trajectory toward that disease? From a functional medicine perspective, this is the area that is most directed at clinical outcome. For example, C-reactive protein (CRP) is one of the trajectory type of markers, which by its early-warning recognition of smoldering inflammation, can help us to understand the course of later disease. In the course of our discussions in Functional Medicine Update over the next year, you are going to hear me speak much more about where biomarker development is going and how it relates to the field of functional medicine. What are some of the candidates-the players-that would help to identify personalized needs? Of the potential biomarkers that are emerging for inflammation, the inflammatory cytokines (including things like Interleukin-1, Interleukin-2, Interleukin-6, and tumor necrosis factor-a) are very interesting. We have all heard these names many times. These are proteins that are produced by components of the immune system or inflamed arteries, which then liberate these bioactive molecules that trigger cells at a distance to put the guards on the gate and generate a phenotype of inflammation. Is TNFa a Central Player in Inflammatory Processes? I have wondered if tumor necrosis factor-a (TNFa) is a central player in inflammatory processes. If it is a central player, why don’t we develop an analysis for TNFa, and why don’t we then develop a broad-scale therapy to block TNFa? That might be the easiest way of approaching the management-or the recognition and then later management-of many inflammatory conditions. But, if you explore that question a little more, you might ask whether TNFa signaling is the same in every cell. In other words, is there only one pattern of expression of TNFa? We often try to make these things a little simpler than they really are in human physiology. You have probably heard of some of the pharmaceuticals that have been approved for the treatment of autoimmune disease (rheumatoid arthritis, for instance) that are TNFa-blocking agents (or that modulate TNFa production). We see good clinical outcome from these blocking agents, but we also see some potential adverse side effects that occur from the generalized activity of these blocking agents. So what is the story around TNFa as either a biomarker or a target for therapeutic intervention? The best way I can get to that is to cite what (probably for most of you) would be a very esoteric article that you wouldn’t really necessarily read, but I hope I can demythologize this. This article appeared in the Journal of Biological Chemistry last year and is titled “Bruton’s Tyrosine Kinase is Involved in p65-mediated Transactivation and Phosphorylation of p65 on Serine 536 during NFkB Activation by Lipopolysaccharide.”7 Now this is probably not the article you are going to gravitate to for light reading. What is it all about? Let me summarize what it really says. It has been shown that NFkB sits in the cytoplasm of cells in a dormant state, bound up with an inhibitor called inhibitor-kB (or IkB), and this IkB-NFkB complex is quiet in a non-activated cell. When an alarm message arrives at the surface of a cell (coming from an outside message or something that would trigger an arousal of the inflammatory process), it is picked up at a membrane receptor on the outside of the cell, and it translated through a very complex network of pathways that involves kinases. That message then weaves its way through the membrane into the cytoplasm of the cell through kind of intracellular kinase relay race. The kinases involved in this relay are very specific for that message that came to the cell. For instance, bacterial lipopolysaccharides might trigger a different relay than do allergic responses, or toxic metals and xenobiotics. The messages from these relays ultimately arrive at the NFkB-IkB complex. Then, through a very sophisticated series of steps, again mediated by specific kinases, the IkB is phosphorylated and it falls off the complex, liberating the NFkB, which then travels to the nucleus as free NFkB. The NFkB is now in the nucleus and its role is to sit down on specific DNA sites to activate the genes that are associated with inflammation. So far, everything is good; I hope you are following. Now the question is: does that NFkB (when liberated) always affect the same genes in every cell so you get the same exact mechanism? Here is where the story gets interesting; the answer is no. Throughout all of this process I have described-the translation of the initial message into the cytoplasm of the cell, the liberation of IkB from NFkB, the translocation of NFkB to the nucleus, and lastly, the sitting down of NFkB onto the genome at specific loci that would up upregulate the expression of the genes associated with inflammation-is a very site-specific and very environment-specific function. A generalized NFkB inhibitor may produce good and bad effects, because there are some cells in which NFkB is playing a very important role in regulating function of the immune system. There are other cells in a person with autoimmune disease where NFkB is excessively activated and its modulation would be beneficial to the outcome of the patient. But if you generally block all activity of NFkB, you get no differentiation of the good from the bad. There are different sites on the NFkB molecules that can be phosphorylated by different kinases under different environmental circumstances that then cause it to identify and to associate itself with different reporter genes, so you would get a different outcome in those cells, which leads to specificity of the response. What am I trying to say is that this process is much more exquisitely complex than we have dumbed it down to be. The reason for that-in a teleological argument, if I can be so bold as to suggest an argument-is that if we had only one path to NFkB, and if NFkB is the only path to all inflammation, then every time we associate with a proinflammatory stimulus, every cell in the body that has NFkB in it (which are all cells) would become inflamed. Clinically, that is not what is observed, right? You know that a patient does not necessarily have every cell of their body inflamed when they come into contact with a proinflammatory agent; they generally have cell-specific types of inflammation. But if we use a general NFkB inhibitor, it does not matter if NFkB is working in a favorable way to modulate immune function or in a dysfunctional way to enhance inflammation-all of those processes would be blocked. This is a little bit like the argument of the COX 1 and COX 2 with the selective COX 2 inhibitors that we learned later produced adverse effects on the favorable effects of COX 2 (on the vascular endothelium). How does the natural system work? It works by very tight regulation of these cell signaling mechanisms through kinases that regulate only certain cells that need to alter their NFkB activation of genes to produce, then, specific types of cytokines. If you could imagine this from a therapeutic approach, what you would really like to have are biomarkers that identify what specific pathways within the NFkB cascade are associated with what dysfunction that will later lead to a disease (not just general NFkB dysfunction). So you would not necessarily just measure TNFa, which comes from the activation of gene expression by NFkB. You would want to know what cells are activated by specific types of cell signaling from NFkB that produce, then, TNFa, and you would want to regulate your therapy, specific to the biomarker that is associated with that process of activation of TNFa. Where I am going with this is to say TNFa is kind of generic. We do not know what cell it came from; all we know is that certain cell types were activated into inflammation through NFkB to produce TNFa, and that that came through upregulation of a specific kinase relay that is unique to that cell line. What we would like to know is what-specifically-needs to be modulated to target that cell line or that tissue type without just a general suppression of all forms of NFkB activation of immune function. That is a new pharmacology, isn’t it? That really leads to personalized medicine. Individual Tissue Regulation of Inflammation and Immunity: Identifying Kinase Pathways What kind of biomarkers might emerge from this concept or this objective? Biomarkers that would identify the individual kinase pathways associated with the individual tissue regulation of inflammation and immunity. In oncology, which is a good example of how this is being harnessed, things are happening with specific inhibitors in which (in the laboratory) tissues are being taken on biopsy and they are analyzed in that patient for that specific kinase. Using a general kinase inhibitor would not work because kinases are very important for the regulation of all sorts of important immune functions. But if you target on specific kinases that are associated with altered cell function in an individual patient, you have a possibility for a cancer therapy that is personalized. That particular strategy is actually being investigated for a number of the new oncology drugs. To me, that strategy is similar to where functional medicine is going around a whole series of other disorders. Those disorders are associated with a variety of complex chronic diseases. We could start by identifying those specific regulators of tissue-specific activation and then the molecules that would be useful for normalizing their function. I think you will learn more about this when you hear our researcher of the month speak because you will see how the environment modulates function. It may be that we have been modulating our function from time immemorial through all the things we are exposed to-by subtle alterations of these cell-specific kinase pathways that regulate our function in appropriate or inappropriate ways (e.g., from toxic foods, toxic environments, toxic thoughts). All these things then create dysfunctions in kinase signaling that are specific to certain cell types that give rise to different types of diseases. Let me close this argument with a less esoteric and a more specific clinical example. Those of you who have been following our discussion of autoimmune disease know that I have proposed a model. It is actually not my model-it comes from the literature, so I can’t claim this was invented here, just that it is communicated here. This is the idea that autoimmune disease is a consequence of building up responses to foreign agents in our body that were really part of the normal immune function of the body. What happens if our host-friendly cells become foreign cells and then the body’s immune system does what it is supposed to do-it forms an antibody or a protective factor or a destructive factor against that foreign substance? How can our body go from being a friend to being a foe-what would do that? Damage to proteins or damage to DNA by radiation or chemicals or various cell physiological mechanisms could take a host-friendly cell and make it into a foreign molecule (like a foreign protein that had a different amino acid-an oxidized or a glycated amino acid or a phosphorylated amino acid) that looks not like the host anymore. A very adept immune system is like a seek-and-destroy mechanism; that is called an autoantibody. Is there evidence for this model? Of course there is-I’ve cited numerous studies from the literature showing that DNA autoantibodies are often not to host DNA, they are to altered DNA. We call them antinuclear antibodies, but they are actually antinuclear-altered DNA antibodies. Estrogen and Autoimmune Disease What about the connection of estrogen to autoimmune disease? We know oral contraceptives affect things like SLE, so it sounds like estrogen is involved. We know that women who are pregnant and have autoimmune diseases often go into remission during pregnancy. And, we also know that women who are postmenopausal and get autoimmune disease often have some dysfunction of estrogen metabolism, or menstruating women often have a flare during their time of the menstrual period when they have autoimmune disease. This doesn’t all seem to fit; it seems inconsistent, clinically. Are we sure these conditions associated with estrogen are associated with 17b estradiol and not altered estrogen (the estrogen metabolites-the “funny”molecules-that can cause clastogenic or mutagenic influences on DNA and other molecules)-the twisted estrogen molecules like the 4-hydroxy estrogen and possibly the 16-hydroxy estrogen? Maybe we are looking in the wrong place. Maybe it is the altered estrogen metabolites that are associated with exacerbation of autoimmune disease. I reported on a clinical study that was published in 2001 in the journal Lupus that indicated that supplementation with indole-3-carbinol in women with SLE actually led to improvement of their symptoms and increased their 2-to-16-hydroxy estrogen ratios.8 I would like to throw out one last concept to you. There is a paper in the Journal of Nutrition titled “Lifespan is Prolonged in Autoimmune-Prone (NZB/NZW) F1 Mice Fed a Diet Supplemented with Indole-3-Carbinol.”9 (This is the animal model for SLE.) These mice were fed a diet supplemented with indole-3-carbinol, a phytonutrient that increases the 2-hydroxylation at the expense of lowering the 4- and 16-hydroxylation (so it is improving estrogen metabolism). What did they find? I won’t go through the whole study, but they found that the estrogen urinary metabolite ratio of 2-to-16 was increased in the indole-3-carbinol-fed mice, and these same mice had a remission of symptoms, and they did not die (death did occur in 70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the animals that were not I3C supplemented). The point I am trying to lead you to is that we are looking for biomarkers that are sometimes far away from what you might think of as the origin of the disease. You might not think of the 2-to-16-hydroxy estrogen ratio as a biomarker for autoimmune disease, but it may one for women who have estrogen exacerbation of their symptoms. For these women, phytonutrient supplementation with 200-400 mg of indole-3-carbinol a day, and following their 2-to-16-hydroxy estrogen ratio, may be very beneficial in ameliorating the course of their disease. Indole-3-carbinol comes from cruciferous vegetables-the broccoli, cauliflower, cabbage, Brussels sprouts family. Does this indicate there are certain foods that might be beneficial for the amelioration of autoimmune disease? A big question that we are going to discuss with our researcher of the month, Dr. John Bright.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month John J. Bright, PhD Senior Investigator and Director of Neuroscience Research Laboratory Methodist Research Institute of Clarian Health 1800 N. Capital Avenue Noyes Bldg, Suite E-504C Indianapolis, IN 46202 (317) 962-8722 Once again we are at that portion of Functional Medicine Update that I think we all are very excited to hear. This month we have Dr. John J. Bright as our guest, a senior investigator and director of the neuroscience research lab at Methodist Research Institute of Clarian Health in Indianapolis, Indiana. Before joining as director of neuroscience research at the Methodist Research Institute, Dr. Bright was at the department of neurology and pharmacology at Vanderbilt University School of Medicine in Nashville, Tennessee. While going through some abstracts related to autoimmune disease, I found that Dr. Bright’s studies in neuroscience and pharmacology to be very pioneering. As I was following a track of his research, I determined that he was also looking at the role that various nutraceuticals and plant-based materials have on the immunological system, pertaining specifically to autoimmune disease. It was a fascinating kind of circular connection that I came to while reading his work. I think his studies are very exacting, very precise, and very interesting. I would like to introduce Dr. Bright to you, the audience of Functional Medicine Update. Dr. Bright, thank you being with us today and sharing your very interesting work. Experimental Allergy Encephalomyelitis (EAE) and Multiple Sclerosis Research JJB: Thank you, Dr. Bland. I’m glad that I can share some of the studies that we have done on autoimmune disease that may benefit many millions of people who are suffering. Autoimmunity is a process in our body. Usually the immune system takes care of our body and is at war to fight against infection. At some point (and due to unknown reasons), immune response damages our own tissues and this is called autoimmune disease. This autoimmune response (attacking individual specific organs like the heart, brain, or pancreas) leads to specific diseases, including multiple sclerosis, rheumatoid arthritis, type 1 diabetes, and myocarditis. There are many autoimmune diseases that effect human health. There is no one hypothesis or theory that explains how these diseases happen, but one thing we know is that there is immune response against our tissues, our cells. We use an animal model for multiple sclerosis called EAE (Experimental Allergy Encephalomyelitis) to learn the pathogenesis mechanisms in this disease process and also to test the different molecules and drugs that may be useful in treating multiple sclerosis or other autoimmune diseases. EAE is a mouse model that we use. You can induce MS symptoms in different animal models, but our experiments mostly are in mouse model. We induce this disease by injecting neural antigens (or proteins from the brain), purified or synthesized in the lab. We usually inject two times (we call this “vaccination”). Two vaccinations lead to the development of a disease like multiple sclerosis. We score the animals by looking at clinical symptoms of paralysis. Usually the paralysis in these mice starts from the tail, and we call paralysis in the tail “score 1;” from there the paralysis progresses toward the anterior. If we see paralysis in the tail and the hind limb, this will be “score 2.” Paralysis in both hind limbs is “score 3.” Paralysis in the tail, both hind limbs, and the forelimbs will be “score 4.” If the animals cannot move or the animals die, this is “score 5.” By using different mouse clans we can induce different types of disease. There are two main types of multiple sclerosis we see in human beings: lapsing/limiting type and chronic progressive. We use SJL-type mice to induce lapsing/limiting disease; they get better after 25-30 days. The whole disease process of our experimental course is something like 0-30 days. When we induce the disease we usually score these animals clinically, and we also take immune cells from the animals and put these cells in culture, trying to learn the mechanisms of how drugs regulate autoimmune cells. We look at the specific signaling pathways that are blocked or regulated by these drugs so we can define the mechanism of the drug effect in these animals. We initially started looking at one cytokine called interleukin-12 (IL-12), usually produced by macrophages, microglia, or dendritic cells in the body. Microglia are macrophage-like cells present only in the brain. We found that if you induce the disease in this EAE model, the levels of IL-12 are higher during the disease and then come back down when the disease goes away (by treatment or otherwise). Interleukin-12 (IL-12) and the JAK-STAT Pathway We thought IL-12 was a good candidate to follow and treated the animals with anti-IL-12 antibodies (neutralizing antibody). There is a p40 subunit that is very important in this disease process, and if you neutralize IL-12, you can inhibit the disease. That was our early finding-we realized that IL-12 was a major player in this disease process. IL-12 gene expression and IL-12-induced function are the two aspects we wanted to study. IL-12 function means IL-12 acts on T cells to make them cells that can induce the disease. We call these encephalitogenic T cells, and they are mostly CD4-positive T cells. IL-12 induces Th1 (or T-helper-1-type) encephalitogenic T cells by signaling through a pathway called the JAK-STAT pathway (“JAK” for Janus kinases, “STAT” for signal transducers and activators of transcription). That is the signaling pathway that IL-12 uses to make Th1-type encephalitogenic T cells in EAE. What we did was use a compound that has been shown to inhibit inflammation; it is a compound that binds PPAR-g (peroxisome proliferator-activated receptor gamma). PPAR-g is a member of the family of nuclear receptors. These proteins sit in the nuclear membrane; if you cross link them with the ligand, it gets activated and inhibits inflammation (that was our understanding of this molecule). Synthetic ligand for PPAR-g has been used as a treatment for diabetes; there is a prescription (FDA-approved) drug for diabetes now. There are natural ligands for PPAR-g and there are synthetic ligands for PPAR-g. In our earlier experiments, we took those natural and synthetic compounds of the PPAR-g ligand family and treated these animals after inducing the disease EAE. We found that both natural and synthetic compounds can inhibit EAE in a dose-dependent manner. We went on to look at the mechanistic action and we found that it inhibits IL-12 production, as well as IL-12 signaling through the JAK-STAT pathway. That was our finding at that time and it was not just a drug effect. We used knockout animals. The homozygous knockout for PPAR-g protein is embryonically lethal, so we used a wild-type, a heterozygous animal for PPAR-g. If you knockout part of the PPAR-g function, the disease in EAE is severe. If the PPAR-g activity is low, the severity of the disease is higher, showing that it has a physiological function in the demyelization process. We believe this may be true in human illness as well (that PPAR-g is playing a role in regulating disease process). We have followed up on this with our interest in nuclear receptor family of proteins. Then we started looking at a different molecule-vitamin D. Vitamin D has been shown to be involved in regulating immune responses. We believe this (that sunlight correlates to disease) because inflammatory or demyelinating diseases are more common in the colder regions where vitamin D has more limits. We tested an actual metabolite of vitamin D-the 1,25-dihydroxyvitamin D3. We treated animals with vitamin D after inducing EAE demyelinating disease and it seems to protect animals from getting EAE. In this experiment, we also looked at the mechanisms of action that involved inhibition of IL-12 production, as well as IL-12-induced function in immune cells. Studying Molecules with Anti-inflammatory Properties: Quercetin and Curcumin With the knowledge that many natural compounds (nutraceuticals or phytochemicals) have anti-inflammatory properties, we selected some molecules to study-the most favored for us are curcumin and quercetin. Quercetin is a phytoestrogen and it comes from these kinds of compounds. Soybeans are rich in flavonoid compounds, as are many fruits and vegetables. In our experiment we used a very purified preparation of the compound quercetin and we injected it into mouse models of MS. The second compound we used was curcumin. Curcumin is a powder or extracted compound from a plant called turmeric. It is an underground stem (a rhizome). You can purify it. Usually it is a yellow-colored powder. People use it in Asian countries as a spice, to color the food products, and (in very low quantity) in their daily meals/food. In ancient days, in Asian countries, curcumin was used for wound healing and for treating inflammatory-type of diseases. We took curcumin and injected it into the EAE animals (doses of 100 and 200 micrograms, or 50 and 100 micrograms-different doses) every other day-IV injections in our animals. We found that curcumin inhibits (dose-dependently) the EAE disease in mouse models, suggesting that it may be useful for treating multiple sclerosis. We found there are different mechanisms involved in this process. At least one mechanism for curcumin inhibition of EAE is by inhibiting IL-12 production, as well as IL-12 signaling through the JAK-STAT pathway. There have been a few reports that curcumin can bind on PPAR-g, so there are connections between these compounds, but otherwise, we don’t know how curcumin inhibits the JAK-STAT pathway. At least we know that if curcumin binds on PPAR-g, PPAR-g may be able to interact with the JAK-STAT pathway and downregulate the signaling pathway leading to Th1 differentiation or encephalitogenic T cell development in the EAE model. There may be so many other compounds out there that may be useful, but we need to study more about their use and their side effects. Generally we believe natural compounds have very few side effects, and hopefully these kinds of compounds will reach patients for their benefit. We need to study more and find support for conducting this kind of research to further understand its mechanistic action, as well as safety and efficacy in human beings. We believe these natural compounds are very important to study and will reach human patients for their benefit. JB: Dr. Bright, I want to congratulate you. That was one of the most remarkable, eloquent, and fluent descriptions of a very complex topic, connecting together a tremendous amount of information in a way that was really quite incredible. Obviously, you’ve practiced that before-that is a very thoughtful way that you articulated that to our listeners. I’d like to go back, if I could, and pick up some of the high spots because many of our listeners are not as familiar with biology or some of these signal transduction mechanisms as a specialist such as you (a neuroscientist), so if you wouldn’t mind I want to emphasize a few of the points by just taking us through some of the things that you’ve said. Let’s start, if we could, by addressing the question I think a lot of people have about animal models. How respected is the EAE animal model to correlate with human disease in the autoimmune area-the MS area? Is it a generally accepted model that has a pretty strong human clinical correlation with its pathophysiology? The EAE Animal Model JJB: I believe this is the best model available so far for studying MS pathogenesis or therapeutic aspects. There are controversies; there are differences. Even among MS patients, the disease is different between patients, so there is no uniform pattern of disease, but overall there are two classifications: lapsing/limiting and chronic progressive. If you see lesions, there is no clear pattern; each individual looks differently. There have been-I think-two or three review articles/opinion pieces recently published about use of EAE as a model. There is confusion about it. If you read the recent review articles on EAE, I think most of the comments state this is the best model available. Until there is a better model, we need to continue to use this one because EAE is what we have used to test and find a useful drug for MS. Any FDA-approved drug now approved for the treatment of MS are drugs tested and approved based on results using EAE. JB: That really answers that beautifully. In past editions of Functional Medicine Update, we have interviewed two investigators that have some overlap with your areas of emphasis: Dr. Colleen Hayes at the University of Wisconsin and Dr. Michael Holick at Boston University Medical School. You probably know Dr. Hayes’ work on vitamin D metabolites and MS, and also Mike Holick who was originally at Wisconsin and was one of the discoverers of the 1,25-dihydroxy-D3 before he moved on to dermatology and immunology at BU. I think their work very closely affiliates itself-and certainly is consistent-with your observations. Have you had communication with either Dr. Hayes or Dr. Holick over your years? JJB: Not really. I know their work and I strongly believe their observations are real and have been confirmed in our studies. By inhibiting the JAK-STAT pathway, we have proven that pathway is important in disease pathogenesis, so we have added at least one step further in the understanding of its mechanism of action. JB: Yes, I think that is what I was going to reinforce. There is a question that has been raised at meetings that I have attended where either Dr. Hayes or Dr. Holick have presented. Very compelling evidence exists, but no mechanism as to how it works. Your work has started to piece together the mechanism through these kinase signaling pathways. I think it is a big step forward in recognizing the importance these agonists (or JAK-STAT) have in how it influences IL-12 and downregulates Th1 activity. It is a very big step forward. When we look at autoimmune disease, people often say there is no clinical autoimmune disease in the absence of high autoantibody titers. From your evaluation of both the literature and your experience, are autoantibodies the sine non quo for the autoimmune process and how do they derive out of the signaling activation that you have described? The Role of Autoantibodies in Autoimmune Disease JJB: In the really early days, people were working mostly on T cells as the target for inhibiting diseases (mostly autoimmune diseases). We now know definitely antibodies are playing a role and autoantibodies will be playing a role in MS, RA (rheumatoid arthritis), type 1 diabetes, myocarditis-T cell-mediated disease, mostly Th1 types of mediated disease. But, during the course of analysis, we and other people have found that antibodies specific to neural antigens are present in humans as well as in the animal models. My point is that even to produce autoantibodies by B cells requires Th1 cells. Th1 means T helper cells. Helper cells help B cells also to make antibodies. Even though B cells are involved, T cells are the prime target and if you target Th1 cells, it will inhibit Th1-mediated tissue damage, as well as help B cells. It will be the target, I think, to go after. JB: That makes very good sense. It is interesting that there is more literature coming out now saying that autoantibodies always have some level of importance. They are part of the body’s defense process; they are not all bad. A zero titer of autoantibodies is not associated with good health and it relates to the distribution of the type of immunoglobulins. If you shift a pattern from an IgG-dominant over to an IgM-dominant, that suggests that you are getting a shift in the personality of your immune system (moving toward autoimmunity). I find it fascinating that we have changed our view about autoantibodies by saying they are not all bad, they are actually part of the natural defense process. JJB: That is what I also believe-that is it part of the natural defense process as well. It is not basically blocking out or inhibiting antibody or Th1 response. We need to regulate-regulate at a threshold where it won’t cause any harm to our tissues, but it will maintain and regulate whatever regular physiological function needs to be taken care of. Is there a Pre-clinical Stage of Autoimmune Disease? JB: Thank you. The next question is, I know, a very controversial question. If autoantibody titers start increasing well before the diagnosis of disease (and I think there is ample evidence for that published in some fairly good journals), then it suggests there is a pre-clinical stage of autoimmune disease that may exist prior to the onset of a frank diagnosis. Does your work (through looking at the signaling mechanism) suggest that early on (if we had proper biomarkers) we could identify the trajectory toward autoimmunity if we could ask the right questions? JJB: We believe in that kind pattern. In our animal experiment (which is a 30-day course), usually the disease peak is around 12-15 days. We did a course of PCR analysis after IL-12 gene expression. In the brain we found that you can detect high level of IL-12 around 6 to 7 days (5 to 8 days before the peak it is coming higher); this is what we call pre-disease. We believe that this pattern may be seen in humans as well, but we don’t get to do a similar kind of analysis (it is hard to identify such a patient before they come to the clinic). If such a study is done, we believe we may be able to identify pre-disease increase in pathogenic antibodies as well as the cytokine level. JB: I think that is a very important message for our clinicians to keep in mind because it has been suggested that there are approximately five fold as many people that have increasing titers of autoantibody prior to the onset of diagnosis than there are people being treated for frank autoimmune disease. If you consider that there are 3 to 4 million people with various autoimmune diseases and you multiply that by five, it is a substantial portion of the population that has a chronic state of immune imbalance that we might call pre-clinical autoimmunity for which the drugs that are used to treat autoimmune disease are probably too harsh. What can be done with these patients to improve their function? Some of your investigations and discoveries related to some of these natural products may come into play. At an earlier stage, they may be the best compounds for modulating these functions. JJB: We believe that natural compounds may play a very important role. Because of a low risk of side effects, we believe that you can start taking low quantities of these natural compounds even if you don’t have a disease. If there is a pre-disease state, you may be able to subvert substantially the possibility of getting clinical disease. One thing to keep in mind is that most of our studies used high doses of these molecules. We used these molecules to inhibit the disease after the onset of disease or during the course of the induction of the disease. People usually eat low quantities of nutraceuticals in their regular diets. If you keep doing that routinely (like people do in some of the Asian countries), you may be able to prevent the onset of these kinds of autoimmune diseases. Correlation between Insulin Resistance, Hyperinsulinemia, and Autoimmune Disease JB: We know in the United States and elsewhere in the developed world there is a rising tide of insulin resistance, hyperinsulinemia, and type 2 diabetes. Your work on recognizing that there is a connection between PPAR-g agonists and the downregulation through the JAK-STAT pathway of IL-12 expression suggests (and I don’t want to put words in your mouth, but I guess this may be a question) that there may be a correlation between insulin resistance, hyperinsulinemia, alterations in the PPAR-g pathway, and exacerbation of inflammatory types of autoimmunity. Does that kind of story that I just developed hold any water or is that making too many leaps? JJB: That is something that we want to study as well. Since all of our experiments with PPAR-g ligands are in an animal model, and since these drugs are taken for type 2 diabetes as a prescription, we are trying to see (in the record) if we can find some MS patients who are type 2 diabetic and are taking PPAR-g ligands by prescription. If we can find some number of patients like that and determine whether they do better or they get worse, or what the relationship is between taking PPAR-g ligands and MS and diabetes health, we can connect it. At this point, we know that PPAR-g ligands definitely inhibit JAK-STAT pathways. Some of those pathways are required for fighting infection because IL-12 is required for Th1 response and Th1 response is required for fighting many of the pathogens. We cannot shut down the whole pathway of Th1 response because then the patient would need to live in a sterile environment. Our objective is to regulate these pathways to achieve a threshold level of autoimmune response that won’t harm the tissue, but will be an immune response to infection. The JAK-STAT pathway is the target; we think it is one of many of these pathways that these kinds of molecules are targeting. We need to remember that these pathways are required for normal physiological function as well. JB: You just said something that I think is very important for clinicians. The drugs-the breakthrough new biologicals-that we have available to the rheumatologists to manage autoimmune disease are these biotech products that are basically anti-TNF-a blocking agents, or they are mimics that bind to receptors. Because of the physiological activity of these compounds, they are capable of really suppressing the immune system. The black box label warnings for these products often warn about tuberculosis or malignancy. What I am hearing from you is that we have to be cautious when we use these drugs because they may have an effect on suppressing immune systems, and if we can intervene early we may get some clinical advantage. JJB: That is what we stress. When we write manuscripts, I put a warning like that in the conclusion. We need to watch the dose we use when we take these drugs because all the pathways are important for normal physiology and fighting against infection or cancer. The timing is very important. I think if we start taking low levels (or a normal dietary level) of these compounds before we get a disease, this may be beneficial in the long run. Published Research by Dr. Bright JB: With that I am going to give our listeners the titles of four of your papers that I think bear on the next question I want to ask so they will have them in their thoughts. One is your more recent paper in the Journal of Neuroscience Research in 2006 titled “1,25 Dihydroxyvitamin-D3 Modulates JAK-STAT Pathway in IL-12/IFNg Axis Leading to Th1 Response in Experimental Allergic Encephalomyelitis.” 10 The next is from the Journal of Clinical Immunology in 2004 and is titled “Quercetin, a Flavonoid Phytoestrogen, Ameliorates Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through JAK-STAT Pathway in T Lymphocyte.” 11 And the next is a curcumin and autoimmune disease study, “Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes;” this appeared in the Journal of Immunology in 2002. 12 And then your review paper, “Targeting Autoimmune Diseases Through Nutraceuticals” appeared in the journal Nutrition in 2004. 13 With that as a background (just so our listeners know you are speaking as an expert) I would like to ask kind of a philosophical question. Within the cellular signaling pathways, antennae that stick out to receive messages are like receptors that are sensing the outside world and translating those messages through these kinases, these complex networks of signaling, to the gene to create different expression patterns that change the personality of that cell (to go from a cell at rest, say, to a cell that is in an inflammation state). Why it is that specific nutrients that we have either consumed or been exposed to (like 1,25 dihydroxy D3 or curcuminoids or quercetin) would influence those pathways? What does this mean about what we eat, the environments we live in, the regulation of our gene expression patterns, and the changing environment that then maps against the diseases that we have seen in prevalence in developed western society? Do you philosophically feel that there is some interesting connection here? JJB: I think so. First of all, I appreciate you introducing some of our published manuscripts with the titles and volumes. We are glad we could take some lead on publishing articles about the use of nutraceuticals in treating autoimmune diseases. Curcumin is a favorite for us. When we presented at a conference in New Orleans several years back, someone wrote an article saying that curry spice can cure multiple sclerosis. There was a lot of attention, and many patients started calling me-“How many teaspoons?”-and then the multiple sclerosis society called me and asked me to send a PDF file to put on their website because many patients were calling and asking about it. At that time, I cautioned many of the patients that this is an animal study and this is a compound we usually use in very low quantities in our daily food and it regulates normal physiology. These are conditions we have to learn more about through clinical trials with human MS before we can say how many teaspoons we should eat. No human being can survive without food. Everybody eats food and everybody gets some kind of nutraceuticals (biologically active functional molecules) through food everyday of our lives. For example, many people eat curcumin from childhood to adulthood. Through the studies we have done, we came to understand one mechanism by which some nutraceuticals regulate body functions. We have shown the JAK-STAT pathway can be regulated by natural products or nutraceuticals or environmental factors. I think there is an interplay between environment and autoimmune disease. When we talk about autoimmune disease, we don’t know the etiology yet, and we believe that environment is one factor which modulates genetics and our behavior. Nutraceuticals can be called behavioral-you choose what you eat, and your choice of food can change the final outcome of your health (through autoimmune diseases or otherwise). We believe nutraceuticals are natural products. Environment can influence molecular mechanisms or physiology, which can lead to the pathogenesis of many diseases, including autoimmune disease. JB: That is a really eloquent answer. I have one last question. It seems what is emerging from your work and work of others is that these environmental factors that signal certain cellular functions through these kinase pathways operate through very complex web-like signaling pathways. That suggests there is more than one mechanism for controlling a disease (a disease is not just a breakdown of one mechanism), and that there is the possibility of synergy among these different compounds that are consumed in a daily diet or that we are exposed to in our environment, and it is not just one molecule at a time, but rather it is multiple pathways responding to multiple molecules that gives rise to the orchestration that we call our function. This is a very different model than the traditional pharmacological model, which is one molecule for one function for one disease. Do you feel that as this emerges-this concept of regulators of intercellular communication from the environment-that we will start looking more at complex arrays of molecules affecting multiple pathways? JJB: I believe so. There is not just one pathway; JAK-STAT is one pathway, but we know there are many other pathways involved in the whole process of autoimmune response, autoimmune disease, and inflammation. These pathways include the MAP kinase pathway, the NFkB pathway, the AKT pathway, and JAK-STAT. I think there is a network among these pathways that leads to the final outcome of the disease. We believe that if we block one of these pathways it will block the whole network. We are trying to learn one pathway at a time. We have recently started using a computer infomatics program to map all the pathways in autoimmune disease (using inflammation and EAE and MS as a model) and to look at novel targets in various different pathways, how they interact, what the directionality of the interaction is, and the strength of the interaction so we can identify novel molecular targets at the junctions of these pathways. There are many approaches like that I think people are taking approaches like this and hopefully not single tract therapy. We believe nutraceuticals have multiple biologically active functional compounds and that they may all work together in concert to regulate these signaling pathways. Curcumin has low bioavailability; that is one complaint we have. People have published that curcumin bioavailability can be increased by other compounds. What we realize from these kinds of experiments is that even one natural or phytochemical and nutraceutical compound can increase the bioavailability of another compound or its action on one pathway. The biomolecules of nutraceuticals help each other to enhance activity on the molecular targets as well as the molecular signaling pathways. These nutraceuticals may help regulate all these networks together, and these molecules together may regulate the network of signaling pathways in a beneficial way for human health. JB: Dr. Bright, I want to compliment you. This has been one of the most information-dense and concentrated-but-eloquent presentations we have been fortunate enough to have and it opens up a whole vision of where our future might be taking us in looking at the role that diet and lifestyle and environment play in both the prevention and management of complex chronic disease. Keep up the tremendous work. You are really a pioneer and we have so appreciated you sharing this information with us. JJB: Thanks so much, Dr. Bland, for the opportunity to share our work and I hope we will have more and more discussion and some of this message will be useful and beneficial for the patients who are suffering with autoimmune diseases. Thank you. JB: Thank you. I am guilty for waxing very philosophical at times and getting very emotive and excited about these interviews but I think my excitement is justified at the conclusion of Dr. Bright’s eloquent presentation. The implications of what he has discussed may be quite dramatic, clinically. When Dr. Colleen Hayes of the University of Wisconson talked about her work and the animal model (the EAE model for MS), she showed that vitamin D metabolite (1,25-dihydroxyvitamin D3), when vitamin D metabolite (1,25-dihydroxyvitamin D3) was instilled directly into the brains of totally paralyzed animals, the animals were walking and then running around the cages in a matter of less than an hour. The dramatic influence of these agonists that may have nutritional origin could be quite significant, clinically. The chapter still remains to be fully written, but the story sounds very fascinating from a clinical perspective. Thanks for being with us. We look forward to being with you next month.  

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Bibliography

1 Cross HS, Bises G, Lechner D, Manhardt T, Kallay E. The vitamin D endocrine system of the gut-its possible role in colorectal cancer prevention. J Steroid Biochem Mol Biol. 2005;97(1-2):121-128. 2 Murtaugh MA, Sweeney C, Ma KN, Potter JD, Caan BJ, et al. Vitamin D receptor gene polymorphisms, dietary promotion of insulin resistance, and colon rectal cancer. Nutr Cancer. 2006;55(1):35-43. 3 Cross HS, Kallay E. Nutritional regulation of extrarenal vitamin D hydroxylase expression-potential application in tumor prevention and therapy. Future Oncol. 2005;1(3):415-424. 4 Boyle RJ, Robins-Browne RM, Tang M. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006;83:1256-1264. 5 Floch M, White J. Management of diverticular disease is changing. World J Gastroenterol. 2006;12(20):3225-3228. 6 Crebs J. Betting on biomarkers: researchers aim for the clinic. Genome Technology. 2006;61:28-34. 7 Doyle SL, Jefferies CA, O’Neill LA. Bruton’s tyrosine kinase is involved in p65-mediated transactivation and phosphorylation of p65 on serine 536 during NFkB activation by lipopolysaccharide. J Biol Chem. 2005;280(25):23496-23501. 8 McAlindon TE, Gulin J, Chen T, Klug T, Lahita R, et al. Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity. Lupus. 2001;10:779-783. 9 Auborn KJ, Qi M, Xiao JY, Teichberg S, Chen D, et al. Lifespan is prolonged in autoimmune-prone (NZB/NZW) F1 mice fed a diet supplemented with indole-3-carbinol. J Nutr. 2003; 133(11):3610-3613. 10 Muthian G, Raikwar H, Rajasingh J, Bright JJ. 1,25 dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/INFg; axis leading to Th1 response in experimental allergic encephalomyelitis. J Neurosci Res. 2006;83(7):1299-1309. 11 Muthian G, Bright JJ. Quercetin, a flavonoid phytoestrogen, ameliorates experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK-STAT pathway in T lymphocyte. J Clin Immunol. 2004;24(5):542-552. 12 Natarajan C, Bright JJ. Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through janus kinase-STAT pathway in T lymphocytes. J Immunol. 2002;168(12):6506-6513. 13 Bright JJ. Targeting autoimmune diseases through nutraceuticals. Nutrition. 2004;20(1):39-43.

Welcome to Functional Medicine Update for December 2006. Can you believe that we are again at another end of a year? How the time flies when we are having fun. Questions and Answers We are very fortunate to have in the ranks of our functional medicine colleagues some people with remarkable minds. These are thoughtful and conscious individuals who are constantly searching for truth. One who stands head and shoulders above most of us is Dr. Sidney Baker. After the Symposium on biotransformation and detoxification held in May of 2006, Dr. Baker asked me a very insightful question related to the presentation of T. Colin Campbell, from Cornell. The question was about the effect of dietary proteins on hepatic detoxification processes, and aflatoxin conversion to the carcinogenic form of aflatoxin on the high animal protein diet. Why is it that in studies where animals are exposed to aflatoxin, vegetable diets do not seem to activate carcinogenesis whereas the animal protein diets do? What is going on? I think that is a very insightful question. It raises the issue of whether it is just protein, itself, or if it is something else that might come along with protein (part of the unique personality of animal versus vegetable protein). I’d like to cite a couple of interesting papers that bear on this. One was in the Journal of Nutrition in 2001, which talks about the inducibility of hepatic CYP4501A enzymes by a known carcinogen in animals fed diets that either had animal protein or vegetable protein.1The authors found that the carcinogen was not activated after a vegetable protein diet, but was after the animal protein, suggesting that the source of dietary protein may have something to do with the inducibility of the liver enzymes that go on to produce the ultimate carcinogens. Another paper described a difference in carcinogen activation between soy protein isolate-fed animals and casein milk protein-fed animals. It appears as if there is something within the constitution, structure, or function of dietary protein that has an influence on CYP450 activation of carcinogens, with the animal proteins having higher activations than the vegetable proteins. This is certainly something worth further explanation. It may help us to someday understand the difference of cancer risk from differing types of diet. Thank you, Dr. Baker, for getting us pointed in this direction. One of the things that we have learned in functional medicine over the years is the importance of the gastrointestinal tract in establishing a tone of overall systemic physiologic function, particularly as it relates to immune function. This issue-the December 2006 issue- is going to focus on gut-immune function and also some collateral activities of the gut as a functional organ, beyond that of its being a conduit pipe that takes things from the north to the south in the digestive process. The gut has multiple functions, and those are the things we’ll be focusing on in the course of this month’s Functional Medicine Update. As you probably recognize, one of the many functions that the gut is involved with is the synthesis of cholesterol. We often think of the liver as being the principal site of cholesterol biosynthesis, which it certainly is, but the gut also plays a role in de novo cholesterol biosynthesis. When a person is on cholesterol-lowering medications, they are influencing not just hepatic de novo biosynthesis of cholesterol, but also having an effect on the gut function. There is a movement among some professionals to use more and more of the statin medications to lower cholesterol. Within this group there is this sense that statins are benign and completely safe and that we should use them aggressively to lower LDL cholesterol below 90, or even below 70 (based on some of the more recent suggestive data). But what are the impacts on immune function? What are the impacts on hepatobilary function? What are the impacts on gastrointestinal function of making statins a part of virtually everyone’s lifestyle in order to get their cholesterol LDL levels below this target of 70 mg/dL? I was very intrigued to see that in a 2006 issue of the British Medical Journal an interesting, controversial article by Swedish investigators was published titled “Should We Lower Cholesterol as Much as Possible?”2 One of the coauthors of this paper is Mark Houston, who is a well-recognized leader in our functional and integrative medicine arena; he is a clinical professor of medicine (internist/nephrologist) at Vanderbilt University School of Medicine. I think this paper is quite a dramatic story that we should be paying serious attention to. Statin Doses and Target LDL Levels The article states that to evaluate whether higher statin doses are safe, and to get people down below the new target LDL level, we would have to go above the equivalent of 80 mg of atorvastatin daily. It has been suggested (from looking at various clinical studies on the use of statins) that the dose of statins would have to be more than 8 times higher than currently used to have the population achieve this target level of LDL. What does that really mean in terms of potential adverse side effects? We know with higher doses of statins overall mortality is not reduced, because the smaller number of cardiovascular deaths in the 80 mg statin group was offset by increased deaths from other causes, leaving a benefit of fewer non-fatal cardiovascular deaths of very marginal significance. What we are really talking about is risk-benefit trade-off. If we look at the actual number of adverse side effects that appear in these higher-dose statin trials, they are much higher (say the article authors) than we normally hear about. Muscle complaints are claimed to occur in less than 1 percent of patients taking statins, but in a study of 22 professional athletes with familial hypercholesterolemia who were treated with various statins, 16 of the 22 discontinued the treatment because of muscle side effects. We also look at other kinds of studies looking at myopathy and rhabdomyolysis and death from renal failure, and, again, in a recent review of statin side effects, 4.2 cases of rhabdomyolysis per 100,000 patient years after atorvastatin were found. If true, it could mean that the side effects are twice as common than previously acknowledged. There are also some other issues that have been discussed in the literature, like mental and neurologic symptoms. We know that cholesterol is vital for the development of function of the brain and nervous system. We can see (in people on statins) functional changes in mental and neurologic function (things like irritability, aggressive behavior, suicidal impulses, and cognitive impairment). In animal trials, statins have been found to be carcinogenic and alter signaling pathways for cell cycling through the farnasyl transferase reactions. This has been suggested to track against the increased cancer seen in these animals. Significant increase in breast cancer was seen in the cholesterol and recurrent events trial (CARE), and so there are these questions that sit in the literature about how safe these products are when used for a long period of time and at ever higher doses to try and get down to these “target” low LDL levels. The conclusion of this British Medical Journal article was that US recommendations for low-density lipoprotein cholesterol concentrations could put most of the western world’s adult population on statins. That might be very great for the companies that are producing the statins, but then the question is: What are the relative benefits versus risks? Doses of statins would have to be more than 8 times higher than the currently used levels if, in fact, the target low LDL was to be the measure from which people were going to be titrated to for their statin dose. Increasing the dose of statins by 8 times was not found to lower total mortality. Adverse side effects in clinical trials are often underreported and any reduction in non-fatal events may be outweighed by more numerous and more severe adverse functional side effects, say the article’s authors. The statin story remains, I think, controversial as it pertains to ever increasing application of that family of drugs to try to achieve more and more aggressive lowering of LDL cholesterol. Getting back to our gastric mucosal model, let’s talk a little bit about the nature of NSAID-induced enteropathy and gastropathy. About 25 percent of the patients on long-term non-steroidal anti-inflammatory drugs (NSAIDs) go on to have some form of gastropathy. In many of these, the conditions can lead to hemorrhagic problems with life-threatening consequences. In a study published in the 1990s, there were at least 12,500 deaths reported annually that were ascribed to adverse effects (fatal outcomes, actually) from NSAID administration, and about 106,000-110,000 hospital admissions annually for gastric bleeding from the use of NSAIDS.3 This is not an insignificant problem. The difficulty is how do you know, early on, whether a person who is taking routine NSAIDs is at risk to a gastric perforation or to a serious enteropathy or gastropathy? Most people are not going to prophylactically be scoped. I have been involved (in research at the Functional Medicine Research Center [FMRC]) in looking at gastric mucosal cell models for estimating relative gastrointestinal toxicity of non-steroidal anti-inflammatory drugs, and, in fact, recently co-authored a paper that was published in Prostaglandins, Leukotrienes, and Essential Fatty Acids. 4 In this paper, a method that seems to be very useful for evaluating relative toxicity to GI drugs using the AGS model-the gastric mucosal cell model for screening various compounds for relative GI safety or risk-was described. It was found that there is a range of different GI risk factors from different non-steroidal anti-inflammatory drugs. Even the so-called selective COX-2 inhibitor drugs that were supposedly safe to the GI tract are found (by this model system) to be at some risk to GI inflammatory problems. I think there has been some relative misleading take-away from individuals in the medical world that the selective COX-2 inhibitors are completely safe as contrasted to the traditional nonselective COX-2 inhibitors (the mixed COX-1/COX-2 inhibitor NSAIDs) that put the GI mucosa at risk. Fecal Calprotectin Test Some type of a functional method for evaluating individual relative risk to NSAID-induced enteropathy is needed. This is where tests like the fecal calprotectin test can be very useful. This test has been used in studies at the FMRC during the past several years to understand the association between the elevation of fecal calprotectin on NSAIDs and the relative risk that that patient might have to a gastropathy. There can be a variety of different responses in different people to NSAID use in terms of how it affects the rising level of calprotectin, the reactive immune protein that is secreted by neutrophils in the GI mucosa. If we are able to use the fecal calprotectin test as a benchmark for looking at relative risk to injury, then we can evaluate interventions that would helpfully lower the relative risk to some kind of a serious hemorrhagic problem or a gastropathic response. Hepatic Inflammatory Response Because the gut is the center of the immune system, as you start having gut inflammation, you start to demonstrate localized inflammatory patterns that then can track to altered gut mucosal integrity and can lead to upregulation of proinflammatory mediators, cytokines, and chemokines. That can then deliver downstream from the gut, these messengers that can enhance liver or hepatic inflammatory response. This seems to be more and more well recognized now. Nonspecific liver injuries that relate to elevated liver enzyme profiles don’t seem to track against a seropositive hep C or hep B (and the person is not an alcoholic), and sometimes we don’t know what the etiology is of these liver profile elevations. We can look at things like metabolic syndrome and nonalcoholic steatohepatitis (NASH), one thing that we know causes liver infiltration of hepatocytes. Another potential cause is proinflammatory mediators from the gut. We start talking about liver inflammatory conditions as being precipitated by gut inflammatory conditions, and then you start looking at things like food allergies or antigenic-presenting phenomena that occur to the GI mucosa. One substance that always rises up in this discussion of things with a problematic nature for the GI tract is gluten (from wheat). If a person has a nonspecific elevation of their liver enzymes and we can’t identify that it is from NASH or alcohol, or a drug, or a viral infection, could it be that this liver injury is precipitated by an upstream antigen-antibody-type response at the GI mucosa? Is an upregulation of the gut-immune defense system and inflammatory mediators being produced in response? There is a body of literature that supports this contention with people who may be gluten sensitive. Once put on gluten-free diets, liver enzyme profiles go back into normal range and gut inflammatory and liver inflammatory conditions go into remission. Chronic gut infections (sometimes euphemistically termed “dysbiosis”) can also induce gut inflammatory responses, which then translate into liver-related problems. In older-age individuals, where you often get this condition called hepatic encephalopathy with psychosis developing, this can be precipitated by the gut inflammation/liver connection to the brain through the glia (the microglia). The microglia is the brain’s immune system, and so there can be an upregulation and an alteration of immune function in the brain with altered neurotransmitters and increased inflammatory agents, activation of glial nitric oxide output, and peroxynitrate being formed. The result is a whole different brain milieu in terms of functional molecules. Long-term use of antibiotics can induce changes in gut flora. Gut flora can then induce changes in gut-immune function. Gut-immune function can change the liver. The liver can change the brain. Now we have a round-robin connection between gastroenterology and neurology. Hepatic Encephalopathy There is a paper that describes all of this web-like connection that appeared in the journal Medical Hypotheses in 2005. It is titled, “Effect of Antibiotics, Prebiotics and Probiotics in Treatment for Hepatic Encephalopathy.” 5 Hepatic encephalopathy has traditionally been treated by putting a person on a substance that will create hyperosmolar diarrhea, like the disaccharide, lactulose, which is generally nonabsorbable. That diarrhea then alters gut flora. It also washes out toxins from bacterial cell wall debris and lowers the load of inflammatory materials, which then lowers the effect on the liver, and then ultimately lowers the middle molecular weight nitrogenous molecule load on the brain. This can help a person come out of the hallucinations that are associated with hepatic encephalopathy. The real name for that should be “gastrointestinal hepatic encephalopathy,” because it is the gut, connected to the liver, connected to the brain. Can prebiotics and probiotics also be useful for managing this kind of a condition? There is a wide body of literature described in this review article that suggests that not just lactulose (as a substance to produce hyperosmolar diarrhea), but also prebiotics and probiotics, work together to help in proper normalization of GI-immune defense (lowering inflammation, lowering liver activation). This can lead to improved microglial function (the brain’s immune system), and reduce the symptoms of hepatic encephalopathy. We often think of hepatic encephalopathy as only being associated with ammonia-producing organisms. We often characterize it as a condition of hyperammonemia. If you look at the literature, you’ll find that the symptoms of hepatic encephalopathy (the hallucinations) are not tracked closely against blood ammonia levels at all, but rather tracked against other nitrogenous putative precursor molecules to neurotransmitters, which are immune-active substances that are produced in the gut and/or liver and are associated with these gut inflammatory conditions. Encouraging the detoxification of the gut, reinoculating with friendly bacteria, and use of prebiotics appears to be part of a favorable clinical protocol. The next step is to give nutrients that are helpful for restoring proper gut-immune defense, like L-glutamine, which we know is a useful amino acid for improving gut mucosal integrity. L-glutamine is a gut fuel (in some respects), as it helps to activate in situ glutathione stores for proper redox balance and gut mucosal recovery of immune defense. There are a lot of different parts to this story, but certainly lowering the load, getting rid of food antigens or allergens, improving prebiotic and probiotic reinoculation of the gut, and then gut restoration of mucosal integrity with nutrients like L-glutamine all seem to be part of this program that connects the gut to the liver. If we see elevated liver enzyme profiles, I think we should take a broader look at the implications other than that of just serology for hepatitis-producing organisms. How might systemic inflammatory conditions be connected to localized gut-immune activation and enhanced immune activities of the gastrointestinal-associated lymphoid tissue (GALT)? There is ever increasing interest in the whole spectrum of autoimmune disorders that may have some connection (in certain individuals) to alteration in gut-immune defense. This connection appeared very strange about 10 years ago, but is now starting to gain more credibility between the activity and function of the mucosal-associated lymphoid tissue (MALT) and the gastrointestinal-associated lymphoid tissue (GALT) and systemic inflammatory responses. Are there any animal models that take a look at this connection? The answer is yes. There are certainly an ever increasing number of well respected animal models where this connection can be studied under controlled conditions. A review appeared just recently in theArthritis Research Journal that is titled “The Genetics of Rheumatoid Arthritis and the Need for Animal Models to Find and Understand the Underlying Genes.” 6 In this particular paper, the authors talk about new animal models that are being used for evaluating the potential of rheumatoid arthritis and the etiology of rheumatoid arthritis, how that connects to certain immune-related genetic characteristics, and what environmental modifiers can modify the genetic expression of these characteristics to give rise to an immunological inflammatory condition that later tracks as arthritis. Rheumatoid Arthritis and Proteus mirabilis Infection of the Urogenital Tract If we think of rheumatoid arthritis (RA) as an autoimmune disease, we get some sense that there could be cross reactivity from epitopes on environmental stimuli leading to superantigens. What environmental factors lead to those cross-reacting epitopes? One family of organisms to consider are those that have urinary tract infection correlation, like Proteusorganisms. There is an interesting paper that just appeared in Clinical and Developmental Immunologythat looks at the relationship between rheumatoid arthritis and Proteus mirabilis infection of the urogenital tract.7 The authors propose that a subclinical Proteus urinary tract infection could be a main triggering factor related to this molecular mimicry and cross reactivity between bacteria and RA-targeted tissue antigens that perpetuate disease through the production of cytopathic autoantibodies. This is a complex world in which we live. There are literally thousands of microorganisms that have their own molecular personalities. On their surfaces sit all sorts of different potential hapten or antigenic components, which may then react with receptor sites on host immune tissue in genetically unique individuals to activate those cells into a heightened stance of inflammatory expression. The urinary tract may seem like a long way away from the joints, but we are all connected together through our immune system. In this particular paper, the authors talk about how this connection may explain why vegetarian diets (diets higher in water and juices that are acidic and contain certain phytochemicals, like cranberry juice) have been useful in certain studies with patients not only with urinary tract infections, but also those who have conjoint arthritis. These patients find that as their diets change and their urinary tract infections improve, their joint pain improves, too, because there is this connection through the immune system between the reaction of receptor sites to antigens (these cross reactive materials-this mimicry, so to speak, between a bacterial antigen and a self antigen). We are starting to learn a lot more about the interrelationships in this complex world, and how they can then be individualized to the patient’s own immune system. We can’t just form rules that cut across all individuals, and we can’t say there is only one cause of an autoimmune disease. We are looking at modifying factors. Gut-Joint Connection in Arthritis and Foods Is there any demonstrable connection between the foods in our diet and their chemical personalities (as it relates to their immunological activity) and cross reactivity with antibodies that are associated with rheumatoid arthritis? That is a question that has been discussed for several decades (at least). As we get better immunological assessment tools, this association becomes more recognized. I am now quoting from a recent paper that appeared in the journal Gut, which describes this connection that couples together the cross reactivity to food antibodies and ultimately joint inflammatory conditions.8 This is a very interesting paper. The title is “The Gut-Joint Axis: Cross Reactive Food Antibodies in Rheumatoid Arthritis.” This was a study that was aimed at patients with rheumatoid arthritis who have differing severity of their condition that seems to track against different dietary persuasions or different foods that they might eat. The authors of the paper wanted to investigate a putative immunological link between gut immunity, rheumatoid arthritis, food antibodies, and general quality of the diet of these individuals who have this food exacerbation. The investigators looked at IgG, IgM, and IgA antibodies to dietary antigens to measure the potential for food allergy in these individuals in serum and jejunal perfusates from 14 rheumatoid arthritis patients and 20 healthy subjects. The antigens that they evaluated were from cow’s milk (a-lactalbumin, b-lactoglobulin, casein: the three most reactive proteins in cow’s milk), cereals containing gluten, ovalbumin (hen’s egg), codfish, and pork meat. In the intestinal fluid of many of the rheumatoid arthritis patients, all three immunoglobulin classes showed increased food-specific activities. Except for IgM activity against b-lactoglobulin, all other IgM activities were significantly increased, irrespective of the total IgM level (so you have to look at the individual class of IgM). The rheumatoid-associated serum IgM antibody responses were relatively much less pronounced. And compared with IgM, the intestinal IgA activities were less consistently raised, with no significant increase against gliadin and casein. Considerable cross reactivity of IgM and IgA antibodies was documented by looking at absorption tests. Although intestinal IgG activity to food was quite low, it was nevertheless significantly increased against many antigens in the rheumatoid arthritis patients. Three of the five rheumatoid arthritis patients treated with sulfasalazine for 16 weeks had initially raised levels of intestinal food antibodies. These became normalized after treatment. The authors conclude, after looking at this fairly small number of patients in the trial (14 RA patients against the 20 healthy subjects), that the production of cross reactive antibodies is strikingly increased in the gut of many rheumatoid arthritis patients. I think that is probably the most significant contribution of this study was looking at intestinal perfusates and examining what the localized production of antibodies through the activation of the gut-associated lymphoid tissue was as a consequence of exposure to their complex diet. Their food-related problems reflect an adverse additive effect on multiple modest hypersensitivity reactions. These may then promote more severe autoimmune reactions in the joints, so they come to the conclusion that this gut-joint axis is not just theoretic, this actually does exist and it is clinically demonstrable that food elimination or improved gut-immune function (normalized gut-immune function) translates to lower systemic and joint-related inflammatory conditions. I think this is very important because often I hear people say that what happens in the gut wouldn’t translate to the joints-they are controlled and isolated and compartmentalized by barriers of defense and whole different physiological control systems. That is an extrapolation of unreasonableness. Both systemic and intestinal humoral immunity is found to be apparent in rheumatoid arthritis patients, with a particularly striking elevation of cross reactive food antibodies in the proximal gut secretions. We now learn from this more recent paper that IgM reactivity against food items was increased in the serum, as well as in the intestinal perfusate, suggesting systemic as well as localized effects. These incremental increases in intestinal antibodies provide striking results suggesting a connection between mucosal immune activation and the pathogenesis of rheumatoid arthritis (at least, we can say, in some patients). I want to emphasize that I think that like all diseases, rheumatoid arthritis is a heterogeneous condition with many different contributing variables. We can’t say one rule covers all patients, but certainly it is a characteristic that is worth looking at (the diet connection to antibody exacerbation of these autoantibodies). Food, therefore, may have an additive effect on other risk factors or contributing factors to the etiology of immune imbalance that is associated with rheumatoid arthritis. The gut-immune defense functions, environmental allergens and toxins, stress factors-these are all contributors to imbalanced immune function that we associate with these arthritis-like conditions. What I have really been talking about in this discussion is a presaging of what our clinician/researcher of the month, Dr. Hanaway, will be saying much more eloquently. That is: What is the immune privilege of the gut in the establishment and maintenance of proper immune response upon exposure to dietary antigens and commensal flora, which can be either friend or foe? We know that the intestines represent a new site for immune privilege. In fact, as early as 1948, Peter Medawar, who was an early transplantation immunologist, coined the term “immune privilege” to refer to the experimental observation that allogenic solid tissue grafts survived for prolonged or indefinite periods of time in specialized sites of the body. This relates to immune allostasis, or control of immune function. The pregnant uterus, ovary, testes, hair follicles, and regions of the eye and brain are among those anatomical sites traditionally classified as immune privileged. This immune privilege was largely due to passive mechanisms and immunological ignorance. In other words, antigenic material was transplanted into the immune-privileged site, but hidden from the systemic immune system, secondary, obviously, to barriers (like vascular barriers) in the absence of lymph drainage. However, if you expose these tissues by opening portals of entry to antigenic insults, they can lose their immune privilege and become no longer naïve (be activated).9 It was later shown that traditional immune privilege sites are privy to lymphatic drainage and, more significantly, by the 1970s, it had been demonstrated that antigen placement in the interior chamber of the eye (a traditional immune privilege site) did, in fact, generate a systemic immune response, even if the response did not lead to graft rejection. As a result, immune privilege was recognized to result from active (rather than passive) immunoregulatory processes. It is how you control this Th1/Th2 type of response and maintain balance. When we look at the gut immune privilege, it is really buttressed and affected by many factors. On the one side, there is food which contains foreign molecules that have to be digested and translated into neutral molecules, relative to the information they provide to the body (at least, not seen as hostile molecules). On the other side, there are two-and-a-half to three pounds of organisms sitting in the gastrointestinal tract that are potentially immunologically active. These organisms could be trophic and have positive impact upon immune function, or they could be parasitic and release caustic chemicals that activate the immune system and cause immunological imbalance and inflammation. Immune privilege of the gut is really maintained by this dynamic tension and balance between intestinal epithelial barriers, phagocytic innate immune cells, tolerogenic antigen presenting cells, and regulatory adaptive immune cells. This gives rise to tolerance to this environment that is within the gastrointestinal system. Imbalances or alteration in regulation leads to dysfunction, and that can be related to mucosal breakdown and to what we call increased permeability (or leaky gut). That exposes the gastrointestinal associated lymphoid tissue (GALT) to immunologically activating substances, imbalancing the teeter-totter of immune defense between the thymus-dependent 1 and the thymus-dependent 2 lymphocytes. What we end up getting are altered chemical communicators (cytokines and chemokines that relate either to things like food allergy or inflammatory bowel disease and activated immune system functions). This concept that is emerging-to look at the gut as the seat of immunity-is a very important concept in functional medicine and complex chronic disease because the conditions that result from this are more than just gastrointestinal in name. We further amplify (or complicate) that with the recognition that the gut is also a very active site for the secretion of many neuroactive substances. It is the site where the majority of serotonin is secreted in the body-I think maybe two-thirds of whole-organism serotonin comes from secretion from the gut associated lymphoid tissue. Protein Consumption and the Release of PYY Gut Hormone We also recognize that various brain neurotransmitters (not just cholecystokinan, but also PYY) are altered by gut-immune defense and the contents of the diet. Recently, one group of investigators has found that the gut hormone PYY is released when a person eats a higher protein-containing food. Signals are sent to the brain that indicate fullness. This is in contrast to empty calorie foods that are devoid of protein, where you get lowered PYY release and a lowered satiety message that is triggered to the brain. This might explain why eating protein in adequate levels has a positive effect on controlling appetite and a feeling of fullness. This recent work has been done by Rachel Batterham and her colleagues at University College London, who have been working to understand diet and its relationship to appetite and obesity.10 I think we can think of the gut as the “second brain,” as Dr. Michael Gershon pointed out in a book by that same name. We can think of the gut as the site for the immune system function. We can think of the gut as having a very important digestive function, in terms of breaking big to small for absorption. And we can think of the gut as controlling water content (fluid balance, electrolyte balance). It is much more of a functional organ than just a conduit-a pipe-that connects the mouth to the anus. This is the theme that is emerging and it is more fully understood if we can start thinking of the gut as a bioreactor. Gut microflora convert primary substances in foods into secondary metabolites (for instance, soy isoflavones get converted by certain enteric bacteria into secondary metabolites like equol, which has a different effect on physiology once absorbed than does the lignan or the isoflavone itself). For example, if you look at some of the factors in Humulus lumulus (hops) that get converted (like isoxanthohumol into xanthohumol) by demethylating bacteria that appear in the gut through fermentation. There are certain types of enteric bacteria that create different types of secondary metabolites that modify physiological function. This story goes on and on in terms of many other examples where fermentation produces secondary compounds that have differing effects on physiology, and this is dependent upon the specific families of enteric organisms to do this. An alteration of those organisms by antibiotics or stress or altered diet or high salt or sweet diets that flatten the villi can all influence the secondary effects of these bioreactors on producing these physiologically active materials. We are much more complicated in our understanding of functional gastroenterology than we previously have taken into account. This leads us into this month’s discussion with our clinician/researcher of the month, Dr. Patrick Hanaway, who is an expert in this whole area of looking at how gut-immune defense flora and mucosal integrity interrelate to a whole series of functional chronic health-related problems. With that in mind, let’s move to our clinician of the month.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Patrick Hanaway, MD Genova Diagnostics 63 Zillicoa Street Asheville, NC 28801 JB: Once again we are at that place in Functional Medicine Update that I look forward to with the greatest anticipation because I have learned so much from the various clinicians and researchers that I have had the privilege of interviewing over the last 25 years. This month I have a chance to speak with a colleague I have admired and respected professionally and who is also a great personal friend, Dr. Patrick Hanaway. He is (I’m sure many of you know) a very important figure in our field of integrative medicine. Dr. Hanaway is a board certified family physician who earned his medical doctor degree from Washington University and completed residency training at the University of New Mexico. He is very skilled in what we would consider the analytic reductionistic form of medicine, having studied traditional Chinese medicine and integrative medicine. He is a true integrator in every sense of the word, but does so in a way that really, I think, exercises the best balance of both hemispheres of the brain. It is a great privilege to have Dr. Hanaway as our clinician/researcher of the month. Patrick, I guess the first question I might ask is, how did you go about making this kind of interesting transition in your career-from being a family doctor to now being a leader in the field of integrative functional medicine? PH: Thank you for that introduction, Jeff. It was really the extension of the path that I had when I was in college and went to medical school. I was of the belief that I was going to learn about health and healing. I had majored in both history and molecular biology. When I learned about biochemistry, I thought I was going to learn about nutrition; I thought I was going to learn about what things people put into their mouths and how that works. I didn’t learn that. I read a book-by you, actually-in 1980 that helped me believe it’s possible that some people were thinking about that concept. As I went through my training and became a family doctor I continued to be interested in how to apply the principles of good medicine-of connecting back to nature and eating the right foods and having vitamins and nutrients that are going to help to maintain optimal wellness because that is what I was interested in. I have had great opportunities to learn tools along the way. JB: I know you have made a very interesting transition, professionally. You and your wife have been in practice together (she’s a physician, as well) at “Your Home for Whole Family Health” in Asheville, NC. Within the last decade you made a pretty remarkable career change to become Chief Medical Officer at Genova Diagnostics, and you’ve really become, I think, a very well respected leader in the area of functional gastroenterology. This, clearly, is kind of what you would call a lifelong learning program. It seems like an interesting evolution of your professional career. Bringing Patients into Balance PH: It is. As you know, there is always a personal story behind it as well. Part of my growing into learning about functional GI illness stemmed from three months of work in Nepal in India, back when I was in my medical training. Getting very sick with amoebic dysentery certainly helped to stimulate my interest in the GI tract, and in learning how to come back into balance. I learned about Great Smokies Diagnostic Lab at that time (in the early nineties) and it helped me-tremendously-to come back into balance. In my clinical practice, I needed to understand how to use tools. As I hung out my shingle, I needed to understand what tools I could use to help bring people back into balance and understand how they are biochemically unique from each other to optimize my healing potential with each person. It was fortunate that I was practicing with my wife in Asheville, and the laboratory you speak of-now known at Genova Diagnostics-was in that town. I told them I would like to do some clinical research. I began to do that and began to see that the opportunity to share these approaches and these tools and this understanding with more of my colleagues was really a way that I could best use my skills to help advance medicine and healing. JB: That’s a wonderful opportunity to segue into what I think is one of the most useful articles that I have seen written in this field of functional gastroenterology, which just happens to be authored by you. It appeared in the September/October 2006 issue of Alternative Therapies under the title “Balance of Flora, GALT [Gastrointestinal Associated Lymphoid Tissue], and Mucosal Integrity.” 11 I think the way you laid this article out is, in part, a manifesto for a change in thinking about integrated physiology or functional physiology. I’d like to (for the sake of the listeners) walk through some of this article and some of the citations that you’ve provided that give support to these concepts, because I don’t believe that these concepts are necessarily held in every quarter of gastroenterology. It is very interesting to see how these thoughts have evolved through your lens and also through the field of clinical and basic science research. With that as kind of a context, maybe you can tell us a little bit, in summary, about gut flora and interrelationship with the gut-immune system (for those who are maybe less familiar with the gastrointestinal associated lymphoid tissue)? A Summary of the Gut-Immune System PH: I’d be happy to. It is interesting that while these things are not commonly remembered and understood, that much of it is a recapitulation of work that Ilia Mechnikov did at the turn of the last century, for which he won the Nobel Prize in Medicine. These are old concepts that we are re-remembering. The big issue is that in our immune system, the way in which we relate and interface with the world-the way in which we determine self from non-self-70{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of that immune system is present in our gut, in our gastrointestinal tract. The way in which it grows, to be able to educate itself (the way in which it learns), is actually through interrelationship with the environment, interrelationship with the food we eat, and also with the “old friends” that we come in contact with: the normal, commensal bacterial flora, and even parasites (worms, viruses). All of these things are what educate our immune system to be able to say, “Are you a friend or are you a foe? Am I going to mount an inflammatory reaction to you, or am I going to say that everything here is okay and I am going to be tolerant of these particular foods or these particular antigens that are presenting themselves?” That entire process is one of being able to set the stage. The most fascinating part in this, to me, is that the way in which you set the stage in the first two years of life has ramifications for what your gut flora will be and what your set point is for the remainder of your life. JB: I think that is a really important concept because-to go back to one of your historic experiences when you were in Nepal-obviously you had an environmental exposure that created a change, probably, in your enteric flora, which caused a change or was interrelated with a change of your gut-immune defenses, and undoubtedly you went back to where your whole system was as an early infant and some of the things that you might have been exposed to and how that developed the ability to respond to that stress. We don’t all go to Nepal, but I guess inevitably we all get exposed to these stressors that then call forth these reserves. PH: We do. Michael Gershon has talked so much about the second brain and this concept that the interrelationship between the gut and the brain. There are more neurotransmitters in the gut than there are the brain, so the stresses that we have in our life have a tremendous impact. It is not just the physical biological influences, but also the psychological stressors that can have an effect on how our gut functions. JB: I know in your article you talk a lot about this concept of tolerance versus intolerance as it pertains to this interface between our enteric immune system and our enteric bacteria. Could you tell us a little bit about how we gain tolerance? Why is intolerance evident in other people? Tolerance vs. Intolerance PH: The immunologic cross talk that is a part of the ongoing education of the gut- associated lymphoid tissue of the immune system is a process where the body is constantly sampling. It is using lymphocytes that are lining the intestinal walls. The intestinal wall, spread out, is as big as a double tennis court. In it, you are putting in antigens-30 to 50 tons of food over a lifetime-and there are bacterial flora that outnumber us ten to one. There are 100 trillion bacteria in our gut and 10 trillion cells in our body. The body is constantly sampling (with the immune system) to say, “Who’s out there?” It samples based upon different kinds of receptors, so called toll-like receptors that are receptors that are set. They are preprogrammed to be able to understand what the appropriate relationship is supposed to be with our environment, and, in the stimulation of that, they either get turned on or they get turned off. That all happens through the inflammatory process and the cycling that you have talked about (through the Nuclear Factor kB and the stimulation of the cytokine system). In the presence of pathogens (like Clostridium difficile or Entamoeba histolytica or E. coli 0157) the process stimulates a cytokine like interleukin-12. Or, it says, “Hey, this is Lactobacillus and Bifidobacter and they are friends that I want to have around,” and it stimulates a counter-regulatory (a non-inflammatory) cytokine, interleukin-10, to slow things down. There are many other cytokines in that cascade, but that is how the body creates the set point. The fascinating thing is that we do see that there are some people who are more predisposed because they have alterations, either in their toll-like receptors or in their inflammatory cascade, where they will mount an inflammatory response in the presence of normal organisms. There is a whole subset of Crohn’s disease that is associated with the NOD2, or toll-like receptor gene, associated with that form of developing inflammatory bowel disease. JB: I know that an article that just recently appeared from an author that you are very familiar with because I think you have had personal contact with him, is a very prominent gastroenterologist, University of North Carolina School of Medicine, Balfour Sartor, who talks about the mechanism of disease (colitis, IBD, and so forth) in Nature Gastroenterology in 2006.12 He has proposed kind of a model that seems like it has general applicability to many of these disorders of immune dysfunction that cut across different diagnostic criteria. Could you kind of summarize what he was speaking to in this article? PH: I’m kind of smiling because the first time I heard him talk I actually thought I was at a Jeff Bland functional medicine meeting because he said the reactivation of disease occurs when environmental factors trigger changes-trigger a break in the mucosal barrier (so-called “leaky gut”)-and they stimulate immune responses and alter the balance between beneficial and pathogenic bacteria in the gut. I have just read a statement from the summary of his review in Nature Clinical Practice Gastroenterology from 2 months ago, and that is something that we have been talking about in the functional medicine arena for more than 15 years. It is fascinating to me to see that the cutting-edge researcher (he is an immunologist and a GI doc), who is speaking to thousands and tens of thousands of people, is converging at the same idea of where balance and imbalance arises from. JB: I remember a number of years ago, we had the fortune of having Dr. Michael Gershon at the Institute for Functional Medicine annual symposium to talk about his “Second Brain” concept and the gut-brain connection. One of the things he was talking about, obviously, was irritable bowel syndrome, which he spent quite a bit of time researching. Out of that seemed to come a connection of functional gastroenterological diseases before you get to this acute pathology that we often think of in gastroenterology (they are always dealing with more the acute illnesses of the GI tract). These functional illnesses have more subtle symptom profiles and may be connected to alterations in the hypothalamic-pituitary-gut axis. I think there is a more recent paper that I just saw in the American Journal of Gastroenterology a year ago talking about the HPA connection to the gut-immune defense and cytokines.13 For the sake of our listeners, could you differentiate kind of a functional gastroenterological collection of disorders from that of a pathologic? What types of things are we actually looking at, clinically? A Continuum of Disorders PH: I would first state that it is my emerging view that these really constitute a continuum and that there is not a set of functional disorders and a set of pathophysiologic disorders that are going on. When we see something that is called a functional bowel disorder, like inflammatory bowel disease, or the new term for kids is “recurrent abdominal pain-RAB,” which are these garbage cans of symptoms that we don’t know what is really going on and so we call it a functional disorder. What we see is there is actually probably something on the order of one in ten people who have IBS who go on to develop inflammatory bowel disease. It may be a precursor in some situations because it is a further extension of that imbalance between the environment and the individual (that gene-environment interaction that is going on). The functional disorders that Michael Gershon talks about are focusing on how we understand this symptom complex of irritable bowel syndrome that now is present in about 15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of all Americans; it is extremely common. We know intuitively that this has to do with the kinds of foods that we are putting into our diet. My own belief, more and more, from a clinical perspective, is that the alterations in gut flora are so extensive that our immune system is not working properly, the gut flora are not doing their normal transformation, detoxification, and metabolic activity to help us to stay in balance with our environment. In more extreme cases, that will then manifest itself as ongoing inflammation that we see in Crohn’s and colitis. As a side note: the Crohn’s and Colitis Foundation has been working with Kaiser Permanente and they are going to be publishing (in the next year) data that shows that the rates of Crohn’s and colitis have doubled in the United States from 900,000 to 1.75 million over the past 9 years-amazing information. JB: This continuum that you are describing sounds like the trajectory that people might travel is through less severe conditions of dysfunctional gut-immune system, and then ultimately moving into more pathologic states, which then means they could pass through things like what we generally call “IBS-like” symptoms. I was very intrigued to see in Gastroenterology in February of this year an article talking about plasma cytokines as a potential biomarker for IBS, again showing a unified concept of inflammation even at the early stages of IBS. Has that been your experience when you have looked at some of these patients with less severe GI dysfunctions? PH: Exactly. We also see that there is a subset of those who have post-infectious irritable bowel syndrome. Those are people who have mucosal markers like fecal calprotectin also being elevated, showing that there is an inflammatory process that goes on that then moves in from the mucosal lining into the submucosa and into the smooth muscle where it interrelates. There is further work out of Canada showing that where the nerve cells come in is right next to where the mast cells and enterochromafin cells are releasing histamines and serotonin. That gives us an understanding of why-when there is an inflammatory process (a low-grade inflammation that is going on)-that there is stimulation of changes in gut motility, bloating, a sense of pain, a sense of fullness associated with IBS. You can see how that inflammatory process, at a low grade, is really generating much of the symptomatology that is going on. In addition to that, when we have that process of low-grade inflammation, this breakdown in mucosal barrier integrity (what the GI docs will call intestinal permeability and what the naturopaths will call leaky gut-describing the same phenomenon), then creates the opportunity for other autoimmune phenomena to occur. JB: That leads us into a clinical question. How does a clinician assess the need of the patient for intervention? Are there specific tests or do we go off clinical presentation as the principal, or is it a combination of functional tests with clinical presentation? Tools for Clinical Assessment PH: It is always a combination of the two. In order to understand the biochemical individuality of a person who is coming in, so that we can use the tools of functional medicine to be able to help bring them back into balance, we can use our tools of understanding the history, listening to the story, seeing how the pieces fit together, using our physical exam to see what imbalances may be going on, and using laboratory testing to give us a further sense of where we are going to get the best opportunity. I forgot to mention the family history, as well. Where do they have a genetic predisposition of having imbalance? Using all of those tools together to be able to drive and apply the right therapeutic modality-that is the thing that is going to get the biggest bang for the buck. JB: Are the tests that are used for measuring gut mucosal integrity a value in this kind of assessment to know how to both track the patient and what treatment regime to use? PH: Certainly. I know you have spoken of Ingmar Bjarnason, before who has done more recent research, not only on NSAIDS and their role and relationship in increasing gut permeability and causing problems with inflammation there, but previous work that he did helping to develop tests like the double-sugar test, looking at intestinal permeability. Those are useful tools to see if there is a breakdown in the gut mucosal integrity occurring. Is there inflammation that is going on? Using tools like calprotectin to be able to tell that. Are there changes in the gut flora? I am excited about work that is being done around the world right now, being able to begin to really describe the microbiome of the gut. Understanding, what are the 400-plus species that are there and how do we help bring people back into balance? In 2006 we are relying on stool culture to give us an idea if the right amount of beneficial bacteria are present in the right balance and are there other bacteria that are not pathogenic, in and of themselves, but in combination (when there is an alteration of the gut flora), they cause a dysbiosis that leads to further inflammation. JB: I’m so excited to hear you talk about that because I recall-this is one of those “back to the future” reflections-a series of lectures that were given back in the 1970s, when I was first starting in this field, by a gastroenterologist from Santa Barbara (Ventura, California) who spoke about stool cultures as a way of assessing functional GI disorders. Obviously, back in the mid-70s that was pretty strange for a gastroenterologist to hear. It seems a little less strange now in 2006-2007 than it did then, but that was pretty advanced (talking about culturing the stool to see if you could pick up imbalanced organisms). PH: I go back to Mechnikov and the work with probiotics (the work with commensal flora and yogurts and natural fermented products). They are-in my belief and in my practice-critical tools for helping to bring balance back to a system that fundamentally becomes imbalanced in most young children during the first 2 years of life, through the use of both vaccines, antiseptic birth conditions, significant amounts of antibiotics, and even the antimicrobial herbs that cause alteration; the lack of breast feeding in our culture, and the introduction of solid foods in a far more rapid phase than our gut (evolutionarily) was meant to be exposed to. JB: I’d like to just go back for a minute to the assessment phase because for some people who may be new to this field, they don’t understand the double-sugar test you described, the lactulose-mannitol challenge test, nor do they probably understand the fecal calprotectin test and how those give different bits of information in clinical management. Could you give us a summary of both those tests? A Summary of Functional Testing PH: Sure. The test for intestinal permeability, developed back in 1985, is pretty simple in nature. You give someone 2 sugars (we give them lactulose and we give them mannitol). Many MDs may remember lactulose as a treatment that causes an osmotic diarrhea. I’ll give small, small amounts of that; lactulose is a relatively large molecule and wouldn’t normally go through the gut wall. Mannitol is a smaller molecule and would commonly go through the gut wall. We can measure, in someone’s urine, how much lactulose and mannitol there is at time 0, and then 6 hours after we give the drink, how much lactulose an mannitol there is, and that tells us how much was absorbed through the gut. We see conditions when there is a breakdown of paracellular junctions; zonulin and other measures are broken down, are not working properly, and the gates open up. These large lactulose molecules are able to move through and we can find them in the urine. Conversely, some people will not only have problems with the lactulose coming through in high amounts, but they will also have inflammation, which causes a breakdown of the villi, the finger-like projections that come out from the lining of the intestine that are part of the absorption process. When those are broken down, it can’t absorb the mannitol properly, and so we can get an indication not only of intestinal permeability, but also of malabsorption that goes on from this very simple test. JB: And how does that connect to or give different information from the fecal calprotectin test that you alluded to earlier? Calprotection: A Quantitative Marker of Inflammation PH: Calprotectin is something that I have been working with in the GI community. We got FDA approval on that just earlier this year and I have been working with GI docs around the world doing research on that marker. It is a marker from the white blood cell, the neutrophil. Sixty percent of the protein in a normal white blood cell is going to have this zinc binding protein called calprotectin. It is released by the white blood cell as a defense mechanism to help bind zinc so bacterial enzymes are not able to work, so it acts as a bacteriostatic measure within the cell. We also are able to use it as a quantitative marker of inflammation. We can find out how much inflammation is going on, determine if irritable bowel syndrome has an inflammatory component in it, use it to be able to determine who (which children, especially) might have not a functional bowel problem but an inflammatory bowel disease going on, and who should be scoped. Further studies are now looking at it as a monitoring tool to follow patients with inflammatory bowel disease. It gives us an insight. There is one other new finding on that that is really fascinating, which takes us out of the realm of the gut, but into the overall inflammatory processes-its role and relationship with disease that you’ve talked about. Calprotectin can be used as an indicator of who’s at risk for developing a myocardial infarction when measured in the plasma; it is more sensitive than hsCRP (data from Circulation in August of this year from Dr. Dan Simon at Harvard). JB: This is again showing unified mechanisms, isn’t it? You don’t just have action in a local area; you have a “think locally, act globally” type of phenomena going on here. You talked earlier (and also very nicely in your review paper) about the use of probiotics. I think most people in our field have some familiarity with these. I was very intrigued when I read this gastroenterology article in February 2006 talking about plasma cytokines as biomarkers for IBS. In that paper they talked about the use of probiotics at the dose of 3.6 trillion organisms per day, which, by most people’s assessment, would be a pretty massive dose of probiotics. Do you have any thoughts about very high dose probiotics, and, if so, what you are really doing? Because it sounds like it may be beyond just reinoculation; you may be actually adding trophic factors or some bioactive components at that level. Probiotics Research PH: Clearly. I think that we have learned that we have been (at least within the probiotic strains that are available commercially over the past 20 years) dealing with more homeopathic dosing patterns, and that in order to really be able to get in to true therapeutic ranges with probiotics we need to go to larger doses. Now, commonly, we see people using 50 to 100 billion colony-forming units with patients with IBS. Data with VSL#3 out of Italy now looking at 450 billion colony-forming units, and they are doing research, as you said, much, much higher at 2.7 and 3.6 trillion colony-forming units as ways of being able to really act as anti-inflammatory measures. When we recognize that the gut has 100 trillion bacteria present in it, using a dose of 2 or 3 trillion is not unreasonable and I think the higher doses of probiotics I’ve found to be very effective and there is still a large margin of safety, using probiotics in this way. There is one thing I also want to acknowledge in this arena of looking at probiotics and imbalances in our gut and it has to do with celiac disease. In the course of my career, from the time I was in med school, celiac disease was first said to be 1 in 3000, and then 1 in 1250, and now the last data says 1 in 133 people have it, and probably 1 in every 50 people who have IBS have celiac disease with true changes going on in their tissue transglutaminases. But data out of Italy also shows us that when people have the right amount of commensal flora, all of the enzymes necessary to breakdown gliadin and gluten are present. Maybe it is not just a genetic factor going on that we are uncovering, but maybe it is that there are such changes in our gut flora that we don’t have the capacity to breakdown wheat like we did before. And those people with the genetic predispositions of DQ2 and DQ8 are those who are at highest risk for not being able to effectively breakdown wheat in their diet. JB: That’s a really important point. I’m really glad you brought that up. In this whole HLA genotype and its connection to these kind of preformed diseases of allergy tends to, I think, reduce some of the other modifying factors, like you have just described, that could influence the expression of that genotype as a phenotype. I think that is a very useful observation and helps us to understand the increase in prevalence of some of these conditions. It is not just sandpile genotypes that we are talking about, it is environmental factors that have modified the expression. That leads to a similar clinical question that I often hear and I know you do as well. Do some of these marker organisms represent the cause or are they effect? Like we hear of Candida infection. We hear about Blastocystis hominis infection. We know these are opportunistic organisms. Do they represent, necessarily, the cause of these problems, or do they come associated with the problems of an imbalanced Th1/Th2-disturbed immune system? PH: I’m looking at the board in my office which has a chicken and an egg on it, which is what that question reminds me of. It really comes down to changing the way we think about health and disease to one of homeostasis and balance-something you have been talking about for years. When we look at organisms, even Blastocystis or Candida, we find that people normally have small amounts of Candida in their gastrointestinal tract; it is not unusual at all. It is about being in the right relationship and in balance with those things. It is when we become out of balance that we have problems. From a laboratory perspective it is sometimes difficult because the people who authorize laboratories don’t want to talk about something that is imbalanced; it is either a pathogen or it is not a pathogen. We find that high amounts of Klebsiella in people who have certain kinds of genetic predispositions and inflammatory processes with leaky gut where those antigens are being presented, are going to have an increased risk of developing some autoimmune disease. That data has been around and published for the past 30 years, and yet it is not to say that if you have small amounts of Klebsiella in your gut that you have to use high-dose antibiotics in order to eradicate it. That’s foolish. It is about how we use our food and our nutrition to help bring us back into balance. JB: That leads, Dr. Hanaway, to really the last question. I wish we could continue this on indefinitely; we have only touched the surface of all the resources you represent. Let me, if I can, talk about these environmental modifiers of GI-immune defense process or function. Clinically, we often hear not just about probiotics but we also hear about prebiotics, the selective substrates from which these commensal (or symbiotic) organisms can selectively grow. You shared with me a very interesting article that opened up a whole new thought for me that some of these prebiotics might play and that has to do with function of the GI-immune tract and biofilms, and how biofilm environmental oligosaccharides might relate to an outcome in the phenotype of favorable immune balance. Can you tell us a little bit about that? That emerging concept of biofilms and the GI system? Biofilms and the GI System PH: It is not only the gastrointestinal tract, one-cell thick and as big as a doubles court, that is actually covered by a film (a film that includes the bacteria). Oligosaccharides are also present; they are helping to create a further barrier function with what goes on in the normal gut. They are a part of the process of how we effectively relate and defend ourselves from our environment. In the paper that you talked about, from BMC Microbiology earlier this year, what they did is they looked at various strains of bacteria and they found that the wild-type strain of people had a good expression of biofilm that was associated with the colonization of normal, good bacteria (normal, good Enterococci in the gut).14 And that the presence of those oligosaccharides in foods (such as you talked about-as prebiotics) can actually influence the formation of that biofilm. So it is not only feeding the bacteria, which is they way in we have thought is the primary role of prebiotics (disaccharide food sources for bacteria), but also in the development of this layer that helps to coat the gastrointestinal tract and helps it to be safe. So there is a whole series of things and we are at the very beginning, at nascent phases, of learning the interaction between prebiotics and probiotics that I heard Mary Ellen Sanders talk about a year-plus ago on this very show. JB: So really when you get to introduce this concept then it starts to connect with this whole mimicry issue of HLAB27, possibly, and by forming the right biofilm you may cover over certain receptors in such a way that you reduce the potential for mimicry. It sounds like this whole communication process with the gut as antennae for the rest of the body’s immune system and how those antennae might be tuned in different ways, depending on the local environment. PH: Exactly. JB: I can’t thank you enough for sharing this time with us. This is-obviously-just the start of what needs to be an ongoing, continued evolution of this discussion. As you point out in your review article, things like the Hygiene Hypothesis and how that interrelates with early stage atopic disorders in children-how that may relate to things like autistic spectrum disorders and how that connects to the Andy Wakefield concepts of immune imbalances in lymphoid nodular hyperplasia in children in autistic spectrum disorder. And how that then relates later to attention disorder, hyperactivity disorders in adults-there is a tremendous connection across many functional characteristics that knows no boundaries in disciplines. This is not owned by gastroenterology, obviously. PH: No, it’s not, and I want to actually give a plug to Joe Pizzorno and our naturopathic colleagues who have helped to champion these ideas and really bring them to the fore, as well, from a clinical perspective because they work. JB: Dr. Hanaway, I want to thank you for helping us with this review paper that appeared in the September/October issue of Alternative Therapies under the title, “Balance of Flora, GALT, and Mucosal Integrity.” I think if people read that article carefully and go back over it they are going to have a whole level of education about this connection that can open up new important therapeutic doors with patients with complex chronic illness. Thanks for all of your contribution, and I hope through this discussion people will be more inclined now to start down the path of functional gastroenterological testing and using some of these tools to assist restoration of the immune defense. PH: Thank you, Jeff, for being there and helping to bring these ideas forward. In the range of clinically useful tools that we have discussed over the years in Functional Medicine Update, I can’t help but feel that this discussion with Dr. Hanaway ranks right at the top because it is so applicable to virtually every patient that comes in with complex chronic disease. The disorders that we have in the late 20th century/early 21st century in chronic disease are immunologically related and certainly the gut plays such an important role in establishing immune defense function, systemically as well as locally, in the GI tract. This whole model that Dr. Hanaway shared with us is critically important and translates directly into clinical practice. We know that you can actually evaluate gut microflora based upon peoples’ diet. You can see that GI mucosal bacteria cluster around certain diets. We know that the immune privilege of the gut is so tightly related to environmental factor of eating and stress and alcohol and chemical exposures and so forth. I think this is one of those extraordinary opportunities to both listen and learn and then to do and start making a difference in your patients. Thank you, again, to Dr. Hanaway for his very lucid and insightful comments.  

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Bibliography

1 Ronis M, Rowlands JC, Hakkak R, Badger T. Inducibility of hepatic CYP1A enzymes by 3-methylcholanthrene and isosafrole differs in male rats fed diets containing casein, soy protein isolate or whey from conception to adulthood. J Nutr. 2001 Apr;131(4):1180-1188. 2 Ravnskov U, Rosch P, Sutter M, Houston M. Should we lower cholesterol as much as possible? BMJ. 2006;332:1330-1332. 3 Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med. 1998 Jul 27;105(1B):31S-38S. 4 Hall AJ, Tripp M, Howell T, Darland G, Bland JS, Babish JG. Gastric mucosal cell model for estimating relative gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. Prostaglandins Leukot Essent Fatty Acids. 2006 July;75(1):9-17. 5 Bongaerts G, Sverijnen R, Timmerman H. Effect of antibiotics, prebiotics and probiotics in treatment for hepatic encephalopathy. Med Hypotheses. 2005;64(1):64-68. 6 Jirholt J, Lindqvist AB, Holmdahl R. The genetics of rheumatoid arthritis and the need for animal models to find and understand the underlying genes. Arthritis Res. 2001;3(2):87-97. 7 Ebringer A, Rashid T. Rheumatoid arthritis is an autoimmune disease triggered by Proteus urinary tract infection. Clin Dev Immunol. 2006 Mar;13(1):41-48. 8 Hvatum M, Kanerud L, Hallgren R, Brandtzaeg P. The gut-joint axis: cross reative food antibodies in rheumatoid arthritis. Gut. 2006;55:1240-1247. 9 Iweala O. Nagler C. Immune privilege in the gut: the establishment and maintenance of non-responsiveness to dietary antigens and commensal flora. Immunol Rev. 2006 Oct;213:82-100. 10 http://news.bbc.co.uk/go/pr/fr/-/2/hi/health/5302054.stm 11 Hanaway P. Balance of flora, GALT, and mucosal integrity. Altern Ther Health Med. 2006 Sep-Oct;12(5):52-60. 12 Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006 Jul;3(7):390-407. 13 Dinan T, Quigley E, Ahmed S, Scully P, O’Brien S, et al. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology. 2006 Feb;130(2):304-311. 14 Creti R, Koch S, Fabretti F, Baldassarri L, Huebner J. Enterococcal colonization of the gastro-intestinal tract: role of biofilm and environmental oligosaccharides. BMC Microbiol. 2006 Jul 11;6:60.

Welcome to Functional Medicine Update for January 2005. It is the beginning of another New Year, one that heralds the 24th anniversary of FMU. Thanks to all of you who have been with us over the years. For those of you who may be new to FMU, we hope you will find it an enjoyable and helpful tool in the development of your practice and in the management of patients with complex, chronic disease. Functional Dermatology In this issue, we are going to focus on a new topic functional dermatology. This subject derives nicely from the December 2004 issue of FMU, which focused on gastrointestinal (GI) immune system function and its relationship to pre- and probiotics. Our interview with Dr. Mary Ellen Sanders helped us to understand much more about the usefulness of various species and strains of bacteria that favorably influence gut immune function. We are fortunate to have a skilled physician for this month’s Clinician/Researcher of the Month interview. Dr. Stephen Chiarello, an internist, and dermatologist will be speaking about his years of clinical experience using integrative/functional medicine. I am going to lay the groundwork for the interview by talking about functional dermatology. The skin is part of the messaging system for the body’s immune function. Therefore, imbalances of immune function are often reflected as dermatological conditions. 12th Annual Symposium on Functional Medicine I have a reason for selecting functional dermatology as this month’s topic. The 12thInternational Symposium on Functional Medicine will focus on The Immune System Under Siege: New Clinical Approaches to Immunological Imbalances in the 21st Century. In preparation for the symposium, it seems appropriate to start off the year by talking about ways of clinically assessing immunological imbalances, beginning with the skin. If we know how to read the skin, it may lead us to a better understanding of where certain immune system imbalances originate. The 12th Annual Symposium on Functional Medicine will be held May 24-28 in Palm Springs, California, at the four-star Westin Mission Hills Resort. I believe it will be one of our most interesting symposia as it relates to integration of the plenary sessions and workshops. We have scheduled a remarkable group of clinicians and researchers who will address immune system challenges that confront our society, their manifestations in terms of certain diseases, and their amelioration using integrative and functional medicine approaches. There will be two pre-conference courses at the symposium. The first has received rave reviews from past participantsDynamics of Practice Management for the Functional Medicine Clinic, to be held on Tuesday, May 24. The second pre-course will be held on Wednesday, May 25–Understanding Immune Modulation from the Thymus Dependent-1/Thymus Dependent-2 Perspective. This course is designed to prepare attendees for subsequent information they will receive at the plenary sessions and workshops. We hope you will join us. Let me return to functional dermatology and discuss using the skin as a marker, a clinical observation point, for imbalances in the immune system. The epithelial tissue shares a common origin across the variety of different tissues in the body, including the gut mucosa, the lining of the eyes, the tongue, the skin, the gingiva of the mouth and periodontal tissue, and the lung mucosa. All of these are similar in some physiology and embryological origin. Where do the skin’s immune messages come from? What triggers some of the inflammatory processes that result in adverse dermatological conditions? The GALT as the Seat of the Immune System Part of the story goes back to the seat of the immune system, the gastrointestinal-associated lymphoid tissue (GALT). We talked about the GALT at some length in the December 2004 issue of FMU. The gut may be the triggering tool for various types of immunological dysfunction, but it is not the only site of origin. Airborne allergens trigger immunological dysfunction, as well as various types of infections and ischemic events. There are multiple triggers that can initiate immune imbalance, but we should always keep the GALT in mind when looking at dermatological problems. In fact, the skin is the reflecting pond of the state of the immune system in the body at large. We need only go through the litany of different dermatological conditions to see the strength of their connections to immunological imbalance, beginning with the most dramatic immune dysfunction of the late 20th century HIV infection. As we age, we may experience increasing levels of skin-related dysfunctions from opportunistic infections, ranging from thrush to various types of skin cancers. Certain autoimmune diseases lead to dermatological conditions, such as scleroderma, myasthenia gravis, or various types of psoriatic arthritis. Conditions related to food allergy, mediated through gut response membrane-binding receptivity, are also associated with skin inflammation, such as urticaria. Responses to certain xenobiotic drugs that can initiate the immune system include rashes, hives, or certain other dermatological conditions. There are conditions associated with dysbiosis that accompany atopy in infants and children, e.g., colic and eczema. In cutting across the full range of the medical lexicon and looking at conditions that are often associated with imbalanced immune system function, there are dermatological signs that reflect an interrelationship between those conditions. The skin is an important reflecting pond that can be used for measuring immunological status. If you did not fully believe that before, you will now, in view of the emergence of new mechanisms related to various skin disorders. Take psoriasis, for example. Psoriasis is a fairly severe skin condition involving flaking, plating, and exfoliation of the skin, with potential for infection. The physiological mechanism that initiates psoriasis is not well understood. It has only begun to emerge over the past ten years. This has culminated recently in a series of interesting papers in The New England Journal of Medicine that set the tone for what we are going to be talking about in this month’s issue of FMU. Immunologic Targets in Psoriasis A recent article appeared in The New England Journal of Medicine, titled “Immunologic Targets in Psoriasis.”1 I want to discuss this article in some detail. If you have been following FMU for some time, and are aware of what is happening in the field of immunology, you will hear some familiar terms. In this article, the authors discuss two new studies describing the positive clinical effect of drugs that were historically used for the management of arthritis, but have now been found to be useful in the treatment of psoriasis, suggesting there may be a common etiological factor associated with arthritis and psoriasis. Both of these conditions have immunological modulators. They may share common triggering effects or mediators which, depending upon the tissue, produce differing symptoms, but both involve inflammatory processes. These drugs, etanercept andefalizumab,modify the expression of various types of proinflammatory cytokines, such as tumor necrosis factor alpha (TNFa) or the aLb2 integrin, also known as leukocyte-function-associated antigen 1 (LFA-1). LFA-1 is important in the process by which T cells cross blood-vessel walls, enter tissue, and are subsequently activated by antigens. This implicates some kind of allergy-potentiating effect that might act as a trigger. If giving a drug that impedes integrin (e.g., movement of lymphocytes) can block psoriasis, this means the signaling process is being blocked, an interaction between the lymphocyte and an antigen. It’s important to note that the antigen might come from a variety of sources, including food. It is interesting to note that etanercept and efalizumab work by different mechanisms, but both drugs have been shown in separate clinical studies to have positive benefit on the remediation of psoriasis symptoms. Because they both treat inflammation from different perspectives, a mechanism seems to be the underlying cause. That is, they may target the same mechanism, even if they work at different places within that mechanism leading to inflammation triggered at the site of the skin. In addition, these drugs have been approved by the FDA for use in the treatment of arthritis, suggesting that there is a common mechanism associated with these inflammatory conditions (e.g., skin inflammation, psoriasis, and arthritis). These drugs have demonstrated efficacy in rheumatoid arthritis and inflammatory bowel disease (IBD), as well as psoriatic arthritis. There are additional anecdotal reports of their efficacy in immune and inflammatory diseases. There are now published papers indicating their value in the treatment of psoriasis. There are a variety of different medical specialties, all of which could call these drugs their ownrheumatologists, gastroenterologists, and dermatologists. Perhaps the drugs know no medical specialty. Perhaps they interact with a mechanism of inflammation. Regarding how these inflammatory conditions specifically interrelate with dermatological problems, it is necessary to take a step back into understanding how biologic agents work. Let us look at LFA-1 and TNFa as they relate to the immunological features of the skin. “Skin is endowed with special features that protect it from injury or infection, and a limited number of factors, including the cytokine TNF-a, transmit danger signals from injured tissue to the immune system. The release of TNF-a from cells in the skin induces the production of other cytokines and chemokines and modifies endothelial surfaces in cutaneous postcapillary venules, facilitating the extravasation of leukocytes.”1 Barrier function is lost, there is a leaky membrane, and white cells cross that barrier. “These leukocytes exit vessels and enter the dermis through a multistep process involving several molecules, including LFA-1. Leukocytes are then attracted along chemotactic gradients and can begin to mediate effector functions, such as the killing of pathogenic bacteria or fungi.”1 The useful purpose of this inflammatory process is to quench infection that could ultimately cause injury. As in any immunological imbalance, when the inflammation is over-activated, a friendly process in the host can become an injurious process, leading to a psoriatic condition. “One of the prominent effector molecules produced by these infiltrating leukocytes is TNF-a. Fundamentally, this process is a form of immunosurveillance of body surfaces for danger signals, a phylogenetically ancient process that is central to innate immunity.”1 This process can be activated by signals coming through the bloodstream that potentiate the skin’s sensitivity to environmental stimuli. There are internal as well as external stimuli that increase the relative activation of this process and can participate in immune imbalance, which becomes like a dog chasing its tail, perpetuating inflammation of the skin. “Adaptive immunosurveillance is the domain of T cells. Each T cell has a different specificity for antigen conferred by its unique T-cell receptor, and getting the right T cell to the right place at the right time is a major logistic challenge for the immune system. This puzzle is solved by the specific migration patterns of different subgroups of T cells.”1 This is where we begin naming various types of T cells as sub-populations. “Naive T cells shuttle between blood and lymph nodesa process that is dependent on LFA-1. Once in lymph nodes, these T cells mingle with dendritic cells that have recently migrated through the lymphatics from the peripheral tissue. These dendritic cells have left the peripheral tissue because danger signals (such as TNF-a) induced their migration and maturation, and they are uniquely powerful activators of T cells that bear the correct receptor antigens they have internalized.”1 Now, there is a potentiated system with increased proinflammatory potential. The Th1/Th2 balance is shifted toward a higher level of inflammatory mediators being produced. “When they are thus activated, nave T cells divide and multiply, express new molecules on their surface, and are instructed to become effector memory T cells. This immunologic memory extends to the anatomical location, so that a T cell that is educated in a skin-draining lymph node will express molecules that facilitate its subsequent entry into skin…”1 This ties into what is also occurring on the mucosal surfaces in the gut and activation of the GALT. This is a similar argument to one we could imply for gut lymphoid epithelial cells, as well as those of the skin itself, again showing the connection between gut and skin. “The pathologic release of TNF-a and other cytokines strongly up-regulates the expression of endothelial E-selectin and ICAM-1, as well as chemokines, on the luminal aspect of the skin vessels…”1 The newly expressed molecules circulating in the skin can more efficiently enter through the vascular bed and begin to initiate the perpetuation of the inflammatory process. Recruitment begins, resulting in a concentration of immune cells at the site of the presumed injury or inflammation, which perpetuates the problem. Overly activated TNF-a contributes to the orchestration of inflammation that continues to be seen as chronic psoriasis. This process is self-perpetuating and is reversible only when the activation of T cells within the lesion is blocked. That is the nature of how immune-modulating drugs have had some success in the treatment of psoriasis or arthritis. They block various steps along the production process for the inflammatory mediators. Given the activity of these molecules, it is not surprising that blocking with LFA-1 or TNF-a has therapeutic effects in psoriasis. This is also true in IBD or arthritis because they share common mechanisms. The mechanisms of the perpetuation of immune imbalance are being interrupted. Most therapies currently available for psoriasis have dose-limiting toxic effects, which seems to be the problem with using some of these medications. Are there things one can do from an environmental standpoint, or by harnessing functional and integrative dermatology, to manage these inflammatory conditions? We are starting to witness the emergence of functional dermatology from a mechanistic perspective, built on environmental modulators of the inflammatory system specific to the epithelial surfaces. Catabolic/Anabolic Balance I have been speaking to the concept of proinflammatory mediators, the cell types they are derived from, and how they are perpetuated. In general, these proinflammatory cytokines are catabolic mediators. They are the same players we associate with other kinds of infectious conditions and malignancies associated with cachexia, muscle loss and, in extreme cases, wasting disorders. It depends upon the place of residence or production of these mediators and the levels that encounter different kinds of physiological shifts in the catabolic/anabolic balance. In general, the higher the production level of proinflammatory mediators, the more catabolic the shift in physiology. In more extreme cases, imbalance of Th1 and Th2 immune system function may be associated with alteration in the catabolic/anabolic balance, shifting toward anabolism, which includes muscle-wasting, cachexia, and many other things we see in acute disorders. It is a question of degree, whether acute or chronic, and where the patient resides on that continuum of events. The skin is a barometer of some aspects of the balance related to Th1/Th2 activity. Treatment Strategies How does one evaluate what type of therapy to use and where to intervene in individuals with psoriasis or problems related to inflammation imbalance in epithelial tissue? We would use the same approach we alluded to in the December 2004 issue of FMU–try to rebalance the immune system. Start with the GALT, move out to the peripheral lymphocytes and to liver-related immune function as encoded through the Kupffer cells (the embedded white cells in the liver), and try to find specific ways of reestablishing immune function balance in those tissues. Clearly, if there is a full-blown state of inflammation in any one of these epithelial tissues, there are drugs derived from clonal biotech procedures for blocking certain aspects of the inflammatory cascadethe TNF-a or LF-1-blocking agents. But in the case of chronic inflammation, it may be best to utilize environmental and functional intervention first. These drugs, if we were to use them too early as treatment modalities, might have potential adverse side effects. Because of their strength in blocking the inflammatory cycle, they may also block the ability of the immune system to function. Inflammation processes occur for a reason, that being to help defend against infection and other things associated with transformed cells that may become malignant. If that function is too greatly suppressed, there is risk of opportunistic infection due to a suppressed immune system, or perhaps secondary malignancy. Proinflammatory mediators such as TNF-a and IL-1 participate in breakdown of local tissue. They create a catabolic shift in metabolism. Therefore, if there is a Th1/Th2 imbalance and activation, there may also be an anabolic/catabolic imbalance, leading to poor tissue integrity. In inflammation, there is a breakdown in the integrity of the skin. We have often talked about “leaky gut syndrome”. One can have “leaky skin syndrome”, as well, as a consequence of an inflammatory process that leads to the breakdown of the skin’s barrier defense against bacteria and exogenous toxins that might have access to the body. I am now quoting from an interesting paper that appeared in Current Opinion in Clinical Nutrition and Metabolic Care that discusses the role of proinflammatory cytokines and how they participate as catabolic mediators in the breakdown of tissue integrity.2 The gut mucosa, the skin, the blood brain barrier, or the pulmonary epithelia, when subjected to high levels of catabolic proinflammatory mediators, all lose their integrity. They become “leaky”; they become penetrable to larger molecular weight substances. That creates a secondary set of conditions that leads to dysfunctions in those particular areas. An interesting report appeared in The New England Journal of Medicine, titled “Treatment of Skin Papillomas with Topical a-Lactalbumin-Oleic Acid.”.3 Alpha-lactalbumin is an immunologically-active milk protein. Investigators developed a specific a-lactalbumin-oleic acid (found in olive oil) complex and tested this in a trial on skin papillomas. They found this specific complex resulted in beneficial and lasting effects on skin papillomas. How does this work? That is an interesting question. This was a double-blind, placebo-controlled trial with 40 patients in which a-lactalbumin-oleic acid or saline placebo was applied daily for three weeks. The second phase involved an open-label trial of another three-week course of a-lactalbumin-oleic acid. Two years after the end of the open-label phase of the study, 38 of the original 40 patients were examined, and long-term follow-up data were obtained. In the first phase of the study, the lesion volume was reduced by 75 percent or more in all 20 patients in the a-lactalbumin-oleic group, and in 88 of 92 papillomas. In the placebo group, a similar effect was seen in only three of 20 patients. From these observations, let us see if we can understand something about the immune system of the epithelium. “Cutaneous viral warts are common, benign, usually self-limited papillomas with a preference for the hands and feet. A wide variety of local therapies based on destruction, keratolysis, immunostimulation, or antimitotic effects have been tried for the treatment of cutaneous warts, but most of the clinical trials of these local treatments have been of low quality.”4 A recent report revealed that simple preparations containing salicylic acid are the only topical treatments for which there is good evidence of efficacy and safety. However, in the paper inThe New England Journal of Medicine, utilizing a topical application of a-lactalbumin-oleic acid on cutaneous viral warts resulted in a significant treatment effect. There is something about this particular type of protein. What does it do? “The protein lipid complex travels through the cytoplasm to the nucleus, where it binds with high affinity to the histones and nucleosomes of transformed cells. Interaction of the complex with histones and chromatin in the nuclei of the transformed cells prevents transcription, cell replication, and chromosomal recombination and causes disruption of the chromatin structure and fragmentation of DNA. Healthy, differentiated cells, in contrast, survive challenge with a-lactalbumin-oleic acid and show no apoptotic changes, making the substance rather specific for transformed cells.”4 The cells have gone through some kind of transformation as a consequence of a viral infection. This story relates to human papilloma virus (HPV) and some of the relative risk factors it has to female cancers. “HPV plays a key role in the development not only of cutaneous warts, but also of laryngeal papillomas, genital warts, vulvar intraepithelial neoplasia, cervical carcinoma and possibly cutaneous squamous-cell carcinoma. To date, more than 90 types of HPV have been identified and their genomes sequenced. More than 100 additional partially sequenced isolates require further characterization.”4 This is a highly intragenus class of viruses associated with these infections. “HPVs may be classified on the basis of their tropism as either genital (mucosal) or cutaneous. Genital HPVs are subdivided into high-risk and low-risk types, according to their malignant potential and cell-transforming capacity in vitro. The cutaneous HPVs may be subdivided into the classic types associated with cutaneous viral warts such as verruca vulgaris and verruca plantaris (the lesions treated by Gustafsson et al.) and the so-called epidermodysplasia verruciformis types. “Numerous hyperkeratotic skin lesions and actinic keratoses develop in organ-transplant recipients, and these lesions have a strong potential to evolve into cutaneous squamous-cell carcinoma.”4 This is tied to UV radiation exposure and sun-damaged skin, a separate category from HPV viral infections or warts. Yet, they share common mechanisms relating to DNA injury, whether viral-induced injury or induction by ionizing UV radiation. Would there be a similar effect on anti-transformation with the a-lactalbumin-oleic acid complex on skin-induced cutaneous lesions as there is on HPV viral infections like warts? By mechanism, there is some argument that it may be anti-transforming in both cases. The hair follicle is a possible reservoir for the epidermodysplasia verruciformis types of HPV. In an immune-compromised or immune-altered situation, the virus starts to proliferate and injures and transforms cells. The a-lactalbumin-oleic acid complex appears to have an interesting effect on modifying transformed cells through an immunological mechanism associated with apoptosis, or cell death, of the transformed cell, leaving the host cell completely untouched. Here is an immunological-specific, environmental agent that seems to work only through regulation of transformed cells, i.e., it becomes a chemotherapeutic agent by recruiting the immune system cells and altering the physiology of the transformed cell in such a way that it undergoes cell death, or apoptosis. This is a remarkable part of the story. A milk protein given in a specific complex with a fatty acid can induce a positive effect when given topically on an epithelial surface that is transformed by a virus, or perhaps transformed by UV radiation injury. What about all the gut epithelial tissue constantly being exposed to some 50 tons of food that is put into our mouths over the course of a lifetime? What information do those food particles and fragments impart to receptor sites of our immune system on the surface of the gut epithelium? That is a question which has not yet been fully answered, but which is certainly at the core of functional medicine thinking. There may be molecules from food that turn on proper immune function and serve as activators of immunosurveillance, and there may be those that turn off surveillance, or that activate specific immunological vigilance associated with inflammation. These may occur at the same time, depending upon individual genetic uniqueness. The food of one can be the poison of another, which comes back to the concept of food allergy and inflammation. The paper on the use of topical a-lactalbumin-oleic acid for the treatment of skin papillomas is more interesting from a fundamental mechanism perspective than it might seem. It begins with a discussion about cell/cell interaction, surface effects on membrane receptors, and the difference between a transformed cell that has undergone immunological alteration versus a host cell. The discussion evolves to how cells respond to these messages, and how the immune system may be recruited into recognizing that there is a foreigner on board and excising it before it has a chance to do injury. This information may lead to new therapeutic tools that can be used for restoring Th1/Th2 immune balance so as to take charge of foreign or transformed cells that create injury while, at the same time, not upregulating and perpetuating inflammatory disorders. The inflammation needs to be localized and controlled, leading to cellular apoptosis and death, and to be quenched and regulated. The process of clonal growth and decline of immune cells is dependent upon the regulation of the Th1/Th2 immune system. The inflammation and immune-recognition process I have been describing relates to an balance between Th1/Th2 lymphoycytes and their function, which is both mediated by and responsive to the states of oxidative chemistry in the tissue. If there is a shift in the inflammatory state by increased production of TNFa and IL-1, there is also a shift in the redox potential of that tissue, leading to a higher state of oxidation. More reactive oxygen species (ROS) are produced during times of immunological upregulation and inflammatory processes. The recognition that oxidants are part of the microbicidal killing process and serve a useful role, is an important part of the developing understanding of the mechanism by which the immune system works. In the same way that anything good at one level may be bad at too high a level, that is the case with oxidants produced during times of inflammation activity. ROS at one level can be a friend to the normal body defense system, but at a higher level, when activated in the skin or gut epithelium and perpetuating a chronic long-term state, can become destructive. That has recently been described in a review in Free Radical Biology & Medicine.5 The author discusses reactive oxygen species in the immune response and how they interrelate to tissue activity and integrity of the immune system, but also tissue injury upon excessive upregulation. The process of tissue-specific inflammation occurs as a consequence of upstream regulation through nuclear factor regulations, such as nuclear factor kappa B (NFkB). NFkB is one of the nuclear regulatory factors released in the cytoplasm from its inhibitor kappa B (IkB) by activation of a phosphorylating enzyme called inhibitor kappa B kinase (IkK). This kinase enzyme phosphorylates the inhibitor, and the inhibitor falls off the NFkB subunits. That allows the NFkB to move from the cytoplasm of the cell to the nucleus, where it sits on the regulatory portion of genes and facilitates the expression of 100 or more inflammatory signals, some of which regulate the production of TNF-a, IL-1, and other inflammatory mediators.6 The activation of NFkB is a tissue-specific process that relates to a specific host tissue. We do not usually talk about generalized inflammation. We talk about tissue-specific inflammation mediated through activation of NFkB that comes from upstream messages delivered to the cell. Those messages could be things such as bacterial wall cell debris like lipopolysaccharides (LPS), or inflammatory cytokines produced by another tissue at a distanceparacrine effects that initiate the release of NFkB in the cytoplasm so it can travel to the nucleus. This begins a multiplication effect that occurs when the oxidative inflammatory storm begins. It may be seen on the skin, but it may have originated somewhere else as a low-grade chronic inflammation, perhaps in the gut or the liver. There are other interrelated processes. It may be localized on the skin as a consequence of a wound, injury, or infection. When the skin is inflamed, we think of oxidative stress, catabolic shift, proinflammatory mediators, and imbalance of Th1/Th2. Where else in the body does inflammation reside? Is it solely linked to the skin, or are there other things of low-grade inflammatory potential going on at the lymph nodes, the GALT, in the circulating white cells, or at the hepatic level? There are a variety of nutrition modulators being observed for these processes, including the amino acid L-arginine, which affects lymphocyte phenotypes of the GALT and which can help regulate the balance of inflammation. There are some good studies being published on the use of supplementary L-arginine for immune balance in the gut. One of these papers appeared in the Journal of Parenteral and Enteral Nutrition.7 Omega-3 Fatty Acids and Gut/Skin Inflammation Omega-3 fatty acids also play an important role in regulating NFkB and the proinflammatory condition, which has been associated with not only the management of the gut, but also of the skin. There are clinical studies utilizing gram doses of omega-3 fatty acids for management of both gut and skin inflammation, again showing common mechanisms. I hope I have left you with some interesting thoughts about the interrelationship of inflammation to clinical conditions in which the skin may be seen as a reflection of imbalance in the immune system. Let’s move to the discussion with our Clinician/Researcher of the Month.

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INTERVIEW TRANSCRIPT

Stephen E. Chiarello, MD 3280 Tamiarmi Trail, Suite #20 Port Charlotte, Florida 33952 JB: It’s time for our Clinician/Researcher of the Month. We are pleased and privileged to have Dr. Stephen Chiarello, who comes to us with a broad range of experience in the field of integrative/functional dermatology. Dr. Chiarello practices at the Dermatology and Skin Cancer Center in Port Charlotte, Florida. In speaking with him and reading the information he passes out to his patients, I can see why he is not only a successful physician, but a successful person. He puts his patients first, and has an innovative way of communicating with them in the mutual development of treatment programs. It’s a great pleasure to have you with us on FMU, Dr. Chiarello. I would like to begin by asking how your career led you into the area of integrative and functional dermatology? Dermatology versus Internal Medicine SC: I am a Board-certified dermatologist, as well as a Board-certified internist. That has helped me a lot. In my dermatology days at Dartmouth, I was constantly at loggerheads about practicing dermatology versus practicing internal medicine. I kept shaking my head and thinking, well, aren’t they both the same? Aren’t they all connected? And they certainly are. You have shown us how everything in the body is connected. I love your statement about the skin being the gut, the gut being the brain, the brain being the skin, and so on. They’re all connected. The thing that pushed me into an integrative/functional approach to medicine was my patients. Our patients are the most important aspect of our practices. Obviously, we’re trying to alleviate problems they present with. Being a specialist, it’s easy to truncate their problems, put them in a box, spit out some kind of preconceived notion, hand them a pill or a cream, and send them on their way. But if we truly want to solve our patient’s problems, we have to look at them from an integrative/functional point of view. We have no choice. What got me into this field was my desire to make a difference in terms of patient outcomes and not use a band aid approach. I often ask my patients if they want a fish so they can have a meal that day, or do they want me to teach them how to fish so they don’t have to come back and see me, and can take care of the problem themselves. Ultimately, my patients and their need to be treated are what pushed me into this field. Of course, I had the combination of both specialties to help me. JB: Yes, it must be useful to see how different perspectives are woven together. Maybe that’s often how people get channeled. Many doctors don’t have the breadth of experience across different disciplines that you had in your training. I’m sure that helped you to make the connections and decide that diseases don’t occur as isolated, independent units. Would you tell us about some conditions you often see that are amenable to an integrative/functional approach, and how they are different from the traditional perspective? SC: A good example is one you have often alluded to and spoken eloquently aboutsyndrome X. I’m also a cosmetic surgeon, and I’ve developed a lot of different techniques for things such as cosmetic skin resurfacing and skin cancer removal. Syndrome X bridges both gaps. I see patients who want liposuction and I see patients with hirsutism. When I see patients on a daily basis, I check them from head to toe. That’s something I have always done. If you don’t look at the whole problem, I don’t see how you can come up with the whole solution. Syndrome X Symptomatology What do I see in someone with syndrome X? For instance, there’s hirsutism. Instead of just using my laser on a hirsute patient, I know there is likely something behind that condition. For instance, it’s a tip-off for polycystic ovary disease in some women. Oftentimes, they are heavy with truncal obesity. They come in for liposuction. Yes, we can take their fat away, but we also create scenarios for them that help them get back to the real problem, the problem of lifestyle choices, or perhaps some genetic predisposition or predilection toward a particular condition. In these cases, it might be fat deposition or hirsutism. Another part of syndrome X which is epidemic in many of my patients is skin tags. I see lots of them. These have also been associated (weakly, but more so than not), with underlying conditions such as malignancies, colon polyps, and acanthosis nigricans, a velvety appearance that occurs mostly in the axilla, but which can be seen in the neck. This is often found in patients with dysinsulinemia, high glucose, or high insulin levels. In a sense, their insulin results in growth hormones on the skin which produce skin tags. They produce acanthosis, an increase in the epidermal velvety appearance. Another common problem is folliculitis. We have both skinny and fat people with syndrome X. Carbohydrate Pimples I see lots of patients with carbohydrate pimples. Whether those pimples are driven by Candida (yeast overgrowth) or bacteria overgrowth, with immunosuppression caused by sugar overloading, I really don’t know, but they are invariably there and are a great tip off for syndrome X. And of course, fat distribution is important. These patients tend to have tinea versicolor, another indication of immunosuppression, as well as fungal infections. I could go on and on. To the extreme, patients might have xanthalasmas or anthomas. Pattern Recognition In doing a complete and comprehensive skin exam, you quickly pick up patterns. I have been pushing dermatologists for years to remember that pattern recognition is so important in what we do. In fact, that’s true for any health professional. Pattern recognition is learned by looking at the whole and then developing, if you will, a library of ideas along with visualization that allows you to quickly get down to the problem later on. You become very good at what you do because you look and you see. Syndrome X is a wonderful example of that. Psoriasis Thirty to 50 percent of my patients have psoriasis, another common condition that is amenable to integrative/functional dermatology. Every patient with psoriasis is out of control and their lives are out of control. It might relate to stress, poor lifestyle choices, being overweight, poor food choices, not taking vitamins, or making poor health choices when it comes to exercise. These are stressed people who are inflamed. They may have a genetic predilection toward psoriasis, but what sets them off is the way they live. If you give them a cream or an injection, you can take care of the fish for that day, but if you create lifestyle changes for them, their bodies take care of themselves, and they return to a non-inflammatory state and a healthier equilibrium. It may not be exactly the equilibrium you want them to be at, but it’s a healthier form of homeostasis, and it gives the body a chance to turn itself around and quiet the psoriasis. I cannot control psoriasis in patients who will not make healthy lifestyle choices. The Paleolithic Diet and Adolescent Acne JB: I’d like to come back for a moment to syndrome X. We had an interview on FMU earlier this year with Dr. Loren Cordain. He talked about the Paleo Diet. He and his colleagues had just published a paper on the Paleolithic Diet (a high, unrefined carbohydrate diet) and adolescent acne. Dr. Cordain’s response to the study was that he felt almost all adolescent acne was a consequence of insulin and glucose dysregulation. When the appropriate diet for stabilizing insulin and glucose was used, the acne resolved. That sounds very reminiscent of what you’ve observed in your practice pertaining to syndrome X, hyperinsulinemia, and some other dermatological conditions. Do you see a connection between the two in your work? Acne, Carbohydrate Restriction, and Stress Reduction SC: I do. The studies originally done on the non-connection between sugar and acne were incorrect. They were studies based on calories and acne, after which they drew the conclusion that sugar was OK. One of Dr. Cordain’s studies was a very small study, but an excellent one. I believe it was done with patients who lived on an island who had the healthier diets versus the poor diets that we’re used to hearing about. I see this every day. Acne is inflammatory. If you look at acne under the microscope, it’s pustular, and full of neutrophils and inflammatory content. Anything that helps to decrease inflammation will help to decrease the manifestations of the acne as well as a predilection for it. I put all my acne patients on carbohydrate restriction. I try to put them on healthy carbohydrates; that is, low glycemic index carbohydrates. I love berries. I try to have them stick with berries and I get them off the high glycemic index type of diet. I also encourage them to exercise. Exercise, of course, helps to regulate glucose and insulin. I also try to get them to learn and apply anti-stress mechanisms in their lives. Nobody can go through life without stress. I try to teach them ways to anticipate their stress levels and turn them into constructive energy rather than the destructiveness that results in inflammation. I believe that if acne is not directly caused by dysinsulinism, it certainly can be terribly aggravated by that particular condition. Acne and Antibiotics JB: Let me propose a kind of “fun” hypothesis that I’d like to get your opinion on. Historically, in adolescents, acne has been treated by administering antibiotic therapy and that has a pretty good clinical effect in causing remission. It’s always felt that the success of antibiotic treatment demonstrates that acne is caused by some kind of bacterial infection. Could it be possible that the real effect antibiotics have is mediated through the gut? Aren’t we synthetically modifying gut flora in such a way that it alters immune function and reduces the inflammatory message from the gut, which has a systemic effect, in combination with the changing hormones of adolescence that influences the skin? SC: Absolutely. That’s thought to be one of mechanisms of how it might work. Tetracycline, in and of itself, is antiinflammatory. I use tetracycline in treating pemphigoid, for instance, which is a bullous immunological process. The tetracycline is antiinflammatory, and it may not be working at all in destroying “bacteria”. Bacteria very quickly become desensitized from tetracycline. Tetracycline might be tagged as an anti-bacterial, but it is also very antiinflammatory. Probiotics, Acne Rosacea, and H. Pylori The question of dysbiosis and gut problems is also very intriguing. I put my patients on tetracycline if they have difficult acne, and it quiets down the inflammatory process. If I don’t use tetracycline, I put them on a probiotic. I use one that has 15 billion bacteria and 16 strains. I tell the patient that acne is inflammatory, and there are certain bacteria in the gut that are very inflammatory and we want to replace them with healthy bacteria. This quiets down their immune system. It gets them back to homeostasis again, resulting in a non-inflammatory state. I see this a lot in my adult patients with acne rosacea. There have been a number of articles, pro and con, about the direct association between acne rosacea and H. pylori. The probiotics have been shown to crowd out the H. pylori in the gut and resolve some of the problems associated with H. pylori and ulcers. Probiotics also help to resolve H. pylori associated with acne rosacea, which is very inflammatory. The Gut/Skin Connection The gut/skin connection is profound. I like to think of the skin and the gut as contiguous. I consider that we are like sophisticated, mobile, coelenterates. The skin is the outside lining that protects us. That connects directly to all the mucosal elements of our bodythe gastrointestinal (GI) tract, eyes, lungs, and so forth. It’s as if we’re in an envelope and we filter food through its inter-aspects. Our envelope is controlled or protected by the inside lining which is connected to the outside lining. They’re always talking to each other and it works both ways. The internal manifestations of skin disease and the external manifestations of internal disease are profound. All we need to do is, as I have mentioned in some of my articles, make the connection. You’ve pointed that out so many times. You have to think outside of the box and make the connections. Connectivity and becoming an advocate for our patients is what we have to do. It’s a tough job. There’s so much information out there. There are so many connections to be made. People like you have made it easier for us to see that we need to make these connections and apply them to our patients in a caring and resourceful way so that they can be effectively put into practice and benefits derived from them. Skin Tags JB: You mentioned a term earlier that may not be familiar to those outside the field of dermatology, and that is skin tags and their relationship to insulin resistance. Would you define what skin tags are? SC: Skin tags are little annoyances that grow out from under our skin. They’re usually seen in the axilla area. They might be on the neck. They are tiny little papillomas. They’re there for no reason and they seem to appear in adulthood, or they sometimes come out early in young, obese patients. I can tell you about my own personal experience with skin tags. I was at one of your lectures in Miami and I had a blood sugar test done. I had eaten a donut and my blood sugar was way up. A gentleman told me that even though I had just eaten, my blood sugar was very high. I was running, exercising, eating all the right foods, and taking vitamins, but my weight was up to 195. I was getting pimples in my hair. I was getting skin tags, and I wondered what was going on. In addition, my blood sugar was up. I was moving, imperceptibly, into the range of syndrome X. I cut out some healthy foods that were calorie-rich, like nuts and seeds, and I stopped eating in-between meals. I dropped 30 pounds, the skin tags fell off, and the pimples resolved. JB: That’s an interesting case history. Thank you for sharing it. At the Functional Medicine Research Center, I have seen reports of many people who come in as a consequence of being involved in one of our clinical trials, but the conditions you just described come with them as part of their overall health profile. They often have resolution while they’re in one of our programssuch as an intervention focused specifically on insulin sensitization or hormone balancingand all the other things seem to clear up, as well. That confirms your concept about the web and the skin being a lens that we focus on to make the connections visible. Examining the Mouth SC: They’re so easy to see. The skin is so available. Unlike some of the other invasive procedures we have to do, where we must guess and look at shadows, the skin is there. It calls to us and says a lot. I love to look inside patients’ mouths because I can see many things associated with poor vitamin and nutrition. Or, I observe what the skin looks like, for example, in smokers. The associations involve many parallels. Macroglossic patients have very slimy-looking tongues. Or, I examine the mouths of patients with gingivitis, which has now been clearly associated with increased incidence of cardiac disease. It seems obvious that if there is an area of chronic inflammation that is going to result in seeding bacteria into the bloodstream, the bacteria are going to end up somewhere and be inflammatory. If they happen to wind up in your coronary arteries, the body is going to create an inflammatory reaction against them. Then, cholesterol comes in and, before you know it, you have plaque. Toothpaste with Coenzyme Q10 When I see this inflammatory situation in my patients, I’ll even go so far as to suggest, and even sell them, a toothpaste I found with CoQ10 in it that I find very helpful. I’m sure my patients wonder why their dermatologist and internist is selling them toothpaste, but it goes back to caring about them. I really care about my patients. As their physician, I want to do all I possibly can for them. I may not be able to do it all, but at least, I can point them in the right direction so they get better. One of the tenets of functional medicine and the way it works is making the connections. And, yes, you have to love your patients enough that you’ll go through the difficult, sometimes frustrating task of guiding them into wanting to return to health. We can coach them. We try very hard, but we can’t make a basket for them. They have to put the ball in the basket themselves. Motivating Better Lifestyle Choices One of the hardest things to accomplish is to motivate patients who are in a “funk” because of poor lifestyle choices. They don’t think straight. They don’t sleep well. They don’t exercise. Their lives are gray and black and physicians need to move them, in a caring way, to a state of health where they can look back to where they were. Oftentimes, they don’t see how their life choices have brought them down a very rocky, miserable path until they come out of it and look back. It’s almost like looking at depression. After you’ve been there, you look back and think about what it was like. When people regain their health, they look back and ask how they got there. The real problem is they did get there, and how do we turn them around? It’s a slow process, and not one that everyone is going to buy into. You need to be very resourceful. That is so important. I can give one of my patients a $2000-a-year program on weight reduction that includes all the nutritional supplements. But I can’t give that to most of my patients because they can’t afford it. So, I’ve come up with a 51 cents-a-day nutritional program for them, which is a compromise, but it’s something they can do, something that pushes them in the right direction. We have to realize what we can do for our patients. We also have to make it possible for our patients to succeed, keeping in mind their limitationspsychological limitations, money limitations, and limitations in terms of where and who they areand try to tailor it in a unique way so they can succeed. Success for them may not be the success we place on ourselves. But even if they do a little bit better, even if they get back to a somewhat improved homeostasis, that’s enough to be encouraging. Offering Hope and Encouragement I also feel we should never discourage our patients. There should be no point at which we dont offer them hope. If you just tell them what’s wrong, that’s discouraging, and you may be beating them deeper into a hole which they’ll never get out of. You need to be very patient, but at the same time, a little detached. We’re coaches, not players. If we understand that, we can go home at night and relax. We can’t take on the burden of our patients. We can only help them take on their own burdens and work through them. I think that’s also true in our own personal lives. I cannot understand how physicians and medical healthcare providers can be good advocates for their patients unless they walk the walk and talk the talk. We all struggle with some of the same issues every day. Should I have this pizza? Shall I run tonight? Shall I take these vitamins? Do I handle my stress situations or do I let myself get out of control? If we don’t address our own problems and deal with them on a day-to-day basis, I don’t see how we can be believable and credible to our patients. Patients love it when I share some of these personal health issues with them and tell them we’re struggling together. That brings the whole thing home and melds the patient/doctor relationship. JB: I want to compliment you. That whole philosophy is the foundation of what we would call the patient-centered medicine concept that underlies one of the tenets of functional medicine. It underlies the tenets of any good medicine, whatever it may be called. The way you’ve articulated it is motivating to all of us. Since you practice in Florida, many patients probably come to see you with problems of aging skin and sun exposure. How do you deal with aging of the skin, skin resurfacing, and the sun-damaged skin complex? Categories of Importance SC: It boils down to categories of importance. I’m a cosmetic surgeon and I have patients who want to look beautiful, or better. Behind that lies another intriguing question. Why do they want to look beautiful and better? For some, it’s the beginning of a whole new lifestyle. Many who come in for liposuction are already motivated. Many of them don’t know how to get healthy again, but this is the first step. I put them on a nutritional program and talk to them about lifestyle changes. I do the liposuction, follow them through, and try to help move them along their way. That’s a nice entry point for those who are looking for cosmetic improvements. Some of my patients who are wrinkled and old-looking are very healthy, but they’ve let their skin get unhealthy. There’s disequilibrium between the way they look and the way they feel. Some of them tell me they feel great, but they feel they look like they’re 105 years old. They ask what I can do for them. I tell them their program might be good from a health standpoint, but that we should try to fix their psyche so they will look the way they feel. That combination is dynamite. It propels these people into energy they’ve never had before. Educating Patients I invented a unique triple procedure on resurfacing skin, the results of which are outstanding. As a physician, it’s wonderful to watch them grow into a new sense of good feeling. When those things are combined, it sings for them. For those with skin cancers or precancers, I do a comprehensive skin exam. Smokers are more prone to cancer. Or, if they’re out in the sun a lot, they’re more incidentally prone to internal malignancies. I tell them about recent articles published in the literature. It gives me a window into looking at their skin and trying to get them to incorporate healthy lifestyle choices. I tell them that if they take antioxidants or use them on their skin to protect themselves, it’s going to make their skin and their bodies healthier. If they’re healthier on the inside, they’re going to be healthier on the outside. Sun Screen and Vitamin D JB: That raises an interesting paradox. As we try to lower the risk to melanoma and use higher SPF formulations, it cuts down on the amount of some of the near UV radiation necessary for activating the precursor of vitamin D (ergosterol), into its vitamin D component. Then we wonder if that person is going to have a vitamin D insufficiency. How do you recommend we handle that apparent paradox? SC: From a clinical point of view, I would be guessing at the chemistry. I try to put all my patients on a nutritional regimen that includes taking extra calcium, magnesium, and vitamin D every day. I tell them not to go out into the sun anymore. In our environment, sun, at 15 minutes a day, is usually plenty to get enough vitamin D and vitamin D conversion. For someone with healthy skin, that’s not going to adversely affect them. For a black patient or anyone with a darker complexion, that’s not going to be a problem. But for someone who’s already beaten himself or herself up royally in the sun, I tell them I’ve removed 20 skin cancers and that they can’t go out in the sun. I make sure they get enough vitamin D, calcium, and magnesium. And I make sure they absorb it. I’ll get a probiotic on board. I’ll make sure they’re eating the right foods. That’s the answer. In this day and age of science, they’re able to have our cake and eat it, too. JB: That’s a marvelous answer. I have one last question about the interrelationship between potential food allergies and dermatological conditions. How do you address that? Food Allergies and Dermatological Problems SC: Food allergies are difficult to put your finger on. It’s difficult for allergists; it’s difficult for nutritionists; it’s difficult for everybody. Elimination diets are tedious and tough, but they’re necessary. My atopic individuals have a tendency toward allergies, hay fever, asthma, migraine headaches, or hives, especially at a very young age, and they often have food allergies. Many outgrow them, but at that point in time, they need elimination diets. I can’t do everything for everybody, nor do I pretend to be an expert in medicine. There’s a time when a physician has to refer to other resourceful practitioners to help him with a patient. That’s when I would call in a nutritional expert and an allergist to work through those diets with a young patient. Dermatitis herpetiformis is a condition that used to be rare, but it’s not rare anymore. As with celiac disease, it’s a very common problem. What’s uncommon about celiac disease is that we havent been very good at detecting it. Food intolerances in our lives are profound; they’re common, and we’re just beginning to recognize them. One very clear cut form of food intolerance is dermatitis herpetiformis, a bullous, painful eruption that usually occurs on extensor surfaces. This condition is associated with gluten or wheat sensitivity. Those patients must go on strict, gluten-free diets if they wish to maintain a skin free of annoying blisters. JB: This has been an extraordinary interview. You have discussed such a breadth of topics. You’ve described the philosophy of your practice and how you relate to your patients, and how you’ve leveraged your background, both in internal medicine and in dermatology, to create an integrative/ functional medicine approach to dermatological conditions. It is truly innovative and very motivating for all of us to hear about. I know this has been time out of your practice today and we very much appreciate what you’ve shared with us. This will be a model for many of us who may be on the fence trying to figure out exactly how we can convert our practices into something that’s more integratively and functionally-based, so as to develop the kind of patient/physician relationships that you’ve described. Thank you so much. SC: Jeffrey, I want to thank you for actualizing this for me. What I’ve done is take the tenets that I’ve listened to so carefully over the years and apply them to my practice, thereby giving myself a chance to act more like a specialist than a technician. That requires the kind of thinking and teaching that you and your institution have been professing for many years. Everyone is taking notice and saying that this standard of care is the way it should be. This is medicine for the 21st century. JB: Thank you very much. That’s a marvelous way to end. We wish you the very best and we’ll check in with you soon.  

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Bibliography

1 Kupper TS. Immunologic targets in psoriasis. N Engl J Med. 2003;349(21):1987-1990. 2 Meguid MM, Pichard C. Cytokines: the mother of catabolic mediators! Curr Opin Clin Nutr Metab Care. 2003:6:383-386. 3 Gustafsson L, Leijonhufvud I, Aronsson A, Mossberg AK, Svanborg C. Treatment of skin papillomas with topical a-lactalbumin-oleic acid. N Engl J Med. 2004;350(26):2663-2672. 4 Bavinck JN, Feltkamp MC. Milk of human kindness?HAMLET, human papillomavirus, and warts. N Engl J Med. 2004;350(26):2639-2642. 5 Grisham MB. Reactive oxygen species in immune responses. Free Rad Biol Med. 2004;36(12):1479-1480. 6 Cuzzocrea S, Pisano B, Dugo L, Ianaro A, Ndengele M, Salvemini D. Superoxide-related signaling cascade mediates nuclear factor-kB activation in acute inflammation. Antioxidants & Redox Signaling. 2004;6(4):699-704. 7 Fukatsu K, Ueno C, Maeshima Y, et al. L-arginine-enriched parenteral nutrition affects lymphocyte phenotypes of gut-associated lymphoid tissue. J Parenteral Enteral Nutr. 2004;28(4):246-250.

Welcome to Functional Medicine Update for February 2005. Once again, we are approaching our annual symposium on functional medicine. By now, you are probably aware of the focus of the 12th symposium-The Immune System Under Siege: New Clinical Approaches to Immunological Imbalances in the 21st Century. It will be held May 24-28, at the Westin Mission Hills Resort in Palm Springs, California. I hope we will see you there. The program is very timely, as it relates to immunological components of many chronic, age-related diseases.There is no better illustration of that than a recent series of articles that appeared in Sciencemagazine discussing the origin of chronic disease. There were two interesting back-to-back articles, titled “Living with the Past: Evolution, Development, and Patterns of Disease,” 1 and “Inflammatory Exposure and Historical Changes in Human Life-Spans.” 2 The authors of the first paper discuss the hypothesis that some chronic diseases in adulthood are influenced by environmental factors in the periconceptual, fetal, and infant phases of early life. I found that very interesting. We often think that chronic degenerative disease appears in mid-life as a consequence of something we did in mid-life. It may be that we should be looking at the genes and environment connection that may go all the way back to periconception, or even the preconception status of the mother and the father and how that may be reflected in the in utero environment. Factors such as nutrition, stress, and environmental toxins in early phases of life may combine to set in motion a trajectory in which genes expressed into function might lead to dysfunction in middle age. We may develop an epigenetic transition to degenerative disease that originated pre-conceptually. This presents an entirely different responsibility for the healthcare system, rather than just waiting until disease develops. The second article in Science discusses the proposal that the reduction in lifetime exposure to infectious diseases and other sources of inflammationa cohort mechanismhas also made an important contribution to the historical decline in old-age mortality. People in cultures with a high incidence of inflammation in childhood and young adulthood had historically higher levels of morbidity and premature mortality for a whole range of diseases, from vascular disorders to cancer to diabetesa constellation of inflammatory-mediated disorders that appears to reflect the mismatch between the genes in that population and their environment. When I say environment, I am including the periconceptual in utero and post utero periods. When we begin to examine this in a broader context for evaluating the origin of disease using inflammatory biomarkers, it leads back to alterations in the immune system, or the immune system under siege. What has gone on that has created the imbalance in immunological function that increases relative risk to inflammatory dysfunction and may also be related to increased risk to opportunistic infections? There is an almost paradoxical effect, because we would assume that if the immune system was upregulated, as it is in inflammatory conditions, that it would pay some dividends in the defense against communicable diseases. However, in any culture, it is possible to have both of those conditions or risks occurring simultaneously. One could have an increasing risk to autoimmune disease while simultaneously having an increased risk to infectious diseases. This is the concept of immunological imbalance mediated through the thymus dependent 1 (Th1), thymus dependent 2 (Th2), and the Th zero (0) innate immune system and how they are juxtaposed, balanced, or interwoven and intercalating one to the other. When there is proper balance, there is good defense against infectious disease and an appropriate response, if necessary, to injury or trauma through the inflammatory system response. However, it does not become overly activated, forgetting what is foe and what is friend, resulting in the immune system being at war with the body. The concept of living with the past-the periconceptual/conceptual in utero/post uteroenvironment, how they interface with gene expression patterns giving rise to the expression of immunological imbalance through alterations of the Th1 and Th2 systems and, ultimately, how that is expressed into the epidemiological record of disease in that cultureis a fascinating, emerging view in medicine, biometrics, and epidemiology. We will be discussing that topic from a clinical perspective in much greater detail at the 12th International Symposium on Functional Medicine. The inflammation connection to these conditions is ultimately tracked as markers of disease in a specific culture. In 21st century language, diseases with inflammatory underpinnings include coronary heart disease, cerebral vascular disease, various forms of malignancy, type 2 diabetes and its implications for vascular endothelial and kidney function, and autoimmune disease. All of these relate to the connection between environment and genes, and expression into patterns of age-related chronic diseases. In the past, management of these conditions has principally relied on the use of agents that manage symptoms of inflammationthe antiinflammatory medications. As Baby Boomers move into their 60s, the prevalence of age-related inflammatory disorders has risen because of the increasing numbers of adults in that age group. Concurrently, reliance on antiflammatories has increased as a pharmacological mechanism for intervening in inflammatory conditions. Recently, the FDA, in concert with behind-the-scenes conversations with Merck Pharmaceutical Company, voluntarily removed Vioxx, or rofecoxib, from the market. Not too many months previously, rofecoxib, a selective cyclooxygenase-2 (COX-2) antiflammatory inhibitor, had been hailed as a great breakthrough in non-steroidal antiinflammatory drugs (NSAIDS), with improved efficacy and safety, along with decreased risk to gastropathy. This particular withdrawal is without precedence in the American pharmaceutical system and, in fact, the global pharmaceutical system, because it represented a 2.5 billion-dollar-a-year product. As a consequence of the tremendous sales volume and increasing excitement about selective COX-2 inhibitors, the category, which includes celecoxib, rofecoxib, and other more recent entries into the market, constituted in excess of a 6 billion-dollar-a-year market. It was the fastest rising new category in pharmaceutical sales in the history of drugs. Removing a major player from the market as a consequence of 18-month post-market regulatory concerns about cardiovascular safety, shook the halls of the pharmaceutical industry in ways that had never been seen before. It has a greater spinoff on other areas beyond that of selective COX-2 inhibitors, and will no doubt result in changes in FDA policies. Certainly, we are starting to see some fairly significant implications. The medical literature has been replete with all kinds of post hoc reviews as to how the removal of Vioxx could happen, and that we knew about the lack of cardiovascular safety, yet did nothing about it. There is an editorial in the Lancet, titled “VioxxAn Unequal Partnership Between Safety and Efficacy” in which the authors talk about the VIGOR trial, the Vioxx intervention trial. Apparently, there were indications of increasing cardiovascular incidence in people taking Vioxx buried in the data from that trial that were overlooked.3 In The New England Journal of Medicine, there were some hard-hitting editorials about the Vioxx debacle. An editorial by Eric Topol, titled “Failing the Public Health-Rofecoxib, Merck, and the FDA,” was a powerful indictment of the regulatory process relative to some of the data in the VIGOR trial.4 There is a table in that editorial which illustrates the number of patients with myocardial infarction (MI) or stroke versus total patients exposed, showing a significant increase in relative risk. These data were not compiled from the VIGOR trial, but the so-called APPROVe study, the Adenomatous Polyp Prevention Study using rofecoxib, that also demonstrated increases in cardiovascular disease or vascular catastrophe, leading to death. There is another good editorial about Vioxx in The New England Journal of Medicine by Dr. Garrett FitzGerald. Some of you are familiar with that name because we have quoted his work in previous issues of FMU. We discussed the concern he raised about the potential cardiovascular risks of rofecoxib and possibly other selective COX-2 inhibitors.5 Dr. FitzGerald’s papers, and those of some of his colleagues, indicated that a selective COX-2 inhibitorone that is not induction-selective, but rather selective for the COX-2 enzyme itselfwould inhibit the activity of the enzyme COX-2 in all tissues where the molecule was accessible to the enzyme, including the vascular endothelium. In the vascular endothelium, COX-2 is a constitutive enzyme necessary for the production of prostacyclin from arachidonic acid. Prostacyclin is an important substance secreted by endothelial cells that juxtaposes and buttresses against the proinflammatory, prothrombotic agent produced by platelets called thromboxane A2. When the vascular endothelium produces adequate levels of prostacyclin to be balanced against thromboxane, there is normal clotting. If, however, there is a reduction in the production of prostacyclin and no significant alteration in thromboxane, the balance is tipped more toward platelet adhesion, platelet clotting, and issues related to thrombosis. That is what Dr. FitzGerald predicted would be the case, particularly when looking at the VIGOR trial data, which suggested increasing cardiovascular incidence. He reminds us that in 1999, he and his colleagues reported that a reduction of prostaglandin I2, or prostacyclin, was seen in the healthy volunteers who had been placed on a selective COX-2 inhibitor. They predicted there might be some cardiovascular risk associated with these compounds. Once again, this reminds us that there is some value in understanding not only the specific function of a drug in a target tissue, but how that molecule interferes, influences, or interacts with other tissues to produce an outcome that may not be initially seen in a normal clinical trial. The outcome may only be seen on post-market surveillance studies after months or years of use of that particular substance. That is what Peter Stone was referring to in his interesting editorial in The New England Journal of Medicine, in which he talks about triggering MI.6 He discusses inflamed volatile plaque and how this process can trigger a major coronary event by alterations in the clotting mechanism and subtle changes in the prostanoids that control and regulate thrombus formation and platelet adhesion. This process can have dramatic effects on cardiovascular health. Traditional NSAIDs are of concern because of their gastropathy risk, selective COX-2 inhibitors are of concern relating to cardiovascular risk, and narcotic medications used for treatment of pain are of concern relating to addiction. An ever-increasing aging population is suffering from various types of inflammation. It takes us back to the origin of inflammation and how we can modulate it in ways that may not require single molecule interventions with antiinflammatories. That seems like a reasonable place to start. We will be speaking about that with our Clinician/Researcher of Month, and I want to lay some groundwork for that discussion. What have we learned about the connection among insulin resistance, hyperinsulinemia, metabolic syndrome, and inflammation? There is an emerging body of literature suggesting that a wide variety of age-related inflammatory conditions can be connected to metabolic syndrome/hyperinsulinemia. This includes a recent paper in the Journal of the American Medical Association, in which findings support the hypothesis that metabolic syndrome contributes to cognitive impairment in elders, but primarily in those with a high levels of inflammation.7 We have also talked about work in previous issues of FMU that connects metabolic syndrome/hyperinsulinemia to endothelial dysfunction and “essential” or idiopathic hypertension. We have seen obvious connections in multiple studies between metabolic syndrome, inflammatory mediators including high-sensitivity C-reactive protein (CRP), and adhesion molecules such as secretory intracellular adhesion molecule-1 (ICAM-1) or vascular adhesion molecule-1 (VCAM-1) and that these are elevated in conditions of metabolic syndrome and hyperinsulinemia. Therefore, every one of these age-related diseases has an inflammatory connection through metabolic syndrome and hyperinsulinemia. Where did hyperinsulinemia begin? Could its trajectory have begun in utero as a consequence of the way the genes were imprinted and expressed? Could epigenetic effects have occurred on the genome expression patterns that ultimately gave rise to a higher susceptibility, or higher sensitivity to insulin resistance and dietary modification of gene expression that is ultimately expressed as type 2 diabetes? It does not result because of eating three doughnuts and living on white bread. It is a complex interrelationship between gene expression patterns that occurred conceptually all the way through mid-life. That brings us to the question of whether carbohydrate is the scourge of our society. As a consequence of altering our gene expression patterns epigenetically through our altered environment, did we suddenly produce a whole generation or two of children who are now uniquely sensitive to carbohydrate? We never changed their genes, but perhaps we changed the way their genes are expressed based upon the environment in which they were conceived, born, and nurtured. That hypothesis prompts other questions, such as why do we see so much autism and autistic spectrum disorders in children? Why do we see so much attention-deficit disorders (ADHD) these days? Are these related, not to genetic changes, but rather to epigenetic changes through altered environment of development in utero and post-utero that create a different outcome of gene expression based upon differing environments? What are things that have changed in our environment over the last 50 years that might lead to these expression patterns? That brings to mind simple things like busier lifestyle, noise, radio frequencies, toxins, and pollution. What about violence, stress, aggression, microwaves, the music we listen to, the media we are exposed to, and the media we are exposed to? We receive so much from all these energy fields. In addition, there have been many changes in our diets. Processed foods include the addition or removal of many components. It is a complex, multi-parameter equation that ultimately leads to the following question: without changing genes, how have we changed the environment that controls gene expression and imprints epigenetic patterns, creating a trajectory toward some of the diseases that appear to be occurring with a higher prevalence in our society? Let me go back to the issue of carbohydrates and metabolic syndrome. Is there something going on relative to the type of carbohydrates and the postprandial state? How does that relate to hyperinsulinemia and alterations in liver, glucose and glycogen control, adipocyte physiology and the fat cell, and all the other regulatory hormones involved with managing blood sugar? This is what David Jenkins and David Ludwig discuss in a recent editorial in the American Journal of Clinical Nutrition.8 It is not just carbohydrates. It may be the matrix in which carbohydrates are delivered that creates the potential for either control of or lack of control of insulin and blood sugar. It has been suggested that we are spending a lot of time castigating the word “carbohydrate.” Carbohydrate is broken down into a lot of sub-carbohydrate types, such as sugars, refined white starch, amylopectin carbohydrate, or unrefined carbohydrates with natural fiber. Jenkins and Ludwig suggest that perhaps we can have our cake and eat it, too, provided the cake is made from healthful fat and low-glycemic index flour. We should also take into account that carbohydrate-rich natural foods contain a variety of phytonutrients or phytochemicals that modify and influence the metabolism of carbohydrate and other nutrients, and also play a role in stabilizing or destabilizing insulin. A white starch product has had its phytonutrients removed through processing. That will have a different effect on overall metabolism and gene expression patterns than consuming the same amount of carbohydrate in a phytochemically nutrient-dense matrix. This may explain why there is a difference in the epidemiological evidence on chronic disease between people who eat white, starch-rich diets and those who eat a diet high in fruits, vegetables, and whole grains. Many papers have shown a reduced risk to major chronic inflammatory diseases in cultures where there is a high consumption of minimally processed fruits, vegetables, and grains. You might want to look at an interesting review in the Journal of the National Cancer Institutethat discusses the benefits of eating minimally-processed diets, and reduction of risk to all the inflammation-related age-associated disorders-not just heart disease and cancer. Mark McCarty is the author of a good article in Medical Hypotheses, titled “Proposal for a dietary ‘phytochemical index.” 10 He proposes that we may need to look at nutrient density using what he calls a “phytochemical index”-not just vitamins, minerals, proteins, carbohydrates, fats, and calories, but the relative density of flavonoids, polyphenols, and the various terpenoid molecules that influence the relative phytochemical density. He points out: “There is ample reason to believe that diets rich in phytochemicals provide protection from vascular diseases and many cancers; direct antioxidant activity as well as modulation of enzyme expression or hormone activity contribute to this effect.” If we look at a diet from a phytochemical-density perspective, we might come to a different conclusion about what is a “good diet” versus a “bad diet,” for carbohydrate consumption. If we completely eliminated carbohydrates from the diet because of their current “bad” reputation, it would result in a bad diet. Where are phytochemicals found? They are found in carbohydrate-rich food. There are few phytochemicals in animal products. Phytochemicals, by definition, are plant-derived nutrients. If you ate a diet exclusively of animal products (unless you were eating certain organs like liver), you would be getting a very low level of some of these phytochemicals, far less than you would get from a plant-based diet rich in minimally processed fruits, vegetables, and grains. Epidemiological studies tell us that there is a strong relationship between insulin sensitivity, lowered cardiovascular disease incidence, and lowered diabetes in individuals who eat minimally processed fruits, vegetables, and grains. There is also lower body weight in those cultures. Perhaps there is a connection between satiety, thermogenics, improved glucoregulation, and lipid regulation that occurs with consumption of these diets. There is a good article in Nutrition Reviews that discusses the epidemiological finding that people in cultures that consume minimally processed fruit and vegetable diets (which are carbohydrate-rich, I might add, because they generally contain a higher level of grains) have a lowered incidence of inflammatory age-related disorders.11 The group of investigators from the Centers for Disease Control and Prevention in Atlanta have done a nice job in this paper. Individuals who consume minimally processed, phytonutrient-rich diets that are reasonably high in carbohydrates (as whole grains), also have favorable benefit from vitamin and mineral density. Plants synthesize vitamins that animals depend upon for their function. One example would be the plant density of vitamins B1, B2, and the rest of the B vitamin complex family, including folate and vitamin B6. A paper in the American Journal of Clinical Nutrition discusses the interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase (MTHRF) 677C®T mutation on homocysteine concentrations in healthy adults-the ATTICA Study.12The Mediterranean diet is not a strict vegan diet. It contains animal products that may be an important source of vitamin B12, but it also has a high level of minimally processed grains, fruits, and vegetables. This diet is associated with very low incidence of homocysteine elevation in those who carry the MTHFR 677C®T polymorphism, where there is a block between the conversion of tetrahydrofolate to 5-methyltetrahydrofolate. These individuals appear to require higher levels of folate in their diet to get an adequate level of 5-MTHFR, a substance that serves as the central methylating agent necessary in the folate cycle to lower homocysteine and to produce S-adenosylmethionine, or SAM. These people may need exogenous folate to lower their homocysteine. In individuals consuming the Mediterranean diet which is naturally rich in B vitamins, who also had an MTHFR 677C®T polymorphism, their homocysteine levels are lower, which would affect their relative risk to heart disease. If you eat a diet rich in phytochemicals, even though it contains carbohydrate, the relative markers to all the age-related inflammatory diseases are lower. This is further confirmed in a paper in the Journal of Nutrition.13 The authors looked at plasma high-sensitivity CRP and its relationship with homocysteine concentrations. It was found that in both Hispanic and non-Hispanic older-age individuals, when consuming minimally processed diets rich in fruits, vegetables (which provides higher amounts of whole grains), their plasma CRP and homocystein1 levels were lower, and their relative risk to vascular disorders and stroke was significantly reduced. This work came out of the Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University. This tells us how important it is not to throw the baby out with the bath water as it relates to phytochemicals and carbohydrates. If we convince people that carbohydrates are bad, we may further aggravate the situation by lowering intake of important phytonutrients in the diet. Many phytonutrients have effects on mitochondrial function and energy production. In a recent study, animals supplemented with vitamin E and coenzyme Q10, two important parts of the electron transport chain and energy production in the mitochondria, were found to have reduced circulating markers of inflammation, suggesting that mitochondrial oxidative stress is interconnected to inflammatory conditions and poor energy production. 14 Dietary supplementation with vitamin E alone reduced the baseline inflammatory status indicated by increased high-sensitivity CRP. Cosupplementation with coenzyme Q10, however, was found to significantly enhance the inflammatory effect of vitamin E, showing synergy on the relationship between those essential substances. Coenzyme Q10 is manufactured in the body; it is not considered an essential nutrient, whereas vitamin E is considered essential because it is not synthesized in the body. We might consider coenzyme Q10 as a conditionally essential nutrient in many people who may have inflammatory stress or oxidative stress, or who are on medications or in an environment that suppresses the biosynthesis of coenzyme Q10. We all know about the relationship of statins to lowering de novo biosynthesis of coenzyme Q10. Here we see that vitamin E and coenzyme Q10 supplementation, taken together, can have beneficial effects on lowering inflammatory potential. As we move the story a step further from the carbohydrate/insulin sensitizing inflammatory connection to phytochemicals, we also need to move toward looking at what might be the seat of inflammatory initiation in the body. That takes us back to where the seat of the immune system is located. We will be discussing the implications of this topic in the plenary lectures and breakout sessions at the 12th International Symposium on Functional Medicine. I am referring to the gut-associated lymphoid tissue (GALT). The GALT is an important part of the immune system, constituting about 50 percent or more of the immune system mass of the body, and producing about 70 to 75 percent of the antibodies generated against specific epitopes or antigens. It is also an important seat for regulating the Th0, Th1, and Th2 immune function, so it is a poising system for the rest of the body. Breakdowns in the gut mucosal integrity leading to what has been euphemistically called “leaky gut syndrome,” or impaired mucosal permeability, can expose the immune system of the gut to various kinds of unfriendly molecules that are part of the gut contents. This initiates upregulation or imbalance of the immune system, the Th1 and Th2 regulation, and triggers inflammatory conditions. Dr. Mary Ellen Sanders eloquently discussed the use of pre- and probiotics in the December 2004 issue of FMU-gut bacteria, friends and foes, and how to alter the balance. There is a recent article by Dr. Rastall from the Food and Bioprocessing Sciences Group, School of Food Biosciences, University of Reading in England in the Journal of Nutrition. He discusses the use of symbiotic forms of bacteria, a probiotic together with a prebiotic targeted at the specific immune function in the host.16 This follows up on Dr. Sanders’ important lesson on the significant role that pre- and probiotics play in gut immune function. Probiotic Consumption in Postmenopausal Women with and without a History of Breast Cancer A woman who is properly metabolizing the contents of her gut and who has proper gut flora, can convert certain types of lignans that are found in unprocessed diets to estrogen-protective substances. Lignans are another part of the phytochemical family found in carbohydrate-rich, minimally processed diets. Lignans can be converted by friendly bacteria into estrogen-protective substances (equols) which have a history of lowering the incidence or risk to breast cancer,17 although it remains unknown what components of the diet may support this conversion. A friendly gut flora produces more secondary metabolites, such as equol. Equol apparently has a favorable effect on estrogen signaling and estrogen metabolism, and can reduce relative risk to a self-proliferative disorder. Equol Inhibits Bone Loss in Ovariectomized Mice The gut and gut flora can play many roles in normalizing immune function, varying from the direct effect of the GALT to the indirect effect through metabolism of various nutrients, including the production of equol from lignans. Equol is a metabolite of diadzein, one of the soy isoflavones, and has been found to inhibit bone loss in ovariectomized animals and to normalize hormone metabolism and estrogen activity.18 Lactobacillus GG Bacteria Ameliorate Arthritis in Lewis Rats Regarding the probiotics and inflammatory conditions, such as arthritis, the takeaway is that gut immune function is an important seat of control over the overall systemic immune system. Diet plays a very important role in modulating the process, even to such things as arthritis risk. You might want to look at a recent article in the Journal of Nutrition that discusses this, titled “Lactobacillus GG Bacteria Ameliorate Arthritis in Lewis Rats. Following our discussion pertaining to the modulation of inflammatory-related disorders, insulin modulation, and gut-associated immune function modulation through pre- and probiotics and maintenance of proper gut flora, let me speak to the role of essential fatty acids in this process. There is a long-standing history indicating that (populations consuming omega-3 fatty acid-rich diets, such as those that go back to the Greenland Eskimo, have a very low incidence of what we now call inflammatory-related disorders, such as coronary artery disease and arthritis. The association that emerged between these observations was that omega 3 fatty acids modulated the arachidonic acid cascade by lowering the production of the 2- series eicosanoids, such as prostaglandin E2, which is proinflammatory, pro-platelet adhesive, and pro self-proliferative. By the 3-series prostaglandins that came through the modulation of metabolism of eicosapentaenoic acid (EPA), we would likely see reduced inflammatory mediation. That process all looked very reasonable, except one could never quite figure out why such a low level of omega 3 fats in the diet seem to have such a profound effect. When we look at the incorporation of omega 3 fats into red cell membranes or other phospholipid components, it seemed to be a small incorporation for a big clinical effect. The question has always arisen as to why there is such a remarkable effect. What has emerged over the past few years is the recognition that omega 3 fatty acids play a role in modulating inflammatory conditions beyond that of causing production of 3-series prostaglandins. They are also involved in direct regulation of gene expression in the cassette of genes involved with the production of inflammatory mediators. This includes not only prostaglandin E2, but upstream from that, things like TNFa,IL-1 and Il-2, and the particular essential fatty acids of the omega 3 family that may act on PPAR receptors, meaning that they may serve as natural thiazolidinedione medications. Some data suggest that they may help stimulate the nuclear orphan receptor PPAR family to properly regulate gene expression. That would have a positive benefit on insulin sensitivity and lowering inflammatory mediators through the effect on gene regulation. This is a remarkable observation that takes us well beyond the simple model of EPA modulating 2-series prostaglandins to recognizing that it has a panoramic effect on altering reporter gene expression pertaining to inflammatory processes. There is a nice review of the concept of omega 3 fats regulating gene expression in Nutrition Reviews.20 It may help us to understand why fish intake, rich in omega 3 oils, is associated with reduced progression of coronary artery atherosclerosis in postmenopausal women. This is discussed in a paper in the American Journal of Clinical Nutrition.21 The authors discuss how fish is a combination of unique proteins, along with unique fatty acids. Proteins in some fish can hydrolyzed into specific antiinflammatory and antihypertensive ACE inhibitor-like peptides. The combination of whole fish containing omega 3 oils with the fish protein may give rise to these remarkable epidemiological observations of lowered inflammatory disease risk. With that information, we are ready to talk with our expert, our Clinician /Researcher of the Month, who will tell us how all of this fits into clinical practice.

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INTERVIEW TRANSCRIPT

Joseph C. Maroon, MD Department of Neurological Surgery UPMC-Presbyterian Hospital 5C, 200 Lothrop Street Pittsburgh, PA 15213 JB: It’s time for our Clinician/Researcher of the Month. This month, we are fortunate to have a clinician that stands head and shoulders above many of his peersDr. Joseph Maroon. I met and heard him lecture recently at an American College of Nutrition meeting. I’ve also reviewed his publication list and his Curriculum Vitae, which represent a vast set of truly remarkable credentials and accomplishments. As a college student, Dr. Maroon was awarded a football scholarship at a major “Big Ten” university where be became a Scholastic All-American. He went on to pursue neurosurgery, his love and specialty of many years. He is widely acclaimed in the field of neurosurgery, and was recently voted as being at the top of his game by his peers. While doing all of that, as well as advancing technologies and techniques, publishing articles, writing books, giving lectures, and dealing with complicated case histories and patient management, he has also found time to continue his commitment to physical fitness and competition. He has been involved in over 50 Olympic distance triathlons, including the Ironman Triathlon in Hawaii. Those of us who have dreamed or aspired to be part of that world can live vicariously through Dr. Maroon’s accomplishments. This is a man who has done it all. He has been able to balance multiple factors of excellence simultaneously. Dr. Maroon has recently become interested in some of the adjunctive roles nutrition can play in medicine. That led me into my first discussion with him. Welcome to FMU, Dr. Maroon. With all the experiences you have had, it might be comfortable to simply enjoy the place you have established in your profession, without the need to grow and change. What led you into taking an additional interest in nutrition that has recently become a part of your practice? Physical Fitness and Nutrition JM: Thank you, Jeffrey. I guess it goes back to my athletic background and my commitment to physical fitness. Although there have been periods when it hasn’t been that way, I’ve maintained a fairly good schedule of athletic commitments throughout my life, particularly over the last 12 years. I’m now participating in Ironman Triathlon distance races. I find that fuel for the body becomes very essential when training and performing in these events. It is clearly noticeable that what you put into the body makes a huge difference. In terms of nutritional supplements, those I’ve gotten into are now very well recognized, such as L-carnitine, coenzyme Q10, the vitamin B complexes, and magnesium. Whether you train at a high level or not, the inflammatory response of the body can be very beneficial, as it is designed to be. It can also create a lot of pain and problemsthe rubor/dolor/ tumor type of syndrome that we learned about in medical schoolredness, pain, heat, and swelling. When this runs amuck, it is now well recognized, particularly by alternative treatment physicians, that many of the diseases we are afflicted withdifferent kinds of arthritis, cancer, heart disease, and stroke, the vascular concept of endothelial membrane breakdown and deposition of fatsis all the common etiology of inflammation. Discogenic Disease I have a fairly large practice of patients with neck and back problems, most often, discogenic in origin. With discogenic problems, there’s desiccation of the disks, subsequent narrowing of the disk space, and everything from arthropathy to spinal stenosis, lateral recess stenosis, and herniated disks. These are not just compressive phenomena, but there is a major inflammatory component. Many biochemical studies have been done on discogenic disease, biopsying and analyzing the cytokines and inflammatory molecules associated with “simple” herniated disks. There are two components. There’s the mechanical compression of the nerve root, resulting in radiculopathy. There is also a very clearcut biochemical phenomenon. The drug companies have clearly recognized this and we get into the arachidonic acid pathway and that arachidonic acid is found in high concentrations in cell membranes, as well as the substances phospholipase A and tumor necrosis factor alpha (TNFa) in the perineural area where disks are herniated. As we know, arachidonic acid is converted by cyclooxygenase (COX) to prostaglandin E2, which is very proinflammatory. This proinflammatory substance causes the constriction of blood vessels. The pain syndromes that we experience increase clotting ability as a normal response of the body to an insult. There are also several things in the brain involving the same pathwaysubdural hematomas, aneurysms, and subarachnoid hemorrhages. These are all inflammatory processes that cause disastrous consequences in the brain, as well as the heart. COX-2 Inhibitors In looking at this pathway, the major pharmaceutical companies realized that if they blocked COX-2 with Celebrex, Vioxx, Beckstra, Advil, Aleve, and ibuprofen compounds, they would have an antiinflammatory effect. It’s a major industry. Approximately 9.4 billion dollars a year is devoted to blocking COX. That’s pretty phenomenal. We also know that when you block COX-1, and to some extent COX-2there is a secondary side effect on the gastric mucosa. Vioxx, a 2.4 billion-dollar drug that preferentially blocks COX-2, was recently pulled from the market because of its cardiac and thrombogenic effects in the body. I suspect there have been preliminary notices about Beckstra and Celebrex and that they may also come under closer scrutiny. Yes, we need to block the inflammatory response, but do we need pharmacologic agents with major side effects to do that? The Inflammatory Process and Omega 3 Fatty Acids In looking into this further, initially quite frankly for myself, I attended an A4M meeting a few years ago and heard Barry Sears speak. I thought, eureka! He so lucidly expounded on the inflammatory process and its deleterious effects on all of the organ systems, particularly in chronic diseases. Barry is a big proponent of omega 3 fatty acids. If you look at the omega 3 fatty acid pathway, eicosapentaenoic acid (EPA) and docosapentaenoic acid (DHA), the main active components of fish oil, work on the COX pathway, but they also enhance the formation of prostaglandin E3 (PG E3), which is primarily antiinflammatory. By competitive inhibition, fish oil acts as an antiinflammatory. I had no concept about that in my practice in the greater Pittsburgh area. I don’t think most physicians recognize the antiinflammatory effect of omega 3 fatty acids. The easiest way to get them, of course, is through fish oil. With that in mind, I began looking at my own patients who come into my office with spinal stenosis, sciatica, radiculopathy from cervical disease, and I asked them what medications they were on. Invariably, they were on one of the COX inhibitors, as well as a muscle relaxant and an analgesic of some kind. When questioned, a high percentage of them complained of complications, particularly gastric complications. I began suggesting that my patients taper off the COX inhibitors and begin taking omega 3 fatty acids, primarily through fish oil supplements and dietary manipulation. I also advised reducing the carbohydrate load. Increased insulin and deposition of fat releases inflammatory cytokines. After dietary manipulation and omega 3 fatty acids, we subsequently surveyed those patients without significant neurological deficits who did not require surgery. Sixty to 65 percent of the 200 patients who had been supplemented with omega 3 fatty acids found in fish oil were able to get completely off the COX inhibitors. This was a very exciting finding. For the last 15 years or so, I have been the team neurosurgeon for the Pittsburgh Steelers. I have also placed the athletes I see in my practice on omega 3 fatty acids. I’ve done this in conjunction with my associates-Dr. Tony Yates, Dr. Richard Rydze, and Jeff Bost. We have worked with professional football players, wrestlers, and swimmers, and found that a significant percentage of them are able to markedly reduce the use of COX inhibitors. These are not double-blind, controlled, randomized studies that I’ve done. This is experience in my own practice dealing with highly motivated individuals and athletes who had been dependent on COX inhibitors for antiinflammatory relief. We found that we’ve been able to markedly reduce the use of those agents in highly motivated athletes. Now, it could be a placebo effect. It’s not the kind of study we intended to design. Regardless, I think the individuals who have been on it have generally been very satisfied with what they perceive to be signif0cant help. Regardless of what they perceive, we know that with omega 3 fatty acids (I recommend in the 3 to 5 gram range), there are many other entities that are benefitted markedly, particularly in the cardiovascular and the cerebrovascular arenas. We know that omega 3 fatty acids inhibit coagulation,1promote basal dilatation, reduce inflammation, and significantly modify plasma lipid and lipoprotein concentrations. I’ve had many patients on omega 3 fatty acids for joint pain tell me they think it’s amazing that their cholesterol has dropped significantly. Others tell me their blood pressure has been significantly reduced. When one looks at the literature on omega 3 fatty acids, there are many very good studies that clearly support their use, particularly in cardiovascular disease and for atherosclerotic problems. In terms of rheumatoid arthritis, there are many papers showing that omega 3s suppress the production of TNFa, as well as interleukin 1b, and supplementation with 2 to 3 grams of DHA and EPA per day markedly reduces (up to 90 percent inhibition) of proinflammatory cytokines in rheumatoid arthritis. My office nurse has lupus arthritis, markedly affecting her hands. She was on Plaquenil for five years. She started taking 3 grams a day of omega 3 fatty acids and after about three months, she is completely off of the Plaquenil, with tremendous improvement in the use of her hands and joints. There are now many papers on the use of omega 3 fatty acids in attention deficit hyperactivity disorders (ADHD) in children. In a recent study, they were used in place of Ritalin, with good effect.22 There are many other benefits of omega 3 fatty acids besides pain relief, in terms of their secondary, or even primary, antiinflammatory response in the body. That is an overview of how I got into these supplements, how I use them, and the results that I’ve seen in my patients. JB: That’s an extraordinary story. I’d like to follow up with a couple of questions. As a clinical professor in the Department of Neurological Surgery at the University of Pittsburgh Medical Center, you must have quite a bit of visibility among your peers and medical school colleagues. What kind of response have you received about using these kinds of adjunctive substances? Does this open up a new dialogue? The Inflammatory Response and Tumor Necrosis Factor Alpha JM: Let me put it this way. I would say generally that the more senior individuals are much less likely to accept this than the residents and younger individuals. I presented this at our resident conference and it’s extremely intriguing from another viewpoint. In terms of the antiinflammatory response to fish oil, that’s one thing. But another agent that I’ve been using, off-label, is Enbrel. Enbrel is a specific TNFa blocker (antagonist), and it’s recommended and used by thousands and thousands of patients with rheumatoid arthritis. Dr. Ed Tobinick in California, as well as authors in Switzerland, have published several preliminary papers on the high concentration of TNFa in the periradicular area of herniated disks in both the neck and the low back. Tobinick has published a fairly large study on using TNFa to block pain in patients with sciatica or radiculopathy.23 We just went through a protocol with our pharmacy committee here in Pittsburgh, and I’m now using this in very selected patients instead of surgery, if there’s no neurological deficit in patients with radicular components of that nature. When it works, it’s clearly, in my opinion, not a placebo effect. There is almost an immediate response. You can’t get any more targeted than that drug in terms of a specific cytokine and pain relief. The concept of inflammation being a major component of radicular syndromes is clearly irrefutable. Now, we need to find agents to block that inflammatory process and hopefully avoid surgery, which I have done with these adjuncts in many of my patients. JB: That leads to an interesting discussion about the role and mechanism of action of the essential omega 3 fatty acids. As you pointed out so eloquently, it’s been felt for years that their role was to block the 2 series prostanoidsthe proinflammatory eicosanoidsby upregulating the production of the 3 series antiinflammatory prostanoids and redirecting the arachidonic acid cascade. More recently, however, there have been indications that omega 3 fats serve as receptor agonists for nuclear orphan receptor families like peroxisome proliferated activated receptors (PPARs), and also modify the expression of the inflammatory cascade in the reporter genes that control inflammatory mediators, including TNFa and IL-1b. It may be that what is being observed clinically is a consequence both of the 3 series prostaglandins and also the modification of gene expression of the inflammatory mediators such as TNFa. JM: That’s fantastic. This has been an incredible voyage of learning for me. Getting into the biochemistry of this has been fascinating. What you just stated is where it’s at in medicine for so many of the diseases that we treat. JB: There’s one other important point you raised. I’m sure my early training was similar to yours, and medicine often focuses on the primacy of disease and that the diagnosis is tantamount to understanding the condition. Therefore, we worked hard with our professors to become skilled at the art of differential diagnosis. That made the assumption that each disease was independent of other diseases, with its own etiology, its own pathophysiology, and its own mechanism. Yet, over the last 10 to 15 years, it’s been found that those distinctions can get very fuzzy. What is consistent among certain diseases, like inflammatory diseases-cerebrovascular disease, cardiovascular disease, type 2 diabetes and insulin resistance, rheumatoid arthritis, and osteoporosis-is that processes are going on, as you indicated, such as inflammation. Perhaps the connector is a process rather than a disease. That would help us to understand more about the variant roles that omega 3 fatty acids play across many different diagnostic categories and many subspecialties of medicine. For instance, you mentioned ADHD. That’s far different than neurovascular effects or something you might see in neurosurgery; something different than a rheumatologist would see; and something different than a cardiologist would see. How might these be connected? How would ADHD be connected to other processes? Obviously, it has something to do with neuronal function, and the inflammatory cascade and cellular signaling. Panoramic Connection between Omega 3 Fatty Acids and Physiological Function The person who first talked about the panoramic connection between fatty acids and function was Dr. David Horrobin, unfortunately recently deceased and what a loss to all of us. Dr. Horrobin, was a medical school professor in Canada for many years, and was castigated by his colleagues. He talked about these myriad effects and was criticized, because people questioned how one agent could be effective for many different clinical conditions. Obviously, that sounds like “snake oil.” It could be that Dr. Horrobin was prescient in understanding that mechanisms were more important than just disease pertaining to the role of fatty acids. Does this sound like a reasonable story to you in terms of your experience? Essential Nature of the Inflammatory Response JM: Jeff, that was beautifully said. The way I look at this is that in one way, it’s as simple as it can be, but the mechanisms are complicated, as we know. It’s simple when you ask what the body’s normal response is. If you take a splinter and stick it into your hand or accidentally gouge it into your arm, there’s an immediate inflammatory response. Monocytes, platelets, and all sorts of biochemical and biomechanical things happen to isolate the foreigner and protect the body from disease. It’s a normal response to an insult to the body. This inflammatory response is evolutionarily and biologically essential for our survival on a day-to-day basis. What happens when we poison our bodies with garbage, such as trans fatty acids that are ubiquitous, and all sorts of other bad stuff we feed ourselves, leading to the body’s response being one of inflammation? It’s the inflammatory response in so many different humoral, cellular, and cytokine ways. The complexity of it is understanding this response. Maybe I’m speaking dogmatically, and I shouldn’t, but very few physicians that I talk to think in terms of the way you just enunciated it. The common hypothesis to most of the diseases we treat involves the inflammatory response of the body to either foreign bodies, foreign proteins, infections, and so forth. The inflammatory response is a great discovery for me, in terms of my own patients. Subdural Hematomas and High-Dose Steroids Let’s take subdural hematomas. When you get a chronic subdural, a neomembrane forms around the blood clot in the surface of the brain. There’s neovasculature of the membrane and it continues to grow. There are many papers now showing that if you put these people on Decadron, on high-dose steroids, it reduces the inflammatory response. The neomembrane doesn’t form and you can obviate recurrent subdural hematomas. Well, in that one instance, the inflammatory response is what you’re blocking. I think you’re right on with that and it’s been my observation, as well. The other observation that is a syndrome and a disease of the medical profession, is that, generally speaking, we still don’t fix the body until it’s broken. There’s very little maintenance. An HMO physician having to see 50 or 60 patients a day doesn’t have time to talk about prevention or preventive medicine. Maybe some do, but I think, and I’m speaking generally, that we physicians are trained, as you and I were, to make the diagnosis of the pathological abnormality after it’s manifested in a disease or syndrome state. We don’t pay much attention until the car is broken, before we fix it. Thoughtful physicians are becoming much more aware of this, moving in that direction themselves, and hence, bringing it to their patients. Omega 3 Fatty Acids and Cardiovascular Disease JB: You have treated us to so many great ideas about the application and implications of not only fatty acids, but the whole thought process of prevention versus treatment. I want to ask one last technical question that I’m sure is on the minds of some of our listeners after hearing you talk about subarachnoid hemorrhage and some of the clotting-related disorders. When Bang and Dyerberg did their first work with Eskimos in Greenland, they observed that people were eating up to 70 percent of their calories as fat, yet there was a very low incidence of cardiovascular disease. But they did indicate that there seemed to be a higher incidence of stroke. Some people feel that increasing omega 3 fatty acids may run the risk of clotting-related disorders. What’s been your experience with that issue, and is this of clinical concern? JM: That’s an excellent observation and explanation. My understanding is that the Inuit Eskimos primarily had hemorrhagic strokes; I don’t think They were thrombotic. That has led to just the kind of apprehension or concern that you mentioned. You also have to remember that they were ingesting 12 to 15 grams a day of omega 3s. The average American diet contains perhaps one gram of essential fatty acids, or omega 3s, per day. In my practice, I will put patients on 3 to 5 grams of omega fatty acids a day. I usually don’t go over 5 grams. In most of the studies in the cardiovascular and cerebral vascular literature, researchers have not administered over 3 to 5 grams a day that I’m aware of. I have operated on many, many patients who were on omega 3 fatty acids. I have not encountered any excessive bleeding tendency or problem in my practice, but that’s not to say that it can’t occur. I’m just not aware of very good evidence indicating that the upper limit of normal is. I think Barry Sears would recommend 5 to 10 grams a day in certain conditions. But if you do that, should you be monitoring hematologic factorsplatelets and things of that nature? Warfarin and Omega 3 Fatty Acids JB: How about patients on Warfarin or other types of coagulation management drugs? JM: I don’t put patients on omega 3s who are on Warfarin. It could be I just don’t do it because in the literature it says you shouldn’t. With low doses, you probably could, but I don’t do that. JB: I think your suggestion is that if theres any doubt, one should be following protime, which we would always want to do with patients on any kind of coagulation management. I can’t tell you how much we appreciate your time. You have an extraordinarily busy schedule, and you are a person with multiple responsibilities. Taking time out to spend with us has been a special treat. Years ago, I met and spent a little time with a gentleman who had the nickname, the “Cod Father” -Dale Alexander- who wrote the first books for consumers on fatty acids. That was back early in the 1960s, and his thing was cod liver oil. If your joints are rusted, take cod liver oil and it will oil your joints. The mechanisms weren’t really known then. It’s fascinating how we’ve evolved through observation and then through reductionistic, analytical, and mechanistic logic to eventually get to where some of these things that seemed so strange at first now seem reasonable, in light of the explanation of the mechanism. You’ve taken us from the elite athlete, such as the Pittsburgh Steeler football player, to the marathon endurance athlete, to the average person who comes in as a member of the walking wounded, to post-surgical and pre-surgical types of applications. That is the future of this type of medicine and medical thinking, and we like to call it functional medicine. Cod Liver Oil JM: Two other brief points, Jeff, if I may. In terms of cod liver oil, we know why we don’t take it the way it was given years ago. It’s because of the odor and the noxious taste. However, new modern manufacturing techniques with micro-distilling products have extracted the mercury, PCBs, and the dioxins, as well as new encapsulation techniques so it won’t be regurgitated. It makes it much more palatable and easy to take. Second, relative to the Pittsburgh Steelers, I want you to know that Dick Rydze, Tony Yates and I take full credit for their 11 and 1 record. JB: I suspected you might have at least a small feeling of pride in their accomplishments. May they go all the way to the Super Bowl and that we see you there. Thanks very much for sharing all this extraordinary information with us. We appreciate it.  

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Orthomolecular Medicine and Functional Neurology – Back to the Future Welcome to Functional Medicine Update for March 2005. We are going “Back to the Future” in this issue. That phrase has been used many times in our culture recently. Our past sometimes resides in the future. That is certainly the case as it relates to the prescience of Dr. Linus Pauling, two-time Nobel Prize winner, and the work he and his colleagues pioneered in the birth of what he termed “orthomolecular medicine,” later to be called “orthomolecular psychiatry.” This edition of FMU will focus on a retrospective review of the birth of this remarkable concept that evolved from molecular medicine into orthomolecular medicine, and then into orthomolecular psychiatry. At the Institute of Functional Medicine (IFM), we call it “functional neurology.” Linus Pauling’s concept has become a component of functional neurology and the intellectual wellspring from which we derive much of our formalism at IFM. Whether a psychiatrist or neurologist thinks he practices any form of orthomolecular medicine today probably does not matter. Over the last 30 or 40 years, this concept, because of its power, insight, and ability to provide answers to complex questions that, in its absence, would be unanswerable, has inculcated physicians through an osmosis effect. This issue of FMU will pay homage to and give credit to the intellectual origin of this idea and look at how it has evolved into our practices in different ways. When we talk with our Clinician of the Month, Dr. Daniel Amen, truly a functional neurologist/psychiatrist, he will explain how he is putting these concepts into practice by using various imaging technologies as assessment tools. Functional Medicine on the Internet It is interesting to go to Medline or PubMed on the Internet, do a search on “functional medicine,” and observe where the term forms clusters in the tens of thousands of hits received. Many of them are focused in the areas of radiology and imaging. Radiology used to be principally focused on diseased tissue, but with the advent of new scanning and imaging technologies, it is now a discipline that examines dynamic changes in tissue. Nuclear magnetic resonance, PET, and SPECT scans provide information about the changing physiological function of tissue. These techniques have changed the whole field of radiology and it is now more aligned with functional medicine. You see the terms, “functional radiology,” “functional endocrinology,” and “functional gynecology.” These are starting to emerge as disciplines that look at the changing patterns of physiology. Let’s go back to the future and ask some questions about what was going on in the middle 1950s that led to the birthing of the concept of orthomolecular medicine by Dr. Pauling and his colleagues. Let us be reminded that ideas do not generally occur in a vacuum. New ideas are born out of the incubator of other people’s great thinking and the advancement of an idea until it gets, as Thomas Kuhn said, to a point where it undergoes a paradigm shift, or the structure of a true revolution. Kuhn, in his classic book, The Structure of Scientific Revolution, introduced the term “paradigm shift.” Using that terminology, he tried to demonstrate that cultural changes and ideas do not occur smoothly. They occur abruptly as the critical mass of an idea is reached. Then, it shifts over very rapidly. That is the “paradigm shift.” That would be true for virtually every great discovery, be it the classic physics of Newton, the relative quantum physics of Einstein, or information science. Great paradigm shifts come about abruptly in the way they are incorporated into culture-the “tipping point,” to use another phrase to describe it. One day, no one is talking about it, and in a short period of time, everyone is talking about it, as if it is “old hat.” Suddenly, everyone believes in it. Over the last 40 years, that has been the story of the evolution of ideas about orthomolecular medicine. The origin of the idea goes back to the turn of the last century, when genetic metabolism diseases of infancy were discovered, the first one being alcaptonuria. Alcaptonuria was considered to be a disorder based on an autosomal recessive gene characteristic passed on from parents to children. From that paradigm shift, it was discovered that many other infant metabolism diseases were passed on genetically. As they were discovered, questions were asked, and the answers gradually came forth. This is similar to what happened with the vitamin revolution. Eijkman discovered thiamine in the early 1920s. Not long after that, we had “the age of vitamin discovery.” Within 10 to 15 years, virtually all of the traditional vitamins, such as the B vitamins and vitamin C, were discovered. People finally knew what to look for. The concept of inborn errors of metabolism resulting in serious and often life-threatening infant diseases was associated with things like dementia and various types of neurodegenerative conditions. Similarly, there was a confluence of ideas about vitamin deficiency diseases, such as niacin deficiency, or pellagra. Recall that the “three Ds” include symptoms we often associate with an acute deficiency of niacin-diarrhea, dermatitis, and dementia-which include adverse effects on brain chemistry. Even beriberi has a dementia-related component because of the vascular effects vitamin B1 and B2 have on perfusion of the brain. There was an interesting connection between the discovery of genetic metabolism disorders of infancy and vitamin deficiency disorders relating to chemical changes in the brain. That raised the question of whether certain people are born with specific genes that may make them more susceptible to vitamin deficiency-related disorders that appear clinically as altered brain chemistry or dementia. It is easy to look with 20/20 hindsight today, but those were the types of questions many were asking during the early 1900s. In 1949, Dr. Linus Pauling, then at Cal Tech, and his post-doctoral student, Dr. Charles Itano, were studying sickle cell anemia. Sickle cell anemia is clearly a genetic-related disorder, the etiology of which was unknown at the time. Dr. Pauling had a broad-based background and he thought across disciplines. He did not think of himself as only a chemist or only an inorganic, crystal metallochemist. He saw himself in the broadest concept of using science and reasoning to try to address broad questions, including things like the nature of anesthetic drugs and the origin of the immune system. Those are things he had explored in that period of time. In terms of sickle cell anemia, an interesting observation was made. Cells from individuals who were genetically inclined toward sickle cell anemia were put in a tube. The tube was degassed by taking oxygen out of the environment and putting it in a magnetic field. The result was a certain kind of deflection of the needle, indicating that the cells were paramagnetic in a certain way. Normal red cells that were not sickled resulted in a different type of effect. The magnetic field from the iron contained in the porphyrin balanced differently than in the sickle cells. By oxygenating the cells and doing the experiment again, a greater difference was found. Most of us would find this observation interesting, but we would want to know what it meant. For Dr. Pauling, this became an area of significant interest. Because his span of interests was so broadcovering everything from inorganic chemistry to biochemistry and cell physiologyhe was eventually able to discern that this difference was related to a phase shift transition occurring in the packing of the hemoglobin molecules in the heme from sickled cells, versus the heme from normal cells. That led to a different kind of packing, or a different kind of crystallization, changing the way the magnetic field and light interacted with the red cell. He began to think about structure/function and what would cause the sickle cells to pack more closely, stick together, and demonstrate this unique sickle effect under the microscope. He believed that the sickle conformation was the effect of something going on within the cell. Knowing that more than 50 percent of the volume of the erythrocyte is hemoglobin, he thought that it had something to do with the packing of the hemoglobin molecules. That, in turn, had something to do with the unusual thing he saw with regard to the iron component of the porphyrin and how they all lay on one another, forming a crystalline-like structure within the erythrocyte of the sickled individual. Eventually, Dr. Pauling wanted to find out what controlled the structure of the way the hemoglobin, or the heme portion, could crystallize the iron-containing component. He thought it must be the globin portion, the protein portion, of the hemoglobin molecule. The large chains of polypeptides wrap themselves around and maintain the conformation of the hemoglobin molecule and ultimately present the heme portion of the molecule (the iron-containing portion) in different configurations, based on the altered tertiary structure of the protein. Dr. Pauling surmised that must be where the genetic differences startin the globin portion of the molecule. Protein sequencing was coming into its own, looking at the exacting kind of chemistry required to do amino acid analysis. Noting the difference in the polypeptide chain of the sickled individual versus the non-sickled individual, Dr. Pauling found that the difference between the globin chains was only one amino acid substituted in the chain. In the chain of hundreds of amino acids, there was only one difference between sickled hemoglobin and normal hemoglobin. That one difference occurred at a very critical point for the conformational integrity of the globin molecule. By substituting a single amino acid for another in someone with that genetic difference, it changed the shape of the globin molecule which, in turn, changed the shape of the way that the heme portion was presented. That changed the packing arrangement of the hemoglobin in the red cell causing it to crystallize, which changed the shape of the red cell. It stretches the red cell, resulting in a sickled appearance, which causes deformation. It cannot go through the capillaries as well and it results in injury. Just as a sickle would slice grain, it slices the vasculature, producing injury and damage. That was Dr. Pauling’s model and it was presented in 1949 in Science magazine in an article, titled “Sickle Cell Anemia: A Molecular Disease”.1 It was the first use of that term that I could find in the literature. It followed beautifully in the definition of a new kind of disease that makes a connection between genes and the environment and how that relates to structure/function relationships and the pathogenesis, or pathology, of a disease. Dr. Pauling proposed that there might be ways of changing the environment. There was no way to change the genes of an individual, but perhaps the environment in which the red cell was bathed could be changed, or the way the genes were influenced could be changed, altering the potential for red cells to pack together and engage in what we call a “sickling crisis.” That was the theme of the 1949 article on sickle cell anemia. The Role of the Environment in Modulating Protein Structure and Function In the 1960s, investigations were conducted by many different groups looking at the role that environment plays in modulating protein structure and function. Dr. Pauling and his group were certainly at the forefront of these investigations. He was very interested in what the origin and lineage of vitamins had to do with physiological function, as that area tended to converge with the origin and function of protein and, ultimately, the regulation of cellular function. Today, that seems like a very obvious connection. It seems, in retrospect, almost simplistic, but at the time, in the late 1940s and early 1950s, just on the heels of understanding the physiology and biochemistry of vitamins, this was quite a remarkable concept-that somehow, there was a convergence of vitamin physiology and genetic function. To have those concepts linked together into a single theory, or theme, led to a remarkable change in people’s beliefs. Before that, it had been felt that beriberi, pellagra, rickets, xerophthalmia, scurvy, kwashiorkor, and marasmus, were conditions that all people would get with equal prevalence if they were deficient in certain nutrients. They were not based on individual differences related to genetic variations. In retrospect, the observation that different individuals would respond in different ways to a deficiency had some support. Recall the concentration camp victims during World War I and II. There was a wide variety in mortality among different individuals that could never be explained, based on the fact that they were all getting similarly deficient diets. People would ask why some would wither and die so quickly when placed on deficient diets and others could seemingly survive for a long period of time. Admittedly, their physiology was injured, but they would survive. The Concept of Biochemical Individuality That leads to Roger Williams’ concept of biochemical individuality. He was pioneering this concept at the University of Texas in the early 1950s, at the same time Dr. Pauling was pursuing his concept of molecular medicine. These two concepts converge beautifully. Dr. Williams coined the term “genetotrophic disease,” a disorder resulting from an individual’s need for specific nutrients for optimal function not being met, which produces suboptimal physiology.2 He postulated that many common societal diseases, including alcoholism, various neuropsychiatric orders, as well as heart disease and diabetes, might be considered genetotrophic diseases, and could be prevented by matching the genetic needs of an individual with specific diets. These were the remarkable paradigm shifts being made by Drs. Pauling and Williams. That leads to the late 1960s when Dr. Pauling published what I consider to be a watershed paper in Science magazine, some 19 years after the initial article on sickle cell anemia appeared. The later paper was titled “Orthomolecular Psychiatry.”3 If you reread this classic article in the 1968 issue of Science magazine, you will find that the concepts are as modern today as they were in 1968. Dr. Pauling spoke about the origin of neuropsychiatric disorders as a consequence of the imbalance between the need for specific nutrients to promote proper brain chemistry and the genetic uniqueness of the individual. Therefore, what might be adequate nutrients to power up the brain in one person may be suboptimal in another, leading to inappropriate brain physiology. Dr. Pauling stated that individual differences related to nutrient need may be vastly greater than previously thought when the Minimum Daily Requirements (MDRs) or Recommended Dietary Allowances (RDAs) were designed. They had a fairly narrow range of what we consider to be requirements for human function. He pointed out that some people fall into categories of deviation far from the mean of the bell-shaped curve, where needs may be much higher, possibly 1000 times the RDA. He gave some examples, such as people with methylmalonic aciduria and Hartnup disease that require extraordinarily high doses of specific nutrients to prevent the buildup of metabolites that can be injurious to individuals with certain genetic characteristics. Dr. Pauling showed that, to promote proper brain chemistry, we need to consider a confluence of ideas between genetic metabolism disorders and nutrient needs. He used some very compelling arguments which, for most medical doctors, were not well understood, such as the Michaelis constant and the binding of an apoenzyme to an coenzyme to create an active enzyme. Nutrient need might be defined on the basis of a genetic binding quotient between the enzyme and its coenzyme (a vitamin-derived material), and that could vary tremendously. In his 1968 article, Dr. Pauling discussed binding disassociation and Michaelis constant values, themes that were probably over the heads of most people, unless they were students of physical chemistry and enzymology. It is ironic that nearly 25 years later, Dr. Bruce Ames published a landmark paper in the American Journal of Clinical Nutrition in 2002, in which he talks about the Michaelis constant. He presents tables of data from literally hundreds of papers that have been published since 1968, demonstrating that Dr. Pauling’s concept about mass action effects to promote enzyme function with various vitamins is, in fact, correct for many genetic metabolism disorders.4 It is not just the frank genetic metabolism orders, but a whole range of variegated polymorphisms that result in differing needs in different people for optimal function. It is a new view of the role that nutrients play in function that came through our traditional concepts of vitamin deficiency and establishment of the RDAs. In fact, the constructs I am describing, those of Williams, Pauling, and Ames, were not incorporated into the development of the RDAs. The Work of Hoffer and Osmond in Schizophrenia We are now in the late 1960s and the birthing of the concept of orthomolecular psychiatrythe use of nutrients at the level of physiological need. Pioneers Dr. Abram Hoffer and his colleague Humphrey Osmond got involved in this work as well, looking at high doses of niacin, pyridoxine and ascorbate in the management of schizophrenia. They originally worked independently, but later collaborated with Dr. Pauling together, and birthed the concept of orthomolecular psychiatry with David Hawkins. It is a fascinating chapter in the history of the application of molecular medicine to psychiatric and neurological function. That leads to the early 1980s, a period in which I had the pleasure of working at the Linus Pauling Institute of Science and Medicine in Palo Alto, California and observing the contributions being made by Dr. Pauling and his colleagues in the evolution of the concept of orthomolecular psychiatry. In early 1983, a meeting was held in San Francisco to honor Dr. Pauling and the years of his contributions. I had the fortune of being one of the presenters at that meeting. Dr. Pauling gave the plenary lecture. The title of his talk was, “The Future of Orthomolecular Medicine.” I want to thank Dr. Alex Vasquez for sharing a PDF file with me that he found on the web. It is the hand-annotated original draft of the manuscript for Dr. Pauling’s speech, which I had the privilege of seeing in 1983 before it was presented, but I had long ago lost my copy. Dr. Vasquez was adept enough at finding this and sent me a copy. It reminded me of the intellectual activity and excitement that was occurring in the 1970s and 1980s around the development of orthomolecular medicine. I would like to quote some of Dr. Pauling’s thoughts to demonstrate how we go back to the future, and how we are relearning old ideas and new ways to make them even more valuable. The following are quotes from Dr. Pauling’s 1983 speech.5 “The reason that I spend time thinking about medical problems, about vitamin C, for example, is that I believe that we are going to solve this problem of finding out how to keep the world from being destroyed in a nuclear war, and that it’s worthwhile to be thinking of making the world a better place for the coming generations of human beings. “One way in which this can be done is by improving the health of people, by cutting down on the amount of suffering caused by hypoascorbemia, as Irwin Stone says, from which essentially everybody in the world is suffering. Only a few enlightened persons, who take 10 or 12 grams a day of vitamin C, are in the fortunate position of not suffering from this genetic disease that we have learned to control, but only just barely, by getting a diet that contains enough ascorbate to keep us from dying, but not enough, it’s turned out, to put us in the best of health. “The other talk that I gave to this symposium that I was attending, was on the role of the physical sciences in modern biology. I talked about one aspect of this, and in fact it’s quite pertinent to what we have all been talking about: about vectors of disease and about the agents that we use to control these vectors of disease, and about the human body and how it functions. “I doubt that I thought much about the nature of life until 1929. I was then carrying on research on the structure of minerals and other inorganic substances. Then in 1929 Thomas Hunt Morgan came from Columbia University, bringing with him Sturtevant and Bridges and Emerson and Tyler. Sturtevant and Bridges were two of the three students who had cooperated with Morgan in developing the theory of the gene, in discovering the gene. It wasn’t known, of course, that it consists of polynucleotides, but they knew a lot about it even though they didn’t know its chemical composition. They kept talking about the specificity characteristic of life. One example of this specificity is that parents have children who resemble them. This resemblance we now know even goes so far as resembling them in terms of amino-acid sequences of the polypeptides that constitute the specific proteins in their bodies, and their specificity in the action of enzymes as catalysts. “Morgan was working on self sterility of Ceiora, the sea squirt. In 1935 and ’36 I was working on diamagnetic oxygen as well as triplet oxygen, the normal state, with the idea that we could tell something about how oxygen molecules are held by hemoglobin molecules in the red cells of the blood. The idea was that we could distinguish between two kinds of combination; one involving a mainly physical force that would leave the oxygen in the triplet state, leave it paramagnetic, and the other chemical combination, the forming of chemical bonds that would make the oxygen molecule diamagnetic. So we measured the magnetic susceptibility of venous blood and arterial blood, and found that the oxygen molecules were held in the hemoglobin molecule by forming chemical bonds. We also found a remarkable change in magnetic properties of the iron atoms when the hemoglobin in the red cells is oxygenated. “I was giving a talk in New York in 1936 at the Rockefeller Institute for Medical Research, a seminar on this subject, and where Landsteiner asked me to talk with him. Karl Landsteiner had discovered the A, B, and O blood groups in 1900, and the others, L and M and Rhesus factor, later on. He had been carrying out experiments in the field of immunology, immunochemistry, and he asked if I could explain his observations. I couldn’t explain them, but he told me a great deal in several days of discussion; he told me a great deal about immunology. I kept thinking about what he had said, and finally I reached a decision as to what I thought was going on that permitted antibodies to show such remarkable specificity in their interaction with antigens. Landsteiner was making azoproteins, using simple chemical substances such as paraaminobenzoic acid, metachloral, orthochloro-benzoic acid or toluic acid, and hundreds of other substituted benzoic acids as well as other substances you could use instead of the benzoic acid. “By 1940, I had reached the conclusion that I knew the answer to the question, the basic answer to the question of the molecular basis of biological specificity, the molecular basis of life. There were two ideas that had been discussed. A German physicist named Pasqual Jordan published a paper in 1940, about the time that I published my paper about the structure of antibodies and the nature of serological reactions. He advocated one of these ideas which is that identical molecules attract one another more strongly than nonidentical molecules because of the phenomenon of quantum mechanical resonance. Max Delbrucks brought this paper to my attention, and I said, ‘I don’t believe that the extra energy of attraction that you get from quantum mechanical resonance between identical molecules can possibly be the explanation, because this extra energy is less than the energy of thermal agitation. It just wouldn’t work. But if, and this was in my paper on antibodies, if the antibody has a combining region that is complementary in its atomic structure, the arrangement of the atoms, to the haptenic group of the antigen, you get strong and highly selective interaction.’ Well, so we wrote a paper in 1940 saying that biological specificity in general results from the detailed molecular complementariness of the interacting groups, and that Jordan was wrong about his idea of quantum mechanical resonance. We also said the gene consists of two mutually complementary molecules, each of which, when they are separated, can act as a template for the synthesis of a replica of the other one, so that gene duplication occurs that way, using one half of the gene for the template for the other half because of its complementariness. Well, of course, some years later examples of complementariness began to show up. The alpha helix and the pleated sheet are arrangements of polypeptide chains in which there are two complementary groups which interact, the NH group of peptide interacting with the oxygen atom of the carbonyl group of another peptide, and that is a highly directed interaction. You can achieve these hydrogen bonds by coiling the polypeptide chain in the helix or by arranging it in a somewhat staggered linear arrangement coming back on itself to make the pleated sheet where the hydrogen bonds are formed laterally. And then, of course, Watson and Crick discovered the double helix 13 years later, in 1953, in which they were able to show that two nucleotides-purine and pyrimidine-form two hydrogen bonds with another and two other nucleotides, purine and pyrimidine, form three hydrogen bonds with one another, and that the gene consists of two polynucleotides which are mutually complementary, adenine combining with thymine and guanine combining with cytosine. “So now by 1948, my students and my associates, Dan Campbell and David Pressman, who worked for several years on this project, had carried out studies of the interaction of antibodies with haptenic groups, hundreds of experiments, a thousand perhaps, determining equilibrium constants. By 1958 we had tied down these ideas, so far as they are concerned with antibodies and antigens, so tidily that there was no possibility of saying that we were wrong. “So molecular complementariness, this tight fit of the complex of atoms of one molecule onto the complex of atoms of another molecule, is the basis of life. Biology now is developing, molecular biology is going along strongly, genetic engineering. We are going to get more control of ourselves, with a better understanding of the nature of our own bodies and the way in which these bodies function. I’m not going to make an effort to predict in detail what the future of orthomolecular medicine will be. I think that it’s been done already, by the participants in this seminar; but I might make a quantitative statement. Someone sent to me a clipping saying that Dr. Pauling says that we can live to be 100 years old, and I in fact had said that, that by proper use of supplementary nutrients and other health practices, people in general could live 25 years longer than they do now, live to be a hundred years old, and lead good lives too, not have a long period of debility as the body begins to fail. “Well, Irwin Stone said that he believed that I could live 50 years; that was 15 years ago when he made that statement, so he would say that he thinks that we can live 35 years more than presently accepted. It may well be that in a generation or two we shall have enough knowledge, especially in the orthomolecular field, to permit people to live to be 110 years old. I think that this is worthwhile: if you can extend the period of well-being, then we shall have extended the ratio of well-being to suffering, and I think that that would be worthwhile.” “I’ve enjoyed myself for many years, after I got through the initial period of not understanding the world very well. I’ve enjoyed myself, and it’s been a special pleasure for me to have been here today and yesterday. Thank you.” This speech was given in 1983. I think it’s back to the future. How far have we come during the past 22 years in the amplification of this concept? The Institute for Functional Medicine is trying to honor and champion the concepts that Dr. Pauling set forth 25 years ago. The emphasis and focus through our Applying Functional Medicine in Clinical Practice training programs, our annual symposium, and our Neuro Module workshops, is an attempt to incorporate these concepts more and more effectively into clinical practice. If we look at what has happened with the sickle cell anemia story since the 1949 discoveries, going forward to the 1960s and later into the 1980s with Dr. Pauling, it is fascinating. We now recognize that you might be able to actually modulate, with specific signal molecules, the production of fetal hemoglobin at the gene level to dilute the sickled hemoglobin and prevent sickle cell crisis. There are a couple of substances now being used clinically to modulate gene expression of fetal hemoglobin. One is hydroxyurea; the other is butyrate. Infusion of butyrate and hydroxyurea has been demonstrated to upregulate gene expression of fetal hemoglobin, which is not sickled, so that it dilutes the sickled hemoglobin and prevents things that Dr. Pauling talked aboutthe protein/protein interactions that lead to the sickle crisis. Dr. Pauling’s prediction in 1949 was very prescient. He asked whether the environment could be changed to modify the outcome of function if you knew something about the interaction of environment with genes of susceptible individuals. This is a presaging of what we are going to be talking about in much greater detail at the 12thInternational Symposium on Functional Medicine coming up on May 24-28 in Palm Springs, California, at the Westin Mission Hills Resort. You may have received information about it, but just to remind you, the title of the symposium is, The Immune System Under Siege: New Clinical Approaches to Immunological Imbalances in the 21st Century. If Dr. Pauling could attend, I think he would be proud to witness how his concepts have evolved over the past 40 years in the kinds of presentations and workshops that will be held at the symposium. We have taken his concepts to a new level as they pertain to the understanding of balancing components of the immunological system, such as thymus-dependent-1 (Th-1) and thymus-dependent-2 (Th-2) lymphocyte function, and how that relates to disorders associated with immunological imbalance. We are on the horizon of an exciting time. We are going to learn from our Clinician of the Month about some of the constructs laid down through the pioneering work in genetic metabolism disorders and the early understanding of the role that vitamins play in the prevention of deficiency diseases. Those two ideas converged into a new theme of medicine called molecular medicine, later to be called orthomolecular medicine. Then came the concepts of biochemical individuality and genetotrophic disease by Dr. Roger Williams, and these have been woven into nutrigenomics and eventually into functional neurology. For most of the last 60 or 70 years in medicine, we held the belief that there is a step function between health and disease. On one side was health and on the other side, disease. We viewed it almost like an on/off switch. One moment there was health and in the next moment there might be a disease. That concept has been pretty much laid to rest over the last 10 to 15 years. Certainly, Dr. Pauling’s insight in 1949 helped us to achieve the tools to address these issues. Now, we are starting to recognize that almost all specific age-related chronic diseases have a gradient effect, a lineage, a precursor marker period, and a subclinical period, and they ultimately arise at a diagnosed disease after significant dysfunction, or when loss of function occurs. The real future of medicine is not in understanding how to diagnose better, but to better understand how to prognose, how to look earlier, how to intervene before the patient completely loses function and requires heroic intervention. There is probably no better part of the body’s physiological system where we can focus this concept than the neurological system. As they grow older, most people are concerned about loss of cognitive function, independence, and self-awareness. Understanding how to move away from diagnosis and to focus on prognosis will give us much better tools to treat many conditions, including attention disorders, learning disabilities, schizophrenia, Alzheimer’s disease, presenile dementia, Parkinson’s disease, multiple sclerosis and others, all of which rob us of productive years of neurological function. It is time for our Clinician of the Month, Dr. Daniel Amen

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INTERVIEW TRANSCRIPT

Daniel G. Amen, MD 4019 Westerly Place, Suite 100 Newport Beach, CA 92660 Web site: brainplace.com JB: In this month’s edition of FMU, we are focusing on functional neurology. On Side 1, we talked about Linus Pauling’s 1968 pioneering article in Science magazine, titled “Orthomolecular Psychiatry.” In that article, he developed a different theme about how we treat neuropsychiatric disorders, setting the stage for how we look at the brain from a functional perspective and how biochemistry plays a role in performance, cognition, mental acuity, and neurodegenerative and neuropsychiatric disorders. This theme takes us into the 21st century and the work of our Clinician of the Month. Dr. Daniel Amen is a remarkable investigator, clinician, and innovator in the area of functional neurology. I don’t know if he shares that term with me, but we’ll get a chance to hear from him in a moment. Dr. Amen is a Board Certified psychiatrist and the founder of the Amen Clinics, Inc. in Newport Beach, California; Tacoma, Washington; and Reston, Virginia. He has done amazing work in helping us to understand how various types of scanning, particularly SPECT scanning, can be useful in assessing altered brain function. This type of assessment often leads to the modification of function without the need for hard-hitting psychotropic or neurologically-modifying drugs. Dr. Amen has a remarkable background that includes many contributions and experiences. He has written some interesting book chapters, including “Brain SPECT Imaging and ADD in Understanding, Diagnosing, and Treating AD/HD in Children and Adolescents: An Integrative Approach,” published in 1999;7 and “New Directions in the Theory, Diagnosis, and Treatment of Mental Disorders: The Use of SPECT Imaging in Everyday Clinical Practice,” published in 1994.8 He has published numerous articles, has made hundreds of presentations, and has written some books that are absolutely required reading. His most recent book is titled Making a Good Brain Great and will be published this year by Harmony Books.9 Books in print that I had the chance to review over the last couple of months include, Preventing Alzheimer’s, with neurologist, William Shankle;10 Healing Anxiety and Depression, with psychiatrist, Lisa Routh, MD;11 Images of Human Behavior: A Brain SPECT Atlas;12 Healing ADD: The Breakthrough Program That Allows You to See and Heal the Six Types of Attention Deficit Disorder13 ; and Change Your Brain, Change Your Life,14 which was a New York Times Bestseller in 1999. That book contains some revolutionary thinking that people talk about all the time. With that introduction, I would like to welcome you, Dr. Amen, to FMU. My first question is, how does a psychiatrist make a transition into radiology and then into functional neurology? It doesn’t seem like the traditional path that most psychiatrists have taken. From Biofeedback to Imaging DA: Thanks for talking with me, Jeff. I feel so blessed about the work I’ve been doing. I got into imaging from biofeedback. Biofeedback is where we measure a person’s body with instruments and then teach them how to change their own physiology. We teach people to warm their hands, breathe in a different way, and even change their own brain waves. When I learned how to do that in the mid 1980s, I was so excited. I started looking at things like depression and ADD from a brain-wave perspective. When I went to my first lecture on brain SPECT imaging in 1991, it made perfect sense to me. Of course we should look at the brain because these are brain disorders. I started to feel very uncomfortable being a psychiatrist because, why were we handicapped? Psychiatry is the only medical specialty that never looks at the organ it treats. I thought that was silly. I loved being a psychiatrist, but I thought we needed more information. When I had the opportunity to learn about these scans, order them on my own patients, and see the dramatic positive response on the part many of them, I was hooked. I thought that I couldn’t do a good job for my patients if I didn’t know what was going on in their brains. JB: It’s fascinating to hear you say that, because I recall that about 20 years ago, I got a notice about a conference on biological psychiatry that I thought sounded very interesting. It followed nicely from my experience with Dr. Pauling at the Pauling Institute in the early 1980s. I felt I should go and see what biological psychiatry was all about. I found out it was all about how to use various types of mind-altering drugs. It had nothing to do with the biological function of the brain. It sounds like you’re truly practicing biological psychiatry. You’re looking at structure/function relationships in terms of psychiatric and psychological dysfunction. Psychiatric Medications and the Brain DA: Absolutely. That’s just what we do. We never make a diagnosis from a scan. The scan has to be put in the context of the patient’s life. But without having imaging information, you’re spending a lot of time guessing. One of the most important things imaging has taught me is that the use of psychiatric medications can be ever so helpful to the brain, or they can really hurt the brain. How would you know unless you looked? What really got me interested in alternatives to psychiatric medications was seeing that often, the medicines I was taught to use for people with anxiety disorders (at the Walter Reed Army Medical Center where I did my training), like benzodiazepines or antidepressants, certainly helped to calm down the brain, but they gave the brain a toxic look. At that point, I wondered if there were other alternatives we should be offering to patients. It was through very high tech0ology imaging that I became much more interested in using alternatives to help balance brain function. JB: I notice that you’re an Assistant Clinical Professor in the Department of Psychiatry and Human Behavior at the University of California, Irvine. I wonder how your concepts hav4 been accepted by your colleagues and students. I suspect the students probably have a different level of acceptance than your colleagues. Would you tell us about what you have observed in terms of acceptance of these concepts by colleagues in your field? DA: When we first started doing this in 1991, people would call me a “quack” and they reported me to the Medical Board. It was quite a wild, negative ride, but I believed in what we did, so we kept doing it. Over the years, there has been a softening of that. I wrote a book once, titled Healing the Hardware of the Soul.15 A colleague of mine, a psychiatrist in Berkeley, sent me a very nice letter. On the outside of the envelope, he wrote: “All truth goes through three stages. First, it is ridiculed (well, I’ve certainly been there). Second, it is vehemently denied. Third, it is accepted as self-evident.” We’re now between stage two and stage three. I teach six seminar courses to the residents at UCI. The powers that be, our Chairman and Residency Director, think what we do is great and they are fully supportive of it, but a lot of the staff who have little training in imaging think it’s a little bit of voodoo. The students, on the other hand, are very excited, interested, and their eyes get big when they observe a suicidal patient and see a scan of his brain that demonstrates a left, temporal lobe deficit. They say, wow! You mean, if I fix that, he’s not going to feel as aggressive or dark and negative toward himself? And I tell them yes, that’s how it goes. It’s like hardware and software; you must balance the brain, and then you have to teach them how to use it better. Doing psychotherapy on people with brain problems is not only a waste of time, but it makes people worse because it demoralizes them. JB: That’s very insightful. Before we get into the specifics, which I want to give you the opportunity to do, I’d like to deal with what is probably the most common question you get from nay-sayers, so we can get it out in the open. I’ve heard people (traditional neurologists, radiologists, and imaging specialists) to whom I’ve talked with excitement about your work, and they have responded that there’s a variation in the reproducibility of SPECT scans that would prevent its use in determining functional changes in the brain at a level at which you could make a specific assessment. Would you speak to that? You probably have more experience than any one of them, and I’d like to get to the truth here with regard to your experience. Reproducibility of SPECT Scans DA: We’ve done 25,000 scans. Each patient gets two scans. They get a rest scan and a concentration scan. When you concentrate, your brain changes in certain areas, mostly the prefrontal cortex and the cerebellum. Other than that, the scans are actually very reliable and predictable. We’ve done scans 12 years apart on people and it’s basically the same scan. At UCLA, Ismael Mena, who was the Chief of Nuclear Medicine at Harbor-UCLA, did a study where he showed that three weeks apart, there’s less than 3 percent variability in the scans. Jonsson et al. have also done a study on the reproducibility and repeatability of the scans.16 The notion that your brain changes with every thought that you have is just not true. But there are some interesting caveats to that. If someone has PMS, her brain changes. I got interested in that because I have five sisters, and I thought that there had to be some brain changes in the middle of the month versus right before they start their period. And indeed, there are. If you have multiple personality disorder (we studied that a number of years ago), the brain changes in each personality. By and large, given those couple of caveats, the brain is very consistent over time. JB: From that, how did you make the observation that SPECT imaging could be useful for the evaluation of conditions like ADD or ADHD? Evaluating ADD and ADHD DA: What alot of people don’t understand about my work is that it is not based on my thoughts. It’s based on a ton of research done by other people. In fact, one of the things that got me excited about ADD was the research with quantitative EEGs, showing that the ADD brain is different at rest versus when they concentrate. When I started doing imaging, there was an article in The New England Journal of Medicine about using PET studies with ADD. PET is a cousin of SPECT. When adults with ADD try to concentrate, they get decreased activity in the prefrontal cortex. On our web site, brainplace.com, you can actually read 1500 scientific abstracts on brain SPECT and PET imaging in psychiatry. Indications for Brain SPECT Imaging I had a really busy practice when I started doing imaging. I was working on a lot of my own patients. At the same time, we were going to the medical literature and finding out what people said about it. In fact, according to the Society of Nuclear Medicine today, there are four standard indications for brain SPECT imaging-dementia, seizures, head injury, and vascular disease. These are things psychiatrists see all the time. Even though we have this reputable organization saying that we should be doing it under these conditions, we don’t. The reason we don’t is that people aren’t trained in it. I think that’s really the bottom line. The students that I train will use it and make it part of their practice. But if you’re not exposed to it, you really don’t even think it exists. JB: There’s a classic we’ve all seen in our lives, that being, if you don’t ask the questions, you’re not likely to get the answers. Certainly, you’ve asked the right questions. Would you tell us about what types of patterns you’ve seen that are interesting from a clinical perspective, and how you categorize them into pattern recognition families. Blood Flow and Activity Patterns in the Brain DA: SPECT looks at blood flow and activity patterns in the brain. We really need to understand that, because we see areas of the brain that work well, areas of the brain that are underactive, and areas of the brain that are overactive. Initially, I was much more nave than I am now. I thought there would be a signature pattern for ADD and a signature pattern for depression. When I didn’t find one, I was disappointed, until I realized that in seeing real people, not all ADD people respond to stimulants. In fact, stimulants make a great many of them worse. it’s the dirty little secret that many psychiatrists don’t talk about, but, in fact, it’s true. Probably one of the most important things I’ve learned is that ADD is not one thing. it’s at least six different things. There’s a pattern in people who get diagnosed with ADD where they have what we call classic ADD. It is pretty healthy brains at rest and they deactivate their prefrontal cortex and their cerebellum when they try to concentrate. It’s very clear. That group actually responds fairly nicely to stimulants. There’s another group. They get diagnosed with ADD very early in life, but stimulants make them significantly worse. In fact, according to our research, 70 percent of the time, stimulants will make them worse. This is a pattern we call the “ring of fire,” which is diffuse, overall increased activity in the brain. Our feeling is that it may be some inflammatory process going on. They may have early bipolar disorder. They may have some sort of allergy, but they meet all 18 criteria from the DSM4 for ADD. But don’t put them on a stimulant because they are going to end up significantly worse. We also see a head injury pattern associated with ADD when there’s damage to the left side of the brain, especially the left frontal and temporal lobe. These are people who clearly have the outward manifestations of ADD, but they tend to have temper problems, irritability, and mood instability. One of my favorite patterns, because I did research on it when I was a child psychiatry Fellow, is what we call over-focused ADD. It’s where ADD and OCD sort of cross each other. You get ADD kids or adults who also tend to be argumentative. If oppositional things don’t go their way, they get upset. Their problem is not so much that they can’t pay attention, but that they cannot shift their attention, so they end up inattentive because they’re always thinking about something five minutes ago. JB: In many school systems in the U.S., there is a very high prevalence of prescription for stimulant drugs to manage behavior in children who are presumably ADD or ADHD. It would suggest, obviously, that some of the children were probably mistreated, based on the fact they weren’t evaluated before they were given a one-size-fits-all remedy. What happens if, after a child goes through your studies and is found not to be a candidate for this kind of medication, they have already been prescribed that medication? Does that result in a resolvable conflict, or are there some warnings you would want to pass on from your experience? DA: Parents, in my experience, tend to be caring and pretty smart. If the medicine is not working, they tend to take the children off it, because they don’t like the side effects. When people come to see us, they’ve often tried six or seven things and come to us with three or four different diagnoses. What I find that works is, the first thing we have to do is clean up their life. We have to clean up their diet, get them to exercise, and get them away from TV and video games, those things in our society that are increasing the expression of ADD. Then, we need a more thoughtful approach to their brain. Our whole goal is based on how we can balance their brain so they “do their lives” better. Most people can do their lives if they have a brain that works right. That becomes the goal. I think there are a lot of people who are misdiagnosed with ADD because we assume it’s one thing. As you said, we have this one sort of treatment fits everybody-one-size-fits-all. it’s a silly approach and we need to be more thoughtful. Recently, the FDA has been all over child psychiatrists about using antidepressants. it’s not that antidepressants are bad or wrong or ineffective. it’s just that one type of antidepressant, like an SSRI, does not fit everybody who is depressed. It’s the knee-jerk reaction that doctors do, because there are all the drug representatives that come to our offices, giving us cookies, buying us lunch, leaving us Paxil pens, and so on. We agree, especially the family doctors and pediatricians, that we’ll think about this SSRI. So, heretry this. But when there is a ring-of-fire pattern, you’re likely to make that person dramatically worse. We simply have to be more thoughtful about what we do. And there are alternativesthe notion of using supplements and vitamins. If it’s not part of your training, you don’t think about it. I have several kids with ADD and I want to use whatever is the safest, most effective treatment for them. Often, I can get supplements to work, so why wouldn’t I start there if they have fewer side effects? JB: That’s an exciting message. I was pleased to see that with your diverse background, through biofeedback and hypnosis and looking at a variety of complementary and integrative therapies, that you’ve developed what I would call a truly integrative functional neurology approach to these syndromes and these conditions. When you look at the integration of these therapies in a child or an adult, how long does it generally take to start seeing clinical effects, and can you then document changes in the SPECT scan over time? DA: Absolutely. It was one of the things that got me excited about things like St. John’s Wort. St. John’s Wort works just like Prozac, except you don’t get sexual side effects from it. It’s cheaper, and you don’t ever have to tell an insurance company you took it, so it doesn’t affect your insurability. But we would see before and after changes. My experience is that it takes a little bit longer, so when I use a natural approach, I feel that we need to do this for about four months. I tell patients that if they do the things I ask them to do for four months, that even if they need medicine, they’re going to need less medicine. People get excited about that. They know we’re going to do a followup scan to see how we’re doing and if we’re doing the right thing. And they get excited. Now, Ritalin works within a half an hour. If you have an ADD family (ADD children come from ADD parents), often they are looking for a quick fix because that’s their attention span. But when you work with them and give them simple ways to follow through, it can be ever so helpful. Having said that, for people who are listening to this tape, if they deal with people with ADD, they should know it’s a family disorder. If you are seeing a child with ADD, you need to screen Mom and Dad because they got it from one of them. JB: That’s very good insight. I’d like shift the focus slightly. Back in the early 1990s, Dr. Clough wrote an article that appeared in the Lancet on the etiology and pathogenesis of Parkinson’s. He introduced a concept in that article called neuroprotective therapy that was picked up in a more recent article in the Journal of the American Medical Association, one on the etiology and pathogenesis of Parkinson’s, discussing that if you knew early enough that the person was losing niagra striatal neurofunction, that you could intervene with neuroprotective therapy. Of course, the questions are, how do you know, and what do you do? Your procedure seems to lend itself nicely to addressing both of those questions. Would you tell us about your experience with Parkinson’s, Alzheimer’s, and other kinds of neurodegenerative conditions? SPECT Scanning and Alzheimer’s Disease DA: I have a lot more experience with Alzheimer’s disease. In my book, Preventing Alzheimer’s, which I wrote with a colleague of mine, I was so taken with the scans, and there’s research evidence to back this up. We can tell five to seven years before there are symptoms whether or not a person is likely to develop a form of dementia. That’s stunning! You have to lose 30 percent of your hippocampus, the structure on the inside of your temporal lobes that’s responsible for memory. You have to lose 30 percent of it before you have your first symptom. If I’ve lost 10 percent, I want to know because I want to do something about it. As we worked on the book, it’s just stunning to me, the risk factors associated with Parkinson’s disease, Alzheimer’s disease, and vascular dementia that we can actually do something about. Diabetes is a risk factor. Depression is a risk factor. Sleep apnea is a risk factor. Heart disease is a risk factor. If only we knew that taking care of our bodies is guarding against risk factors for Alzheimer’s disease, we’d do a much better job of it when we’re in our 20s, 30s, and 40s. I’m convinced that the information that you put out and that I put out should be part of curriculums in schools. I like the lyrics in one of Paul Simon’s songs “When I think back on all the crap I learned in high school, it’s a wonder I can think at all.” His song, “Kodachrome,” starts with that. What are we doing if we’re not teaching these kids? I am so excited. I just started a 12-week course for 9th graders called “Making a Good Brain Great.” It’s all about the practical brain science one needs to know about. There are things we do in the beginning of life that set us up for trouble at the end of life, and the people who need the information don’t have it. JB: That’s a great admonition and a rallying cry for our listeners. I appreciate that insight. I recently saw a few papers in the literature that suggested conditions like post traumatic stress syndrome (PTSD), chronic fatigue, and multiple chemical sensitivity, were early-stage markers for later-age dementia, suggesting that there may be some shared common mechanism with regard to brain chemistry or brain chemical dysfunction. Do you have any experience with those conditions, like PTSD, CFS, or chemical sensitivity? Post Traumatic Stress Syndrome DA: I do with the first two. We have had a lot of experience with PTSD. When you get traumatized, it flames your emotional brain. The chronic stuff that goes along with having an emotional brain on fire, starts to kill cells in your hippocampus, so that’s a nightmare. When I first heard about CFS, my colleagues were saying that these were really psychiatric patients, people who are depressed or people who are hypochondriacs, until I started looking at their brains. It’s easy to call somebody bad if you don’t look. But as soon as I started looking at CFS, I went “ouch.” These people have severe deficits in their brains. No wonder it predisposes them to a dementia-like process, because it’s tearing up significant amounts of brain function. The overall decreased perfusion in their brains is dramatic. When you look at it, it’s clear they’ve had some form of toxic exposure from some toxin or from a brain infection. That’s the cool thing that scans do. They teach you to be more empathic and they teach you to ask better questions. I work with Harold Burstein, who is the Director of the Psychiatry and Law Program at Harvard. We wrote a paper together on imaging and quark. Harold says that imaging doesn’t give you the answers. It teaches you to ask better questions. If you have a patient with CFS that comes to your office and you can’t really decide whether they have a difficult personality or do they really have a serious disorder, when you look and you see the damage in their brain, you don’t treat them like they’re a crock. You treat them with great respect, as if, in fact, they are suffering. JB: That leads to a question that probably has no discrete answer, but I’d like to get your wisdom of your intuition to the question. Clearly, what you have just described is a kind of medicine that encompasses a lot of thoughtfulness on the part of the clinician, a lot of pattern recognition, and both deductive and inductive reasoning. It’s an integration of not only scanning technology and imaging, but it’s also the integration of therapies like biofeedback, nutrition, hypnosis, allergy, or orthomolecular medicine. These cut across many medical subspecialty disciplines. How long does it take for a doctor to get adept at this, or is it something that by becoming skilled in the art, one can start making contributions fairly early? Time Frame for Developing the Necessary Skill DA: I think if you’re well trained, and if you have a good basic knowledge of psychiatry and an open mind, you can learn what we do fairly quickly; I’d say six months to a year of being immersed in it. I think what you and your organization bring to the table is another critical piece that doctors should be exposed to. For me, after looking at it over 10 or 12 years, I wish it was integrated into my training so that I could use it. This is the most exciting time to be part of psychiatry, because we are going to change so radically in the next 10 or 15 years. It’s going to look completely different, and to be part of that change is exciting. What we find is that when you learn something new, your brain makes a new connection. One of the ways to keep your brain healthy over time is 1) be excited about what you do and, 2) keep learning new things. It’s the perfect time to be involved in this kind of medicine. JB: For those of our listeners who want to get started down this road, I would urge you to read some of Dr. Amen’s books. They are stunning. You should start with Change Your Brain, Change Your Life, which was published in 1999 and continues to be reprinted. It’s a classic, and it will open your mind to the tremendous opportunity Dr. Amen is talking about. Is there anything you might guide our listeners to doing? You have four clinics, one in Virginia, two in California, and one in Tacoma, Washington. Are there things you might suggest they could do to step into this area? DA: I have a fourth clinic in Fairfield, outside of Napa in northern California. That is actually our “mother ship,” and was our first clinic. I think reading Change Your Brain, Change Your Life is a good place to start. I’d poke around on the web site. There are 300 color images on brainplace.com that people can look at to see the different conditions and what kinds of scans go with it. And then, I’d just poke around in the scientific abstracts until you get comfortable in your own skin. This isn’t smoke and mirrors. This is something that’s based on hard science, and it’s very exciting. One of my favorite books is Healing the Hardware of the Soul. It gives you a different thought pattern about your patients. It’ll put you on a better path. JB: I can’t tell you how much we appreciate your spending the time with us today. We will all be your students as this technology and integrative procedure makes its way forward. Thank you so much for your contributions. DA: Thank you, Jeff. It’s been a real pleasure. The Functional Medicine Assessment It struck me, in thinking about Dr. Kornberg’s extraordinary comments, that when we start looking at the functional medicine model from 30,000 feet in a kind of broad-brush evaluation, the approach is very different from that of the traditional differential diagnosis, which is to try to know more and more about less and less, so that you can ultimately get a specific diagnosis. The functional medicine assessment, so eloquently described by Dr. Kornberg, is to keep moving up to higher levels of organizational perspectives to look at where the interconnections occur, and then to drill down into the individual mechanisms of action related to each of the nodes on the matrix. There is a sense that we are moving back and forth between a telescope and a microscope with the functional medicine model. There is a broader-based perspective and then a very small perspective, and a personalized approach for the patient is developed, based upon the interrelationship between the connection of the whole and focusing therapeutic energies into implementation to the individual components. Oxygen as a Therapeutic Agent What is one of the most important elements that all air-breathing organisms need to be concerned with, as it relates to dysfunction? That, of course, is oxygen, which is about 20 percent of the air we breathe. Often, we forget about air and water as being very important parts of therapy. Every traditional form of healing, from the dawn of medicine, had something to do with delivering air or oxygen to tissues. It could be deep breathing, yoga, exercise, various types of physical medicine, or dance-any number of things up through aerobic exercise and later, into mechanical intubation. I am talking about making sure that oxygen delivery and respiratory gases are properly controlled. Low levels of oxygen in tissues produce oxidative stress, which is associated with inflammation and tissue injury. We want to make sure that tissues are properly oxygenated, and that a person is delivering oxygen to things like the monooxygenase enzymes, which are the cytochrome P450s, the various detoxification enzymes we have talked about that require oxygen for their activity and for proper function to detoxify endogenous and exogenous toxins. Water as a Therapeutic Agent Water is also a very important therapeutic agent, because hydration is critically important for establishing appropriate environmental conditions within cells, tissues, and organs for their function. Dehydration increases the solute concentration and changes enzyme function, cellular activity, and membrane transport. Proper hydration becomes an extraordinarily important part of any therapy in making sure that there is proper balance of intra- and extracellular fluids. The nature of the medications many patients take may alter their intra- and extracellular fluid balance and can lead to intracellular dehydration. Anyone who has overdone alcohol sometime in his or her history recalls the effect that it has on intracellular hydration. It produces a dehydration effect and makes one very thirsty because the cells become dehydrated and, as a consequence, there are toxic symptoms. I want to make sure we recognize that sometimes the simplest things become the most important for proper breathing, delivery of oxygen, and proper fluid intake for intracellular hydration. Again, that obviously ties into the topics that Dr. Kornberg was speaking about as part of the matrix-concepts of GI function, immunological function, hepatic detoxification function, oxidant balance, redox balance, neuroendocrine balance, and body/mind balance. These all interrelate as components of the web in the matrix to things as simple as proper delivery of oxygen and proper fluid intake. What we have outlined in the course of this issue of FMU is a model that has sprung out of nearly 20 years of the emergence and evolution of functional medicine. It paves the way for increased application of this model to a variety of different complex, chronic disorders that do not necessarily fit into a tidy diagnostic profile. I am holding the Textbook of Functional Medicine, which relates to the themes and concepts described in this issue of FMU. This is an 800-page embodiment of the spirit of what we have been talking about for nearly 20 years. I hope you will have a chance to read the textbook and spend some time getting the kind of mastery of these techniques that will allow you to help your patients more effectively. Thanks for being with us. We will see you in April.

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Bibliography

  1 Pauling L, Itano HA, Singer SJ, Wells, IC. Sickle cell anemia a molecular disease. Science. 1949;110(2865):543-548. 2 Williams RJ. Concept of genetotrophic disease. Nutr Rev. 1950;8(9):257-260. 3 Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(825):265-271. 4 Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(M)): relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002;75(4):616-658. 5 Pauling L. The future of orthomolecular medicine. Orthomolecular Medical Society Conference; San Francisco: May 8, 1983. 6 Williams VL. Pathways of innovation. A history of the first effective treatment for sickle cell anemia. Perspectives Biol Med. 2004;47(4):552-563. 7 Amen DG. Brain SPECT Imaging and ADD. In: Understanding, Diagnosing, and Treating AD/HD in Children and Adolescents: An Integrative Approach. Incorvaia JA, Mark-Goldstein BS, Tessmer D, eds. Northvale, NJ: Jason Aronson, Inc.; 1999:183-196. 8 Amen DG. New Directions in the Theory, Diagnosis, and Treatment of Mental Disorders: The Use of SPECT Imaging in Everyday Clinical Practices. In: Koziol LF, Stout CE, eds. In: The Neuropsychology of Mental Disorders. Springfield, IL: Charles C. Thomas; 1994:286-311. 9 Amen D. Making a Good Brain Great. 2005; New York, NY: Harmony Books, Division of Random House. In press. 10 Amen DG, Shankle WR. Preventing Alzheimers. New York, NY: Putnam Publishing Group; 2004. 11 Amen DG, Routh LC. Healing Anxiety and Depression. New York, NY: Putnam Publishing Group; 2003. 12 Amen DG. Images of Human Behavior: A Brain SPECT Atlas. Newport Beach, CA: Mindworks Press; 2001. 13 Amen DG. Healing ADD: The Breakthrough Program that Allows You to See and Heal the Six Types of Attention Deficit Disorder. The Berkley Publishing Group: New York, NY; 2001. 14 Amen DG. Change Your Brain, Change Your Life. New York, NY: Three Rivers Press; 1998. 15 Amen DG. Healing the Hardware of the Soul. New York, NY: The Free Press; 2002. 16 Jonsson C, Pagani M, Johansson L, Thurfjell L, Jacobsson H, Larsson SA. Reproducibility and repeatability of 99Tcm-HMPAO rCBF SPET in normal subjects at rest using brain atlas matching. Nucl Med Commun. 2000;21(1):9-18. 17 Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuriathe effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med. 1983;309(8):448-453. 18 Craig SA. Betaine in human nutrition. Am J Clin Nutr. 2004;80:539-549. 19 Brehm A, Pfeiler G, Pacini G, Vierhapper H, Roden M. Relationship between serum lipoprotein ratios and insulin resistance in obesity. Clin Chem. 2004;50(12):2316-2322.

This entire issue of FMU will focus on the future of primary care and its relationship to the management of chronic disease. There is an increasing aspiration for health throughout the whole life span. “Survival curves have assumed an ever more rectangular form,” to quote from Dr. James Fries’ classic article which appeared in The New England Journal of Medicinein 1980, titled “Aging, Natural Death, and the Compression of Morbidity.”1 Many people now aspire to reach the age of 90 and still be able to engage in going back to law school, do computer programming, play the piano, and a host of other activities. We want to continue to have high vitality, experience low rates of chronic illness, and compress morbidity into the last few breaths of life. That is the theme of Oliver Wendell Holmes’ classic poem, titled The Deacon’s Masterpiece Or, the Wonderful One-Hoss Shay: A Logical Story, in which he provided one metaphor for the perfect life span. He talks about a horse-drawn carriage that ran beautifully for 100 years with no problems. “All of a sudden, on the centenary of the great Lisbon earthquake, the Wonderful One-Hoss Shay collapsed into a mound of dust, going to pieces all at once, and nothing first-just as bubbles do when they burst.”2 That is what most of us aspire to in terms of our life span. We would like to compress illness into the very end of life and be functional up until that time. That is mapped against what is really happening in the United States-the emergence of a new, dominant form of healthcare problem called “chronic disease.” In the past 50 years, chronic disease has become increasingly prevalent. There are significant differences in how physicians and practitioners manage chronic disease versus how they manage acute disease. Chronic disease has now replaced acute disease as the principal cause of disability and use of health services. As I mentioned in a previous edition of FMU, Dr. Halsted Holman, from the Stanford University School of Medicine, wrote an editorial that appeared in the Journal of the American Medical Association, describing the use of medical services and health expenditures for the management of chronic disease and that it now constitutes 78 percent of all healthcare expenditures. Chronic disease also dramatically transforms the role of the patient. As Dr. Holman points out: “The differences between acute and chronic disease are substantial. Acute disease is episodic. The patient is usually inexperienced and passive while the physician administers treatment.” Therefore, the patient is passive and the practitioner is active. The patient becomes almost a victim. The practitioner is the person who fixes” it. That is the traditional model. “There is commonly a cure and the patient returns to normal. None of this is true for chronic disease. Chronic disease is continuous. There is rarely a cure. The patient usually lives indefinitely with the disease and its symptoms, with persistent treatment and with multiple consequences, including necessary behavioral changes to forestall worsening of the disease, social and economic dislocation, emotional turmoil, financial fear, lowered self-esteem, and depression.” Often, patients present to a primary care provider who is focused on complete coverage of health problems and who deals with fibromyalgia, chronic fatigue syndrome (CFS), chronic arthritis, headaches, malaise, and chronic gastrointestinal disturbances such as chronic irritable bowel syndrome (IBS). The complaints are common-fatigue and low-grade pain. “As a result, the patient becomes experienced, is often more knowledgeable than the physician about the effects of the disease and its treatment, and has an integral role in the treatment process.” Chronic disease requires a practice of medicine quite different from that used for acute disease. “With chronic disease, the nature of care changes.” 3 As Dr. Holman points out, the problem is that we are not educating practitioners about how to manage chronic disease. Graduates from the most esteemed medical institutions are extraordinarily adept at diagnosing and treating acute disease, but their skills in managing chronic disease are primitive. Yet, patients with chronic disease constitute 78 percent of healthcare expenditures. This is called “dissonance”; there is a mismatch between the need and the reality. With the future of primary care medicine in mind, there is a wonderful editorial written by Drs. Michael Whitcomb and Jordan Cohen in The New England Journal of Medicine. Some of you may have heard of Dr. Whitcomb. He is a very strong advocate for changing medical school education. He is affiliated with the Association of Medical Colleges in Washington, DC. In this editorial on the future of primary care, Drs. Whitcomb and Cohen state: “During the early and mid-1990s, a consensus emerged among physicians and healthcare policy makers that the United States would have a substantial surplus of physicians by the end of the decade. Most people who held this view also believed that the surplus would be limited to non-primary care physicians and that, by contrast, the supply of physicians planning to practice primary care medicine would be barely adequate. “Now, only a few years later, studies are beginning to suggest that the country may soon be facing an overall shortage of physicians, and market signals suggest that, in some regions, shortages may already exist in some specialties. 4“ The recent trend may be a harbinger of a real crisis in primary care medicine-one even more severe than the one predicted in the early 1990s. “Moreover, during the time they spend in out-patient care settings, few students (or residents) have the opportunity to observe the provision of optimal care for patients with chronic disease. Few outpatient teaching sites have established contemporary models of chronic-disease management, in which teams of heath care professionals are guided by the principles of patient-centered care and are supported by the information-technology systems needed to provide high-quality ambulatory care.” However, few students have access to these learning systems and become adept and skilled in their implementation, meaning that we are not only seeing a potential shortage of physicians, but even a greater shortage of doctors in primary care who are trained to manage the epidemic of chronic disease. There is a good diagram in the Whitcomb/Cohen article, titled “Match Results According to Primary Care Specialty, 1989 through 2003.” Since 1989, there has been a dramatic decline in the number of primary care family practice physicians being trained. We are seeing an increasing need that is not offset by an increasing array of trained professionals. The objectives to rectangularize the survival curve and compress morbidity into the last few moments of life may be unrealistic, based upon the healthcare services we now have. They were built to support the edifice of crisis care at the expense of not having a good chronic care management system. As Drs. Whitcomb and Cohen point out: “However, as others have noted, neither family practice nor internal medicine-the two specialties that provide most of the care for adults with chronic diseases-has yet redesigned its residency programs to encompass the knowledge, skills, and attitudes residents must have to care for such patients. Unless these changes are made-and made soon-the practice of primary care medicine seems destined to become the province of nurses and other nonphysician health care professionals.” Whitcomb and Cohen stress the necessity for a chronic disease management system that would be patient-centered and focused on new information technology systems. I would like to add that this is what functional medicine has been talking about for nearly 20 years. This is the focus of what we have been trying to teach, and what our learning systems are all about-the connection of information systems to patient-centered care. This is supported by a multitude of papers, two of which I would like to cite, that are indicative of this relationship. The first is titled, “Mediterranean Diet, Lifestyle Factors, and 10-Year Mortality in Elderly European Men and Women.”6 This is the HALE Project (Healthy Ageing: a Longitudinal study in Europe), a very interesting, long-term study. It is comprised of individuals enrolled in the Survey in Europe on Nutrition and the Elderly: a Concerned Action (SENECA) and the Finland, Italy, the Netherlands, Elderly (FINE) studies. It included 1507 apparently healthy men and 832 women, aged 70 to 90 years in 11 European countries. This cohort study was conducted between 1988 and 2000. After looking at hazard ratios of various lifestyle and diet considerations, the authors concluded that, among individuals aged 70 to 90 years, adherence to a Mediterranean diet and healthful lifestyle was associated with a more than 50 percent lower rate of all-cause and cause-specific mortality. If we could prescribe a drug that would lower mortality of all causes by 50 percent, wouldn’t that be a blockbuster? We are talking about the use of a Mediterranean Diet and regular physical activity A companion paper is titled “Effect of a Mediterranean-Style Diet on Endothelial Dysfunction and Markers of Vascular Inflammation in the Metabolic Syndrome.”7 This also appeared in the Journal of the American Medical Association and discusses work done in the Department of Geriatrics and Metabolic Diseases in Italy. The investigators assessed the effect of a Mediterranean-style diet on endothelial function and vascular inflammatory markers in patients with metabolic syndrome. After two years, patients following the Mediterranean-style diet consumed more foods rich in monounsaturated fat, polyunsaturated fat, and fiber and had a lower ratio of omega-6 to omega-3 fatty acids. Total fruit, vegetable, and nuts intake, whole grain intake, and olive oil consumption were also significantly higher in the intervention group. The levels of physical activity increased in both groups by approximately 60 percent, mainly by walking for a minimum of 30 minutes per day. It was concluded that a Mediterranean-style diet is effective in reducing the prevalence of metabolic syndrome and its associated cardiovascular risk. Reductions in high-sensitivity C-reaction protein (hs-CRP), interleukin-6 (IL-6), interleukin-7 (IL-7), and interleukin-18 (IL-18), markers for immunological functional changes, were also realized-hs-CRP levels, P=.01 and IL-6, P=.4. We are talking about remarkable changes in inflammatory patterns and improved insulin sensitivity with the implementation of a diet and lifestyle program When we refer to the Mediterranean Diet, we are not necessarily talking about a diet that is very high in protein and low in carbohydrate. In fact, this diet is reasonably high in carbohydrate. However, the carbohydrate is highly unrefined, fiber-rich, and plant-phytonutrient rich, which has a different physiological effect on function than does carbohydrate containing white starch or sugar. You have heard me say in numerous issues of FMU that we have misplaced our concern about carbohydrate as a villain or culprit for the cause of metabolic syndrome, diabetes, and heart disease, and that it is the type of carbohydrate that is important. We should be concerned about all the agents necessary for appropriate metabolism and physiochemical control, including gastric emptying and moderate release of glucose. We should therefore be speaking more about glycemic load and glycemic response for all foods, rather than simply talking about percentages of protein, fat, or carbohydrate. The need to construct a healthy diet often gets confused by popularized diet books and an icon’s name, rather than referring to the fundamental things we have learned about the physiology and physiochemistry of the dietary components. What is the glycemic response and the insulin response in healthy subjects after consuming various types of high-fiber, carbohydrate-rich meals? Are there some individuals, such as a subset of type 2 diabetics, who are more carbohydrate-sensitive? These questions have been asked in many studies. I want to cite one recent example that appeared in the American Journal of Clinical Nutrition, titled “Glycemic index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and middle-aged women.”8 This is one of many papers with the same theme-a diet high in rapidly-absorbed carbohydrates and low in cereal fiber is associated with increased risk of type 2 diabetes. That is not true in the case of a high, slow-release carbohydrate in cereal fiber. It may promote a reduction in the relative risk of type 2 diabetes, metabolic syndrome, and insulin resistance. Glycemia, Insulinemia and Food Proteins What about the argument that eating more protein leads to less carbohydrate intolerance? Many papers have dealt with that topic. One of them is titled “Glycemia and insulinemia in healthy subjects after lactose-equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins.”9 The authors of this paper point out that it can be concluded that food proteins differ in their capacity to stimulate insulin release, possibly by differential abilities to affect the early release of a messenger molecule called incretin. Incretin hormones and insulinotropic amino acids may stimulate higher insulin output, insulin resistance, and glycemia. From reading this paper, it is evident that differing food proteins may have remarkably different effects on postprandial insulin and glucose levels. In this report, milk powder and whey showed an insulinemic effect. We need to keep in mind that the big categories-carbohydrate, fat, and protein-do not really tell us everything we need to know clinically about how individual foods affect particular glucose and insulin responses. Whole Grain Intake and Insulin Sensitivity Whole grain intake is more than just carbohydrate. Grains contain a rich array of soluble and insoluble fiber, as well as hundreds of different phytochemicals. All of these have influence on insulin and glucose control through their effects on absorption, liver enzyme activities related to gluconeogenesis, glycogen synthesis, adipocyte physiology, centrally mediated appetite, and peripheral cells such as muscle cells. It is a much more complex story than just giving glucose from starch. We are talking about all the signaling events that occur through complex, unrefined, or partially unrefined food that is also high in complex carbohydrate. I am summarizing from a review paper that appeared in Nutrition Reviews.10 Are high-protein and low-carbohydrate diets the answer to the question? We need to ask, what type of protein is included? What type of carbohydrate has been removed? What is the overall diet composition in individual food responses? What I have just said has been discussed in an interesting paper in the Lancet, titled “Atkins and other low-carbohydrate diets: hoax or an effective tool for weight loss?”11 The authors state: “The apparent paradox that ad-libitum intake of high-fat foods produces weight loss might be due to severe restriction of carbohydrate depleting glycogen stores, leading to excretion of bound water, the ketogenic nature of the diet being appetite suppressing, the high protein-content being highly satiating and reducing spontaneous food intake, or limited food choices leading to decreased energy intake. Long-term studies are needed to measure changes in nutritional status and body composition during the low-carbohydrate diet, and to assess fasting and postprandial cardiovascular risk factors and adverse effects.” To compress morbidity, rectangularize the survival curve, and develop an effective chronic disease prevention and management program, diet must be used in a more prudent way than simply jumping on the bandwagon of fads that are commonly making someone financially successful, but that may not be in the best interest of the individual patient. As we move to a higher complex carbohydrate, minimally processed type of diet regime, what about the relative effect that the allergenic component of grains might have-things like gluten and reactive proteins? There are certain grain-related products that are low in or devoid of gluten. One grain that has been discussed for some time is oats. There was an interesting article recently published in The New England Journal of Medicine, titled “Gluten Contamination of Commercial Oat Products in the United States.”12 The author states that there is quite a bit of published literature suggesting that people with celiac disease or gluten sensitivity can consume moderate amounts of uncontaminated oats because they are low to devoid in gluten. However, some recent studies have looked at various types of commercially available oats to examine the extent of their gluten content. It has been found that there is a high variability from batch to batch, suggesting gluten contamination of some of the oat products, perhaps not native to the oats, but as a consequence of contamination due to being processed in the same plant where wheat had been processed. People are being urged to recognize that contamination of commercial oats in the United States with wheat, barley, and rye, is a legitimate concern for people with severe gluten sensitivity. Therefore, people should not conclude that these grains are gluten-free. They would probably be low in gluten relative to wheat, but there may be some contamination. I wanted to share that insight because people have been known to experience a reaction to oats and think it is due to gluten content, but it may be that the oats were contaminated with the gluten-containing grains. In this culture, at a time when we are moving into epidemics and pandemics of things like metabolic syndrome, type 2 diabetes, obesity, CAD, and hypertension, we are witnessing a physiological function change to a different homeodynamic state. The term “homeostasis” is often thought of as meaning that a person is stable around a certain healthy condition, but someone can be homeostatic with diabetes or hyperlipidemia. The question is, how does one modify the environment in such a way as to create a different gene expression pattern so that homeostasis is concentric, overlaps good health, and achieves the objective of rectangularizing the survival curve. When the wrong information is delivered to the genes in the form of a bad diet not matched to a person’s needs, a poor lifestyle, or toxic exposure, those genes respond in a state of alarm and create an environment in the body-the so-called phenotype, the phenomics of the individual-that is shifted toward being unwary, ill at ease, uncomfortable, and prepared to do battle. This is called immunological activation, or immunological imbalance. It is part of the new clinical problems we are seeing in the 21st century, and they can be influenced by many variables-not only diet, but stress, toxins in the environment, endotoxins in the gut, chronic infection, and mechanical trauma, such as over-training in athletes. There are myriad things that can shift the balance in the immunological system, creating in various tissues the message of not feeling at home and being safe because of inflammation. We will be speaking to that topic at great length at the 12th International Symposium on Functional Medicine-how to recognize imbalances in the thymus-dependent 1 (Th1) and thymus-dependent 2 (Th2) immunologically-based system, and what can be done clinically to restore proper balance between the innate immune system and the acquired immune system. As phenomics are shifted to an inflammatory state, all sorts of other parameters change. The cellular physiology at organ-specific levels starts to change. Body mass is accreted, generally as central body fat, so the body mass index (BMI) increases. It becomes like a dog chasing its tail. Increased visceral adipose tissue and the hypertrophic adipocyte, the fat cell, begin to produce their own inflammatory mediators that trigger more inflammation. This becomes like a round robin, a spiraling upward. As discussed in a recent series of papers, as abdominal fat is increased, insulin sensitivity goes down, inflammation goes up, and the relative risk of heart disease, dementia, and cognitive decline all increase. I am quoting from an article in the Journal of the American Medical Association which looks at the effect of various hormone modulators on abdominal fat and insulin action in elderly women and men.13 When the balance of inflammatory mediators is shifted through altered gene expression patterns, the central set points of our physiology are being influenced, the so-called homeodynamic set points, which have to do with the neuroendocrine-immune system-the interrelationship among the nervous system, the endocrine system, and the immunological system. They are all one super system, all interrelated, one to the other, by receptor physiology and signaling mechanisms and the passing around of information molecules that alter their function. The endocrine system is changed; the immune system is changed; and the nervous system is changed, as a consequence of the shift toward inflammation. That is why the metabolic syndrome is associated not only with inflammation, but with the risk of cognitive decline, as was pointed out in an article in JAMA, which found support for the hypothesis that metabolic syndrome contributes to cognitive impairment.14 The mechanism could probably be postulated as being related to activation of certain types of microglial function in the brain associated with apoptotic cellular injury of neurons, leading to loss of neuronal reserve and ultimate cognitive decline in certain regions of the brain associated with memory and cognition-the executive centers of the brain, so to speak. We are beginning to see a unified concept emerging as to how these variables are shifted in the environment and how they influence a wide range of diseases. For convenience, we put them into a differential diagnosis and ship them off to specialty medicine as if they were not connected. They are all part of the lack of an effective chronic disease management system that encourages looking at early warning signs that deal with these dysfunctions before they become acute. Truncal fat, or central adipose tissue, contributes to inflammation and relates to many different diseases-stroke risk, heart disease risk, neurological risk, and even renal disease risk. There is a strong correlation between truncal fat mass inflammation and end-stage renal disease. One paper you may want to look at was published in the American Journal of Clinical Nutrition, titled “Truncal fat mass as a contributor to inflammation in end-stage renal disease.”15 The authors found that there is a strong relationship between inflammatory biomarkers such as IL-6 and hs-CRP and regional fat distribution in patients with end-stage renal disease. This chronic inflammatory response is an important contributor to the atherogenic lipoprotein profile seen in uremia and the relative risk to heart disease and continuation of renal failure. The fat cell plays an important role in the whole system. The adipocyte, which used to be thought of as only a storage tissue for extra calories in the form of triglycerides, is now seen as a signaling part of the endocrine system. It is a central player in neuroendocrine-immune imbalance. Obesity researchers have now inched closer to their long-sought goal of understanding how a fat cell burns up calories without causing obesity and how it signals inflammation and messages of alarm at distant sites.16 Endocrine regulation of energy metabolism relates to the milieu of various molecules floating around in the system that express alarm. For instance, things like leptin, resistin, hs-CRP, IL-6, or adiponectin, an interesting molecule in the news that is produced by the adipocyte cell. Adiponectin tends to balance against the properties of resistin. Whereas resistin stimulates insulin resistance, adiponectin, produced by the white cells and fat cells, causes insulin sensitivity and is an antiinflammatory. This information was reviewed in an interesting paper in Clinical Chemistry.17 Therefore, one could hypothesize that individuals who change from a traditional American diet to a Mediterranean Diet are likely to have higher adiponectin levels, indicative of improved insulin signaling and reduced inflammation signaling. Certain people have specific single nucleotide polymorphisms (SNPs) and are more susceptible to oxidative types of reactions and lipoprotein abnormalities associated with the inflammatory profile. For instance, an individual with the 219G®T polymorphism in apoE appears to be more sensitive to saturated fat in the diet, which increases his or her susceptibility to inflammation in response to a diet rich in saturated fat, and increases the relative risk to coronary atherosclerosis, metabolic syndrome, and type 2 diabetes. There are “yellow canaries” that carry higher susceptibilities in their genes to certain types of environmental changes. They are the early-warning individuals in society with increasing prevalence of certain diseases associated with environmental changes. This topic is discussed in an article in the American Journal of Clinical Nutrition.18 What about the use of various types of essential fatty acids of the omega-3 family-for example, a-linolenic acid from flax, or EPA or DHA from fish-to support different gene responses? The literature is replete with good studies indicating the positive role that omega-3 balanced diets or omega-3 supplemented diets have on reestablishing proper balance in the neuroendocrineimmune system and the inflammation profile. For instance, there is a paper in the Journal of Nutrition that discusses an a-linolenic acid-rich diet that reduces inflammatory and lipid cardiovascular risk factors in hypercholesterolemic men and women.19Fish oil (DHA and EPA)also has a positive role in reducing cardiovascular risk and lowering inflammatory potential in women. When there is inflammation, it does not stop with a single disease such as CVD. It cuts across a whole range of age-related chronic diseases. We have established a good background for the discussion with our Clinician of the Month. How do we take all this research and apply it effectively in patient management in the new type of primary care?

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INTERVIEW TRANSCRIPT

Michael Wald, DC, CCN, DACBN Advanced Medicine of Mt Kisco 213 Main Street Mount Kisco, NY 10549 JB: It’s time for our Clinician of the Month. This month, we are going to speak with Dr. Michael Wald, a chiropractor who also has a Master’s Degree in Nutrition. For more than ten years, he has used his education to create an outcome situation in his clinic that has evolved into a striking model for the definition of a successful functional medicine practitioner. At Advanced Medicine of Mount Kisco, New York, Dr. Wald has delivered the quality of care that functional medicine has to offer to literally thousands of patients. I have known him for more than ten years, and it is a privilege to have him with us as a spokesperson for the clinical application of functional medicine. Welcome to FMU, Michael. I’ve seen your practice grow tremendously over the last ten years. To what do you attribute its success? Growth and Vision MW: First of all, thank you for having me on FMU, Jeff. I hope to contribute something to that very important question. My success, in terms of the growth of my practice, is pretty consistent with my growth and vision. When I first began practicing chiropractic and integrating nutrition, I had a certain base of knowledge and a certain way of framing it intellectually. That translated into how I recommend things for patients. Over the years, being exposed to new information and problematic patients or difficult cases forces one who is up to the challenge to ask where the answers might be for this or that patient. From that exploration, I realized that there is no one area of medicine or natural medicine that can provide all the answers. In the process of grappling with question4 and thinking about my contributions to people, to my life, and to the world, I took certain practical steps on a daily basis to create a visible space in my Advanced Medicine of Mount Kisco practice that would provide structure, and where people could go for real approaches that represented an expression of my expanded view of things. Not a place that pretended to have all the answers, but one that was committed to finding or creating answers for people, either by ourselves or with the help of other colleagues. Essentially, my success has to do with my commitment to not staying the same. Simply put, I continue to be willing to change and to think about not only new information, but also the information I thought I had some understanding of at one level, but which transforms over time into something new, and how to practically apply it. That lends itself to the growth of a practice because people get better. They are able to speak about it to other people in their lives, which grows a practice and stimulates me to move forward. JB: As I hear you speak, there are three things that come to mind that would characterize my impression of your personality and how you have employed information in your practice. First, you are a seeker. I’ve always noted that in you. You appear to be a person with an insatiable thirst for learning and creating new opportunities to do better. Second, you are very strong in your advocacy to continue to advance and grow, expand, and be better in managing the complex health problems your patients present with. Third, there is a level of fearlessness on your part to actually take things you’ve learned and put them into practice. The third step is probably where a lot of people get hung up. There’s a barrier that prevents them from moving from what they know to what they do. Through your advocacy into your fearlessness, how do you reach the point of delivering those new things successfully in your practice? Successful Delivery of New Concepts into Practice MW: Fearlessness is an interesting way to describe it, but I think that’s very accurate. Think about this for a moment. It’s whether practitioners are secure in the commitment to do whatever it takes to help live lives they can love, because that’s what it comes down to. People don’t get excited about taking lots of vitamin pills or altering their diet and lifestyle, but they might get excited if they know it’s part of a plan to help them increase and maintain a higher quality of life. I remind myself every morning before I come to my office that I am here to make a contribution to people, and the best way of demonstrating that is through my sincere enthusiasm. That can’t be faked. People pick that up, and that’s where the so-called fearlessness comes from. I am so committed to people just having fun, and sometimes health is necessary for that. People recognize that commitment and I will not stop in the face of anything. Let’s talk about a patient who just doesn’t get it. He/she just doesn’t understand the natural functional model, but for some reason, the family has dragged him/her into my office. If I wasn’t fearless, I would just sit back and listen to them converse about what I call limitatio5s. I could do that. I don’t have to care about what they choose to do or not to do, but I prefer to acknowledge that the patient has a certain way of thinking about things and I try to introduce a different framework. I might not do that if I wasn’t fearless and committed to recognizing a patient’s limited thinking about the information and trying to help reframe it. That’s far better than being fearful and not acknowledging that there is some difficulty in the mind of the patient. If I don’t help manage that, patients won’t stay around and wouldn’t comply well even if they did. In short, the fearlessness comes from an enthusiasm and a deep commitment to help manage the patients’ emotional limitations. JB: That’s beautifully stated and is one of the major pillars of functional medicine-patient centeredness-which is what you are speaking to. As the patients’ advocate, you help them to recognize that there are options, they don’t have to be mired down in whatever chronic conditions have reduced their quality of life; there are options to explore, to work on, and to practice. That leads to my second question. We both recognize that,presently, the biggest challenges in the healthcare system are in the area of chronic disease. There are many skills that you have in your tool kit related to the successful management of complex, chronic diseases. If you were talking to your colleagues and they asked you what skills they should develop, what things would you tell them have been very valuable in putting together a chronic disease management strategy? Components of A Chronic Disease Management Strategy MW: That’s quite a loaded question and I’ll attempt to narrow down my response. Through conversations I’ve had with literally hundreds of practitioners, doing professional workshops, and through emails and phone calls with practitioners of many different types who have visited my office over the years, the main limitation is not being well-grounded in a commitment on the part of practitioners to share their enthusiasm. It has to start there. We have many wonderful tools, procedures, lab tests, and other approaches from a natural perspective, but if practitioners don’t consider how to intelligently manage these things for each individual patient, I think it becomes quite disjointed. I commonly see patients who have been to very competent practitioners who are knowledgeable, but from what I can tell, after asking the patients what has and has not worked, the patients say they didn’t understand the relationships, the testing, or why these things were being done. One of the most basic concepts I’ve narrowed down about what it takes for practitioners to be fundamentally successful, is that they need to present everything in their armamentarium, but they also need to acknowledge what the patient needs to hear so they can attempt to do these things. JB: You just said something very profound that I want to make sure gets the proper shrift from our listeners. The way I interpreted what you said, and it’s an “aha” for me, is that you set up a context of healing in your practice, rather than focus on procedures and techniques, the tools that people often get very caught up in. You try to put together the tools that can be applied to a system of healing, but the first priority is setting it up by recognizing that it exists, and that the patient has ownership. That’s what I heard you say, versus getting caught up in the procedures, the tools, and whether one uses A or B. Is that correct? A System of Healing and The Importance of Good Communication MW: That’s absolutely correct. From a practical perspective, it might look as simple as this. Let’s say a patient presents with a history of multiple sclerosis (MS). One of the tests we might perform is a homocysteine test, which is well known for its relationship to cardiovascular disease. Sometimes, a practitioner might overemphasize that. In other words, we can do a sophisticated test, but we need to relate it to why the person is there, and we need to further relate it to how, if we correct it, it might affect the patient’s quality of life. In summary, we always want to bring back everything we’re doing to the condition for which the patient is there. That means we need to have a conversation with the patient about what his/her goals and expectations are, and give them what they need, as opposed to what we think they need. We can ask and the patient will talk and let us know. This is where we get to practice our listening skills. Then, when we make recommendations, we create a value. This goes back to the success that you mentioned earlier and what goes into success in clinical practice. We’re not just talking about financial success, but clinical success. It comes by always making sure the patients get the value of the service relative to their needs. Who would want to have extensive testing without understanding the value relative to their concerns? If we have an opportunity to frame the testing relative to their needs, value is created. There’s also greater compliance. We have very good compliance with the majority of our patients, which we know is necessary. We have to pay attention to always fulfilling their emotional needs at any point. Are they connecting the technology, the evaluations, and the testing that we might do and our recommendations for what’s important for them? JB: That’s a good summary of your philosophical approach and how your patients see themselves within your practice. You are serving in a special king of primary care model. When I say special, I mean you are using techniques that are probably not standard for simply diagnosing disease and providing a pill-type strategy. How do you see the future of primary care changing, given the complex problems of the patients, and knowing some of the limitations present in our system are related to the way primary care is being practiced? What is your view of the future of primary care? The Future of Primary Care MW: My view of the future is something that I am, at least in part, experiencing now in my real life and my real practice. We talk about the future, but it’s really what’s happening now in our lives. The doctor or practitioner of the future will maintain an open-mindedness, first of all, and will be constantly on guard against getting in the way of the patients’ healing process. For example, I might be asked by a patient what I think about a therapy. I might have an emotional reaction that might be initially negative, but I’ve trained myself to get out of my own way, if I don’t have a clue. Even if I do have an opinion, it’s only my opinion, and this is what I need to relate to the patient. Practitioners can get in their own way. The future of primary healthcare and my vision of it, is one that removes the practitioner from the total decision-making process and proactively involves the patient in his or her health care, recognizing that no area of health care has all the answers. It was a big “aha” for me one day several years ago when I was treating many difficult patients and feeling a bit discouraged. It occurred to me that there may be answers for these people somewhere else and that I didn’t have to do it all myself. That simple observation took a couple of years for me to digest-that primary care necessitates recognizing the limitations and scope of our practices, and developing an array of other support sources that might fit the growing and ever-changing needs of patients over time. When I get a phone call from a patient who asks if I can help with a problem, I may not be familiar with that problem. If not, I do a search on my computer and I may find there’s a doctor in another country who might have something to provide, or perhaps a doctor in the next town from mine. I refer that patient out and they get help. I put the needs of the patient first, knowing my tools might be limited. That is the fundamental vision I have of the practitioner of the future. It involves a certain amount of guidance for the patient and providing other options for them. Those options may not provide all the answers, but it’s part of a process, and we encourage our patients for feedback. This is done in a functional medicine practice. Patients are extremely bright and very practical. They come in with loads of research they’ve read. To acknowledge that wealth of information and proactivism is such a gift. It’s something that is not routine in regular medical practice, but it is included as a necessary part of my vision of the primary healthcare provider of the present and the future. JB: That’s very insightful. If I can recap, you’re talking about a multidisciplinary team that would be formed to help meet the needs of that particular patient. The patient is part of his or her own team and looking at a system of healing in the context of a systems approach. This is what we try to get across in the Applying Functional Medicine in Clinical Practice training program-looking at things from a systems approach and recognizing that everything is connected to everything else through a web. It sounds like that’s part of the model you are communicating to your patients when they come in to your practice. The Process of Referral MW: Absolutely. And what deserves some emphasis is not merely having other resources and practitioners that you can refer patients to, but being able to coordinate that care into a functional medicine concept. Often, patients will tell me that they looked at all the wonderful information I gave them and that it made great sense, but when they presented it to their primary healthcare provider, endocrinologist, or gastroenterologist, they completely dismissed it. We have to have a conversation with a patient before a referral is made, explaining the process. We need to ask them please not to expect that all doctors will agree with everything we’ve discussed. We are referring them because other practitioners offer something I believe they need. If the other practitioner does agree or has some knowledge in the area, that’s great, but we don’t expect it. With that simple conversation, patients will come back and tell me that their doctors reacted exactly as I said they would. Either the practitioner didn’t think much of the information or, on the other hand, they might say it’s pretty remarkable and that they have some knowledge in this area. But at least you’ve forewarned the patient so that no further rift is created. Many of the patients don’t understand why a seemingly intelligent practitioner doesn’t “get it.” I try to explain that each physician has a specialty and that they think in terms of a disease paradigm. They are very good at managing disease. I explain that we are talking about prevention, predicting, and also managing what might be considered the dis-ease with an emphasis on the dysfunctional aspect of things. Once they understand that, comments other practitioners may make are heard very differently by the patient. Does it undermine what we are trying to do? No, it doesn’t undermine the expertise of the standard practitioner or the allopathic practitioners we refer to. In that way, we’re not right; they’re not wrong; and we can frame everything for people so they can get what they need without my getting in their way. JB: That’s a beautiful model and it relieves the patient from being in the middle of a conflict between two health practitioners. That’s also part of healing-reducing stress. Let me move to some short questions to get some specifics out of your philosophy. You undoubtedly have patients who are talking about longevity, quality of life, or what we might call healthy aging. How do you deliver information related to the aspiration of healthy aging? The Concept of Healthy Aging MW: Healthy aging is a concept that most people can wrap their heads around because they equate it to their quality of life. We distinguish for them that it’s not necessarily living long-that may or may not happen-but it’s living longer during the non-disability stage of life, living longer during active periods of life. I constantly bring people back to the limitations in their lives, physically, mentally, emotionally and socially. As we discuss the different findings and make recommendations, we always bring it back to how it would enhance how they live. For example, if a patient has difficulty just carrying her three-year-old child, taking her supplements or eating in a particular way might help her gain greater strength and energy so she can do that. That has more of an impact and is ultimately what we’re trying to do. JB: With that in mind, you mentioned diet, and I know that this is a commonly-shared human experience. We all have different eating patterns. Is there a specific diet that you employ for your patients? How do you approach the diet question? The Question of Diet MW: Regarding the diet, there are certainly some basic concepts. For example, consuming four to six servings of fruits and vegetables each day, drinking four to six glasses of clean water per day, not smoking, minimizing alcohol intake, exercising each day, eating organic food when convenient, not overcooking food, and proper preparation of foods. These are fundamental concepts that we review with every single patient. It’s important to emphasize that we don’t take a specific dietary approach to each person. We rely on the results of laboratory tests. Probably more important than that, we rely on what the patient’s concerns are, what their health goals are, and what type of dietary intake might be most appropriate for what period of time? Perhaps it’s a short-term effect we’re looking for. After that, we move into more long-term dietary approaches. Based on a combination of different factors that gives us information to recommend this or that food. For example, if the person has MS, we would want to consider a Swank-type of dietary plan, but we would want to emphasize more than the traditional Swank approach-higher intake of omega 3 fatty acids, for example. Perhaps we would test that patient for gluten sensitivity. We might want to recommend increased intake of omega 3s, perhaps less from fish that is contaminated with mercury, as an example, so that we finally come up with something that is truly most reflective of their needs. JB: Obesity, type 2 diabetes, and metabolic syndrome, all of which have been called lifestyle diseases, are growing by epidemic proportions. You must see a lot of these types of patients in your practice. Often, they present with many complications. How do you approach them, given the kind of personalized approach that you’re using, and are there specific accessory nutrients you find useful? Approach to Obesity, Type 2 Diabetes, and Metabolic Syndrome MW: There certainly are. In terms of what nutrients, that would be somewhat based on clinical knowledge, but also on what the patient may have attempted on his or her own. In fact, just this morning, I sat with many patients who are taking what looked like the textbook-perfect nutrients for their hypertension, diabetes, or cerebrovascular disease, and it didn’t seem to result in making much difference. We use healthy aging biomarkers. We will do a series of evaluations that might include bioimpedance testing, bone density testing, arterial stiffness markers, along with tests for cholesterol and muscle strength. In terms of some of those chronic conditions you mentioned, most people who are listening to this audio tape know that with a diabetic, we want to think about magnesium. Magnesium is one of the more common mineral deficiencies in diabetics. We might give them magnesium. What if that patient has a loose stool, as well? We might not be able to manage them with the appropriate dose of magnesium for beneficial effects, so we might want to give them a form of magnesium that doesn’t affect the bowel, called magnesium glycinate. We might also want to match that magnesium need relative to red blood cell magnesium value, which is certainly more accurate than a serum or plasma magnesium value. If we give chromium, for example, we want to make sure the person has a favorable glycemic response to that particular supplement. I’m not necessarily saying that we’re going to be testing each of these parameters with every individual. We never just prescribe a single element for a particular patient. But we do want to see real-world changes. That means we have to involve the patient in measuring blood sugar. We want to look at their glycated albumin, for example, or their glycosylated hemoglobin. We want to look at their red blood cell magnesium over a period of time, and given reasonable compliance, we continually tailor their nutritional needs. JB: I would like to ask one last question. There are certain things you have probably observed as being very fundamentally important tools. That goes back to a question I asked earlier. If a doctor was to ask you where he or she should start, what would be the first two or three things that you, Dr. Wald, from your years of experience, might suggest to work on in developing competency? Developing Competency MW: My first suggestion would have to be to develop the proper communication skills. I was one of those practitioners that had so much to say, but it was not being synthesized in the minds of my patients. One needs to be able to quickly assess how patients hear things. So, first would be to work on communication skills. There are many wonderful books, tapes, and organizations that offer material to help practitioners acquire and practice those skills. I need to underscore that, because all the tools we have will be limited if we don’t have the communications skills to match them. Second, as I gather information over the years, I immediately implement into my daily practice any concept if I feel is worthwhile. For example, when I became familiar with bioimpedance testing, I immediately implemented it with virtually every patient. When I learned about the prevalence, let’s say, of increased homocysteine levels in the population, that became a routine test for my patients. It might be true of any number of other factors. By immediately integrating new concepts, the learning curve is tremendous. Practitioners are limited in the sense that there is so much to learn. Well, one learns by doing. Immediately implement new concepts into your practices and you will learn at an extremely rapid and practical pace. You retain that information and then it starts to grow. JB: You have given us some extraordinary insight into some of your tools. I want to recap a quick summary of my takeaway from the experience you shared with us. First of all, be a seeker; be out there as an advocate for your patients. Develop the communication skills to leverage what you’ve learned effectively by meeting the patients where they want to be met, and finding out how to match your communication with their listening. Be proactive about implementation. The best way of getting things to work is to practice by doing them rather than just by thinking about them. Get past the barrier of resistance to actually implement things, and start to develop more confidence with them as you gain experience. Be very willing to work within a team setting without pointing fingers and placing blame, and try to put the patient at the center of his or her own system, and to match their needs with available resources. That sets you up as the central practitioner, or kind of gate-keeper, or liaison or the integrator of their system, which is probably what they have been missing-someone to assist them through the morass of sometimes complex and confusing information. Be there for the patients to provide that kind of support and communication. This becomes the cornerstone of what I would say characterizes a very effective functional medicine practice. In addition to that, of course, are all the individual skills related to procedures and techniques, but the system of healing that you described seems to be the character that differentiates your successful functional medicine practice. MW: Thank you, Jeff. JB: We want to thank you, Dr. Wald. This has been exactly what I’d hoped we’d be able to share-going from esoterism to the reality of the daily world, which is where these things really work and make a difference in the lives of patients. You have our great admiration and respect for what you’re doing, and thanks for sharing it. MW: Thank you. Above all, have fun doing it. Once again, I want to thank Dr. Wald for the eloquent discussion on his philosophy and how he is implementing functional medicine in his role as a primary care practitioner. Rheumatoid Arthritis Increases Risk of Coronary Heart Disease (CHD) I want to pick up from the previous discussion on Side 1, that being the connection between inflammatory conditions and many diseases, not just heart disease or arthritis. One might ask if a person has an inflammation, does that set up risk to other diseases? Does a person with arthritis have increased risk to heart disease? A person with increased inflammation associated with arthritis might have increased risk to cancer because of its inflammatory component. The literature is now supporting the connection of diseases on the basis of shared mechanisms. For instance, a recent paper discussed rheumatoid arthritis increasing the risk of CHD as a consequence of inflammation and injury to the vascular endothelium.20 As the inflammation potential is increased by increased hs-CRP levels, the relative increase of risk to many diseases, not just heart disease, is statistically present. That might also indicate why certain medications or treatment programs that lower inflammation will also lower the risk to so many diseases, as Dr. Simon Lu and his colleagues from Harvard talked about in the paper I described earlier. Statins and Rheumatoid Arthritis For instance, it has recently been observed from a number of studies that statins used to lower lipids also lower inflammatory mediators. Not only do they lower the risk to CHD, but they also tend to lower the incidence and severity of rheumatoid arthritis. Statins serve as antiinflammatory agents as one of the pleiotrophic modes of action. I am now referring to an interesting series of Letters to the Editor in the Lancet that discusses the role and relationship between statins as disease-modifying agents in reducing the progression of arthritis.21 These are stories that go beyond a single disease. They go to mechanisms, and that is what the functional medicine curriculum has been trying to teach over the years-to better understand shared mechanisms so we are less focused on individual diseases, as if they were independent of all other diseases-and talk more about underlying mechanisms that create dysfunction in older age and are interrelated with gene susceptibilities. Measuring CRP for Risk Prediction Before Percutaneous Coronary Intervention Measuring hs-CRP may provide a helpful biomarker, not only for assessing relative risk to heart disease, but for many other variables associated with chronic disease. There are a couple of interesting editorials that appeared recently on the use of C-reative protein (CRP)for predicting the relative risk of adverse outcome in pre-surgical patients. These editorials appeared in Clinical Chemistry.22 ,23 One paper was written from a U.S. perspective; the other from a European perspective, and indicated that patients with elevated pre-surgical levels of CRP had a much poorer prognosis when they had percutaneous coronary intervention than those with low CRP levels. The suggestion is, lower the inflammation potential before going through a procedure that would increase the relative inflammation and might, in itself, precipitate other adverse events. The inflammation story is also associated with alteration in the reduction/oxidation potential of the cell. What does that mean? When certain types of antioxidants are used, they may also have antiinflammatory effects. How does that work? It is a complicated cell signaling story and beyond the scope of this issue of FMU, but let us say that it is something like a storage battery. If your car can only start when the battery voltage is above 12, and if the voltage drops to 11.5, the car does not have the proper cranking power and the engine will not start. Even though there is battery power, it is not enough to trigger the starting mechanism. The same holds true for redox potential. As there is a reduction in the intracellular battery power, the redox potential is measured by the ratio of things like oxidized and reduced glutathione, ATP to AMP ratios, and the FADH to FAD ratios. If these switching battery voltage gates are low in discharge, meaning the cell is under oxidative stress by that mechanism, lack of reducing potential shifts cell signals over into the inflammation pathway. There is a close correlation between oxidative stress and inflammation. As cells undergo oxidative injury, and the battery voltage goes down, the ATP to AMP ratio goes down, the FADH to FAD ratio goes down, and the oxidized-to-reduced glutathione levels go up, the genomic and proteomic messages increase inflammation signaling. That suggests that certain antioxidants serve as antiinflammatories. If there is an association between inflammation and insulin resistance, then antioxidants might also serve as insulin-stimulating substances. Take vitamin E, for instance; Vitamin E is an antioxidant in lipid-soluble regions of the cell. If it is an antioxidant, it should improve redox buffering and lower the potential in certain tissues for inflammatory mediator production, and that might subsequently have a positive impact on insulin sensitivity by lowering inflammation. Have there been any clinical studies in which vitamin E has been shown to have an insulin-sensitizing effect? In both animals and humans, lower intake of vitamin E has been associated with decreased insulin sensitivity and a higher incidence of insulin resistance and metabolic syndrome.24 ,25 ,26 By knowing something about the mechanism, we can almost abstract something about the clinical impact. Antihypertensive Effect of Alpha Lipoic Acid Supplementation What about lipoic acid? That is another interesting nutrient. There are a variety of studies showing that lipoic acid will improve insulin sensitivity and glucose removal. It will also lower blood pressure, presumably because of its favorable effect on endothelial function due to the proper regulation of endothelial redox potential and lowered inflammatory mediators in hypertensive animals. I am now quoting from a review paper in Current Topics in Nutraceutical Research about the use of lipoic acid.27 Generally, doses in these hypertensive animals ranged between 10 and 500 mg/kg per day. The authors suggest it is time to study this in humans. Diet and Nitric Oxide Synthesis Last, what about the emerging story on nitric oxide (NO) modulation, using conditionally essential nutrients like L-arginine and 5-methyltetrahydrofolate (5MTHF)? There is now emerging evidence that endothelial function and endothelial NO are improved, and oxidative stress and inflammation are reduced, by supplementing individuals with insulin resistance and/or inflammatory mediators with endothelial dysfunction with 4-6 grams of L-arginine, along with 1 mg of 5MTHF. A review of dietary factors and NO can be found in the Annual Review of Nutrition, titled “Regulation of Nitric Oxide Synthesis by Dietary Factors.”28 There is also an interesting animal study that appeared in the Journal of Nutrition on how dietary L-arginine supplementation enhances endothelial NO synthesis in streptozotocin-induced diabetic rats.29 I hope I have given you some additions to your tool kits as to how to employ different strategies for achieving the objective that Oliver Wendell Holmes talked about-the One-Hoss Shay. Where is primary care going? How do we manage chronic disease? I believe a functional medicine model provides an answer to those questions. We will see you in May.

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Bibliography

1 Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980;303(3):130-135. 2 Kennedy D. Longevity, quality, and the one-hoss shay. Science. 2004;305:1369. 3 Holman H. Chronic disease-the need for a new clinical education. JAMA. 2004;292(9):1057-1059. 4 Whitcomb ME, Cohen JJ. The future of primary care medicine. N Engl J Med. 2004;351(7):710-712. 5 Rimm EB, Stampfer MJ. Diet, lifestyle, and longevity-the next steps? JAMA. 2004;292(12):1490-1492. 6 Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean Diet, lifestyle factors, and 10-year mortality in elderly European men and women. JAMA. 2004;292(12):1433-1439. 7 Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome. JAMA. 2004;292(12):1440-1446. 8 Schulze MB, Liu S, Rimm EB, Manson JE, Willett WC, Hu FB. Glycemic index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and middle-aged women. Am J Clin Nutr. 2004;80:348-356. 9 Nilsson M, Stenberg M, Frid AH, Holst JJ, Bjorck IM. Glycemia and insulinemia in healthy subjects after lactose-equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins. Am J Clin Nutr. 2004;80:1246-1253. 10 McKeown NM. Whole grain intake and insulin sensitivity: evidence from observational studies. Nutr Rev. 2004;62(7):286-291. 11 Astrup A, Larsen TM, Harper A. Atkins and other low-carbohydrate diets: hoax or an effective tool for weight loss? Lancet. 2004;364:897-899. 12 Thompson T. Gluten contamination of commercial oat products in the United States. N Engl J Med. 2004;351(19):2021-2022. 13 Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men. JAMA. 2004;292(18):2243-2248. 14 Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292(18):2237-2242. 15 Axelsson J, Qureshi AR, Suliman ME, et al. Truncal fat mass as a contributor to inflammation in end-stage renal disease. Am J Clin Nutr. 2004;80:1222-1229. 16 Accili D, Valenti L. Turning up the heat in the fat cell. Nature Med. 2004;10(11):1168-1169. 17 Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem. 2004;50(9):1511-1525. 18 Moreno JA, Perez-Jimenez F, Marin C, et al. Apolipoprotein E gene promoter -219®T polymorphism increases LDL-cholesterol concentrations and susceptibility to oxidation in response to a diet rich in saturated fat. Am J Clin Nutr. 2004;80:1404-1409. 19 Zhao G, Etherton TD, Martin KR, West SG, Gillies PJ, Kris-Etherton PM. Dietary a-linolenic acid reduces inflammatory and lipid cardiovascular risk factors in hypercholesterolemic men and women. J Nutr. 2004;134:2991-2997. 20 Wang L, Feng G. Rheumatoid arthritis increases the risk of coronary heart disease via vascular endothelial injuries. Med Hypotheses. 2004;63:442-445. 21 Bhatia GS, Sosin MD, Connolly DL, Davis RC. Statins and rheumatoid arthritis. Lancet. 2004;364:1853. 22 Morrow DA. Preprocedural C-reactive protein for risk prediction before percutaneous coronary intervention (PCI): a US perspective. Clin Chem. 2004;50(9):1489-1491. 23 Biasucci LM, Biondi-Zoccai GG. Preprocedural C-reactive protein for risk prediction before percutaneous coronary intervention (PCI): a European perspective. Clin Chem. 2004;50(9):1492-1494. 24 Ford ES, Mokdad AH, Giles WH, Brown DW. The metabolic syndrome and antioxidant concentrations. Findings from the Third National Health and Nutrition Examination Survey. Diabetes. 2003;52:2346-2352. 25 Manning PJ, Sutherland WH, Walker RJ, et al. Effect of high-dose vitamin E on insulin resistance and associate parameters in overweight subjects. Diabetes Care. 2004;27(9):2166-2171. 26 Tsujinaka K, Nakamura T, Maegawa H, et al. Diet high in lipid hydroperoxide by vitamin E deficiency induces insulin resistance and impaired insulin secretion in normal rats. Diabetes Res Clin Pract 2005;67(2):99-109.. 27 Vasdev S, Gill V, Longerich L. Antihypertensive effect of alpha lipoic acid supplementation. Curr Topics Nutraceutical Res. 2004;2(3):137-152. 28 Wu G, Meininger CJ. Regulation of nitric oxide synthesis by dietary factors. Annu Rev Nutr.2002;22:61-86. 29 Kohli R, Meininger CJ, Haynes TE, Yan W, Self JT, Wu G. Dietary L-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats. J Nutr. 2004;134:600-608.

Recently, in The New England Journal of Medicine, there was an article that discussed health care in the 21st century.6 This was Dr. William Frist’s Shattuck Lecture that was quite remarkable, particularly in the context of what Dr. Oz shared with us. Dr. Frist states: “I would like you to meet a patient from the year 2015. He lives in a world in which years ago America’s leaders made tough but wise decisions. They built on the best aspects of American health care and unleashed the creative power of the competitively driven marketplace. These changes resulted in dramatic improvements to the U.S. health care system-lower costs higher quality, greater efficiency, and better access to care.” This is an interesting perspective as to what we might see as we move forward from the lessons of the late 20th century. This lecture is based on work Dr. Frist has done in the area of health care in his role as Senate Majority Leader. He has both a physician’s role and a legislative role. He believes that the high quality, rich information and common-sense efficiency inherent in the care of patients in 2015 are all within our grasp. He sees the medicine of the future being built upon a web-based mentality that will include much better access to medical information. He states: “Today, however, we are saddled with glaring inefficiencies, high and rapidly rising health care costs, growing ranks of the uninsured, chasms in quality, and health care disparities. Health care spending in the United States is the highest of any industrialized country, making up nearly 15 percent of our gross domestic product. Today’s average premium for an insurance policy for a family-$9,086 a year and rising-represents 21 percent of the national median household income of $42,409. We spend approximately $5,540 per person per year on health care in the United States.” There are some certainly some encouraging things that have come out of the application of medicine over the last 100 years. Remarkably, life expectancy has increased from 47 to 77 years of age. However, that is slightly skewed on the basis of lowered incidence of infant mortality. When infant mortality is reduced, the median average life expectancy is greatly increased. Nonetheless, we must take heed and give remarkable thanks for that improvement. Dr. Frist continues: “Yet there are troubling signs that we are not getting a good return on our investment. We have uneven access to care, with the number of uninsured people climbing annually, most recently to about 45 million. The overall quality of care in the United States is not what it should be, especially in light of how much we spend. According to a recent RAND study, Americans-even in the best of circumstances-receive only about 55 percent of the recommended care for a variety of common conditions. “Although we have made massive investments in medical research, we clearly have underinvested in the research and infrastructure necessary to translate basic research into results.” This certainly applies to the chronically ill patient. As we have said in previous issues of FMU, these patients constitute about 78 percent of healthcare expenditures. “For example, it takes our physicians an average of 17 years to adopt widely the findings from basic research. The health care sector invests dramatically less-some 50 percent less-in information technology than any other major sector of our economy.” Dr. Frist asks what we might focus on to make this view of a patient in the year 2015 become a reality. He says that first, we should focus on patient-centered health care. “The focus of the 21st-century health care system must be the patient.” This has been a theme, a condition, and a primary under-riding principle of the Institute for Functional Medicine since its inception in 1991. Secondly, Dr. Frist says we should allow the healthcare system to be consumer-driven and allow more consumer voice to be present in the decisions we make about procedures and therapies, and engage the patient more in the understanding of what they are getting for the money they are paying. Third, we should make the healthcare delivery system more provider-friendly so that in the transformed healthcare system, we reestablish and promote the value of the doctor/patient relationship and get the third-party provider out of the exam room, which interferes with the sanctity of the relationship between the provider and the patient. Fourth, Dr. Frist says we should go to universal electronic health records in order to capture information about a patient longitudinally so that over time, we have the information to paint a mosaic, or a picture of the individual’s trajectory of health, rather than trying to make decisions on the run based on a specific crisis or incident. These people come with a history which is translated into their therapy and medical needs. Next, he talks about healthcare coverage for children and low-income Americans, and making health care affordable by increasing personal responsibility, allowing people to know what their options are, stimulating them, encouraging them to participate in their own therapies, and providing therapies they can actually do something about. Rather than prescription dosing regimens, we need to look at lifestyle interventions, environmental changes, nutrition, and exercise programs. As this moves forward, Dr. Frist says we should be focusing on the security of long-term care. As people age, they suffer from more illness. We are more and more concerned about how the baby-boomer population will have proper care delivered at a time of economic deficiency. We can already see that starting to happen as it relates to the reframing of the Medicare system. Last, we need to translate science into actual, palpable and demonstrable evidence-based cures. “During the last decade, the practice of medicine will change dramatically through genetically based diagnostic tests and personalized, targeted pharmacologic treatments that will enable a move beyond prevention to preemptive strategies.” I like that concept. I call it “personalized preventive medicine.” Dr. Frist refers to it as “preemptive strategies” to personalize to the needs of the individual and prevent the need for high-technology and expensive intervention later on. You can see from Dr. Frist’s Shattuck Lecture and his view of health care in the 21st century, that these have been the underlying principles of functional medicine since its inception, and they have also been part of this tape series for the past 20 years. We are seeing an increased global burden of various types of chronic, degenerative, age-related diseases that, with the increasing demographic shift or transition of the population to older age, is putting a tremendous financial burden on the system. Hypertension is one of those diseases, as well as cardiovascular disease (CVD) and cancer. For the remainder of this month’s FMU, I would like to focus on the cardiology connection that Dr. Oz so eloquently discussed, and move from that into type 2 diabetes and its implications for heart disease and cancer. Last, I would like to share a few thoughts on the malignant or oncogenic potential that results from some of the things that are occurring. That leads to a different frontier of how we might deliver the patient-centered medicine of 2015. If we look at the global burden of hypertension as a marker for these major disease trends, we are taken with articles such as one that appeared recently in the Lancet, talking specifically about the global burden of hypertension from a worldwide perspective.7 Overall, we are going to see an estimated total number of adults with hypertension increasing from 972,000,000 in the year 2000, to over 1.56 billion people by the year 2025, a nearly 60 percent increase. Delivering medical services to that need around what would be considered pharmacotherapy is a tremendous financial burden, not to mention the management issues related to patient visits with their physicians. This leads us into looking at what might be some of the lower technology, functional ways of approaching this problem. Dietary Impact on Hypertension I am talking about the delivery of functional medicine to major issues of chronic health management in the area of vascular disorders, which leads to how we might manage hypertension more effectively in its pandemic stage of growth. That takes us back to the DASH study and dietary approaches to the treatment and prevention of hypertension. The results of that study, which we shared with you in a number of previous issues of FMU, indicated that a diet higher in unrefined, complex carbohydrates, such as those found in fruits, vegetables, and whole grains, lower in refined animal products (which add saturated fat) and vegetable oils that have been altered by partial hydrogenation, as well as in salt and simple sugars, significantly reduced the incidence of hypertension. In many people, the effects on systolic and diastolic blood pressure can be comparable to those that would be achieved with a first-generation, antihypertensive drug, or a stage-1 antihypertensive drug, but would not involve the same risks to adverse side effects. Folate Intake and Hypertension Part of the story that is an interesting variation on a theme is, if you eat a minimally-processed diet, you are not only getting rid of things you don’t want to consume, but you are also getting higher density and intake of things you do want to consume that may have been removed in the highly-processed diet, such as vitamins and minerals. One of the vitamins related to hypertension that has been in the news recently is folic acid. It may not be obvious how folic acid intake could have an effect on vascular tone and function in the control of blood pressure, but if you have seen the recent paper in the Journal of the American Medicine Association, titled Folate Intake and the Risk of Incident Hypertension Among US Women,”8 you know that folic acid may play a role in the maintenance of vascular tone, which is presumably as a consequence of its secondary effects on vascular smooth muscle reactivity. For example, this may involve nitric oxide (NO) output by the vascular endothelium. NO, released by the vascular endothelium, is manufactured by way of the conversion of the amino acid arginine into its byproduct citrulline through the enzyme activity of endothelial NO synthase (eNOS). That process is facilitated by a coenzyme called tetrahydrobiopterin. Tetrahydrobiopterin is a substance manufactured in the body as a biopterin molecule, a Pter molecule. The biopterin is ultimately connected to folate chemistry. There is a folate-scavenging, or biopterin-scavenging pathway that requires 5-methyltetrahydrofolate for tetrahydrobiopterin to be synthesized in the body. Folate may play a role through the biosynthetic pathways in the manufacture and control of tetrahydrobiopterin levels, which regulate the activity of eNOS and have an important function in monitoring or controlling vascular smooth muscle tone and blood pressure. This is not just all speculation coming only from epidemiological associative studies. In intervention trials, high-doses of 5-methyltetrahydrofolate or folic acid were associated with decreased blood pressure and improved vascular reactivity in humans. There is an emerging recognition that nutrients present at higher doses in an unrefined diet may have a favorable effect upon vascular function and blood pressure control beyond that of reducing salt and saturated fats. Many new reasons are likely to emerge over the years to explain how phytochemicals and various nutrients found in a minimally-processed diet have dramatically different effects on vascular function than similar calories in highly processed foods. Does this relate to genetics? Are we just measuring a genetic susceptibility factor? That is the wild card that is changing the face of medicine that Dr. Frist talks about in his Shattuck Lecture. How will we personalize medicine based on individual characteristics? In the absence of looking at cohorts of reactivity, we may be led to false assumptions looking at the class effect of the group at large. Recently, in Nature Genetics, there was an article which discussed the genetic control of disease and whether race matters.9 In this article, the authors come up with a pretty remarkable concept that there is greater diversity of function at the cellular level among people of any single race than there is between members of different races. We are seeing the end of the concept of race. It may be more important to know your biochemistry than your skin color, eye color, hair color, height, or gender. These are important concepts, because we have often classified individuals just based on age, structure, or gender, not looking at how we would classify them on the basis of their genotypic control of cell function. That is what is described in this article. The authors state: “Now, a new study reviewing 43 disease-associated gene variants suggests that the effects of gene variants may be largely consistent across different racial’ or ethnic’ groups.” This leads us to recognize that race or ethnicity is not as important as genotypically-controlled biochemistry. I think Dr. Roger Williams, who developed the theory of genetotrophic disease, published in 1950, would be applauding if he were still with us. If we look at the takeaways from the model, such as hyperhomocysteinemia and its relationship to vascular disease, not everyone has a polymorphism that requires high doses of B6, B12, folic acid, and betaine in order to enhance homocysteine metabolism. Individuals who carry certain nucleotide polymorphisms are those who may, therefore, depend on higher levels of these nutrients for proper function. In some cases, if the frequency distributions of these polymorphisms is fairly small, and they are not taken into account in a trial design, their effects may get lost in the “noise” of a randomized, double-blind, placebo-controlled trial, in which one regresses to the mean and is able to define the average results of a population that may be highly stratified and polymorphic. As we learn about the differences among people at the genotypic, metabolomic, and phenotypic levels, we begin to see that stratification of research to different genotypes might lend different outcome variables for their management. Regarding homocysteine, if a person has the methylenetetrahydrofolate reductase polymorphism, the non-wild type, they may require higher doses of folic acid and B12. However, there may be many other different polymorphisms related to homocysteine metabolism that have different sensitivities. In a study in the American Journal of Clinical Nutrition, individuals with trisomy 21 were monitored with respect to homocysteine metabolism and the need for higher levels of nutrient intake relative to improving function in Down syndrome children who may have altered homocysteine metabolism.10 The genetic relationships to the major chronic, age-related diseases are being examined. We begin to see that the name of the disease is not as important as understanding the etiology of the disease. It’s a little bit like the discussion I just had on race. Perhaps we have seen the end of the term “race”; perhaps we are also seeing the end of the term “disease.” It’s more important to know the mechanism and the individual characteristics leading to the cluster of signs and symptoms that we call a disease, than being able to name it, assuming that it’s an independent variable shared in common by all people that present with those signs and symptoms. This is taken from an interesting paper on genetic factors in type 2 diabetes that appeared in Science magazine. 11 The authors state: “The intensive search for genetic variants that predispose to type 2 diabetes was launched with optimism, but progress has been slower than was hoped.” It has been assumed that we would find just a few genes that might regulate the function of an individual who would, in the absence of proper regulation, present with the symptoms of type 2 diabetes. However, the more this is evaluated, the more genes are found that interrelate as a family, and that may couple together in their function to give rise to the expression of what we call type 2 diabetes. They start looking at the PPAR gene variants, mitochondrial genome variants, and the insulin signaling genes and their variations. There is tremendous variation in the different types of metabolic principles that cluster together with similar signs and symptoms that we call a disease. The proper treatment for those individuals may, however, be better served by focusing on their individual genetic and metabolomic needs, rather than just on the class of disease management. As we go from complex to simple, the interesting thing about this, as Dr. Oz stated, is that there is a difference between complexity and making something simple. Simple doesn’t mean that you lose all the facts; it means that you make them clear. This is the same as it pertains to the concept of using genomic information. That is what the authors speak about at the beginning of their article, “Genetic Factors and Type 2 Diabetes.” I was talking about type 2 diabetes. One of the genetic families of characteristics that appears to modify insulin sensitivity, giving rise to type 2 diabetes, are those genes found in the mitochondrial genome-extra nuclear DNA that has come principally from our mothers. Mitochondrial dysfunction and its association with type 2 diabetes is ever-increasing. Agents in the environment, drugs, excess alcohol, chemicals, or even radiation that would damage mitochondrial DNA, have been associated in animal and human studies with the onset of insulin resistance, hyperinsulinemia, and type 2 diabetes. Mitochondrial Dysfunction and Type 2 Diabetes Perhaps there is a connection between mitochondrial toxicity, mitochondrial energy, or mitochondrial oxidative damage and the relationship of lowered insulin response, lowered bioenergetics, and what we later call type 2 diabetes. This has been well defined in a number of studies and reviews that have been published over the last few years. One you might want to look at is titled, “Mitochondrial Dysfunction in Type 2 Diabetes,” that appeared in Sciencemagazine.12 The authors state: “Maintenance of normal blood glucose levels depends on the complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by the pancreatic b cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia.” That is where we get the varying forms of metabolic syndrome that finally result in frank type 2 diabetes. “Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.” That is both the skeletal and liver non-responsiveness to the insulin message, and a loss of function of the endocrine b cells in the pancreas. Agents that would cause destruction of mitochondria in those tissues will contribute to the onset of diabetes. What could do that? At first level, you could have things like autoantibodies against endocrine glands that could cause damage to tissues. Secondly, you could have chemical injuries, such as in chemically-induced diabetes, such as streptozotocin in animals and many other drugs and chemicals that are injurious to hepatic cells. The most classic example is the medication used to treat acquired immunity deficiency disease syndrome (AIDS), in which there is injury to mitochondrial function, which results in lipodystrophy, type 2 diabetes, and cardiopathy. This is a secondary manifestation of the drug. This may be a time-compressed example of what occurs to people who, over life, continue to be exposed to low-grade mitochondrial toxins, oxidative injury, toxic xenobiotics, toxic stress, molecules such as oxidized catecholamines, and under-nutrition. We need to bring the mitochondrial connection to type 2 diabetes up on the radar screen, and begin to examine how one defends against injury to the liver, skeletal muscle, and the b cells of the pancreas. Obesity and Type 2 Diabetes How does obesity play a role in the onset of type 2 diabetes? In the past, we thought that obesity caused diabetes, but there is more and more evidence indicating that the onset of type 2 diabetes occurs through a process that involves altered adipocyte fat cell physiology that leads to accumulation of lipid and hypertrophic adipocytes, ultimately leading to obesity. It may be some underling mechanism that couples the two of them together, and may also connect to endothelial injury, such as from oxidative stress at the endothelium, and altered arterial cell wall dynamics that we call atherogenesis and cerebrovascular disease. A series of metabolic changes from different genomic signaling connects to many of these age-related disorders. This is discussed in an article in Science magazine, titled “How Obesity Causes Diabetes: Not a Tall Tale.”13 The author states: “The epidemic of obesity-associated diabetes is a major crisis in modern societies, in which food is plentiful and exercise is optional. The biological basis of this problem has been explored from evolutionary and mechanistic perspectives.” In an appropriate signaling environment, the adipocyte cell upregulates the expression of inflammatory mediators that cause white cells to stick to the vascular endothelium. Injury to the vascular bed alters endothelial nitric oxide (NO) production, then uncouples NO and produces things like peroxynitrite, which leads to oxidative injury to the vascular bed. All of these are atherogenic risk factors and can be coupled together with certain lipid risk factors, but may be partially independent from those lipid risk factors, or at least associated, not directly related. The question is, what triggers the adipocyte fat cell so it evolves into a personality of inflammation that leads to the production of adipocytokines? Could it be that the information molecules that the adipocyte is exposed to such as from an altered diet, lifestyle, or environment, are creating gene modification? Is there a certain set-point-a calorie intake-to the point where we trip the adipocyte into alarm physiology, which is like a dog chasing its tail? These questions have not yet been answered, but we know that many of the things that are triggered after the adipocyte cell accumulates a certain threshold level of fat are related to increasing insulin resistance, increasing oxidative injury, and increasing risk to heart disease. These particular conditions were built into our genes to help protect against the most significant risk to human survival throughout our history, which was starvation, not excess calories. In states of deprivation, these pathways were advantageous to help to store glucose in the right places for support of crucial tissues, such as the immune system. Perhaps the peripheral cells were made insulin resistant intentionally as an evolutionary benefit to salvage glucose or allow for energy generation even when glucose was at a minimum, in order to drive the immune system to maintain defense against infection and help the individual to survive to the next period in time. The question of what we consider disadvantageous as genetic characteristics has to be put through the lens of exactly what the environment of choice is. At one time, what might have been very advantageous, such as thrifty genes in the Pima Indians, may now be considered disadvantageous, given our current “Super-size Me” opportunities. We ought not to jump to the conclusion that the solution to this problem is starvation, and that by just taking calories away from people, we’re going to solve the problem. If the wrong types of calories are taken away, and people continue to eat a lower level of the wrong foods, we still have the problem of inappropriate signaling that can initiate inflammatory processes. Once this occurs, the adipocyte triggers inflammatory messages and the inflammation doesn’t stay localized. It is not “think locally, act locally”; it is “think locally, act globally,” because inflammatory mediators have impact on many other tissues, and this connection can account for such diverse relationships as those seen with type 2 diabetes, metabolic syndrome, and dementia. The mechanisms by which these are connected are becoming better understood. Diabetes, Obesity and the Brain There is a good discussion of diabetes, obesity, and the brain in Science magazine.14 The authors talk about the dysregulation of insulin and glucose and how it interrelates with inflammatory mediators coming from the adipocyte, which creates an environment that precipitates brain oxidative injury, neuronal apoptosis, and dementia. It is not just localized type 2 diabetes; it is not just coronary artery disease; and it is not just cerebrovascular disease. It is metastatic changes, oncogenic insult, angiogenesis, and things like dementia that are all connected together by these mechanisms. It is now known that inflammation is an important progenitor marker in CHD. It is correlated, in part, with serum lipids, but it also has its own independent risk factor. A number of papers have been published in The New England Journal of Medicine go into this topic in greater detail, looking at inflammatory markers and the risk of CHD in men and women. In one report, it was shown that elevated levels of inflammatory markers, particularly high-sensitivity C-reactive protein (hsCRP), are associated with increased risk of CHD. 15 Lipids (such as dense LDL particles and total serum cholesterol) were still found to be important indicators, but hsCRP levels above 3 mg/L were also important to consider. In secondary prevention trials, where individuals have already sustained a heart attack and are on aggressive statin therapies, it has been shown that the patients who do the best are those who maintain a low level of CRP. Even if their serum lipids come down remarkably, if their hsCRP levels remain elevated, they have a much higher incidence of secondary heart attack and sudden coronary death. A paper by Paul Ridker and his colleagues at Harvard discussing this issue was published in The New England Journal of Medicine.16 In a companion paper, by Steven Nissen and his colleagues at the Cleveland Clinic, ultrasonography was used to observe the progression of atherosclerosis. It was demonstrated that patients on secondary prevention who maintained lower levels of hsCRP after aggressive intervention with statins had a significant reduction in the rate of thickening in their arterial lumen. 17 When we look at comprehensive nutrition and lifestyle variables, we find that these factors can affect inflammatory burden, and management of these variables may have a positive effect on lowering the incidence and risk of many of the age-related diseases that constitute the majority of medical expenditures. How does that relate to things like postmenopausal heart disease? That is a big question that has been sitting in the literature for some time. Why is it that women who lose their ovarian estrogen secretion show an incidence of heart disease that is comparable to men of the same age? This has been an active area of investigation for the last several years, particularly in light of the HERS Trial and the Women’s Health Initiative trials, which did not find positive roles for Premarin and Provera in lowering the incidence of vascular disease risk. People have been asking exactly what is going on. In previous discussions in FMU, I talked about the role that estrogen has in modifying inflammatory processes, and that it is seen as a kind of anti-inflammatory by a woman’s gene response elements. As she loses estrogen secretory ability, the inhibiting molecule for expression of various inflammatory genes is taken away. These genes may then become expressed, particularly if they are triggered by proinflammatory agents, which suggests that estrogen may be related to heart disease by its influence on inflammation. A paper in the December 2004 issue of Science magazine titled, “COX-2-Derived Prostacyclin Confers Atheroprotection on Female Mice” addresses this inflammation connection.18 The authors looked at the prostacyclin molecule (i.e., PGI2,),which is principally derived from vascular endothelial COX-2 activity. This is the same COX-2 that is blocked by selective COX-2 inhibitors and commonly used for arthritis pain. I’ll come back in a few moments to discuss that implication. What would COX-2 have to do with atheroprotection in a female mouse? By keeping COX-2, which is a housekeeping enzyme, alive and well in the vascular endothelium, one activates production of prostacyclin, which robs platelets of their coagulation ability so they don’t adhere or stick together as readily, they don’t form thrombi as easily, and there are favorable effects on smooth muscle function. Prostacyclin has an important role in the housekeeping activities of the vascular system. If there was any relationship between estrogen and COX-2, it could have an effect on the balance between prostacyclin, which prevents platelets from sticking together, and thromboxane A2, which is produced by the platelets and causes them to stick together. It’s the equilibrium between these agents that gives rise to proper coagulation and proper wound healing or clotting. In this study, the investigators looked at female mice that had relative protection from cardiovascular disease. They reported that estrogen acts on an estrogen receptor subtype A5; to upregulate the production of the atheroprotective prostacyclin (PGI2) by activation of COX-2. This suggests that chronic treatment of premenopausal women with selective inhibitors of COX-2 could, therefore, undermine the protection from CVD. Blocking COX-2 activities with a selective COX-2 or an NSAID drug may further increase the risk of thrombus formation. In light of what has recently happened with the withdrawal of rofecoxib from the marketplace and the shadow that has been cast on celecoxib, there is an interesting paper that appeared in the Journal of the American Medical Association, titled “Arthritis Medicines and CVD Events-‘House of Coxibs.’” The “House of Cards” concept, according to Eric Topol, was built on the idea that something very unstable could fall over. He says the “House of Coxibs” is a little like the “House of Cards.” Dr. Topol is at the Cleveland Clinic, and has done quite a bit of work on the mechanisms of selective COX-2 inhibitors.19 He points out that it is not just rofecoxib (Vioxx), and valdecoxib, but also celecoxib (Celebrex) these may all be showing a class effect because of blocking COX-2 in all tissues that could result in increased risk to heart disease. In his article, he discusses data from a large intervention trial for celecoxib. Results of the trial demonstrated that, at 400 mg and 800 mg a day of celecoxib, there were statistically significant increases in the incidence of cardiovascular events as compared to placebo. Dr. Topol points out that specifically blocking COX-2 in all tissues, (which downregulates the production of proinflammatory mediators like prostaglandin E2), also blocks the production of things like prostacyclin (PGI2) in the vascular endothelium, which increases the risk of platelet adhesion and thrombus formation. Again, this shows us how all these things fit together in a web. If we ask if statins are the right choice for the prevention of atherosclerosis, we see that they may have pleotr9phic affects, serving both as antiinflammatories and hypocholesterolemic agents. Dietary and lifestyle interventions focused on the same principles of modulating the signaling related to inflammation, as well as lowering lipids, could have dramatic pleotrophic effects in lowering the incidence of CHD and stroke, as well as type 2 diabetes and other manifestations of dysinsulinism. Anything that increases inflammation might be considered problematic. That could be chronic infection or inflammation from chronic trauma. What about dietary variables in refined and processed diets? One of those on the list of candidates for concern is partially hydrogenated vegetable oils that can alter cellular fatty acid composition and structure. Up to 40 percent of some solid vegetable fats that have been partially hydrogenated are found as transconfigured double bonds, which are not the natural cis form of double bonds found in edible oils. If we look at the relationship between trans fatty acid intake and systemic inflammation in apparently healthy people, we find that there is an interesting strong association between the two. I am now quoting from a paper in the American Journal of Clinical Nutrition.20 This work was done by a group from the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School. They expanded this observation by investigating the effect of trans fats in patients with established heart disease and found a strong association between trans fats consumed in the diet and systemic inflammation. Dietary intervention should remove the bad things, as well as increase the good things. The good things, as I mentioned earlier, are those that have gotten on the list of problematic foods. These are the complex carbohydrate-rich whole foods and whole grains, which now, in this age of “protein is good and carbohydrates are bad,” have been forgotten. We want to bring them back. Intake of whole grains, bran, and germ is strongly associated with a reduced risk to CHD and a reduced incidence of inflammatory conditions. This has been demonstrated in many papers. There have been studies recently published in The New England Journal of Medicine on the Mediterranean Diet, inflammatory markers, and CHD risk. A paper in the American Journal of Clinical Nutrition talks about support for the reported beneficial association of whole-grain intake with CHD.21 It suggests that bran components of whole grains could be a key factor in this association. That leads to the conundrum of this month’s FMU-vitamin E. Vitamin E has a long, interesting history. It goes back to the work of the Shute brothers in London, Ontario, and to the early work at the University of California Berkeley where, in a laboratory, it was found that vegetable oils, when stripped of certain unsaturates, would no longer be able to support reproduction in animals. The family of molecules that had been stripped out by processing the vegetable oil was called the birth-giving molecules, tocopherols0 or vitamin E. The common chemical name for vitamin E tocopherol-was coined in 1924 from the Greek words “tokos” meaning childbirth and “pherin” meaning to bring forth. In the early 1940s, vitamin E gained a reputation for being an aphrodisiac vitamin because it had a positive effect on sexual vitality. That evolved from the concept that if vitamin E was not present in the diets of animals, they could not have proper offspring. It really had little to do with libido, but it was promoted and overly-advertised from that standpoint. It did appear to be an important agent in the diet, and it eventually became listed as a vitamin, a life-necessary substance that our body cannot produce. In early studies on the chemistry and biology of vitamin E, it was found to be a family of many molecules, not as simple as vitamin C, ascorbic acid. It was a member of different isomeric and conjugate forms of a phenolic molecule-alpha, beta, gamma, and delta forms, with a phytyl side chain in the chromane ring-and existed as a natural enantiomer of the RRR form as the chiral, or optically isomeric pure form. The first studies on vitamin E, such as those by the Shute brothers, were done with semi-purified mixtures of vegetable oil that contained a mixture of tocopherols and tocotrienols. However, as we moved forward in technology, a bioassay was developed to determine potency of vitamin E preparations, because these were semi-pure concentrates and extracts of vegetable oils and researchers wanted to define the specific potency and necessary molecules. From that research, the exudative diathesis bioassay and the rat fetal resorption assay were developed. One was in chicks and the other in rats. Obviously, people don’t take vitamin E to prevent rat fetal resorption. There is no direct connection between this bioassay and why humans take vitamin E. However, it was found that of the various forms of vitamin E used in the rat fetal resorption assay, the alpha form of the RRR tocopherol was the most potent, so it was given the nomenclature of highest potency. Everything that was less effective in preventing rat fetal resorption was given a lower potency, based on its designated units. This would be the beta, gamma, and delta forms of tocopherol. We have gone through many years thinking that the alpha form was the most potent (meaning “important”) form of vitamin E. In reality, we don’t know that to be a fact. There is now evidence to suggest that it is not necessarily the most “important” form, and that perhaps the beta, gamma, and delta forms are more active in specific ways. In plant oils, the alpha form is generally lower in composition than the gamma tocopherol form. If you eat a natural mixture of oils, you will get alpha, beta, gamma, and delta, only a small percentage of which would be the alpha form, which we now say is the most 1otent form, and the one used in various natural vitamin E preparations. That is the backdrop for a recent paper in the Journal of the American Medical Association, titled “Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer,”22 in which the results of the Heart Outcomes Prevention Evaluation Trial (HOPE) and HOPE-TOO Trials are discussed. These are the intervention trials using 400 IUs of vitamin E as natural RRR tocopherol. The HOPE Trial was an international, multi-centered, double-blind, randomized, two-by-two, factorial designed trial, evaluating either an ACE inhibitor versus placebo or vitamin E versus placebo, in patients at high risk for cardiovascular events. These patients were eligible for the study if they were at least 55 years old, had a history of coronary or peripheral artery disease, stroke, diabetes, had not had previous heart failure, and did not have an injection fraction lower than 40 percent. It was a large trial-9541 patients, randomized into two groups, one receiving 400 IUs of vitamin E per day and the other group a placebo. The results were not at all encouraging. In fact, it was found there was no cardioprotection or cancer protection afforded by the vitamin E intervention. In the editorial that follows this paper, the authors state: “In the past decade, a number of prospective, randomized, placebo-controlled, 3- to 6-year clinical trials have been published, testing the effect of vitamin E and other antioxidant vitamins or their combinations on clinical manifestations of cardiovascular disease and cancer. These trials have surprisingly yet consistently shown that commonly used antioxidant vitamin regimens (vitamins E, C, beta, or a combination) do not significantly reduce overall cardiovascular events or cancer.”23 We would come to the conclusion that perhaps vitamin E is not all we thought it was. The point I would like to make is quite significant relative to everything we have discussed in this issue of FMU. That is, is it a single molecule of purity that produces good outcome? In other words, is it alpha tocopherol that is presumed to have the highest potency, but that potency comes from rat fetal resorption? Or, is it a combination of vitamin E molecules found in natural sources? I’d like to quote from a remarkable paper that appeared in the Journal of Nutrition, titled “Potential Synergy of Phytochemicals in Cancer Prevention: Mechanism of Action.”24 The author states: “The additive and synergistic effects of phytochemicals in fruits and vegetables have been proposed to be responsible for their potent antioxidant and anticancer activities. The benefit of a diet rich in fruits and vegetables is attributed to the complex mixture of phytochemicals present in these and other whole foods. This partially explains why no single antioxidant can replace the combination of natural phytochemicals in fruits and vegetables in achieving the observed health benefits. Thousands of phytochemicals are present in whole foods. These compounds differ in molecular size, polarity, and solubility, which may affect the bioavailability and distribution of each phytochemical on different macromolecules, subcellular organelles, cells, organs, and tissues. The balanced natural combination of phytochemicals present in fruits and vegetables cannot simply be mimicked by pills or tablets.” That is consistent with a recent review, titled “Vitamin E: Underestimated as an Antioxidant,” in which the author discusses the natural mixture of vitamin E, not a single molecule-D-a-tocopherol-taken out of the mixture.25 I hope this provides you with some interesting food for thought” as we close this month’s FMU.

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INTERVIEW TRANSCRIPT

Mehmet C. Oz, MD New York Presbyterian Hospital Columbia University 177 Fort Washington Avenue New York, NY 10032 It’s time for our Clinician of the Month. Over the last more than 20 years, I have had the pleasure of interviewing some remarkable clinicians and researchers who are cutting a new swath to the future of health care. It has been a major part of my education to listen to them and to read their work. I have been deeply affected by their perspectives, what they have done, and how they have done it. Our clinician this month is an individual who, from his years of life, has achieved remarkable accomplishments. As testament to that, and as you will learn throughout the course of our discussion, not only does he represent an academic medical success story, but he is a tremendous clinician/technician who has integrated many unique concepts into his practice (at some peril, I’m sure) that are different from those of his colleagues. On top of all that, he has also managed to raise a marvelous family. He has been married for 19 years and has a wonderful wife whom I have known for many years. She is the daughter of one of our previous FMU Clinicians of the Month, Dr. Gerald Lemole, a cardiologist at the University of Pennsylvania. Dr. Lemole was our guest on FMU in November of 1998. It is with great privilege that I introduce Dr. Mehmet Oz, Vice-Chair of the Department of Surgery and Professor of Surgery at Columbia University. He also directs the Cardiovascular Institute in complementary medical programs at New York Presbyterian Hospital. He is the author of a wonderful book, most fitting for the general public, titled Healing from the Heart (Dutton Penguin Putnam; 1998). He also has a new book, published in April of this year, which I can hardly wait to read. It’s titled, You: The Owner’s Manual (Harper Collins; 2005.) The best way to introduce Dr. Oz is to cite a few of his papers. They demonstrate the breadth of his contributions and experience. In 1998, he co-authored an article that appeared in The New England Journal of Medicine titled, “Implantable Left Ventricular Assist Devices,”1 which demonstrated his scope of expertise in the area of heart transplant surgery and the pioneering of new surgical techniques in vascular medicine. In 1999, in The New England Journal of Medicine, he co-authored a paper titled, “Alternative Medicine-The Case of Herbal Remedies.”2 He published an article in Circulation in 1998 titled, “Evidence for Unconscious Memory Processing during Elective Cardiac Surgery,”3 showing the mind/body connection that has been part of the multiple things he has looked at related to improving effectiveness in medicine and vascular biology. In the Journal of Thoracic and Cardiovascular Surgery in 2000, he and his colleagues published an article titled, “Use of Alternative Medicine by Patients Undergoing Cardiac Surgery,”4 a topic I would like to discuss with him during this interview. Dr. Oz also published an interesting report in JAMA in 1998 titled, “Complementary Medicine in the Surgical Wards.”5 We are remarkably fortunate in capturing Dr. Oz for this interview. He has just come out of surgery. With that introduction, Mehmet, it’s wonderful to have you on FMU, and thanks for joining us. Would you tell us a little bit about your background and what led you to some of these remarkable life experiences? MO: You asked me how I got started. I was raised in a fairly traditional household, learning about medicine the way most folks do-through the eyes of a child being taken care of by a pediatrician with the same indoctrination that most folks have when going into the medical profession. Several things happened along the path that changed my life. One was the fact that I was raised partly in Turkey and I saw the world from a very different perspective. As a son of Turkish immigrants, I appreciated how differently things look when you’re not looking from the same vantage point as is everyone else in your community. I distinctly remember meeting my wife’s parents. You mentioned that my father-in-law was a great cardiac surgeon at Christiana Medical Center. Even more impressively, my mother-in-law is a caregiver. Now, what does being a caregiver mean? She’s one of the almost 50,000,000 people in our country who take care of other people. We all know who they are. They’re the people we go to when we need advice. Those folks play the role of a primary caregiver in most communities. I watched her raise herbs in the garden and give advice on micronutrients and mind/body techniques. She had a network. She knew who would go where and she understood a lot about the functional medicine that you speak so beautifully of. I watched that transition. When I was in medical school, I remember being dragged off to a conference in Washington, DC, where the keynote speaker was Jeffrey Bland. At the time, I was still quite timid about my exploration into integrated approaches, but I heard you speak, and I don’t pay you false kudos-it was remarkable. I was a young scientist, going through medical school indoctrination, and you expressed your vision so beautifully from a scientific perspective-that we don’t take enough advantage of the body’s biochemistry. We don’t look at how food, medicines, herbs, micronutrients, and even the mind, influence how the body functions. It reawakened me to the fact that health and disease are not binary processes. You are not one or the other; you are a spectrum. That, together with other leaders in our field, took a generation of folks like myself, graduating from medical school, to change the way we viewed what medicine was going to do for our patients. You mentioned one interesting paper in The New England Journal of Medicine about mechanical hearts and left ventricular assist devices (LVADS). These are mechanical pumps placed into the hearts of folks who are dying, to keep them alive. These folks are desperate. They will do anything it takes, and they will experiment with their lives. They’re trying to crawl back from the precipice of death. Those folks, for me, created the practice of using some alternative approaches, because they were out there looking for solutions and teaching me. From that educational process, we created the integrative medicine center. I think that’s a pretty robust, but straightforward discussion of why I got interested in what you do so well. JB: That’s a marvelous introduction to several of the questions I hope to touch upon. I’d like to codify our discussion into three areas and hopefully, we can discuss each one during this interview. One area relates to your perspective on medical technology and cardiology. That gets back to what you just mentioned-LVAD implants-and how patients define function in their lives differently than a person who is looking for optimal performance in a marathon. It’s all part of the continuum-function relates to everyone. I’d like to discuss how technology interfaces with life decisions and alternative opportunities for improving function at all stages. Second, I’d like to talk about the concept of what complementary and alternative medicine is, as applied to cardiology. Does it have a useful role, and how do you manage the risk/benefit equation so that people are not put at undue risk? Third, I didn’t mention in my introduction that you have an MBA from Wharton Business School in Health Care Finance. I want to ask some questions about your perspectives on financing in the healthcare reimbursement system. Those are the three areas I hope you will feel comfortable discussing. Medical Technology and Cardiology MO: Let’s start with technology. The amazing thing about health care, and I’ll bring a little finance into this, is what drives costs is not inefficiencies, and not just errors, although I think many would agree that the most expensive thing to do is deliver bad health care. But technology does usually deliver value. Because it does, people want to pay for it, and they see that investment as saving years of life. Ventricular assist devices, defibrillators, and different stents in coronary bypass surgery, are examples of that. But they are not where we should be investing most of our effort. They provide a continuance of life and they improve quality of life quite dramatically, but they’re the wakeup call, and we need to get that wakeup call to occur earlier. Much of what you’ve taught, and I want to applaud you for it, is the need to get folks to realize earlier in the course of life that there are challenges occurring in their bodies and often, they don’t have the insight they need to be aware of what the challenges are. That was the reason we wrote the book, You: The Owner’s Manual. We wanted to provide an expos on your own body so that you feel comfortable making some of the minor adjustments (and sometimes, major checkups), that one would have to get, because things just didn’t sound, look, or feel right. The technology we use in medicine is cool, fun, and hip, and I’ve been proud to be involved in developing some of it, especially the minimally invasive approaches. It solves the problem for folks who have fallen off the tightrope of life. But we need to take a step back. Some of the newer technologies, like 64-slice CT scanners, provide remarkable insights into what the heart, lungs, and brain are doing in the body. These are useful because they show us earlier that there are problems, but they’re also potentially dangerous because sometimes they show us too much. By that, I mean they have a high false-positive rate. We become nervous about things that are not important. Nonetheless, when used appropriately, they’re wonderful wakeup calls, resulting in folks starting to take the necessary proactive steps to avoid some of the major interventions down the road. JB: One of the interesting things you’ve touched upon is how people make changes, which reminds me of the Stages of Change model that James Prochaska talks about-going through the stages of enlightenment into putting a plan into action. It appears that you have to get people’s attention. I recall an illustration of that when my executive assistant came in to my office one day and told me she had seen an unbelievable TV show on which a doctor from New York had been the guest. She said he showed human organ pathology on national TV and that it had been very gripping. She said she’d never known what your insides look like if you didn’t take care of yourself. Well, that was you on that TV show and I’ve since had a chance to see a video of it. It was very effective at getting people’s attention. Would you tell us how you get people to look seriously at, or to think about these things when they can’t see inside their bodies? Life-Changing Imagery Techniques MO: Advertising 101 is, don’t take the intelligence of your audience for granted. People are smart. They can see through makeup stories and dumped-down versions of what reality is. Unfortunately, we have spent a lot of time doing that. We create these images. For example, for coronary artery disease, it shows your sink blocked up with a hairball and, just like you’d pour Drano down there to clear out the blockage, we need to do the same thing to your heart. That imagery, besides being false, is misleading and makes folks think about their disease in a different way than they should be visualizing it. I’ve tried to move away from simplifying to just making it simple. There’s a big difference. To me, making it simple means that I’ll show you what an aorta looks like in someone who has abused his or her body. It has plaque distributed throughout the entire aortic system, blocking off the blood supply to the kidneys, thus causing hypertension and kidney failure. That’s reality. That’s what it really looks like. I can also draw you a cartoon of it, but if I’ve lost the element of reality, you’re not going to believe it, because it’s not as tangible; it’s not up close. What we did on that TV show, and we have others planned along the same vein in the future, was to get folks to change their lives. I’ve received so many kind notes, some to the effect that many people had been advised to stop smoking, but when they saw me show the lung cancer and the lungs with emphysema of people who had died, that hit home for them. We need to move outside the ivory towers of academia where we have a lot of this knowledge, and move it into the mainstream, but we can’t do it by just mainlining information. We need to put the information in context, and the reality of disease does that quite effectively. JB: Do you find that your colleagues are receptive to opening the slit and allowing different wavelengths of enlightenment to come through? Do they ask about sick hearts and sick environments in a different way? Complementary and Alternative Medicine MO: I’m seeing more of that, and it probably takes us to the second major area of discussion-complementary and alternative medicine. The problem is that being a doctor is a religion, as if you were indoctrinated into the priesthood. You understand the way the body works, and if you work your tail off for four years in college, four years in medical school, and for seven years of residency, you think you know it all. If you don’t know it, it’s not out there. It’s not true; it’s not real. You tend to pooh-pooh some of the findings being made by folks who came from very different disciplines. The paper we published in Alternative Medicine about patients undergoing heart surgery brought light from my specialty as to the huge credibility gap occurring in medicine between doctors and their patients. We ask patients, for example, whether they have spoken to their doctors about the use of alternative medicine. Seventeen percent of people said yes. Then we asked, if their doctor wanted to know, would they tell him? Only a third of the people said they would. Why? Because some of them were nervous about destroying that precious covenant they have with their doctors, and I understand that. But others felt that their doctors didn’t know anything about this, anyway. If he’s going to pooh-pooh it, why bother asking? We need to reestablish that connection. For me, complementary and alternative medicine, or integrative medicine, is really the globalization of medicine. Think about that. We’ve got banks; they’re global. All of our financial institutions are pretty much global. We’ve got global media setups. But we don’t have global medicine. Medicine has remained remarkably provincial. When we start to bring in therapies that work in other parts of the world and bring them into our own system, we call them alternative or complementary or integrative. But, in fact, it’s the globalization of our field. JB: That’s a magnificent perspective and very interesting. That opens up some extraordinary opportunities for discovery. For instance, when you ask that question, you start to look at papers such as the one you co-authored, titled “Evidence for Unconscious Memory Processing during Elective Cardiac Surgery,” in which you asked a question about whether there are certain auditory imprints that occur during the time of anesthesia that may have an effect on either the patient’s memory or experience, or even how they may travel out of the experience in terms of recovery, based on the fact that the mind/body connection is pretty strong. Memory Patterns and Anesthesia MO: It worked beautifully for some of us, but let me take that one step further. What that paper did, which was the study on what happens to the brain waves and subsequently to memory patterns, especially implicit memory, in other words, conditioned memory, on patients undergoing heart surgery. What it did was to study why we have anesthesia. Now, think about that. Many of your listeners have had anesthesia. Everyone knows someone who’s had anesthesia. We all know how it works. That’s startling isn’t it? We don’t really know why it is you fall asleep when we administer inhalation gas anesthesia. We use it, and we assume the patients are asleep because after all, when they wake up, they don’t have any recall, but is that the same thing? Not having recall is different from not having any input. We studied what happens to brain waves and we found that, in fact, when people hear sounds in their ears in the operating room, their EEG readings reflect that there’s a level of awareness. It’s throughout the operation, even when we’re operating on their heart with their chest open. When we stop their heart, it’s still present. So, we know they’re aware. By the way, I had lots of wonderful collaborators-psychologists, psychiatrists, and criminologists (they’re very good at looking at memory and implicit memory). We got together and created some word pairs. Jeff, I’ll ask you a question. What color comes to your mind if I say the word black? JB: Red. MO: Most people will say white. Black/white is a typical color pattern that most people will gravitate to. After I put you to sleep, if I play the word pairs black/brown in your ear, and you awaken from surgery; you never hear it again. The day you’re going home, I ask you what color comes to mind if I say the color black. People will almost always answer brown. So, we can actually change how you would respond to a question, or perhaps even a stress, by conditioning you during the course of anesthesia. These are insights that are profoundly important to a field that took anesthesia for granted and assumed because we didn’t study it as well as we could have, the impact of the head-on memory. JB: Now we go back and interface with complementary and alternative medicine. How do you prepare a patient for surgery during the preoperative period, the surgery period, and the postoperative period? Clearly, that may have some impact, along with the procedure itself. Preparing Patients for Surgery MO: There are several companies that now make audiotapes that I find very useful. Peggy Huddleston has written on these, and Belleruth Naparstek has published a series of tapes. We have taken some of these tapes and modified them for our patients, but the Naparstektapes are wonderful guided-imagery tapes; they can focus on sleep, if you desire, or pain, or anxiety, or there’s an interoperative tape. We provide these to our patients. They’re relatively inexpensive; we actually subsidize it to make it very inexpensive, in order to help them be proactive in getting ready for their procedures. This is a logistically simple technique to deliver so we do it frequently, but there are other examples. In fact, on these tapes, I try to get patients to take deep breaths after a procedure to feel confident, and to not sense the pain as much-get them to take charge of the recovery process that we have for too long ignored. JB: Let me bear on your thoughts about a few things that I’m sure come across your radar screen periodically when patients are using what might be called alternative or botanical medicines. I’m sure there are a variety of potential interactions that many of these substances might have with traditional cardiac drugs. Do you worry about botanical medicines in cardiology? Are there those you feel fairly comfortable with? Do you take it on a case-by-case basis? How do you deal with that issue? Botanical Medicines MO: There are some things I fear with patients. The first is, herbs are drugs. You need to know what you’re doing with them. There are folks who know what these drugs do, and they can use them effectively. It’s not that I’m against using herbs; I just want to know what they are so I can help you. For example, we know that many of the “Gs,” ginkgo biloba, ginger, ginseng, and garlic change either lipid function or inhibit coagulation factors. If I’m going to thin your blood with some of my drugs, and you’re self-medicating effectively because you’re taking high doses of garlic, then you’re not going to have the kind of coagulation profile that I want you to have. You’re likely to bleed. So, let’s have this discussion. Let’s talk about which botanicals do what. I promise you that I will not make decisions because I don’t know; I’ll make decisions because I’ve thought about it and have asked around. That’s quite effective. Coenzyme Q10 There are some guidelines. For example, I give coenzyme Q10 to patients routinely prior to surgery, because we have done our own work on this. There’s also published data from other institutions showing that hearts tolerate the procedures we do better if patients have been taking coenzyme Q10. I’m very quick to give patients fish oils following surgery, in part because we think they may play a role in reducing the amount of depression that patients have, and the duration of the depression after surgery. In fact, there is a nice study looking at postpartum depression, demonstrating the value of 2 grams of fish oils post-partum. We’re in the middle of a randomized trial looking at the same thing in adults undergoing heart surgery. There are things that offer a lot of opportunity and potential. We offer those when we can, but we definitely want to know what patients are on. That’s one of the big challenges we have in American medicine, because we weren’t trained in botanicals so we don’t know. Then, we look at the usual cheat booklets to try and figure out who does what and when. If patients don’t mention these to us, we start to build a big credibility gap. JB: Let me address an issue that is obviously very controversial and I’m sure you’re getting questions about it, and that’s vitamin E. Do you have a position, or is this still open for further discussion? Vitamin E MO: With vitamin E, I’m telling patients that the most recent study that was done that argued that it actually may hurt patients, was one that looked at whether vitamin E allowed Lipitor or cholesterol-lowering drugs to do what they’re supposed to do. It wasn’t a study looking at vitamin E as sole therapy. I’m coming away with the belief that if you’re already taking a drug for cholesterol management, a lipid-lowering drug, a statin, then your vitamin E dosing probably shouldn’t be as high as it was in the past. I’m not going to completely change how we manage vitamin use in our patients based on a single study, but there’s a cautionary note there. If you’re not on a lipid-lowering drug, I don’t believe that vitamin E has a negative profile that would mandate its stoppage. What do you think? JB: This has been an interesting evolution, with the various epidemiological and intervention trials. The March 16 JAMA papers have probably created another stage of controversy because the HOPE trials were controlled intervention trials with vitamin E, looking at 400 IUs in patients to prevent cardiovascular events and cancer. That study is a prospective, randomized, clinical trial of fairly good size and the data looks real. I have a long-standing affiliation with vitamin E, going back to the early 1970s with some of my first research, but I think we need to take a look at where these confounders may be coming from and do some cohort analysis to see if there are subtypes of individuals on whom, for reasons that we don’t understand, vitamin E is not having a favorable effect. MO: When your aunt calls you and says she’s on Lipitor and they want to reduce her vitamin E, what do you tell her? JB: I would say, given the studies that have now been published, that keeping the intake of vitamin E (a combination of diet plus supplement), between 100 and 400 IUs a day is probably the safe, prudent approach for today. JB: As you have broadened your scope of thinking and your communication of these concepts, you can influence people with a sense of a different reality than they may be familiar with. What about the criticism, controversy, and scrutiny that often affects people’s ability to communicate to their colleagues? Has that been an issue for you? MO: It has been an issue, in that sometimes we’re not as open as we should be about true motivation. Some folks have criticized me about some of our research and I sometimes feel that the criticism is perhaps harsher than it would have been if it had been a paper on a more mundane, less inflammatory topic. On the other hand, I must give my colleagues credit because overwhelmingly, they have been supportive in letting me do what we’re supposed to do in an academic center, which is research. As long as we’re actually studying what we’re doing, my colleagues have been very supportive. That’s the reason we offer clinical services such as massage to almost every patient who comes to the heart center. In fact, about 96 percent of patients are offered massages. We teach yoga. We have some guided imagery classes. We can do some of the things that I want to do. We don’t have full range-for example, with acupuncture. But it’s a reasonable start for Columbia University, which is an institution that has a strong tradition and has people in it who have strong beliefs. This brings us to the third topic you brought up, which is what am I doing in healthcare policy, and what’s going on in that arena. In many ways, what I’m seeing in medicine and in the behavior of my colleagues, is a concern about where the field is going and, particularly, a beginning sense of nihilism about how we’re going to deal with some of the challenges in health care in this nation. I’m not a pessimist. I think we can fix the problems, because there’s one root cause of most of the challenges we face-an implosion of trust in the system. The solutions we should be coming up with to deal with challenges ranging from affordable health insurance for all to health information systems that are functional, and even to malpractice and health justice systems that are useful, is to make sure they build trust in the system. The Issue of Lawsuits For example, the issue of lawsuits. A lot of folks want to put caps on lawsuits. That doesn’t really build trust. It may cut costs, but to build trust, you want to, for example, have health courts. Instead of having a malpractice lottery, where one person wins and so many others are hurt by a mistake, let’s make the mistake public so people can learn from it and it’s not being hidden. At the same time, let’s make the settlements fast, so people who are hurt are given compensation quicker, and physicians aren’t laid out for months trying to defend themselves. Medical information is perhaps a better example for this tape. We have so much information in the system, but we don’t share it. We have rules that restrict us from sharing it and we have a reticence, for malpractice reasons and also in terms of being open, about what’s really going on in our practices. We should break those barriers down. We should be using this data to drive evidence-based solutions. Even if we don’t have randomized trials, at least we’d know from large groups of patients and doctors, what happens in reality when certain things are being done. Patients ought to have access to that, as well. Folks, like the bright ones who listen to your tapes, ought to be able to look at the data and see that such and such a heart center has a higher mortality and here’s 15 other things I know about them that could change my decision to go there or not go there, and here’s what happens when they use ginkgo biloba in surgery and here are the results of coenzyme Q10 and heart failure. They can begin to pull some of this data to the forefront, even though we don’t have the larger-scale, randomized trials that we so much desire. JB: That was eloquently stated. In August of 1998 on FMU, I interviewed Regina Herzlinger from the Harvard University School of Business. She had just published her book, Market Focused Health Care, in which she advocated that if we allowed people to really understand what they were paying for indirectly in the healthcare system, and used the same market forces that we have in any other competitive field, that we might see a leveling of the playing field and actually improve cost effectiveness and patient recruitment into the program. I think this is the theme you are leading us to-put the light of day on the whole system and get away from self-reinforcement of the double-blind, placebo-controlled, randomized clinical trial, which really focuses on one molecule against one endpoint. That loads the dice in favor of pharmacology. Let’s look at everything on the same playing field from a true evidence-based perspective. Looking at Things from an Evidence-Based Perspective MO: Absolutely, and it comes back to one overarching concept which is, being a professional involves always putting the patient first. It involves having a body of knowledge that we will advance, and it involves policing each other, unfortunately, but that’s what professionals are supposed to do. There’s also a fourth element to professionalism. That is, you have to have a civic responsibility that you acknowledge and act upon. It would be a tragedy if we lost our voice. We’ve got to regain our voice. I drafted something called The Covenant for America, which is an effort by physicians to regain their voice by stating clearly not self-interest issues, but broadly, what do we think ought to be happening in health care? Just get it out there, so that folks who don’t spend their whole life thinking about health, like our political leaders, and like many of our civic leaders can read this document. A lot of doctors who looked at this think this is good for us, so maybe we ought to move toward affordable health care for all. They feel strongly about having better health information systems. Let’s make that capital investment. Folks like you and me and others, ought to out there hammering the message that this is what doctors think is best for America. It’s not about us; it’s about America. JB: I’d like to acknowledge something. I know it’s the end of your day, and that’s it’s been one filled with technology, emotion, and other things that required your full attention, both from a humanistic and professional perspective. The answer to the question, what is functional medicine, or what is function, comes down to the kind of abilities you have demonstrated in this interview to bring the full sense of who you are as a human being to these questions. They are not always easy questions, and we don’t have all the answers. We need to interface them with the real aspirations, fears, and desires of people and try to be a little better with service each day, and do it in such a way that you feel you’re part of the system-not above or separate from it. You’ve conveyed that beautifully. It’s quite remarkable to know about the things that have gone on throughout your day and the different types of regimentation you’ve had to face, and then see you center yourself and be present for this discussion, That embodies what functional medicine is all about. I want to thank you. MO: You’re very kind. I’m a big fan. Keep up the great work. JB: You do the same, and we’ll be in touch soon. What a great pleasure to talk with Dr. Oz and get his sense of where we are going, where we have come from, and how we can improve the healthcare system.  

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Bibliography

1 Goldstein DJ, Oz MC, Rose EA. Implantable left ventricular assist devices. N Engl J Med. 1998;339(21):1522-1533. 2 Oz MC, Rose EA, Lemo2e GM. Alternative medicine-the case of herbal remedies. N Engl J Med. 1999;340(13):1056. 3 Adams DC, Hilton HJ, Madigan JD, et al. Evidence for unconscious memory processing during elective cardiac surgery. Circulation. 1998(98);II-289-II-293. 4 Liu EH, Turner LM, Lin SX, et al. Use of alternative medicine by patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2000;120:335-341. 5 Oz MC, Whitworth GC, Liu EH. Complementary medicine in the surgical wards. JAMA. 1998;279(9):710-711. 6 Frist WH. Health care in the 21st century. N Engl J Med. 2005;352:267-272. 7 Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217-233. 8 Forman JP, Rimm EB, Stampfer MJ, Curhan GC. Folate intake and the risk of incident hypertension among US women. JAMA. 2005;293:320-329. 9 Goldstein DB, Hirschhorn JN. In genetic control of disease, does ‘race’ matter? Nature Genetics. 2004;36(12):1243-1244. 10 Fillon-Emery N, Chango A, Mircher C, et al. Homocysteine concentrations in adults with trisomy 21: effect of B vitamins and genetic polymorphisms. Am J Clin Nutr. 2004;80:1551-1557. 11 O’Rahilly S, Barroso I, Wareham NJ. Genetic factors in type 2 diabetes: the end of the beginning? Science. 2005;307:370-373. 12 Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384-387. 13 Lazar MA. How obesity causes diabetes: not a tall tale. Science. 2005;307:373-375. 14 Schwartz MW, Porte D. Diabetes, obesity, and the brain. Science. 2005;307:375-379. 15 Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med. 2004;351:2599-2610. 16 Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28. 17 Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29-38. 18 Egan KM, Lawson JA, Fries S, et al. COX-2-derived prostacyclin confers atheroprotection on female mice. Science. 2004;306:1954-1957. 19 Topol EJ. Arthritis medicines and cardiovascular events-House of Coxibs.” JAMA. 2005;293(3):366-368. 20 Mozaffarian D, Rimm EB, King IB, Lawler RL, McDonald GB, Levy WC. trans Fatty acids and systemic inflammation in heart failure. Am J C0in Nutr. 2004;80:1521-1525. 21 Jensen MK, Koh-Banerjee P, Hu FB, et al. Intakes of w1ole grains, bran, and germ and the risk of coronary heart disease in men. Am J Clin Nutr. 2004;80:1492-1499. 22 The HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E Supplementation on cardiovascular events and cancer. JAMA. 2005;293:1338-1347. 23 Brown BG, Crowley J. Is there any hope for vitamin E? JAMA. 2005;293:1387-1390. 24 Liu RH. Pote6tial synergy of phytochemicals in cancer prevention: mechanism of action. J Nutr. 2004;134:3479S-3485S. 25 Pfluger P, Kluth D, Landes N, Bumke-Vogt C, Brigelius-Flohe R. Vitamin E: underestimated as an antioxidant. Redox Report. 2004;9(5):249~-8254.

Welcome to Functional Medicine Update for June 2005. One of the themes we have followed over the years in FMU is the relationship of dysfunction to chronic disease. As we have said on many occasions, the burden is shifting from acute disease to chronic disease. That is represented beautifully in a paper that appeared in the Journal of the American Medical Association, titled “The global burden of chronic diseases. Overcoming impediments to prevention and control.”1 This is a manifesto to the need for a better solution for management of chronic disease, which now accounts for 78 percent of healthcare expenditures. We need to manage chronic disease with a prevention and functional medicine-based strategy. In this article, the authors state: “Chronic diseases are the largest cause of death in the world. In 2002, the leading chronic diseases-cardiovascular disease, cancer, chronic respiratory disease, and diabetes-caused 29 million deaths world- wide. Despite growing evidence of epidemiological and economic impact, the global response to the problem remains inadequate.” We still do not have a healthcare system that is focused on delivering appropriate services to individuals in various stages of chronic, age-related diseases. This article calls for a more concerted strategic and multi-sectorial policy approach, underpinned by solid research in the area of chronic diseases, which is essential to help reverse the negative trends in their global incidence. That has been the major focus and impetus between where we started the functional medicine movement and how far it has evolved in 2005. We would like to think that functional medicine plays a role in providing an epistemology, or a methodology for the evaluation and management of chronic disease at a more cost-effective level, focusing on the origin of disease at the mechanistic level rather than the treatment of disease at the symptomatic level. There are many markers of concern about chronic disease in our society. The economic markers are certainly one indicator, but there are also the indicators of human suffering. There is no better example of that than the rising prevalence of age-related, chronic diseases that used to be relegated to older age, but which are now being seen in adolescents, and even younger children. The obesity epidemic, its relationship to type 2 diabetes, and even early-age vascular autoimmune diseases, are starting to appear with greater frequency in children and adolescents. This was relatively unheard of when I was being trained in biochemistry in the late 1960s. Now, it has become a much more common theme in clinics around the world, and certainly here in the industrialized United States. We wonder how this could happen at a time when we are spending twice as much per capita on health care than any other country; yet, statistically, we are 11th in healthcare outcomes. We also wonder how this could happen in light of all the new pharmacological, diagnostic, and surgical technologies that allow us to treat so many diseases that were previously considered untreatable. Yet, what we find is that the answer to many of these chronic diseases is not found in crisis treatment, but rather in better understanding the early origins of the mechanism of the dysfunctions, and correcting them before the system is broken, or in a state of pathology. That comes through in hundreds of articles that are published in top-tier journals, but yet still sits languishing for lack of proper application. We see that as we look at the incidence of metabolic syndrome and type 2 diabetes in children and adolescents. One only needs to read the article in The New England Journal of Medicine, titled “Obesity and Metabolic Syndrome in Children and Adolescents.”2 The prevalence of metabolic syndrome has increased significantly over the last decade and a half, and the prevalence of type 2 diabetes and cardiovascular disease has followed it, particularly in the adolescent population. In this article, the authors point out that the prevalence of the metabolic syndrome is high among obese children and adolescents and increases with worsening obesity. Biomarkers of an increased risk of adverse cardiovascular outcomes are already present in these youngsters, indicating that as they move into their 20s and 30s, they are likely to be high users of medical services because they will have complications of type 2 diabetes and cardiovascular disease at a much younger age than ever before. This is reminiscent of what Rudolph Virchow talked about in the 19th century. In 1847, he wrote about the origins of vascular disease, calling it an “inflammatory disorder.” However, it was so uncommon in the 19th century that it was almost an esoteric sidebar and not seen with any level of frequency. Perhaps it was even overlooked to some extent. As we moved into the 20th century, vascular disease became more and more prevalent, as did cancer, and it became the watchword of support for medical centers, with development of coronary artery bypass surgery. This is a profitable surgery, with many drugs and procedures involved, such as stenting and various types of technologies used to manage heart-related dysfunction. We are starting to see a similar trend in the 21st century, as these conditions begin to penetrate into the younger-age population. From the standpoint of economics, this trend is capable of bankrupting the disease-care system. Recently, in The New England Journal of Medicine, there was an article discussing that for the first time in the recorded history of the human species in the Western world, based on mean average demographic trends, it appears that children born today may have a lowered life expectancy than that of their parents.3 That trend has never been seen before. In regard to Medicare benefits for the children of today, the older-age individuals of the future, they are in peril because the system may be bankrupt by the time they need the services. There is an increasing rise in the prevalence of chronic disease at a younger age, and decreasing financial support for its management. That is definitely an economic motivator for change. We are at the place right now where change has to occur, either by altruism and forthright thinking, or by absolute economic requirement. We are reminded of that when looking at a particular case history published in The New England Journal of Medicine.4 . This type of case has become much more common in today’s clinics. The patient is a 49-year-old woman with a panoply of health-related problems. At presentation, she is obese, with a body mass index of 52 kg/m2. She has elevated blood pressure and diabetes. She has apparent ischemia and a number of other problems common to severe obesity, including narrowing of disk spaces in her vertebrae and intermittent leg pain, hyperlipidemia, and episodes of depression. This woman has many accompanying problems as a consequence of all her difficulties. She is on eight different medications, some of which could be interacting with one another. What does one do about this patient? In our technology-minded society, we consider gastric bypass surgery, which may be the treatment of choice for someone who is in this serious a state of impairment. In this case, the patient has gone from chronic into acute. The reason why gastric bypass surgery was recommended is because it does not seem to result in the same degree of protein/calorie malabsorption as some of the other procedures. It does appear to induce neurohumoral effects that result in the decrease of appetite, accelerated postprandial satiety, and diminished emotion-based or reward-based eating. This calls into question to what degree the gut is the seat of emotion. When a portion of the gut messaging system is remove, (it is part of the neuroendocrineimmune system), the connection between the gut hormones and the brain hormones is modified. In his book, The Second Brain, Dr. Gershon explained how these regulatory compounds or triggering molecules travel back and forth from the brain to the gut. By disconnecting the signaling of the gut, some of what is called emotion-based, or reward-based eating habits are disconnected. I find this fascinating because people often talk about eating as being totally controlled by the lateral nucleus of the hypothalamus, meaning centrally-mediated. It seems more likely, if we are to learn something from gastric bypass surgery, that there is also something happening at the gastric-hormonal-neuroendocrine level. From a functional medicine perspective, it reminds us of the web of interaction of the gut hormones with the beta cells of the endocrine pancreas, with the effects of adipocyte signaling, adipocytokines, central mediation, muscle cell physiology, and the important metabolic role the liver plays in managing calories or energy economy through lipids and sugar. It is the web of interacting messages that gives rise to a person eating when he or she should not be doing so. That brings up the question, why do people with many extra stored calories in their body fat (about 3500 calories per pound of fat) always seem to be hungry and need to eat more? It is as if the body is saying it does not have enough energy. There seems to be something paradoxical related to the signaling molecules that regulate nutrient sensing, metabolic function, and ultimately the appetite. We have a lot to learn. Case histories of gastric bypass surgery patients should help guide us in understanding that just dealing with simple calorie restriction, putting people on psychological adjustment programs, and trying to cut down their calories, is not the total answer to the problem. In people who have had gastric bypass surgery, we need to be cautious about problems related to selective nutrient difficulties, particularly some of the micronutrients that become commonly insufficient after this procedure. Some at the top of the list include iron, calcium, vitamin B12, vitamin D, and vitamin K. There are significant indications of deficiency in those nutrients after undergoing a bypass surgery procedure. Vitamin D is very important for the regulation of calcium phosphate levels in the blood and parathyroid gland function. Generally, people should be supplemented with vitamin D because more than 60 percent of gastric bypass patients have secondary hyperparathyroidism from malabsorption of calcium and vitamin D. Vitamin B12 deficiency is also very common in gastric bypass surgery patients. Supplementation with B12, folic acid, and calcium should be considered. Complex signaling mechanisms interrelate with environmental triggers, nutritional status, exercise patterns, stress-related function, and signals through gene expression patterns to what evolves as metabolic obesity, type 2 diabetes, insulin resistance, and ultimately, lipid abnormalities and coronary heart disease. A pharmacological approach to this situation that has been suggested is outlined in an article I reviewed previously by Wald and Law, titled “A strategy to reduce cardiovascular disease by more than 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36},” that appeared in the British Medical Journal in 2003.5 It was an interesting and controversial article in which the authors proposed that cardiovascular disease could be reduced by more than 80 percent in people 55 years of age and older by giving them a pill that contained six different ingredients. It would not be necessary to go through the complex process of lifestyle adjustment, nutrigenomic signaling alteration, or exercise repatterning. The pill would contain six ingredients, including a statin, folic acid (for homocysteine), a baby aspirin (for its anti-platelet effect), and half strengths of a beta blocker, an ACE inhibitor, and a diuretic. All six ingredients in one pill, the authors hypothesized, would result in a good formulation for people age 55 and older, and would reduce the relative incidence of vascular disease by more than 80 percent. Rather than accept that as a hypothesis, let us look at the model that underlies the rationale for the polypill, which is that lowering lipids and homocysteine, managing platelet and renal function, and stress-related hormones and their interrelationship with insulin sensitivity, is an important part of an overall prevention program. I would call it a functional medicine-based program for improving health outcome and lowering the burden of chronic disease. Rather than getting caught up with six molecules in the polypill, perhaps we should get caught up in the six mechanisms they are describing. As I mentioned previously, in the December 2004 issue of the British Medical Journal, there was a good article, titled “The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}.”6 The authors of that paper described that one could achieve the same benefit as a polypill by designing the dietary intake correctly to send the right nutrigenomic signaling messages to improve function associated with the etiology of CAD by similar mechanisms, if not identical, to those of the five synthetic molecules in the polypill (folic acid is considered a natural substance). This is a different strategy for reducing the burden of chronic, degenerative disease. A very elegant screening approach for lipoproteinsthat includes lipoprotein subtyping has been developed over the years, and is available from laboratories such as Berkeley Heart Labs or Atherotech. The laboratories are also developing various ways of screening lipoprotein subparticles for atherogenecity. The relationship between apolipoprotein concentration and risk to future CAD has been shown in many different studies. It has been concluded that apolipoprotein(a) predicts risk of angina and that this risk is substantially increased with high concomitant LDL cholesterol. Small apo(a) size predicts angina with greater strength and is more independent than other types of lipid parameters. Presumably, it gives more specificity to the evaluation of vascular risk. These are called extended cardiovascular risk factors, getting into lipoprotein fractionation analyses. I am reporting from an article that appeared in Clinical Chemistry.7 This comes from work being done at Harvard on extended cardiovascular risk factors. Intervention with lipid-lowering agents, such as statins, modifies lipoproteins, reducing various small-particle size atherogenic proteins, and alters serum triglycerides. Depending upon the statin used and the individuals taking it, there are different degrees of response. Primary prevention of CVD with statins in patients with elevated triglycerides and low HDL (meaning they are candidates for type 2 diabetes) is improved. This is all on the basis of randomized multicenter trials showing that intervention with statins in people with that risk factor-dense LDL particles with increased triglycerides and lowered HDL-improvement of serum lipid patterns and be achieved and reduce cardiovascular risk. Now, physicians are going beyond gross cholesterol/HDL ratios into lipoprotein profiling, looking at things like surrogate markers for type 2 diabetes and metabolic syndrome, which is the triglyceride-to-HDL ratio. That is becoming part of a profile called the extended risk factors for vascular disease. The trial I just mentioned is a multicenter trial on patients with an elevated triglyceride/low HDL complex, and its relationship to vascular disease. The paper appeared in The Lancet.8 The takeaway from this discussion is that we went from gross serum lipid analysis to lipid fractionation into the LDL, HDL, and VLDL families, and now into subfractionation into apo(a) and apo(b), looking at apo(e) isoforms such as apoE1, 2, 3, and 4, and eventually developing a better atherogenic risk profile based on these lipid particle sizes. Aggressive statin therapy in people with lipid abnormalities lowers atherogenic lipoproteins and is clinically correlated with reduced incidence of CVD. The question that has been raised is whether we are treating with statins the cause or the effect. Perhaps the statins, which have been found to be pleotrophic, (meaning having multiple functions other than blocking HMG CoA reductase, the cholesterol rate-limiting enzyme in the liver), also influence inflammatory parameters and inflammation of the artery wall. Perhaps the effect of statins is, in part, through their antiinflammatory effects, or perhaps the antiinflammatory effects have a clinical correlation with the cholesterol-lowering effects. Perhaps they are mechanistically connected. That is where the research is just starting to open up a potential connection. The connection has the potential of being related to the topology of the membrane. As cholesterol is removed from the blood and enters into the lipid environment of the cell’s membrane, its structure is changed. Therefore, the membrane-bound receptors that sit on the surface of the cell, an endothelial cell for example, pick up different signals from the composition of their membranes, which is influenced by what is in the blood around them. They may be picking up different inflammatory messages based upon the cholesterol composition in their membranes. Or, it is possible that inflammatory message signals at far different sites can alter cholesterol synthesis, resulting in changes in blood cholesterol concentration and, eventually, in the lipid bilayers of membranes, which alter the cell’s structure and function. Whether it is inflammatory mediators that cause the cholesterol changes, or the cholesterol changes that alter the inflammatory sensitivity and mediators, is still open for discussion. There is clearly some degree of interrelationship between the two, even though inflammation and serum lipids are partially independent processes. Let me move to the subject of folic acid. The homocysteine argument has continued to emerge since Kilmer McCully first brought it to our attention nearly 40 years ago. Now, there is generally a more widespread understanding that elevated homocysteine is an atherosclerosis and cerebrovascular risk factor. An interesting paper published out of the prospective Kuopio Ischaemic Heart Disease Risk Factor Study that investigated the relationship between serum folate, homocysteine, and the incidence of acute coronary events, found that the hypothesis that high circulating homocysteine was a risk factor for acute coronary events in male populations free of heart disease, does not seem to be true.9However, the investigators found that moderate to high serum folate concentrations are associated with a greatly reduced incidence of acute coronary events. This raises the question, is there something about folate beyond the issue of homocysteine that is related to cardioprotection? That is an interesting theme that I have been talking about for some years. In 2004, I discussed a paper that appeared in the Journal of the American Medical Association that indicated that women with higher dietary folate intake, as menstruating younger women, have lower blood pressure than women of the same age with reduced folate intake. This did not appear to be related to homocysteine. The mechanisms of these observations are starting to be seen as a consequence of better understanding of the physiology of the endothelium and its relationship to vascular smooth muscle tone in the artery system. As there is an alteration in endothelial function, there is an alteration in smooth muscle tone-it is more constricted, less dilated, and the pressures increase. What is the connection between folate and endothelial function that would indirectly relate to the modulation of blood pressure? That is a good question, and the answer seems to be emerging through a better understanding of how folate regulates endothelial nitric oxide synthase (eNOS) activity. I will be discussing that in greater detail in this issue of FMU, but eNOS is the enzyme responsible for converting arginine in the endothelium into the amino acid citrulline, and producing nitric oxide (NO) as a byproduct. NO used to be thought of as the elusive endothelial relaxing factor. It is secreted into the adjacent smooth musculature of the arterial system, thereby causing muscle relaxation and lowering blood pressure. This work won the Nobel Prize in Medicine in 1998 for Ignarro, Murad, and Furchgott. The discovery of the role of NO in human physiology has now revolutionized our thinking about small molecules and the influence they have on a wide range of tissue function, in this case, endothelial function specifically. Tetrahydrobiopterin It turns out that the cofactor for the conversion of arginine to citrulline in the production of NO is tetrahydrobiopterin. Tetrahydrobiopterin is a folate-requiring cofactor in cellular physiology. It is found in high levels in endothelial cells in the conversion of arginine to NO through eNOS. Therefore, it is possible from studies that have been published, that enhanced levels of folate have a direct effect on vascular tone through their influence on eNOS activity and the production of more NO. Here is a non-homocysteine-mediated effect on vascular function that may help to explain why folate and vitamin B12 have been found useful in lowering the incidence of heart disease, even in the absence of elevated homocysteine. I come back to the Finnish study that did not show a correlation between homocysteine and sudden coronary events, but did show a correlation with folate. We are bearing here slightly on an interface between vascular biology, serum lipids, and the concept of immune function and inflammation. It is a somewhat swirling pattern that is emerging when we talk about the reduction of risk and incidence of cerebrovascular and cardiovascular disease. Clearly, the arterial garbage collector that picks up a lot of this lipid and may modify the inflammatory potential is the lipoprotein called high density lipoprotein (HDL). Most individuals would say that HDL is a “good cholesterol” because it is able to remove lipid from circulation that may be atherogenic. It is a reverse flow of potential atherogenic lipid. Individuals with low HDL levels are those who have been found to have higher incidence of CVD. Conversely, people with high HDLs have lower incidence of CVD. HDL exists in several isoforms, some of which may be more atherogenic than others. We probably should not just talk about generic HDL. Before we get into the specific isoforms of HDL, I want to talk about HDL modification. HDL is a good cholesterol, until it has been potentially chemically modified in the vasculature by undergoing oxidative modification. What is it that oxidizes HDL? It is an enzyme called myeloperoxidase. Myeloperoxidase is a white-cell enzyme involved in the Klebanoff reaction, the reaction that produces hypochlorite, or bleach, that is part of the chemical warfare armamentarium that our bodies use to kill foreign invading cells. When white cells are activated, they produce higher levels of activity of myeloperoxidase, which increases hypochlorite production. Myeloperoxidase activity also increases the conversion of HDL to damaged HDL. It has recently been found that oxidative injury to HDL changes “good cholesterol” into “bad cholesterol,” meaning it converts friendly HDL to unfriendly HDL. This is an interesting new twist on the story because it connects the inflammatory mechanism with the lipid mechanism through the HDL modification pathway. An antiinflammatory apoA1, when converted into a proinflammatory form by myeloperoxidase, results in injury to HDL, which becomes atherogenic. This is a fairly remarkable new discovery. I am now citing one of a series of papers in Nature Medicine that talks about the atherogenecity of oxidatively injured HDL. 10 People are now starting to look at myeloperoxidase levels. In fact, we cited a paper that appeared in the Journal of the American Medical Association in 2004 that showed a close correlation between the relative incidence of CVD and myeloperoxidase activity levels, potentially a new prognostic marker, another one of the extended risk factor markers. If we think of myeloperoxidase as being an indirect inflammatory marker, then this connects inflammation to serum lipids to atherogenecity. Metabolic control of serum lipids is very important. Control of the status of lipids so they do not undergo oxidative injury is important. Lowered inflammation is important. Proper vascular biology related to eNOS is important, and increasing HDL levels is favorable. How can that be done? There are different protein hydrolysates that have been shown to increase HDL levels. There have been some interesting studies showing that fish protein hydrolysates and certain soy proteins can actually increase HDL levels. I am now quoting from the Journal of Nutrition.11There are certain dietary signals that are more than just protein, carbohydrate, and fat, but specific types of molecules in our diet that may have a favorable effect on elevating gene expression of the HDL lipoprotein, or apolipoprotein. That raises the question as to whether there are specific types of foods that contain elements that can speak to the genes in such a way as to activate favorable cardioprotective outcomes. It is more than just restricting calories, and it is more than just restricting fat and increasing protein, or decreasing carbohydrate. There is something about the messenger molecules, the dietary signals we are sending from specific foods, that relate to the outcome we call relative disease risk If we marry this to recent data on statins, it opens up some interesting questions. If we look at statin research, we know that aggressive or intensive intervention with statins has been demonstrated to lower acute coronary syndromes. This is discussed in one of a series of papers that appeared in The New England Journal of Medicine, in which intensive statin therapy was called a “sea change” in cardiovascular prevention, trying to get LDL levels lower than 100 mg per deciliter.12 ,13 When LDL is around 70, the risk or incidence of cardiovascular disease is reduced even more. However, in more recent studies published in 2005, it has been demonstrated that intensive statin therapy results in greater reductions in both lipids and high sensitivity C-reactive protein (hsCRP). In addition, the decreases in lipids and CRP is associated with reduced progression of atherosclerosis. It is not as simple as looking solely at LDL cholesterol, but it is also necessary to look at serum inflammatory markers. I am citing here from a The New England Journal of Medicine, 2005.14 It is not just lipid levels. As we see more and more evidence being published, there is something pleotrophic about the mechanism of action of statins. They may affect the lipids and endothelial inflammation in some people. I am now quoting from a review that appeared in the Journal of the American Medical Association, titled “High-dose statins in acute coronary syndromes. Not just lipid levels,” in which the authors talk about the dual responsibility, or effects of statins.15 C-reactive protein, as a measurement of inflammation, is not only an inflammatory marker, but could also be a direct agent that relates to relative risk of injury to the arterial endothelium. We think of intracellular adhesion molecules as being indicative of injury. We think of proinflammatory cytokines, such as IL-6. We think of myeloperoxidase and we think of hsCRP. As has been pointed out, hsCRP is not the be-all and end-all for cardiovascular risk due to inflammation, but it is a good screening tool. Values chronically elevated (above 1.5 mg/dL) may suggest an increasing relative risk to vascular disease. Levels of hsCRP can be elevated solely by a cold, the flu, or running a marathon, but they will usually come back to normal after recovery. It is when there is a consistent elevation of hsCRP over time that we talk about the “arteries on fire,” and their relationship to cardiovascular disease. A discussion of this topic can be found in Medical Hypotheses.16 There is a distribution of elevated C-reactive protein in the population at large. This is discussed in a study in Clinical Chemistry, in which the authors talk about the fact that people with more insulin resistance, metabolic syndrome, and high triglycerides/lower HDL also generally have increased hsCRP levels.17 It is a bell-shaped, non-parametric distribution of hsCRP in our population, skewed to the higher level, meaning we are already a culture in inflammation associated with the increasing risk of CVD. Coxibs and Cardiovascular Disease How does the use of the selective coxib drugs relate to this? As they were being used for the treatment of osteoarthritis, in some people they actually increased coronary events, because by blocking all COX-2 enzymes, they also block favorable enzymes that produce friendly eicosanoids in terms of the control over blood flow parameters. In this case, the selective COX-2 inhibitors, such as rofecoxib, and even celecoxib, have been associated with increased vascular events, due to blocking production of prostacyclin (PGI2) in the endothelium. As Garret FitzGerald recently discussed in The New England Journal of Medicine, coxibs are associated with cardiovascular disease because of the non-tissue-specific inhibition of regulatory substances from arachidonic acid, which are prostaglandins associated with housekeeping functions, like PGI2 from the vascular endothelium.18 In a further editorial in The New England Journal of Medicine, author Eric Topol contends that the drug companies were failing the public health by not bringing to light the fact that these anti-arthritic drugs were also having adverse cardiovascular effects due to blocking important prostanoids in an untenable fashion.19

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INTERVIEW TRANSCRIPT

Erminia M. Guarneri, MD, FACC Scripps Clinic Division of Cardiology 10666 North Torrey Pines Road La Jolla, California 92037 JB: It’s time for our Clinician/Researcher of the Month. Last month, we had the pleasure of interviewing Dr. Mehmet Oz from Columbia University, and we were all rewarded by the comments he made concerning how he sees medicine evolving. On this theme, we couldn’t be more pleased to have cardiologist and internist, Dr. Mimi Guarneri as our guest this month. In 1999, she founded, and is now Director of, the Scripps Center for Integrative Medicine. Dr. Guarneri received her Bachelor’s Degree in English Literature from New York University, a Master’s in Bioengineering from The Polytechnic Institute of New York, and MD from SUNY Downstate. She is also board certified in holistic medicine, and an assistant clinical professor of medicine at the University of California/San Diego. In addition to her many accomplishments, she is a remarkable person, and I have had the privilege of getting to know her over the last few years. To elaborate on her background somewhat, Dr. Guarneri is co-author of a paper published in the American Journal of Cardiology (1999), titled “Quantitative angiographic analysis of stent restenosis in the Scripps Coronary Radiation to Inhibit Intimal Proliferation Post-Stenting (SCRIPPS) Trial.” Another of her papers was published in 2003 in the American Journal of Cardiology, titled “Improvement in medical risk factors and quality of life in women and men with coronary disease in the Multicenter Lifestyle Demonstration Project.” She also has a paper currently in press on how biofeedback increases heart rate variability in patients with known coronary artery disease. Heart rate variability is a very important function of heart health-the more variable, the more degrees of freedom, the more degrees of entropic freedom, the healthier the heart. All these things demonstrate Dr. Guarneri’s wide range of interests. Mimi, it’s a privilege to have you on FMU. The first question I want to ask is, how do you get to cardiology from an undergraduate degree in English literature and a Master’s Degree in bioengineering? MG: Thank you for that wonderful introduction, and that’s a great question. Literature has always been a love of mine, and when one goes to college, there are many opportunities. Most of the other premed students were majoring in biology and chemistry, which are certainly important. I was always fascinated with those subjects, as well as reading Shakespeare and Homer’s poetry. I’ve always worn two different hats. The bioengineering was a wild card, because for a short period of time, I thought I could make a difference by devoting myself to the research side. Then I realized that medicine is my love, because people are my love. I decided to go to medical school and the rest is history. JB: I understand from Dr. Bonakdar, your colleague at Scripps, that you recently decided, for reasons you will probably share with us, that you needed to go back and focus on a Board certification in nuclear cardiology. Is that correct? MG: Yes. One of the things we learned here at the Integrative Medicine Center is that the more we can bring into the center that blends Western medicine with alternative medicine, the more well-rounded we are. To that endeavor, because one of my passions is prevention of disease and to be able to detect disease early, we put a significant amount of resources and energy into creating what’s called an early detection center. That includes quite a bit of technology, with CT imaging and PET, which stands for Positron Emission Tomography imaging, for the heart. To be prolific and able to read these scans, one needs to be Board certified in nuclear cardiology. My ultimate goal with all of this is not only to identify disease early so as to prevent it, but to test some alternative modalities and integrative interventions utilizing this technology. JB: Well, congratulations. Dr. Bonakdar also told me I should have great respect for anyone who has accomplished this goal, because nuclear cardiology is known to be one of the more difficult Board certifications, requiring a lot of study. Some people need to take this exam a couple of times. You passed it with flying colors on the first time through, while still overseeing the directorship of the Integrative Medicine Center and all of your other responsibilities. It’s another measure of you as a person, and we are all in awe. It’s pretty impressive. MG: Thank you. JB: With your background and broad range of interests, how did you ultimately become the founder of the Scripps Integrative Medicine Center? That might be somewhat risky with your background. What led you down that path? Initiation of the Scripps Integrative Medicine Clinic MG: I don’t think it’s risky. I came to Scripps to put stents in coronary arteries. I was doing what I call advanced plumbing-fixing vessels that already had evidence of narrowing from cardiovascular disease (CVD). I would put in seven to ten stents a day. Then I would go up to the ICU to see my patients and they would be eating roast beef sandwiches or beef stroganoff. They would go home the next day with absolutely no instruction about lifestyle changes, proper nutrition, nutraceuticals, or stress management. After you do this for a while, you begin to realize the old Chinese saying about what insanity is-doing the same thing over and over and expecting a different result. That rings true in cardiology. The more we were stenting and sending people home, the more they were coming back. Not only were they coming back with re-stenosis or lesions within their stents, but they were coming back with new lesions. A lot of that is because we weren’t taking the time 0o turn the faucet off, literally. After watching this year in and year out, I started to realize that we needed to do something radically different for our heart patients. That’s where we began-with the heart patients. Ironically, of course, in the beginning, ten years ago, teaching heart patients about nutrition and exercise was considered alternative medicine. JB: As I recall, you originally started with Dr. Dean Ornish’s program at the center. We have had the privilege of interviewing Dr. Ornish on FMU. Clearly, that’s evolved as you’ve gained experience and have seen what works and what doesn’t related to developing the best approach to the personalized needs of the patient. Tell us about how you started down this path, from your mission to its implementation. Scripps and Dean Ornish’s Research MG: It’s an interesting story. I came out of the cath lab one day and Dean Ornish was talking to one of my colleagues. He introduced himself and said he wanted us to be a site for his research. I asked him what the focus of his research was, and he explained that it was a low-fat, vegetarian diet; yoga; meditation; exercise; and group support for heart patients. I looked at him as if he was a little bit crazy because my whole paradigm was one of stenting and doing the high technology piece. Long story short, I said I would be happy to be the principal investigator for Scripps, because I’ll do just about anything for research-and off we went. The first thing I had to do was to get trained myself, so I enrolled in one of Ornish’s retreats in northern California. I went to the retreat with a cholesterol of 320, a type triple A personality, and enormous amounts of stress in my daily life. I began to do the retreat as a heart patient. I came out one week later and I was a vegetarian. I was doing yoga two hours a day and, more importantly, I had learned an enormous amount from the patients who were there. I started to see people’s lives change, just in one week of intensive intervention. By that, I mean insulin levels were being cut in half, and chest pain was going away. I thought this research needed to be taken seriously. That’s how we went forward in the beginning-being part of what’s called the Multicenter Lifestyle Heart Trial, of which Scripps was one of the research sites. JB: With your mechanical mind, as well as your broad-based humanistic perspective, did you feel that there would be ways of putting this into an institutional setting and making it work? That’s always been a challenge-going from conceptualization to practice. Incorporating Integrative Medicine into Cardiology MG: Absolutely. I looked at what we were doing inside the research program. When the research was over, I thought that we couldn’t let it go. At that time, people were randomized to go into the lifestyle change program or have a stent or a bypass. So, it was randomization of lifestyle change versus stenting and bypass. Ronnie King and I looked at this and agreed that we needed to do both. That’s when we embraced the term, “integrative medicine.” We thought that’s what we were really about. It’s OK to have a stent if you need one. It’s OK if you need a bypass. But why should we stop there? We decided to combine the lifestyle changes with the intervention and birth an integrative medicine center. We went forward with that concept and it was embraced on some level by the physicians because we called it integrative medicine. Quite frankly, the term alternative medicine in a conservative healthcare institution has some negative stigma to it. We called it integrative medicine and said we were going to start from the heart, because that’s what we do best. We began to do what we like to refer to as a more personalized medicine approach-not one diet fits all, not one group of nutraceuticals fits all, and not one exercise program fits all. We began to slowly, but steadily build a program to incorporate heart patients who had surgery or stenting and, of course, people who wanted to prevent any of these situations who were at high risk. Incorporating A Pain Management Program About three years into the program, we looked back again. We were exercising people and what did they have? They had joint pain, muscle pain, aches, and arthritis, and I didn’t want any of my heart patients on excess amounts of pain relievers. At that time, I was concerned about blood pressure and GI side effects from non-steroidals. Many of my patients have renal insufficiency. There are drugs that can affect their GI tract. That’s when we thought that in addition to doing lifestyle changes with heart patients, we needed a pain management program. That’s when Dr. Bonakdar came aboard to lead the way in that arena. Slowly, but surely, the pain management program has grown. We have incorporated many of the technological pieces into the integrative center that we were previously sending out. For example, we decided we wanted to be “high tech/high touch.” Frankly, in a hospital system, you can be as high touch as you want, but it doesn’t pay the bills. This is getting down to the brass tacks of being successful. Medicine considers success financial success, as well as the success of helping someone. Without financial success, we would not be able to exist. We decided to do everything under one roof, including the best of technology, CT, PET imaging, stress testing-all of the things we would do at the hospital-along with acupuncture, yoga, meditation, tai chi, nutrition counseling, herbal medicine and so on. And that’s where we are today. JB: For those listeners who haven’t had the privilege of visiting your facility, it’s an amazing blooming of right/left brain hemispheres, of east and west, of cultural and ethnic diversity, and with a very remarkable laboratory demonstrating that these things can live in harmony. It has a wonderful feeling to it. Debates are ongoing as to what the real versus perceived benefits of integrated cardiology are. We might believe that certain things are good, but our colleagues might ask us to show them the reality, the facts, and the evidence base. In any field, there are points of exaggeration where things don’t measure up under scrutiny. What would you say the real versus perceived dilemma, or dialectic, is right now in integrative cardiology? Issues in Integrative Cardiology MG: There is a lot of data in good medical journals. Looking back at the early research of Dean Ornish, for example, he was able to demonstrate that in certain populations of patients, the progression of vascular disease can be halted. More importantly, 91 percent of the patients in the Ornish research studies became angina free. Their endothelial function improved because of stress management, a low-fat diet, and the benefits of exercise. If you look at nutraceuticals, the area in which you are an expert, Jeff, no one can dispute the fact that certain supplements have good data for the heart. For example, if I want to raise someone’s good cholesterol (HDL), there’s nothing out there. Maybe there’s some research on synthetics going on right now, but there’s nothing out there better than niacin to achieve that goal, in my opinion as a cardiologist. If I want to lower homocysteine levels, I think the data is good for the use of B vitamins. If we need to, we can certainly pull out data on anything we do here at Scripps and justify it; for example, even exercise in heart patients. Half the number of hospital readmissions are patients who are doing cardiac rehab, and yet almost every hospital in the country cuts cardiac rehab programs because they don’t make money. The Need for a Paradigm Shift What we need is a paradigm shift. We need a paradigm shift to the point where physicians get compensated for keeping people well. That’s the big issue. Physicians don’t get compensated for that. They get compensated for putting in devices and doing surgery, which I’m not against, but there’s more to medicine than that. Any area you can think of, whether it’s exercise, stress management, biofeedback, or nutraceuticals, we can quote you good literature as it applies to the heart, and there’s no cardiologist in the country who would say that nutrition, lifestyle changes, managing stress, anxiety and worry, and exercise, or dealing with someone’s diabetes, is not going to improve cardiovascular outcome. Most physicians don’t do it because they don’t have the resources that allow them to do it. JB: I often hear from people who are not ready for change that they are fearful of liabilities and, in our society, if one is not Board-certified and in the stream of their peer service organization, it’s too much of a liability. What about the liability issues? The Issue of Liability MG: It doesn’t matter what kind of medicine you are practicing. You need to do what’s within your scope of practice, knowledge, and understanding. If there’s research behind it, then it’s just medicine. It’s not integrative medicine; it’s not alternative medicine; it’s not Western medicine; it’s just medicine. If it’s been demonstrated to work, then you use it. As a physician, for me personally, I could not sleep at night if I was doing something that I was even remotely concerned about regarding liability issues. Then, I’m doing something that is out of scope, perhaps of good judgment, or so on. That’s not what’s going on here, at least at Scripps. And that’s how I choose to practice. For example, if I’m giving someone magnesium for the prevention of cardiac arrhythmia, there’s research to support that. I don’t really worry about liability. Maybe I don’t worry about it because I’m not doing anything that I consider radical. JB: That’s well said. I’ve had a couple of conversations with very well respected cardiologists who said they don’t think there’s anything to the inflammation/atherogenesis story and that they don’t worry about things like hsCRP or inflammation. What’s your position on that? Inflammation and Atherogenesis MG: I’d be shocked, because I go to the big meetings and inflammation is the buzzword. Most cardiologists in academic circles are talking about inflammation. I’ll give you a good example. Within the last year, we had two major lipid studies published. One is called “Reversal;” the other was called “Prove It.” In the lipid study, “Prove It,” they took high-risk people with cardiovascular disease and randomized them to two different types of statin therapy-one was a high dose of Lipitor and the other a dose of Pravachol. What they found at the end of the day was that both drugs reduced the HDL the same amount. For example, if you take people who had a 40 percent reduction with Pravachol and people who had a 40 percent reduction with Lipitor, for some reason, the people who took the Lipitor had more plaque regression. The question is, why? Is LDL so smart that it knows the difference between two statins? I don’t think so. When they examined the data more closely, they found Lipitor had a much more profound effect on hsCRP. I point this out because here’s a perfect example of LDL-lowering with different clinical outcomes that can only be pointed to based on hsCRP. You know better than anyone, and certainly better than I do, that this is just one small tip of the iceberg marker for inflammation. We now know, and I believe this, that on every level of atherosclerotic plaque, when LDL comes into the subendothelial space, it becomes oxidized. That turns on inflammatory cytokines that lead to adhesion molecules pulling in white blood cells. We know now that inflammation is involved in every step along the way. I would challenge almost any cardiologist who has been in practice for at least a few years, that they will have patients with cholesterols of 120 and 130 with coronary disease, and the only risk factor is inflammation. We know there is a very high risk for CVD in patients with rheumatoid arthritis (RA). Inflammatory diseases are associated with a very high risk of vascular disease. I don’t think we can throw inflammation out. As a matter of fact, we’ve been focusing on LDL for a long time, and maybe we’ve been missing the boat. JB: The reimbursement issue is another area that is responsible for why people don’t change to integrative approaches. Patients can’t get reimbursement. The issue of Reimbursement MG: As healthcare consumers, we have to take health care more into our own hands. What I encourage people to do is get medical savings accounts. You can put aside a piece of your earnings, or a piece of your salary so you can use it in a way that you and your physician deem you need. You may determine you cannot go to a program because you don’t meet the criteria. For example, let’s say you want to attend a cardiac rehab program. You have to have had a heart attack or a stent or an angioplasty or surgery before you can get into a cardiac rehab program. There has to be some sort of devastating event or, more importantly, a nutrition consultation. I would challenge most people to call their insurance company tomorrow and tell them they’ve put on some weight, and that they just want to learn how to eat healthy. Ask if they will pay for seeing a nutrition counselor. Invariably, the answer will be, “only if you have diabetes.” I encourage my patients to set aside a portion of their salary so they can choose to spend it in a medical savings account the way they want to spend it. If they think acupuncture is what they need for their muscle spasms, or tennis elbow, or back pain, then at least there’s money they can pull from. We have to be more creative because we are all healthcare consumers. We have to be savvy about this kind of thing. As the old joke goes, should I go into a lifestyle change program or have a bypass? Oh, I think I’ll have the bypass because that’s what my insurance covers. We need to get people out of that mindset. JB: You interface at the integrative medical center with the other departments at Scripps. You have conversations with colleagues across multi-disciplines of specialty. How do you deal with some of the political and communication-related issues? Is it just information? Is it opening up the opportunity for discovery? How do you handle those complicated interfaces? Political and Communication Issues MG: We’re in a 320+ physician group. Integrative medicine is a separate division, which we’re proud of, the same as cardiology and rheumatology are separate divisions. Just like anywhere else, when you forge change, there will be people who embrace it and those who fear it. Fear is what brings about opposition. The more we can be mainstream with the other physicians, the more they know we’re there to help the patients. The more they trust that what we’re doing is evidence-based and has research behind it, the more we build bridges. For example, in the department of neurology, many, but not all, of the neurologists have embraced the pain management program, and they will send us complicated patients who can benefit from biofeedback or massage, particularly for headaches. We get rheumatology patients, patients with fibromyalgia, and we get cardiology patients, of course, because I’m a cardiologist. Slowly, but surely, you have to work within your system. It’s very important to have physicians who are not afraid to be on boards like the IRB. Dr. Bonakdar is on the Scripps Pain Management Board. We’re working with everyone else. That’s how you deal with a lot of the potential politics and opposition. Not to say it’s perfect, but our goal is one of education. Believe me, we have been branded by people who don’t come and visit us because they don’t know who we are at this alternative center. They think we’re doing all sorts of things that we don’t do at all. We always invite people to come, see what we’re doing, and spend some time with us. We have a very active teaching program for interns, residents, and Fellows so we can get the word out in a meaningful way. JB: One last question. It strikes me in getting to know you, Dr. Oz, and others in your field, that you are quite remarkable people. You’re semi-fearless, very intelligent, well schooled, tireless workers, and you take on a lot more responsibility than the average person does. It raises the question that a lot of people coming into this field might ask, and that’s whether it is expecting too much of the average doctor to make this transition. Are we saying that you have to know everything and be everything to be successful? I want to raise that question because clearly, you are a very exceptional person. Is there still room for people who don’t necessarily have all the necessary background skills and commitments that you have? Making the Transition to Integrative Care MG: You don’t have to know everything. You can always surround yourself with people who are more knowledgeable in a particular area than you are. One of our pharmacists is far more knowledgeable than I am, for example. You can educate yourself and get to the best of the knowledge. Any physician can do that. The real challenge is being able to stand up to the system, look at your patients and ask what you can do differently for them. In other words, how can I make it better? For me, that came with an integrative medicine attachment to it. I looked at my heart patients and realized we didn’t have exercise programs, proper nutrition or nutraceutical counseling, stress management, or a pain management program. How can I be the change that I want to see (to use the words of Ghandi)? That’s where the courage comes from-standing up and saying you’re not happy with the way it is, and that you want something different for your patients. That’s really what it takes from a physician to get something like this going. It takes the willingness to run against the herd, or away from the herd, and realize that the way you’re doing it is good, but you can do it a little bit better. JB: That is such an aspiration of what we’re trying to create in our vision and mission. Thank you very much on every level, both technically and philosophically, for sharing time with us. We’re all motivated by vision. All of us sometimes need to draw from our colleagues who are pulling the oars and moving in the same direction. You’ve given us a tremendous resource to draw from. Thank you so much and keep up the tremendous work. MG: Thank you, Jeff. Regulation of Nitric Oxide Synthase and Cardiobiology Following up on some of Dr. Guarneri’s comments, I would like to embellish a couple of concepts that we were discussing during the first part of this month’s issue of FMU. They have to do with the regulation of eNOS and its relationship to cardiobiology. This is a fascinating area in which we are developing an ever-increasing understanding. It is becoming clear that individuals with deranged endothelial function due to insulin resistance, hyperinsulinemia, oxidative stress, or inflammatory activity, may also benefit from enhancement of eNOS activity through the use of supplemental arginine and antioxidants, and 5-methyltetrahydrofolate, or folic acid. The combination of those nutrients helps to regulate eNOS output, causing vascular smooth muscle to relax, improving vascular tone, improving insulin sensitivity and lowering inflammatory potential, because it lowers the uncoupling of eNOS and its production of oxidants. There is a variety of positive influences in people with damaged endothelial function by supplementing with the amino acid arginine and various antioxidants, including polyphenols, vitamin E, vitamin C, and 5-methyltetrahydrofolate, or folic acid. According to Dr. Ignarro, one of the 1998 Nobel Prize winners, the doses I am talking about are in the range 6 to 9 grams a day of arginine and 2 mg of folic acid (that could be 2 to 5 mg, depending upon the degree of endothelial dysfunction). If you are going to use high doses of folate, you want to make sure the patient is properly repleted with regard to vitamin B12. Last is the use of a complex antioxidant that contains polyphenols, bioflavonoids, vitamin E, and vitamin C. That can be secured from the diet or from supplements. This approach has been demonstrated in cardiobiology by people like Dr. John Cook at Stanford to improve endothelial function, improve blood pressure, and regulate some of the oxidative chemistry going on in the vascular wall. I am quoting from two review papers in the Lancet that follow up on a discussion of increased NO-derived production in the failing human heart.20 ,21 When NO is produced in the vasculature, part of it becomes connected to hemoglobin to form nitrosyl hemoglobin, which has some physiological importance in terms of cell signaling and cellular regulation. There is a wonderful series of articles published in Free Radical Biology and Medicine on the physiologic, pathologic, and therapeutic implications for hemoglobin interactions with NO.22 ,23 ,24 ,25 I would encourage you to read these articles if you are interested in looking at hemoglobin/NO cooperativity. One of the principal signaling mechanisms that has evolved in the human body over time is the S-nitrosohemoglobin signaling pathway, which is an oxygen-dependent mediator of NO delivery to vascular smooth muscle cells, thus helping to regulate vascular tone and blood flow. Central to this is the concept that the interaction between NO and hemoglobin was deficient. What happens if one has anemia or poor nitrosyl hemoglobin formation is that less time release is available for NO to regulate vascular tone, and there is more vascular injury and more risk to hypertension. This is discussed in a review that also appeared in Free Radical Biology and Medicine. Iron Overload and Cardiovascular Disease This raises an interesting question. When we think hemoglobin, we think iron and we think NO. What about iron overload and cardiovascular disease? Is there some kind of a balance, and what is the interconnection? I think there is some misunderstanding about iron and CVD. There is no question that excessive levels of free iron are associated with the so-called Fenton reaction, the production of oxidants, and the alteration of redox signaling in the vasculature. In these situations, iron is either excessive relative to the binding capability, or released through tissue injury of free iron that directly participates in the Fenton catalyzed reaction of super oxide into hydroxyl radical, a very promiscuous oxidant. In situations where the iron is bound to transferrin or within hemoglobin, there is not much risk of oxidative injury. In fact, this is discussed in a good review article, titled “Iron, oxidative stress, and disease risk,” that appeared in Nutrition Reviews.27 The authors talk about evidence that shows how excessive iron is found in many diseases but that it has not yet been shown to be a causative factor. Although iron can participate in oxidative reactions to generate free radicals under in vitro conditions, its involvement in vivo as a cause of progression of disease is questionable. It appears that only if iron is lost as free iron from tissue iron stores and not as bound through hemoglobin or other iron-binding proteins, that these types of reactions are catalyzed. It may be a combination of iron reserve in addition to other precipitating underlying inflammatory or traumatic issues that liberates free iron to participate in oxidative injury. For instance, consider a hemorrhage. At the site of a hemorrhage, there is blood loss, and that blood will lose its iron as free iron, and that can engage in prooxidative chemistry. That is why minimizing blood loss and tissue blood accumulation is very important to lower the risk to oxidative injury and secondary effects from a trauma to that tissue. Experimental studies have consistently shown that iron is a critical catalyst in generating oxygen free radicals via Fenton chemistry. Epidemiological studies conflict on the association between stored body iron markers and disease outcomes, including CHD. Stored body iron markers common in epidemiological studies, such as serum ferritin, transferrin saturation, iron, or iron-binding capacity, are actually inappropriate to investigate the harmful health effects related to iron overload. Oxygen free radicals are produced only by free iron, but stored iron markers reflect iron bound to ferritin or transferrin, which is not able to deliver free iron, but rather is sequestered catalytically so that it cannot generate some of these oxygen free radical effects. It is generally believed that free iron rarely exists, except in iron-overload with 100{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} transferrin saturation. However, some recent studies find non-transferrin bound iron or the intracellular labile iron pool in the presence of triggers disturbing iron homeostasis. These triggers can be such things as alcohol consumption, physical trauma to tissues, ischemia, or even inflammatory mediation on those tissues that releases the intracellular labile iron pool, which can participate as a catalyst in the Fenton reaction. Research on the relationship of iron to disease outcomes should investigate these labile iron pools because they are the ones that seem to be most problematic in inducing free radical oxidative injury. These factors may explain why there have been conflicting results between serum markers of stored body iron and diseases that relate to epidemiological outcome studies.28 I would urge everyone not to jump on the anti-iron bandwagon too quickly. I fear that when people start worrying about iron as the cause of heart disease, they actually start producing a situation of anemia in some patients which, ironically, increases the labile iron pool by ischemic events, and increases oxidative injury rather than decreasing oxidative injury. The story is proper hemoglobin hematocrit levels, making sure not to push a patient into anemia, and not being overly concerned about iron until there is excess dietary iron intake. For instance, some supplements in pregnancy formulas deliver 75 to 100 mg of elemental iron. That may be excessive, so we have to look at everything as a parabolic dose response curve. Mercury and Cardioprotection A heavy metal that deserves some consideration in a cardioprotection program is mercury. There is more and more evidence coming out looking at the atherogenic effect of excess mercury exposure. This comes through fish, as well as through other sources of mercury and its relationship to heart disease. There is a nice review of this topic in Nutrition Reviews,29looking at total body mercury exposure from fish and other dietary intakes, and amalgams, how they release their mercury content, and how this ultimately influences function. What I have tried to emphasize in this review, following up from Dr. Guarneri’s beautiful discussion about CVD prevention, is that much of the burden of chronic disease we are experiencing is modifiable, not necessarily through the use of a polypill, but a polymeal or a polydiet lifestyle approach toward modulating gene expression patterns. That is the focus of the functional medicine model which emphasizes the mechanisms of disease, rather than just their outcomes. Thanks for being with us. We look forward to being with you in July.

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Bibliography

1 Yach D, Hawkes C, Gould CL, Hofman KJ. The global burden of chronic diseases. Overcoming impediments to prevention and control. JAMA. 2004;291(21)2616-2622. 2 Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350(23):2362-2374. 3 Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005;352(11):1138-1145. 4 Pratt JS, Cummings S, Vineberg DA, Graeme-Cook F, Kaplan LM. Case 25-2004: A 49-year-old woman with severe obesity, diabetes, and hypertension. N Engl J Med. 2004;351(7):696-705. 5 Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. BMJ. 2003;326:1419. 6 Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. BMJ. 2004;329(7480):1447-1450. 7 Rifai N, Ma J, Sacks FM, et al. Apolipoprotein(a) size and lipoprotein(a) concentration and future risk of angina pectoris with evidence of severe coronary atherosclerosis in men: The Physicians’ Health Study. Clin Chem. 2004;50(8):1364-1371. 8 Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696. 9 Voutilainen S, Virtanen JK, Rissanen TH, et al. Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr. 2004;80:317-323. 10 Fogelman AM. When good cholesterol goes bad. Nature Med. 2004;10(9):902-903. 11 Wergedahl H, Liaset B, Gudbrandsen OA, et al. Fish protein hydrolysate reduces plasma total cholesterol, increases the proportion of HDL cholesterol, and lowers acyl-coA:cholesterol acyltransferase activity in liver of Zucker rats. J Nutr. 2004;134:1320-1327. 12 Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504. 13 Topol EJ. Intensive statin therapy-a sea change in cardiovascular prevention. N Engl J Med. 2004;350(15):1562-1564. 14 Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352(1):29-38. 15 Nissen SE. High-dose statins in acute coronary syndromes. JAMA. 2004;292(11):1365-1367. 16 Li JJ, Fang CH. C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases. Med Hypotheses. 2004;62:499-506. 17 Ford ES, Giles WH, Mokdad AH, Myers GL. Distribution and correlates of C-reactive protein concentrations among adult US women. Clin Chem. 2004;50(3):574-581. 18 FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med. 2004;351(17):1709-1711. 19 Topol EJ. Failing the public health-refecoxib, Merck, and the FDA. N Engl J Med. 2004;351(17):1707-1709. 20 Hare JM. Spatial confinement of isoforms of cardiac nitric-oxide synthase: unraveling the complexities of nitric oxide’s cardiobiology. Lancet. 2004;363:1338-1339. 21 Damy T, Ratajczak P, Shah AM, et al. Increased neuronal nitric oxide synthase-derived NO production in the failing human heart. Lancet. 2004;363:1365-1367. 22 Patel RP, Gladwin MT. Serial Review: Biomedical implications for hemoglobin interactions with nitric oxide. Physiologic, pathologic and therapeutic implications for hemoglobin interactions with nitric oxide. Free Rad Biol Med. 2004;36(4):399-401. 23 Kim-Shapiro DB. Serial Review: Biomedical implications for hemoglobin interactions with nitric oxide. Hemoglobin-nitric oxide cooperativity: is NO the third respiratory ligand? Free Rad Biol Med. 2004;36(4):402-412. 24 Rassaf T, Feelisch M, Kelm M. Serial Review: Biomedical implications for hemoglobin interactions with nitric oxide. Circulating NO pool: assessment of nitrite and nitroso species in blood and ti0sues. Free Rad Biol Med. 2004;36(4):413-412. 25 Frehm EJ, Bonaventura J, Gow AJ. Serial Review: Biomedical implications for hemoglobin interactions with nitric oxide. S-nitrosohemoglobin: an allosteric mediator of NO group function in mammalian vasculature. Free Rad Biol Med. 2004;37(4):442-453. 26 Zhang Y, Hogg N. Serial Review: Biomedical implications for hemoglobin interactions with nitric oxide. S-nitrosohemoglobin: a biochemical perspective. Free Rad Biol Med. 2004;36(8):947-958. 27 Reddy MB, Clark L. Iron, oxidative stress, and disease risk. 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Welcome to Functional Medicine Update for July 2005. In the Wall Street Journal in 1991, there was an amazing report that still strikes me as being of significance today. It was a report about a gentleman who lived just outside of Dallas, Texas. He was a successful petrochemical engineer who, like all of his neighbors, cherished his home, his garden, and his lawn. One Saturday afternoon, he was manicuring, mowing, and pruning his lawn, using the appropriate fertilizer to make his little plot in the world aesthetically attractive. The following day, he wasn’t feeling very well. He had a headache and general malaise, and it didn’t get better. On Monday morning, he felt worse and his condition deteriorated throughout the rest of the week. Over the course of the next month, he became seriously ill and he went to his physician. He was jaundiced, with elevated liver enzymes, and it appeared that he had some type of idiopathic inflammatory condition of the liver. The condition worsened until it got so bad that he had fulminant liver failure and required a liver transplant. After six years and 20 doctors, liver biopsies, CAR scans, radioactive brain flow studies, and many months of anguish, it was recognized that his problem must have been a consequence of his exposure to the biocides and weed killers in the fertilizer he had used on his lawn, in combination with regularly taking cimetidine (Tagamet) for his hyperacidity. The combination of cimetidine with its effect on a cytochrome P450 (probably 1A2) enzyme in the liver, and exposure to a biocide requiring detoxification via that P450 pathway for elimination from the body, led to a dangerous and perilous outcome which, in his case, was serious liver dysfunction. This case contributed to the eventual warning on the medication label about the simultaneous use of cimetidine and exposure to environmental toxins.1 Similarly, acetaminophen was also implicated in a case of serious liver failure, which ended up in court. The origin of this story goes back to a 39-year-old man who was drinking wine every night and taking extra strength acetaminophen. He ended up with a kidney transplant and sued McNeil Consumer Products for not having an appropriate warning on their product. As a result, in 1995, the FDA Advisory Committee recommended that all over-the-counter pain relievers such as acetaminophen carry the alcohol warning: “If you generally consume three or more alcohol-containing drinks per day, you should consult your physician for advice on when and how you should take this product and other pain relievers.” Now, although in fine print, there is a warning label on this medication concerning the use of alcohol simultaneously with acetaminophen. And, although the risk is generally considered to be related to the amount of alcohol, data indicate the way a person handles alcohol is a factor. Therefore, some people may be more susceptible to this effect at lower amounts of alcohol consumption than three drinks per day. 2 What am I speaking to here? The focus of this month’s FMU will be on the liver, or functional hepatology. Where do these unusual idiopathic, liver-related problems come from? Why is chronic liver disease now associated with 3 billion dollars of healthcare expenditures annually for conditions of unknown origin? What is the origin of chronic liver problems? Why are we seeing more hepatitis C, biliary cirrhosis, cholangitis, and other types of problems with no specific focus of origin or etiology? It is those questions I want to focus on in this month’s FMU—a first in our 23-year history—looking specifically at the liver from a functional hepatology perspective. In order to do this, we need to mention Dr. Sheila Sherlock, one of the primary investigators who helped us understand the metabolic, immune, and endocrine functions of the liver. Dr. Sherlock, who recently passed away, would certainly be considered one of the great pioneers in our more modern understanding of liver function. Liver Function When we talk about the liver, we are talking about a variety of truly remarkable functions. In fact, as we go through the list, we wonder how we could even speculate on living a normal, healthy life without high-level liver function. The liver is a metabolic organ; it is an immune organ; it is an endocrine organ. As a consequence, it controls much of the switching of nutrients and signaling molecules, the relationship of immune defense and elimination of potential endogenous and exogenous toxins, and the handling of metabolic recycling of nutrients (glucose, fatty acids, and amino acids). It is the organ of choice the body uses to detoxify the toxic, nitrogen-containing molecules that we call amino acids. When I say toxic, I say it somewhat tongue in cheek, because amino acids are certainly necessary in the diet for the support of proper protein nutrition. But the nitrogen atoms in protein molecules, as part of the amino acid structure, are uniquely difficult to eliminate from the body, and require a specialized detoxification pathway found almost exclusively in the liver, called the urea cycle. The Urea Cycle Humans get rid of nitrogen through a complex, neutral, non-pH-modifying, nitrogen-containing excretory product called urea. This is in contrast to other animals that can eliminate nitrogen by way of ammonia release, and who have a whole different physiological system for handling the pH effects that the ammonium ion has on both extracellular fluids and tissues. In the human, however, the excretory route for ammonia is the neutral molecule, urea, which is two ammonias stuck to a carbon monoxide molecule to make it a urea molecule—a neutral pH and electrolyte-neutral species. The liver engages in this very unique process for detoxification and elimination of extra nitrogen that comes, in part, from excess dietary protein. Albumin Synthesis The liver also plays a very important role in synthesizing specific plasma proteins, not the least of which is the major plasma protein albumin, upon which are bound and transported many substances that are delivered at adjacent and distant sites where they are taken up by tissues. Albumin synthesis is a very important part of liver function. Apoliprotein Synthesis What about apoliproproteins, the protein constituents necessary for transportation of the fat-soluble substances like lipids, which are water insoluble and, therefore, insoluble in plasma? They need to be transported in a conducted-tour mechanism around the body on a water-solubilizing agent, which is an apolipoprotein synthesized by the liver. Emulsification of Fats What about the emulsification of fats? Fats in and of themselves cannot be well absorbed into the body because they are fat soluble, and the body is principally made up of water. They need to be emulsified with detergents in the digestive tract in order to get them into a form, a so-called micelle, so they can ultimately be taken up as small particles into cells and used as metabolic fuel. This occurs by way of emulsification with bile. Bile is composed of three constituents—cholesterol and its esters, bile salts derived from cholesterol by way of hepatic metabolism, and lecithin as an emulsifying phospholipid, which is also synthesized by the liver. Fat, Protein, and Carbohydrate Metabolism and Cholesterol Synthesis The liver plays a very important role in fat, protein, and carbohydrate metabolism. It is also the major organ for synthesis of cholesterol. An important physiological regulatory step occurs when 3-hydroxy-3-methylglutaryl CoA is converted to mevalonic acid. The enzyme responsible—HMG-CoAcan be inhibited by a variety of physiological factors, probably the most important of which is the intracellular level of cholesterol. HMG-CoA reductase is the enzyme that statins presumably block to prevent cholesterol synthesis in the liver. This is only a partial list of liver functions. To fully understand the liver’s importance and functionality in human physiology would require a lifetime of work. It is an extraordinarily dynamic organ that can also regenerate itself. It can hypertrophy; it can be smaller in size when it is not stressed for its work. It can be regenerated when it is injured. There can be an extraordinary number of messenger molecules that influence liver function, including things like erythropoietin and other types of neurosensory and neurologic hormonal substances. Kupffer Cells, MALT and GALT The liver is a very important, dynamic tissue that is engaged in real-time functional change in response to the environment. Its unique function is, in part, encoded in the genetics of the individual, and therefore another demonstration of the gene/environment connection. It is composed of a variety of different cell types. One cell type that occupies about 10 percent of the liver mass is called the Kupffer cell, which is an embedded white cell having to do with the liver’s immunological function. The Kupffer cell takes its messages from the information it receives by way of the hepatoportal blood that passes by the gastrointestinal (GI) mucosal system. The GI mucosal system is where most of the body’s immune system is clustered. About 60 percent of the cells and about 75 percent of the antibodies are manufactured and are present in the mucosal-associated lymphoid tissue (MALT) and the GI-associated lymphoid tissue (GALT). These activated tissues in the gut send signals by way of intercellular communication and signal transduction. The Kupffer cells in the liver pick up messages, such as those from interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-a), and interferon gamma. Those relay batons are taken up and transmitted by the liver cells, which secrete autocrine and paracrine types of substances and inflammatory mediators that can alter immunological function systemically as well as regionally. The liver might also be considered an immune organ with an inflammatory capability or personality. Oxidative Stress in the Liver Dr. Helmut Sies, father of the term “oxidative stress,” first studied many of these oxidative reactions in liver tissue. The liver is actively engaged in what are called oxygenase enzyme activities, the combination of oxygen with various molecules to produce hydroxylated or oxygenated outcome derivatives. Those enzymes can influence localized tissue by releasing oxidants that can damage adjacent cellular function and, in the case of redox control, can uncouple mitochondria in the liver, thereby releasing electrons to become oxidants and further serve as pathogenic agents to induce hepatotoxicity, or oxidative stress in the liver. The reduction/oxidation association with cellular physiology has been, to a great extent, studied in liver tissue because it is such an active oxidative organ involved with the oxidative/reductive chemistry of life through mitochondrial function and the combination of oxygen with enzyme function to produce oxygenated derivatives. Hemoglobin Metabolism, Porphyrins, Anabolism, and Catabolism Porphyrin and hemoglobin metabolism also takes place in the liver. Bilirubin is an indicator of hepatobiliary dysfunction that is, in part, a breakdown product from hemoglobin through porphyrin metabolism. It is also associated with liver function and has multiple responsibilities for building things up (anabolism), such as proteins, triglycerides, phospholipids, and glycogen, and breaking things down (catabolism), such as detoxification and metabolic catabolic reactions that occur in the liver to reduce high-energy food molecules—fats, protein, and carbohydrates—into small molecules like carbon dioxide and water, plus energy. That is catabolism—converting big molecules to small ones. The liver is both an anabolic organ and a catabolic organ and it carries out both of those functions simultaneously. It is not as if we can make a general statement to the effect that the body is in anabolism or the body is in catabolism. It is undergoing both of those processes, and the liver is a dynamic organ in which those things are engaged in real time all the time—breaking things down and building things up. Environmental Changes and Liver Function There is pressure on liver function as the environment changes and various substances to which the liver is exposed are altered. Obviously, one of those substances is drugs, or pharmaceuticals. Others are alcohol, and the type of nutrition that we are consuming. The liver also has to deal with byproducts of gut bacterial metabolism—enteric bacteria—that release their own byproducts into the portal blood, arrive at the liver, and must be metabolized. Liver Function and Increased Central Body Fat Certainly, in the 21st century, we also need to consider the liver-related stress that accompanies increased central body fat accumulation. If a person has a lot of visceral adipose tissue, that fat has access for secretion into the portal blood that goes directly to the liver various adipokines, or reactive inflammatory molecules that come directly from fat cells deposited in the visceral adipose tissue. There are a lot of things going on in the liver simultaneously and it may be the interrelationship between liver functional reserve and the liver stress factor that ultimately starts tipping the balance toward the increasing prevalence we see of these chronic liver diseases of unknown origin. I want to go through a few of the more sensible things that come out of this discussion from a clinical perspective. First, what feeds the liver? How does the liver get its nutrients? It can only get its nutrients from the nourishment that is provided to it from food. Food is processed through the digestive system and ultimately delivers the broken-down components as small molecules that get absorbed in the portal blood and ultimately transferred to the liver. In the simplest terms, we think of glucose and other small sugars coming from carbohydrate, free fatty acids or triglycerides coming from fat, and amino acids or very small peptides coming from protein, but this is only a part of the story. There are many other molecules that also come from the diet. Hepatic Encephalopathy There are other molecules that come by way of absorption from the GI tract that can induce alterations in liver function. They include things we associate with hepatic encephalopathy. We really should call this GI hepatoencephalopathy because the molecules of origin were derived from the gut through bacterial fermentation; when they arrived at the liver they couldn’t be adequately scrubbed from the blood, and thus they were delivered into plasma to the brain, where they can produce chemical mimetic effects on brain biochemical behavioral influence. There is an interrelationship between molecules produced in the gut and those that serve as putative neurotransmitters or neuromodulators in the brain, as connected through the liver into the blood. Treatment for Hepatic Encephalopathy When we talk about a patient who has a psychosis or hallucinations of hepatic encephalopathy, it is an interesting case in point. The traditional treatment of choice would be to put them on something like lactulose, which causes diarrhea and purges the GI tract, while trying to feed them intravenously and take a load off their gut. Another approach that has been used is to put these patients on a low-protein diet and give them an elemental, or lower-allergy diet, which also lowers the load of strange metabolites on their brain and reduces some of the central nervous system effects. Obviously, the use of a low-protein diet is to lower the load of nitrogenous waste products from bacterial putrefaction. The bacterial putrefaction of protein can produce funny nitrogenous materials, such as cadaverine and putresine. The names alone suggest their origin. These are biogenic amine compounds that can modify function. They are middle molecular-weight molecules and, in cases of compromised liver function, a person might end up with a problem related to the ability to purge them, after which they get delivered into the blood where they can have an effect on tissues. That is one example of something that comes directly from the gut into the liver that has to be processed. Quick-Release versus Time-Release Carbohydrates In simple carbohydrate diets, quick-release carbohydrates end up as simple sugars, such as a pure glucose, during first pass into the liver. That can lead to hyperlipidemia and hypertriglyceridemia associated with sugar intolerance. The liver is a sentinel organ for absorbing the metabolic insult from rapidly metabolized and absorbed carbohydrates in the form of simple sugars. That also tells us something about the difference between a complex carbohydrate, in which simple sugars are time-released, as compared to the quick-release form, such as those found in a candy bar. These time-released carbohydrates may contain the same number of grams of glucose, but the kinetics of glucose absorption and the effect it has on liver fat synthesis are vastly different — glucose that is time-released over hours, such as that from unrefined complex starch (versus a highly purified simple carbohydrate mono- or disaccharide), can influence the endocrine system in a different way. Formation of Bile Salts in the Liver The liver is a metabolic organ that takes information from food. The liver also synthesizes bile and it does so through the manufacture of bile acids, which are hydroxylated derivatives of cholesterol; 7-dehydro-cholesterol is a product of the first rate-limiting step in the formation of bile salts. This dehydrogenation reaction, the synthesis process for bile salts in the liver, can be activated by such things as vitamin C or magnesium. Therefore, nutritional status plays a role in improving bile acid synthesis and encouraging proper composition of bile where the emulsifying fat-solubilizing components of bile are the bile salts that come from cholesterol. It is interesting that when a person has an elevated blood cholesterol level, they often have a low bile salt level because of a block in the dam, so to speak, that prevents the cholesterol from flowing downstream. The way the body gets rid of cholesterol is by conversion to bile and excretion in feces. If there is a blockage in the dam, there is not as much conversion of bile. There are light-colored stools, fat malabsorption, cholecystitis, and increased risk to coronary heart disease (CHD) because of hypercholesterolemia. Does that mean that high cholesterol and bile-related problems such as cholestatic disease are interrelated? The answer is yes. Heart disease and gall bladder disease are interrelated. By improving bile acid synthesis, cholesterol is lowered and two things are accomplished at the same time. Increasing functionality of fat digestion lowers the risk to CHD and also lowers the risk to gall bladder disease. When we begin to look at liver function as a web, we see that there is a lot of interconnection between the individual and his or her environment, genotype, and outcome, as it relates to the multiple functions of the liver. Detoxification One of the most interesting emerging themes in medicine is the development of what is called pharmacogenomics, or pharmacogenetics—the genetic tendency toward fast, slow, or normal metabolism of specific molecules due to genetic differences in the detoxification phase 1 and phase 2 systems. People with recurrent adverse effects from various medications may have unique polymorphisms of the detoxification enzyme systems that make them “yellow canaries,” whereas other individuals can tolerate the same dose on a body surface area basis. I am always intrigued when I think about this. Of all the human functions that have been studied, the one that appears to have the greatest difference among apparently healthy people is the first-pass detoxification of various substances. There have been data published showing that the difference between one presumably healthy person and another in how they detoxify a substance can vary by a factor of threeorders of magnitude, or a thousand-fold. I know of no other physiological function in normal individuals that can vary so widely as that of the pharmacogenomic control of detoxification. This explains the “yellow canary” effect we often see in the population with environmentally sensitive individuals. We wonder why they seem so exquisitely sensitive at such low exposure rates, and often it is implied that they may be suffering from a psychogenic illness. It may all be in their minds, but perhaps it is in their minds biochemically as a consequence of toxicity related to the fact that they are slow metabolizers of a particular substance. Or, they may be on the other side. They may be rapid metabolizers who have much higher turnover than slow metabolizers for a specific substance. In that case, their genetics are such that for that particular substance, the blood level never gets into a therapeutic range and that person does not have a good response with a specific drug because they eliminate it so rapidly. Grapefruit Juice and Liver Enzymes This discovery has been exploited to some extent. In fact, Sheila Sherlock was involved with some of these discoveries because it was found that the rate of first-pass detoxification for some substances could be slowed down by administering a material that could block or retard the activity of that cytochrome P450 enzyme. In the case of the cytochrome P450 phase 1 enzymes involved with the metabolism of birth control pills and the very expensive organ-rejection inhibitor, cyclosporin, which costs thousands of dollars per administration, the substance called naringenin appears to retard the rate of detoxification in excretion, resulting in blood levels that are kept higher for a longer time. This is a flavonoid found in grapefruit, and that is why you will now find people talking about being cautious about drinking grapefruit juice when on medication because it can alter the rate of detoxification, or the effectiveness of that medication. It lowers the activity of specific cytochromes, inhibiting to some extent the activity of those enzymes keeps the molecule of interest in the body longer, resulting in improved activity of that drug. This has been used in the field of transplant surgery. In fact, I first saw this described in the journal Transplant 10 years ago. Surgeons were showing that if you have a patient on cyclosporin, administering 300 cc of grapefruit juice a day can greatly increase the efficacy of that drug because the body retains it longer and it does not get detoxified right away.3 There is another part to that story. That is, by blocking that enzyme, it could not detoxify something that you needed to get rid of through a specific pathway, like the enzyme cytochrome P450 1A1. We have certain bifunctional inducers in our diet that modulate both phase 1 and phase 2 detoxification activity, and they can be used for normalizing or personalizing the diet intake for a patient with specific hepatic detoxification abnormalities. For instance, cruciferous vegetables have an effect on detoxification by upregulating phase 2 quinone reductase and glutathione S-transferase, resulting in better phase 2 detoxification to balance out the altered phase 1 detoxification, and trying to keep the system in balance to eliminate molecules in a safe way by minimizing the formation of intermediary toxic molecules, the so-called biotransformed intermediates. The diet can be used selectively to personalize the needs of the individual for improved detoxification function—another rapidly emerging and interesting field in medicine that falls under the banner of pharmacogenomics. It is interesting as it relates to prescribing patterns of various prescription drugs. As science has started to develop an understanding of these inducible phase 1 and phase 2 enzyme systems and how they are influenced by various drugs, there is now a test that can screen very rapidly for the pharmacogenomics of detoxification enzymes that identifies the toxic genome relationships and the ability of the genome to regulate the enzymes involved with detoxification. It is now being suggested that patients should be screened by these tests before putting them on certain drugs, so their potential for adverse effects is known. These tests determine whether a patient is a slow or fast metabolizer. Patients should be screened for potential adverse response to the drug Imuran based upon an MTPT assessment of their genotype. This is the methylthiolpurine transferase enzyme involved with the detoxification of that drug. Slow metabolizers should not be put on that drug for fear of adverse response, or the dose should be adjusted appropriately. Similarly, recall the story I described in the beginning of this issue of FMU, which describes what happens when taking cimetidine and experiencing concurrent exposure to toxic biocides. There is an increased risk for adverse side effects because the cimetidine blocks the detoxification of various biocides and therefore makes a person more susceptible to xenobiotic toxicity. A person should be off medications that could adversely affect detoxification if they are going to be exposed to these xenobiotics. Alcohol and Liver Detoxification That same theme applies to alcohol consumption. Charles Lieber, whose name I have brought up in previous issues of FMU over the years, is a highly regarded primary investigator in the area of alcoholism and understanding alcohol’s mode of action on inducing liver dysfunction. He has talked at length about the alcohol addiction problem, but more interestingly, he has discussed the adverse influence of alcohol on detoxification pathways. One of the things he has shown, and I believe he was the first to demonstrate this in primates, is that when a considerable amount of alcohol is consumed, it goes beyond normal metabolism in the liver (through alcohol dehydrogenase), to activate a second detoxifying system—the cytochrome P450 system (cytochrome P450 2E1). When this enzyme is upregulated by excessive alcohol consumption, it produces a very high level of oxidized intermediates in the liver which have to be detoxified by phase 2 conjugation with glutathione. Therefore, the depletion of glutathione can occur very rapidly in a person who is abusing alcohol, particularly if he or she is not eating an appropriate diet. That results in the accumulation of these very toxic materials because they have nowhere to go. They basically cannot be detoxified by glutathione conjugation. In these cases, patients end up with a hepatic-induced neurological illness called delirium tremens (DTs). The treatment of choice for these patients in the ER is to administer the compound N-acetylcysteine, or Mucomist by intubation or gastric tube, which seeks to trap the free radical oxidants generated in the liver by upregulation of CYP 1E2, in an attempt to block oxidative injury to the liver. What Dr. Leiber points out is that the variation among individuals and how quickly they can develop liver injury due to this process is quite dramatic, based upon their genetic uniqueness related to glutatione S-transferase activity and oxidative chemistry. This is discussed in a review paper in Critical Review of Clinical Laboratory Science.4 It shows that inhibiting liver injury (cirrhosis) in an alcoholic, can be accomplished by blocking the oxidative damage due to depletion of glutatione. Glutathione, N-acetylcysteine, and various antioxidants can be used to try to promote proper function. This is another example of how nutrition interfaces with liver function, providing protection against the environment. We certainly consider the liver as an important barrier organ for defending and protecting us against toxic endogenous and exogenous substances. The Liver and Its Role in Transamination and Deamination That takes us into the role of the liver in transamination, deamination and rearrangement of protein through the process of the so-called transaminase enzymes, which are activated by coenzymes such as pyridoxal phosphate. Vitamin B6 becomes a very important part of the liver protein metabolic sufficiency argument. Just as with patients on high carbohydrate diets who need high doses of vitamin B1 to properly metabolize carbohydrate, individuals on a high protein diet need adequate vitamin B6 in order to manage their amino acids. There is also cholesterol biosynthesis. Cholesterol is manufactured in the liver and is transported out of the liver into the plasma by apolipoproteins manufactured in the liver. Those are genetically controlled, as well. This is a feedback process through the LDL receptor, which Brown and Goldstein have told us about.5 The 4R Program™ That takes us back to the control of liver function upstream which is, in part, related to what is going on in the GI tract. What about the use of the 4R Program (remove, replace, reinoculate and repair), for improving GI and hepatic function? There is a marvelous paper discussing the use of pre- and probiotics for the management of hepatic dysfunction in hepatic encephalopathies, and it demonstrates a role for reinoculating the gut and establishing proper gut floral integrity and gut immune function to support hepatic function and brain chemistry. This article appeared in Medical Hypotheses.6 As we begin to explore this in greater detail, we see that the liver has many remarkable effects, one of which I have not discussed in detail, that of immune function, which includes the Kupffer cell function of the liver and how it responds to immunological activators. Just as with all other white cells of the cell-mediated innate immune system, the particular activity of the Kupffer cells is modified by exposure from the portal blood to various types of proinflammatory mediators—IL-1, IL-2, and TNFa;—which are products that are often released by the systemic immune system or GI-associated immune cells. When improving liver function in people with various types of inflammatory liver diseases, including cholangitis, biliary cirrhosis, and hepatitis, one needs to be concerned about viral titers, as well as lowering the load of proinflammatory materials—food allergens, antigens, xenobiotics, and heavy metals—and then trying to improve liver antioxidant defense, redox cycling, and detoxification abilities. The general theme that emerges is that perhaps many chronic diseases of fatigue, muscle pain, sleep disturbances, restlessness, and all components of a low-energy syndrome are, in fact, related to slight over-burden of the liver’s detoxifying and regenerative abilities. Although liver function tests may be “within normal range,” the functional ability of the liver is to process these materials and to eliminate them effectively, but not deliver secondary metabolites into plasma that could alter cell membrane receptor activity at distant sites, producing suboptimal function, as if the body was “under alarm.” That brings us back to what kind of diet, life style, and therapeutic programs would help to enhance or normalize these detoxifying and cellular regulatory capabilities. That leads to one of the fundamental tools in functional medicine that goes beyond the 4R Program for restoration of GI immune function. There is a concomitant program called metabolic detoxification using an elemental diet, one that is very rich in the nutrients necessary for support of proper phase 1 and phase 2 detoxification that gives rise to an extraordinary positive potential outcome in patients with chronic liver and gut-related dysfunctions that are seen as symptoms of unknown origin and which may be related to dysfunction of the gut and liver interaction. That leads us to our COM interview that will take this discussion to a whole different level and should add some clinical tools to your tool kit.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Burton M. Berkson, MD, MS, PhD 1155 Commerce Drive Las Cruces, New Mexico 88011 bberkson@nmsu.edu JB: It’s time for our Clinician/Researcher of the month, and we are very fortunate to have Dr. Burton Berkson as our guest. We interviewed Dr. Berkson on FMU in June 1996 and have been following his work related to the modulation of hepatotoxicity and hepatic oxidative stress. I want to mention one anecdote before we get into our discussion. I often receive feedback from people about what they’ve learned from the material in FMU. I received more feedback from my previous discussion with Dr. Berkson on FMU than from any other in the last 23 years. One gentleman told me that Dr. Berkson’s therapy represented one of the most remarkable tools he has used in his medical practice. He had two patients with progressive liver failure who were candidates for liver transplants. Introducing what he had learned from Dr. Berkson some years ago led to recovery in both of those patients. Neither of them needed liver transplants and very good liver function was resumed in both cases. Those are miracles, by any stretch of the imagination. But the difference between miracles in reproducible medicine that become the standard of practice is an understanding of why they are miracles. That’s what Dr. Berkson has helped us to understand. I want to briefly cover some of Dr. Berkson’s background. His training included a variety of very high-level science experiences, including a PhD from the University of Illinois, followed by work in clinical mycology as a visiting scientist at the Max Planck Institute. He was an assistant professor at Rutgers University. He moved from emergency medicine to the establishment of his own integrative medicine center in Las Cruces, New Mexico. That is a wide swath of experience and accomplishment. It’s with great pleasure, Burt, that we welcome you back to FMU. BB: It’s a pleasure, Jeff. JB: For those who were not fortunate enough to have heard our first interview, let’s revisit your experience with amanita mushroom poisoning and how that led you to some insights and “ahas.” This would be a good place to start before we move on with the discussion. Treatment of Mushroom Poisoning with Alpha Lipoic Acid BB: Back in the late 1970s, I was an internal medicine resident in Cleveland, Ohio at one of the university hospitals, and I was asked to take care of two people who had hepatotoxic mushroom poisoning. I was told that there was really no hope for them. Their livers were shot, it was impossible to get liver transplants, and I was told that they would surely die. PhDs are always looking for new things, so I called Washington, DC and spoke to Dr. Fred Bartter, who was then chief of endocrinology at the National Institutes of Health. Dr. Bartter told me he was using alpha lipoic acid as a treatment for diabetic neuropathy and that his patients appeared to regenerate organ tissue after receiving it. He sent it to me, I gave it to my two patients with mushroom poisoning, and it regenerated their livers.7 It was remarkable. JB: Did you find that the liver enzyme levels in these patients came down in a fairly rapid fashion? Did it take weeks, months, or years of therapy? What was the rate of response? BB: The rate of response was about two weeks. When they came in, their liver enzyme levels were in the thousands. Within two weeks, their liver function was normal. JB: When I heard you present this information for the first time, I had a sense of incredulity of how something that is so powerful and so useful is not a standard of practice, and not on the lips of every practitioner who is seeing the increasing prevalence of liver-related problems. Why? BB: Dr. Bartter and I were the principal investigators on lipoic acid for the FDA. We went to most of the pharmaceutical companies, but they had no interest in lipoic acid because it was a drug that had been patented by the Germans and they weren’t able to get full exclusivity to it. It seems that in order to get a drug through the FDA, it costs hundreds of millions of dollars. If they manufacture it and don’t have full exclusivity, another company can compete with them, and they don’t get a return on their money. I think this is one of the major reasons, but there are other reasons, too. Dr. Bartter and I published two papers on 79 people with severe hepatotoxic poisoning.8 They had acute hepatic necrosis. These 79 people had to be declared terminal before Dr. Bartter and I would administer to them at various medical centers across the country. All we did was give them alpha lipoic acid, and it regenerated the livers of 75 out of the 79 patients. Most of them are still alive today and I am in contact with them. When we first went around speaking about this at various universities, the first question would often be based on the fact that Dr. Bartter was the chief of endocrinology at NIH, and probably the world expert on diabetes and kidney disease, so people would ask what right he had to treat liver disease? Dr. Bartter would often refer to me because I had discovered that livers could be regenerated easily with lipoic acid, and perhaps other organs, too. That would result in a response to the effect that I was a microbiologist, and if I wanted to work on liver disease, “why didn’t I become a board-certified hepatologist?” There is a kind of arrogance in all professions where, if you’re in a field somewhat different from the field they’re in, they feel you’re encroaching on their turf and they just don’t like to hear that. I think that’s part of the problem. If we had been hepatologists, this probably would have been more readily acceptable to them. JB: I recall a number of years ago, we interviewed Dr. James Goodwin from the University of Texas School of Medicine. He had written an article that received quite a bit of attention, titled “The Tomato Effect,” in which he talked about why things are not discovered and why things lie dormant for a long period of time.9 He followed that up with another interesting paper that was published in the Archives of Internal Medicine in 1998, in which he talked about what you’re referring to, which he called “the guild.”10 He asked why nutritional therapies had been the least accepted therapies in medicine and why they have such vitriolic, contradictory, and damning literature in some of the traditional medical textbooks. He pointed out that if you look at the language in some of the classic medical books that students learn from, the concepts of nutrition, particularly supplementation with specific m0cronutrients, are vilified with language that you don’t find in any other field, and he asked why. He concluded that when people are speaking about these things, they step out of “the guild.” He used Linus Pauling as an example, saying that if you keep within the guild, as you mentioned (the closely held specialties), then everybody feels he or she is part of the club, no one will look bad, and everybody is in a comfort zone. Once you take it to the public, or out of the guild, you become like Galileo. The problem with Galileo, he pointed out, wasn’t his heliocentric view of the universe. That was already well known from Kepler. He took his view out of the language of the scholars, which was Latin, into the language of the people, which was basically Italian. When he did that, it really broke the trust of the guild. It sounds like that’s analogous to what you’re describing with lipoic acid. BB: I think it is. Also, I remember years ago, I once heard a lecture by a female economist. She said that there are many good ideas, but no good idea really becomes accepted by the general public and the people involved unless there’s big money behind it. I don’t think any big corporation would be interested in alpha lipoic acid as a drug (that’s where the money is), unless they get good exclusivity on it and make a great return on their money. Right now, it appears that would be difficult. JB: Let’s go back and explore what you’ve learned in terms of dosage and safety concerns. Everything at some dose is toxic, including air and water. We always want to know where the parabolic dose-response curve safety range lies. What dosage have you found useful in these applications? BB: It depends on the person. LD50 studies were done for intravenous lipoic acid. These studies were done years ago at the White Sands Primate Research Center in Alamogordo, New Mexico. The work was done by Hill and Couch. They found that giving primates 100 mg per kg killed most of them. Intravenously, it would be quite a bit less than 100 mg per kg. They asked me to do the electron microscopy on the livers of the animals that had died. I’ve yet to publish it, but it’s almost ready. It seems that lipoic acid in very high doses causes the mitochondria to explode. It seems to rev up mitochondrion oxidative respiration and they seem to break apart. The cristae fall apart; the membranes fall apart. When I looked at the necropsy specimens from these animals, there were large necrotic areas in the liver, in the heart, and in the large muscles of the leg. It seems that lipoic acid is a very effective mitochondrial stimulant and, in very high doses, it probably works so quickly and effectively that there’s just not enough oxygen or acetyl CoA available, and they just heat and blow up. It was an amazing discovery that we made on this autopsy tissue. When Dr. Bartter and I started out in the 1970s, we used to give the patients (intravenously at first, with humans), a test dose of 50 to 100 mg of lipoic acid, just to make sure we weren’t dealing with any allergies or sensitivities. We’d work up to about 100 mg four times a day IV. As time went on, I found that lipoic acid doesn’t only work for acute liver disease, but it’s also very effective for chronic liver disease, such as hepatitis C and B, primary biliary cirrhosis, autoimmune hepatitis, and a whole range of things. I went up to anywhere between 100 mg to, in some cases, 600 mg IV for these patients. In addition, they’re all on 300 mg orally twice a day. JB: Can you get the same results without IV administration, or is it very important to deliver directly to the portal blood by IV? BB: For many of our patients with liver disease, just the oral administration is effective. The people I see with hepatitis are usually folks that have been told there’s no hope. They’ve been through the interferon and ribavirin therapies, or other therapies—Imuran and prednisone for autoimmune hepatitis. Oftentimes, they have full-blown cirrhosis and they come in with portal hypertension, esophageal varices, ascites, and they look like they’re about to die. These people have oxidative stress in all the tissues of their bodies. We usually start them on an oral program, but we also give them alpha lipoic acid IV one or twice a day for five to ten days.11 One person came from North Africa with a whole entourage of cooks and bodyguards. He was an important man there. He stayed for three months and seemed to do very well after that period of time. He had been told by someone at one of the big northeastern medical schools that there was no hope; he should just go back to Africa and die. When he left our place, he was doing very well. JB: You mentioned an interesting sidebar that I want to pick up on, and that is the drug, Imuran, which is used in some types of autoimmune, proliferative disorders that involve inflammation of the liver. Imuran is an interesting example of some of the problems encountered in genetic uniqueness relative to oxidative liver injury. That has to do with the polymorphism of the enzyme methylthiopurine transferase, or MTPT. If a person is a slow metabolizer type and is given Imuran, it can be life threatening because of liver toxicity. BB: I’ve seen that many times. In fact, I know people who have autoimmune hepatitis. They’re doing very well. They have a positive ANA (anti-nuclear antibodies). They go to a hepatologist and they’re put on Imuran and prednisone and they start degenerating very soon after that. When they come to our office, we have to wean them off those drugs and get them on a more sensible program. JB: It was Dr. Helmut Sies who first coined the term “oxidative stress.” He is the author of the book, Hepatic Oxidative Stress. That is the terminology we would apply to some of the conditions at the cell biology level that you are describing. The cells in the liver are undergoing some kind of mitochondrial uncoupling, producing increased levels of oxidants that cause the redox potential of the cell to be overwhelmed, leading to oxidative inflammatory disorders. That relates in part to the pharmacogenomics of the individual, the basic genetic underpinnings. Do you find from patient histories that there are certain characteristics that make them more susceptible to some of the liver-related autoimmune or inflammatory disorders? The Role of Emotional Stress in Liver Disease BB: I always ask our patients a question when they first come in that most of them have never been asked—have you suffered any severe emotional stress over the past several years? This is especially so with hepatitis C patients. Almost all of them say yes—they had a divorce, or they lost a family member and were very depressed for a long time. I explain to them that they probably experienced high cortisol levels during that period of time and probably became immunosuppressed. Hepatitis C viruses, for example, might have been relatively dormant. When they’re immunosuppressed, they become active and these people get sick. Then, I usually ask about their diets, such as how many vegetables they eat a day. It’s really depressing to see how many Americans just eat meat and potatoes and fast food every day. Many of these people have very poor diets. Then, I ask if they use alcohol, smoke, and what their occupation is. If they are a house painter or a mechanic, they might be subjected to hepatotoxic solvents every day, which interferes with immunity. I take all of these things into consideration. A paper was published several years ago, I think it was in 2000, by Seeff and Miller, where they studied patients with the hepatitis C virus (HCVV) for 45 years.12 They looked at thousands of HCV-positive patients. It seems that if these patients had decent lifestyles, took good care of themselves, and didn’t drink and smoke, now they’re in their 70s and 80s, and they don’t even know they have liver disease. But the people that get sick are the ones that have gone through terrible stress and have poor lifestyles. It’s the same old story over and over again with any disease. If people take good care of themselves, they seem to do very well. If they don’t, they get sick. JB: From the way you’ve described this, there seems to be a connection among hepatitis C and chronic diseases such as Epstein Barr or chronic fatigue or fibromyalgia syndromes. It seems that they cluster around similar etiological principles. Have you noticed any similarity among those conditions? BB: It all seems to be like the chicken pox/shingles effect. I see it over and over again, even with cancer. JB: You’ve extended your work with lipoic acid to look at other liver-specific protecting agents—antioxidants, or modulators of the inflammatory pathway. Have you found that other agents—silymarin, for instance—synergize or improve the activity of lipoate, or does it stand by itself? Importance of B Vitamins BB: Lipoic acid appears to be the rate-limiting factor for the production of energy from the mitochondrion. Carbohydrate or protein is eventually converted into pyruvate, but acetyl CoA is the food for the mitochondrion. What changes that pyruvate into acetyl CoA? There is the pyruvate dehydrogenase complex, but it doesn’t work without the cofactor, alpha lipoic acid. It seems that when people are young, they seem to produce plenty of lipoic acid and they get plenty of energy out of their mitochondrion. But when people become ill or get older, they produce less alpha lipoic acid and they have less energy. They get a less efficient mitochondrion and a sick cell. What goes on during this period? Well, you lose a lot of the B vitamins, the B complex vitamins. They’re depleted in this process. For example, thiamine, niacin, biotin, and others, too. We always include a sufficient dose of B complex vitamins when people are taking alpha lipoic acid. I know Dr. Will Taylor from the University of Georgia and his work with selenium. From what I get out of his work, it seems that these viruses, the retroviruses such as HIV and hepatitis C, and perhaps all viruses, seem to, in one way or another, monitor selenium levels. When selenium levels go up to a certain point, even though the virus is probably not an organism but just an infectious chemical, it thinks the person is healthy. But when selenium levels go down, a virus thinks the person is sick and starts replicating. Therefore, we always give 200 mcg of selenium twice a day to people with liver disease. In many cases, it seems to keep the hepatitis C virus in check. Use of Silymarin to Treat Liver Disease Back in the 1970s when Dr. Bartter and I were visiting scientists at the Max Plank Institute, we learned about silymarin, the extract from milk thistle. We always add 300 mg of silymarin, four to six times a day to the regimen because we know that it protects the liver cells from further damage and it’s a great antioxidant, too. That’s what we do for hepatitis C. A Case History of Metastatic Prostate Cancer Eight years ago, I had an unusual experience. A man came into our office with metastatic prostate cancer. He also had lupus and rheumatoid arthritis. He had been to one of the large medical centers and they told him that he was going to die; the prostate cancer was in his bones; there was no hope; he was finished, and he had only a few months to live. He came into my office asking me if I could help him nutritionally and that if he was in bad pain, could I possibly give him some narcotics. I said I’d be glad to help him and told him I had some ideas. He asked me if I’d ever heard of Dr. Bernard Bihari in New York and I said that I hadn’t. He heard that this doctor cured somebody with metastatic prostate cancer and asked me what I thought about that. I told him he should get right up there to see him, and he did. I didn’t see the man for probably three years. Finally, he came in and looked good. I asked him how he was doing and he said he had sinus trouble. This area of the southwest has a lot of blowing dust this time of the year and many people suffer from bad allergies that eventually turn into sinusitis and create problems. I asked him about his prostate cancer and he told me it was cured. His PSA went from about 12 down to 0.1. Then I asked him about the lupus and rheumatoid arthritis. He said that was gone, too. I asked him what he was doing. He told me Dr. Bihari put him on low-dose naltrexone. Are you familiar with that? JB: Yes. It’s a beta endorphin-blocking agent. Naltrexone and Liver Disease BB: Just a very small amount—3 mg at bedtime—seemed to cure the whole problem. It seemed to control the lupus and the joint pain. I started putting our people with autoimmune disease, our lupus patients, on this at bedtime and weaning them off methotrexate and prednisone. We have about 60 of them and they’ve gone from very sick people on very dangerous drugs to completely normal, healthy people. I thought that it worked for autoimmune diseases like lupus, it will probably work for autoimmune hepatitis and primary biliary cirrhosis. I started all of our autoimmune hepatitis and biliary cirrhosis patients on it and got the same fantastic results. We added that to our autoimmune regimen. JB: That is a great clinical pearl. Have you had a chance to speculate on the mechanism of action, or is it still open for discussion? BB: The more I learn, the less I know. And the older I get, the more I realize that I really don’t understand everything that’s going on, but I think what it does is modulate the immune system with autoimmune disease, and it’s probably related to the opioid blockade and the release of endogenous endorphins. The immune cells, especially the Th1 cells, all have opioid receptors and I guess this just gooses them to start doing their work properly. JB: That’s a very exciting clinical observation. That’s where great new breakthroughs come from—making these observations and then finding out how to reproduce them in other patients. Thank you so much. It’s fascinating to hear about the evolution of your story and observations. In May of 1997, I interviewed Dr. Will Taylor on FMU about his work on selenium and HIV aids, and the whole viral spectrum and its relationship to selenium. That’s another chapter in this ongoing saga. To reconnect with you nine years after our initial interview and examine the evolution of your clinical concepts, adding the naltrexone wrinkle, shows how good observers and clinicians can continue to refine and evolve the success of their therapies. As I mentioned in the introduction today, in 1996, when I first interviewed you, the feedback from the listeners about the experience they had in applying your concepts was absolutely remarkable. It sounds like we’ve added another level to that, and I’ll be anxious to see how it’s received by the clinicians in our audience. Thank you, Dr. Berkson, for being the observer and the clinician that you are, and for your willingness to share time with us. I can assure you this news is going to spread far and wide. I want to thank Dr. Berkson for his very informative talk. It added to the substance of the interview we had with him on FMU in 1996. We continue to learn old things in new ways. Naloxone in the Treatment of Autoimmune Disease One of the things Dr. Berkson mentioned that I want to follow up on is the association of naloxone with the treatment of autoimmune disease. That was an interesting “aha” for me, and I would like to add a couple of thoughts about why that seems reasonable from a biomedical perspective. The naltrexone molecule, and the related molecule naloxone, block the mu opioid receptor and the methionine-enkephalin (met-enk) receptor associated with endogenous analgesia. If you use something that blocks those receptors, it seems that it would increase pain and disability, rather than lower them because they are the endogenous opioid receptors. There is a story I would like to share with you that comes out of the observations that Dr. Berkson shared with us. It goes back to Nobel Prize-winning work from Sune Bergstrom’s laboratory at the Karolinska Institute in Sweden. Unfortunately, Dr. Bergstrom passed away in August 2004 at the age of 88. He won the Nobel Prize in Medicine and Physiology in 1982 after isolating and elucidating the chemical structure of prostaglandins. He was the first person to study the physiology of prostaglandins. He and his colleagues have been actively involved in this researchat the Karolinska Institute for many years. They spawned literally thousands of scientists that have been working in this field. Two of those scientists, still members of the Karolinska faculty, are Bengt Samuelsson (a co-recipient of the Nobel Prize) and John Vane, who eventually demonstrated aspirin’s mechanism of action. This is one of the premier centers in the world for research on inflammation. The group at Karolinska, with Dr. Bergstrom as one of the contributors, looked at the effect of naltrexone on met-enk-induced bone loss. Bone loss, or osteoporosis, is, in part, a bone inflammatory disorder. In the Journal of Bone Mineral Research in 1998, this group published a paper that looked at the role of met-enk inhibition in osteoblastic function.13 Osteoblasts are the bone cells involved with bone reformation. It turns out that met-enk levels, these endogenous opioids, inhibit osteoblast growth and function. Naltrexone blunts the effect of met-enk and allows the osteoblast cells to continue to grow and function in cell culture assays. By blunting the met-enk activities in bone cell, using naltrexone, osteoblastic osteogenic activity may be preserved. Etiology and Treatment of Hepatitis That is somewhat of a departure from the concept of autoimmune disease, but consider that perhaps Dr. Bergstrom’s observations are not that paradoxical. I want to talk specifically about hepatitis and its induction by viral infections, chemicals, or alcohol. One of the intercellular molecules, Fas, a CD95 protein, induces hepatocyte apoptosis in cytotoxic activity related to neutrophils that are infiltrating the liver. These are major events leading to what we clinically call hepatitis. It has been reported that endogenous and exogenous opioids, particularly morphine-like derivatives, via direct interaction with Fas CD95, sensitize splenocytes to Fas-mediated apoptosis and upregulate FAS messenger RNA formation. That subsequently modulates white blood cell neutrophil activity (cell-mediated defense), which causes hyperreactivity with liver tissue leading to an injured liver through oxidative stress and the release of hypochlorite and other oxidants. This is a Fas-induced hepatocyte apoptotic process associated with cirrhosis. The most interesting part of this story is that it has recently been shown that blocking the opioid receptor with low doses of naltrexone reduces liver damage and consequently increases the survival rate of animals after they were administered a liver-injury substance. This was reported in the Journal of Hepatology.14 It appears that there is no association between hepatotoxicity and naltrexone, and it appears to very effectively influence the reduction of acute viral hepatitis, according to a recent review published in the journal, Addiction and Biology.15 The authors state that during the past decade, naltrexone has been shown to be safe and effective in the treatment of pruritis associated with severe jaundice caused by severe and sometimes life-threatening cirrhosis and other liver diseases. This amplifies and supports the point made by Dr. Bergstrom. On the other side of the coin, a person taking morphine, which activates these mu and met-enk receptors, enhances hepatitis C virus replication. A paper in the American Journal of Pathology reports the ability of a morphine drug to increase hepatitis C virus replication in vitro .16 This appears to occur through the pathways I was describing earlier, through the mu receptors. Both alcohol and morphine will enhance hepatitis C replication through those processes. 17 Naltrexone appears to block those activated processes through the mu receptor, which may interfere with liver injury. We are learning about how some of these environmental agents work through liver signaling processes that are connected to opioid receptors on liver cells, particularly the embedded white cells in the liver, and blocking them with naltrexone or one of the opioid receptor antagonists, can have positive influence on the course of liver recovery. Obviously, we want to remove the precipitating factors—alcohol and/or morphine—but we want to decrease liver oxidative injury and apoptosis. In his discussion, Dr. Berkson talked about the use of lipoic acid, silymarin, and selenium. He spoke about Will Taylor’s work on selenium and its activation of antiviral effects. He also talked about low-dose naltrexone, 3 mg at bedtime, for patients with autoimmune disease. We are talking about the reduction of hepatic toxicity, the interrelationship between glutathione levels in the liver induced by N-acetylcysteine and/or lipoic acid protection. Naltrexone plays a role in preserving those pathways for glutathione synthesis in the liver, as well. This has been reported in the Journal of Pharmacology and Experimental Therapeutics. Treatment of Primary Biliary Cirrhosis What about specific examples of the use of naltrexone for the treatment of primary biliary cirrhosis? There is a good review that was published last year in the journal, Drugs that discusses the role that various medications have in the induction of primary biliary cirrhosis through upregulation of hepatic oxidative injuries.19 The endogenous opioid receptor antagonists, such as naltrexone, may be effective for lowering pruritis and inflammatory conditions associated with autoimmune hepatitis. Dr. Bergstrom left us with a powerful vision for a field that needs some help. The agents we are using today, such as interferon and Imuran, are not the answer to the problem, particular in the area of chronic liver disease. The functional hepatology argument—environmental factors, genes, and diet—is where the solution may emerge, because the gut delivers a lot of its messages to the liver. The liver picks up those messages and transmits inflammation to the rest of the body. Dealing with this as a system at the functional level may provide a much better solution for remediation of the excessive 3 billion dollars of healthcare expenditures that occur every year because of chronic liver disease. I hope we have given you some new information of interest this month. We look forward to being with you in August.

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1 http://www.majidali.com/canary_page_3.htm 2 http://dm.olemiss.edu/archives/97/9710/971006/971006N2alcohol.HTML 3 http://nutraingredients.com/news/ng.asp?id=58624&n=wh10&c=gswicrscgdweqgt 4 Lieber CS. Hepatic, metabolic, and nutritional disorders of alcoholism: from pathogenesis to therapy. Crit Rev Clin Lab Sci. 2000;37(6):551-584. 5 Brown MS, Goldstein JL. Lowering plasma cholesterol by raising LDL receptors. 1981. Atheroscler Suppl. 2004;5(3):57-59. 6 Bongaerts G, Severijnen R, Timmerman H. Effect of antibiotics, prebiotics and probiotics in treatment for hepatic encephalopathy. Med Hypotheses. 2005;64:64-68. 7 Berkson B. Thioctic acid in treatment of hepatotoxic mushroom (Phalloides) poisoning. N Engl J Med. 1979;300(7):371. 8 Bartter FC, Berkson B, Gallelli J, et al. Thioctic acid (Alpha lipoic acid) in the treatment of poisoning with alpha-amanitin. In: Faulstich H, Kommerell B, Wieland T, eds. Amanita Toxins and Poisoning. Badan-Baden, Verlg Gerhard Witzstrock; 1980;197-202. 9 Goodwin JS, Goodwin JM. The tomato effect. Rejection of highly efficacious therapies. JAMA. 1984;251(18):2387-2390. 10 Goodwin J, Tangum MR. Battling quackery. Attitudes about micronutrient supplements in American academic medicine. Arch Intern Med. 1998;158:2187-2191. 11 Berkson B. A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. ~i1Med Klin (Munich) (German Journal of Internal Medicine). 1999;94(Suppl 3):84-89. 12 Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in 2ealthy young adults. Ann Intern Med. 2000;132(2):105-111. 13 Elha3san AM, Lindgren JU, Hultenby K, Bergstrom J, Adem A. Methionine-enkephalin in bone and joint tissues. J Bone Miner Res. 1998;13(1):88-95. 14 Jaume M, Jacquet S, Cavailles P, et al. Opioid receptor blockade reduces Fas-induced hepatitis in mice. Hepatol. 2004;40(5):1136-1143. 15 Brewer C, Wong VS. Naltrexone: report of lack of hepatotoxicity in acute viral hepatitis, with a review of the literature. Addict Biol. 2004;9(1):81-87. 16 Li Y, Zhang T, Douglas SD, et al. Morphine enhances hepatitis C virus (HCV) replicon expression. Am J Pathol. 2003;163(3):1167-1175. 17 Zhang T, Li Y, Lai JP, et al. Alcohol potentiates hepatitis C virus replicon expression. Hepatol. 2003;38(1):57-65. 18 James RC, Goodman DR, Harbison RD. Hepatic glutathione and hepatotoxicity: changes induced by selected narcotics. J Pharmacol Exp Ther. 1982;221(3):708-714. 19 Oo YH, Neuberger J. Options for treatment of primary biliary cirrhosis. Drugs. 2004;64(20):2261-2271.

Welcome to Functional Medicine Update for August 2005. I think it would be noteworthy for us to spend this issue of FMU revisiting some of the topics that were so eloquently discussed at the 12th International Symposium on Functional Medicine—The Immune System Under Siege: New Clinical Approaches to Immunological Imbalances in the 21st Century. I’d like to reiterate a couple of thoughts for those of you who weren’t fortunate enough to be there. For those of you who were there, perhaps this will remind you of some of the high points and clinical takeaways. We started off the plenary sessions with an eloquent presentation by Dr. Esther Sternberg, Director of the Integrative Neuroimmune Program at the National Institutes of Mental Health. The theme of her presentation was, does stress make you sick? Dr. Sternberg did a very nice job of reviewing a tremendous body of recent information related to the neuroendocrineimmune system. It followed very nicely from the precourse discussion by Dr. Ilia Elenkov, who had also been at the National Institutes of Mental Health. He described some of the remarkable relationships between the outside and inside worlds, and the signaling processes through which the neuroendocrineimmune system modulates function across many organ systems and gives rise to conditions as disparate as depression, inflammatory bowel disease (IBD), multiple sclerosis (MS), coronary artery disease (CAD), and cancer. The concept of the stress connection to illness—pioneered by Hans Selye some 40 years ago—helped to focus the broad-based mechanisms of dealing with complex, chronic diseases of the immune system We would be remiss if we didn’t acknowledge that in the spring of 2005, a major new document was published by the Institute of Medicine (IOM) of the National Academies. The book is titled Complementary and Alternative Medicine in the United States,by the Committee on the Use of Complementary and Alternative Medicine by the American Public, Board on Health Promotion and Disease Prevention.1 It is now available for purchase from the Library of Congress and the IOM, and is a manifesto for what is happening in the changing environment of health care today. I urge you to read this book. I believe it contains tremendous insight pertaining to the resistance of accepting some of the concepts that were described at the 12th symposium. It seems so self-evident to those who have been in this field for some time, but for others who may be outside the field, complementary or alternative still means “scientifically unproven.” Dr. Sternberg helped us to understand why the acceptance of some of these ideas is so complex, and that they cut across disciplinary boundaries and are easily compartmentalized into silos. The book, Complementary and Alternative Medicine in the United States,demonstrates the complexity required in understanding how one cuts across disciplines of organ-system thinking. The book goes through a number of very interesting concepts that pertain to the acceptance and rising popularity of CAM in the United States. About 27 billion dollars a year are spent on CAM therapies. Forty-two percent of Americans report that they have used at least one CAM therapy. Less than 40 percent of these individuals tell their doctors about their CAM visits, because they feel they wouldn’t understand. In 1997, 629 million visits were made to CAM providers and 386 million visits made to primary care doctors, suggesting that there are almost twice the number of visits to CAM providers as there are to primary care providers in the U.S. each year. Dr. Stephen Straus, Director of the NIH’s National Center for Complementary and Alternative Medicine recently praised the report and said it is: “an achievement that elevates the discussion of CAM beyond the advocacy and skepticism that has long hampered the evaluation of CAM science. It will further the scientific investigation of this new field, increase its legitimacy as a research area, and ultimately improve public health.”2 We are witnessing a change in the paradigm, a changing of the guard, a transition to a healthcare system that better integrates techniques and strategies that will be directed toward the chronically ill patient, rather than focusing primarily on the application of research for the management of acute disease, with an absence of understanding how to set up a chronic disease management system that will draw from the replicable components of the CAM tradition. This theme was certainly borne out through the discussions at our 12th symposium. Each investigator outlined the basic science, the underlying physiology, and the connection of their discipline to the broad arena of chronic disease prevention and health management. We moved from Dr. Sternberg’s presentation into that of Dr. Michael Holick, who talked about how vitamin D modulates immune and inflammatory processes. This resulted in a standing ovation from the attendees for the brilliant and eloquent tour de force that Dr. Holick presented about how vitamin D is more than just a vitamin to prevent rickets. Its interrelationship with immunological function, neurological function, cardiovascular function, and endocrine function, illustrates its principal role as an important prohormone in the regulation of gene expression, and ultimately, the defense against many chronic diseases of aging. We proceeded into a discussion of gene/environment interactions underlying immunological function. Dr. Peter LeSouef from the School of Pediatrics and Child Health at the University of Western Australia, did a magnificent job of outlining aspects of the gene/environment interaction with immunological problems, focusing on Th2-dominant conditions, such as B cell-mediated asthma and eczema, showing that the concept of the environmental hygiene theory of asthma is too simplistic, and that there are remarkable relationships between the environment and asthma that go beyond those of specific genotypes. He showed that there are greater diversities of response to the environment in one individual ethnic group than there are across all ethnic groups, suggesting that race is not the determinant for asthma, but that the environment is a primary factor. He went on to point out that 65 percent of asthma cases appear to be environmentally related, whereas only 35 percent are related to genotype. There is a genetic linkage, but it’s not the overwhelming cause of the increasing prevalence of asthma and atopy—the Th2-mediated immunological disorders. That was a theme that ran through the entire week of the symposium—conditions that modulate the subtle immunological balance between Th1 and Th2 immunological functions, one being more related to innate immunity, the other more to acquired or adaptive immunity. It was pointed out that imbalances, infections, trauma, ischemia, poor-quality diets, and psychological stress can relate to dysfunction in that balance, tipping it toward a Th1-dominant or a Th2-dominant condition. Systemic inflammatory conditions like rheumatoid arthritis (commonly considered Th1-dominant), have their own constellations of inflammatory mediators, such as interleukin-1 (IL-1), interleukin-2, (IL-2), or tumor necrosis factor alpha (TNFa). Th2 conditions are associated with adaptive or acquired immunity, which have to do with a different family of cytokines, such as interleukin-4 (IL-4), interleukin-10 (IL-10), and interleukin-12 (IL-12), and the different constellations of conditions associated with these cytokines which are more tissue-specific, such as asthma and eczema. As we went through the week, we recognized that the best medicine for the management of many of these conditions is the one that leads to normalization, or balance, of the imbalanced immunological, neuroendocrine functions. That is an overview of what was achieved throughout the week, beginning with the precourse and working through the plenary sessions into the workshops. In a symposium of this breadth, it is difficult to leave with the takeaway. Rather, there are many factors contributing to the dysregulation of the immune system that cut across many different clinical conditions, ICD9 diagnostic codes, and subspecialties of medicine. No one “owns” this particular area of concern; it is part of all of medicine. We learned that beautifully from the eloquent presentation by Dr. Colleen Hayes from the Department of Biochemistry at the University of Wisconsin, who talked about the vitamin D endocrine system and its relationship to autoimmune diseases, specifically focusing on multiple sclerosis (MS). In her discussion, it was obvious that there are many variables that influence the balance of the immunological system and, as a consequence, regulate signaling at the gene expression level, creating the outcome in the cells, tissues, organs, organ systems, and the whole body that we call function or dysfunction. Her topic was well organized, magnificently presented, and resulted in another standing ovation. That was followed up with a magnificent presentation by Dr. Burton Berkson. Many of you will recall that he has been a guest on FMU on two occasions. He talked about the work he shared with us on FMU related to hepatic inflammatory disorders and what he calls his “triple therapy”—use of lipoic acid, selenium, and silymarin for the management of various types of hepatic, inflammatory, oxidative stress-related illnesses. He went through a number of case histories and experiences with patients, and the basic science behind them. He was very convincing about the important therapeutic role triple therapy plays in these conditions. Last in the plenary sessions, we finished up with a call to arms by Dr. Wafaie Fawzi from the Harvard School of Public Health. Dr. Fawzi is the principal author of work published in The New England Journal of Medicine pertaining to nutritional supplementation in individuals who are HIV positive, in which he demonstrated clear evidence that nutritional intervention with greater-than-RDA levels of specific nutrients can enhance survival, lower infection, and attenuate some of the adverse consequences of AIDS in people living in sub-equatorial Africa. That reminded us that sometimes inexpensive therapies can be very important for supporting proper immunological function. That was mirrored in the precourse presentation by Dr. Meydani from Tufts University School of Medicine and the Human Nutrition Center on Aging in Boston, describing her work on the impact of nutrients on immunological function. She showed that vitamin E plays an important role in improving immunological function in older-age individuals. She conducted a dose-response clinical intervention trial which I thought was quite fascinating, showing that somewhere around 200 IUs per day seems to be the maximum effective daily dose of vitamin E for the promotion of good immunological function. At too low a level, there is lowered activity; and at too high a level, there is also a lowered activity. Instead, there was a bell-shaped, parabolic dose-response curve, which I think we can say holds true for many, if not virtually all things. There is a parabolic dose-response curve for water and for oxygen. Too little, and we die of dehydration or hypoxia; too much, and we die of hyperhydration or hyperoxygenation. The parabolic dose-response curve is similar in many substances. We want to be “in the zone” for optimal regulation. This zone is individualized to some extent in each person. That’s why personalized medicine becomes very important, and why the medicine for the averages is probably going to produce the outcome of the averages relative to health care. As we move in the direction of personalizing medicine in the post-genomic era, it takes us beyond asking the question of what the diagnosis is, to understanding what the functional medicine assessment is. What are the antecedents that trigger the mediators that ultimately result in the signs and symptoms that are expressed in the patient? How does that relate to interactions with and alterations of the neuroendocrineimmune system? It is that complex system that seems to be the switching device between external agents in the environment and internal functional changes in the neuroendocrineimmune system. The symposium helped to bring greater clarity in these areas and gave us some new tools and insights. We had a number of remarkable workshops that dealt with specific implementation of these concepts. Dr. Robert Rountree’s workshops on nutrient interventions to regulate Th1 and Th2 function were stellar, including a tremendous review of the literature and a lot of clinical wisdom. These perturbing environmental factors play a major role in modulating immunological, endocrine, and neurological functions that ultimately give rise to a trajectory of either high function or disease. We should remind those of you who may not have had the privilege of attending the symposium, or those of you who might have felt overwhelmed by what you experienced there, that you might want to acquire the symposium tapes. They will turn out to be classics relative to the evolution of this field. I wish every one of the contributors to the IOM’s book on CAM might have attended the symposium. Had they been there, I think we would have been able to raise the bar even higher, with the understanding that many of these concepts have very strong, scientific underpinnings and that they fulfill the criteria of the rule of reasonableness, in terms of their effectiveness and safety. With that in mind, let’s focus this issue of FMU on some of the impact of what we learned about the neurological system at the symposium. There were a tremendous number of outcome variables related to the presentations on immune function that had a relationship to the neurological system. There are immunological cells embedded within the nervous system—the microglial cells. They get their messages, in part, from the neurological system, but also from the environment and cues from the immune system. We learned at the symposium that there are routes of entry across the blood brain barrier (BBB) for immune system messages from the Th1 and Th2 cytokines that can modify the functional outcome of the microglia, and which then communicate with the neurons through the release of second-signal messengers, such as nitric oxide (NO). That means that the brain can be influenced by the immunological status of the host. When you have the flu, your brain does not feel capable of carrying on high-level function. In the case of a very bad flu, where there is a serious immunological upregulation, you not only have a fever, but you also have all sorts of “funny thoughts.” Your brain chemistry is disturbed as a consequence of the high load of various inflammatory mediators that are trying to defend against the infection. The antigen-presenting cells, the dendritic cells, and the interrelationship they ultimately have with response to immunological activators, can influence brain chemistry. This may explain, in part, why it is that some individuals who are gluten sensitive present with neurological-related symptoms—perhaps the interrelationship between immune upregulation and brain chemistry connects to neuronal apoptosis, or cell death and dementia. I am speculating here, but it has been recommended that patients presenting with non-specific neurological problems, such as gait disturbances, should have gluten-sensitivity testing for presence of anti-gliadin or antiendomysial antibodies, The dendritic cells link the innate (preformed) and the adaptive or cognate (specificity and memory) immune systems through the B cells, the Th2 system. As these specialized antigen-presenting cells have profound influence over immune response, they induce specific leukocyte populations that release their own types of immune modulators, the Th1 and Th2 cytokines. There is a tremendous amount yet to learn about the basic biology of these dendritic cells; however, we now recognize that the toll-like receptors that sit on the surface of the innate immune system sense pathogen-associated molecular patterns, and go on to release substances that influence the Th2 system, or the acquired immune system. These are in communication, one with the other, through the toll-like receptors that appear on the surface of the innate immune system. This finding has ramifications for clinical immunotherapy protocols, and provides a satisfying link between the morphology of the dendritic cells and their migration into other tissues. The active movement of membrane extensions of the dendritic cell, like phagocytosis, and the simultaneous disappearance of various podosomes, suggests a coordinated redeployment to fuel the pathogen-driven increase in endocytosis.3We see this vigilant system in real time, morphing its way through the body’s tissue, doing a “seek-and-destroy” type of recognizance mechanism, or mission. That explains how, even in the brain, immune cells can be found doing seek-and-destroy. If they are activated, they can produce their own oxidants as these phagocytic cells do, through the generation of chloride ions that go on to produce superoxide and hydrogen peroxide, and even possibly hydroxyl radical through the Fenton reaction, so it increases oxidative stress. One of the things we can say about activating the immunological system is that it is associated with increased oxidative stress. Or, oxidative stress is often associated with immunological alteration. They go hand in hand. This raises questions about things in our diets that are commonly associated with being immunological activators, such as gluten. Gluten is food for some, but may be poison for others. The question is how early to expose the immunological system to a potential antigenic stimulant for something that can activate toll receptors and initiate a memory effect of alarm in immune cells. That leads to the concept of infant exposure to glutinous grains or cereals.4 In the Journal of the American Medical Association, there is an article, titled “Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease.”5 The authors state that there should not be early introduction of gluten-containing grains to a nave immune system in infants at risk of celiac disease, which was defined as the presence of HLA-DR3 or DR4 alleles, or having a first-degree relative with type I diabetes. They are waiting six to eight months before introduction of cereal grains containing gluten. It is dependent on the immunological uniqueness of the infant as to how susceptible they might be. Once the system is primed, as these authors discuss, there is a tolerance problem that may persist throughout the rest of that individual’s life because of a heightened response to that potential antigenic protein. The authors discuss the relative frequency of CD4-positive individuals and those who carry specific genetic risk factors such as HLA, DR3 or DR4 alleles who have increasing sensitivity to gluten in their diets. The next area I want to discuss is emotional stress, as a toxic event that can prime or modify the immunological system and the balance between Th1 and Th2. There is an interesting article that appeared in The New England Journal of Medicine, titled “Neurohumoral features of myocardial stunning due to sudden emotional stress.”6 The authors looked at how neuroendocrineimmune functions are modified by sudden, acute emotional stress. In this paper, it was shown that emotional stress could precipitate severe, but reversible, left ventricular dysfunction in patients without coronary disease. In the absence of elevated cholesterol, hsCRP, and triglycerides, these individuals had left ventricular dysfunction following a serious stress response. The exaggerated sympathetic stimulation is probably central to the cause of this syndrome, and demonstrates the close connection between the hypothalamus/pituitary/adrenal (HPA) axis and myocardial function. This was one of the features of the Selye stress model that Dr. Sternberg addressed in her presentations at the 12th symposium. As a consequence of these catechol-driven functions in the vascular system, we also recognize that heart rate profiles during exercise are very important predictors of sudden death and may be one of the better diagnostic tools for defining whether a person is at risk to sudden cardiac death. I am now quoting from a paper that appeared in The New England Journal of Medicine.7 The authors of this paper found that the heart-rate profile during exercise and recovery was a predictor of sudden death, and was probably more predictive than things like serum lipids and other traditional cardiovascular risk factors. This was a study done in 5713 asymptomatic working men between the ages of 42 and 53 years, none of whom had clinically-detectable cardiovascular disease. They underwent standardized graded exercise testing between 1967 and 1972. Data were examined on the subjects’ resting heart rates—the increase in rate from the resting level to the peak exercise level—and the time it took for recovery back to their basic resting pulse and the pulse level after one minute, post-exercise. It was found that the more resilient the heart function (the faster the heart rate went up on exercise), the more it was able to recover after exercise and come back down to the resting pulse. All were indicators of good cardiovascular function. I would call it cardiovascular organ reserve, to continue to use the term we have employed over the years. As the resting pulse goes up, as the differential between resting and exercise pulse goes down, and as the rate of recovery of pulse is slowed, it demonstrates lowered plasticity in the cardiovascular system and indicates increased relative risk to sudden cardiac death upon a precipitating event. The concept of homeodynamic function—plasticity and organ reserve as measures of functionality—as contrasted to looking for alterations in an EKG that are suggestive of cardiopathology, may be a better marker for picking up earlier states of dysfunction that are modifiable by intervention. That raises the question of cardiac rhythm variability, or the so-called heart math approach. I find autonomic tone and its relationship to cardiovascular risk profiles to be a very important part of our learning system. These are the dangers of chronic fight or flight, the chronic stress effect on vascular function. I owe Dr. Jayne Alexander, one of our functional medicine colleagues, a thank-you for tipping me off on an extraordinary paper published in the Mayo Clinic Proceedings.8 I believe it is a valuable tool to add to our assessment armamentarium. The title of this paper is “Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.” This is work done by Brain Curtis and James O’Keefe in the Mid-America Heart Institute of Saint Luke’s Hospital and University of Missouri, Kansas City. They looked at things that were traditional biochemical markers of hypertension and cardiovascular function, such as angiotensin-converting enzyme, calcium effects, relationship with serum lipids, congestive heart failure, and left ventricular function. They found that autonomic dysfunction is a very powerful risk factor for sudden coronary events. Confirming what was discussed in the recent New England Journal of Medicine paper, looking at heart rate recovery after exercise, a five-year mortality was extraordinarily lower in patients who had very rapid recovery, compared to those with low recovery rates after exercise. To extrapolate, we could say that fine structure EKG or electrocardiogram diversity may be seen as increasing physiological degrees of freedom that indicate plasticity that indicates organ reserve. Highly trained athletes who are very fit have a tremendous amount of fine structure variability in their heart rhythms, whereas in people who become less healthy and lose cardiovascular reserve eventually becoming ill and having cardiopathies, the fine structure simplifies and their EKG gets simpler rather than more complex. The more complex EKGs are associated with biological variability, which is associated with fitness. When I say fitness, I mean physiological biological fitness, as contrasted to those individuals with simpler EKG patterns. Of course, the simplest is a flat-line EKG, which we associate with death. The point the authors are making in this article on autonomic tone, however, is that it is driven by adrenalin, by the flight or fight response, and causes lowered heart rate variability, poor recovery after exercise, and is as important a risk factor as any specific risk factor that has ever been evaluated for determining the relative risk to sudden coronary events. Therefore, things we ought to be looking at clinically are a resting heart rate greater than 90 beats a minute, inability to achieve 85 percent of predicted maximum heart rate on a treadmill test, and abnormal heart rate recovery, which is failure to decrease heart rate 12 beats per minute during the first minute after peak exercise. When you take your peak exercise pulse rate, you sit down and rest for a minute after exercise and, if it doesn’t come down 12 beats, it’s an indication of poor recovery and abnormal heart rate variability, meaning failure to change heart rate, or the resting rate interval, by 10 beats per minute during one minute of slow, deep breaths after exercise. These are indications of significant reduction in what might be called vascular fitness, or vascular plasticity. This study on autonomic tone related to cardiovascular risk ties beautifully together with the paper in The New England Journal of Medicine on heart rate profile during exercise. As you do cardiovascular testing, the concept of heart rate variability during and after exercise, resting pulse rate, and recovery rate are extraordinarily important in defining some of the things related to the psychology, neuropsychology, and neuropsychoimmunology of stress driven by the autonomic nervous system. Hemodynamic Responses to Stress Let’s talk about hemodynamic responses to stress and their relationship to plasma homocysteine. If we are talking about immunological, neurological, and endocrine imbalances based on clinical chemistry, one that has emerged is the Kilmer McCully concept of hyperhomocysteinemia, or elevated homocysteine levels in the blood. Researchers have been looking at ways of modulating homocysteine levels in the blood and also looking at the effect that high homocysteine has on endothelial function. It might be endothelial function of the vasculature, which could include not only the cardiovascular system, but the brain system itself, and how these interrelate to a variety of clinical outcome variables. I was pleased to see a paper in the Journal of Nutrition, titled “Oral L-arginine improves hemodynamic responses to stress and reduces plasma homocysteine in hypercholesterolemic men.”9 It follows nicely from the presentations Dr. John Cooke from Stanford University made at our symposium a few years ago in Tucson, AZ, during which he described the work he had been doing in the area of cardiovascular biology, looking at the role of arginine supplementation in improving vascular endothelial function. first in baboons and then in humans. It has been shown in other studies that L-arginine, administered intravenously, substantially reduces blood pressure and peripheral vascular resistance in patients with vascular disease. In this Journal of Nutrition study—a randomized, placebo-controlled crossover study with oral arginine at 12 grams per day for three weeks—hemodynamic factors were studied in 16 middle-aged men with hypercholesterolemia, at rest and after two standardized stressor tasks: a simulated public speaking task and a cold pressor. As expected, the stressor task increased blood pressure and heart rate but, relative to placebo, L-arginine lowered cardiac output by 4 liters per minute, decreased diastolic blood pressure by approximately 2 mm Hg, had a positive impact on the pre-ejection period, and lowered plasma homocysteine by about 2 umol/L. The change in plasma L-arginine was inversely correlated with a change in plasma homocysteine. Contrary to results of previous studies with L-arginine administered intravenously, oral L-arginine did not affect total peripheral resistance or plasma insulin. Oral L-arginine also did not affect plasma glucose, CRP, or lipids. The pattern seems to be consistent with the hypothesis that oral L-arginine reduces blood pressure when administered in fairly high doses—in this case, about 12 grams per day, given in 3 to 4 gram divided doses. Diets high in L-arginine derive protein primarily from nuts and fish, as they are higher in L-arginine composition and lower in L-lysine composition than meat protein. These diets are also associated with lowered levels of CRP, inflammatory mediators, and reduced blood pressure. This may be one of the many variables that influenced the outcome of the DASH trials, in which vegetable-based diets were employed to stop hypertension and lower blood pressure. Not only is blood pressure related to calcium, magnesium, and potassium, but it may also be related to things like amino acid composition, with increased arginine dietary intake in the vegetable proteins. I am now quoting from a paper, titled “Association between dietaryarginine and C-reactive protein,” that appeared in the journal, Nutrition.10 The results of this study showed a strong inverse relationship between dietary arginine intake and a CRP level that persisted after controlling for other factors that can influence CRP. The authors conclude that individuals may be able to lower their risk for cardiovascular disease by consuming more arginine-rich foods, such as nuts and fish. It is interesting to note that arginine’s effect on endothelial NO causes vasorelaxation and has a positive effect on endothelial redox levels. Could similar effects be achieved by giving a drug like sildenafil? Sildenafil, or Viagra, influences NO through its effect on the signaling molecule cyclic guanosine monophosphate cGMP, sosssss might that have a positive effect on cardiovascular function in some individuals? Ironically, there is now emerging evidence that sildenafil is being used in individuals with specific types of cardiopathies. I am now quoting from a paper that appeared in Nature Medicine.11 The author states that Viagra, or sildenafil, operates by increasing the levels of cyclic GMP in target cells. This mechanism underlies the discovered action of how it may improve heart function in individuals with hypertrophic heart activity. By modulating these endothelial NO functions via cyclic GMP in endothelial cells, there can be some very profound, positive, normalizing effects. I am not advocating sildenafil; I’m advocating a diet that is immune-modulating that contains nutrients that help to regulate endothelial NO function. What about simple things, like play and exercise? Can they help prevent immunological imbalance that can lead to an inflammatory response that can result in things like amyloid buildup in the brain? That’s a fairly interesting concept—that by proper play and proper exercise, one can protect the brain from amyloid buildup. That’s not just speculation. Recently in Science magazine, there was a wonderful article that described work that is being published on how play and exercise in animals is able to protect against neuritic plaque, or amyloid buildup, and may thereby be seen as a preventive agent for things like Alzheimer’s disease.12 What about neurotoxicity that relates to heavy metal association, things like mercury and lead? We come back to revisit old things in new ways, and certainly those also influence neuroendocrinemmune function and can lead to neurobehavioral dysfunction. In a recent paper in JAMA, the authors state that the data do not provide strong support that blood mercury levels are associated with worse neurobehavioral performance, but if we look closer, we find that increasing blood mercury levels were associated with worse performance on Rey complex figure delayed recall, but with better performance on a test for manual dexterity.13Certainly, the response to heavy metals is very individualized and may influence specific functions differently. We learned that from Vera Stejskol many years ago, the scientist from Ostra who showed us that there can be an extremely large variation of response to heavy metal toxicity from person to person. What about neurotoxicity that relates to heavy metal association, things like mercury and lead? We come back to revisit old things in new ways, and certainly those also influence neuroendocrinemmune function and can lead to neurobehavioral dysfunction. In a recent paper in JAMA, the authors state that the data do not provide strong support that blood mercury levels are associated with worse neurobehavioral performance, but if we look closer, we find that increasing blood mercury levels were associated with worse performance on Rey complex figure delayed recall, but with better performance on a test for manual dexterity.13Certainly, the response to heavy metals is very individualized and may influence specific functions differently. We learned that from Vera Stejskol many years ago, the scientist from Ostra who showed us that there can be an extremely large variation of response to heavy metal toxicity from person to person. Follow-up Testing Among Children with Elevated Screening Blood Lead Levels Don’t forget lead. We know that lead has a detrimental effect upon brain biochemical and neurocognitive function. There is a good article in JAMA on the follow-up testing of children with elevated blood lead levels, showing increased neurobehavioral difficulties.14 This confirms what we learned nearly 30 years ago from work accomplished at Mass General Hospital, showing that children with marginal elevations of blood lead levels had reduced neurocognitive performance and behavior. There is much about the immune system that interfaces with the neurological system that interfaces with the endocrine system that gives rise to dysfunction. We are talking about good science based upon good medicine. Perhaps functional medicine from this perspective would be considered the best medicine for these kinds of chronic problems. That leads us into our Clinician of the Month. We are excited to share advancing concepts related to the neurological implications of these concerns.

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INTERVIEW TRANSCRIPT

Clinician of the Month David Perlmutter, MD Commons Medical and Surgical Center 800 Goodlette Road, Suite 270 Naples, FL 34102 JB: It’s time for our Clinician of the Month. One of the dominant themes at the 12th International Symposium on Functional Medicine was the topic of neuroendocrine immunology relating to complex disorders that cut across subspecialties of medicine. It’s difficult to isolate individual organ systems. We need to look at things from a systems biology level to understand conditions like multiple sclerosis (MS), systemic lupus erythematosus, or inflammatory bowel disease (IBD). That message came through loud and clear at the 12th symposium. Following up on that theme, I thought it would be timely to revisit a clinician visionary whom we have had the privilege of talking with before—Dr. David Perlmutter, a neurologist in Naples, Florida. Dr. Perlmutter has helped all of us with his perspective on functional neurology and how it relates to immunology and endocrinology. For those of you who may not be familiar with Dr. Perlmutter’s background, he graduated from Florida State University and the University of Miami School of Medicine, and did research in neurosurgery and microneurosurgery at the University of Florida. He has been in private practice in Naples, Florida for a number of years, where he established the Perlmutter Health Center, which focuses on complex relationships related to neurological function. He has been a pioneer in the area of hyperbarics and nutritional intervention, and is the author of the best-selling book, The Better Brain, published in 2004. He has received a tremendous amount of media attention for his work and his book. Welcome back to FMU, Dr. Perlmutter, and thanks for spending some time with us. DP: It’s my pleasure. JB: Let me go back and pick up from where we left off in May of 1999 when you were last on FMU. At that time, you painted a mosaic of what functional neurology looked like. There was an article on Parkinson’s disease in the Journal of the American Medical Association a couple of years ago that reminded me of the picture you painted in 1999, suggesting that even JAMA was picking up on recent trends. What has changed in the field you have so significantly contributed to? Recent Trends in Functional Neurology DP: I’d like to paint a better picture and come to you from a position of more optimism, but I’m afraid I’m not seeing a lot of progress, at least from the general purveyance of neurology to the American populace. We don’t focus on prevention of disease at all, and yet we know that diseases like Alzheimer’s and Parkinson’s have obvious causes and should be considered preventable. Over the past couple of years, I’ve been doing a lot more mainstream media education, along with educational pursuits with our peers. I’ve been trying to get the word out in the mainstream that these are diseases for which we have no cure and yet, they are preventable, and that this is where the emphasis needs to be. You mentioned JAMA. I would call attention to other publications by the American Medical Association, such as the Archives of Neurology. In fact, in January of 2004, they published an article that demonstrated that individuals with the highest levels of vitamins C and E had a much higher risk reduction for Alzheimer’s disease.15 There was another report that those with the highest levels of DHA had a 70 percent risk reduction for Alzheimer’s disease. These articles were followed in October 2004 by a very interesting report in The Lancet that demonstrated that the main drug used for the treatment of Alzheimer’s—donepezil—doesn’t work.16 Here we have a situation where the public is being led to believe they should live their life, come what may, and then, suddenly, when you don’t have both oars in the water at the same time and you’re starting to forget where you put your keys, there’s a pharmaceutical rescue called donepezil, and that’s going to be the way out. We see this drug advertised on the evening news every night, and in every trade magazine. We now know that the drug doesn’t work. There is no drug to cure Alzheimer’s and yet, there’s powerful information indicating that there are very important risk factors to which we should pay attention, things we have talked about for a long time—antioxidants, risk markers such as homocysteine or C-reactive protein (CRP), and even genomic testing looking at the apo E alleles. It’s difficult to conceive of a way to light a single candle in the darkness, when the darkness is almost overpowering the American population with media, convincing them that lifestyle doesn’t have any role to play and that when these problems arise, whether it’s heart disease, hypertension, malignancy, depression, or dementia, that there’s going to be a quick drug fix. Unfortunately, this is the American way and it’s taken hold. We’re going to stay out there and try to be the candle in the darkness, but it’s very difficult to see what’s happening to the American population, both young and old. For example, the rates of autism from the 1980s to the present have increased tenfold, to the extent that one in every 166 children is going to be autistic. We know there are powerful risk factors that are modifiable. Based on genomic testing, we know there are individuals who can be identified to be at risk for that problem. We can make changes in their environment. We can identify these kids up front and make changes to reduce risk and therefore the incidence of these devastating issues. JB: That’s a good way to start this discussion. When I look back to when I started in this field in the late 1960s, there was an analogous ongoing discussion related to the prevention of heart disease. The principal thought at that time about diet and heart disease was the polyunsaturate-to-saturate ratio. That’s what most people were focusing on. The problem was really everybody else’s problem, because there wasn’t a marker for individual risk to heart disease. With the development of the fingerstick cholesterol test and the Framingham Study, people could determine their own cholesterol number. The risk went from somebody else’s to his or her own specific risk. Coupled very closely with that was the development of the statin drugs for management of that indicator. There might be some kind of analogy here, because you’ve articulated very clearly that we have a near epidemic of dementia-related disorders that is going to increase in frequency with an aging population, yet we’re not responding in the way that we should to prevent unnecessary health expenditures and human suffering. Is this analogous to the heart disease issue? Dementia-Related Disorders DP: I think it is. I think it’s very clear that the most important factor in raising public awareness is the development of a drug to treat a specific illness. We’ve seen that with attention-deficit hyperactivity disorder (ADHD) and we’ve seen it with cholesterol, as you pointed out. What has caused the rise in public awareness of cholesterol is creation of the cholesterol-lowering drugs. Why have 90 percent of the patients I see every day never heard of homocysteine? Because there’s not a drug fix for homocysteine and therefore, they’ve not been made aware of it. The control of the media and the role it plays in terms of public awareness is absolutely vast. You brought up the issue of cholesterol. Certainly, we’re all aware of the new information indicating that individuals involved in determining what the safe levels of cholesterol are, have been involved in some way with the pharmaceutical industry which is, in many ways, an issue that needs more attention. Therefore, the edicts they issue, in terms of what a safe cholesterol level should be, are influenced by the manufacturers of the various drugs to lower cholesterol. There are significant issues regarding the safety of cholesterol-lowering drugs. There’s a large segment of the population who develop transient myalgias, muscle pain, and disability from those drugs, and a certain percentage of them are left with permanent issues with reference to muscle dysfunction which ultimately, is probably going to turn out to be a mitochondrial dysfunction at the level of muscle. There’s a 16-fold risk of neuropathy in individuals taking statin drugs. There is a report in the journal, Neurology that was published just three or four days0ago from researchers at Johns Hopkins, titled “High total cholesterol levels in late life associated with a reduced risk of dementia.”17 Now, what did I just say? I said that dementia risk was reduced in individuals with the highest cholesterol levels. Maybe cholesterol does play some important, positive roles in our physiology. Cholesterol is a precursor to hormones, but it also functions in the brain as an antioxidant. These researchers demonstrated in individuals of age 70 that the risk of dementia was decreased by almost 70 percent in those in the highest quartile of total cholesterol. That tells us it’s time to take a step back and reevaluate, at least from a general population perspective, exactly what we are doing when we pump the population full of these statin drugs that have such devastating effects on enzyme pathways, which can modulate and reduce the availability of important antioxidants like coenzyme Q10. Shouldn’t we take a step back when the FDA is considering making statin drugs over-the-counter, like they’ve done in England? We now see that, in fact, cholesterol is not such a terrible thing; that perhaps it’s there for some important reasons. JB: You hit on some very important issues. Cholesterol became a buzz word because it was easily analyzed and was associated with a relative risk that came out of epidemiological studies. One might ask the same question relative to dementia-related illnesses. Are there any functional markers that you could see using in patients for evaluation of functional neurological problems before the onset of dementia, the same as we do with cholesterol for heart disease? Functional Markers for Evaluating Neurological Problems DP: Oh, absolutely. We’ve been talking for a long time about the role of free radicals and the role of antioxidants in reducing risk. One of the studies we like to use is looking at urine lipid peroxides. We use that as one of the four key markers of risk prediction in terms of neurodegenerative conditions like dementia and Alzheimer’s, along with CRP, homocysteine, and looking at the apo E alleles. An article about the idea that oxidative damage may relate to cognitive decline was recently published in the journal, Neurology.18 Researchers at the University of Kentucky in Lexington demonstrated a direct correlation in risk for minimal positive impairment all the way to early Alzheimer’s disease, and correlated that risk with measuring the TBAR study, which is something that you and I have been lecturing about for years. Now, it turns out that there is a direct relationship, which we all suspected. But even more importantly, the pathological changes taking place in the brain, i.e., the development of the so-called neuritic plaques in the superior and middle temporal gyrus regions of the brain, has a linear correlation with measurement of the thiobarbituric acid reactive substances, which is a simple, at-home study that has profound implications. Taking it a step back, what can a person do lifestyle-wise that might modify these fats by action of free radicals? There’s perfect support for the role of antioxidants. That supports the study I talked about earlier about reduced risk of Alzheimer’s in people with the highest levels of vitamins C and E. So, absolutely, there are things that can be done that are not overly invasive, such as looking at studies of serum or urine for thiobarbituric acid-reactive substances, which is a simple test. We can look at high sensitive CRP (hsCRP) as a marker of inflammation, knowing that the balance of various fatty acids in the body plays a very important role in the inflammatory cascade, and therefore has a bearing on the outcome of that test. We can look at homocysteine, recognizing that risk for Alzheimer’s will double at the level of 14 and above. We owe Dr. Kilmer McCully a great debt for bringing homocysteine to the public’s attention, because it’s desperately important. Finally, we can look at the apo E profile to determine who is at increased risk for carrying the apo E4 allele. When we identify people who carry that allele, we know it has a direct relationship on the outcome in terms of the thiobarbituric studies. Carrying the apo E4 allele downregulates the brain’s antioxidant protective abilities and, therefore, places a person at increased risk for diseases like Alzheimer’s, and also increased risk for having a worse outcome following head injury, having a more rapid decline following the diagnosis of amyotrophic lateral sclerosis (ALS), and an increased risk of having prolonged seizures following a seizure in childhood—a variety of issues that we all now know are antioxidant-dependent. JB: That leads to a thought that you pioneered in the functional medical community, and that’s the connection of these antioxidants to the glutathione/glutathione disulfide couple, one of the principal antioxidant systems in the body. In fact, in terms of numbers of molecules, it is probably the most prevalent antioxidant system in the body. What’s the status of your extraordinary work with intravenous glutathione and some of the work that you are going to be engaged in? Treatment of Neurological Disorders with Intravenous Glutathione DP: We stumbled into the glutathione thing about 12 years ago with one of our patients on whom we were using glutathione. I had attended a lecture on chronic fatigue and one of the lecturers mentioned that low levels of glutathione had been noted in chronic fatigue patients. We started giving glutathione to our patients with chronic fatigue. I had one patient carrying that diagnosis and a diagnosis of Parkinson’s. And it was one of those “aha” moments, as Jeff Bland would say. When we gave him the glutathione, he got out of his wheelchair. You hear stories like that, and I’m such a non-believer, but when I watched that happen in my office, I had to take notice and pursue it. As Pasteur said, “chance favors the prepared mind.” We began digging deep and found that a study had been done in Italy that demonstrated significant improvement in people with CFS receiving intravenous (IV) glutathione. We researched it and began using it with our Parkinson’s patients. Over the years, as I’m sure you’re well aware, glutathione has become a real focal point as a key brain antioxidant, as a chelating agent in the body, a key player in hepatic detoxification and, therefore, a very important focal point in neurodegenerative conditions. We’ve been able to obtain an IRB for a research study giving IV glutathione to Parkinson’s patients, and we are one patient away from completing the study. We’re very excited about being able to publish the results which, hopefully, will demonstrate that this IV glutathione is effective, not only in symptom management, but also in terms of reducing the progression of the disease. The code hasn’t been broken, but I’m hopeful that it’s going to prove positive. Along the way, so many other literature citations have come out that support the contention that glutathione may play an important role. There is a study due to appear in the Proceedings of the National Academy of Science where researchers looked at glutathione-S-transferase activity. They found in Drosophila, the fruit fly that carried a mutation of the parkin gene which led to the degeneration of the dopaminergic neurons, that the loss of function of these dopaminergic neurons because of the parkin gene mutation was enhanced when there were mutations of the glutathione-S-transferase S1 gene, and that with overexpression of the glutathione-S-transferase S1 gene, there was profound suppression of the neurodegeneration.19 The abstract went on to indicate that this finding could lead to potential therapeutic interventions in the treatment of Parkinson’s disease. That certainly sounds like great support. The whole idea that these genetic risk factors can be played upon by environmental exposures is central to where functional medicine is these days. That is, we recognize individuals with certain genetic mutations and, therefore, risks, may or may not express disease unless acted upon by an environmental factor. That certainly would support, for example, the recent finding of these temporal and geographic variations in ALS. This would not be expected if it were a purely genetic issue, nor would it be expected if it were purely an environmental issue. There’s interplay between individuals at risk and subsequent environmental exposure. Indeed, the work done recently by Dr. Jill James in Arkansas identifying these genomic issues with reference to glutathione in at-risk children for autism, makes a very strong case for a reassessment on the art of science.20 According to science, there is no link between thimerosal exposure (either ethyl mercury found in thimerosal or methyl mercury found in foods and fish), in women who are pregnant and the subsequent development of autism. Now that we recognize that there are profound genetic risk markers for glutathione-S-transferase activity, we should redo those studies and determine whether or not children who carry those genetic markers are at increased risk. Then, science might indicate that this is a very fundamental strong indicator, and it would offer a strong explanation as to why kids are now developing autism at the rates I quoted earlier. JB: I want to go back to the glutathione question. I had a couple of interesting conversations with your colleagues at the 12th International Symposium on Functional Medicine, two of whom gave me anecdotes from their experience using intravenous glutathione in patients with various types of viral liver-related conditions, like hepatitis C or chemical hepatitis. They both reported that using your procedure in those conditions led to significant improvement—reduction of liver enzyme profiles and reduction of inflammation in patients with those liver inflammatory disorders. If you think of the liver as part of the immune system, which is part of the nervous system, which is part of the endocrine system, then perhaps these observations you’ve made specific to the brain are generalized to many conditions associated with enhanced upregulation of immune inflammatory conditions. DP: What is the bottom line in terms of how any of these inflammatory issues ultimately cause illness? I think we all recognize that it disrupts mitochondrial activity. That’s been one of the motivating forces for us to expand our usage of IV glutathione to a variety of illnesses. To take it past the viral hepatitis, we have included IV glutathione as a very integral part of our protocol in treating chronic Lyme disease. We have found that coupling IV glutathione, along with hyperbarics and an appropriate antibiotic regimen, has been a very powerful approach to getting these people back on their feet, quite literally, for a disease that many of my mainstream colleagues still choose to believe doesn’t exist. They tend to look at Lyme disease as a fairly monophasic event—you’re diagnosed, you’re treated with an antibiotic, and then you are better. We now know that patients with Lyme disease are debilitated long term and that this issue does not just necessarily go away with a quick blast of doxycycline. It’s also been shown quite recently that Lyme disease Ultimately does its damage by causing mitochondrial dysfunction in a variety of tissues in the body. Getting back to liver disease, there’s no doubt that hepatitis and other inflammatory issues of the liver are vastly improved when using IV glutathione, and also to provide other oral nutritional precursors to upregulate glutathione production. We’ve seen hepatitis C viral counts go down dramatically following the inception of IV glutathione therapy. The real issue of late for me has been the questions raised by my neurology colleagues about blood brain barrier penetration of the glutathione. I don’t have any doubt that this penetration is vast and significant, because of the systematic improvement that we all observe. I’ve been working at the M.D. Anderson Center in Texas, and we are about to start a study giving glutathione intrafecally to sheep, with the understanding from the University of Miami that once we’ve completed the study and demonstrated safety, we’re going to move ahead with treating ALS patients with intrafecal pumps delivering glutathione 24/7. It’s certainly taking it a lot further out of the box than the IV glutathione, but I think it’s time to make the box a little big bigger. JB: That’s certainly very consistent with one of the things we learned at the 12th International Symposium. We saw some brilliant data, showing that even large 56 kilodalton molecules—members of the cytokine family—can travel across the blood brain barrier (BBB). I recall one of the remarkable slides of the BBB and there was a big X across it, with a note—”it’s not as impermeable as we thought.” There may be transport mechanisms or actual portals of entry for larger molecules that were previously unrecognized, that allow the brain to have a relationship with the rest of the body in ways that we now are only starting to recognize. Pathophysiology of Multiple Sclerosis DP: To get back to clinical applications, I hardly ever treat an MS patient during an acute flare-up with a protocol of IV solumedrol or steroids. My feeling about MS is that we may have been led down a path that needs reevaluation, much as we have been with cholesterol. If I may be so bold, I’ll say that MS may not fundamentally be an autoimmune disease. I know that statement is going to raise a lot of eyebrows, because that’s been the thesis for a number of decades. It’s been the justification for all of the developed pharmaceutical interventions. But I would propose that we should consider that there are a variety of bits of data that need to be reevaluated in light of the possibility that the fundamental issue in MS may actually be a metabolic, or even an energetic failure, an energetic issue, which thereafter paves the way for this hyperimmune response. The models that have been used for MS over the years have been the cases of acute disseminated encephalomyelitis in humans and the experimental allergic encephalomyelitis, EAE, in laboratory animals which, in many ways, are somewhat similar to MS, but in many other important ways, have very little to do with MS when you look at the pathophysiology of that disease. Those are both acute and monophasic issues where there is specific damage to myelin which follows damage to the endothelium. In reality, MS is nothing like that at all. The hallmark of those two diseases is a huge lymphocytic infiltrate. In fact, many times in MS, there’s very little lymphocytic infiltrate around the plaque. Scientists claim that because of autoreactive T cell clones to brain antigens, that’s an indication that of an autoimmune acute disease. As a matter of fact, we see those antigens in other neurologic problems. We see antigens directed against myelin in a variety of other neurologic issues, including stroke, where that rise may be as high as 7-fold. We see complement activation, which is talked about as being a hallmark of MS, in head injury and other neurodegenerative conditions. I think it’s time to reevalaute this, especially in light of new data using functional MRI proton MR spectroscopy, showing that there is widespread neuronal loss, even at the very earliest stages of this disease. When you scan specifically for N-acetyl-aspartate (an indication of functionality of brain tissue), this is a very early predictor of risk of relapse in MS, indicating that the very first event may be an energetic event, a loss of neuronal function preceding the inflammatory reaction. Shouldn’t we be paying more attention to neuronal energetics and preserving neuronal function, using the techniques that we’ve talked about to upregulate mitochondrial activity and to salvage mitochondrial activity into optimal function? Things like coenzyme Q10 and, when need be, techniques to upregulate glutathione availability and production, and even more aggressively, IV glutathione. I’ve seen the proof in the pudding in my own practice when patients have come in with the acute throes of a MS flare-up. We choose not to load them with steroids. Instead, we give them IV glutathione and see resolution of symptoms, often within hours, when it might take several days with steroids and choosing a therapy that doesn’t have the down side or the risks of steroids. In fact, it has virtually nothing but an up side. JB: That was a remarkable, optimistic, and encouraging note. It is an interesting perspective that fulfills the rule of reasonableness. Thanks for sharing that. We have just a few minutes left. I would be remiss if I didn’t ask you a question that is probably on the minds of many of our listeners. Between May 1999 and the present, are you aware of any new clinical tools that you’re really excited about, perhaps not comparable to IV glutathione, but those that have been added to the tool bag over a six-year period that look interesting? Future Clinical Tools in Neurology DP: We’re looking at a couple of things. I’m sure you’re aware of Dr. Patricia Kane’s work. She has added phosphatidylcholine to our glutathione protocol because of its role in membrane activity. I think that’s going to turn out to be very exciting. Regarding trends, cranial magnetic approaches may also prove to be pretty exciting. We’re seeing a lot of interesting work coming out of several laboratories, and I know you’re aware of that information. I think that’s going to come into its own very soon. There are a lot of new techniques using some time-honored nutritional supplements. We’re quite excited about the role of resveratrol acting as a COX-2 inhibitor, not only in neurologic issues, but even in terms of malignancy. The biggest and most exciting thing is new recognition of the expanding role of the fatty acid DHA as a COX-2 inhibitor and even more important, in terms of its role in genetic expression. I know that’s an area of much importance for you. The role of DHA in general health is going to become much more widespread and much more understood by the general public. Foods will soon be enriched with DHA because of the important role it plays in gaining public awareness. Getting back to something I think I spoke to at the 9th IFM symposium in Ft. Lauderdale, Florida about fatty acids and immune modulation and the role they play in brain health, it’s exciting that it looks like science is revisiting that. We’ve come full circle in recognizing that there is some very important new information about the modulation of genetic expression with the fatty acids, which we’ll be getting into in the years to come. JB: In closing, I want to say that as the seventhwinner of the Linus Pauling Functional Medicine Award, you continue to uphold the tradition and honor of that award with very high integrity. We’re all pleased with the kind of reception you’ve received from your book, The Better Brain, and the positive ways in which you’ve affected people by believing that many neurological disorders are not irreversible and that, in fact, the brain can heal. That’s a major change in what I learned about neurology. You’ve served as a beacon, and we really appreciate your continued leadership. Thanks for being with us today. DP: Jeff, it has been an honor. Gulf War Illness I would like to add a few follow-up concepts to Dr. Perlmutter’s wonderful explanation of the progress occurring in the area of functional neurology. After 14 years, I would like to revisit the problems of veterans connected to what is now accepted as Gulf War Illness. Approximately 11 percent of the deployed veterans from the Gulf War have reported significant health problems similar to things we attribute to toxicity. They have a whole range of differing clinical symptoms. Questions have been asked as to whether these are real or psychogenic, or whether it is a post-tramautic stress syndrome. People have said that these veterans were exposed to all sorts of potential causal factors that may have had adverse impact upon their neuroendocrineimmune systems, things like multiple vaccinations, exposure to organophosphate pesticides, prophylactic use of nerve-agent pretreatment compound pyridostigmine bromide (found in the cerebral spinal fluid of some of the veterans when they returned to the U.S.), inhalation of depleted uranium dust, exposure to low doses of the nerve agent sarin after the destruction of chemical munitions, and exposure to the fumes of burning oil wells. All of these things together produce a total load. Perhaps the conditions we were seeing in these veterans were not just post-traumatic stress syndrome; they were a combination of post-traumatic stress that was overlaid with modulators of neurological function. In England, there is a dramatic reevaluation now ongoing to look at the potential association between exposures during the war and the disabilities of these veterans. For those of you who want to learn more about this, there is a good discussion that recently appeared in The Lancet.21 I take a personal perspective on this, because a number of years ago, I was asked to present at the Bureau of Veterans Affairs and the Department of Environment Medicine on some of the studies we had done on detoxification enzyme profiles and whole-body toxicity in veterans who had symptoms of Gulf War Illness. We found significant alterations in their urinary organic acid profiles and significant alterations in their acetaminophen challenge detoxification results. After I presented that information, I recall the cab ride back to the airport after the meeting. I happened to be with one of the high-ranking officials in the cab, and we were alone. We got into a discussion about this, and he said that, off the record, he would like me to know t1at this is a real problem, but the difficulty is, we do not really know what to do about it. What I think will happen is that it will smolder until it goes away because if we took it seriously, we’re not sure exactly what to do about it. That discussion has remained resonant in my mind for the past 10 years, because for many things we see that are chronic in nature, we have some fairly good evidence as to what the etiological factors are, but because we do not know how to put that through the traditional medical system to get an outcome, it is easier to either avoid the problem or say we do not have enough data, than it is to try to do something. The situation is similar with lead intoxication in children. If it was acknowledged by our government to what degree this problem occurred in the United States, it would force action, and we are not sure we have enough money to chelate every child with elevated blood lead levels that might have adverse neuropsychological or biobehavioral effects. These are political and economic issues that often overlay and complicate some of the fundamental issues related to the connection between an exposure and a dysfunction. Homocysteine and Fracture Prevention That also relates to the homocysteine story, which has been continually considered controversial, even in the face of all the evidence amassed over the last few years. Now, we see elevated homocysteine is associated with fractures and spontaneous imperfections in bone density and bone formation. I am quoting from recent papers in the Journal of the American Medical Association, showing that folate and vitamin B12, when given at high doses, can help prevent hip fractures in patients who have had a stroke. Factors Affecting Deoxynucleotide Synthesis and DNA Methylation in 1-Carbon Metabolism Homocysteine problems are genetically linked through various polymorphisms, such as the methylenetetrahydrofolate reductase (MTHFR) polymorphism that is present in 20 percent of the population, or 1 in 5 people. This and other related polymorphisms indicate an increased risk of homocysteine-related dysfunction. People with these polymorphisms may also have increased risk of changes in DNA methylation. This was discussed in a marvelous paper recently published in the Journal of Nutrition, showing that people with the MTHFR 677C®T polymorphisms have increasing relative risk of altered DNA methylation, which may relate to potential carcinogenesis.24 What we are starting to witness is the transition of medicine from silos of individual specialties to general themes surrounding mechanisms; by understanding that, we can better discuss the relationships of genotype to environment to produce specific outcomes. This leads to the concept of personalized medicine that Dr. Perlmutter was talking about, and it was the focus of the 12th International Symposium on Functional Medicine with regard to immune imbalance. This theme will be continued throughout the year, and we look forward to sharing how we are going to travel into the 2006 symposium year, which will be focused on detoxification and the environment/gene interaction.Thanks for being with us. We will talk to you next month.  

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Welcome to Functional Medicine Update for September 2005. This month, we are going to cover one of the most complex, but also clinically relevant topics we have had the fortune of exploring over the past few years—neuroendocrine immunology. Another way it might be expressed would be body/mind/nutrition and the modulation of inflammatory and immune disorders. We focused on this topic at the 12th International Symposium on Functional Medicine. The takeaway from that meeting was extraordinary. A great deal of thought-provoking material was presented at the plenary sessions and workshops. There was so much depth and density of infrmation that it was hard to take it all in over the course of the four days of the symposium. Since then, I have distilled some of the information and done some reflecting on it. With the help of one of our plenary lecturers, Dr. Esther Sternberg, from the National Institute of Mental Health at the National Institutes of Health, I would like to revisit some of he topics we discussed during the symposium that might be of clinical value I want to begin by introducing the immune system, which is regulated by a variety of factors from within the body, such as regulatory T cell subsets that produce things like chemokines, complement, and antibodies, and by factors outside the body, including different hormones and neurotransmitters or neuropeptides in the microenvironment of individual cells. There is a whole milieu of different messenger molecules that serve as mediators for action at a distance, both autocrine and paracrine factors, and the immune-modulating molecules that have been found to have a great variety of effects on different cell and tissue types. The central nervous system (CNS) afects the immune system through the neuroendocrine humoral outflow via the pituitary and through direct neuronal influences via the sympathetic, parasympathetic and sensory innervation of peripheral tissues. Thus, circulating hormones or locally released neurotransmitters and neuropeptides regulate major immune function, such as things related to allergy like antigen-presenting cells and, ultimately, the release of various types of cytokines, modulators that can affect work at a distance.1 What happens locally might have a global effect on the body. These compartmentalizations of immune, neurological, and endocrine system function, which we often study in chapters contained in anatomy and physiology textbooks, represent a web of interacting variables that alter function and allow for the proper physiological response to changing environmental stimuli. As with any web, when any component is distorted, the web itself changes. It is not just a single entity or a single function within the complex, interacting relationships in the neuroendocrine immune system, but rather, it is that any alteration in the web deforms or perturbs the whole shape or function of the web. We can get systemic effects from these perturbations of the neuroendocrine immune system. It has been proposed that the balance of immunological function is related to the equilibrium between the thymus-dependent 1 (Th1) and thymus-dependent 2 (Th2) lymphocyte responses. This leads to the balance of various types of immune-modulating substances that have impact upon the endocrine and nervous systems, resulting in a push/pull or feedback system related to environmental messages translated into immunological function, which influence endocrine and nervous system functions that, in turn, send out their own messengers, which ultimately have feedback effects upon the immune system. In self-regulation, all of the systems in this marvelous web somehow interact in such a way as to give normal immunological vigilance, normal immunological response, normal inflammatory balance, and proper nervous and endocrine system function. In a system that is perturbed by exogenous or endogenous sources, the distortion of the web leads to alterations in the function of individual systems—nervous, endocrine, and immune. Furthermore, depending upon the nature of the perturbation, the strength of the stimulus, and the response in the individual to that stimulus, which is based upon individual genetic and environmental factors, different types of symptoms can arise. Hans Selye encountered a great deal of resistance from his colleagues when he proposed the stress mechanism of disease, because he was talking about so many different diseases that seemed to occur from a similar, non-specific condition that he termed “stress.” At the time, if you believed that each disease was independent in and of itself, and that it had its own specific etiological agent separate from that of any other disease, it would seem strange and probably not realistic to propose that a general mechanism (in this case, what Selye termed “stress”) produces the phenotype seen in so many different diseases. Peptic ulcer disease, heart disease, adrenal-related problems associated with hypertension, stroke, and ultimately, as we will learn in greater detail from Dr. Sternberg, even autoimmune diseases, in which imbalances of Th1 and Th2- mediated lymphocyte function are central, are part of this extensive list of stress-associated conditions. An alteration in neuroendocrine immune system function results in an array of chronic symptoms that are very hard to put one’s diagnostic finger on, and these symptoms often occur well before presentation of a defined disease. These would be things like recurrent fevers of unknown origin, sleepiness, fatigue, muscle pain, loss of appetite or increased appetite, decreased libido, and decreased response to various environmental agents and toxins as a consequence of altered detoxification pathways. All of these things are clinical manifestations of alteration of the neuroendocrine immune web. Immune responses are regulated through antigen-presenting cells (APC)—monocytes/macrophages and natural killer cells that are components of what we call our innate immunity. They are also regulated by T lymphocytes that make up the Th1 and Th2 systems that are components of adaptive or acquired immunity. Innate immunity allows for instruction that enables the downstream adaptive immune function to select appropriate responses to the environment. There are alterations in the Th1 and Th2- modulated production of messenger molecules. There is a constant dynamic interaction between the environment and the sensory perceptions of the individual and their translation into the response of the Th1 and Th2 equilibrium, which alters the mediating molecules and the function of the neuroendocrine immune system. There could be focal infection, for instance, or exposure to a small toxic molecule, toxic stress, a mechanical injury, or poor alignment leading to poor distribution of mechanical forces in the body, such as through the spine. All of these things could serve as precipitating events that would be manifested through the neuroendocrine immune web to produce symptoms that could be quite diffuse and non-specific, depending on the individual. These alterations can result in things like Th2-dominant conditions, which are called allergy and atopy, to Th1-dominant conditions that are normally associated with systemic inflammation, like arthritis. The clinical conditions that can arise out of alterations in neuroendocrine immune function cut across every subspecialty of medicine. There is a strong interest in the Th2 responses that were initially directed at the protective effect seen in various helminthic infections that, I believe, is where they were first discovered and eventually seen to have a pathogenic role in allergy. The innate immune system, recently called the primitive immune system (Th1 responses and phagocytic responses of monocytes and macrophages) plays an interacting role with the Th2b cells that secrete antibodies. There is a web of interaction and communication between these cell lines that results in the function of the immunological system. We would not clinically separate a condition of chronic infection—for instance, a root canal gone bad leading to a low-grade dental infection—from an environmental exposure to a xenobiotic chemical, food allergen, or a highly distressful experience in life. All of those are perturbing factors to the equilibrium between Th1 and Th2, and the immunological status of the neuroendocrine immune system. Diseases named through ICD9 codes that come out of these interactions would not have been seen historically as emerging from or related to alterations in the neuroendocrine immune system through the complex connection between environment, genes, and neuroendocrine immune signaling. As we will learn later in this issue, even conditions within the autoimmune family, such as systemic lupus erythematosis and rheumatoid arthritis, are related to alterations in neuroendocrine immune function, and the hypoactive hypothalamus-pituitary-adrenal axis (HPA) has to do with alterations in neurochemical and immune response, which can set the stage for the alteration of immunity associated with arthritis. We are witnessing the emergence of a fundamental, scientific underpinning of what Dr. Selye started to bring to our attention some 60 years ago, from which the term “stress” was coined out of physics and appropriated into biomedicine. It is the most commonly used term in all of the language of biomedicine today. It is interesting that although the term “stress” is frequently used in all the research quarters of the world, it still hasn’t “arrived” as the clinically important topic it probably deserves to be, in terms of therapies. The body has evolved very adept mechanisms for managing the perturbing factors that lead to stress. Stress, in and of itself, is probably not damaging. The damage occurs when the control mechanisms for the management of an environmental change, which is translated through the HPA axis, are no longer able to be properly managed and lead to distortions of the web of the neuroendocrine immune system. The person begins to suffer from distressful conditions associated with alteration in these messenger molecules. Often, we focus on one of those messenger molecules—the adrenal steroid, cortisol. Cortisol travels with altered mediators of the other families of the nervous and immune systems. If we looked at the web in total, we would not see cortisol changing by itself. We would see it as a marker for alterations in the whole of the neuroendocrine immune system. How does the brain protect itself from certain kinds of adverse responses from long-term stress? This has been a topic of discussion within the basic sciences and the neurosciences for some time. Recently, we have begun to see some mechanistic understanding emerge as to how the brain has evolved the ability, over millennia, to protect itself from conditions that ultimately might result in altered neurochemicals, neurotransmitters, and immune agents that could produce things ranging from depression to neuroinflammation. I am now talking about acute stress, or post-traumatic stress syndrome. An interesting review paper was published in Nature Neuroscience that followed from another paper I saw in the same journal. The latter paper was titled “Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus.”2 The review paper talks about how the impact of traumatic life events is often gauged by how well people appear to cope with their experience.3 The concept of coping is an important feature of living in the 21st century. We have to cope with a lot of things. We are on sensory overload most of the time dealing with time compression. The nervous system has to mobilize the neuroendocrine immune system’s coping abilities. Obviously, there are psychological control processes that can buffer the adverse consequences of stress, but there are also neurophysiological, or neuroendocrine immune processes. It has been suggested that the interaction occurs between the prefrontal cortex, one of the “executive centers” of the brain, and the serotinergic system, which projects diffusely around the dorsal raphe nucleus. There are conditions under which psychological control over stress could be inferred in experimental animals. Rats exposed to inescapable shocks showed significantly more gastric ulceration and higher levels of stress hormone than rats receiving the same quantity, intensity, and scheduling of shock, but with the opportunity to voluntarily turn a wheel and stop the shock stimulus. That leads to the concept of both intentionality and locus of control. Built into our coping systems is the locus of control—the escape valve. Locus of Control There is a takeaway from this, not to focus so much now on neurochemistry, but on real-life clinical situations. How do we get a person to introduce a locus of control into his or her life when they have a runaway system of distress working within the neuroendocrine immune system and they have lost their ability to cope, both physiologically and psychologically? The concept of establishing locus of control is a very important therapeutic guide, or potential tool. We cannot control everything in the universe as much as we might like to. The sun still rises in the east and sets in the west, and there are variables in our lives that we have to deal with as givens. What we can do in the face of those things that are dealt to us is to develop some guidelines as to a locus of control along the road of response; in other words, some sense that we are not out of control and just victims of circumstance. That has a dramatic impact upon altering the function of the neuroendocrine immune system. When we feel that our lives are out of control and there is no escape, there is a sense of hopelessness. We have a different neuroendocrine immune milieu of triggering or mediating molecules than if we introduce a locus of control. There is a whole series of studies focused on this story from a neurochemical and neurobiological perspective. The article I referred to in Nature Neuroscience on controlling stress discusses this issue at some length—control mechanisms by which stress occurs through the serotinergic processes and raphe nuclei resulting in an altered sense of coping. Let’s translate this into a therapeutic example—a visit to the dentist. We may not look forward to this because it is going to require some drilling for the dental procedure. For most of us, the dental drill does not represent an enjoyable experience. The dentist tells you that the procedure is going to require drilling and that he will do all he can to make you comfortable, but he doesn’t tell you what to expect or how long the procedure might take. The moment the drill hits your tooth, there is a neuroendocrine immune response to your perceived lack of control because you are not sure how long the procedure will take. The neuroendocrine immune response to uncertainty about the length of the procedure produces a different collection of messenger molecules than if the dentist had told you the procedure would take about 10 minutes and that you should indicate any discomfort by raising your hand. In that case, a different array of messenger molecules from the neuroendocrine immune system is produced because you sense a locus of control, which has a physiochemical, neurochemical effect and influences the web of the neuroendocrineimmune system. If we use the simple model I just outlined as a metaphor to other conditions in life, what we should be doing to assist patients who are out of control and suffering from distress and a runaway alteration in neurochemical mediators, is to try and introduce the concept of a locus of control. What can be introduced that leads to a feeling of being in control? The concept of locus of control not only has a psychological impact, but it has a neurophysiological impact on neuroendocrine immune system function. If that person is going to be confronted with long-term alterations in his or her environment that could produce adverse effects of distress over some period of time, developing these markers for a locus of control is a very important clinical objective. I am suggesting hypothetical situations and asking whether one could develop a locus of control. Let’s say you have received a sudden diagnosis of cancer. That is a stress factor, in and of itself. Based on that response, how could you develop a locus of control? Obviously, there are many ways you could do that. One might be to decide to become informed about the particular type of cancer. Another might be to examine the treatment options and be involved in the selection of the treatment, interfacing with practitioners who will communicate with you, giving you a sense that you are part of the solution, not just the problem. Through that process, one develops a different connection to the neuroendocrineimmune system that results in a collection of molecules floating around in tissues that produces a different response of that complex system. These are some small examples of a general theme relating to the concept of locus of control, which has both psychological and neurophysiological endocrine and immune influences. The Role of Nutrition Taking that a step further, let me introduce the concept of nutrition. Often, we feel that the body/mind connection may be strong, but there is very little evidence that the mind is connected to the state of nutrition. Neurophysiologists, psychiatrists, neurologists, and psychologists often feel that there is very little their disciplines have to do with nutritional status and the outcome in patient response. I would like to change that perspective and spend a moment explaining why I think nutrition is part of this, and why I started this discussion by saying we were going to focus on the interface between environment and genes through the neuroendocrineimmune system, and how they relate to nutritional status. This is an emerging story that is absolutely fascinating. Just as the Selye stress mechanism has evolved tremendously in our understanding over the past 10 to 15 years, so has the understanding of the role that nutrition plays in modifying brain chemistry and neuroendocrine immune function. I am going to focus on just one part of the story because to do an exhaustive job in understanding the role that nutrition plays in neurochemistry, immunity, and endocrinology would take many days of discussion. I will focus on one emerging point of the sphere—hypothalamic function related to fatty acid intake. You might ask if fats in our diets have some influence on hypothalamic function or if the hypothalamus is sensing fatty acids and can discriminate different types of them; for instance, saturated from unsaturated and omega 6 from omega 3. That is the theme that is emerging. There is a review in the journal Nature Neuroscience that comes out of some very interesting work done at the Albert Einstein College of Medicine Diabetes Research & Training Center in New York.4 These investigators looked at selective regions of the brain, including the hypothalamus, and found that they are capable of gathering information on the body’s nutritional status. The hypothalamus is the seat of things like appetite and satiety, and it appropriates different neuroendocrine immune responses to the rest of the body and also has effects on programming metabolic responses to the availability of food and calories as fuel. This direct metabolic signaling in the hypothalamus is regulated, in part, by hypothalamic sensing of fatty acids. That is pretty remarkable—that there are receptor sites that will pick up information from dietary fats. To understand this in great detail would not be possible from the standpoint of time, but let me hit some of the high spots. When we consume dietary fats, we normally eat them as triglycerides that are broken down into free fatty acids by lipase enzymes. Triglyceride lipase in the intestines is emulsified by bile salts. They are distributed through the lymphatic system ultimately back to the vasculature, and they make their way to the liver, where they are resynthesized and redistributed into the blood as apolipoproteins or as chylomicrons. “Plasma long-chain fatty acids are bound to albumin and cross the blood-brain barrier mainly by simple diffusion in the unbound form. Unbound fatty acids can also be derived from hydrolysis of lipoproteins by lipoprotein lipases with the blood or the cerebral capillary bed. Overall, chylomicrons are likely to be a major circulating source of brain fatty acids after meals, whereas a combination of unbound fatty acids and locally hydrolyzed lipoproteins contribute to the brain fatty acid pool during fasting. A small proportion of fatty acid entry may also occur through direct uptake of lipoprotein particles mediated by lipoprotein receptors in the luminal surface of the cerebrovascular endothelium. Overall, the access of circulating free fatty acids to the CNS is generally proportional to the plasma concentration of fatty acids.”4 In the case of a person with hypertriglyceridemia who has a lot of saturated fat occupying the triglycerides, the brain is going to be exposed to higher concentrations of saturated, long-chain fatty acids. Conversely, if there are higher levels of omega 3-rich triglycerides or free fatty acids, the brain will be exposed to higher levels of these fatty acids. There is a mechanism by which fatty acids can be taken up and influence brain function. The ultimate effect of these fatty acids is not only to serve as energy fields, as fats always do, but also as a signal within the hypothalamus. Circulating nutrients can be derived from exogenous (such as food intake), or endogenous (liver glucose production) sources, and central neural circuits concomitantly modulate both exogenous and endogenous sources of energy, in keeping with a negative feedback system of appetite control and satiety. Circulating long-chain fatty acids signal the body’s nutritional status to hypothalamic energy centers. The intracerebral ventricular administration of oleic acid, an omega 9 fatty acid, is sufficient to inhibit food intake and liver glucose production in the presence of similar circulating long-chain fatty acid concentrations. We know from animal studies using instilled or directly administered fatty acids into various regions of the brain, that fatty acids have effects on appetite, energy production, and metabolic functions in the liver, such as glucose metabolism and glycogen synthesis. In light of these findings, the investigators asked whether a physiological elevation of circulating levels of long-chain fatty acids (LCFAs) could generate a measurable increase in the LCFA-CoA pool within discrete regions of the hypothalamus and generate a metabolic signal of energy, which would ultimately alter things like appetite and energy economy at the liver and at the muscle cell. A sustained 2 to 3-fold elevation in circulating LCFAs was found to double LCFA-CoA concentrations within the mediobasal hypothalamus. This increase was found to influence a whole series of metabolic functions, including beta oxidation, glycogen synthesis, and fatty acid metabolism at the liver level in animal studies. This is an interesting observation—that dietary fat plays a role in modifying brain hypothalamic function and that differing components of the fatty acid family have differing effects. If we look at long-chain saturated fatty acids, they have a different second-meal effect, or satiety-producing effect than omega 3 fatty acids. There is now evidence indicating that omega 3 fatty acids play a role in hypothalamic function in such a way as to lower appetite and improve thermogenesis, or the lipolytic breakdown of fatty acids. It would be possible to propose that consumption of fats, in this case the omega 3 family of fats specifically, could serve as appetite regulating and therefore, as weight loss agents. Does that sound paradoxical? I said that the consumption of fat could cause weight loss. That sounds very counter-intuitive. I am not talking about boatloads of fat; I am talking about the amount of omega 3 fatty acids necessary to promote proper hypothalamic and cellular signaling that results in appetite regulation and improved metabolic function. This is a fairly remarkable, perhaps even paradoxical, role that various fatty acids play in regulating neurochemical function pertaining to metabolism. Part of the role these fatty acids have on function has been determined to be a consequence of the influence they have on gene expression. Fats have been thought to be calorie-rich storage nutrients that were basically providing energy economy to the body, but certainly not carrying gene expression messages, that is to say as information molecules. But, as has been pointed out in a variety of reviews over the past few years, including one that recently appeared in the journal, Lipids, we now know that there are a number of well-recognized mechanisms by which specific fatty acids regulate gene expression.5 They regulate the expression of genes involved in lipid and energy metabolism. In particular, two transcription factors—sterol regulatory element binding protein-1c, or SREBP-1c, and the peroxisome-proliferated activator receptor a (PPAR a)—have emerged as key mediators of gene regulation induced by fatty acids. SREBP-1c induces a set of lipogenic enzymes in liver. Polyunsaturated fatty acids (PUFAs), particularly omega 3 oils, but not saturated or monounsaturated fatty acids, are known to suppress the induction of lipogenic genes by inhibiting the expression and processing of SREBP-1c. The unique effect of the PUFAs suggests that the SREBP-1 may regulate the synthesis of unsaturated fatty acids for incorporation into glycerolipids and cholesterol esters. PPARa plays an essential role in metabolic adaptation to fasting by inducing the genes for mitochondrial and peroxisomal fatty acid oxidation, as well as those for ketogenesis in mitochondria. Here we are talking about almost a thiazolidinedione-type effect that omega 3 fatty acids have by serving as PPARaagonists, or like fibrates, to use an example, that are known to be alpha agonists to increase lipolytic enzyme activity and break down fat. What I am trying to illustrate is that the fatty acids of specific families have effects both centrally, through hypothalamic functional In the past, we have always focused our attention on the fatty acids themselves, not so much looking at their downstream metabolites. Now, there is more and more evidence indicating that fatty acids, particularly the omega 3 and 6 families, are converted into eicosanoid derivatives, which can have a variety of influences on the body. Beyond the eicosanoids, new families of fatty acid metabolites that have unique effects and serve as neuroprotectants are now being found and studied. These are the resolvins that come from both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), omega 3 fatty acids, and that serve as precursors to what have been termed neuroprotectins and resolvins. It is interesting to note that there is a differential effect of EPA versus DHA in the modulation of neuroendocrine immune function. One might think of EPA-rich oils as being best for modifying inflammation, and DHA-rich oils as being better for modification of lipids (triglyceride-rich particles) and for modulation of neurochemistry. In part, these docosatrienes and their interrelationship with neuroprotectins and resolvins, form a matrix of protection in the nervous system that modulates neuroendocrine immune function. They are both neuroprotective and antiinflammatory. There is a good review of these resolvins, docosatrienes, and neuroprotectins in Current Opinion in Clinical Nutrition and Metabolic Care.6 In view of the many beneficial actions attributed to these omega 3 fatty acids, these resolvins, docosatrienes, and neuroprotectins derived from them are being found to be some of the putative molecules that participate in the protection against neuroinflammation and alteration to the neuroendocrine immune system. Another interesting paper that discusses resolvins, docosatrienes, and neuroprotectins appeared in the journal, Lipids.7 The authors discuss that these mediators were only recently identified as metabolites from EPA and DHA, and they have potent bioactivity in resolving inflammatory exudates in which tissues are enriched with DHA. The trivial names resolvin (resolution-phase interaction products), and docosatrienes were introduced for the bioactive compounds from these novel series, since they possess potent anti-inflammatory and immunoregulatory actions. It is not just the fatty acids, in and of themselves, but also their metabolites that are of interest. Once the question of metabolites has been raised, there is differentiation from one individual to another. That also begs the question about cholesterol. Cholesterol has had such a “bad rap,” as if it is only a bad molecule and we should lower it with statins. Cholesterol is an important molecule for cell membranes as a precursor to hormones and to bile salts. We certainly want to keep cholesterol in mind as being a good molecule, despite the negative press it has received. In the mammalian brain, cholesterol plays an important role in determining and maintaining healthy function. Low levels of cholesterol in the brain are associated with neurodegenerative disease in animals, which raises the question, what is the best cholesterol status and how does it relate to brain function? In one animal study, it was shown that CNS demyelination is associated with low cholesterol levels, and that cholesterol-deficient oligodendrocytes actively enriched cholesterol and assembled myelin with more than 70 percent of the cholesterol content of wild-type myelin.8This shows that cholesterol is an indispensable component of myelin membranes and that its availability in oligodendrocytes is a rate-limiting factor for brain maturation. There is a lot that is special about cholesterol, as was described in a paper in the journal, Lipids.9 Cholesterol plays an important role in neurochemical function. It raises the point of everything in balance, everything with omega 3, omega 6 fatty acid ratios, and even cholesterologenic enzyme processes may all play important roles in protecting neuroendocrine immune function. If cholesterol is too low, it may have an adverse effect on the cholesterol pool and unexpectedly have an adverse effect on neurochemistry. Omega 3 fatty acids are important and omega 6 fatty acids are important. Even arachidonic acid has an important role to play in maintenance of proper neuroendocrine immune function, as does cholesterol in cell membranes and myelin. Let us move to the Clinician of the Month, who will help us to better understand the interface between environment and neuroendocrine immune function and ultimate disease entities

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Esther Sternberg, MD Director, Integrative Neural Immune Program National Institute of Mental Health National Institutes of Health Building 36, Room 1A-23 36 Covent Drive, MSC 4020 Bethesda, MD 20892-4020 JB: It’s time for our Clinician/Researcher of the Month. This month, we are fortunate to have a person who fits into both of those categories—Dr. Esther Sternberg, Director of the Integrative Neural Immune Program and Chief of the Section on Neuroendocrine Immunology and Behavior at the National Institute of Mental Health at NIH. Those of you who were fortunate enough to attend our 12th International Symposium on Functional Medicine in Palm Springs had the pleasure of hearing Dr. Sternberg present there. All of us were rapt as she outlined the story of her own personal background in this area and, of course, the contributions she has made to the field, and how it is evolving. I was first brought to understand more of Dr. Sternberg’s work in reading her book, The Balance Within—The Science Connecting Health and Emotions (W.H. Freeman; 2000). This book should be required reading for all of us in this field. It is the Magna Carta of laying the groundwork for understanding the connections between body/mind, the immune system, and diseases that result from immune dysregulation. Dr. Sternberg’s work is highly valued. In fact, she has established the field of neuroimmune interactions and collaborative networks and other interdisciplinary fields, including women’s health. She’s currently highlighted in the National Library of Medicine Exhibition on Women and Medicine under the title, “Changing the Face of Medicine.” It’s with great privilege and pleasure, Esther, that I would like to introduce you to our Functional Medicine Update audience. You were a family doctor at one time after receiving your MD in Canada. You were trained in rheumatology at McGill University and now you’re in neuroimmunology at the NIH. That’s an interesting path. Would you tell us how you got there? From Family Practice to Neuroimmunology ES: First, it’s a great pleasure for me to speak again to this audience and it was a great pleasure to speak at the meeting in Palm Springs. This audience is very receptive to the issues of the mind/body connection and the science that explains how these phenomena that we have recognized for thousands of years—that stress can make you sick; that believing can make you well; and that the social world has effects on health. We know now that is based in very strong science—the anatomical, hormonal, and neurochemical connections between the brain and the immune system—and that breaking those connections results in disease. How did I get into this? Well, as you said, I did start off as a family doctor. At that time in Montreal, family practice was not yet a full-fledged specialty, so after my internship, I went into general practice. I loved it. I loved the interaction with patients. It was immensely rewarding to work with families of all ages and to actually see that interventions that I instituted did help. There’s nothing more rewarding in medicine than that—the immediacy of helping people get through difficult spots in their lives. But after two years in practice, I looked down at my work sheet and noticed that about half my patients had some kind of aches and pains and the other half had some kind of mood problems—anxiety and depression—and I didn’t feel well enough prepared to deal with either of those issues without going back and getting further training. I picked rheumatology and went back and got my specialty training in rheumatology at McGill University and the Royal Victoria Hospital. I was fully planning to go back into practice at the same clinic where I was a family practitioner. In the last months of my fellowship training, I was called to see a patient at the Montreal Neurological Hospital who had developed a scarring inflammatory autoimmune disease that resembled scleroderma. The only thing that he had been exposed to was an experimental drug for epilepsy that was designed to change brain serotonin. That experience, seeing this man in excruciating pain with what was clearly an autoimmune inflammatory disease, appeared to me to be linked in some way to changing brain serotonin. That convinced me that the brain has got to have something to do with autoimmune inflammatory disease. That was in1978/1979. And I had no idea how that link could occur. There was some evidence in the literature to suggest that serotonin metabolism might be abnormal in scleroderma at that time, but the evidence was very thin. It was that patient that propelled me into a research career. I got together with a biochemist at McGill—Simon Young—and together we did research on this subject and on control subjects who had been treated with that drug and who did not develop any illness.10 We published that paper as a lead article in The New England Journal of Medicine. That’s how research is. You see a patient; you do the study; you do a lead article in The New England Journal of Medicine. It turned out that was unusual, to say the least. But it did propel me into a research career, and I subsequently went to St. Louis where I trained in immunology, and then came to NIH to continue pursuing the concept, or the question, that the brain could have something to do with autoimmune inflammatory disease. It was not an easy task because, at the beginning, those mentors that I worked with in the field of immunology and rheumatology didn’t believe that the brain and the immune system could have anything to do with each other. It was the day when immunologists saw the immune system as completely independent, because immune cells could be cultured in tissue culture dishes and could function perfectly normally. The assumption was made that the immune system, since it works perfectly well outside the body, doesn’t need the body to function, and this is true and false. Of course, the immune system works perfectly well outside the body, but when you put immune cells back into the body, they work very differently because they’re exposed to many different nerve chemicals, hormones, and factors that do change the way they function. At the beginning of my cellular immunology career, I wanted to test the effects of serotonin on macrophage activation—something that certainly doesn’t sound flaky. It sounds very molecular, very cellular, but I was told by a supervisor that I was going to ruin my career. For some perverse reason, that only spurred me on to continue to do these studies and, indeed, I found that serotonin does change macrophage activation and drugs that block serotonin interfere with that. Finally, when I came to NIH, I decided that testing drugs in tissue culture really isn’t going to lead to understanding how the system works in the whole organism, nor would it lead to finding therapeutic interventions or new drugs. I did some studies on rats that were prone to developing arthritis and their very closely genetically matched cousins that are resistant to developing arthritis. I tested an anti-serotonin drug in these animals and, much to my surprise, rather than curing the animals with arthritis, the anti-serotonin drug killed the animals that were supposed to be resistant to arthritis. That was a great shock. It looked to me as if the animals were dying in septic shock. The way you induce arthritis in animal models, in rats, is that you expose the rats to any one of a number of proinflammatory triggers, or antigens. In this case, they were bits and pieces of streptococcal cell walls. What happens when you do that—give an animal strep cell walls—if there is no protective mechanism to prevent the immune system from overshooting, they could potentially die from septic shock. And that’s in fact what happened. When we gave the anti-serotonin drug, and then when we gave a group of corticoid antagonists, we were removing one of the body’s important mechanisms of preventing the overshooting of the immune system through the anti-inflammatory effects of the glucocorticoids. The way I figured that out was at midnight when the student who was working in the lab called me and said that something had gone horribly wrong, and that all the rats were dying. Having been used to being in family practice and doing house calls, I did a house call on the rats in the middle of the night. I realized that it wasn’t all the rats; it was just what were supposed to be the control rats that had received both the strep cell walls and the anti-serotonin drug. I knew that the drug had been developed for hypertension. By the way, it is not in use and was never developed further after this experience. A lot was known about what it did to the brain and one of things it did was to block the hypothalamic pituitary adrenal axis. I realized at that point that perhaps, by removing the HPA stimulus to cortisol, glucocorticoid production, that that was taking away the body’s anti-inflammatory control through glucocorticoids in the immune system and allowing for the precipitation of shock. That’s what led me to hypothesize that the hypothalamus and a blunted HPA axis response and resultant blunted glucocorticoid response, could be associated with susceptibility to arthritis in the arthritis-susceptible rats and that conversely, a hyper-responsive HPA axis could be associated with resistance to arthritis in those animals. That hypothesis turned out to be correct. In fact, it has now been shown across species and across diseases from chickens with thyroiditis, some strains of mice with lupus, rats with a variety of autoimmune inflammatory diseases, and humans with Sjogren’s syndrome, lupus, rheumatoid arthritis, CFS, irritable bowl syndrome, fibromyalgia, asthma, dermatitis—that all have a blunted hypothalamic- pituitary-adrenal axis response to a variety of stimuli. It’s also been shown through intervention studies in animals that interrupting the axis at any point, whether it’s at the hypothalamus, the pituitary, the adrenals, or the level of the glucocorticoid receptor, turns an otherwise inflammatory resistant animal into one that is so susceptible to inflammation that when exposed to bacterial products, they will die from septic shock, and that giving glucocorticoids reconstitutes this axis and prevents the overshooting of inflammatory responses. That was the trajectory of my career that led from an observation of a single patient that convinced me that this field was an important one to pursue. JB: Not only is that a fascinating story, one of a great scientific series of discoveries, but it also obviously raises so many interesting questions about what Pasteur was quoted as saying: “Chance favors the prepared mind.” How are people prepared to make these observations? I was struck when I heard the story. I know a little bit of this, having heard you speak and having read your book, so I’m asking a question for the rest of the audience that hasn’t had the privilege of being familiar with that. It sounds like the HPA axis dysregulation associated with shock and autoimmune type situations through blunted glucocorticoid action, is somewhat reminiscent of hypoadrenalectomized animals. When we think of McGill University, we think of Selye and I know a little bit about your history so perhaps you could tell our audience about the connection of your history to Selye. It seems that sometimes we weave an interesting web in our lives. Hans Selye’s Research on Stress ES: You’re right and until I wrote the book, it didn’t occur to me that not everybody in the world grew up knowing Hans Selye. That may sound like an odd thing, but he was such a familiar figure to me. He and my father were professors in the same department of medicine at the University of Montreal. It’s true that Selye and my father had started off at McGill and then moved to the French university. Montreal, at the time, was divided very much along language lines. McGill was the English university and the University of Montreal the French university. As a child, I grew up visiting my father’s lab and my sister and I would play on the stairwell at the University of Montreal and between floors, we would occasionally wander onto the floor where Hans Selye’s labs were. I describe in my book, recollections of this very imposing figure and I also went back and talked to Selye’s former colleagues, very close friends of my family, and former students to try to piece together a picture of this man who was the person who brought the word “stress” into the dictionary of virtually every language around the world. He borrowed it from the physicists and used it in the way that we understand it today, as the perturbation of the response of an organism to the various perturbations in the environment that we experience. It’s an interesting story, the story of Hans Selye and his hypotheses and his attempts to prove them and to bring them to the rest of the world. It’s an example of a man who was convinced of an idea, who was well ahead of his time and was rejected in many ways because at the time, there was not enough evidence to prove the connections in the way that we have today. JB: I’ve always wondered why Hans Selye, at least more recently, wasn’t awarded a Nobel Prize in Medicine and Physiology, given that stress is the most often cited word in the Index Medicus. Perhaps at the time there wasn’t enough data, or whatever the reasons were for not selecting him, but it seems that now, it’s a tremendous oversight. Glucocorticoids and Stress ES: Well, I can’t speak for the Nobel Committee, but I can say that Nobel prizes are never awarded posthumously. It may be that he was way ahead of his time. Also, he made observations that were correct, but he made some predictions based on those observations, based on the knowledge that was available at the time that turned out to be wrong. His observations were right and the general concepts were right, but the direction of his predictions turned out to be wrong. He predicted that there would be a proinflammatory hormone discovered in the adrenal glands, and then glucocorticoids were discovered to be anti-inflammatory. The Nobel Prize was awarded to Hench, Kendall, and Reichstein who used glucocorticoids to treat rheumatoid arthritis. So, the prize was awarded for some part of that axis. It just was thought at the time that glucocorticoids were not physiologically important in regulating inflammation. It was thought that they were pharmacologic agents, which is an odd interpretation, since they were discovered in the adrenal glands. I suppose that scientists should have figured out that if they’re in the adrenal glands, they must be doing something there physiologically. But they were used from the very beginning in pharmacological doses. The connection between how those glucocorticoids got released from the adrenal glands—that there was a connection from the brain, the hypothalamus, the pituitary, all the way to the adrenal glands, that was the physiological release mechanism that could occur during situations of stress. It took a long time for that concept to be accepted. Possibly another reason for the resistance on the part of the academic community to accept the notion that stress was real is that it was a notion that was around for thousands and thousands of years. Going back to the ancient Greeks and Romans, as I do in my book. The Romans, when they discovered the Greek temples to Asclepius, the Greek God of Healing, wondered why it was that these temples were always built on the tops of hills away from the noise and bustle and dirt of the city, away from the stress of the city. Why is it that these temples were built in such a way and how is it that being in such a situation overlooking a beautiful ocean with fresh water source and good healthy food and social support and sleep and music and dreams. How is it that all that helped patients to heal? I think part of the issue is that these concepts were around for thousands and thousands of years and it’s something your grandmother told you. How could that possibly be real? I think it was so embedded in the popular culture that it was hard for the academicians to believe these concepts until we could understand them in the language of science. JB: It’s very interesting. A few years ago, I had the pleasure of interviewing Dr. James Goodwin, a professor of medicine at the University of Texas School of Medicine in San Antonio. You may recall a paper he wrote that appeared in JAMA some years ago, titled “The Tomato Effect.”11 His model, when he reviewed it, (he had a pretty interesting rationale for this, based upon looking at textbooks of medicine and the way they language things), is it’s not that things like Selye’s work were outside the range of good thinking. It was what they did in transgressing what he calls the covenant or the guild, by writing to the general public. He uses Galileo as an example. He said that Galileo was not the first person to talk about the heliocentric view of the universe. Kepler had done it years before, but Kepler wrote in the language of scholars, which was Latin, and Galileo wrote in the language of the people, which was Italian. Once you do that, you break the covenant. I guess he proposed that Selye did the same thing. It caused him to be an outlier within his own community because he took it to the public and didn’t keep it within the guild. Academicians and the Public ES: There’s no question that was part of it. I describe that in the book and the hushed conversations that my parents used to have over dinner, purposely not in English, so that my sister wouldn’t understand them, but we did. And the faculty generally did resent Selye’s grandiosity and attempts to communicate to the public. It has taken the scientific community until now, and even now, many of us who communicate with the public are still disparaged, much less so now than even five years ago, but there’s no question that there is a feeling amongst academicians that if you do talk to the public, you’re a lesser academician. I strongly disagree with that. Obviously, I wouldn’t be going around lecturing and writing books for the lay public if I did agree with that. I think that it is our responsibility as scientists to return as much of the knowledge as we have to the public in an interesting and palatable way. It is our responsibility. Public information is public health. I think the public has got to know about the new advances that are happening, as they happen. JB: I also had the pleasure of interviewing Dr. Robert Sapolsky on a couple of occasions, and obviously he’s come at this from his experiences and his research over the last 20 years in a slightly different way as a primatologist, but he has drawn similar types of conclusions in the field in which you’re working. And Dr. Ilia Elenkov, as well. In those conversations, there seems to be a common denominator, even today, among the three of you, and perhaps I’m being presumptuous in saying this, but still within our medical academic community, there is a resistance after 50 years to accepting the important role that these factors play in complex chronic age-related diseases, and the importance of building therapies that address the connections among these conditions. Evolution of a Sea Change ES: I think there is resistance, but much, much less so now than even ten years ago. I first started working hard at bringing the field to the awareness of the academic disciplines from which it sprang in the mid 1990s. I did several international conferences and workshops in a variety of locations, including NIH. It was very hard. There was a lot of resistance to doing the first few of these conferences, especially the first one. There was resistance from the academic disciplines, the parent disciplines of neuroendocrineimmunology. There’s been a sea change. I would say that since 1996, when I did the first of these conferences, to 2001, when I did a follow-on conference, together with the MacArthur Foundation at NIH, there was a very palpable difference, a huge difference in the acceptance of the field by the community, a very rapid sea change that had to do with the exponential accumulation of very, very solid molecular neuroanatomical, physiological neuroimaging, genetic immunological studies in this field that proved beyond a shadow of a doubt the many, many connections between the immune system and the CNS and how when those connections are disrupted, disease results. I think that it was the weight of the science that eventually convinced the parent disciplines that this stuff is real. JB: I’d like to gothrough a quick list with you of conditions that I know have, at least historically, been linked to some of the stress/immune responses, and see if you feel that in each of these areas, the science is advancing in making the connection more real. The ones I’m thinking about are heart disease, cancer, diabetes, and dementia. Do you feel that in those four areas, there is increasing strength of the connection, or are some of them still just speculations? Stress and Heart Disease ES: I think there is increasing evidence in all of those areas, at different levels. Of course, there’s evidence in heart disease that there’s an important element of inflammation. I was recently at a Directions in Research workshop, sponsored by the National Center for Complementary and Alternative Medicine, where there was a lot of discussion regarding trying to track the changes in brain function that occur during stress, all the way down to the effects on heart rate variability by the autonomic nervous system and potential effects on CVD. These are studies that are well beyond the realm of what was previously considered “flaky” mind/body medicine. These are solid neuroscience, physiological, and cardiovascular studies. I think the field has informed a lot of different aspects of CVD. Stress and Diabetes You asked about diabetes. Similarly, there’s very clearly an immune component to diabetes. I wouldn’t put that in the category of mind/body, however. I think one of the things that happens when a field becomes established and accepted, is that it can become part of many disciplines. It can become part of the explanation or understanding of pathogenesis of many different diseases. Stress and Cancer It’s difficult to study stress effects on cancer, but there are outstanding studies by David Spiegel, who showed that certain kinds of psychological support groups definitely prolonged life span in breast cancer patients. There was some controversy about that with a recent study that failed to find this effect, but the important point that David Spiegel made was that when he carried out his first intervention study 15 years ago, these sorts of interventions were not standard practice, and they are now. Now, it’s very hard to find a control group where there aren’t standard practice interventions using psychological support, anger management, or these sorts of psychological interventions. These interventions have become standard management, standard therapy, because we understand their importance, and we understand that they work. JB: That leads to a question I’ll bet you’ve been asked many times. We now have solid science. Your work and that of your colleagues has started to unravel this complex web of interaction of outside environment to inside neuroendocrineimmine function. What will be the way that this gets clinically integrated? Is it going to be pharmacology, or is it going to be self-regulation, or a combination thereof? Where are we on the therapeutics that one takes out of this? Clinical Integration of Neuroendocrine Immune Concepts ES: I think there’s no question that it’s all of the above. When you look at the advances and potential new therapeutics based on the understanding of these connections between the CNS and the immune system, they span the entire gamut. For example, one of the things we didn’t talk about, but which you alluded to when you asked about dementia, is that when cytokines are overexpressed, or inappropriately expressed in the CNS, they can cause nerve cell death. On the other hand, cytokines and immune cells can be very important in nerve cell survival and regeneration, and they play an important physiological role in maintaining and pruning nerve cells during development. That is a huge area of advance that helps to understand the pathogenesis of diseases like multiple sclerosis or infectious diseases of the brain like neuro-AIDS or nerve trauma or dementia. Very interesting advances in therapeutics in these diseases have come from this. For example, Michal Schwartz of the Weizmann Institute has shown that the use of specific activated T cells can prevent paralysis and actually reverse it, even up to 10 days after spinal cord injury.12 This is a huge advance. She has shown this very clearly in animal models so there are the beginnings of testing to prepare for potential human use. The hurdle in this mode of treatment is not going to be whether it works; it clearly works. The question is going to be how to treat humans with specifically activated T cells without risking the development of multiple sclerosis. There are tremendous potential advances in this area, but a lot still needs to be worked out. Treatment Approaches Similarly, the interleukin-1 receptor antagonist has been shown again in animal models to reduce the area of stroke by about 50 percent. There are many potential biologic and pharmacologic treatments, therefore, that come from understanding these connections that are molecular and at a cellular level. And similarly, understanding that stress can make you sick by an overreaction of these stress hormones, an over-suppression of immune responses, and interventions that reduce stress, therefore, can potentially ameliorate or prevent such effects1 It gives credence to the use of many psychological interventions, many salubrious activities like meditation or prayer, certainly exercise, as adjuncts to treating many diseases. JB: I think you’ve set a vision as to where we’re heading in medicine. Some people would call it integrated, but let’s just call it good medicine, that leverages out of these discoveries. I want to thank you, Dr. Sternberg, both for the contributions and your vigilance. I know this hasn’t been an easy path for you, but clearly, it’s creating tremendous value for all of us in the clinical world. I want to thank you for sharing. For our listeners, Dr. Sternberg’s book is required reading—The Balance Within: The Science Connecting Health and Emotions. It’s the seminal kind of work to get us started in this field. Thank you again for all your contributions and we’ll be following your work very closely as we move forward. ES: Thank you so much. It’s been a great pleasure talking to you, and it has been very rewarding for me to see this field embraced by practitioners who can really make a difference, who are at the forefront of instituting these approaches. Nutrition and the Neuroendocrine Immune System I would like to follow up from Dr. Sternberg’s extraordinary insight with a few closing comments about the nutrition connection to neuroendocrine immune function. I was talking earlier about fatty acids and the role they play in hypothalamic and central and peripheral nervous system function. The nervous system is composed of a specific composition of lipids. They are an important part of the brain’s structure and function. As we move to a better understanding of how fatty acids are metabolized, we need to recognize that in certain situations where there is auto-oxidation of fatty acids, that the oxidation products may be associated with oxidative stress. That is correlated with a variety of degenerative disorders, including things like heart disease, diabetes, kidney dysfunction, dementia, CNS function, neurodegeneration. Does this mean administering supplementary omega 3 fatty acids will increase oxidative stress and lead them into a state that might be called biological rancidification, meaning we are increasing the potential damage by administering fatty acids? I have heard some individuals say that because we know omega 3 fatty acids are so easily oxidized, we had better give high doses of antioxidants to prevent them from being damaged when they are consumed as supplements. Dr. Trevor Mori and his colleagues at the Western Australia School of Medicine, a very large group, focused on hypertension and conducted many studies in which they looked at the role fatty acids play in vascular diseases. They have come to recognize that the oxidation products of fatty acids, called the isoprostanes, play important roles in their human vascular disease.13 The isoprostanes are a family of fatty acid oxidation products that have a chemical similarity to prostaglandins. They are like twisted prostaglandins that can have some adverse effects on the way prostanoids are normally received by cell receptor systems. Elevations of isoprostanes, particularly plasma F2-isoprostanes, have been associated with increased oxidation of fatty acids in the body and oxidative stress. F2-isoprostane levels have been studied in individuals before and after high-dose EPA and DHA supplementation. Much to the contradiction of our prevalent thinking, subjects who are supplemented with fairly high doses (up to three times a day of an EPA/DHA mixture, have lower levels of F2-isoprostanes after the consumption of fatty acids, the omega 3 fatty acids, than before taking these fatty acids.14 It’s as if it serves as its own antioxidant, so to speak, if I can use that term euphemistically. I believe there is now fairly strong evidence from this work that when an individual is properly metabolizing fatty acids in the absence of antioxidant consumption, the omega 3 DHA/EPA serves as its own antioxidant, meaning it helps to balance redox properties in the body. If you were to see elevated F2-isoprostanes, it would indicate that individual is undergoing increased oxidative stress and you would look for the source. It is probably not as a consequence of consumption of increased omega 3 fatty acids. It is probably due to ischemia, infection, or upregulation of the inflammatory system through immune dysregulation. These would undoubtedly be the more likely sources, or heavy metal toxicity, metallothionine alterations, glutathione peroxidase/glutathione reductase deficiencies. All those things that are related to altered cellular redox, not just because of supplementation with omega 3 fatty acids. Studies in patients with coronary artery calcification have demonstrated a strong correlation between increased concentrations of F2 isoprostanes. Even young, healthy adults who have increased calcium artery scores appear to have increased evidence of oxidative injury through elevated F2 isoprostanes in their plasma.15 In the journal, Clinical Chemistry, there is a review on oxidative stress and vascular disease, looking at the results of isoprostane measurement.16 The authors state that over the last 20 years, there is overwhelming evidence indicating that oxidation of lipoprotein plays an important role in the development of atherosclerosis, and that the pathophysiology resulting in atherosclerosis is closely correlated with increased plasma levels of isoprostanes which, once again, implicates inflammation and oxidative stress with the etiology of coronary artery disease. Association of F2-Isoprostane Levels and Angiotensin II Type 1 Receptor—153A/G Gene Polymorphism Responses people have to increasing oxidative stress in their environment as a consequence of imbalance of the neuroendocrine immune system are polymorphic, meaning genetically unique. For instance, with isoprostane levels associated with angiotensin II type 1 receptor polymorphisms, some individuals have much higher levels as a consequence of the 153A/G polymorphism versus those that have the wild type. This was published in the journal, Free Radical Biology & Medicine. Nutrigenomics and the Future of Dietetics Practice In closing this issue of FMU, I want to talk about clinical dietetics as it relates to a nutrigenomic concept. I was pleased to see in a recent issue of the Journal of the American Dietetic Association, a mini review of articles talking about the role that nutrigenomics will play in the future of clinical dietetics and nutritional therapies.18 One of the most compelling of these articles was written by our own Ruth Debusk, RD, PhD, titled “Nutritional genomics in practice: where do we begin?”19 She states: “Nutritional genomics which studies the genome-wide influences of nutrition, has far-reaching potential in the prevention of diet-related disease. It is highly likely that during the next decade the nutritional supplement and functional food industries will continue robust growth in response to advances in nutritional genomics research and its applications. Parallel to this growth will be impressive progress in understanding the specific influence of certain food components on metabolic pathways and on long-term risk for disease.” Parenthetically, I would say that much of this will come through our better understanding of how genomics interfaces with function of the neuroendocrine immune system and how nutrition plays a role in modulating these functions.20 In closing, I would like to say that this means that one size does not fit all and, as Selye pointed out, stress is variant in its response. As we saw from Dr. Elenkov at the 12thInternational Symposium on Functional Medicine, you can take different strains of rats and show one strain that is very responsive to a certain stress factor, such as an allergen or an immune stimulant, and another that is more responsive to psychosocial stress. Vastly different clinical outcomes result from genetic uniqueness. The medicine for the future is personalized and it is built around the neuroendocrine immune system and its interrelationship with the environment. The body/mind connection lives on to be a major tool in the future of a functional-based medicine. We look forward to sharing with you in September.

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Bibliography

1 Elenkov IJ.Neuroendocrine effects on immune system. In: Adrenal Physiology and Diseases. Chrousos G, Ed. www.endotext.org/adrenal/index.htm. 2 Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8(3):365-371. 3 Robbins TW. Controlling stress: how the brain protects itself from depression. Nat Neurosci. 2005;8(3):261-266. 4 Lam TK, Schwartz GJ, Rossetti L. Hypothalamic sensing of fatty acids. Nat Neurosci. 2005;8(5):579-584. 5 Nakamura MT, Cheon Y, Li Y, Nara TY. Mechanisms of regulation of gene expression by fatty acids. Lipids. 2004;39(11):1077-1083. 6 Serhan CN. Novel eicosanoid and docosanoid mediators: resolvins, docosatrienes, and neuroprotectins. Curr Opin Clin Nutr Metab Care. 2005;8:115-121. 7 Serhan CN, Arita M, Hong S, Gotlinger K. Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirin-triggered epimers. Lipids. 2004;39:1125-1132. 8 Saher G, Brugger B, Lappe-Siefke C, et al. High cholesterol level is essential for myelin membrane growth. Nat Neurosci. 2005;8(4):468-475. 9 Mouritsen OG, Zuckermann MJ. What’s so special about cholesterol? Lipids. 2004;39(11):1101-1113. 10 Sternberg EM, Van Woert MH, Young SN, et al. Development of a scleroderma-like illness during therapy with L-5-hydroxytryptophan and carbidopa. N Engl J Med. 1980;303(14):782-787. 11 Goodwin JS, Goodwin JM. The tomato effect. Rejection of highly efficacious therapies. JAMA. 251(18):2387-2390. 12 http://www.proneuron.com/News/Cov98_00/Cov98_00_18.html. 13 Mori TA, Woodman RJ, Burke V, Puddey IB, Croft KD, Beilin LJ. Effect of eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and inflammatory markers in treated-hypertensive type 2 diabetic subjects. Free Rad Biol Med. 2003;35(7):772-781. 14 Mori TA, Beilin LJ. Omega-3 fatty acids and inflammation. Curr Atheroscler Rep. 2004;6(6):461-467. 15 Gross M, Steffes M, Jacobs DR, et al. Plasma F2-isoprostanes and coronary artery calcification: the CARDIA Study. Clin Chem. 2005;51(1):125-131. 16 Young IS. Oxidative stress and vascular disease: insights from isoprostane measurement. Clin Chem. 2005;51(1):14-15. 17 Ormezzano O, Cracowski JL, Mallion JM, et al. F2-isoprostane level is associated with the angiotensin II type 1 receptor—153A/G gene polymorphism. Free Rad Biol Med. 2005;38:583-588. 18 German JB. Genetic dietetics: nutrigenomics and the future of dietetics practice. J Am Dietetic Assoc. 2005;105:530-531. 19 Debusk RM, Fogarty CP, Ordovas JM, Kornman KS. Nutritional genomics in practice: where do we begin? J Am Dietetic Assoc. 2005;105:589-598. 20 Vickery CE, Cotugna N. Incorporating human genetics into dietetics curricula remains a challenge. J Am Dietetic Assoc. 2005;105:583-588.

Welcome to Functional Medicine Update for October 2005. We are already preparing for the 13th International Symposium on Functional Medicine, which will take place on April 19-22, 2006 at the Tampa Marriott Waterside Hotel & Marina, a beautiful five-star resort. The symposium will focus on: Managing Biotransformation: The Metabolic, Genomic and Detoxification Balance Points. There are so many aspects of detoxification that I thought it might be useful to devote several months of FMU to some preliminary information about it. I want to begin with what functional medicine has to do with the barriers of defense. Some of you might think this is a somewhat esoteric topic. How do the barriers of defense relate to detoxification and toxicity? Hopefully, by the end of this issue of FMU, you will see that they play an important role in regulation and defense against potential toxic exposure. There is probably no one who has described the epithelial barriers better than our own master teacher, Dr. Sidney Baker. In his lectures, writings, and books, he has spoken so eloquently about barriers of defense, the mucosal surfaces, and the fact that we are enfolded, protected, wrapped, and cloaked against exposure to potential toxic substances, both internally and externally, as a consequence of these membranous barriers. As Dr. Baker has pointed out, the gastrointestinal mucosal barrier, when stretched tight so that all the villi are laying flat, would occupy an area almost equivalent to a doubles tennis court. This very large, membranous barrier defends us from the environment and is involved with selective permeability, pulling in the good things and rejecting the bad things. These barriers of defense play very important roles in maintaining health against a hostile environment. The membranes are not confined to the mucosal surfaces; they also include the enfolding of membranes within every cell. It might be the endoplasmic reticular membrane, or the cellular membrane, or the nuclear envelope membrane, or the membrane that surrounds the mitochondria. We are composed of all these metabolic and physiologic processes that occur on the surfaces of specific topological structures called membranes. These membranes become both the barriers and an active part of our cellular organelle systems. Both on a gross level (epithelial level), and a cellular level (membranous level), we think the barriers of defense play a very important role as a fundamental principle in functional health. In our Applied Functional Medicine in Clinical Practice training program, we spend quite a bit of time talking about the basic core principles that differentiate a functional medicine approach by viewing a patient through the lens of histopathology, rather than the traditional, differential diagnostic methodology, which looks at the endpoints of a process of loss of function, arriving at some determined or agreed-upon point of pathology. Well before that, however, signs and various biochemical changes occur that reflect changing function. One of the principal, early-stage changes that often occurs is in the barriers of defense, leading to breakdown or loss of selective or active transport, which influences the function of the cell, tissue, organ, or organ system, until it eventually leads to a pathology. A discussion of the barriers of defense in physiological systems includes the role they play in protecting against exposure to injurious substances, either endogenously or exogenously produced, as well as the active role of these membranous surfaces to pull in what is necessary from the outside world by active transport, or get rid of things from inside the cells of the body that are not necessary. These would be the excretory processes of membranous surfaces. All of these become a dynamic and important part of understanding functional physiology. It is with that in mind that we are going to focus our attention this month on the epithelial barriers in human health and disease. Undoubtedly, some of what I am going to be saying will be review and perhaps repetition for many of you who are well inculcated in the functional medicine model. But I believe it is important to set the ground rules for all of us as we move forward to this month’s Clinician of the Month interview. I will begin with some basic principles, as I have come to understand them over the years. First of all, the tissue level barriers have physiological function. They are not like dams. They have dynamic function, and we actually see these epithelial and membranous barriers as being part of our organ systems involved with the homeodynamic processing of environmental information. Barriers not only separate fluids, but they also do very important work by resorbing solutes from different compartments, or secreting substances. In doing so, they establish gradients across themselves. These gradients are maintained as a consequence of energy processes. Whenever there is a high concentration of something on one side and a low concentration on the other, metabolic work requiring energy has to be done in order to maintain that concentration gradient. This energy requires the same cofactors and intermediates from which all other processes in cells derive their energy—the high-energy-containing molecule adenosine triphosphate (ATP), the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH), the reduced form of flavin adenine dinucleotide (FADH2), and the reduced form of nicotinamide adenine dinucleotide (NADH). These are particular high-energy and electron transfer molecules that are formed as a consequence of aerobic metabolism, or mitochondrial oxidative phosphorylation. There is a connection between biochemical energetics and membrane function that is important to keep in mind. Concentration gradients that are maintained by membranes require an energy process, which is tied to oxidative chemistry and mitochondrial oxidative phosphorylation—glycolysis, aminolysis, lipolysis—the things in intermediary metabolism that we have discussed. These gradients are used to establish other gradients—for instance, the sodium or potassium gradients. All of these concentrations are maintained through proper membranous function and structure. What constitutes a barrier? An epithelial barrier, or even an endothelial barrier that lines the surface of our vasculature, that one-cell-thick lining, has several elements related to its function. There are luminal secretions, such as mucus or unstirred layers on top of the apical cells, and there are the epithelial or endothelial cells per se, which maintain things like various messenger molecule sensitivity. There are proteins bound or embedded within the epithelial or endothelial barriers, which are receptor sites that pick up messages and transmit them from outside the cell to inside the cell through signal transduction processes. The point I am trying to emphasize is that we should not think of the epithelial barrier as being static and simply a structure, like collagen. We should think of it as a dynamic, fluid, mosaic model that is aggregating and disaggregating, changing its personality in real time, binding certain messenger molecules and transmitting them to the interior of the cell, and altering the phenotype of cells based upon environmental signals that are picked up on these membrane receptor surfaces. Epithelial Barrier Function What do we know about the function of the gut epithelial barrier? There is a high turnover rate. These cells are in a very caustic environment; the pH changes from very acidic to more basic. Microbes proliferate and produce their own irritant chemicals to which the epithelium has to respond. It has to maintain its integrity; if it does not, the epithelial barrier breaks down. Its intracellular junctions (called “tight junctions”) can be compromised; a breakdown of the intracellular junction leads to paracellular flux of materials, sometimes called “leaky gut” syndrome, where larger molecular-weight molecules that were previously excluded now become permeable to the gut and have access to the internal compartments across the barrier. There is also transcellular flux, where substances are transported directly across the epithelial cells themselves. This does not require breakdown of the tight junctions, and is different than leaky gut syndrome. Leaky gut syndrome would be defined as a breakdown of the tight junctions and an increase in paracellular flux by osmotic diffusion across the membrane, leading to vasolateral membranous exposure to the substances that were previously excluded. Microorganisms in the Gut The gut environment is home to many different types of microorganisms. Certain disease organisms seem intent on getting into the stromal and/or vascular fluid compartments from the luminal compartment. One of the things that prevents that from happening is the epithelial barrier of defense. The epithelial barriers have immunological function, particularly in the gut, with production of mucus and secretory IgA antibodies that help to defend the gut mucosal barrier against potential injury due to opportunistic infection in the gut. When we begin to look at this dynamic process, we recognize that GI microorganisms can play an important role in modifying gut mucosal barrier function. We think of microorganisms as being in three families. There are the symbiotic bacteria that participate in immunological upregulation and have a tropic effect on gut immunity. There are commensal microorganisms that find a friendly place and do not harm the host. Last are the parasitic organisms that can result in damage to the GI mucosal environment and the immunological system of the gut, and produce disease, resulting in things like compromised intracellular junctions, paracellular flux, and leaky gut. A leaky gut lets the larger molecular-weight molecules slip through the mucosal barrier and enter into portal circulation. Other parts of the body, principally the immune system, get exposed to these substances. There may be a downstream hepatobiliary effect, and a systemic effect through immune cells, which may be communicated to barriers at a distance, such as the blood-brain barrier (BBB). From that, we begin to see the emergence of clinical conditions like hepatoencephalopathy. We should call it GI hepatoencephalopathy, because it is the gut connected to the liver connected to the brain. If there is compromised GI function, breakdown of paracellular junctions, and absorption of these potentially toxic molecules, they are taken to the liver. If the liver’s system for managing those toxins is compromised or overwhelmed, there is a relay system that sets these activities into systemic circulation through either direct or indirect effects of the immune system on the BBB. This leads to potential putative neurotransmitters, or neurotoxins being delivered, or an upregulation of the gut’s immune system, which leads to an upregulation of the liver’s immune system through the Kupffer cells and, ultimately, an alteration of the immune system of the brain—called the microglia—leading to potential of neuronal injury or apoptosis, or accelerated brain cell death as a consequence of exposure to these toxic molecules. Celiac disease, for example, has long been associated with neurological disorders, including dementia,1 ,2 and it is becoming more clear that gluten sensitivity, short of full-blown celiac disease, is probably a factor in many of these conditions. We could hypothesize the connection from intestinal injury to dementia as a result of gluten sensitivity in the following way. The gut mucosa breaks down, activating the immune system and hepatic Kupffer cells; these processes, unchecked (as, for instance, by the continuing ingestion of gluten), eventually cross the blood-brain barrier and begin to create alterations in the brain’s immune system (the microglia) that can lead to neuronal injury or apoptosis—accelerated brain death—as a consequence of exposure to these toxic molecules. Food for one may be the poison of another. Not everybody gets dementia from eating wheat, but those individuals who may have a unique connection between a gut messenging system and, ultimately, a brain neuronal activation through glial cell upregulation, may be at risk. When we look at this story from a functional medicine perspective, we have to look at it as a web. We cannot look at each of the compartments in isolation. We cannot just ask what the gastroenterologist, hepatologist, immunologist, or neurologist would say. It is part of a system of understanding how these agents are connected through these mechanisms. It begins with alterations in function through immunological and defensive barrier changes, leading to the greater absorption of some of the potential immunological or toxic-activating molecules. Diarrhea One of the clinical manifestations of microbial dysfunction in the gut is diarrhea. Diarrhea illustrates how epithelial barrier dysfunction leads to disease pathology. Diarrhea can occur for many reasons. Diarrhea from inflammation relates to cell death and ultimately leads to blood in the stool. Non-inflammatory diarrhea can be due to secretory and osmotic effects. Secretory diarrhea generally occurs when the small intestine and, to a lesser extent, the large intestine, secrete large amounts of electrolytes and water in excess of their resorptive capacity. This is generally a consequence of what is called “dilution as the solution to pollution.” If there are toxic bacteria present, such as Shigella, that are producing “funny” metabolites, the body has the ability to try and dilute the concentration by pulling water from the cells into the GI contents, which results in diarrhea. Unfortunately, electrolytes come with the water and a serious case of a Shigella toxin can eventually lead to electrolyte imbalances and dehydration. In developing countries in the world, this can lead to infant death. Even in a healthy person, a severe case can be very compromising. Those of us who have experienced traveler’s diarrhea know how uncomfortable that is. Secretory diarrhea is caused by bacterial toxins and enterogenic viruses. Osmotic diarrhea is very similar and occurs when solutes that are water soluble and unabsorbable remain in the bowel and retain water, such as lactulose. It is often used to treat hepatic encephalopathy. A non-absorbable sugar is given, which produces a hyper-osmolar condition in the gut and it pulls a lot of water from the cells and creates diarrhea. It overloads their absorption capacity. Diarrhea can be produced in almost anyone if he or she drinks enough salt or eats enough high-solute-containing materials that are not easily absorbed. It will cause osmolar shock that causes dilution that results in diarrhea. H0157 E. Coli The toxic forms of diarrhea related to the release of various toxins from certain parasitic bacteria include the serious cases of enterotoxic E. coli that produced the “hamburger crisis” from the fast-food chains some years ago—the H0157 E. coli. This is a very serious toxin that may lead to a breakdown of gut mucosal function. It stresses the liver and ultimately has a toxic effect on the kidneys. The cause of death was often renal failure in the children that had a fatal outcome from exposure to this bacterium. That is the outside edge of toxicity. Well before that, however, there are many bacteria that produce less serious conditions that result in more chronic problems—things like the Clostridium perfringens enterotoxin, which causes increases in gut permeability and is physically associated with the production of a variety of inflammatory proteins from the gut mucosa. Clostridium difficile is another bacterium, an anaerobe that causes antibiotic-associated diarrhea and colitis. Many people who are on long-term antibiotic therapy end up getting an overpopulation of this parasitic organism, which is associated with many toxic effects leading to GI mucosal breakdown, absorption of other molecular-weight molecules from the gut, and hepatic- and immune-related stress from a functional medicine perspective. In infants, these conditions can also be caused by viral infections, such as rotaviruses, which cause severe secretory diarrhea. The virus infects columnar epithelial cells and inhibits the absorptive capacity of these cells, causing a net secretion of water and salts, giving rise to watery diarrhea. Since that we are always exposed to these potential pathogens out there in the world in which we live, how do we maintain a healthy gut? The gut mucosal lymphoid tissue helps to protect us. Someone once asked me why more than 50 percent of the immune system of the body is clustered around the intestinal tract. I never received a direct pipeline of divination on understanding that, but the logic most people use teleologically is that the gut mucosa is so rich in immune function because, over the course of living, we will be exposed to nearly 20 tons of foreign molecules in what we eat, which have to be converted into friendly molecules by a process of adjustment and by immune tagging so that they look like friends. The immune system defends us against foreign molecules and foreign “critters.” The second largest organ (in mass) in the body is the GI enteric bacteria; something like 2 kg of bacteria live in the human GI tract. These organisms produce the results of their own metabolism and waste products and exhibit their own personalities. Our gut mucosal immune system has a responsibility for managing all of that, and it is quite a task. That probably explains why so much of the immune system is clustered around the gut through the gut-associated lymphoid tissue (GALT) and the mucosa-associated lymphoid tissue (MALT). These are present to help protect against injury to gut mucosal barrier function. Barrier Function and Allergens When we think about this barrier function, we also have to recognize that not only microorganisms, but molecules can induce injury to the mucosa. Some of these would be called allergens, which are known to affect barrier function. The immune system is normally in a luminal compartment (a fluid compartment opposite the lumen in nearly all cases for epithelial tissues). Environmental allergens contact the organism through its luminal compartments; for instance, nasal airways or bronchi in GI mucosal lumens. Allergens will not cause an inflammatory response (the source of their bad reputation) unless they gain access to the interstitial compartment on the other side of the barrier. There has to be some type of breakdown of the mucosal epithelium of the nasal airway, bronchi, or the GI mucosa, for a significant allergy response to result. We think of exposure to something as triggering an allergy, but it is exposure leading to mucosal breakdown that leads to the effects on the immune system. In instances of chronic allergic rhinitis, nasal mucosa has exhibited not only desquamation of the epithelium, but also increased permeability of epithelial junctions. Dust-mite allergens have been found to possess several proteolytic enzymes capable of causing progressive breakdown in the mucosal barriers. They have a stealth system to break down our defense, allowing entry of antigens into the immune system. These proteases are both cysteine- and serine-specific and they lead to well-known cleavage sites in the mucosa and open the portals of entry to gaining access to the immune system. The Immune System and Inflammation The immune system, once activated, may lead to inflammation. When one thinks about the immune system from a compartmental or barrier point of view, it is striking that it is often an endothelial or an epithelial barrier away from the action source itself. Downstream, ultimately, the inflammation occurs from the upstream breakdown of the mucosal barrier. Microorganisms normally first enter the body by colonizing luminal compartments, simply because these compartments have the most contact with the environment. If there is a dysfunctional relationship between the bacteria on the mucosal surface, it “engages the enemy,” and ultimately can lead to the breakdown of the mucosal surface, exposing the immune system to the debris or secondary metabolites that activate the immune system. Although the changes may be seen locally with rubor, calor, or dolor, the redness, heat, and pain of inflammation, they can have systemic effects because the immune system is in a state of alarm and these processes are not isolated in one tissue. They can travel through the blood stream by the activation of things like tumor necrosis factor alpha (TNF- a), interferon gamma (IFN- g;), interleukin-1 (IL-1), or interleukin-2 (IL-2), the proinflammatory cytokines, which can lead to an activation of the immune system and potential systemic effects. It is important to recognize that breakdown in barrier function and activation of the immune system can be associated with a state of chronic inflammation, which produces effects on all sorts of different tissues. With few exceptions, the expression of a barrier function alteration is known to be associated with chronic inflammatory conditions. You might ask if inflammation causes a barrier function breakdown, or does a barrier function breakdown cause inflammation? The answer is, both. It is a cycle. One can approach it from either perspective. An inflammatory process can trigger a breakdown or a breakdown can trigger inflammation due to immune upregulation. Barrier Function and Coronary Artery Disease, Inflammatory Bowel Disease, and Colon Cancer Diseases previously not considered as being associated with breakdown of barrier function are now being seen as possibly having an early etiological connection to this breakdown. In coronary artery disease (CAD), there is arterial endothelial cell dysfunction and loss of barrier function on the endothelium, initiating aspects of the pathophysiology that leads to atherogenesis. We think of inflammatory bowel disease (IBD), such as Crohn’s disease. We also think about relative risk of certain types of colon cancer associated with gut mucosal barrier dysfunction and inflammation that leads to alteration in gene expression patterns, oncogene mutagenesis, and ultimately, cancer. A wide variety of different conditions may result from breakdown of barrier function across different diagnostic profiles and different medical specialties.3 There is no organ left behind. “The function of the gut mucosa is dependent on its cellular constituents, as well as on its assembly into a cohesive unit. The developing gut faces unique challenges as one of the longest and largest organs in the body and also because it is constantly interfacing with external factors through the diet.”4 As I mentioned, we will eat nearly 20 tons of foreign molecules over the course of our lifetime. Our gut mucosa has to differentiate the friend from foe. It has to extract the nutrients and reject all the toxins over the course of living. The location of the GI mucosa deep within the body has, until recently, hampered investigation, but now the patterning of the gut along its longitudinal and radial axes is one of the most fascinating issues that pertain to the development, function, and homeostasis of the GI organ. Gastroenterology is undergoing a tremendous revolution in thinking because it is now being seen that the GI system is a messenger system to the rest of the body through not only the barrier function, but through the gut immune system and all the various tropic effects and mediators that are produced by the gut, even things that trigger functions in the brain leading to satiety, or things that trigger functions to other members of the endocrine system that cause secretion downstream. The gut may be a very important translator of external stimuli into systemic functional changes. This was beautifully described in a series of articles that appeared in Science magazine titled, “The Inner Tube of Life, that describe gut function very well. These articles appeared in the March 25, 2005 issue.4,5 ,6 I think you will find these articles quite informative, because they paint a picture of the gut as a dynamic functional organ that is more than just a tube; it is a very important part of the signaling system and the immune regulation of the body that has effects on distant sites (or, for other medical specialties, so to speak). What about self-renewal of the gut mucosa? The intestinal epithelium represents an exquisite model for the study of stem cell biology because the gut mucosa constantly has to regenerate itself. It is likely the simplest mammalian study model for tissue self-renewal, yet it features multi-potent stem cells, transit-amplifying compartments, and several binary lineage decisions that require cells to create daughter cells that are of the same integrity as the parent cells. The function of the mammalian intestinal epithelium poses formidable challenges by being able to maintain integrity after exposure to toxins in the environment, either the skin as epithelium, or the gut mucosa being exposed to its contents. Anatomy of the Small Intestinal Epithelium If we think about structure and function as being tied together, the anatomy of the small intestinal epithelium demonstrates the tremendous evolutionary adaptation through natural selection to, functionally, be able to maintain the balance between being a barrier protective function and being a dynamic organ. The microvilli with their cells embedded, the crypt-villus junction, allows the cells to have personalities of both defense and transport. The goblet cells, the entero-endocrine cells, and the absorptive epithelial cells, which are all derived out of stem cells in the gut mucosa, are redifferentiated upon the gut mucosal turnover, probably every 7 to 10 days. There is a constant shedding and reformation of the gut mucosa, just as there is on our skin, but perhaps more dynamically in the gut mucosa. Malnutrition and Stress and Rapid Tissue Turnover In the case of malnutrition or high stress, these rapid turnover tissues (that have high tissue specificity and embryological development), may also be most rapidly affected by temporal undernutrition, malnutrition, or stress. That is often what happens. We often notice that the first signs in people under stress or who are not eating right often happen in the mouth—canker sores, changes in tongue texture, chapped lips, or chylosis at the corner of the mouth. The rapid turnover tissues start to be reflective of the stress in life, or undernutrition. In a nutritional assessment, we often ask the person to stick his or her tongue out to see if they have geographic tongue, hairy tongue, dark tongue, or poor tongue color. We look at their lips and gums for gingivitis. We look at the mucosa in the oral cavity. All of these signs are indicative of what is going on. This is the lining of the surface. We can’t look at the pulmonary epithelium or the GI mucosal epithelium as easily as we can look in the mouth, so we often use that as our indirect, or surrogate assessment tool for evaluating barrier function. B Vitamins Certain vitamins play a big role in helping to prevent injury to the mucosa in the tongue and the epithelium in the mouth. B vitamins are very important in the energy-processing systems of the body. Recall what I said in the introduction. When our energy processing systems, our mitochondrial oxidative phosphorylation, and our Krebs cycle activities are compromised, barrier function rapid turnover cells cannot get the proper energy necessary for regeneration. This is the underpinning of what leads to bleeding gums in scurvy (vitamin C deficiency), or the various things we see with thiamine deficiency, with beri beri in the oral cavity. When we discuss how molecular metabolic function connects to whole-organism observations, one of the signs and symptoms we see is related to breakdown in epithelial function. What about host-bacterial mutualism in the human intestine? Starting with the first moments of life after delivery, the inoculation of our GI tract with bacteria is ongoing throughout life. The distal human intestine represents an anaerobic bioreactor and it is producing secondary metabolites from the fecal bacteria that live in the southern hemisphere portion of our GI tract, principally in the colon, but they can find their way up into the rest of the small intestine, even as far up as the esophagus and into the oral cavity.6 In people who have very deranged GI mucosal function or immune function, such as individuals on immunosuppressive drugs or those who have been taking very strong chemotherapy, we will often find disturbed bacterial dysregulation, which leads to proliferation into what is called small bowel proliferation, even into the esophagus. The bacteria do not necessarily have one place in which to stay. If there is a change in the GI pH, a change in the peristaltic action, a change in electrolytes, and a change in immune function within the gut, these bacteria can travel up through various junctions and be seen throughout the whole of the GI tract. Now, there is a risk of bacterial overgrowth, breakdown of barrier function, and what we call leaky gut that can be in the small intestine. The distal human intestine, however, is where most of this microbiological activity occurs. It is anerobic in nature. These organisms are fermenting various substrates. We call them bioreactors. They are producing their own secondary metabolites, and they have an enormous effect on the immune activity of the gut. If there is a lot of gram-negative bacterial overgrowth and death, things like lipopolysaccharides are released. These lipopolysaccharides are very powerful immune-activating agents that, in severe cases, can produce things like septic shock, activation of immune system nitric oxide (NO) output with vasorelaxation, low blood pressure, and hypotensive death. That is the extreme case. In the milder cases of chronic imbalances, there are symptoms that are more diffuse and hard to understand-“feeling crummy,” as Dr. Robert Sapolsky has described it. There are many organisms in the gut that play important roles in helping to defend against parasitic organisms. There is now evidence that even those organisms that we might have thought were parasitic may be mutually beneficial at low levels, such as H. pylori. Due in part to the work of Barry Marshall and his colleagues, H. pylori has been tagged with the reputation of being a toxic organism leading to peptic ulcer disease. But there is now strong evidence to indicate that some level of H. pylori may be considered desirable as a commensal, or perhaps even symbiotic organism, because it helps to defend against esophageal cancer, and esophageal inflammatory injury and breakdown. There is a wonderful review paper that appeared in the February 2005 issue of Scientific American, titled An Endangered Species in the Stomach.7 In this article, the author points out that colonization of H. pylori may increase the risk of stomach disease, but it protects against esophageal disorders. There is some kind of balance between the two that is very important. If H. pylori is completely eradicated, the risk of peptic ulcer disease and stomach cancer might be lowered, but there may be increased the risk of Barretts esophagus, adenocarcinoma of the esophagus, and acid reflux disease, which appears to be more prevalent in the absence of H. pylori rather than its presence. I am suggesting that we should be mindful not to tag a bacterium too quickly as always being bad. It is balance and looking at the personality in concert with other bacteria. Eradicating one type of bacterium in the gut may not always produce the most favorable outcome. How is proper function of healthy flora in the gut established? One clinical way of doing so is with the use of pre- and probiotics. This is an important part of functional medicine therapy for GI-related disorders. There is an interesting review that appeared in the Journal of Nutritiondescribing the important role of probiotics in modifying both GI and systemic disease risk8The authors discuss probiotics, which are the live bacterial cultures we consume that are documented to survive through the GI mucosal digestive process, and ultimately can have anti-inflammatory or anti-diarrheal, and anti-allergic effects in infants, children, and adults, and help to balance thymus dependent-1 (Th1) and thymus dependent-2 (Th2) immunological function. Some of the greatest, simple therapeutics in GI medicine are the pro- and prebiotics. Prebiotics are the selective foods to feed the friendly gut bacteria, such as the lactobacillus acidophilus or the bifidobacteria. They are things like arabinogalactans, orfructans, or fructooligosaccharides. These are specific substrates upon which the friendly bacteria can ferment and proliferate, producing butyrate as a secondary byproduct in the colon. Butyrate enhances the defense of the GI immune system. Its production in situ is an important part of immune defense in the gut and can be improved through the consumption of pre- and probiotics, helping to maintain proper gut mucosal integrity and metabolism. This was discussed in a paper that appeared in Carcinogenesis.9 The 4R Program Pre- and probiotics are important therapeutic tools and become part of what in functional medicine is called the 4R Program. Some of you know that the four Rs stand for remove, replace, reinoculate (where the pre- and probiotics occur), and repair. Repair is the use of things like pantothenic acid, L-arginine, L-glutamine, and zinc in a non-irritating form to improve mucosal integrity. Let us now move to the interview with our Clinician/Researcher of the Month.

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Kenneth Fine, MD EnteroLab 10851 Ferguson Rd Suite B Dallas, TX 75228 JB: It’s time for our Clinician/Researcher of the month. This month, we are fortunate to have a gastroenterologist who represents both of those categories—Dr. Dr. Kenneth Fine. Dr. Fine pursued his medical education at the University of Missouri, Kansas City, School of Medicine, and his post-graduate training in gastroenterology and internal medicine at Baylor University. He was later on the faculty at Baylor and was actively involved in functional gastroenterological research from both the clinical and experimental sides. He is now the medical director and director of operations for EnteroLab, a reference laboratory in the area of GI assessment that we will be talking about. Dr. Fine brings a rich background of experience in the area I would call the “sweet spot” in functional medicine—the role the gut has in modifying or modulating function systemically, and the interrelationship between GI function and liver function and how that can influence other inflammatory functions throughout the body. It is a great privilege to have you with us, Dr. Fine and we welcome you to FMU. I would like to ask what led you to study diarrheal disorders and moving from there into so many areas relating to functional gastroenterology? KF: First of all, I would like to thank you for having me on FMU today. It’s a great honor to tell you stories about my past research and where I think it’s going. My original interest started early in medical school, when I became intrigued with nutrition. Obviously, the intestine is the conduit for all of the nutrients in the body, for the most part. It was my desire to be at the best institution and work with the best researcher that I was aware of at the time—Dr. John Fordtran. That led me to Baylor University Medical Center to do my medicine residency, and I did a three-year fellowship with Dr. Fordtran. He has been a pioneer and the world’s expert in both diarrheal diseases and intestinal physiology for decades, and he is still active there. It was my association at that institution, which is sometimes called a “quaternary referral center,” that led to my present focus. When the tertiary referral centers can’t come up with diagnoses for chronic diarrheal disorders and very complicated inflammatory disorders of the bowel, they would be referred to Baylor from all over the world. I was fortunate enough to come under Dr. Fordtran’s mentoring to the point where I eventually had my own research program in the microscopic form of colitis, as well as in celiac disease and gluten sensitivity. While I worked with Dr. Fordtran, my research was generally morein the area of diarrheal disease. I was the director of the specialized laboratory for functional and diagnostic testing. We called it the GI physiology laboratory. My experience at Baylor and working with a great researcher, Dr. Fordtran, led me to all of my present positions today. JB: That’s a tremendous background. I’m sure you have everyone’s attention now because when an expert speaks, people listen. Let’s go from there into an area you have published highly on, that of chronic diarrhea and its various causes and diagnoses. Perhaps you would give us a summary of how one differentiates the causes of acute versus chronic diarrhea. Differentiating Acute from Chronic Diarrhea KF: Differentiating acute diarrhea from chronic diarrhea is very important because most of the causes of acute diarrhea are usually infectious contact—short-lived exposure to a medication, or a supplement that might be new. Once diarrhea progresses beyond four to six weeks, we usually differentiate it as being chronic. Then, there are some very simple things that should be done. They are usually diagnostic tests to differentiate the causes and possibly the different routes of diagnostic evaluation to take. In my field, we always say, “the proof is in the pudding.” Therefore, fecal analysis is of paramount importance in the assessment of not only diarrheal disease, but probably all GI disease, whether there are inflammatory cells or derivatives of inflammatory cells, such as lactoferrin, which is the stool test we have pioneered, looking at causes of inflammation. We can use a very simple analysis of fecal sodium and potassium to determine if osmotic diarrhea is present. That is always caused by ingestion of some osmotically active agent that dilutes the sodium and potassium concentrations to a point where it’s mainly the presence of some other osmotic factor. Magnesium is one that we’ve published on. We found that 4 percent of people referred to our quaternary referral center were either having chronic diarrhea from magnesium supplements or antacids or, every now and then, it will even be what we call “surreptitious laxative abuse,”where a patient is taking laxatives. It is kind of a psychiatric disorder. Fecal Fat Analysis There is also fecal fat analysis. If someone is experiencing malabsorption, that puts it into a totally different category of disease, separate from others in which a different approach would be taken. That’s how we settled into the area of fecal analysis, which is the best service we can give to clinical practitioners, referral laboratories, and the public—that there is so much to be learned from some simple analyses. Of course, we have since found how frequent food sensitivity, particularly gluten sensitivity, can be, even in something like chronic diarrhea. JB: In at least a couple of your publications, one in the journal Gastroenterology in 1999,10 and the other in Gastrointestinal Endoscopy in 2000,11 you talk about how one might look at the major etiological agents associated with chronic diarrhea. From your clinical experience, if you were to evaluate those, how would they rank as 1, 2, and 3 in terms of precipitating triggers for chronic diarrhea? You mentioned magnesium being in the 4 percent range. How would you rate those precipitating causes? Causes of Chronic Diarrhea KF: It depends most on the clinical setting. The more refractory and/or the more difficult in diagnosing a problem, the more the list changes. We have found that microscopic colitis accounts for as much as 50 percent of chronic diarrhea at the tertiary referral stage, although now, it’s better known and biopsies have become a standard part of colonoscopic evaluation. Before we knew about that, the diagnosis would be missed because the mucosa looked normal. It comes down to what setting you’re in. The main causes of chronic diarrhea are inflammatory bowel disease (IBD), ingestion of some agent, or food sensitivity, such as we talked about. Our understanding of the magnitude of the problem is growing, with 50 percent of people with irritable bowel syndrome (IBS) being found to be gluten sensitive, if you actually look inside the intestine, either with jejunal aspiration or with our fecal testing. In terms of functional causes, for the most part, it comes down to food and flora. It’s now well known that almost all chronic inflammatory disorders of the gut are directed at either the food or the flora in the gut. With many animal models of chronic IBD, simply introducing a greater number of bacteroiodes species, rather than lactobacillus species, or a chemical insult, will lead to attack of the normal flora that now becomes immunogenic, with loss of immune tolerance. Suddenly, you have colitis rather than no reaction to all those bacteria. Non-Steroidal Antiinflammatory Drugs (NSAIDs) and GI Disorders I want to mention the widespread use of NSAIDs, which obviously impair the mucosal barrier, the permeability barrier of the gut. Those drugs are a pretty common cause of GI problems, whether it be ulcers at the top or inflammation at the bottom. JB: I want to follow up on one of the comments you made. Is there any evidence that certain types of IBS are precursors of IBD and/or microscopic colitis, or are these two separate disorders that don’t have an interrelationship? IBD versus IBS KF: They sound more similar when you use the acronyms than they probably are. IBD, inflammatory bowel disease, is typically Crohn’s disease, ulcerative colitis, and now, microscopic colitis. Those are inflammatory disorders directed at flora that has changed in such a way that there’s not enough protective “good bacteria” to keep the genes that are probably hypersensitive to gut stimulation from reacting. It should be mentioned that the diagnostic test for Crohn’s disease has now been found to be a serum test against dietary yeast, Saccharomyces cerevisiae. That, in itself, may play a large role in causing these inflammatory disorders. IBS, irritable bowel syndrome, is a separate disorder that, to some extent, has a different epidemiology and is more of what we call functional bowel disease, but what that’s really boiling down to mean is that to a large extent, the neurologic function is abnormal. Either the motility is slow and therefore causes more bloating symptoms, allowing bacterial overgrowth to occur as a secondary phenomenon, or there’s also hypersensitivity of the neuroafferent stimuli so that they respond and sense greater pain at smaller stimuli, such as a smaller pressure and size of distension of the intestine. I would look at those separately. I would say there is a common denominator, because in both disorders, food sensitivity plays a role, and it’s always been known that people with IBD have a pretty high (more than double, almost triple), frequency of serum antibodies to gliadin and, to some extent, the milk proteins, than normal people do. It’s always been either cast off as a false negative, or maybe something secondary to the abnormal permeability. When you think about the function of mucosal protection and permeability, attention should definitely be paid to exposure to food antigens and bacterial antigens leading to the inflammatory response. That’s how I would boil those down. JB: That’s very helpful. Let’s move from there into the other topic you alluded to—assessment. You have been actively involved in looking at and developing different assessment tools. In one of your articles in the American Journal of Gastroenterology in 1998, you mentioned the neutrophil protein, lactoferrin for assessing inflammatory causes of chronic diarrhea.12 You also mentioned other stool tests. How would clinicians approach this diagnostically in working up the patient to do an evaluation? GI Diagnostic Tests KD: I was hired as the director of the GI Physiology Laboratory at Baylor University Medical Center to improve the service and the methodology. I saw most of these tests as being of yesteryear. To an extent, some of the tests in GI analysis are still decades old—intestinal biopsies for celiac sprue or 72-hour fecal fat studies. These are things that came out of the 1950s for biopsies and the 1940s for 72-hour fecal fat, and it’s interesting as a historic note, that that test was originally a test of intestinal function in celiac patients. It was developed by the biochemists who worked with William Dickey, the pediatrician who discovered the link between gluten and celiac disease. It was my goal to see what could be done to make diagnostic testing easier on the patient, easier on the clinician, and easier on the laboratory. If you’ve ever seen a laboratory filled with buckets of stool, you’d appreciate the fact that anything that could be done to reduce the volume and numbers of 72-hour collections is favorable to everybody. We applied an existing test for inflammation (fecal white cells were the standard for inflammation). These tests have been done less frequently than in the past. Laboratory technicians, because they are operator-dependent, became less and less skilled. In addition, the test itself has its own variability because of trying to find white cells floating in the fecal water. We applied a test developed by a company, primarily to detect acute diarrhea, and tried to differentiate acute bacterial infectious causes of diarrhea from mostly viral and other causes of acute diarrhea by the presence of fecal white cells. We applied that to the chronic diarrheal states and found that, for the most part, in chronic diarrhea, if there is evidence of fecal neutrophils, which, in the case of our test is a lactoferrin, then that almost always is either Crohn’s disease or ulcerative colitis. Because the test offers a semi-quantitative analysis of the severity of the inflammation—if it’s 2+ or 3+ rather than 1+—then it’s always one of those two disorders. Microscopic colitis is a T cell infiltrative disease with rare neutrophils. Most cases are going to be negative, but sometimes there are enough neutrophils to be positive; however, they will always be of the 1+ lower quantitative assessment of the amount of information. Then, if there’s no inflammation, it pretty much rules out active colitis, either Crohn’s disease, ulcerative colitis, or any cause of mucosal disruption. Microscopic colitis is different because the integrity of the mucosa remains intact. We’re still looking at other potential fecal tests to hopefully be able to diagnose that without having to go to biopsy. The next test of paramount importance is the fecal fat test. You have to get a way outside of these quaternary and possibly tertiary referral centers. You’ve got to get away from 72-hour collections because they’re somewhat intractable; they’re so dependent on collection, because the output is calculated from the measured fat concentration, multiplied by the total collection, somewhat like a 24-hour urine collection. If there are any collection misses at all, the analysis is going to be falsely negative. We were able to improve upon the old, qualitative microscopic fecal fat analysis by Sudan stain testing, and we developed a quantitative analysis that perfectly linearly correlated with 72-hour collections. This was published in the American Journal of Clinical Pathology in 2000, showing that one stool with this quantitative fat analysis could determine, with a numeric expression, whether someone had malabsorption or not, and that could be followed over treatment to see if there was improvement.13 Those are two tests that must be applied. Magnesium and Diarrhea What we call a fecal osmotic gap, which requires a fecal sodium and potassium, can easily differentiate osmotic diarrhea from some ingested agent. Truthfully, if it’s going to be magnesium (and we’ve found that’s the most common ingested osmotic agent in causing diarrhea), a lot of times just asking the patient if he or she is taking antacids or vitamin and/or mineral supplements. I was a magnesium researcher, not only of diarrhea, but also of magnesium absorption, so a lot of times, I’ll look at supplements containing magnesium. The dosing of magnesium in most supplements is excessive, to the point where more than half of the magnesium will be absorbed. If taken more than once a day, there may be enough to cause chronic diarrhea. So, those are the three initial tests. I also published a study showing that in the assessment of chronic diarrhea, if there is going to be an endoscopic procedure, it does not have to be a full colonoscopy. The shorter and less invasive test, not requiring sedation, is the 60 centimeter flexible sigmoidoscopy with biopsies which is adequate. If that’s normal, you can essentially rule out microscopic colitis and, as long as the fecal lactoferrin is negative, you’ve also ruled out Crohn’s, colitis, and ulcerative colitis. Those are probably the simple things. Of course, I cannot speak on the subject without mentioning the importance of the fecal antigliadin antibody to test for gluten sensitivity, which turns out in the most exclusive patient populations. Those for whom all of the other disorders tend to be diagnosed, may account for as much as 50 percent of chronic diarrhea. JB: That’s a wonderful segue. That’s exactly where I hoped we were going next. I was very impressed with your paper in the American Journal of Gastroenterology in 2001, looking at celiac sprue and its association with autoimmune liver disease,14 as well as your paper in the American Journal of Gastroenterology in 2000 on the high prevalence of celiac sprue in people with certain HLA-DQ gene polymorphisms.15 You looked at things like anti-endomysial antibodies and tissue anti-transglutaminase antibodies, andcorrelating that with dietary gluten and small intestinal pathology. It seems to me that there is an emerging recognition of something that has been rejected by traditional gastroenterology for some time—that the concept of gluten immune sensitization is more prevalent than we previously thought. It sounds like that’s where your work is taking us. Celiac Sprue-Like HLA-DQ Genes KF: The paper on celiac-like genes and the one on the small intestinal pathology in patients with microscopic colitis, really kicked the door wide open on this whole field. It was so important to me that I felt obligated to bring this researchand fruits of these diagnostic tests directly to the public. That’s how I ended up in a career of public service, rather than in a traditional academic medical career. Microscopic colitis is a chronic inflammatory disease with a T helper cell-mediated chronic inflammatory response. When we looked at the HLA genetics, we saw that 64 percent of the population had the HLA-DQ2 gene that is normally highly associated with celiac disease. Ninety to 95 percent of American celiacs have an HLA-DQ2 gene. We always tend to think of it as the celiac gene, and the product of that gene does, indeed, bind gliadin and present it to the immune system as an antigen. If you have that gene, you are binding gliadin in your gut and presenting it to your gut-associated mucosal system as an antigen. Whatever reaction you get from there is under further genetic control, environmental control, and a lot of other factors, both intraluminal to the gut, as well as possible external environmental factors. Under the microscope, microscopic colitis looks like a total villus atrophic lesion of the small intestine. There are no villi in the colon like there are in the small intestine, but when you have celiac disease, all those villi go away (in the worst cases, there is total villous atrophy). What you are left with is a chronically inflamed, flat mucosa with an abnormal surface epithelium infiltrated with T cells, which we call inter-epithelial lymphocytes, as well as lymphocytes in the lamina propria. There is a histologic lesion that smells like celiac disease. There is a genetic propensity of the celiac genes in this disorder, and yet, if you look at serologic assessment of anti-gliadin, anti-endomysial, or tissue transglutaminase antibodies, you do not see any greater expression of those in the serum of those patients than you do in a normal population. It should be mentioned that even in a normal population, 10-12 percent of people will have antigliadin antibody in their serus. Already, we know that 10 percent of “the normal American population” is walking around with an antibody to gliadin in their blood. There were three lines of past research that led me to my search for an antibody in the stool. The first were studies in gluten-sensitive patients who did not have villous atrophy. The first study was published in 1980, titled “Gluten-sensitive diarrhea without evidence of celiac disease.”16 The researchers had eight patients with chronic diarrhea. Everything else seemed normal. They did a very detailed analysis of small intestinal pathology. Although there was no villous atrophy and no significant chronic inflammation, they did some sophisticated counting techniques and found that there were more plasma cells than not, and that the patients responded to a gluten-free diet. These patients were diagnosed in a celiac center, so they obviously had a focus on that potential. There were subsequent studies in 1996 and 2001, one of which looked at IBS patients where they did a small intestinal aspiration and found anti-gliadin and even anti-casein, the milk protein antibody, inside the intestine, along with the DQ2 gene. Those patients also got better on a gluten-free diet. There was a third study, and I take my hat off to this group because they are still following this line of research. We are following similar lines of research where I’m doing fecal testing. In their initial study, they took intestinal biopsies and put them with gluten in vitro. They found that suddenly, the otherwise normal-appearing mucosal biopsies would start to express more of the HLA antigens, as well as produce anti-endomysial antibody in the fluid of the Petrie dish. We now know that you do not have to have villous atrophy for your intestine to react to gliadin and that you can get better on a gluten-free diet. That’s what all of the studies showed. There was even a fourth study out of Finland in 2001. That was one line of research. The other line of research was the fact that serologic tests were not finding all of the people with celiac disease, especially if they had anything less than total villous atrophy. There were a couple of studies on that. One was out of England; the other was out of the Netherlands. They found that only 31 percent of celiacs that had partial villous atrophy (not total villous atrophy), had serologic positivity of either anti-gliadin or anti-endomysial antibodies. I took that piece of information back to my microscopic colitis population. None of them had total villous atrophy, and almost all of them had minimally expressed inflammation of the small intestine. I began to think that perhaps they were like celiacs who don’t get villous atrophy and don’t get serologic positivity. There was a third line of research done over a 30-year period by Dr. Anne Ferguson in England. She did an intestinal lavage procedure where they would wash out the gut contents and measure the effluent for anti-gliadin, IgA, and IgM. She always called it a “celiac-like pattern of anti-gliadin antibody.” You could have more anti-gliadin antibody in your intestine than normal, much like a celiac, which is why they use the term “celiac-like,” and we also used it in our research, but you did not have villous atrophy. They always thought those people were latent celiacs, meaning that at some future point, they would become celiacs. We extended on her research, but obviously, doing an intestinal lavage on everybody to be assessed for gluten sensitivity is not practical. Why no one did it in the stool before we did, I can’t say. I have to think that maybe it’s because laboratories and personnel tend to be a little phobic about stool. Because my upbringing was in that field, it certainly was no issue for us. Lo and behold, we found that about 75 percent of patients with microscopic colitis, 50 percent of people with chronic diarrhea, and 100 percent of people in the control group with untreated celiac sprue, had these antibodies in their stool. In celiac disease overall, there’s only about a 75 percent positivity of these antibodies in the blood. We haven’t turned back from that fact because not only are there a large number of people with diseases, but about 2 1/2 times the number of people with anti-gliadin antibody in their serum can be found to have this in their intestine, which is the precursor of getting some expression, either eventually as a disease or as a serologic antibody. JB: I want to compliment you. That is a very technically complicated story and you’ve done a marvelous job of condensing it down into understandable components. I hope our listeners will go back and rerun this discussion several times, because there are so many positive things buried in what you just discussed. Serology may not be the sine qua non for picking up gluten sensitivity relationships. There is a functional continuum of sensitivity, all the way from what we would consider traditional sprue, to the sprue-like conditions. That marries itself to the whole functional medicine concept. Also, to look at the various parameters in the stool that interrelate various sensitivities in the diet to functional diarrheal disorders. You have painted a magnificent picture. I can see why you have taken your discoveries to the general public. For our listeners, more information about what Dr. Fine is talking about and the tests that he developed can be found on his website at www.enterolab.com. There is also a good discussion about the history and the diagnostic usefulness of the tests on the website. I want to thank you, Dr. Fine. I wish we had more time. This has been extraordinarily interesting for me. We’re going to add a bibliography of your papers in the reference section on the summary cards for this issue of FMU. I’m sure people will be checking in with you for further discussion. You have opened our eyes to another whole chapter on functional gastroenterology. KF: Thank you very much. People can contact my staff or myself, or go to our website. I also have my own not-for-profit institute called the Intestinal Health Institute (www.intestinalhealth.org). We are devoted to improving intestinal and overall health and, ultimately, better health, hope, and happiness for the entire public health system. We are very supportive, not only of the clinicians, but the patients themselves. I like to help people before they become patients. If they’re already ailing, we can be of service to them directly. There are lectures for physicians on our website. The research to date is also listed there. There’s a long essay on the whole story, basically the transcript of a talk I have given. We answer all questions by email from any doctors or patrons that have interest. We are there to be of service in the name of healthy intestinal and overall health. JB: Thanks for spending time with us today, and we’ll be checking back with you in the future. Immunity, Inflammation, and Allergy in the Gut What we have learned is that the gut mucosa, as an epithelial barrier of defense, is exposed to allergens, toxins, and parasites, all of which can activate the immune system, leading to inflammation or allergy. That can create barrier function breakdown, leaky membrane through transcellular or paracellular transport, and ultimately result in systemic effects. The gut immune system has the challenge of responding to these pathogens while remaining relatively unresponsive to other food materials that lead to what is sometimes called tolerance.17 When proper immune function in the gut starts early in life, we have tolerance to certain molecules and intolerance to other exposures. One of the reasons you do not want to expose an infant to potentially antigenic substances too early is that you may lose the tolerance effect and produce a memory in certain T cells that sets the child up to become allergic to those materials throughout much of his or her life. You do not want to give them cow’s milk too early, or feed them a lot of wheat-based products too early, before the immune system of the gut is fully developed, so they can develop the proper tolerance. Bacteria in the gut play an important role in maintaining the epithelial immune balance. Inappropriate bacteria or organisms can upset that balance and alter Th1 and Th2 activity. The use of pre- and probiotics is important for restoring proper immunological function in a compromised gut. Removing antigens, allergens, toxins, and parasitic organisms may be very important. There may be times when antibiotic therapy is necessary to sterilize the bowel so it can reinoculated with friendly bacteria to reduce the load of potential antigenic substances. The Gut and Omega-3 Fatty Acids Another therapeutic tool that is very important for GI health is omega-3 fatty acid supplementation. This is another in the long list of potential applications of omega-3 fatty acids. In the Journal of Parenteral and Enteral Nutrition, an article appeared which is very useful in understanding the connection between omega-3 fatty acids and gut mucosal integrity.18 The authors looked at the relationship between omega-3 fatty acids and liver, gut mucosa, and tumor tissue inflammatory functions. This was an intervention trial with patients who were supplemented with therapeutic diets pre-operatively They were given supplements with fish oil containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). They were given about 3.7 grams a day of mixtures of these polyunsaturated fatty acids as fish oil. The phospholipid fractions in plasma were examined on the day of surgery. They looked at the various effects the fish oil supplements had on liver function and gut mucosal function and found that preoperative administration of omega-3 fatty acids has an impact on the EPA and DHA levels in liver, gut, and tumor cell membranes. That suggests to me that post-operative inflammatory response after major abdominal surgeries may be lowered by pre-operative administration of these fatty acids. The omega-3 fatty acids modulate Th1 and Th2 balance toward lowering inflammation (the Th1-dominant type), into a more Th2-balanced activity. This was demonstrated in a recent study published in the Journal of Nutrition.19 In a controlled series of studies in animals, fish oil increased the percentage of Th2-polarized cells because it suppressed Th1 cell frequency, lowering the proinflammatory mediators produced through Th1 activity. Dietary Supplementation of Omega-3 Fatty Acids Dietary supplementation of omega-3 fatty acids with folic acid, vitamin B6, and vitamin E has been shown to improve function in individuals with peripheral vascular disease, with improved walking distance, decreased pain, and lowered risk factors, such as the inflammatory markers like intercellular adhesion molecule-1 and high-sensitivity C-reactive protein, after supplementation with a combination of omega-3 fatty acids, folic acid, and vitamins B6 and E. This clinical study was published in the Journal of Nutrition.20 Sixty patients were randomly allocated to two groups. One group received the EPA/DHA supplement, which was about 1 gram a day of a combination of EPA/DHA, and also B6, E, and folic acid at what we would consider normal nutritional therapeutic levels, not mega-nutritional levels. The improvements seen in this group after intervention illustrate very clearly that enhanced intake of those nutrients was very helpful. Because all of these things are connected in the web of functional outcome, when we improve GI mucosal integrity and function through omega-3 fatty acids, we establish better endothelial function, hepatobiliary function, membranous function of the BBB, and reduction of cardiovascular disease and cancer risks, because all of these things are interrelated through the web of life, the homeodynamic balance seen through barrier function and the dynamic activity of membranes. This is discussed in the Journal of Medicinal Food.21 I hope you now have a sense of the important role that barrier function plays in defending against toxins, and how it is seen as part of the detoxification/biotransformation cycle. We will be exploring these topics in greater detail as we move toward the 13th International Symposium on Functional Medicine.

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Bibliography

1 Bushara KO. Neurologic presentation of celiac disease. Gastroenterol. 2005;128(4 Suppl 1):S92-97. 2 Siqueira Neto JI, Costa AC, Magalhaes FG, Silva GS. Neurological manifestations of celiac disease. Arq Neuropsiquiatr. 2004;62(4):969-972. 3 Mullin JM, Agostino N, Rendon-Huerta E, Thornton JJ. Epithelial and endothelial barriers in human disease. DDT. 2005;10(6):395-408. 4 Stainier DY. No organ left behind: Tales of gut development and evolution. Science. 2005;307:1902-1904. 5 Radtke F, Clevers H. Self-renewal and cancer of the gut: two sides of a coin. Science. 2005;307:1904-1909. 6 Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915-1920. 7 Blaser MJ. An endangered species in the stomach. Scientific American. 2005;292(2):38-45. 8 Salminen SJ, Gueimonde M, Isolauri E. Probiotics that modify disease risk. J Nutr. 2005;135:1294-1298. 9 Pool-Zobel BL, Selvaraju V, Sauer J, et al. Butyrate may enhance toxicological defence in primary, adenoma and tumor human colon cells by favourably modulating expression of glutathione S-transferases genes, an approach in nutrigenomics. Carcinogenesis. 2005;26(6):1064-1076. 10 Fine KD, Schiller LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterol. 1999;116(6):1464-1486. 11 Fine KD, Seidel RH, Do K. The prevalence, anatomic distribution, and diagnosis of colonic causes of chronic diarrhea. Gastrointest Endosc. 2000;51(3):318-326. 12 Fine KD, Ogunji F, George J, Niehaus MD , Guerrant RL. Utility of a rapid fecal latex agglutination test detecting the neutrophil protein, lactoferrin, for diagnosing inflammatory causes of chronic diarrhea. Am J Gastroenterol. 1998;93(8):1300-1305. 13 Fine KD, Ogunji F. A new method of quantitative fecal fat microscopy and its correlation with chemically measured fecal fat output. Am J Clin Pathol. 2000;113(4):528-534. 14 Fine KD, Ogunji F, Saloum Y, Beharry S, Crippin J, Weinstein J. Celiac sprue: another autoimmune syndrome associated with hepatitis C. Am J Gastroenterol. 2001;96(1):138-145. 15 Fine KD, Do K, Schulte K, Ogunji F, Guerra R, Osowski L, McCormack J.. High prevalence of celiac sprue-like HLA-DQ genes and enteropathy in patients with the microscopic colitis syndrome. Am J Gastroenterol. 2000;95(8):1974-1982. 16 Cooper BT, Holmes GK, Ferguson R, Thompson RA, Allan RN, Cooke WT. Gluten-sensitive diarrhea without evidence of celiac disease. Gastroenterol. I1980;79(5 Pt 1):801-806. 17 MacDonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science. 2005;307:1920-1925. 18 Senkal M, Haaker R, Linseisen J, Wolfram G, Homann HH, Stehle P. Preoperative oral supplementation with long-chain &#969;-3 fatty acids beneficially alters phospholipid fatty acid patterns in liver, gut mucosa, and tumor tissue. J Parenteral Enteral Nutr. 2005;29(4):236-240. 19 Zhang P, Smith R, Chapkin RS, McMurray DN. Dietary (n-3) polyunsaturated fatty acids modulate murine Th1/Th2 balance toward the Th2 pole by suppression of Th1 development. J Nutr. 2005;135: 1745-1751. 20 Carrero JJ, Lopez-Huertas E, Salmeron LM, Baro L, Ros E. Daily supplementation with (n-3) PUFAs, oleic acid, folic acid, and vitamins B-6 and E increases pain-free walking distance and improves risk factors in men with peripheral vascular disease. J Nutr. 2005;135:1393-1399. 21 Shahidi F, Miraliakbari H. Omega-3 (n-3) fatty acids in health and disease: Part 1—Cardiovascular disease and cancer. J Medicinal Food. 2004;7(4):387-401.

Welcome to Functional Medicine Update for November 2005. It is a pleasure to be with you as we prepare for what is going to be one of our most exciting symposia—Managing Biotransformation: The Metabolic, Genomic and Detoxification Balance Points—which will be held April 19-22, 2006 at the Tampa Marriott Waterside Hotel & Marina in Tampa, Florida. For those of you who have been attending our symposia on a regular basis, I want to emphasize that the date is earlier than usual. As a consequence of conflicts with the Mother’s Day and Memorial Day holidays, we are holding the symposium in April. The weather should be beautiful in Tampa at that time of the year, and we look forward to being with you. In preparation for the symposium, I thought it would be useful to talk about some of the major areas of learning that relate to biotransformation and detoxification. One of those is metabolism. When I say the word “metabolism,” many of you may be experiencing a reaction. Think of wall charts, the Krebs cycle, intermediary metabolites, memorization, and trial-by-fire exams to reproduce a grade for your instructor at a level of proficiency that will enable you to move on to the next course. That kind of negative experience with metabolism science can prohibit the effective inclusion of some of these concepts into clinical practice. Clearly, in the course of this issue, we are not going to be able to do a complete tour de force on metabolism, but I thought we could start by introducing some of the principles that underlie the role that evaluation of metabolism can provide in managing some of the complex problems that patients present with that relate to altered detoxification and biotransformation. With that in mind as an objective for this month’s FMU, I would like to move into how things have evolved over the past decade, as we begin to examine metabolic relationships to chronic illness. Most of us studied some of the extraordinary discoveries that were made about the metabolic pathways during the first part of the 20th century. The pioneering work done in this area by early investigators was absolutely extraordinary. It is interesting to study the history of how different intermediary metabolites were discovered and analyzed, and the number of dedicated and exacting investigators who put together the metabolic pathways that ultimately became the charts that we all either have on our walls or have seen copies of. These are multiple-page charts that reflect the intermediary steps that take large molecules to small molecules, or small molecules to large molecules. Breaking large molecules into small ones is called catabolism; building up large molecules from small ones is called anabolism. The anabolic/catabolic pathways are included in the field of intermediary metabolism. Intermediary Metabolism We often think of intermediary metabolism as the source of energy of the body, and this is done through aerobic oxidative phosphorylation in the human species. These are the energy-producing pathways. There is much more to the metabolic pathways than just the energy-producing pathways. What has been learned over the last 50 years is that many intermediary metabolites are, in and of themselves, bioactively involved in other pathways. When we begin to look at these intermediaries in a much more realistic physiological manner, we see that they make up a complex web of interwoven wheels. Why did all these pathways evolve? Each is like a single puzzle piece, and they all fit together to form a mosaic called physiological control. An intermediate (e.g., pyruvate, lactate, phosphoenolpyruvate), in and of itself, is a stepping stone toward another metabolite, but each one of those intermediates also has its own biological activity, and they feed back into other pathways. That leads to a very interesting interconnectivity concept of metabolism, not just individual pathways running in isolation, as you might see them on a wall chart. These pathways occur in time; they change. They are like the tide; they can rise and fall, based upon what flux of need is traveling throughout the body. Different tissues have varying levels of activity in different pathways, the liver being a very active organ involved with intermediary metabolism. We thought the fat cell, or adipocyte, was less active in the energy-producing pathways, but now we recognize that it has more activity relating to the production of adipokines or adipocytokines, which are neuroendocrine modulators that come from fat cells. The differing tissues show differing activities in these metabolic pathways, and they can change in time based upon need, or as it pertains to changing environment, age, stress, and the like. Obviously, we are talking about complexity. To take just a snapshot of metabolism and try to understand the whole of the body from it is simplistically nave, because we need to develop a running record of how metabolism works under different circumstances to understand each individual. With that limitation, we are still able to make some first-pass better understanding of the individual characteristics of a person by looking at certain metabolic patterns and profiles. When we do that, we are led to asking what to analyze. What specific markers would be useful for understanding aspects of metabolism? Do we look at the outcome of metabolism, the so-called Plato’s myth of the cave, where we are looking at the shadows and the surrogate markers, or do we look at the actual intermediary metabolites themselves and try to piece together the patterns from the inside out? These are all important questions that I hope we will be able to address, at least partially, over the course of this month’s FMU. Certainly, this month’s Clinician/Researcher of the Month, Dr. Richard Lord, an expert in this field, will give us some guidance on this issue. I think you will find his comments to be very helpful, especially if you are new to this field. With all of that as background, let us now move to what has often been called the nutritional phenotype. What I want to address is how we are contextualizing the most recent understanding of nutrient effects on metabolism from a biomedical and health perspective. In the past, most of us thought our metabolism was hard-wired, based upon our genes. Based on what we received from our mothers and fathers, these genes determined our metabolic profiles, and in cases of inborn errors of metabolism inherited from our parents, we could get the “bad luck of the draw.” In those cases, conditions such as Tay-Sachs, Wilson’s, Gaucher’s disease, or megaloblastic anemia might be present. Therefore, the concept of metabolism was to look at either the genetic alteration of metabolism (in the extreme case, inborn errors of metabolism), or to examine it in pathological cases (such as diabetes or other metabolic disorders), and assume that the absence of either a genetic metabolism disorder or a frank metabolic disease seen during infancy meant having adequate and normal metabolism. But as we began to study these pathways more fully, we recognized that there are variations on a theme that we all possess, based on our genetic uniqueness, and that these variations give rise to different responses to the environment—stressors, infection, and different states of arousal to different stimuli. This, in part, is a reflection of our uniqueness as an individual. The markers we might start examining in order to look at some of these metabolic outcomes include panels such as urine or plasma organic acids, urine or plasma amino acids, or fatty acids, which would be either red-cell fatty acids or plasma fatty acids. Various aspects that relate to vitamin and mineral nutriture might also be included in a metabolic profile. I am building up a fairly broad array of potential tests with literally thousands of different data points, which could confuse someone who is used to making a chemical assessment of the body based upon a comprehensive multi-analyte profile, such as a SMAC 24, where only 24 variables are examined, one at a time. In the case of metabolic assessment, we may be looking at hundreds of variables. That obviously becomes very complex, and we have to start examining patterns. Rather than individual analytes, one at a time, we have to look at how they interact in patterns. This defines what has been called the phenotype of the individual, the metabolic phenotype. We now know that nutrients and nutritional status play a role in determining our phenotype. The phenotype is the expression of our function that arises out of the pleuripotentiality of our genes. What does that mean? It means that our genetic inheritance does not, in and of itself, dictate exactly how we are going to function at any one moment. Rather, it is a potential for how we might respond to a specific set of environmental stimuli. The actual phenotype, or our expression of function, is a mix between our genetic potential and the environmental response factors that give rise to our phenotype. We talk about genomics being translated into proteomics, which are translated into metabolomics, which ultimately are translated into phenomics, or the phenotype. How a person is functioning and what his or her physiological status is, with respect to each specific nutritional and lifestyle input to gene potential, defines what has been called the nutritional phenotype. As we look at the nutritional phenotype in the age of metabolomics, we begin to see that there is an interesting interface between gene potential, and nutrition and lifestyle inputs, and how those influence protein expression through mRNA into proteins such as enzymes and ultimately, into metabolic control points. When examining organic, amino, or fatty acids, we are not only looking directly at what a person has eaten, but also indirectly at how the control points in the nutritional phenotype are influenced through aspects of metabolic, proteomic, and genomic control. Our understanding of the relationships among nutrition, integrative metabolism, and health is being revolutionized by advances being made in genomics. Obviously, this interrelates with complex physiological function such as detoxification and biotransformation. The detoxification enzymes are part of the complex array of enzymes that defend us against an imperfect environment. The environment has never been perfect for humans, so we have had to defend ourselves through natural selection over time against these imperfections, and that is part of our detoxification and biotransformation system. Our detoxification enzyme system, be it either the phase 1 cytochrome P450 or the phase 2 conjugase enzymes, is controlled by a series of genes. In fact, when we begin to look at these families, we find they go way back in history, which means that this has been part of the evolution of mammals since their early beginning. Animals could not have survived without a detoxification system; therefore, we see them as very highly diversified—polymorphic enzymes that control the metabolic principles associated with detoxification. The cytochrome P450 enzymes are the oxidative mono-oxygenase enzymes, so they are involved with oxidative chemistry, and therefore influence oxidative stress and interface with mitochondrial oxidative phosphorylation. There are indirect associations with metabolic function, oxidative chemistry, mitochondrial chemistry, and ultimately, with oxidative stress. With that in mind, this ties a different strategy into how lifestyle, diet, and environment influence disease and/or wellness, and regulate the gene expression that becomes our metabolic outcome—the metabolome—which defines our phenome, or phenotype. The practitioner of the 21st century must understand genetic uniqueness, as well as the antecedents that precede the onset of chronic symptoms, and what triggers influence production in an individual of various messenger molecules and various metabolic outcomes. The patterns derived from a patient’s history, family history, evaluation of the environment and diet, and certain biochemical markers, are then used to piece together a mosaic as to the etiology of chronic symptoms. That leads to a tactical approach toward the amelioration of the symptoms and, hopefully, directing attention toward the triggering causes that reinitiate these particular processes leading to long-term, chronic illness. A very interesting article was published in the Journal of Nutrition, titled “The nutritional phenotype in the age of metabolomics.”1 It was written by a Blue Ribbon panel of investigators whose names are quite well known in the nutrition research community, from the American Society for Nutritional Sciences. It was a long-range planning committee. When they started looking at the concept of the nutritional phenotype, they describe the fact that most of us were trained in assessing nutritional status using things like anemia, body mass, protein levels in the blood, albumin levels in the blood, and various markers for insufficiency that might pick up occult scurvy, beriberi, pellagra, xerophthalmia, rickets, or marasmus. They are now saying that if we really want to modernize the concept of the nutritional phenotype, we need to be looking at biomarkers beyond that of just physical attributes that define the metabolic effects of nutrition. These are things like insulin resistance and metabolic syndrome, where we are looking at the triglyceride-to-HDL ratio, which is a surrogate marker for insulin sensitivity. As the triglyceride-to-HDL ratio goes up, we start to see that the person with a higher degree of insulin resistance has more relative risk toward dysinsulinism and problems associated with diabetes, heart disease, or vascular disorders. As we look at these surrogate markers that indicate altered metabolism, it opens the door to go to the next level and ask what caused the elevated triglyceride-to-HDL ratio. What is the metabolic cause? We start digging deeper by looking at things such as organic, amino, or fatty acids, vitamin and mineral levels, or doing other types of functional physiological testing in order to define the nutritional phenotype and how that arose from various aspects of genomic, proteomic, and metabolomic function. You will notice I am talking about functional measures. I am excited about how often the terms “functionality” and “function” are slipping into the medical and nutritional literature. More and more, it is being recognized that in order to understand metabolic effects, we need to understand function, especially at the cell, physiological, and organ-specific levels. The nutritional phenotype and its connection to functional measures of metabolic sufficiency takes us into a series of differing multidisciplinary assessments, looking at nutrition, family history, exercise, and the psychology of patients, as well as the environment in which they live and the kinds of environmental exposures they face, which leads to a different type of evaluation tool and panel of investigation. What are the opportunities and challenges of being involved with metabolomics in assessing the origin of chronic illness? That leads us to another wonderful paper in the American Journal of Clinical Nutrition, coauthored by a variety of very well-known investigators in the field of metabolomics, including Dr. Helen Roche, who is actively involved in the genomics of metabolic syndrome and its relationship to diet.2 Metabolomics has been widely adopted in pharmacology and toxicology, but has not been used much in human nutrition. Only recently has this term started to weave itself into this arena. For those of us who have been in the field of molecular medicine for decades, this is an old concept; but for contemporary nutrition training, it is a new concept. The ultimate goal is to understand the effects of exogenous compounds on human metabolic regulation, and these compounds could be food and nutrients, or they could be things like toxins. All of these things influence metabolic outcome through the signaling pathways. The application of metabolomics to nutritional research is full of unique challenges. Little is known of the extent to which changes in the nutrient content of the human diet elicit changes in metabolic profiles. There are only a few experts in the field who have spent their lives studying that, one of whom we will have the fortune of listening to later on this tape-Dr. Richard Lord. Moreover, the metabolic signal from nutrients absorbed from the diet must compete with myriad, non-nutrient signals that are absorbed, metabolized, and secreted in both the urine and saliva as a consequence of toxins in the environment, or substances produced by endogenous organisms with their own metabolic personalities. These are symbiotic, parasitic, or commensal bacteria in the gut that are also producing substances that the body has to manage, detoxify, and excrete. It is the total load of these messages or signals-some coming from the diet, some coming from endogenous metabolites, and some from exogenous environmental sources-that triggers alteration in metabolic function. That is why this field is both exciting and complex, because it is not as easy as just taking a number from a lab test, coming back with a diagnosis, and administering a single agent for remediation of the symptom. In this case, it is necessary to look at patterns, and the complex interaction of the environment with the genes and the lifestyle of the patient. The outcome of this type of strategy is to better define how that person expresses chronic complaints, rather than just uncoupling the complaints by giving a symptom-suppressing medication. We are seeking the origin of the complaint based upon the interface of that patient with his or her environment. This is obviously the strategy that leads to personalized medicine, which many people feel is the medicine of the future. It still has not been put into a mechanized form where it is an algorithm that can be easily plugged into the computer to produce a solution. It forces the clinician who chooses to engage in metabolomic thought and intervention to become familiar with pattern recognition through his or her own thought process. This is exciting and challenging. Interaction of genes with the environment is a complex process. The outcome of all of this is that if you start asking these questions, even at a simplistic level, it leads to possibly discovering how a patient evolved to the illness they are expressing, with symptom severity, frequency, and periodicity. The results may be very different than simply reading the signs and symptoms and trying to come up with a diagnosis. Let us take this general discussion to one that is more specific. Let us look specifically at protein and reflect on its metabolomic effects. Protein is a very interesting family of macronutrients. We think of it as the building blocks of our endogenous protein; that is, we eat dietary protein to help build our own proteins in situ. Proteins are complex. They are composed of amino acids, like little beads on a chain, which are broken down into polypeptide chains and then into individual amino acids by digestive processes. The amino acids are transported across the lumen of the gut through active transport and passive diffusion, and ultimately reach the liver, where they can be resynthesized or modified through transamination into other molecules. Eventually, a series of endogenous proteins are produced—rebuilt from the individual amino acids—based on the genetic template of the individual. Albumin One of the major plasma proteins is albumin, which is synthesized in the liver, and is a major transport protein in the blood. Albumin is uniquely high in its percentage of what are called branched-chain essential amino acids. People have asked why albumin, a major plasma protein, has such a high level of essential amino acids. One of the teleological explanations is that because the body needs to maintain adequacy of the essential amino acids, which are not able to be made from other amino acids and must be consumed directly in the diet, albumin is a control or message protein. Albumin is very high in the essential amino acids and, when a person is on an amino acid-deprived diet, or on an imbalanced diet that does not have adequacy of the eight essential amino acids, particularly the branched-chain amino acids like leucine, isoleucine, and valine, the level of plasma protein albumin is decreased, resulting in hypoalbuminemia. There is at least a partial relationship between dietary protein adequacy and dietary protein quality, and the levels of the major plasma protein serum albumin. What do we know about these amino acids, other than that they are very important in building the structural substances, like collagen and elastin, that make up our connective tissue, and catalytic proteins that make up the enzymes that regulate function of metabolism in all cells? Beyond that, some amino acids can have direct metabolic activity and serve as putative precursors to neurochemical messaging substances. For instance, the amino acid tryptophan is the precursor to the serotinergic family of neurotransmitters. Phenylalanine, another essential amino acid, is the precursor to the dopaminergic amino acid family through adrenaline and noradrenaline. These amino acids play roles both as parts of protein and as single amino acid-active biological response modifiers. The amino acid glutamate has neurochemical reactivity in the brain. Arginine plays a role in nitric oxide production. Glutamine plays an important role in muscle and gut physiology, and the list goes on. We have all heard about lysine and its role in herpes management. Clearly, it is not just proteins as a combination of amino acids, but also amino acids by themselves that may have effects on metabolic function.3 When we eat protein, we are eating information. You have probably heard me say in the past that I believe food is information. It is more than just raw calories; it contains information molecules that modulate function through serving as mediating substances for various functions. Depending upon what information we eat, our genes and our books of life, as encoded by our genes, are read in different ways. If we eat information that is dysfunctional, we get a dysfunctional read, or an alarm, which produces a different outcome than if we eat information that speaks to our books of life in a way that produces harmony. This is a general descriptive illusion as to how diet plays a role in modulating gene expression patterns and ultimately, proteomics and metabolomics. We are really eating information as it pertains to the processing of gene expression patterns through mediators, these nutrient signaling pathways. Let’s go back to protein. Recently, a number of papers have appeared suggesting that protein-rich diets induce satiety, as contrasted to highly refined carbohydrate diets.We might ask why a high-protein diet would induce sustained reductions in appetite ad libitum calorie intake and thereby lower body weight, despite compensatory changes in diurnal plasma leptin or ghrelin concentrations. One of the explanations is that it seems to have an effect based upon the influence some of the amino acids have on the neurochemical signaling mechanisms that regulate appetite. This may be either from the gut-brain connection, the hypothalamus connection, or from other tissues that, like the liver, help regulate signals to the brain that ultimately control appetite at the lateral nucleus of the hypothalamus. In a paper in the American Journal of Clinical Nutrition looking at satiety, energy balance, and adipose tissue physiology, and its relationship to dietary protein or carbohydrate intake, the investigators found that an increase in dietary protein from 15 to 30 percent of calories at a constant carbohydrate intake produced a sustained decrease in ad libitum caloric intake that was mediated, it seemed, by increased central nervous system leptin sensitivity, and resulted in weight loss.4 If we ask if there are bioactive ingredients in food beyond that of just calories, I believe the emerging answer is yes, and that these help to regulate metabolic function. Unfortunately, we got “washed” with the George Atwater concept of the calorie. Certainly, the calorie is a valuable concept. I do not want to throw the baby out with the bath water. But the calorie would imply that all calories are processed in the same way, regardless of the food that they are delivered in. Whether it is a calorie coming from fat or one from protein or carbohydrate would really not matter, because they are all energy units, which is the ability to do work, or to produce heat. Now we recognize that different nutrients may have differing influences on how those calories of potential energy are actually converted into various forms of metabolic energy. That is a remarkable change in our understanding of the role that diet and nutrients play in the regulation of metabolism. Dietary Protein and Satiety Could there be a satiating induction by dietary protein? The answer appears to be yes, in part. There is a nice editorial that appeared in the American Journal of Clinical Nutrition, titled “The satiating power of protein—a key to obesity prevention?”5 In this paper, the author states that if we really look at the inclusion of higher amounts of protein than previously recommended, that now appear in the guidelines from the Institute of Medicine, that there is no clear evidence that a high protein intake increases the risk of renal stones, osteoporosis, cancer, and cardiovascular disease. High protein intake does appear to be associated with lowered hunger and improved satiety, and thereby may help lower excess calorie intake and body fat accumulation. This ties back to the relationship to glycemic response to a meal and neurochemical messages received by the hypothalamus that regulate appetite. Dietary protein affects metabolism in more ways than just as a source of calories or building blocks for endogenous protein. The Effect of Different Proteins on Insulin Levels Insulin action can be modulated by dietary proteins and their constituent amino acids. Different proteins may have different effects on postprandial insulin levels. This is another important part of the story. We often generalize these nutritional influences on metabolism, thinking that if we use the words “carbohydrate,” “fat,” or “protein,” that they are inclusive to all carbohydrate, fat, or protein. But specific to protein, we now know that is not true. Differing proteins—animal or vegetable proteins—have differing amino acid ratios and different amino acid percentages, which influence their effects on genomics, proteomics, and metabolomics and the outcome into the nutritional phenotype. If we ask what type of dietary protein most influences postprandial insulin levels by helping to smooth them, it turns out to be various vegetable proteins, as contrasted to animal proteins. It is a much more complex metabolic web than we previously thought. We thought just eating so many calories would lead to feeling full, and we would lose weight. Now, we are beginning to see that different signals picked up by different nutrient-sensing receptors influence metabolic outcome in ways we did not previously understand. As a clinician, perhaps it is enough to say that certain dietary proteins produce differing effects on postprandial insulin and that we shouldn’t lump everything together and tell patients to eat a high-protein, low-carbohydrate diet and everything will turn out fine. What kind of carbohydrate, what kind of protein, and at what particular level? Let us move on to how the branched-chain amino acids (BCAA) are involved in specific functions beyond that of building up structural or enzymatic proteins. BCAAs play roles in brain function. Certainly, the work of John Fernstrom in the Department of Psychiatry and Pharmacology at the University of Pittsburgh School of Medicine is foremost in that area.6 He was previously with Vernon Young at MIT. Dr. Young recently passed away in an untimely manner, and what a tragic loss to our field. He was one of the most important, principal investigators in the area of protein and amino acid physiology. Dr. Fernstrom has continued to study the role that amino acids have on central nervous system function. BCAAs influence brain function by modifying amino acid transport at the blood-brain barrier (BBB). Transport is shared by several of the large amino acids, notably the BCAAs and the aromatic amino acids, which include phenylalanine and tyrosine. Therefore, there is competitive activity for transport of the BCAAs versus the aromatic amino acids. BCAAs versus the aromatic amino acids High exposure to BCAAs can drive particular amino acids into the brain via these transporters, modifying the ratio and/or amount of amino acids, like the aromatic amino acids, which serve as precursors to the dopaminergic neurons. We might say that neurotransmitters such as dopamine and ultimately, adrenaline and noradrenaline (derived from phenylalanine and tyrosine), may be modified by high exposure to BCAAs. In some cases, that may be desirable if a person has an overactive dopaminergic pathway. In other cases, it may not be so desirable, because it may imbalance the appropriate production of dopaminergic neurotransmitters. These are bioactive substances and, to use amino acid therapies, we have to be somewhat cautious about the premise that a little is good so a whole lot more ought to be better. We ought to be thinking about balance. Brain Amino Acid Requirements, Toxicity, and Leucine That leads us to ask if we could get into a toxicity relationship with excessive intake of these brain-active amino acids. The answer is certainly yes. For example, let’s look at the relationship of leucine and glutamic acid with respect to toxicity. Glutamic acid is an important excitatory neurotransmitter in the brain and the intra-synaptic glutamate level must be kept low to maximize the activity and not overly activate the cells through the glutamate pathway. “The brain must also provide neurons with a constant supply of glutamate, which both neurons and glia robustly oxidize. The branched-chain amino acids (BCAAs), particularly leucine, play an important role in this regard. Leucine enters the brain from the blood more rapidly than any other amino acid. Astrocytes, which are in close approximation to brain capillaries, probably are the initial site of metabolism of leucine. A mitochondrial branched-chain aminotransferase is very active in these cells. Indeed, from 30 to 50{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of all a-amino groups of brain glutamate and glutamine are derived from leucine alone. Astrocytes release the cognate ketoacid [a-ketoisocaproate (KIC)] to neurons, which have a cytosolic branched-chain aminotransferase that reaminates the KIC to leucine, in the process consuming glutamate and providing a mechanism for the “buffering” of glutamate if concentrations become excessive.”7 The process I am describing, which sounds very complicated, ultimately helps to control the brain concentration of these branched-chain ketoacids, and interrelates with glutamate and neuroexcitation. Imbalances can lead to a depletion of glutamate and a consequent reduction in the concentration of brain glutamine, aspartate, alanine, and other amino acids. This results in a compromise of energy metabolism of the neuron, which ultimately interrupts the malate-aspartate shuttle in the brain, lowers protein synthesis, and increases oxidative injury in the neurons in the central nervous system. Here is a case where if you gave too much of the BCAA leucine, you could interrupt proper brain biochemistry, brain regulation of neuroexcitation, and mitochondrial neuronal function. To date, studies suggest abnormal levels may only occur when a metabolic defect blocks metabolism of BCAA, such as Maple Sugar Disease, and suggests these amino acids aren’t toxic at reasonable levels in healthy individuals. But, high dosages over extended times has not been adequately studied to form secure conclusions. We start to see that there may be places for safe and effective use of BCAA therapy, but we shouldn’t assume that any dosage is going to be safe and effective. In fact, we ought to be looking at the individual responses in people by evaluating their amino acid balances and their clinical outcome criteria. That, of course, results in our starting to understand more about intermediary metabolism beyond that of just inborn errors of metabolism, and understanding what panels and what tests might be employed to at least take a look at the metabolomic uniqueness of that patient and to titrate therapies against their metabolic web. There is probably no one better that I can think of to help us understand this interconnection and how to approach assessment than our Researcher/Clinician of the Month, Dr. Richard Lord who, for 30 years, has been making this his principal point of study.

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INTERVIEW TRANSCRIPT

Richard Lord, PhD Director, Science and Education Metametrix Clinical Laboratory 4855 Peachtree Industrial Blvd. Ste 201 Norcross, GA 30092 JB: It’s time for our Researcher/Clinician of the month. We’re very fortunate to have someone who will guide us in the area of metabolism, which, for most of us, was a rite of passage in school. You probably recall that your basic metabolism or biochemistry course was something you had to do, but which you weren’t looking forward to. We are going to revisit metabolism in terms of functionality. I know no one better to help us through the daunting process of understanding metabolic pathways than Dr. Richard Lord. Dr. Lord received his PhD in biochemistry from the University of Texas in 1970 and went on to post-doctoral fellowships at the Clayton Foundation Biochemical Institute, the University of Arizona, and the National Institutes of Health. He served as professor of chemistry for 10 years at Life College, where he was instrumental in the initiation and design of a Bachelor of Science degree program in Nutrition Science. He has been actively involved in educating people in our field for the better part of 20 years. He maintains a very high technical content of information. Along with Dr. Alexander Bralley, he is co-author of Laboratory Evaluations in Molecular Medicine (Institute for Advances in Molecular Medicine; 2001), which I consider a landmark book in our field. He currently serves as the director of science and education for the Metametrix Laboratory in Norcross, Georgia. It is with great pleasure, Richard, that I welcome you to Functional Medicine Update. When most of us learned about metabolic disorders, we learned about them in the context of genetic metabolism and disorders of infancy, the inborn errors of metabolism, such as Tay Sachs, Wilson’s, Gaucher’s, Hartnup disease, or phenylketonuria. We were somewhat biased that these things were very uncommon in the population at large, because these genetic metabolism disorders are very rare on a frequency basis, so we could forget them, unless we were going to refer to a specialty in medicine that was focused on these conditions. Now, we have a better understanding of biochemical diversity, which Roger Williams first brought to our attention. It is recognized that perhaps some of these conditions are more frequent than we thought. And, there are less severe conditions that are not controlled by one point gene mutation, but may have polygenes involved. That opens the door to being more attentive to metabolism. You were telling me off-line that the example of phenylketonuria is probably a good place to start our discussion—to understand the difference between a frank inborn error of metabolism and milder forms of it that may exist more frequently in populations. What are your thoughts? Frank and Mild Incidences of Phenylketonuria RL: It’s a pleasure to join you today, Jeff, and to be able to discuss some of these concepts with you. Your introduction certainly takes me back a way. When I was getting my degree in Texas, the lab that I occupied shared a wall with Roger Williams, who was a Professor Emeritus there at that time. Little did I know how much the ramifications of his work would have on my life. When I was there, I became aware of what was going on. There was a great team of researchers focusing on nutritional science, including Karl Falkers, Lester Reed, and William Shive. I read Dr. Williams’ book on biochemical individuality and nutrition against disease, and became pretty impressed with the knowledge base. I decided it was the kind of thing I wanted to pursue. Finally, I got the opportunity to move into this field and, during the 10 years I was teaching, I tried to impress upon the students the importance of the underlying biochemistry. Genetic Mutations in Phenylkotonuria Just recently, I have tried to write another version of a chapter on amino acids, and find myself right in the middle of the whole issue of the genetic diversity that you just mentioned. For example, as I write on phenylalanine and tyrosine, most clinicians will have enough recall to know that has to do with phenylketonuria (PKU), a disorder that’s tested on neonates in virtually every state. A small percentage of the population has a manifestation that has to be dealt with immediately after birth to prevent developmental disorders. I came across an updated table on the number of genetic mutations involving that disorder that manifests to one degree or another. It turns out there are over 400 of them. Many of them are in the phenylalanine hydroxylase enzyme, preventing proper conversion of phenylalanine to tyrosine, resulting in an accumulation of phenylethylamineand phenylacetic acid. There is a whole separate group that involves a different enzyme that creates the cofactor. We have the enzyme itself and we have to be aware that it can create a metabolic block. If it has its cofactor, then it may be able to limp along, but you may have a perfectly good enzyme that doesn’t have a cofactor because another enzyme has a problem. The enzyme GTP cyclohydrolase is involved in the conversion of tetrahydrobiopterin (BH4), and now known to produce a whole different set of underlying metabolic conditions which manifest as the same type of thing you see in PKU. In fact, it’s still a type of PKU. It frequently happens. It’s funny how events juxtapose in our lives. Right after doing this research and delving into it for a few days, I got a consultation call about a plasma amino acid profile on an adult woman who had manifestation of various chronic conditions. She had a high/normal phenylalanine (almost high), and a completely low tyrosine. I proceeded to inform the physician that he needed to consider BH4. Of course, he hadn’t heard about that. I hadn’t been saying much about it in consultations until I renewed my focus on it. It just reminded me of how the procedures work in this field. Those of us who have the luxury of some time to delve into the scientific literature, become aware that there is a whole new spectrum of information that we can apply to day-by-day clinical conditions, and then we actually see a clinical condition that solidifies our understanding of how relevant these otherwise esoteric-appearing scientific reports can be. JB: Richard, you have touched upon some really exciting thoughts. As you were speaking, I was reminded of the paper that appeared in The New England Journal of Medicine in 2002 on mild-to-moderate forms of PKU that they were able to ameliorate, not by putting the infant or child on a low-phenylalanine diet, but by giving them supplemental doses of BH4, which is exactly consistent with what you just described.8 Sometimes, we think these genetic conditions are hard-wired and there’s nothing we can do about them. But then, we see that there are plasticities around how some of these enzymes may function, based upon coenzyme binding or, as Bruce Ames or Linus Pauling have talked about, mass action effects, and that might help to override some of these genetic small points in the pathways. Tetrahydrobiopterin RL: Exactly, and now, it turns out that using BH4 in some areas is fairly routine in PKU, just to assure that you have adequate cofactor. We see that in one of the very earliest genetic conditions, we are still evolving in our general medical understanding of giving the patients a little BH4. Now, we are gleaning the reasons that these things fit together this way. Of course, as I’m sure you can appreciate, Jeff, once you latch on to a concept like that, and your understanding and knowledge base fits in nicely with what you’ve known before, it immediately leads to other connections to this web that we talk about. For example, BH4 is extremely susceptible to oxidative damage, and it’s one of the reasons it should be considered a conditionally essential nutrient, even though human tissues can produce it. Even if you have an adequate GTP cyclohydrolase without any mutations that make it a warped enzyme, you still may have oxidative stress that impinges on your ability to sustain BH4 levels. Now, we’re into considering antioxidants and how to avoid oxidative stress, the inflammatory cascade, and so forth. Isn’t it fascinating how it goes on and on? JB: You’ve done a marvelous job in the book that you and Dr. Bralley authored, and also in your teachings over the years, to focus on and emphasize the web-like attachment. When the web is distorted at any point, the whole of the web is distorted. It’s not just one cell, because they’re all interconnected. As I recall, there’s a BH4 salvage pathway in cells that allows it to be resynthesized as it’s broken down. That requires 5-methyl-tetrahydrofolate through the methylene-tetrahydrofolate reductase enzyme. What if a person has a double (homozygous) MTHFR polymorphism, which is not that uncommon (10 to 15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} penetrance in the population)? Perhaps they would be more likely to have a low BH4 level. If the individual has a covariable low GTP cyclohydrolase, there is a double-barreled problem. I recall some papers in which they’ve given high doses of folic acid and have seemingly overcome some low levels of BH4. Have you seen any studies that show that folic acid could help to stimulate high-dose BH4 activity? RL: Yes, certainly. That’s one of the factors. In some studies on vitamin C helping, it wasn’t just mechanistically tied to the regeneration pathway, but probably into the whole oxidative damage and removal of the BH4. That’s just one other aspect of the web of interactions that plays in. We see it playing out in the data that we look at in fascinating ways, also. I look at it this way. For every well-known, well-established genetic inherited disorder of metabolism, there are many others, literally hundreds of other finer mutations, or finer alterations of the enzymes involved that result in manifestations that you may or may not even detect, depending on how closely you look. That is true for one enzyme, such as phenylalanine hydroxylase, and now we have the GTP cyclohydrolase, but there are other enzymes involved, as you mentioned, in tetrahydrofolate regeneration. Then, you understand that when a given patient is sitting in front of a given practitioner, at any point in time, with some manifestation of their condition due to their genetic disorders, the chance that you can modify it becomes very great. JB: That is the reason for a clinician spending some time with this material. Often, I’ve heard clinicians say that they didn’t go to medical school or to health sciences school to become a biochemist. I don’t believe your objective, and it certainly is not mine, is to make everybody into biochemists, but there’s some level of understanding of these connections that results in the ability to construct a different house. If all you have is a hammer, then you’re going to produce a certain kind of house, but if you have a big tool kit, you’re going to have more diversity in how you can build a complex structure. Focusing on Specific Markers RL: Exactly. You reminded me of how much more relevant it is for a practitioner who’s out there struggling with having to go back and learn biochemistry. They’ll ask me (and I’m sure they ask you), where they can get a book to refresh them on biochemistry. Of course, I taught from the literature for 10 years. You don’t want to send them back to that level because it’s complicated. They want to know what part is the most important, as any student does. Of great assistance is for them to put their hands on some real information. We produce laboratory results. If a doctor orders a test profile, we’re able to tell him or her that we’ll look at some things and ask some questions. When I was in practice doing clinical things, I sort of hung my hat on whether the patient who comes in with a skin condition had a problem with fatty acids, vitamin A, or zinc. It could be any of those things and you would like to be able to settle the issue. You can order a mineral profile and check the zinc, and it looks normal. OK, let’s move on. Taking that approach, you learn how to direct your attention at specific points of markers that can guide you to the problem. JB: That’s very well said, and for most of us, we learn by doing or by teaching. You can study it, but it’s never fully codified in the neurons until you do it and actually see how it works. I think you’re right; learning by doing is the way to learn these particular pathways. One of the questions that often comes up when we start the doing is, what level of some of these substances can be used safely, and what levels are required? There is still the resident feeling that as you go to higher doses of even nutrients, that you’re just producing expensive urine and you’re not actually producing any benefits. Here’s another example of why the testing can be useful, because you can track clinical response to changes in objective criteria based on the metabolic profile. You’re not shooting in the dark. You have a much more objective set of criteria upon which you’re judging the success of therapy. Tryptophan RL: Right. In fact, I’d take that a degree further. Not only do excessive nutrients produce expensive urine; they can actually become part of the toxic burden because they have to be metabolized. It just loads up the liver system. For example, there’s one area that we see routinely in looking at our laboratory data that illustrates that, and that is tryptophan. I’ve got a lot of mixed emotions about tryptophan status and how many people are still reluctant to deal with it. Certainly, the companies that handle amino acids, may be reluctant because of the old bugaboo that came up from the unfortunate incidence of some impure tryptophan that was produced. On the other hand, it produces these wonderful sleep effects and it also produces serotonin that helps mood disorders and so forth. There’s a swing back to using tryptophan, but we see cases where tryptophan is being loaded at perhaps a gram or two a day, or just a gram or so at night. We monitor tryptophan pathway metabolites, particularly the kynurenineand serotonin pathways. The Kynurenine Pathway The kynurenine pathway is a fascinating system because it’s the pathway that you first learn about in nutritional studies which allows tryptophan to be converted to niacin. You have to have B6 and then you can make niacin from tryptophan. It turns out that the intermediates of that pathway are wonderful markers for B6 insufficiency. We measure xanthurenic acid and it’s a byproduct of the kynurenine pathway from tryptophan. If it goes high, it means you don’t have enough B6; at least, that’s one likely interpretation. We see cases where the patient has been loaded up with lots of B6, perhaps 100 mg or more in some cases, and this has gone on for quite a long time. Now, they’ve been monitored and they should be fairly well replete in B6. Then, we do a test and find a high xanthurenic acid. We have to go back and ask if they’re taking tryptophan. I had a case not too long ago that we’re tracking now. The basic problem in this individual, who is a high-powered executive, was that he couldn’t sleep. The practitioner was giving him L-tryptophan and it was loading up the kynurenine pathway so heavily that even with adequate B6, his xanthurenic acid was very high and, at one point, his quinolinic acid went high, which is a product of the macrophage kynurenine pathway that, it turns out, impacts the brain and can have counterproductive clinical outcome because it tends to induce insomnia. So, we have to be careful. When you see that, you need to back off on the tryptophan and deal with the other issues. For example, that patient had a low magnesium. When you see that red cell magnesium is low, maybe that’s where you can focus the intervention. My emphasis these days is to help practitioners understand that once they grasp the power of nutritional therapies in general, and when they focus those therapies, the power of the intervention goes up exponentially. JB: That was a marvelous specific example. I think everyone could get their arms around that. For those individuals who have not been in the field as long as you have, you were referring to the eosinophillic myalgia syndrome, or EMS, that occurred in the late 1980s from the Showa Denko- produced tryptophan from Japan that unfortunately had unusual impurities in it—formaldehyde tryptophan dimers—that created an immune response that unfortunately led to death in about 37 people, and thousands of other people were adversely affected. It’s always important for us to recognize what we’re doing, how we’re doing it, and the purity of the materials we are using. I was also intrigued to hear you talk about the quinolinic acid story. We’ve heard a lot recently about neuroactive agents in methyl-D-aspartate, or NMDA receptor sites, and how that causes neuronal activation leading to hyper-excitability. Quinolinic acid is one of those compounds that serves as a mimetic of NMDA activation. When we talk about hyper-arousal or neuroexcitotoxicity, we have to be very mindful that these compounds we consider as food-derived materials, like tryptophan or phenylalanine, based upon their metabolism and the sensitivity that individuals may have, can have a variety of effects, from beneficial to not-so-beneficial, in fact even deleterious. I think you’ve made that point very clear. Let’s not shoot in the dark. If we’re doing metabolic medicine, let’s have the right objective markers to know what we’re doing. For the people getting into this field, sometimes there is a level of confusion with the literally hundreds of different tests that can be done. From your experience, how would you recommend starting? Would it be organic acid testing to look at Krebs cycle intermediates? Would it be fatty acid testing? Would it be amino acid testing? Normally, a doctor will probably not order a full metabolic profile because of the expense to the patient. They have to pick their way through the discovery process. What Lab Tests to Order RL: That’s a question we get constantly here at Metametrix. Which tests should I order? Which one is the best test that you have? Of course, that can be answered in a variety of ways. In a general sense, the widest spectrum of information that you are likely to get would be, for example, the organic acids, if you wanted a single profile of testing where a single specimen would be sent and we would do a profile. The range of information you get from organic acids is broader than probably any other test you could order. We understand that you’d like to investigate the entire network of nutrient interactions. But, as you say, you can’t always do that. However, you can make certain decisions, depending on the patient you’re asking the question about. For example, if the patient is in mid-life, and a depressive, bi-polar type patient (they are fairly common), I tend to lean toward doing amino acid testing. In interventions with amino acids (depending on the other aspects of the history), we recommend doing free-form, custom-blended amino acids because this has had such a wonderful history of helping that kind of patient. That’s not to say that you don’t want to go ahead and investigate things like a specific biotin deficiency marker, dysbiosis markers, and that sort of thing, but the amino acids rise on the scale of importance for that type of condition. If you have evidence that it’s a recent onset of symptomatology and the patient was working around paint or other toxic substances, you might want to do some toxic metal testing. You can use history and symptoms to guide you to specific testing. That’s a little better than just generally asking the question, what’s the best test? JB: That’s a very salient bit of information and really helpful guidance. When the listener has a chance to read your book, if they haven’t already done so (Laboratory Evaluations in Molecular Medicine), I think it would help them to see where differing tests, or panels of tests, can give different kinds of information so they can, as you said, match the patient, symptoms, history, and antecedents with what questions they’d like to ask, based upon what insight those various tests can provide. I think that’s a good guide—to make sure you understand the patient before you start calling for the tests so that you can align the two strategically. RL: Exactly. Then, of course, frequently, once you make a decision and you order, let’s say, the amino acids and that scenario, and you get it back and let’s say phenylalanine is high and tyrosine is low. Well, then you’d like to go and investigate factors that might pertain to BH4. Currently, there’s no direct test for that cofactor, but there are tests for the oxidative status parameters that are so strongly affected. You might go ahead and start the BH4. Another scenario with amino acids would be to start arginine, because you see arginine/citrulline are way out of balance and you have a patient with hypertension in which you’d start arginine on anyway. In the case of phenylalanine/tyrosine imbalance, you might decide to investigate oxidative stress and lipid peroxides. You might assess the 8-OHDG oxidative damage markers, or measure serum vitamin E, CoQ10, and so forth. In the case of arginine, you might look at ADMA to see if that’s a problem, and then folic acid, if that’s causing the ADMA. You wind up being able to pursue specific lines of investigation through the testing, depending upon what you initially see. JB: You can hear Dr. Lord speak with great fluency about things that, for most of us, still probably sound like new words—like 8-OHDG, which is hydroxydeoxyguanosine, and is a measurement of oxidative damage to DNA, or asymmetrical demethylarginine, ADMA as a way of indirectly assessing endothelial nitric oxide sufficiency. When you’re dealing with someone that has 30 years of experience like Dr. Lord, these patterns come easily. What he and I are both advocating is that the only way to really start down this road to develop a level of competency is to learn by doing. You really have to start asking some of these questions about metabolism and be able to deal with your fear about not knowing everything. I don’t believe there’s anyone in the world, no matter how brilliant, who understands the whole metabolomic web. It’s still emerging before our eyes, and it’s doing so in real time. It’s not a time-lapse photograph as a two-dimensional chart on the wall; it’s a three-dimensional, time-dependent phenomenon that is happening with our age and with our environment. It’s always in dynamic change, so it is a challenge. Carnitine and CoQ10 Markers RL: The really cool thing about my job, Jeff, is that we’ll get the question about which tests, and we respond that the organic acid testing has the most powerful and widest range. A doctor out there will say OK, and a lot of times they’ll still start treating organic acids as their new metabolic functional medicine serum chemistry. They’ll run it on new patients and call in, and if they see something they can’t figure out, we’ll do consultations with them. We start by advising them to look at carnitine and Q10 markers, and they may be high. There may be a real problem with Q10 and there’s not just one, but four or five markers confirming over and over again that Q10 is a metabolic issue in that particular patient. So, we advise them to definitely put Q10 on the list. We go through the whole thing, looking at biotin, B12, folic acid, neurotransmitters, and the detox markers you see in dysbiosis. After we do a few cases like that, what happens so often is that the doctor will pauseand then say, “Wow! You can really see inside the patient, can’t you!?” At that point, you grasp their excitement and it renews your conviction that this is such a powerful and understandable tool. Once you look at it that way, you just have to learn the associations. The compounds you didn’t know how to pronounce last week you now see if they’re high, the patient is in need in CoQ10, or biotin, or whatever. And now you can see that and focus the intervention. Dosage of Supplements Let me go back to your supplement-dosing question. At that point, I sense that even with experienced practitioners, some confusion lingers when we start talking about dosing and when to go to high-level dosing. I have to point out that if you’re talking about the general population and what level of CoQ10 everyone should take, well, you can put a limit on what’s generally safe for people to take, but that’s really not the question you are asking. When you have information on your desk that says the patient sitting in front of you has a specific biotin depletion state, you want to go up to that very aggressive supplementation for a given interval of time. The rule of thumb is, let’s say, 90 days. I always advise a reevaluation after 90 days. Don’t just keep them there, tell them to take a certain regimen, and that’s the end of it, because they may simply become depleted if it’s not a genetic condition. They can taper off of it; tell them what foods to eat, and they’re on their way. You’ve done your optimization of their health. JB: You have given us insight that is absolutely invaluable. For many people who may be new to this field, the whole concept of doing metabolic evaluation may appear to be outside the scope of what they’d even considered to be part of their assessment toolkit. You’ve opened up the door for learning in a way that hopefully has shed some light in the corners. A lot of people turned off the lights in the corners of metabolism after they got through the course, and now you’ve turned the lights back on. Your advocacy about how this can open up potential solutions to complex problems that appear untenable and intractable, is a great advocacy. I want to thank you, Dr. Lord, for your years of work, and for sharing your insight with us. No doubt, you have helped to get a few other people started down the path to using these tools effectively in managing some of their complicated patients. RL: You’re more than welcome, Jeff. It’s great to be working alongside of you and your wonderful history and contributions to the field. JB: Thanks a million and we’ll talk to you soon. Markers of Dysbiosis In his discussion, Dr. Lord alluded to dysbiosis markers. I want to add a couple of thoughts at the end of this month’s discussion that tie back to the detoxification and biotransformation topic for our symposium next April. That is, the endogenous bacteria that constitute two-and-a-half to three pounds of highly-metabolically active living organisms in the colon, and even in the small intestine, have their own metabolic personalities, and they produce secondary metabolites that our bodies have to manage and detoxify. Some of them may be trophic and immune-stimulating. Others may be toxic and require activity of the detoxification pathways to eliminate them from the body. The gut is tied to a whole series of potential neuroactive metabolites. We certainly can see that in patients with hepatic encephalopathies. One would necessarily call that gastrointestinal hepatic encephalopathy, where patients develop hallucinations as a consequence of an overload of these metabolites coming from the gut that are not properly cleansed by the liver through the detoxification systems, and end up crossing the BBB and having an effect on neurochemistry. We used to think these hallucinations were a consequence of hyperammonia, but it turns out that they are not very closely correlated with gut ammonia levels. They are more closely correlated with the concentration of middle molecular-weight amino acid molecules in the blood, or things like spermidine, cadaverine, and putrecine. The names alone suggest their origin. These particular bioactive amines, which are derived from proteins, can induce significant changes in brain biochemistry. There are specific protein fragments called peptides that are partially digested and can be absorbed reasonably intact, or they may directly affect receptors on the GI mucosa that influence the gut-brain signaling process. As Dr. Gershon told us in his book, The Second Brain, the gut has a tremendous propensity and capability to generate neuroactive molecules. In fact, the brain, which produces about one third of the body’s serotonin, is also influenced by the gut, which produces two thirds of the body’s serotonin. We have a second brain, that which is associated with gut physiology. Genes, the Gut, and Schizophrenia This has been beautifully discussed and evaluated by Gwynneth Hemmings of the Schizophrenia Association of Great Britain, Institute of Biological Psychiatry. Her work is seminal in understanding the connection between genetic uniqueness, gut physiology, and various types of mental disorders, including schizophrenia. In an article that appeared in Medical Hypothesis, Gwynneth Hemmings and her colleague, Dr. Wei, talk about the relationship between schizophrenia and celiac disease, which both involve a genetic component.9 They indicate that there are several lines of evidence that have shown a genetic relationship between these two conditions. “Celiac disease is characterized by damage to the microscopic finger-like projections called villi, which line the small intestine and play a significant role in digestion, due to an inflammatory condition caused by a reaction to wheat gluten or related rye and barley proteins.” This may induce various types of alterations in gut function and what has often been called a “leaky gut,” or changes in intercellular junctions that lead to middle molecular-weight molecules passively diffusing across the gut mucosal barrier and gaining entry to the systemic circulation, which could influence CNS function. To support this hypothesis, which Hemmings and Lei propose, a conditional test was conducted to look at the combined effect of the CLDN5 gene, which is involved in forming intestinal barriers and the DQB1 gene that is associated with celiac disease. In looking at these linkage studies, Hemmings and Lei suggest that these two genes may work together in conferring a susceptibility to schizophrenia, and this gut connection to brain biochemistry seems to be very real, particularly related to specific genotypes. When Dr. Lord was talking about dysbiosis, he was referring to metabolic byproducts of certain types of bacteria—gut flora—that induce altered neurotransmission or function, which can result in systemic effects, not just regional effects, in the GI system. This is a dramatic example of what we call the web in functional medicine. You cannot look at just a single point. If any one component of the web is distorted, the whole of the web is distorted. You have to look at distant sites to see what the impact might be. I believe the Hemmings’ contribution to our understanding is a very important part of our model of how bioactive agents from foods may work through a metabolic profile to ultimately induce what appear to be entirely unrelated symptoms. Their model is that permeability alteration in the gut, which may be caused by infection, or physical, chemical, or genetic reasons, induces the intake across the permeable membrane of various antigen-inducing substances, such as an epitope from gluten, which then binds to certain HLA class-2 molecules, like the DRB1 or DQB1, on antigen-presenting cells, and then induces CD4 T cell response, activating the Th1 cells that induce inflammation and the production of mediating molecules called the inflammatory cytokines—TNF-a, IL-1, and so forth. This leads to destruction of the villous structure of the small intestine, ultimately leading to malabsorption syndromes and malnutrition, and one starts getting alteration in the metabolism of these bioactive amines that may induce brain biochemical disturbances, categorized as affective or behavioral disorders, or schizophrenia. Models such as this, which are now testable, are tied together by the underlying concept of genetic uniqueness, and have started to open the door for a better cross-discipline understanding of the origin of various complex conditions. Psychiatry does not own schizophrenia. It is, in part, a metabolic disorder; it is a genetic disorder; it is a gastrointestinal disorder; and it is an immunoneurological disorder. Therefore, it is a functional disorder that requires a functional approach built on a gene-environment interactions. It is an interesting example of the connections between genomics, proteomics, metabolics, and phenomics. The phenome, or the phenotype, is schizophrenia. The origin of that phenotype develops by the interaction of genomics, proteomics, and metabolomics with the environment. This is a different approach toward managing an individual patient, rather than to put him or her on a class of drugs known to block the endpoint of specific neurochemical function and induce what some people would call a metabolic disturbance in their brain biochemistry that brings the signs and symptoms of the condition under control, probably without ever addressing the origin, the triggers, or the mediators of the condition, in and of itself. I always find it interesting when people talk about biological psychiatry, when they are really talking about the use of psychotrophic drugs, rather than looking biologically at the psychiatric manifestations from the origin at a functional level—the genomic, proteomic, and metabolomic levels. That is what Gwynneth Hemmings is talking about in her paper and why I think this is such important part of our emerging understanding. Gilbert’s Syndrome If we were to take this model that I have been describing and map it back against the question of detoxification, a case in point might be Gilbert’s syndrome. Gilbert’s is a genetic-related condition. When I learned about it in school some 30 years ago, I was taught that it was a hard-wired condition. People either had it or they did not. It had to do with glucuronidation defects. People with this condition were not properly detoxifyiong bilirubin, because it was not being correctly glucuronidated and people got easily jaundiced. It was called a benign condition with no physiological concerns. Everybody called it a “genetic anomaly.” Over the years, however, things have changed dramatically, because now it is recognized that glucuronosyl transferase polymorphisms are many, not just a single gene mutation. There are varied forms with different degrees of severity of Gilbert’s, in some cases fairly severe. Simple sleep disturbances or alterations in the diet can lead to jaundice. In other cases, it is much milder in its penetrance. People who have defects in the glucuronidation of bile may have insufficiencies of glucuronidation of other endogenous and exogenous molecules. Therefore, their level of detoxification function for many substances may be modified, affecting more than just the bile. Recent studies by researchers like Joanna Lampe at the Fred Hutchinson Cancer Research Center have demonstrated that diet can play a role in modifying glucuronidation. In a 2005 Journal of Nutrition study, Lampe and coworkers found that individuals with a specific polymorphism in the glucuronidation gene called UGT1A1, had reduced bilirubin concentrations with increased intake of cruciferous vegetables, whereas those individuals with the most common genotype of UGT1A1 did not. This result suggests that the individuals with this polymorphism may be at greater risk of cancer from toxic substances that should be removed via this pathway, but may also have greater opportunity to decrease that risk through dietary intervention.10 What I have talked about in this issue is the connection between detoxification and biotransformation with metabolic effects in the diet-gene interaction. This is the nutritional phenotype I referred to at the beginning of this discussion, and which Dr. Lord so eloquently discussed. I hope I have given you some food for thought, as we start moving toward the 13thsymposium next April, in defining what biotransformation and detoxification really mean in the age of nutritional phenomics. Thank you, and we look forward to being with you next month.

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Bibliography

1 Zeisel SH, Freake HC, Bauman DE, et al. The nutritional phenotype in the age of metabolomics. J Nutr. 2005;135(7):1613-1616. 2 Gibney MJ, Walsh M, Brennan L, Roche HM, German B, van Ommen B. Metabolomics in human nutrition: opportunities and challenges. Am J Clin Nutr. 2005;82(3):497-503. 3 Hutson SM, Sweatt AJ, LaNoue KF. Branched-chain amino acid metabolism: implications for establishing safe intakes. J Nutr. 2005;135:1557S-1564S. 4 Weigle DS, Breen PA, Matthys CC, et al. A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations. Am J Clin Nutr. 2005;82:41-48. 5 Astrup A. The satiating power of protein—a key to obesity prevention? Am J Clin Nutr. 2005;82:1-2. 6 Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005;135:1539S-1546S. 7 Yudkoff M, Daikhin Y, Nissim I, et al. Brain amino acid requirements and toxicity: the example of leucine. J Nutr. 2005;135:1531S-1538S. 8 Muntau AC, Roschinger W, Habich M, et al. Tetrahydropbiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002;347(26):2122-2132. 9 Wei J, Hemmings GP. Gene, gut and schizophrenia: the meeting point for the gene—environment interaction in developing schizophrenia. Med Hypotheses. 2005;64:547-552. 10 Peterson S, Bigler J, Horner NK, Potter JD, Lampe JW. Cruciferae interact with the UGT1A1*28 polymorphism to determine serum bilirubin levels in humans. J Nutr. 2005;135(5):1051-1055.

Welcome to Functional Medicine Update for December 2005. This has been quite a year in functional medicine. We have had an opportunity to explore and share some extraordinary ideas from the experiences and thoughts of leaders in our field. Most interestingly, as we move into 2006, we are leaving behind a very important legacy for the future development of functional medicine—its first textbook, published by The Institute for Functional Medicine. I could not be more proud of the dedicated individuals who collaborated on this project—Sheila Quinn, Senior Editor, and Dr. David Jones, President of IFM. They have worked extraordinarily hard on the development of this textbook, which will be published this month. I believe you will find this book immensely valuable. To coin a phrase, it provides “news to use.” It contains important information from which strategies can be developed for personalizing patient interventions across a wide range of chronic diseases. It will help thoughtful clinicians to significantly improve patient outcomes. It contains over 800 pages and thousands of references, with 47 authors from many disciplines, all working toward a central theme. It has undergone blinded review by independent experts, is consistent in style and readability, and is a testament to the evolution of this field over the last 20 years. If you have not yet had a chance to see a copy of this book, I strongly recommend it. It will help guide you in ways to properly use functional medicine concepts in clinical practice. I also want to remind you that the 13th International Symposium on Functional Medicine will be coming up April 19-22, 2006 (a little earlier this year) at the Tampa Marriott Waterside Hotel & Marina in Tampa, Florida. One of the keynote plenary presenters is going to be this month’s Clinician/Researcher of the Month—Dr. T. Colin Campbell. We will be focusing on detoxification and biotransformation at the symposium. Please mark the dates on your calendar. This is going to be a very auspicious event, with superb speakers, informative plenary lectures and workshops, and an excellent overall meeting format. In this month’s FMU, I am going to focus on one of the themes that will be explored at the 13th International Symposium on Functional Medicine having to do with the question of whether or not our present diet is toxic. Just to pose that question will raise some fairly strong comments. What do I mean by “present diet?” What do I mean by “toxic?” Before these questions can be answered, we must first understand the definitions of the terms. The diet I am talking about is one of standard fare. It is highly processed, shelf-stable, convenient, reasonably inexpensive, and is available to virtually everyone across the United States. We have been characterized as the “fast-food nation,” with a diet of “white,” of over-consumption, and of under-nutrition. Whatever that means to you, it is probably the diet that most of your patients are eating, no matter what they are telling you. Over time, they have probably been consuming foods that are represented by those characteristics as the majority of their calories —shelf stable, “white,” high in fat, high in sugar, and highly refined. Let me move to the next definition. What does “toxic” mean? Toxic refers to some metabolic influence of the exposure that induces activities in the complex web of metabolomic interaction leading to tissue injury. As contrasted to a poison that might have an acute toxicity, I am referring to chronic toxicity where, over time, the appearance of specific metabolites that would not normally be present in a healthy physiology, eventually induce injury to tissues, producing a chronic, cumulative influence that is likely to lead to degenerative disease. That disease might evolve over decades of living before it is finally observed. Therefore, it is hard to pin down a specific etiology agent for it because it evolves so slowly. It is like the Chinese water torture of one drop of water at a time on one’s forehead. Each drop in itself is not a major problem, but it is likely that years of single drops will create a significant problem. The term “diet toxicity” sounds exaggerated, but the outcome is exactly what the term implies. People get diseases prematurely that are not necessarily preordained, and for which heroic medical intervention is required at great expense and often discomfort to the patient with some relative risk. The term “toxicity,” as I am applying it in this month’s FMU, may not be the traditional terminology a toxicologist would use, but I believe it will fulfill our definition of toxicity. Once again, I will pose the question—is today’s standard diet toxic? The outcome of a toxic diet would be the major chronic age-related diseases—coronary artery disease, cerebrovascular disease, hypertension-related disorders, cancer of various forms, digestive disorders, and various other inflammatory conditions. It is interesting to ask why esophageal reflux disorder, or GERD, is becoming so prevalent. It is almost as if everyone has to take an appropriate H2 blocker, proton pump inhibitor, or antacid so they can cope with normal daily living. Why? Why is it that we are seeing such a steep increase in upper GI-related disorders, and assuming it is OK because we have all these new drugs to keep people’s gastric juices and esophageal function under control? One has to ask what the cause is, rather than just what the effect is. I want to focus the rest of this issue on a measurable implication of a toxic diet, and that is the epidemic of metabolic syndrome. The debate is no longer about the prevalence of metabolic syndrome and what its diagnostic criteria are; these are now well established. But defining metabolic syndrome in such a way that it sounds like a discrete pathology that is either present or absent results in apparently reducing the number of people who are affected by underlying insulin resistance and, potentially trivializing that condition until people start showing up with premature heart attacks and strokes, and wondering where they originated. We will have medicalization of those conditions with new stenting, new bypass surgeries, and new medications, but, we will not have asked the right questions, early enough, however, about the relative toxicity of the diet and its relationship to the incipient markers of later-stage vascular dysfunction, which is one possible outcome of metabolic syndrome. What is metabolic syndrome? According to Eckel, Grundy, and Zimmet, in an article published in the Lancet: “The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity.”1 There are many people, including Dr. Reaven, who might challenge that metabolic syndrome is simply a result of obesity, although he agrees that it is a factor. Metabolic syndrome also appears to have genetic factors, as well as other lifestyle factors, such as amount of exercise, involved in its etiology. It is not obesity or its covariables alone that cause metabolic syndrome, at least in all people with the syndrome. If that were the case, how could we explain the individual who is very thin who has metabolic syndrome and insulin resistance? There are cases of people with low body weight, who are perhaps excessively lean, that have metabolic syndrome, as well. It is not obesity alone that causes metabolic syndrome. Metabolic syndrome is defined in various ways, but generally, an individual with this condition has slightly elevated fasting triglycerides and slightly lowered HDL levels, increased blood pressure (at least, marginal elevations of systolic pressure), and often elevated blood uric acid levels. They generally have central obesity, as we mentioned, with increased waist-to-hip ratios and an elevated body mass index (BMI). They often have elevated dense LDL particles. None of those by itself is the sine qua non for metabolic syndrome. A constellation of variables is associated with the diagnostic markers of metabolic syndrome. The principal diagnostic marker would be found by doing an insulin clamp study on an individual, the so-called euglycemic clamp, when insulin and glucose are infused to evaluate the relative sensitivity of that person to the infusion. That is not a technique that is going to be routinely used in diagnosis, so the surrogate markers are used, such as triglyceride over HDL ratio, or various types of homeostasis models for glycemic or insulin response. Inflammation as a Marker of Metabolic Syndrome Another hallmark of metabolic syndrome is inflammation. This is a more recent emerging concept—that the pathophysiology of metabolic syndrome seems to be largely attributable to insulin resistance, with excessive flux of fatty acids through the liver inducing or associated with a proinflammatory state reflecting increased levels of proinflammatory cytokines and eicosanoids. The increased risk for vascular injury, endothelial injury, hypertensive dysfunction, renal problems, and cerebral vascular problems associated with metabolic syndrome, may be a consequence of the metabolic markers or mediators of inflammation. Obesity and Inflammation Central obesity, or visceral adipose tissue, produces its own complex array of proinflammatory molecules, such as tumor necrosis factor alpha (TNF-a), interleukin 1 (IL-1), and interleukin 6 (IL-6). These messenger molecules also add to the production of proinflammatory signals, along with activated macrophages and an inflamed vascular endothelium. When a person has an occlusion, these are all sites or loci in the body where there is increased production of proinflammatory mediators. These mediators are also associated with the metabolic syndrome. There is also some evidence that the pathophysiology of metabolic syndrome may actually begin in the perinatal period. Often, we start thinking about a chronic, age-related, degenerative disease when the person becomes middle-aged, and then we become worried about it. Yet, the origin of many of these disorders may have occurred in utero. There is a sequel of events that may have started the moment the sperm met the egg in the uterine environment that travels post utero into the infant period, the toddler period, and later into adolescence and adulthood. Let me give you an example from a paper that was published in the journal, Nutrition,titled “Pathophysiology of metabolic syndrome X and its links to the perinatal period.” 2 In this paper, the author states: “Increased consumption of energy-dense diets by pregnant women and lactating mothers suppresses the activities of D-6 and D-5 desaturases not only in maternal tissues but also in fetal liver and the placenta, resulting in decreased plasma and tissue concentrations of long-chain polyunsaturated fatty acids w-6 arachidonic acid (AA), w-3 eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).” We know of the importance of DHA in the infant for ocular and neurological development. “EPA, DHA, and AA have negative feedback control on tumor necrosis factor-a and IL-6 synthesis. Hence, EPA, DHA, and AA deficiencies induced by an energy-dense diet increase generation of tumor necrosis factor-a and interleukin-6, markers of inflammation that in turn decrease production of endothelial nitric oxide and adiponectin to induce insulin resistance in maternal and fetal tissues.” In fact, insulin resistance can be induced in animals by infusing very small amounts of TNF-aor IL-6, or even prostaglandin-E2 (PGE-2). PGE-2 can induce insulin resistance. There is a fairly close correlation between inflammation and insulin resistance, regardless of BMI principles. “Increased concentration of tumor necrosis factor-a and interleukin-6 enhance expression and activity of 11b-hydroxysteroid dehydrogenase type 1 enzyme, which produces abdominal obesity, insulin resistance, hyperlipidemia, hyperphagia, and hyperleptinemia, characteristic features of metabolic syndrome X.” 11b-hydroxysteroid dehydrogenase type 1 produces regional cortisol. One thing we know about people with metabolic syndrome is that often their body changes into the apple shape, with an increased waist-to-hip ratio that seems to resemble a physiognomy like that of Cushing’s disorder. They do not have a primary, adrenal hyperplasia, however. There is something else going on, which is regional cortisol production induced by adipocyte activation of 11b-hydroxysteroid dehydrogenase type 1, which is induced in its gene expression by exposure to the proinflammatory Th-1-inducing cytokines, such as TNF-a and IL-6. If there is an upregulation of inflammation in the maternal diet and environment, there is stimulation in the fetal liver and in the adipocyte for production of these genes, or activation of the expression of these genes, associated with regional production of cortisol and other metabolic effects. The takeaway from this discussion is that during pregnancy, lowering the load of proinflammatory materials in the diet and increasing the level of long-chain polyunsaturated fatty acids, particularly EPA and DHA, may be very desirable during the perinatal period in preventing ultimate development of metabolic syndrome through the gene-activation processes. Of course, that model holds true, not just in utero, but post utero, as well. It also raises the implication that one of the surrogate markers for the assessment of the metabolic syndrome is not only triglyceride/HDL ratios above 4, but also evaluation of various inflammatory mediators, including high-sensitivity C-reactive protein (hsCRP). There was a nice report in Clinical Chemistry looking at the relationship between CRP levels and cardiovascular event survival probability.3 It has been found that as CRP goes from less than 1 mg per liter to 1-3 mg per liter to greater than 3 mg per liter, the incidence of cardiovascular events goes up remarkably. The Kaplan Meier survival curves of those events were pretty dramatic, demonstrating that keeping hsCRP at a level less than 1 is pretty important. It is a push/pull, chicken-and-egg argument. It is all part of the web. Insulin resistance induces oxidative stress and inflammation, and around it goes in a feed-forward cycle. One of the agents in the diet that has been associated with the production of inflammatory, insulin resistance responses is the simple carbohydrate, fructose. There has been a considerable increase of fructose in the diet as we moved from cane and beet sugar to that of corn-derived sweeteners, the high-fructose corn syrup sweeteners. Fructose intake has been associated with the prevalence of obesity, as well as hepatic lipogenesis and hyperlipidemia. Although it does not increase insulin and leptin, or suppress ghrelin (which suggests that it has a different effect than glucose on energy balance through an endocrine mechanism), it may have an increased tendency, if consumed at high levels (high is dependent on the eye of the observer), to induce hypertriglyceridemia and an altered effect on the triglyceride/HDL ratio, which we have already said is associated with metabolic syndrome. In an article on dietary fructose that appeared in Nutrition Reviews, titled “Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism,”the author, Peter Havel (whose name is familiar to those of us in nutrition circles), discusses that chronic hyperinsulinemia relates to hepatic lipogenesis and may contribute to hypertriglyceridemia.6 This has been seen in animals and in humans in some limited trials with excessive fructose intake. The rodent model is the animal on whom many of these studies have been done, and it turns out they are very sensitive to fructose in the diet. They can be induced into hypertriglyceridemia quite easily with increased levels of fructose in the diet. Human metabolism of fructose, however, differs from that of rodents, and the ability to produce simple hypertriglyceridemia with increased fructose is not as obvious. However, there is a level, a threshold at which, in certain individuals, excessive intake, particularly as corn syrup-sweetened beverages, induces hypertriglyceridemia and may be associated with one of the etiological factors implicated in metabolic syndrome and insulin resistance. The connection between fructose and insulin resistance is not a trivial one. In a paper that appeared in Diabetes, investigators conducted a human study looking at high-fructose diets that stimulated hepatic de novo lipogenesis and caused hypertriglyceridemia and insulin resistance.7 Seven apparently normal men were studied on four occasions: after fish oil supplements of 7.2 grams per day for 28 days; after a six-day, high-fructose diet corresponding to an extra 25 percent of calories; after a fish oil plus high-fructose diet; and after a control diet. Following each condition, fasting fractional levels of de novo lipogenesis and glucose production were evaluated using 1-13C sodium acetate uptake and 6,6-2H2glucose into various fractions of lipids. It is a very nice study. I want to emphasize that increasing fructose intake to constitute 3 grams fructose per kg body weight did induce dyslipidemia and hepatic and adipose tissue insulin resistance, whereas the 7.5 grams per day of fish oil reversed dyslipidemia but not insulin resistance. A lot of people have jumped on the bandwagon who believe that fructose causes metabolic syndrome and insulin resistance. But again, I want to say, everything in balance. According to Tolman’s Law of Pharmacology, everything is toxic at some level, including air and water. The real question is, at what level does fructose become “lipid toxic” or hepatotoxic? It appears that is when fructose is upward of 25 percent or more of calories. Let’s assume, just for math purposes, that the person was consuming a 1600 calorie-a-day diet. Twenty-five percent is 400 of those 1600 calories. If we talk about it as 4 calories per gram, that’s 100 grams or more of fructose that a person would have to be consuming to get up to that level. One hundred grams of fructose, or more, is a very high load. About the only time you will see that is if a person is on a high-sweet diet and consuming high fructose corn-syrup sweetened beverages. Yes, fructose is hypertriglyceridemic, and yes, it can induce insulin resistance in humans, but the amount needed to document the effect is very high. We have talked about the toxic dietary components of high fat, highsugar, and white flour. What about the converse? Can one formulate a diet regime with low toxicity? That leads into studies like those that have discussed the effect of a Mediterranean-style diet on endothelial function, and markers of vascular inflammation in patients with metabolic syndrome. There was a nice paper published in the Journal of the American Medical Association in which the authors conducted a human intervention trial with 90 subjects who were instructed to follow a Mediterranean-style diet. They received detailed advice as to how to increase daily consumption of whole grains, fruits, vegetables, nuts, and olive oil.8 Another 90 patients in the control group followed a prudent diet, which consisted of 50 to 60 percent of calories as carbohydrate (not specifying unrefined, necessarily), protein level 15-20 percent of calories, and total fat less than 30 percent of calories. It was comparable to the American Heart Association’s Step 1 Diet. After two years, patients following the Mediterranean-style diet consumed more foods rich in monounsaturated fat, polyunsaturated fat, and fiber, had a lower ratio of omega-6 to omega-3 fatty acids. Obviously, their total fruit, vegetable, and nut intake (about 270 grams a day), and whole-grain intake (about 103 grams a day), was also significantly higher than the control group. The level of physical activity in both groups was about the same, and the outcome was quite dramatic. At two years of follow-up, the patients in the Mediterranean diet group had significantly improved insulin sensitivity and reduced serum concentrations of hsCRP and IL-6. There were many individuals who had metabolic syndrome both study groups (40 of 90 in the Mediterranean-style diet group, versus 78 of 90 in the control group). It was concluded that the Mediterranean-style diet may be effective in reducing the prevalence of metabolic syndrome and its associated cardiovascular risk. That follows on with a paper by David Jenkins, et al, from the University of Toronto School of Medicine, Department of Nutrition, published in the American Journal of Clinical Nutrition,and a classic study that I have referred to in the past. The title is, “A direct comparison of a dietary portfolio of cholesterol-lowering foods with a statin in hypercholesterolemic participants.”9 These were individuals who did not have heart disease or diabetes, but who did have a history of elevated lipids. There were 34 hyperlipidemic participants—20 men and 14 postmenopausal women. They all completed three different treatments with a washout between each: a control diet group on the AHA’s Step 1 diet; a diet very rich in plant sterols, soy protein, and various viscous fibers; and the AHA’s Step 1 diet, along with a statin (Lovastatin). It was found that in the AHA Step 1 diet group, the diet did not have a very positive effect on inflammation or insulin markers, but the group on the portfolio of cholesterol-lowering foods (2000 mg per day of phytosterols rich in beta sistosterol, along with soy protein and the higher soluble fiber) had a very marked reduction in triglycerides, improvement in insulin sensitivity, and a lowered level of inflammatory mediators. As Dr. Jenkins and his colleagues point out, dietary combinations may not differ in calories, or even in macronutrient percent calories, but they may differ significantly in their impact on metabolic outcome. In fact, when this dietary portfolio of cholesterol-lowering foods was compared with one of statins and an AHA Step 1 diet, both regimens were about the same regarding the ability to lower lipids and improve function. One might ask what a toxic diet is, because it might suggest that even the AHA Step 1 Diet has some residual toxicity. If it was an optimal diet, you would not see the improvements observed with the cholesterol-lowering foods (the plant sterol-rich, soy protein-rich, higher viscous rich fiber diet), which had a much lower glycemic index. I mentioned soy, and probably I should talk a bit about the soy connection to cognitive function. Recently, a study from the Psychopharmacology Research Unit, Centre for Neuroscience, King’s College London at the Guy’s Campus in London and the School of Pharmacy in Brunswick Square in London, titled “Soya administration and cognitive function in post-menopausal women” was published.10 The authors of this paper in Current Topics in Nutraceutical Research conclude that, under more controlled conditions, inclusion of soy in the diet has a positive effect on cognitive function in postmenopausal women. The other feature that we have not talked about in any of this work, which I think deserves attention, is what happens when you refine a diet very rich in plant phytochemicals and phytonutrients, into a “white” diet, and you make it a diet rich in calories, but low in associated nutrients? This change fuels the overconsumptive/-undernutrition state. This is the diet that we have defined as toxic, which delivers a lot of potential energy in the way of calories, but not the right kind of supporting players in order for those calories to be properly metabolized. Historically, we have eaten diets somewhere in between vegetarian and carnivore, because we have the incisors of the carnivore and the molars, or grinding teeth, of the herbivores. When we eat these types of varied diets we are not just getting protein, carbohydrate, and fat alone. We are getting non-digestible fibers, and literally tens of thousands of phytochemicals in the coloring materials of those foods—pigments, phenols, glycosides, flavonoids, and so forth. What effect do these natural phytochemicals have on insulin sensitivity, and on cellular signalling and function? This question is only now being seriously addressed. In the past, we thought we could remove these non-nutritive items. They were not vitamins and they were not minerals, so we could just take them out of food and do our studies with animals, and it would be the same as if they were still included, because they were considered benign. Now, we recognize that is not true. These phytochemicals can have unique, tissue-specific effects on function. If we want to know what the role of a complex diet is in modulating genomic expression, proteomics, and metabolomics into the phenomics of the organism, we need to look at the role that phytochemicals have on function, as well. This is an opportunity to do new, detailed research, and as this research is done, we will uncover the fact that vegetable diets (by nature, the only diets that can contain phytochemicals) have a different effect than that of highly processed diets, or diets rich in only animal products. This is, in part, what Mark McCarty talks about in his hypothesis article in Medical Hypotheses, titled “Potential utility of natural polyphenols for reversing fat-induced insulin resistance.”11 Eating a complex diet with all these phytochemicals influences gene expression, proteomic, and metabolomic function, and can have a salutory effect on the way calories are processed into functional energy. This is a very important point of differentiation between the partially refined diet and the highly refined, nutrient-dense diet that may stimulate a toxic outcome. It is time for our Clinician/Researcher of the Month.

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INTERVIEW TRANSCRIPT

T. Colin Campbell, PhD Jacob Gould Schurman, Professor Emeritus of Nutritional Chemistry Project Director, China-Oxford-Cornell Diet & Health Project Division of Nutritional Sciences Cornell University Ithaca, NY JB: During our ongoing paradigm shift, we have been very fortunate to hear from some of the great minds in this field. This month is no exception. We are privileged to have Dr. T. Colin Campbell, a name that I’m sure is familiar to many of you. He has been a leader in our field for many years. He is the Jacob Gould Schurman Professor Emeritus of Nutritional Biochemistry at Cornell University, and the project director of the China-Oxford-Cornell Diet and Health Project. This study was the culmination of a 20-year partnership of Cornell University, Oxford University, and the Chinese Academy of Preventive Medicine. Dr. Campbell also has a rich and impressive publication list. It’s wonderful to have the opportunity to share in his wisdom, background, and history. His graduate training took place in the late 1950s, and what has happened since that time in the areas of nutritional science, genomics, nutrigenomics, epidemiology, animal science, and all of the aspects of human biochemistry that we didn’t yet know back then, is quite amazing. Dr. Campbell has helped to shepherd that, and he has been present through this whole revolution. I thought it might be useful for Dr. Campbell to share his historical perspective, as well as some of the extraordinary things he describes in his landmark book (one that should be in all of our libraries)—The China Study.12 This represents the largest health and nutrition study ever conducted. Some people call it the “Charles Darwin work of nutrition.” If you haven’t read this book, you certainly should put it on your reading list. It opens up tremendous opportunities for understanding the revolution we are now engaged in, and the implications and importance it has in global health and stemming the tide of the ever-rising burden of chronic, age-related disease. Welcome to FMU, Dr. Campbell. As I read your original research articles, I found it fascinating to see how your intellectual stream of thinking may have started what the embryonic ideas were, and how it related to some of the observations you made about dietary protein, detoxification, and hepatocarcinogenesis. How did you get into this field and make those first observations? Protein in the Diets of Malnourished Children in the Philippines TC: I want to thank you for your invitation and for all of those kind comments. I started on a dairy farm, and went off to school to do my doctoral dissertation on trying to figure out how to produce animal protein more efficiently for consumption. I went to the Philippines to set up a nationwide program to feed malnourished children. One of the objectives, not just for me, but for all those working in the field at that time, was to make sure the children got enough protein. Along the way, as sort of a side observation, I learned that there were kids there getting primary liver cancer at age 4 and under, which is very unusual. That disease tends to occur in mid- to older-age. I learned that the kids who were consuming the most protein tended to come from families who were consuming a western diet. We were trying to push more protein, in a sense; yet those who were getting the highest levels of protein were having problems, and possibly getting liver cancer, as well as other types of cancer. Animal Study on Protein and Liver Cancer At that time, there was an experimental animal study done in India, that showed esssentially the same thing. When rats were given aflatoxin, which is a very potent hepatocarcinogen, it caused liver cancer. When the rats were given either regular levels of protein at 20 percent of calories, compared with other rats given protein at 5 percent of calories thinking that the animals given more protein would be at an advantage, in terms of resistance to aflatoxin—in fact, the reverse turned out to be the case. The results were remarkable. It wasn’t necessary to have a statistician on board to see whether or not it was significant. It was essentially like a 100 percent score. The rats who got the most protein got liver cancer, and the rats who got the least amount of protein did not, and that was consistent with what I had seen in the kids. It was just putting one and one together, and not only getting two, but maybe more. Protein and Metabolism of Aflatoxin I embarked on a long series of studies that were funded, for the most part, by the National Institutes of Health (NIH) and, to some extent, by the American Cancer Society and the American Institute for Cancer Research. It was all public money. We explored that question, starting out to confirm the observation that higher levels of protein could turn on that tumor. The second question was to try to figure out how it worked. In the field of science, if we know how something works, we have a lot of confidence in what we’re seeing. We had a continuous NIH grant to work on that for about 19 years. We looked at it in great depth. We first wanted to know whether the protein affected the metabolism of aflatoxin by the so-called drug metabolism enzyme system. And, indeed, it did. And it was remarkable—very strong. Higher protein increased the enzymatic activation of aflatoxin to produce an electrophilic reactive metabolite that covalently bound to DNA. We were at the forefront, in a way, even though we didn’t have a lot of tools to work with. In any case, higher protein levels increased the activation of the aflatoxin to form more of these DNA adducts which, in turn, represented intiation of a lesion. It seemed as if every time we looked for a mechanism, we found one, which was another observation in itself, and kind of exciting. It wasn’t just a single mechanism; it was a whole bunch of changes in enzyme activities and other sorts of physiological biochemical events that converged to create that response. We went beyond that to look at the question concerning the infective protein promotion. We knew in those days that promotion seemed to be a reversible process of the cancer initiation. I knew that higher protein intake increased the activation of aflatoxin, but all that might be cancelled out if, in fact, it didn’t do the same thing during promotion. We looked at that and found that the higher protein levels actually increased promotion, as well. It grew the tumors essentially. It was acting a bit like fertilizer, growing the grass faster; in this case, growing the tumor faster. We also learned that multiple mechanisms operating in an almost symphonic manner were working to produce that result. At the same time, we learned that whereas we could move the tumor forward in its progress by feeding higher protein, we could also reverse the process by feeding lower protein. That was an exciting observation. Plant versus Animal Protein Probably, the next most significant thing we observed was that the protein we were using was casein, or animal protein. We tried some plant proteins, like wheat and soy protein, and they did not promote tumor development. That was very clear and very distinctly different, although I stated that in quite simplistic terms. We were focusing on the idea that we had an animal protein on the one hand that promoted tumors, and plant proteins that did not. I thought that was quite striking. It was in-depth as far as the details were concerned, but we didn’t explore the protein, so it was limited in that sense. We eventually got involved in doing a survey in China, a human, nationwide study, to see why cancer occurred in some places in the country much more commonly than in other places. The Chinese Government had established that cancer rates were highly localized across the country. Together, with colleagues from the University of Oxford and the College of China, and some others, we organized this big study in China, a large cooperative study funded by the NIH and the Chinese Government. We wanted to measure as many things as we possibly could because I had suddenly become interested in looking at the question concerning the relationship between diet and disease in a much more comprehensive manner, rather than focusing on one thing at a time. The rat studies we had done were interesting and informative, but I wanted to go beyond that and look at things in a larger context. The China Study I guess the rest is history. In the China study, in rural China at least, they don’t consume much in the way of animal foods. It goes from something in some areas, to almost nothing, to perhaps 20 percent of calories in other areas. We were looking at that end of the curve where not much animal food was consumed. I didn’t think that we would see a whole lot. We measured things in so many different ways—we took blood and urine samples, food samples, asked questions, and analyzed the responses for all manner of things. It gave us an opportunity to look at the question of the relationship of diet and lifestyle with disease formation in a much more comprehensive way. What we came away with was quite startling. It confirmed the impressions that I had from the animal studies—mainly, that putting some animal food in the diet wasn’t a very good idea. The consequences were more than just creating more cancer; they were also associated with creating more heart disease, more diabetes, and more this and more that—the kinds of conditions we get here in the western countries. Conversely, whole plant foods—vegetables, fruits, grains—seem to have this very exciting property of keeping these diseases at bay. They even reversed these diseases. It was a combination of the experimental animal studies and the human studies, together with an emerging literature on the part of many other laboratories, as well. The whole story started to gel into a thesis for me—that here in the west, we’re not doing things the right way. We’re consuming a diet that is causing problems across the board, one that is very rich in animal-based foods, for starters, and also a diet that is very limited in whole, plant-based foods. To the extent that we use plant-based constituents, we usually end up extracting the stuff out of the plants, making junk food, and eating that at convenience stores. We’ve got a diet of rich, fatty animal foods, together with junk food, and leaving out the best parts. The result is that we are getting ourselves into some serious trouble. As one does research and goes through the years, one may make a discovery, after which one moves on to the next thing. But I have developed a great passion for the idea that nutrition ought to be the premier biomedical science for the future. There’s no doubt in my mind about that. I’ve also become aware that the public is very confused about what nutrition really does. Our professional colleagues are confused. I think your institute, by the way, has got the right name—Institute for Functional Medicine. I’m sure you focus a great deal on food. That is the way of the future; there’s no question about that. It seems to me that it’s more of a question of stopping long enough in research and the practice of medicine to deliberate on this idea. It’s not simple; it’s complex biologically, but we can begin to understand the process and become aware of how profound its effect is. I’ve gotten to the point where I believe that a plant-based diet with lots of variety is the ideal. That diet works in so many exciting ways. It keeps mischievious genes under control; there’s a lot of good evidence showing that. We did some of that ourselves. To a considerable extent, it attenuates the effects of toxic agents we are exposed to. It reverses advanced diseases. The same diet that prevents disease tends to also be useful in treating people with diseases far along, and we can see reversal. JB: I’m awestruck. I’m sure all of our listeners are. Because what you speak of so easily and so fluently is a manifesto for change. It translates from academia and the research to the lives of people, suffering, and premature loss of human potential. There are many sociological, philosophical, and humanitarian implications of what you’re saying. That’s one of the reasons I was drawn to the Pauling Insitute, where I worked for Dr. Linus Pauling for three years. There are some bigger issues that derive out of this science than just the discoveries, one of which is the implication on people’s lives throughout the world. I’d like to go back and pick up several things you said. Perhaps the profundity was not fully appreciated by some of our listeners. Let me start with the presumption of a scientist. Often, we feel that scientific investigators are a product of their own bias and their own environment, but great scientists are those that can shake off their bias and see the world in a different way. I’m reminded of the Goldbergers when they discovered that pellagra resulted from niacin deficiency. They were bacteriologists and were sent to find the infectious organism that caused pellagra. In the process, they were able to see through their own bias. Similarly, you are a product of a dairy farm. You must have had to fight off your presumptions, because I’m sure you grew up on those great farm breakfasts. Was that a complicated transition as you began to make these discoveries? TC: Yes, it was. It was very complex. One advantage for me is that I remained the skeptic of our own research as it began to unfold. I was probably a severe skeptic, which made me look harder to really prove true what we were looking at, and my colleagues did the same along the way, as well. Although we were generously funded for many years by NIH, most of the proposals and arguments that were made at that time were focused more on how cancer works. We were using protein as a model to explore that process. But, as I started to focus more on the agent itself, namely protein, I started to get in trouble with my colleagues. They didn’t seem to want to believe that. I mean, who in the world in their right mind would question the protein present in cow’s milk? That had almost become legendary as the most awesome and important nutrient of all. I certainly had been raised in that culture. But as I said, we didn’t need statisticians around to tell us what we were seeing. It was there; it was very clear. Honesty is what ought to be driving this research. It’s was a matter of being honorable to the research, and it was also a matter of being honest with the taxpayers who pay for our research. I’ve always felt a great responsibility to the public who pay taxes, some of which goes toward public funding. We got the results, and if it was something that people didn’t even like that much (a lot of people didn’t), I still felt responsible for telling them what we did with their money. It also meant a lot because there were people getting disease that I thought didn’t have to happen. People can be mended. I’ve come to believe that the whole western model of relying on treating disease at the end stage with harsh drugs is the wrong model. We went down the road many years ago, intentionally or unintentionally, to use drugs to treat the endstage disease, and along the way, we forgot about food. We forgot about nutrition. We never defined it right; we didn’t understand it. We’ve got to get back on track. JB: When you were talking about your early discoveries, the role of protein in carcinogenesis, the dual effects of exposure to aflatoxin, and higher-protein animal diets, it sounds like it relates closely to the focus of our upcoming 13th International Symposium on Functional Medicine in Tampa next April on biotransformation and detoxification. Having read your papers, it seems that in those animal models, you were looking at certain isoforms of inducible phase 1 cytochrome P450 enzymes that were upregulated by the protein amino acid constitution of higher-animal protein diets. They had a covariable effect on activating carcinogens to biotransformed intermediates, or procarcinogens to carcinogens, which led to an increase of the hepatocarcinogenic load. It’s a very interesting gene/environment observation, It’s a case study as to how there may be polymorphisms of those genes with different levels of susceptibility, and when higher animal protein diets are added to that, as well as exposure to an imperfect environment, it results in chemical soup. Suddenly, there is a different matrix effect in society as it relates to what medicine is doing, new therapies, and new drugs to treat those conditions. Does that seem like a reasonable takeaway from your observations? TC: Yes. I know you have been working in this field for many years, and you said it perfectly. I couldn’t say it better. JB: That leads to a juxtaposition. What you’re implying is reduced protein, but with all the insulin resistance, obesity, and diabetes, isn’t too much carbohydrate the problem? Cutting down on protein suggests increasing carbohydrate. That seems paradoxical. How do you respond to that? Low-Carbohydrate Diet TC: I think the low-carbohydrate diet is one of the greatest hoaxes that has been put on the American public in recent years. It just doesn’t make sense, although I have to give credit to part of that story to those who are proposing it. Simple carbohydrates are really what they’re talking about, although they use the term, carbohydrates or “carbs.” They didn’t make it clear that they were talking about simple carbohydrates. They began to question whether high-carbohydrate diets are a problem. The diet I’m talking about that has the greatest chance of reducing and controlling disease is, in fact, a high-carbohydrate diet. They’re simply wrong. They didn’t really understand, I’m sure, what they were talking about in this regard. When I think of carbohydates, I think of foods that are high in carbohydrates and that means, for the most part, carbohydrates in the natural form, the complex form. That kind of diet is best. The simple carbohydrates like sugar and white flour are not good kinds of carbohydrates. I give them credit for that. Excess Protein in the Diet I want to point out one other thing before I forget it. When I’m talking about high-protein diets, I’m obviously not questioning the nutritional value of protein. Obviously, we need protein. It’s a terribly important and essential nutrient, and we need it at a certain level. The problem I have with protein, and we explored this in great detail ourselves, is that its effect in increasing cancer, blood pressure levels, and things like that, occurs when we are consuming an excess of what we need. It’s the excess protein I am referring to, but unfortunately, and interestingly, most of the American public actually consume excess protein. Some people consume a lot of excess protein, and the low-carb diet people are all of a sudden coming along and talking about reducing carbohydrate intake dramatically. Well, what are they going to replace it with? They’re going to replace it with fat and protein. They admit that and they want diets high in fat and protein. While that may lead to what appears to be a short-term benefit, namely weight reduction, for starters, that’s not going to last and those people are going to have huge problems in the future by doing it that way. JB: That leads me to a question related to many studies that have appeared in the literature. I don’t want to put words in your mouth, or lead you into an area that is uncomfortable for you, but I have reviewed literally thousands of papers that have appeared in the peer-review literature over the last many decades on the role of macronutrients on physiological effects in either animals and humans. It strikes me that the things that don’t get controlled in these diet studies, at least from my observations, are those that are not considered very valuable—the non-nutritive components of plant foods. When they talk about a diet of so many calories percent protein, carbohydrate, and fat in a study, they never control for what the level of all these other, say, non-digestible fibers (that’s not always the case because it might be a fiber study), such as flavonoids, polyphenols, or the rich array of phytochemicals that are present in unrefined foods. We look at myriad studies in which one of the more important variables was never controlled for, and then we make sweeping conclusions about the outcome of the difference between carbohydrate, fat, and protein-rich diets, which really is irrelevant to the way the foods would have affected function if we had controlled all the variables. Am I way off on this? Healthy Benefits of Plant Food TC: No. You’re absolutely right. There’s a whole lot of stuff that is indicated, in plant food, in particular. They contain a whole array of chemicals that have healthful activity. There’s no doubt about that. There are the flavonoids, a whole variety of fibrous factions, antioxidants, and so forth. I’ve been using the word “countless” to indicate the number of different kinds of chemicals that are present in the food we consume, especially in plant-based foods. There’s an array of chemicals that, from what we’ve been learning, have impressive properties. What’s really impressive, too, is that those things tend to work together when we consume them in the form of food. There are so many different kinds and, as you said, we don’t control for that, for the most part. At least, we ignore them when we’re doing our studies. We end up focusing on a few things that we do know something about, but we’ve ignored all the rest of it that is part of everyday life for all of us when we’re consuming food. JB: At the level of mentorship you are at now, and as a senior scientist with wisdom in this field, do you ever get the feeling that we’ll look back at this period of research development period 50 to 100 years from now, and see some of this work as being very silly? We are pursuing new-to-nature molecules for the treatment of disease. We define nutrition in a partitioned fashion, as empty calories, without looking at the full complement. Will we appear as foolish to the future generation as the barber surgeons doing blood-letting in the previous century appear to us? TC: I’ve become a little cynical about the way to do science, the way we practice medicine, and especially the way we develop food and health policy. I have been very active in that for a long time, too. I’ve gotten to the point of referring to our present day as the dark ages of science. Maybe that’s too harsh, because we are also learning a lot of great things. Unfortunately, we take the information that we get and try to quickly adopt it to some kind of solution or product or something to sell, without trying to understand it in terms of what nature did for us. That’s always what a struggle is about. You do what you think is right from a societal point of view, and you do the best you can. Basically, after discovery, we’ve done the wrong thing. JB: If there’s any doubt in the minds of our listeners as to how this all fits together, your book, The China Study, is an irrefutable legacy to a different model. I believe that the very exacting work you’ve done with your colleagues at Oxford and the Chinese Academy of Preventive Medicine collaborative study with Cornell, is a tremendous gift for learning to all of us. Your work, coupled with what Walter Willett and many others are doing to redefine the food pyramid and move out of the box that holds more of the same, as we see the rising epidemic of obesity continue to occur, is where the solutions will be found. I applaud and thank you for your years of dedicated service as a public servant, researcher, and agent of change. Your work is going to make a real difference. I hope everyone who is a thinking person will have a chance to read The China Study. TC: Thank you. That’s very kind of you. JB: I wish you the very best, and hopefully, we’ll catch up with you down the road. Good luck in continuing to fuel the fire of change and spread the news. TC: I know we’re on the same path. JB: We certainly are, and the best to you. 2005 Nobel Prize for Physiology or Medicine for Bacterium Work I would like to follow up from Dr. Campbell’s comments with one last thought about the concept of a “toxic” diet. In 2005, the Nobel Prize for Physiology or Medicine was awarded to Dr. Barry Marshall, a gastroenterologist from Nedlands in Australia, and Dr. J. Robin Warren, a pathologist at Royal Perth Hospital.13 They were collaborators in the development of the view that an infectious, opportunistic organism called Helicobacter pylori is associated with peptic ulcer disease and some problems related to carcinogenesis of the upper gastrointestinal tract. This was a remarkable discovery. You may recall that they had to fight uphill against medical dogma that held that psychological stress and acid was the cause of stomach and duodenal ulcers. Now, we recognize that it must be a much more complex interrelationship between immunochemical function and stress, and that H. pylori infection is a multiple etiology. Stress may induce altered immune function, which may set the stage for increased prevalence of infection with the opportunistic organism, H. pylori. That ultimately leads to an immune response to the stealth organism embedded in the GI mucosa that induces the normal immunological vigilance, which is associated with the production of oxidants that cause inflammation and tissue damage associated with the ulcer. It is a much more complex etiology than had been previously thought, and the treatment of choice that derives out of this is not just H2 blockers or proton pump inhibitors, but rather anti-infectious medications that euphemistically have been called triple therapy—bismuth, metronidazole, and an antibiotic. That is an interesting piece of the history of medicine—overcoming bias, seeing the world through a different lens, and commitment to the hypothesis. Dr. Marshall was so committed to his hypothesis that he cultured a whole bunch of H. pylori organisms, orally consumed them, and came down with the infection. In effect, he actually gave himself radiologically-identifiable peptic ulcer disease. That surely is commitment to the hypothesis. It reminds me of the Goldbergers’s research, when they injected and ingested the blood and skin scrapings of individuals with pellagra to show that it was not infectious. In Dr. Marshall’s case, it was infectious, so that was more problematic. That is such an interesting part of the history of medicine. It raises the question about opportunistic organisms in the GI tract and their relationship to broad-ranging implications, not just GI disease, but other disorders, as well. That takes us back to a discussion we have had previously in FMU having to do with a toxic diet. What happens if one induces an unfriendly dysbiotic bacterium or parasite to grow in the gut that produces secondary metabolites or some alteration of immune function that could be construed as a toxic response? It is not just the direct effect of the diet; it may also be an indirect effect through the alteration of the GI flora and how that can influence function. Revisiting the Work of Dr. Andrew Wakefield We discussed one of the most profound implications of this situation that has neurotoxicity implications, coming from the work of Dr. Andrew J. Wakefield. He has received such incredible notoriety for his observation, and controversy, as well. Dr. Wakefield, a pediatric gastroenterologist at a well-established medical school in London, along with his colleagues, published what is now considered one of the most classic and a highly controversial papers in the literature. It was so controversial that a board, a censure committee, was assembled to study its veracity, as well as the research and literature that went into it. There were editorials in the Lancet that went on for several issues, talking about the study outcome, with responses from Dr. Wakefield. It has been quite a story. The paper was titled “Ileal-lymphoid-nodular hyperplasia, non-specific colitis and pervasive development disorder in children.”14 That was followed up with another paper that appeared in the American Journal of Gastroenterology, titled “Enterocolitis in children with developmental disorder.”15 Dr. Wakefield observed that the ileal-lymphoid-nodular hyperplasia seen in children during a GI exam was uniquely correlated with high prevalence of autistic spectrum disorder (ASD) in children—a kind of cross diagnostic criteria. The more he studied it, the more he thought there was something to it. He attributed some of it to early-stage immunization with measles, mumps, and rubella vaccination (MMR), the relationship it had to altered immune system function through the GI mucosal immune system, and how that could have an effect on brain biochemistry through upregulation of certain components of the immune system, causing brain glial cell immune system dysfunction called autistic spectrum disorder. This has created a huge controversy, because some individuals in the public health arena thought Dr. Wakefield was attacking immunization, that it would cause prevalence of measles, mumps, and rubella as a result of parental fear, and that there was no strong evidence in the literature that this was true. That was one of those great moments in scientific discovery, not unlike the work of Barry Marshall. Recently, Dr. Wakefield published another very interesting paper in the European Journal of Gastroenterology and Hepatology following up on the same theme, titled “The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder.”16 In this paper, he and his colleagues looked at the prevalence of non-specific ileo-colonic lymphoid nodular hyperplasia (LNH) and found that it was significantly geater in the ileum and colon of ASD children, compared with controls (whether or not controls had co-existent colonic inflammation). Once again, the authors conclude from this more extensive study that ileal colonic LNH is a characteristic pathologic finding in children with ASD and GI symptoms, and is associated with mucosal inflammation. Differences in age at colonoscopy and diet do not account for these changes. The data support the hypothesis that LNH is a significant pathological finding in ASD children. They did, however, find some very interesting features about the diet of children who were on gluten and casein exclusion (grain and dairy product exclusion), who had behavioral improvements that were reported after putting them on exclusion diet. They state: “The rationale for diet includes the removal of precursors for exorphins with their potential for neurotoxicity. (This would be like casomorphin or glutomorphins.) In addition, the potential for an effect of these diets on the associated intestinal lesion merits consideration, given the immunogenic potential for gluten and casein in the gastrointestinal mucosa.”16 Many times, children with ASD-like symptoms, when placed on a diet that eliminates gluten and casein, appear to have improved function. That raises the question, are there toxicities in the diet that are unique to the individual, based on each person’s immunological vigilance system? Recall that more than 50 percent of the immune system is clustered around the gut. Perhaps it has something to do with the communication between food and the gut mucosal immune system. This is a fascinating additional chapter to our discussion of what constitutes a “toxic” diet, and how we would “detoxify” a patient who may have immunological responses that have adverse effects on immune system function which, in this case, may weave their way not only through hepatocellular changes and systemic immune system changes, but also central nervous system immune changes, through glial cell activities. In the editorial that follows Dr. Wakefield’s paper, titled “The intestinal lesion of autistic spectrum disorder,” Dr. Jeremy Jass reviews the significance of lymphoid nodular hyperplasia in the intestinal tract of children with ASD. He states: “The distinction between physiological and pathological lymphoid hyperplasia of the intestinal tract is of importance in the context of a possible causative link with autism.” What we are really talking about is a functional change in the lymphoid system. These are not pathological changes seen in these children. Functional change of this kind of hyperplasia could result in increased intestinal permeability, causing a “leaky gut,” to use that term euphemistically. “This could result in increased intestinal permeability to peptides of dietary origin which may then lead to disruption of neuroregulatory mechanisms required for normal brain development. Alternatively, there could be a primary defect in the translocation and processing of factors derived from the intestinal lumen. These possibilities deserve further investigation and should not be lost in the fog of the controversy regarding the role of measles/mumps/rubella vaccination in the aetiology of autistic spectrum disorder.”17 My takeaway from all of this, as it has evolved, is that if a child has ASD, clinicians would be well served to at least look at gluten and casein elimination diets to see if symptoms might improve; to look at GI function and health; and to recognize that things like pro- and pre-biotics may be helpful in inducing proper immune function in the gut. Two Case Reports of the Use of Probiotics in the Treatment of IBD A recent paper by Drs. Steven Faber, Scott Rigden, and Dr. Dan Lukaczer at the Functional Medicine Research Center, reported improved effects on GI function in individuals with irritable bowel syndrome with theuse of pre- and probiotics.” This paper appeared in Alternative Therapies.18 As we weave all of this together, the term “dietary toxicity” is broader than just that of a poisonous effect. It has an effect on functional physiology through the genomic, proteomic, and metabolomic influence, and a secondary effect through gut flora and its metabolic byproducts that can influence function. I think Dr. Campbell opened our eyes to the important role the diet may play in the myriad chronic, age-related diseases, through the toxic link. Thanks for being with us. We will see you again in January.

Welcome to Functional Medicine Update for January 2004. It is always exciting to start a new year. My colleague Jay Johnson reminded me that we are starting our 22nd year of this audio magazine. A lot has happened over the course of those 22 years. Some of the visions we had when we first started this service to practitioners around the world were then in the realm of fantasy. They have evolved into new opportunities with the evolution of science resulting in improvement of health outcomes, the role of nutrition in those changes, and how lifestyle, environmental modification, and construction of a personalized program for genomic health outcome are defining the course of the new medicine. It is an exciting time. As we reflect on where we were 22 years ago, although everything we said was not exactly correct from a 2004 perspective, certainly the direction we established appeared to be very much “on target.” 11th International Symposium on Functional Medicine We are preparing for the 11th International Symposium on Functional Medicine, to be held May 11-15, 2004 at the Westin Bayshore Resort, next to Stanley Park, in Vancouver, British Columbia. We believe this will be another step forward in the evolution of our model and the way functional medicine is seen. The focus of the 2004 symposium will be on the rising pandemic of diabetes and its cost to the healthcare system and the individual. In this particular issue of FMU, in preparation for that symposium, we will focus on an area that does not appear to be directly related to diabetes. I hope by the end of this issue, you conclude that insulin resistance, hyperinsulinemia, and metabolic syndrome and their relationship to diabetes are, indeed, connected to malignancy and cancer. We will move from the discussion of diabetes to broader areas. This month we will focus specifically on preparing ourselves for the insulin connection to malignancy. The Insulin Connection to Malignancy Many people still feel that cancer results as a consequence of being born with cancer genes, that if we have the BRCA1 and the BRCA2 genes and other inherited factors, we are going to get cancer. This is based on the deterministic model, the Mendelian concept that we are locked in and controlled by our genes, with little plasticity. That model is rapidly changing, and we have talked a lot about how genes are expressed in different ways in different environments. There is no area in which that is more true than in cancer, where it has been recognized that the combination of heritable and environmental factors weave together to give rise to the phenotype of cancer. That topic was discussed in a study you may be familiar with, which appeared in the July 13, 2000 issue of The New England Journal of Medicine. Titled “Environmental and Heritable Factors in the Causation of Cancer,”[1] this study was done in Sweden, Denmark, and Finland in collaboration with the Karolinska Institute. Investigators examined 44,788 pairs of identical twins and, as they grew up, asked what the relative concordance of cancer incidence was in the twin siblings. The assumption was that if cancer was principally genetically related, or heritable, there would be a strong concordance between twins. Environmental Link to Cancer The results were remarkable. With the exception of a few types of cancer where heritable factors were strong (colorectal, prostate, breast), the researchers found that no more than 10 to 15 percent of risk for sporadic cancers could be identified as being strictly hard-wired into the genes. The other 85 to 90 percent was related to what washed over the genes—the environment, the experience. The results reveal there is much room for modifiability of the cancer phenotype and preventing the genotype from becoming the cancer phenotype. This is an optimistic view. One may wonder what happens in the case of those individuals who already have cancer. Can changing the environment have any beneficial outcome? We know that is true on some level, because therapeutic intervention—surgery, radiotherapy, or chemotherapy—is a change in the environment, in some cases a dramatic change, designed to alter the course of the expression of the cancer. Changing the Course of Cancer The real question is whether a more moderate, less invasive environmental change can affect the cancer process. This type of change would have to do with diet, lifestyle, and environmental factors in the adjunctive or perhaps even primary treatment of cancer. That is a much more controversial area than cancer prevention. It would be presumptuous to say we have all the answers. By the end of this month’s FMUtape, however, you will have some of the answers to that question. We will make some progress in laying the groundwork regarding the direction of this field and what some of the opportunities are for assisting patients down the path of recovery from cancer using adjunctive nutrition, lifestyle, and environmental interventions. We are talking about gene/environment interaction in the etiology of cancer. What does it mean, and how can we measure it? That was the topic of a commentary that appeared in the journal Carcinogenesis.[2] The author of this paper reviewed data on various genotypes that may have higher susceptibility to cancer and asked if one could define, using genotypic or SNPs evaluation, those individuals who might have a higher sensitivity to their environment or their diet relative to certain incidence of cancer. Of course, the factor that is most obvious is tobacco smoking. Doll and Peto conducted a landmark epidemiological investigation on smoking and lung cancer incidence.[3] According to these investigators, if all associations between a condition and a disease were as clear as the link between smoking and lung cancer, the field of epidemiology and its relationship to medical therapy would be much less ambiguous. The relative correlation coefficient is so strong that it almost obviates the necessity for high-powered statistics. Smoking, Lung Cancer, and Genotype We know, however, that certain genotypes are more likely to get lung cancer from smoking than others. Even in those cases, there is environmental modifiability. Dr. Mary Claire King, one of the discoverers of BRCA1, published an article in Science magazine this year discussing breast cancer and the BRCA1 and BRCA2 genes. She explained that even though 80 percent of women with the homozygous recessive BRCA1 mutations end up getting breast cancer 20 percent with the same mutation do not.[4] What is different between the 20 to 30 percent who do not get breast cancer and the 70 to 80 percent who do? Dr. King indicates there are environmental modifiers, even for very significant hard-wired determinants for malignancy. That is the topic of the Carcinogenesisarticle. There are certain genotypes that may give rise to increasing risk to oncogenic hazard. In and of themselves, however, they do not predispose one to a certainty of getting cancer. It is when they are modified in their expression by various environmental factors that the risk increases. Environmental Modifiers and the Course of Cancer We will discuss those environmental modifiers in the course of this issue of FMU. Included among those modifiers are oxidative stress, free radical pathology, and the interactions between carcinogens and DNA. These are primary factors in environment-related carcinogenic injury. Various cell-signaling messages cause cell proliferation and increase DNA turnover and mitogenesis. Increased angiogenic signals cause blood vessel formation and a greater feeding of small islet cells or islands of malignancy. Investigations have discovered ways that diet, lifestyle, and environment influence the progression of cancer, from its initiation all the way to becoming a palpable or diagnosable tumor. Diet has been identified as one of the major determinants for the expression of the genome into the phenome called cancer. In the 1980s, Dr. Bruce Ames discussed this topic in a Science magazine paper titled “Dietary Carcinogens and Anticarcinogens: Oxygen Radicals and Degenerative Diseases.”[5] Dr. Ames, then chairman of the Department of Biochemistry at the University of California/Berkeley, explained that our diets have always contained cancer-producing substances, or carcinogens. They have also been rich in anticarcinogens in their natural, unprocessed form—agents that help defend against the injurious process of carcinogenesis. The implication in this article is that as our diets have changed over the years, they have tended to increase the potential for carcinogenic insult, with reduction of the density of the anticarcinogens as we have removed fiber, vitamins, minerals, and phytochemicals, and made our diets “white.” We have taken out all the colored and textured materials and fed them to our pets in pet food supplements, a practice that has led to healthy and springy pets but resulted in tired and worn-out pet owners. Carcinogens and Anticarcinogens in Food By reducing the number of anticarcinogens and increasing the potential of carcinogenic exposure, Dr. Ames suggested we have tipped the balance into increased oncogenic risk. Our food is not completely benign with regard either to protection against or promotion of cancer. Deep-fat frying of fat-rich foods, for example, can result in metabolites or breakdown products—oxidation products of fatty acids that may be carcinogenic. Char broiling meat may produce pyrrolizidine alkaloid materials that are potential carcinogens from the charring activity on the meat protein. Many things we do to our foods and many things that are already in our foods could be viewed as potential carcinogens. Removing that carcinogenic potential and getting higher density of anticarcinogens in our diet, which means consuming a diet of color, texture, and variety, appears to be associated with the prevention of cancer. Changing Diet, Changing Risk An article in the Journal of Nutrition looked at the nutritional changes in our overall public health and public nutrition system and their association with the increased prevalence of certain diseases. By modifying the diet—increasing consumption of whole grains, fresh fruits, vegetables, fiber-rich foods, and nutrient-dense foods, and getting more phytonutrients—we might, according to this article, turn back some of the increasing incidence of specific, age-related cancers.[6] That is easier said than done, because we are seduced by marketing to consume foods that bring high profit to the producer but low nutrient value to the consumer. These highly marketed foods are shelf-stable, sweet or salty. As a result, they now represent the mainstay of the diet of the youth of our country. We can see the resulting changes in disease prevalence. Returning to a diet that contains more fresh produce and whole foods sounds wonderful in theory, but in reality it is complicated. It will require a different social consciousness than that with which we have been living since the emergence of “Space Food Sticks” some 50 years ago. We have packaged foods from preprocessed information and added chemicals with the assumption that if they were good enough for the astronauts, they are good enough for us. That mentality, established in the 1950s, continues to influence the way we think about our diets today. We have to overcome a cultural bias and turn back to foods associated with a lower incidence of cancer. One of the first things we have to do to bring about this change is to alter the way nutrition science is integrated into healthcare education and the way it relates to interventions for both the prevention and treatment of cancer. Dr. John Milner addressed this topic in a recent paper in the Journal of Nutrition.[7] Dr. Milner is in the Nutritional Science Research Group, Division of Cancer Prevention, at the National Cancer Institute. He has been an eloquent spokesman for the need to introduce better education about nutrition for health providers. According to Dr. Milner: “Increasing evidence points to numerous dietary components that modify cancer incidence as well as the biological behavior of tumors.” These inhibitory or stimulatory effects depend not only on the dietary component examined, but on a number of factors, including the cellular DNA profile, which leads us into the concept of nutrigenomics and how specific genotypes may be more responsive to specific nutrients than others. Misleading Research “Unfortunately,” Dr. Milner continues, “the diet and cancer research domain is strewn with studies that were inadequately designed to monitor biological endpoints, used invalid biomarkers, or monitored irrelevant intakes or exposures.” In other words, a lot of misinformation is floating around today. In many cases, no cohort analysis was done; studies didn’t stratify individuals with higher sensitivities to certain things. We have made general conclusions based on averages. Eventually, you can boil all data down to the mean so you know everything about someone who does not exist. This is the statistically average person who is not representative of any real person. Nutrigenomics We are beginning to look in much more detail at individual diets or dietary components and they way they influence specific genotypes in terms of nutrigenomic or nutrition expression patterns. We need to integrate this genomic concept into the education of healthcare providers so they can begin to look at patients as unique individuals rather than using the rule of averages. As Dr. Milner goes on to point out: “We must effectively communicate, within a responsible bioethical framework, the potential value of knowledge about genes and gene products.” That is still a big challenge for the educational system of healthcare providers. Practitioners who came up through the education system over the last 30 or 40 years received little or no nutrition education. This is an area in which naturopathic medical education is in a leadership position. A foundation of its education is the role of nutrients, diet, lifestyle, and the environment in modulating function through a variety of different disease states. We can learn a lot from the curriculum of the naturopathic medical education system. With regard to the specifics of the type of diet we might transition to, I am reminded of a paper published in the Journal of Nutrition co-authored by our own Dr. Robert Lerman from the Institute for Functional Medicine. Another author of this paper, titled “The Macrobiotic Diet in Cancer,”was Dr. Lawrence Kushi, son of Michio Kushi.[8] In this paper they looked at the relative effects of macrobiotics as a dietary principle for modulating cancer incidence. The authors state: “Macrobiotics is one of the most popular alternatives or complementary comprehensive lifestyle approaches to cancer. The centerpiece of macrobiotics is a predominantly vegetarian, whole-foods diet that has gained popularity because of remarkable case reports of individuals who attributed recoveries from cancers with poor prognoses to macrobiotics and the substantial evidence that the many dietary factors recommended by macrobiotics are associated with decreased cancer risk. Women consuming macrobiotic diets have modestly lower circulating estrogen levels, suggesting a lower risk of breast cancer.” Diet and Gene Expression in Cancer We recognize similarly altered hormone levels in men using the macrobiotic diet as their principal focus, and lowered incidence of prostate cancer. At present, this information is built principally on empirical evaluative studies. It can, however, be tied to fundamental principles of science that are now evolving to explain how specific dietary components, macro- and micronutrients as well as phytonutrients, influence gene expression and the phenotype of the individual to prevent the initiation, propagation, angiogenesis, and metastasis of cancer. It opens the door for us to understand both the prevention and possible therapeutic value of specific types of diets built around constructs like the macrobiotic diet. One of the components of whole-food diets rich in unrefined fruits, vegetables, and whole grains is a higher content of other phytochemicals. One of those phytonutrients is the family of phytosterols, plant cholesterol-like molecules that do not have cholesterol activity. They are not precursors to hormones as is animal cholesterol. Examples of these phytosterols are b-sitosterol, campesterol, and stigmasterol, found in foods such as soybeans and many other whole-vegetable products. The phytosterols not only help lower plasma cholesterol when they are consumed in higher quantities in the diet, but recently they have also been suggested as having a role in lowering the incidence of cancer, possibly through their effects on immune function, cholesterol synthesis, and cell growth.[9] Phytosterol Consumption and Cancer Intervention trials have compared diets containing several hundred milligrams of purified phytosterols against placebo in men with benign prostatic hyperplasia. These trials showed a significant reduction in BPH in the men consuming the phytosterols. This research shows, basically, a positive impact on function of the prostate in men consuming higher levels of these phytosterols. Similarly, it appears that phytosterols may have favorable effects on reducing the risk of breast cancer. Phytosterols also appear to have a favorable effect on reducing the risk of colon cancer. We are starting to see it is not only the ratio and type of protein, carbohydrate, and fat in the diet that is important, but also the additional substances found in the unrefined diet called phytochemicals, or phytonutrients like plant sterols. We also know the importance of the type of dietary fat consumed. This is an emerging theme. The omega 3 fatty acids appear to be “anticarcinogenic” to some extent, compared to omega 6 or the highly saturated fatty acids. This topic was discussed in a paper in Nutrition Research.[10] I was one of the authors of this paper, along with Dr. Ewan Cameron, who was at that time medical director for the Linus Pauling Institute of Science &amp; Medicine, and Dr. Richard Marcuson, the biostatistician at the Pauling Institute. In this study, we examined the effect of various oils on mammary cancer in C3H mice, which are bred to get spontaneous breast cancer. We accelerated the cancer process in this strain of animals by exposing them to dimethylbenzanthracene (DMBA), a known carcinogen. We put them on a controlled mouse-chow diet, one that was enriched in the same levels of different fatty acids, either safflower oil, corn oil, fish oil, linseed oil, or lard. We looked at saturated fat, monounsaturated fat, linoleic acid-rich oils, omega 3 a -linolenic acid, and also omega 3 eicosapentaenoic acid (EPA). Mouse Study Results The scope of the study was fairly large. We studied 300+ mice divided into six groups. One group did not receive carcinogens at all, and all of the animals were coded. The veterinarian at the Pauling Institute evaluated the animals throughout the 40 to 50 weeks of the study. The study was ended early when 80 percent of the animals in two groups had extensive tumors, whereas in two groups few animals showed tumors. It did not require much statistical analysis to see that something remarkable had occurred. The assumption was initially made that one of those two groups must be the placebo group of animals that did not receive the carcinogen and was on the mouse-chow diet. When the code was broken, however, we found that assumption was false. The group showing the fewest tumors was the linseed oil group, and very close in results was the fish oil group, rich in EPA, the omega 3-enriched oils. The oil consumption seemed to have a remarkable effect on the progression of breast cancer in this animal model. We concluded there is something about fatty acid composition of the diet, as well as fat amount that affects the potential for progression of a cancer, in this case a form of breast cancer. That study was published in 1989. Since then, many other studies have been published, and human epidemiological work has been done. It appears there is certainly some relationship between dietary fat type and incidence of breast cancer. Oxidation of Omega 3 Fatty Acids I want to add a caveat. Omega 3 fatty acids are highly unsaturated and thus very susceptible to oxidation. The breakdown products of oxidized omega 3 fatty acids are acids and aldehydes which, in their own right, can be potential carcinogens. When I talk about the health benefits of omega 3 fatty acids, the assumption is that they are fresh (not deep-fat fried or subjected to high-temperature or prolonged oxygen exposure.) Flax, for example, is very sweet for the first hour or so after it is ground. If it sits around for half a day, though, it gets bitter. That is a consequence of the spontaneous production of lipid peroxides present in the highly oxidizable a -linolenic acid. It can easily undergo rancidification. Omega 3 oils need to be protected against oxidation. Studies of diets rich in non-oxidized omega 3 fatty acids appear to show a dramatic ability to help modify the risk and progression of tumors. The vitamin and mineral component of diets might also influence oncogenesis. Folate is an example. We have followed the folate story in FMU for nearly 15 years. We are beginning to recognize that single nucleotide polymorphisms (SNPs) are related to altered folate metabolism. We have frequently talked about the methylenetetrahydrofolate reductase, or MTHFR 677C® T polymorphism that is seen in about 20+ percent of the population. The homozygous recessive, so-called TT subtype, is found in about 10 percent of the population. Individuals with that polymorphism seem to have difficulty with folate metabolism and conversion to 5-methyltetrahydrofolate, the active methyl transfer form of folate that helps convert homocysteine ultimately into S-adenosylmethionine (SAM). In cases of MTHFR polymorphism, the requirements for proper management of folate chemistry are higher, and lower levels of folate intake can lead to methylation problems that can affect cancer risk. This is an interesting, emerging story. A number of papers, extending back to the 1960s, show that folate-deprived diets in animals made them much more susceptible to carcinogens. We are beginning to recognize that one of the detoxification processes of the body is driven by methylation, and that methyl groups come through the SAM/homocysteine pathway that uses 5-methyltetrahydrofolate. Contributors to Folate Insufficiency The authors of a recent paper in the Journal of Nutrition describe the MTHFR 677C® T polymorphism as increasing the relative risk of folate-related problems. They state that alcohol intake above one drink a day on top of an MTHFR 677C® T polymorphism is associated with folate insufficiency.[11] When we think about stress, dietary problems, genetic polymorphisms, and carcinogen exposure, we see how diet, environment, and genes are linked in their effects on the incidence of initiation of a tumor. The role of folate in colon cancer development has been studied extensively. One study points out that even though dietary folate intake and folate levels are inversely associated with colorectal cancer risk, caution is important because there is evidence in animal models that excessive folate(supraphysiological levels) may promote the progression of established neoplasms.[12] Folate chemistry is interrelated with microscopic neoplastic changes in cells in the colonic mucosa and substances that are always present in the contents of the colon. Among those contents are potential carcinogens; bacteria have fermented or metabolized specific constituents and produced secondary metabolites like nitrosamines, nitrous compounds, or oxidized sterols that may be in situ carcinogens. The folate story becomes important for maintenance of proper mucosal architecture and mucosal defense systems. Again, MTHFR polymorphisms, folate insufficiency, and other factors are emerging from the folate/cancer connection. Phytonutrients called polyphenols help lower the inflammatory response and lessen its potential role in both angiogenesis and metastatic events. A variety of substances have beneficial effects. They include isoflavones found in soy; polyphenols in various fruits and vegetables; and resveratrol (cinnamic acid polyphenol derivative that also participates in some of these processes), found in grapes and grape skins. Polyphenols that are catechin-like or ellagic acid-like serve as profound modulators of certain processes related to inflammation and to potential metastasis. A complex diet rich in color—blue, green, and orange—has some benefit. The effect is not derived from just one nutrient at a time. I am referring to an article in the Journal of Nutrition.[14] As we lower the expression of inflammation by downregulating the inflammatory enzymes like cyclooxygenase, we lower the relative risk of metastasis and angiogenesis, particularly in epithelial and mucosal tissue. Epidemiological studies have associated consumption of green tea, which is high in EGCG, with lowered cancer incidence. EGCG has been demonstrated to be a down-regulator of certain types of inflammatory function in the gut. Information is emerging to describe the mechanism of EGCG and its potential influence on the cancer process.[15] Drinking a couple of cups of green tea per day appears to be an effective way of increasing total phytonutrient exposure and, possibly, to modulate, regulate, or affect physiological processes in an effort to prevent cancer or possibly provide adjunctive cancer treatment. Other cancer-preventive foods are the cruciferous vegetables—broccoli, cauliflower, Brussels sprouts, and cabbage. These vegetables, which have a unique odor when cooked, contain sulfur- and nitrogen-based phytochemicals called glucosinolates. Digestive enzymes break down glucosinolates. An enzyme called myrosinase, which is present in the cells of the plants, also aids in this breakdown process when the crucifers are chewed. Myrosinase breaks down glucosinolates and liberates a secondary set of chemicals into the body, such as indole-3-carbinol (I3C) and phenylisothiocyanate, into hydroxy-3-butene and sulforaphane. These substances affect gene expression in specific ways to upregulate the expression of various cytochrome P450s or phase II detoxification enzymes like quinone reductase or glutathione S-transferase. Certain vegetable products may have unique abilities to improve detoxification of chemicals and help regulate specific cell functions. A recent study of MCF7 in human breast cancer cells found that I3C, one of the glucosinolate metabolites from cruciferous vegetables, could arrest the cycle of proliferation of the breast cancer cells in culture.[16] This study suggests I3C not only has a detoxification effect, but also a cell cycling effect, causing a slowdown of the rapid proliferation rate of the cells. This has also been shown in human prostate cancer cells, showing G1 cell cycle arrest and increased apoptosis of transformed prostate cells when exposed to I3C.[17] An array of glucosinolate-rich foods may participate in regulating cell cycling and downregulating the message of oncogenesis. That also holds true for the cress family of vegetables—garden cress, winter cress, summer cress, and watercress. All of these cresses have glucosinolates that help prevent preneoplastic lesions and genotoxic effects. For example, beneficial compounds in garden cress were discussed in an article in Carcinogenesis.[18] Limonene-Induced Regression of Mammary Carcinomas Limonene, a monoterpene derived from citrus, alters prenylation and farnesylation of various substances having to do with cell cycling, cell regulation, and cell turnover. Farnesylation and prenylation are biochemical modifications of proteins and other molecules that occur in the body. These processes are part of manysignaling pathways and are a way the body uses to change how aprotein functions. When given at higher doses to animals, limonene promotes regression of mammary carcinomas. In fact, some early investigative work in human intervention trials has been done at the National Cancer Institute using limonene in supplemental doses to see if it can have a positive effect on regressing malignancy. One paper that discusses the limonene-induced regression of mammary carcinomas appeared in Cancer Research.[19] This paper explains how monoterpenes block farnesylation and isoprenylation and have an impact on cell cycling and gene expression. It discusses some of the epigenetic effects that relate to the oncogenic process and metastasis. We are talking about the way diet and lifestyle communicate with the genes. Food is information. Our lifestyle contains information from which our genes receive a message that creates the phenotype. Cancer is not inevitable. It is modifiable through the information you send to your genes. The genes will respond in their expression patterns to the messages to which they are exposed by forming alarm or cell-proliferative messages. Cancer may be a disease of disordered energy that appears in a society that is too time-urgent and overwhelmed with energy processing. That energy flows through our bodies, resulting in undirected, uncontrolled, non-differentiated clonal effects. Diseases reflect societal processes of uncontrollable energy. A good diet may help quiet, direct, and keep coherent the information and energy that travel through our bodies and regulate cell function and differentiation. This is a metaphorical discussion of evolving molecular biology and molecular oncology. It goes together with the epidemiological conclusion that the best diet is one that is less processed, richer in color, and higher in specific phytochemicals, vitamins, and minerals. Cultures that have consumed such diets historically have had lower incidence of certain types of cancers, particularly those commonly seen in the Western world, which are cancers of the immune and endocrine systems. We are sending ourselves many signals of proliferation, and we need to quiet them down and get them to rest. In mid-life we should be a state of cells at rest, regenerating daughter cells to be consistent with parent cells and staying in check throughout the course of a long mid-life for 50 years or more. That message comes through in this research. On side 2, we will see how a clinician/researcher views this picture and translates esoteric, fundamental information into clinical management programs.

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INTERVIEW TRANSCRIPT

Clinician of the Month D. Barry Boyd, MD, MS Integrative Oncology, LLC 239 Glenville Road Greenwich, CT 06831 JB: It is time for our Clinician of the Month. This month we are privileged to have an individual with a tremendous background in the management of cancer oncogenesis. He will explain how that subject can be approached from different perspectives and where this field is headed. We are fortunate to have someone with a broad base of understanding and the ability to examine these issues from different perspectives. Dr. D. Barry Boyd has been a speaker at cancer conferences sponsored by Dr. James Gordon and is himself an esteemed oncologist. Dr. Boyd has a master’s degree in nutritional biochemistry from Columbia University, and he received his MD at Cornell University. He has been an adjunct clinical professor of medicine, working in oncology and hematology at Yale University School of Medicine in Connecticut. In his private practice he has achieved a balance between the traditional way he was taught and the integration of his skills and training into a broader-based practice. That does not often occur in today’s world of medicine. Dr. Boyd, it is a privilege to welcome you to Functional Medicine Update. BB: Thank you, Jeffrey. I appreciate your offering me the opportunity. It’s wonderful work you are doing, as well. The Transition from Traditional to Functional Medicine JB: How did you make the intellectual transition from the way you were trained into looking at other alternatives as you moved through your career? BB: My original training was in medical nutrition at Columbia’s Institute of Nutrition. Then I went on to medical school, studied oncology, and went into the practice of medical oncology. Shortly into my practice, it was my patients who caused me to change. They didn’t drag me kicking and screaming, but they got me more and more involved in appreciating the growing evidence base in nutrition and cancer. I had four years of nutrition in graduate school and one hour of nutrition in medical school. I always tell my patients that they spend about 30 percent of their waking day either thinking about, shopping for, preparing, cooking, or eating food. Yet physicians know virtually nothing about nutrition. My patients brought me back to this, and I’ve developed a growing expertise because of my biochemistry background in nutrition and cancer. The surprising thing is the enormous amount of information that is out there. Unfortunately, many patients don’t know where to get this information. The field of nutrition is very broad, and it’s difficult to sort it out. This got me interested. As a result, because nutrition is often characterized as alternative medicine, I developed more and more expertise in other areas of complementary medicine. I am now much more involved in that. I also run the Integrative Medicine Program at Greenwich Hospital. Integrative Medicine Program at Greenwich Hospital JB: We are obviously talking to the right person. You probably understand both the positives and negatives, and what are reasonable and realistic expectations. Would you tell us something about the program at Greenwich Hospital? How does it work? How does a patient gain access to your program and what kinds of things can they expect? BB: We did a series of surveys of other integrative medicine programs. We looked at common programs like the one at Beth Israel Hospital. A lot of the bigger centers run such programs. We briefly entertained the idea of joining with the Mind Body Institute at Harvard, but when we essentially became a hospital of Yale, we realized that the Harvard/Yale Mind Body Institute wouldn’t work. It works in football games, but we didn’t think the collaboration would work. What we did when I outlined this program was to develop it around disciplines. Even though we are medical oncologists and nutritionists, the real approach was to look at every discipline and then form integrative approaches within each area. For instance, in medical oncology we developed a massage program on the oncology floor. We moved on to treat patients’ family members with massage because of the role of stress in the caregivers. We moved massage therapy into the OB and certainly into the neonatal side. Each time we introduced a modality into a different specialty, it was concurrent with research, so we tried to do little pilot studies that would bring physicians on board. When we started, we had a committee of two physicians and three staff members. By the time we were established, we had about 50 members of the medical attending staff, which is a large number of people who are interested but were afraid to admit it. It’s been very successful because we approached it from a discipline standpoint rather than what I call the “potpourri” approach, which is to open up a free-standing center and offer acupuncture, massage therapy, homeopathy, and naturopathy. This way, we convince the physicians that these modalities work, that they are important, and that they can be integrated. What I call integrative medicine is truly integrating it into the body of care within the hospital. Third-Party Reimbursement JB: That is exciting. Have your patients had success getting third-party reimbursement for some of the services? BB: As you know, that’s difficult. Oxford is a participant because we’re one of the areas in which there’s a significant inroad with them. They have a complementary medicine program. We have certified acupuncturists. In addition, we have a significant amount of funding to help provide care for patients who don’t have the ability to remunerate. With massage therapy, we initially had funding for a one-month study, and within two weeks, that was funded in perpetuity. We have a full-time massage therapist, and it’s free to patients. We also have small funded programs in preoperative relaxation for elective surgical patients. They provide a small stipend and the nurses are trained to do this. You can use funding; there are areas where some of the managed care companies will pay. The goal of the research, though, is to provide evidence that it’s good quality medicine and they should pay it. Growing Interest in Complementary/Alternative Medicine JB: That is very forward-looking. I had the privilege of speaking at the Dana Farber Cancer Institute last year as part of one of their Lenny Lecture Series. Dana Farber has a complementary/alternative medical unit sponsored by the Lenny Program. I was impressed by the number of doctors from the entire New England Medical Center complex who were interested. When I gave my lecture, around 150 staff physicians from different departments were in attendance. It indicates to me that interest is growing. BB: The future is very bright because the residents in training are fascinated. Many of them are interested in this. It’s very different from the skepticism among people who were trained 10, 15, 20 years ago or longer. Those earlier-trained practitioners are more ingrained and view this as quackery. We need to show them there’s a huge world out there of other things that we avoid. Clearly, nutrition is the heart of this, and that’s what patients want to know about. Nutrition in Prevention and Therapy JB: That leads me to the question that was raised when I was at Dana Farber. Do we see nutrition more in a preventive mode, or do we see it also as applying to an adjunctive therapy mode affecting the way a patient who has cancer is treated? BB: In my early work, as I would lecture patients, I would devote a lot of time to cancer prevention and nutrition. There was a lot of work early on about macro- and micronutrients and prevention. With low-fat diets and breast cancer, an enormous body of epidemiological work up until the Nurses’ Health Study suggested that relative fat intake had very little to do with breast cancer. The same thing applied to fiber, and you know about beta-carotene and the whole issue with lung cancer and how that turned out to be a pro- rather than an anti-carcinogenic intervention in heavy smokers. The fascinating question to me is, can you bridge the gap between prevention and treatment? I explored the relationship between the insulin IGF system and cancer, which has clearly exploded in the last year with the research, particularly with the American Cancer Society study. The biology of cancer strongly suggests there is both a preventive and a therapeutic role for the relationship between insulin and IGF-1 growth factor stimulation in both the development of cancer and in its impact on prognosis and therapy. This has been the heart for me. I see this insulin connection and the IGF system as a target that has an impact both on cancer etiology and how you do when you get cancer. Nutrition and the Stages of Cancer JB: Do you believe nutrition plays a role in each of the stages of cancer? If we think of the stages as initiation, propagation, angiogenesis, and metastasis, do you think nutrition is related to each those steps? BB: Clearly, it is; in some cases it has a different role and in some cases the relationship is overlapping. Let me explain. The initiation phase of malignancy, of course, is the initial mutagenic, genotoxic event that damages the DNA. Obviously, that initiation event can be a predetermined, inherited defect, or it can be something based on exposure. From the standpoint of nutrition, one of the most interesting areas is the post-initiation event, which is really tumor promotion. That reflects anything that enhances cell proliferation. Clearly, there’s a role between, for instance, red meat and colon cancer. One thing we know is that the way you cook the meat may lead to high levels of aromatic hydrocarbons that are pro-carcinogenic. That’s one setting in which nutrition is important because the nature of food preparation can increase carcinogenic exposure. In addition to that, of course, is contamination—the presence of carcinogens within foods as part of the initiation event. Nitrosamines and Vitamin C Nutrition plays a role in the third part of initiation. Gastric cancer was very common at the turn of the last century. First of all, there was no refrigeration so people ate smoked and pickled foods. As a result, high nitrite exposures led to increased nitrosamines in the GI tract. A concurrent thing that suppresses nitrosamine production in the stomach is the presence of high levels of vitamin C. Also, back then you didn’t have fruits and vegetables. Thus you had a “double whammy” of the high levels of carcinogens in foods combined with low levels of vitamin C from fresh fruits and vegetables to suppress that, so the initiation event was much more likely for gastric cancer. Gastric Cancer today Now the whole nature of gastric cancer has changed. It’s probably less likely that it’s nitrosamine related and more likely that it’s related to distal esophageal, obesity-related events, combined with Barrett’s esophagus. We’re seeing an influx or a high incidence now of this other type of gastric cancer. That’s sort of a model for the initiation and the relationship with nutrition. My area is in the role of promotion. What stimulates cell proliferation in terms of the likelihood of evolving from a preneoplastic lesion to a fully neoplastic lesion with the acquisition of additional genetic effects is something that requires ongoing enhancement in cell proliferation. A variety of cell signals are potentially modulated by nutrition. That is also linked to prognosis. Once you have a malignant tumor, if you continue to have high levels of tumor promoters, you will concurrently evolve into having a much more aggressive and rapidly progressive cancer. IFG-1 Insulin and Cancer Promotion JB: That’s a wonderful segue into the discussion of IGF-1 insulin and its relationship to promotion. Clearly, that’s an area in which you have been a leader in creating understanding. Would you tell us more about that? BB: There are some fascinating models about the insulin/cancer connection. One is the growing evidence that we have been very reductionistic in the way we look at diet and nutrition. As you remember, Doll and Peto did two studies. One was a multi-national study, and the other was in the United States looking at lifestyle factors and cancer. Of course, smoking was high on the list. But in general, diet was very high, affecting between 30 and 40 percent of cancers. The range of error was fairly significant, though, as they said. That led to epidemiology. First there was the idea about fat and breast cancer, and colon cancer and the relationship with fiber. As you go back and look carefully, it turns out that those relationships fall apart to some degree. Correlation or Cause? What may be missing is that they’re correlative rather than causative. For instance, we dissect broccoli to look for the indole-3-carbinol to see how it affects estrogen metabolism. It may not be any one constituent; it may be the whole. One of the ways that may be explained is the relationship of diet and obesity to the growing recognition of the metabolic syndrome. As you know, Gerald Reaven was the first to define syndrome X. What I think has culminated our interest in this was the recent American Cancer Society prospective study.[20] They looked at more than 900,000 men and women over 18 years of age and discovered that obesity was markedly related to an increased risk of mortality from almost every cancer, with the exception of lung cancer. Virtually every other cancer was related, including myeloma, Hodgkin’s disease, and lymphoma. The Role of Insulin The intriguing thing is that insulin and insulin receptors are present on virtually every cell and often upregulated on cancer cells. The connection between obesity and cancer has been looked at in a variety of settings, such as in colon cancer, postmenopausal breast cancer, and prostate cancer. If you start to dissect it, there is evidence that insulin and IGF-1, which is often upregulated, are connected to that. Intriguing data are being worked on in a parallel fashion on the concept of caloric restriction and aging. A significant amount of research is now targeting the idea that insulin and IGF-1, particularly insulin receptors, are linked to that effect. By limiting levels of IGF-1 and cell proliferation, calorie restriction may enhance survival and actually reduce the incidence of malignancies as a result. It’s a fascinating and growing body of work. Insulin Signaling and PPARS Activity JB: The concept of cellular signals that stimulate cell proliferation is a big area. You are obviously implicating insulin and some of its related stimulatory factors, like IGF-1. That also implies that nuclear regulatory factors may be influenced in how genes are expressed in some of these cellular proliferative processes. This then suggests things like peroxisome-proliferated activator receptors, or PPARs. I would presume there’s a connection between insulin signaling and PPAR activity. BB: Yes. As you know, the data are growing that indicate it may be part of the modulator of insulin activity. There is evidence that upregulation of PPARg through dietary fashion will limit not only insulin resistance, but also may reduce obesity in animals. A variety of nutritional and dietary interventions will upregulate that. One study recently looked at an ethanol extract of licorice as a way of inducing this.[21] One of the intriguing things in the field of nutrition and so-called integrative medicine is to look at supplements and how they may be beneficial. That’s another area. Cell Signal Factors The other fascinating part where there’s so much overlap of cancer is with some of the cell proliferative signals that are linked to the insulin response element within the cell that is stimulated both by IGF-1 as well as insulin. In this case, they will concurrently activate a series of growth factor pathways. One is mitogen-activated kinase, and the other is phosphoinositol-3 kinase (PI3K). The intriguing thing is that both those pathways lead to an increase in proliferation and a reduction in apoptosis. If you look at high insulin levels, for instance in breast cancer, they are clearly linked to poor outcomes and poor prognosis. There’s evidence that it’s also potentially linked to a higher grade of tumor. If you look at some of the studies, insulin and IGF-1 act through those intermediate pathways affecting cell cycling and proliferation, those same pathways are clearly similarly linked to poor prognosis. In other words, abnormalities in PI3K and mitogen-activated protein (MAP) kinase, these intermediate pathways in cell proliferation, are found to be a poor prognostic factor in breast cancer, much like high insulin is found to be a poor prognostic factor. That may very well be the mechanism by which insulin is working in upregulating this, reducing apoptosis, and cell proliferation. More intriguing is the idea that insulin might not only do that, but may interfere with therapy because many of the pathways involved in killing cancer cells, either chemotherapy or hormonal therapy, may be interfered with if we block apoptosis by ambient high levels of insulin. NSAIDs and Cancer JB: This is fascinating. When you introduce things like MAP kinases, that starts to interrelate with the inflammation pathway because that’s the start of the signal transduction pathway in inflammation. That raises another question. Why do some nonsteroidal antiinflammatory drugs seem to have a lower cancer potential? You’ve introduced insulin signaling with inflammation and antiinflammation, so it sounds like an expanding web. BB: One area in which I am greatly interested, as you can tell, is the concept that the metabolic syndrome with hyperinsulinemia is linked and may be the modulator of obesity and cancer mortality in this relationship. Not only is hyperinsulinemia and its potential effect on IGF-1 a part of this, but, potentially independently, metabolic syndrome is classically a proinflammatory state with high levels of interleukin-6 (IL-6) and C-reactive protein (CRP). Concurrently, in virtually every cancer, independent of stage, the presence of high levels of IL-6 and CRP is a negative prognostic factor. There seems to be this interaction with the inflammatory pathway, both with hyperinsulinemia and potentially on poor outcomes with cancer. It may be that insulin works through the insulin receptor; it may be the metabolic syndrome and the state of inflammation itself plays a role in cancer. The other thing we haven’t touched on is the relationship between stress and emotions and their potential influence on the metabolic state. Stress and the Metabolic State JB: Would you explain for our listeners how the modulation of those hormones could influence this pathway? BB: One thing that intrigued me was the concern about stress and its impact on cancer. Probably the best way to put it is that there are two sides to this. There are people in conventional oncology who feel there is absolutely no relationship between stress and cancer. I think they feel it places too high a burden on patients’ emotional states, in the sense that they’re responsible for their cancer. Second, they don’t understand that there could be a biologically plausible explanation for the effects of stress on cancer. One of the intriguing and long-standing paradigms in the field of integrative medicine is the concept that chronic stress leads to impaired immunity and cancer causation or progression, which has many flaws. The other problem is that people draw away from conventional medicine because they’re afraid it will impair their immune system, and therefore the cancer will grow. Cancer and HIV The first thing I do, and I’ve written a paper on this[22], is to dissect the concept that immune surveillance and your own immune function play a huge role in cancer. Most epithelial cancers are not well regulated by your own immune system. They are essentially hidden, if you will, because of immune tolerance. A good example is the HIV population. Most AIDS patients, despite the fact that they’re profoundly T-cell immune-deficient, get only malignancies that are linked to viral oncogenesis, whether it’s the Papilloma virus or herpes virus related to Kaposi’s sarcoma. Intriguingly, in a large epidemiological study, people with AIDS on an age-adjusted basis, did not get high levels of epithelial cancers. In fact, they were slightly lower than anticipated based on their age. T- cell immunity, despite all of our assumptions, had very little impact on epithelial cancers. I think when you look at a variety of other models for this, you see the same thing where there’s transplantation and immune suppression. They’re mostly linked to Epstein-Barr lymphomas, to Papilloma virus, etc. Chronic Stress and Metabolic Syndrome The intriguing thing to me is that stress may not be working at all through this pathway. An alternative is the fact that chronic stress has been well demonstrated now. There’s a fascinating body of literature on both the hypothalamic/pituitary/adrenal axis effects and sympathetic and parasympathetic enervation of the adipose tissue. There’s now an enormous connection between chronic stress and the development of the metabolic syndrome. Chronic stress can actually lead to that state and its consequent effects on both insulin and inflammatory mediators. It’s a fascinating way that may actually be a better explanation. It is also a way of explaining why stress reduction really does matter. Clinical Applications JB: That is an eloquent description of a very complex pathway. It opens up all sorts of opportunities for clinical application. In the remaining minutes we have, I’d like you to touch on how you take this information that, for the average patient, is probably a little bit more about mechanisms than they want to know, and get it worked into a program that they can actually apply. BB: I do two things. One is, we’re involved in research. One of the fascinating areas, very quickly, is whether chemotherapy actually induces a metabolic syndrome. We know that breast cancer patients gain weight after adjunctive chemotherapy. We know that weight gain after adjunctive therapy may have a negative prognostic effect. I believe that chemotherapy actually enhances the risk of the metabolic syndrome so I target weight gain. I have two nutritionists who work with me, along with several people working in stress reduction, and I have a traditional Chinese medicine program in my own practice. We all target this together. We look at initial anthropomorphic measures. We look at waist-to-hip ratio, which is a good measure of the typical metabolic syndrome associated to adiposity. Mid-abdominal weight gain is more closely linked to the metabolic syndrome. We then follow patients on treatment. We monitor their nutritional status. We obviously target them with a modification of what I call the Mediterranean Diet, which looks at a combination of the Atkins (not high fat), limited carbohydrate, moderate fat, moderate protein, with a greater emphasis on the Mediterranean approach. The Mediterranean Diet We know from the Lyon Heart Study that using the Mediterranean Diet lowered cancer incidence. There are epidemiological and clinical studies indicating a benefit with that, and it causes weight loss. It’s a fascinating way to deal with that. We also measure all the standard things—triglycerides, HDL, fasting insulin levels at the beginning, and then we monitor those. I’ve had several very interesting case reports; one is a patient with pancreatic cancer who is insulin resistant. We treated his insulin resistance with vigorous diet and exercise. We also gave him a variety of supplements, including N3 fatty acids, a -lipoic acid and a couple of other measures to reduce his insulin resistance. We got his insulin levels down and he went into complete remission with chemotherapy with his pancreatic cancer. He went out of remission when his insulin levels went up. We readdressed that and he’s back in remission again. It’s a single case report. We have several other patients like that now who seem to be responding the same way. It suggests the idea that in addition to giving chemo, you need to treat the metabolic state of patients. It may impact how they respond to treatment. Educating Physicians JB: This is extraordinary. I know you’re going to have a greater opportunity at our 11th International Symposium on Functional Medicine coming up in May to talk about this. I believe you’ll also be doing a workshop. It sounds like we’ll need more time with you to fully develop this concept, but it’s certainly very exciting. And it makes sense from the emerging endocrine and cell signaling components of cancer. BB: Exactly. That’s the beauty of it. And what I’m interested in doing is, as you are doing—educating physicians about the fact that there’s a science behind this. If they appreciate the science, then they understand that it’s not just medication and radiation. There’s much more to treating cancer patients. Nutrition Therapy JB: That’s a very optimistic view, and it certainly answered my initial question about prevention versus adjunctive therapy. It sounds to me as though this may emerge as a primary therapy in those patients whose promotion is driven by cell signals related to insulin. BB: Right. The other beautiful thing about it is that I always tell my breast cancer patients who are on adjuvant therapy that they have to remember that many women with adjuvant therapy don’t die of breast cancer. They get a heart attack four, five, ten, or twenty years later. This essentially targets the chronic diseases of the 21st century. Not only may it reduce the risk of second cancers, but it is also clearly beneficial from a vascular disease standpoint. It’s much more holistic, if you will, than just cancer. Obesity and Insulin JB: I don’t want to put you on the spot, but I’d like to get your opinion on one interesting sidebar that you raised for me. If I heard you correctly when you were talking about obesity and insulin, obesity or the visceral adipose deposition (apple body shape/waist-to-hip ratio increases) is an effect of a metabolic transition that occurs having to do with the arrangement of insulin and other signaling molecules. Rather than obesity causing this effect, it’s a covariable that comes as a consequence. Did I hear that correctly, or did I overstate what you said? BB: It’s the chicken-or-egg issue. Is visceral obesity a result or a cause? I think for many people who are doing work in this field, visceral deposition is certainly a marker and a predictor of that. Some people feel that increasing visceral obesity, which is clearly linked to central obesity, causes insulin resistance, partly because those adipose stores may be more rapidly mobilized. There’s a higher level of free fatty acid flux that increases the insulin-resistant state at the cellular level. I think it may be causative, but it’s not 100 percent clear. Diet and Hormone Modulation in Cancer Management JB: Thank you. I guess the bottom line is that if we put a person on a good weight management program and we can modulate these hormones, whether it’s a chicken or an egg, it will improve the patient’s condition. BB: Yes, I think that’s the bottom line. Interestingly, one last mention is that Pi-Sunyer at St. Luke’s at Columbia in New York, who has done a lot of work on this, has described the non-obese insulin-resistant patient who has occult visceral obesity. That’s an area that particularly interests me. We have to be careful not to assume that if you’re not classically overweight with a high body mass index, you’re free and clear. People need to be assessed for that rather than assume that’s okay. And you don’t have to lose 100 percent of your overweight. The Diabetes Prevention Program has demonstrated a reduction of diabetes incidence by a modest weight reduction, along with exercise. But the key is to get started, to get those things done, and that will improve your metabolic state and, hopefully, also impact on your cancer. Thin/Fat Patients JB: I really appreciate your mentioning that. Dr. David Heber at UCLA discussed that topic in regard to women who did not have significantly elevated BMI; I think their BMI was in the 25-26 range. Body composition analysis using bioimpedance, however, revealed they had increased percent body fat, less body muscle, and metabolic syndrome-related problems. This could be what Covert Bailey called the thin/fat person who may be at risk. This has been a fascinating discussion. We look forward to hearing more at the 11th symposium coming up in May in Vancouver, BC. Dr. Boyd left shared a large amount of dense information with us. I am sure you were stimulated by his comments related to signaling, cell proliferation, insulin, insulin-like growth factor-1 (IGF1), and the way they interrelate with metabolic syndrome and abdominal obesity. His comments may open up many doors to information not previously fully understood regarding ways to apply these concepts in the macrobiotic diet and other fundamental diets used for cancer prevention and remediation. Licorice Extract in Ameliorating Diabetes, Abdominal Obesity, and Preventing Hypertension Dr. Boyd mentioned a paper that appeared in the Journal of Nutrition, titled “A Licorice Ethanolic Extract with Peroxisome Proliferator-Activated Receptor-g Ligand-Binding Activity Affects Diabetes in KK-Ay Mice, Abdominal Obesity in Diet-Induced Obese C57BL Mice and Hypertension in Spontaneously Hypertensive Rats.” 21 This animal study ties together everything Dr. Boyd was talking about. I want to quickly review it. Insulin resistance, abdominal obesity, hypertension, and dyslipidemia are closely linked in what we call the metabolic syndrome. They represent the “deadly quartet” of syndrome X. The clustering of these risk factors in what we call the metabolic syndrome not only relates to increasing risk of diabetes, but also to increasing risk of heart disease. As Dr. Boyd has pointed out, these factors are also related to increased incidence and risk of certain types of cancer, such as colonic, breast, and prostate cancer. Nuclear Receptors There is something about adipocyte differentiation and physiology and its interrelationship with insulin and insulin signaling, and the connection to metabolic syndrome that correlates with self-proliferative disorders that are of oncogenic concern. That is an interesting emerging story. Part of it may be related to the gene expression modifiers, the nuclear regulatory factors, those of the so-called the orphan nuclear receptor family, peroxisome-proliferated activated receptors (PPARs). There are the a ,g , and d forms of PPARs, each one of which has a slightly different influence on physiology. PPARg is a predominant molecular target for insulin-sensitizing agents. It was first discovered when the family of thiazolidinedione drugs came on the scene and seemed to be insulin-sensitizing. Now we have found that many nutritional and other agonists are natural substances that modify PPARg activity. It is not just the thiazolidinedione drugs like troglitazone, pioglitazone, or rosiglitazone; it is also natural substances like omega 3 fatty acids, conjugated linoleic acid, DHEA, and other things that have been found to influence the signaling of these orphan nuclear receptors, the PPARs. PPARg may therefore be an important part of the regulation of the whole signaling process we see manifested as metabolic syndrome, abdominal obesity, insulin resistance, hyperinsulinemia, and ultimately influencing cell signaling. Insulin is not just a glucoregulatory hormone; it also influences the expression of protein tyrosine kinases, which then influence cell signaling, cell proliferation, and the oncogenic process, as Dr. Boyd described. Animal Study of Licorice Phytochemicals and Insulin Sensitivity In this particular study, the investigators wanted to look at animals that were already genetically predisposed toward obesity or hypertension. They measured their PPARgactivities and gave them an ethanolic extract of a family of licorice phytochemicals that purportedly modulated insulin sensitivity. The results are quite interesting. The investigators were able to demonstrate that both the spontaneously hypertensive rat and the diet-induced obese mouse, when administered this particular licorice extract, had improvement in their glucose regulation, meaning higher insulin sensitivity. They had altered blood lipid profiles, with less prevalence of dense LDL, meaning purportedly lowered risk to cardiovascular disease, and they had lowered intra-abdominal adipose tissue. The Role of Calorie Restriction This occurred without changing the number of calories in the diet; I want to emphasize that. We seem to think that calories are the prima facie requirement for increasing body fat deposition, but it may be metabolic effects that occur relative to how the calories are processed and where they are disposed of, that also leads to changes in body composition. Things like insulin resistance or PPARg inactivity may, according to this work, also be associated with how these calories travel to the body and where they end up as storage forms in lipid storage adipocytes associated with visceral adipose tissue accumulation. Licorice Extracts in Disease Prevention and Management The investigators suggest these findings indicate that the licorice ethanolic extract is effective in preventing and ameliorating diabetes, ameliorating abdominal obesity, and preventing hypertension in the spontaneously hypertensive animal. They suggest this licorice complex of phytochemicals would be effective in preventing and/or ameliorating metabolic syndrome and its potential effects on oncogenic events, such as Dr. Boyd described earlier. I hope you can see that this is a web as we continue to emerge and amplify this topic. You cannot look at a variable in physiology as a single endpoint. You have to look at its interconnectedness to other functions. The Web of Disease Obesity connected to lipid metabolism connected to insulin signaling connected to cell/gene expression patterns connected to cell proliferation and mitogenic index. These are all part of an emerging view of the way chronic degenerative age-related diseases may be connected together and just differ in their expression based on genetic uniqueness. The signals we send to our genes in our modified environment of the 21st century may be increasing the expression patterns into the phenotype of specific diseases that just happen to be those that we most confront in our medical centers. Those diseases are coronary heart disease, cerebrovascular disease, malignancies, and diabetes, which is now a pandemic. I hope this helps you see why we feel that the 11th International Symposium on Functional Medicine focused on the rising pandemic of diabetes, is a justifiable topic to spend time on with leaders in the field. It is not just diabetes alone; it is also heart disease, dementia, inflammatory conditions, coronary heart disease, and malignancy. We will be exploring those in greater detail as we move forward. Dr. Boyd left us with some interesting insights. You can see how environment plays a role in the modification of disease. We will talk again in February.  

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Welcome to Functional Medicine Update for February 2004. In this issue, we will focus on a topic that will be covered at our upcoming 11th International Symposium on Functional Medicine in May—“The Coming Storm: Reversing the Rising Pandemic of Diabetes & Metabolic Syndrome .” We will extend the discussion beyond diabetes to insulin resistance and hyperinsulinemia. This month we will discuss estrogen hormones, natural management of estrogen imbalances, and interrelationships with the insulin signaling pathway, the peroxisome-proliferated activated receptors (PPARs), and some of their effects on the metabolism of progesterone, estrogen, and testosterone. Pharmacogenomic Uniqueness A recent paper illustrates the controversy brewing in the world regarding the best way to intervene with patients with complex, chronic age-related diseases. This article describes a presentation made by a senior researcher, a vice president at GlaxoSmithKline (GSK), who talks about the efficacy of pharmaceutical drugs for the management of chronic health conditions.[1] I believe everyone at the conference was surprised to hear this speaker state that most prescription medications do not work on most people who take them. Dr. Allen Roses, worldwide vice president of genetics at GSK, said, “Fewer than half of the patients prescribed some of the most expensive drugs actually derived any benefit from them.” This is the first time that a mechanism has actually been ascribed to explain why this is the case, and it ties back to the area of pharmacogenomics—the unique differences from person to person and how they respond and metabolize specific substances. Dr. Roses was an academic geneticist at Duke University Medical School for many years before he joined GSK as a vice president. He further stated: “Drugs for Alzheimer’s disease work in fewer than one in three patients, whereas those for cancer are only effective in a quarter of patients. Drugs for migraines, for osteoporosis, and arthritis work in about half the patients. Most drugs work in fewer than one in two patients, mainly because the recipients carry genes that interfere in some way with the medicine. The vast majority of drugs—more than 90 percent—only work in 30 or 50 percent of the people. I wouldn’t say that most drugs don’t work. I would say that most drugs work in 30 to 50 percent of people. Drugs out there on the market work, but they don’t work in everybody.” Doctors often think when a drug is approved that it will influence all their patients in similar ways. Mass Marketing of Drugs But, as pointed out in the article, “This goes against a marketing culture within the industry that has relied on selling as many drugs as possible to the widest number of patients.” This type of drug marketing led to a culture that sold one drug to lots of people, assuming that anyone with a particular diagnosis would get a specific kind of response. Now, with pharmacogenomics, we realize the response may vary greatly from one individual to another based on genetic uniqueness. This discussion is also related to this month’s theme—the modification of hormonal balance in women as part of the endocrine web, the symphonic orchestration of the messenger molecules that control cellular/tissue/organ function. Recently, the American Association of Clinical Endocrinologists developed some medical guidelines for the clinical use of dietary supplements and nutraceuticals in the modulation of these endocrine complexities.[2] Published in Endocrine Practice, this paper is more than 50 pages long and contains 550 references. In this review of nutraceuticals in endocrine practice, the authors discuss alternative medicine and the definition of alternative care. They state that the problem with alternative medicine is often that the therapies are offered without explanation of mechanism. The Functional Medicine Approach The functional medicine approach to endocrine and metabolic disorders is discussed in Point 5 of the document: “Physicians should remain abreast of not only advances in traditional medicine but also evolving alternative medical practices. Sorting through the seemingly endless lexicon that is articulated by alternative care practitioners is particularly challenging&ldots;. Nonetheless, analysis of alternative options may yield advantages. First, such studies can be informative and lead to ‘lateral thinking’ in innovative applications of proven therapies. Second, they can stimulate new ideas for the design of scientific medical research. Third, they can assist discussions with patients contemplating such therapies&ldots; One alternative practice that is gaining popularity is ‘functional medicine.’ This term is used by some healthcare practitioners to describe a clinical approach emphasizing (1) the physiologic and biochemical uniqueness of each patient; (2) the ability of laboratory tests to detect such uniqueness; and (3) the importance of minor symptoms to guide prevention of and therapy for suboptimal health, degenerative disease, and chronic illness. The over-arching teleologic principle is that individualized nutrition, based on a person’s unique genotype and phenotype, can produce a state of optimal health. ‘Functional foods’ are defined as foods that contain, in adequate concentrations, one or more substances that have a positive effect upon physiologic function. In functional medicine, complex theories involving the psychoimmune-neuroendocrine axis are blueprints for natural interventions. Data from scientific studies and non-scientific studies are applied to buttress an argument against polypharmacy with traditional medicines and to favor lifestyle changes and the use of a wide variety of dietary supplements/nutraceuticals. ‘Nutrigenomic’ and ‘nutriproteomic’ therapies are nutritional interventions directed at genomic and cellular mechanisms of disease. An example would be the genomic screening of children early in life, (perhaps in utero) for methylenetetrahydrofolate reductase polymorphisms. A potential treatment would be to increase the dietary intake of folate or the neutraceutical 5-methyltetrahydrofolate. This approach would theoretically then help prevent pediatric leukemia, which has been linked to altered folate metabolism.” Functional Status It is exciting to see that the functional medicine model is at least on the radar screen and described in clinical guidelines that appear in various forms, especially medicine. This month, we will discuss the specialty medicines of endocrinology and obstetrics/gynecology, and the role lifestyle, diet, and environment can play in those disciplines. We are really measuring functional status. Many disorders, including fibrocystic disease of the breast, cervical dysplasia, uterine fibroids, preclinical polycystic ovary syndrome, perimenopause, and premenstrual syndrome (PMS), would not be considered diseases as such, but rather conditions. We might call them functional physiological disturbances or endocrine imbalances. Our Clinician of the Month, Dr. Allan Warshowsky, will discuss a functional medicine model approach he has been using for the management of complex endocrine symptom clusters.We are really talking about how to measure functional status. A recent issue of Arthritis & Rheumatism, the journal of the American College of Rheumatology, contained a series of papers discussing measures of general adult functional status.[3],[4] It was interesting to see how many different ways there are to assess function, including psychological function, somatic function, physical function, cognitive and mental function, and physiologic function. We are aware of the Short-Form Medical Outcome Survey questionnaire (SF-36). This questionnaire evaluates quality-of-life issues and various disabilities from a functional level and can be helpful in mapping back against psychological and physical dysfunctions that may be present prior to the onset of a cleanly defined disease that fits an ICD9 code. Well before that, there can be functional decrements. Measuring Functional Capability and Performance The first article in Arthritis & Rheumatism discusses measures of adult general functional status, using the Barthel Index, the Katz Index of Activities of Daily Living, Health Assessment Questionnaire (HAQ), MACTAR Patient Preference Disability Questionnaire, and the Modified Health Assessment Questionnaire (MHAQ). All of these questionnaires measure aspects of functional capability in the absence of a clean diagnosis. The second review paper discusses adult general performance tests. This is a way of getting physical measurements in the office for evaluating functional status. These include the Berg Balance Scale for measuring equilibrium; the Dynamic Gait Index (DGI), Gait Velocity, Physical Performance Test (PPT), Timed Chair Stand Test, Timed Up and Go, and the Tinetti Performance-Oriented Mobility Assessment (POMA). These are ways to evaluate, at a gross level, certain aspects of peripheral and central nervous system activity, the immune system, structural balance, and how those assays track against physiological and physical functioning. Early-Warning Measurements These are tools for evaluating early-warning signs in patients who present with symptoms of differing severity, intensity, and duration that may be indicators of later-stage, more serious problems. For instance, patients who begin to lose smell and taste acuity are often at higher risk for Alzheimer’s disease. This may be an early warning functional assessment test to measure loss of taste and smell. When we begin to examine these markers, we are led to a different set of questions beyond just diagnosis. It relates to physical, physiologic, cognitive, and mental functioning.   Hormonal imbalances track early on in terms of changed symptoms in the absence of diagnosis. In perimenopause there is a significant change in hormone levels from period to period. Women do not simply suffer from low estrogen that results in flushing, night sweats, cognitive and sleep disturbances, depression, and dysphoria. Estrogen levels change rapidly in perimenopause, from very high to very low, and the metabolism of the intermediaries may trigger many of the symptoms associated with menopause. There can be an imbalance of one form of an androgen/estrogen to another form, and a progesterone insufficiency relative to estrogen excess in the moment. These are the kinds of things that create the whipsaw effect on physiology seen as functional changes in outcome that questionnaires like those I just described can pick up, well before there is a clean diagnosis. In fact, we should not view menopause as a disease. It is a condition, a normal transition that most women go through in their fifth decade of life. It is the severity of the experience that is the real concern, the symptoms and signs that result as a consequence of altering hormone values and how they influence physiological, cognitive, mental, and physical functioning.An article in Nutrition Today is titled “Managing Menopause Naturally?” [5] The answer to that question is yes; it has been done throughout much of human history. When exogenous hormone replacement was not available, women had to manage menopause naturally. The real question is whether we can improve the transition with supplements like black cohosh, soy isoflavones, cruciferous vegetable glucosinolate concentrates, or various other types of adrenal adaptogenic substances like licorice. Do these substances influence the transition into menopause? Can they affect the symptoms that women experience, such as night sweats and flushing? Alternative Medicine Review contained a paper titled “Hot Flashes—A Review of the Literature on Alternative and Complementary Treatment Approaches.” [6] The author discusses various medications that have traditionally been used in attempting to modify hot flushes and night sweats and compares them to natural interventions. Some natural interventions use selective estrogen response modulators in the form of isoflavones or lignans. Others may remove gut dysbiosis and improve digestive function. You might consider that the human body operates like a machine. The “operator” uses feet on two pedals simultaneously—the accelerator and the brake—to balance out cellular function. The balance metabolism of estradiol through the 2-hydroxy pathway becomes an important part of modulating function. Cruciferous Vegetables The cruciferous vegetables, rich in glucosinolates, help increase 2-hydroxylation. The catecholmethyltransferase enzyme transfers a methyl group from S-adenosylmethionine (SAM) to the 2-hydroxyestradiol to produce 2-methoxyestradiol and 2-methoxyestrone. These estrogen-braking substances, which are anti-mitotic—anti-cellular proliferative—tend to calm down the estrogen message of estradiol which is cellular proliferative and increases mitotic activity. We see the relationship of diet to function playing out in terms of signs and symptoms that the patient experiences. Women do not all respond identically to these interventions. In the same way that they respond differently to medications, people respond differently to diet and lifestyle interventions. We are biochemically unique. There are 2 to 3 million different single nucleotide polymorphisms (SNPs) in our genome of 30,000 to 35,000 genes, and they code for many different variations on a theme. Estrogen can modulate xanthine oxidase activity, but it does so by an estrogen-receptor-independent mechanism. You might have relationships between estrogen and estrogen metabolism on vastly different physiological functions unique to the individual, such as in purine metabolism, xanthine oxidase, or oxidative stress. When the enzyme xanthine oxidase is upregulated, it produces superoxide. Superoxide in the presence of nitric oxide (NO) can react very rapidly chemically to produce peroxynitrite in the body. Peroxynitrite is a powerful irritating, nitrosylating reagent that injures proteins, resulting in altered protein function. Oxidative Injury An immune-upregulated proinflammatory state, coupled with altered estrogen metabolism, can produce an outcome of oxidative injury. These are weblike effects; they do not work in isolation. A symptom is not the result of one factor alone; it results from the weaving together of a variety of factors. Xanthine oxidase activity and its interrelationship with postmenopausal inflammation are discussed in the journal Antioxidants & Redox Signaling. [7] The authors explain that when estrogen declines, the conversion of xanthine dehydrogenase/xanthine oxidase activity increases, and xanthine oxidase produces more superoxide. This may be another component of postmenopausal lowering of estrogen, increasing the incidence of inflammatory conditions and oxidative stress in women. It might also tie together with a variety of oxidative-related and inflammatory-related disorders such as arthritis or heart disease in postmenopausal women. These relationships are individualized to a woman’s own genetic uniqueness. Her response to drugs is modified by her genetic uniqueness; so is her response to her environment, lifestyle, and diet. This topic is discussed in a paper in the Journal of the American Medical Association, titled “Association between Estrogen Receptora Gene Variation and Cardiovascular Disease.”[8] In this article, the authors explain that certain types of polymorphisms of the estrogen receptor have a much higher statistical correlation with cardiovascular disease, and that estrogen receptor variation has the potential to explain recent conflicting data regarding the effects of hormone therapy on cardiovascular disease susceptibility in women. Some women may carry SNPs of the estrogen receptora sensitivity. On hormone replacement therapy, these women may have a lowered risk to cardiovascular disease, whereas other women may have an elevated risk, depending on how that polymorphism receptor responds to the environment, i.e., the hormone. Again, individualization, customization, and personalization indicate where we are going. In fact, that was the subject of an editorial that appeared in the New England Journal of Medicine. That article on hormone therapy discussed customized approaches to women, individualized therapy, not just one-size-fits-all; consider what the body mass of the person is, give a dose responsive to that body mass, and look at individual needs.[9] The effect of many nutritional agents is to modify estrogen metabolism as agonists/antagonists. It is an adaptogenic effect: the highs go down and lows come up. An agonist effect is when low goes to high; an antagonist effect is when high goes to low. It tends to normalize around a setpoint. This is what has traditionally been called an adaptogen. Soy isoflavones have this effect, serving as agonists/antagonists of estrogen metabolism, or adaptogens of estrogen response. The author of a recent paper in Medical Hypotheses points out that estrogen agonists and antagonists like soy isoflavones may downregulate growth hormone signaling and therefore have an influence on a variety of effects, including insulin sensitivity through IGF-1 and IGF-1 binding protein, and they may impact lipoprotein(a), which may explain how estrogen can modulate cardiovascular risk and insulin sensitivity.[10] It is a web. The endocrine system contains an interconnected series of signals that create specificity of outcome as function in cells and tissue. This concept of functionality is more than idle banter. It contributes to our understanding of how to manage patients with complex, chronic health problems related to the imbalance of these chemical messengers or signaling substances, such as the sex steroid hormones. What relation does this discussion have to breast cancer and hormone replacement therapy (HRT)? We recently discussed the results of the Million Women Study. This is the largest study ever done looking at the effect of HRT on breast cancer incidence. It indicated there was a statistically significant and meaningful increase in breast cancer risk and incidence regardless of the type of estrogen used, whether it was estradiol or mixed equine conjugated estrogens. All forms of estrogen, if unbalanced in delivery and metabolism, may pose a risk when administered exogenously. Even endogenous estrogen, if it is not properly metabolized and excreted, may pose a risk. That is why two years ago, the Institute of Medicine suggested that estrogen is a carcinogen. Estrogen and Cancer Risk It is unusual to think that a natural substance in the body could be a carcinogen, but estrogen or its metabolites, if they are out of balance, inappropriately metabolized, or elevated could, in fact, pose a carcinogenic risk. The Million Women Study appeared to indicate that.[11] It is also important to remember that estrogen can be manufactured in tissues outside the ovaries. Breast and adipocyte cells, for example, particularly visceral adipose tissue, will manufacture estrogen. This estrogen can be converted into estrogen metabolites like the 4-hydroxyestrogens, which are the catecholestrogens that Dr. Rogan and others have discussed with us; they can be very caustic and cause injury in DNA adducts that pose carcinogenic risk. The breast itself can generate estrogen. There is the isoform of cytochrome P450 (CYP) in the breast that can convert estrogen directly into the 4-hydroxyestrogens—CYP 1B1. Recent papers on polymorphisms of CYP 1B1 and their relationship to postmenopausal breast cancer risk have indicated a strong correlation between CYP 1B1 gene polymorphisms and estrogen metabolism. There is no strong influence of risk to breast cancer, however, because other modifying factors may affect the way that plays out in the phenotype. [12] In other words, you may have a CYP 1B1 polymorphism, but secondary factors of how those catecholestrogens are metabolized by methoxylation or by glutathione conjugation may render these potential 3,4-quinone estrogens detoxified before they have an injurious effect on DNA. It is not just a single point gene mutation or a single SNP that creates an outcome in a phenotype called breast cancer. It is a pattern of genetic uniqueness coupled with environmental exposures and dietary selections that ultimately gives rise to the outcome. The Functional Medicine Approach When we talk about a functional medicine approach to endocrinological outcome, we take into account this web of interacting variables and look at the way hormones influence insulin, IGF-1, IGFBP-1, and lipoprotein synthesis such as apolipoprotein A1 or B1. All of these are part of the web of understanding how the individual woman responds to her environment. The conversion of the hydroxylated estrogens such as 4-hydroxyestradiol into the nontoxic byproducts involves methylation. Methylation is performed by catechol-O-methyltransferase. It requires the presence of a methyl donor called S-adenosylmethionine or SAM. SAM comes from proper activity of the folate cycle. Polymorphisms in the folate cycle may impair the ability of the body to produce proper levels of SAM at the necessary site. These are polymorphisms like the MTHFR 677C® T polymorphism, which we discussed in earlier issues of FMU. A relationship between a polymorphism of the methylenetetrahydrofolate reductase gene and folate and riboflavin status as it tracks into homocysteine can affect the methylation of homocysteine ultimately through that cycle to produce SAM. A paper published in the Journal of Nutrition discussed that combined marginal folate and riboflavin (vitamin B2) status affects homocysteine methylation in people who have the homozygous MTHFR 677C® T mutation.[13] Having that polymorphism means being unable to handle lower levels of riboflavin and folate as well as a person who does not have that SNP. Therefore, methylation is impaired, increasing homocysteine and decreasing methyl hormone levels, and that can have a different dynamic on the web related to risk. In a study by Dr. Lynn Bailey, titled “Folate, Methyl-Related Nutrients, Alcohol, and the MTHFR 677C® T Polymorphism Affect Cancer Risk: Intake Recommendations,” the author explains that alcohol causes increased turnover and loss of the B vitamins, including riboflavin, pyridoxine, and folate.[14] A MTHFR 677C® T polymorphism makes one more folate-dependent. Increased alcohol consumption lowers folate status and sufficiency of the folate cycle. It lowers SAM levels and influences relative cancer risk when an individual is exposed to the same level of carcinogens that would not pose a risk for someone who has proper folate chemistry. We cannot say that a single exposure to a carcinogen is the risk. Nor can we say that consumption of a single drink of alcohol is a risk. We cannot say a single dietary insufficiency of B6, B12, folate, and B2 is a risk. Nor can we say that, in isolation, a MTHFR polymorphism is a risk. But when all of these occur together—frequent consumption of alcohol, poor diet, high stress, a MTHFR polymorphism, exposure to environmental xenoestrogens that increase hydroxylation to the 4 family, or perhaps taking mixed conjugated equine estrogens—they may paint a picture of higher risk. Individuals respond differently to dietary isoflavones based on their individual metabolism. These would be things like the soy isoflavones daidzein and genistein. When a person responds to these isoflavones, the response has principally been found through estrogen receptor b rather than estrogen receptor a . This is interesting because estrogen receptor b is present in higher amounts in osteoclastic and osteoblastic cells in bone, as contrasted to estrogen receptor a , which is very high, for instance, in the ovary and the breast. If you preferentially activate or modulate response of estrogen receptor b, it is reasonable that the result would be a significant effect on bone dynamics. This would be like the SERM raloxifene, to use an analogy from the pharmaceutical industry, in which a substance is working more in bone than in breast. Dietary Isoflavones and Bone A review paper in the American Journal of Clinical Nutrition looked at dietary phytoestrogens and their effects on bone.[16] The authors did a meta-analysis of 24 different studies—17 in vitro studies of cultured bone cells, 24 in vivo studies of animal models for postmenopausal osteoporosis, 15 human observational/epidemiologic studies, and 17 dietary intervention studies. They looked at the role of isoflavones on bone dynamics, bone cell physiology, or on bone loss in women. Their collective data suggest that diets rich in soy isoflavones have bone-sparing effects in the long term. Current evidence suggests that, when coupled with weight-bearing exercise as simple as a regular walking program, isoflavones may have beneficial effects on retention of bone and prevention of fracture risk similar to those of the SERMs, possibly without some of the risks of adverse side effects from the synthetic molecules. Is HRT Necessary? Some people believe HRT of some type is necessary because one cannot get all the benefits from a natural approach that can be derived from artificial hormone replacement. The evolving story appears to contradict that belief for most women. If a woman exercises, has lower stress, eats a high-quality diet, makes sure she’s getting adequate levels of calcium, magnesium, vitamin D, and vitamin K, and adequate levels of the isoflavones that modulate estrogen receptivity, activity, and metabolism, the outcome can be positive. Vitamin K, vitamin D, methylation, calcium, and soy isoflavones all frame a pattern of intervention. It is not a single agent, but a complex intervention using diet and lifestyle that is consistent with what women traditionally did in cultures that did not have access to these pharmaceuticals. Once they got through the age of infectious diseases and childbearing, their transition to menopause in older age was quite good. A series of effects can occur as a consequence of hormone imbalances. One of those conditions is fibromyalgia. Fibromyalgia might be seen as a complex condition that results from an imbalance in the neuro/endocrine/immune system. A recent article in the journal Arthritis & Rheumatism discussed the Fibromyalgia Impact Questionnaire (FIQ).[17] If one looks at the questionnaire used to evaluate fibromyalgia, with trigger points, tender points, and certain disabilities, one can see they tie back to what appear to be immunological and neuroendocrine imbalances. Fibromyalgia may be a heterogeneous disorder, not a single disease, with different variegated forms that lead to myalgic pain, fatigue, sleep disturbances, cognitive dysfunction, and immunological suppression.[18] We should probably concern ourselves with individualized therapy for fibromyalgia patients, rather than assume one size fits all. Dietary Modification in Fibromyalgia Dietary modification plays a role in modulating the signs and symptoms of fibromyalgia. A paper in Complementary Health Practice Review discusses dietary modification of fibromyalgia.[19] This dietary modification consists of getting rid of dietary excitotoxins such as monosodium glutamate, lowering inflammatory potential and improving redox potential by lowering oxidative stress, improving bowel flora, and lowering some of the central nervous system immunological activation through the microglia. What Dr. Alan Logan recommends for dietary modification of fibromyalgia is the exact approach we have been discussing from our research over the last ten plus years. Dr. Scott Rigden has achieved remarkable results in chronic fatigue syndrome (CFS) and fibromyalgia patients with a hepatic resuscitation program to improve GI and hepatic detoxification. He normalizes oxidative stress by using balanced levels of redox-active substances such as lipoic acid, coenzyme Q10, vitamin E, and N-acetylcarnitine, and rebuilds membranes using essential fatty acids of the omega 3 family. Lipid Replacement as an Adjunct to Therapy for Chronic Fatigue, Anti-Aging and Restoration of Mitochondrial Function Some work has recently been done on the use of omega 3 fatty acids as an adjunct to therapy for both CFS and fibromyalgia. A paper appeared in the Journal of the American Nutraceutical Association, written by Dr. Garth Nicolson of the Singer/Nicholson team who developed the fluid mosaic model of the lipid bilayer of membranes.[20] This model is now viewed around the world as the “plum pudding model” of cellular membranes, in which the proteins embedded in the lipid bilayer transport substances across the membranes selectively. Dr. Nicolson talks about lipid replacement using omega 3 fatty acids as an adjunct to therapy in CFS and fibromyalgia to help build back mitochondrial cellular and cytoplasmic membranes. That would generally be done after reducing oxidative stress. Intervention would begin with a detoxification program, go on to antioxidant therapies or redox mitochondrial resuscitation programs and last, rebuild membranes with essential fatty acid supplementation. High levels of omega 3 fatty acids should not be given to people who are in extraordinary oxidative stress because they can be peroxidized and undergo “biological rancidity.” That stage of the therapy would begin after minimizing the oxidative stress. A Metabolic Basis for Fibromyalgia and Related Disorders A review paper in Medical Hypothesis discusses management of fibromyalgia and CFS. It examines the metabolic basis for fibromyalgia based upon the model of neuroendocrineimmune balance.[21] That will take us into our discussion with our Clinician of the Month. We will look at women with endocrine disturbances and obstetrical/ gynecological problems from a holistic functional medicine perspective.

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INTERVIEW TRANSCRIPT

Clinician of the Month Allan B. Warshowsky, MD, FACOG, DABHM 165 West End Avenue, Suite 1K New York, NY 10023 JB: It’s time for our Clinician of the Month. For the past several months we have been following the theme of hormone metabolism and balance, with particular emphasis on estrogen, progesterone, and androgens. Today we follow up on those research discussions with some “news to use” from an obstetrician/gynecologist who is at the forefront of this field, dealing with these problems in his patients on a daily basis—Dr. Allan Warshowsky. Dr. Warshowsky is a graduate of Downstate Medical Center at the State University of New York and has worked extensively in obstetrics and gynecology for more than 30 years. For the past decade, he has focused on integrative medicine, managing complex patient problems in the area of women’s health. There is no more interesting time to collaborate and work in this area. The Women’s Health Initiative Study and new data have changed the thinking on the issue of hormone replacement therapy. Dr. Warshowsky’s Background in Women’s Health Issues With great enthusiasm I welcome Dr. Warshowsky to Functional Medicine Update. He plays a role in managing women’s health issues both in his private practice and as Director of the Women’s Program at Beth Israel’s Continuum Center in New York City. Welcome to FMU, Dr. Warshowsky. AW: Thanks very much, Jeff. It’s a pleasure to be on FMU and to have an opportunity to talk about some of the things I’ve been doing over the last 10 years. It’s been an interesting decade in terms of women’s health from the perspective of hormone replacement, hormone balance, and a lot of new information on the catecholestrogens. Listening to FMU for the past several years, we have heard about a lot of new information, a lot of controversy, and a lot of new questions on these issues. It seems that every time we learn something, it opens up an entirely new avenue of exploration. I’ve been working with a holistic or integrative approach to women’s health for 15 to 20 years, perhaps even longer. When I started in medicine, I was dealing with issues of premenstrual syndrome (PMS), which wasn’t regarded as a true clinical entity, but I found that women were really suffering. Back in the mid 1970s, I found that when I supplemented these women with a few vitamins, worked with them to clean up their diet, and actually listened to them (giving a mind/body therapeutic effect), they started to improve. The Need for Individualized Therapy Soon after that, I found that women were not dealing well with the “one size fits all” therapy of menopause, using Provera and Premarin. There were many negative side effects related to Premarin, and I found that by using bioidentical hormones, those identical to what the human ovary was producing, and individualizing care, I got better results, fewer negative effects, and better therapeutic effects on alleviation of symptoms. In continuing to develop and evaluate my own therapeutic programs, I started dealing with issues of hormone imbalance in the reproductive years. Fibroid tumors of the uterus were a major issue. I was concerned about unnecessary hysterectomies and other unnecessary surgeries. Doing a lot of surgery myself at that time, I noticed that normal-size uteruses were being removed for conditions such as bleeding. I knew at that time that if I was doing a more integrative or functional approach, I could alleviate those symptoms and the need for surgery was certainly diminished. Developing an Integrative Approach I put together programs from an integrative or functional approach that would alleviate a lot of the symptoms. I found I could no longer just deal with a uterus or an ovary in terms of helping to alleviate some of the common symptoms and conditions associated with fibroids, PMS, or polycystic ovaries. I started looking at some of the other issues, such as gastrointestinal (GI) problems like detoxification, inflammation, and sugar dysregulation. Certainly, the hormonal imbalances involved more than estrogen and progesterone. They also involved adrenal and thyroid hormones and the hypothalamus-pituitary axis (HPA). Issues such as emotional states were also important, because they seemed to affect hormone imbalance and, in looking at the limbic system, which affects the HPA, we can see an emotional component that would affect hormonal balance. Instead of simply looking at estrogens or progesterone, and conditions associated with the uterus and ovaries, my focus became one involving the total body, looking at GI dysbiosis states or permeability problems, yeast and bacterial overgrowth and parasites. Whole-Body Effects on Balance of Hormones All of these seemed to be affecting how hormones were balanced or imbalanced. Liver detoxification and other detoxification systems in the body also came into play. If the GI tract was not functioning adequately, the body’s detoxification capabilities carried an additional burden, and that led to an imbalance of hormones. It wasn’t just giving hormones, or working with hormones in a replacement sense; it was working with detoxification and GI issues before we could affect a hormone imbalance. Then we started looking at sugar dysregulation and insulin levels. We found, certainly in the case of polycystic ovary conditions, a major piece is related to sugar dysregulation and insulin resistance. (I’m now finding this in other conditions of hormone imbalance as well, such as fibroid tumors or functional ovarian cysts.) In turn, that will affect estrogen/progesterone balance and, more importantly, inflammation in the body. The Inflammation Connection From this viewpoint, I moved on to look at inflammatory states, because we know that increased insulin levels, sugar dysregulation, and deposition of adipose tissue in the body are going to increase inflammatory messenger molecules that will also have a major impact on hormone balance. From an initial approach of just looking at what’s going on in the pelvis, as a traditional obstetrician/gynecologist is trained, my approach now encompasses the entire body. That includes the emotional state of the patient, and trying to put the whole body back into balance rather than just trying to work on a small piece of it, without acknowledging all the other issues that come into play. Developing a Practice Based on Communication JB: That is a very impressive program. Obviously, it deals with the patient as a unique individual, rather than hammering her into some diagnostic criterion and then treating her as if she were a diagnosis. I imagine that also increases the complexity of your life, both from a professional perspective and in the way you integrate these things, including the business perspective. It takes time to ask the right questions and engage in proper communication. How have you gone from that highly mechanized setting of the traditional approach built on efficiency, to this model built around relationships and understanding? AW: I’m glad you asked that question. I decided about four years ago that I was going to stop doing obstetrics because I couldn’t devote the amount of time necessary for a good obstetrical practice in addition to doing this kind of integrative or holistic approach to health care. Before that, I had been doing both. I had been setting aside a couple of days a week just to see integrative medicine patients, and to devote the amount of time necessary. A new patient would require an hour to an hour and a half. Revisits would be 30 to 45 minutes, so I would devote two days a week just for these kinds of patients, but I found that with my obstetrical practice, I’d be canceling my hours frequently because I’d be up all night. Fee-for-Service Practice Four years ago, I stopped doing obstetrics and devoted myself to this kind of approach to health care. At the same time, I also stopped taking all managed care. I took myself out of that loop completely, where I was dependent on reimbursements through insurance companies, and I became a fee-for-service practitioner. I found it made no difference for the patients who needed this kind of approach. They had already been to half a dozen or more physicians with their chronic complaints. There is no good ICD9 code for these chronic conditions, and there really aren’t good treatments for them. Medical treatments just deal with symptoms, and surgical treatments simply remove the tip of the iceberg, the piece of the problem that we can see. None of this gets to the “why” of the problem. I see several conditions that stand out as the “why” of the problem—inflammatory imbalances, what we call the Th1/Th2 imbalances; immunological issues; hormone imbalance; GI detoxification issues; and certainly, sugar dysregulation issues. The conventional approach wasn’t looking at any of the “whys.” To look at the “whys,” you need the time; especially in Manhattan, you need to be able to pay your bills and monthly overhead charges. Getting Out of Managed Care Getting out of managed care was very helpful. I have found over the last few years that I don’t need to do surgery any longer. Most of the surgical procedures I was doing are no longer necessary because of this particular approach. For the cases that do need surgery, there’s always somebody around that would be happy to do it. The patients then come back to see me because they still want this kind of care for their chronic issues. That was the direction I decided to take, and I’ve been very happy with it. I’ve changed my identity. At this stage in my life (I’ve been in practice over 25 years), I never thought I would move completely to another field of medicine. It has been very fruitful and satisfying, however, because patients with these chronic conditions, for whom there is no good conventional therapy, are getting better. When I ask myself, what have I done? I’ve given up my identity. I loved doing obstetrics; I delivered three of my five children. I enjoyed doing surgery. What have I done? Then a woman will come in and thank me because after having gone to half a dozen doctors over the last half dozen years with no improvement, and after being on my program for three months, her menstruation has been normalized. Her energy level is better; her mood is better, and her husband wants to thank me. These kinds of comments, which I get on a regular basis, keep me going and show me not only the efficacy but also the utility of this kind of approach. It seems phenomenal to me; it amazes me all the time. Dr. Warshowsky’s Reputation JB: In my very busy travel schedule, I frequently get to the New York City area. I can testify as to how many people have been your patients. Through interesting and sometimes second-level connections, your name comes up in conversation and I’ll hear that “Dr. Warshowsky is a savior,” that they’ve never been treated as they are in your program. They say, “It’s an amazing form of medicine,” and “Every doctor should be like that.” Obviously, your reputation precedes you. You are making a big difference. AW: Thanks, Jeff; I appreciate that. When I hear things like that, especially from patients, it keeps me going. I know I’m on the right track. When I see a patient who has really severe fibroids, for example (I can think of two or three patients who have actually come in from the hospital after having blood transfusions for their fibroids), I put them on a program which certainly includes evaluation of the GI tract. I find that more than 90 percent of the time, the GI tract is full of bacterial imbalance, yeast overgrowth, and very often parasites that haven’t been picked up. Doing a gut restoration program and supporting liver detoxification, dealing with sugar dysregulation issues and the inflammatory states, and putting them on a simple program to begin dealing with stress reduction and a nutritionally-rich program, within three weeks, most of these people start to feel better. Bleeding Issues When I deal with bleeding issues, I do a lot of herbal therapies and other antiinflammatory therapies. I would say that within three to four weeks, 80 to 90 percent of these people are incredibly improved in terms of their energy, their state of well being, resolution of their sleep issues, and clearing up of their skin problems. They are extremely thankful. If I follow them over a couple of months, their menses lighten up and the pressure and pain symptoms all seem to subside. For the first time in years, they feel they can get out of their houses during their menstrual periods. They don’t have to be confined to the bathroom because they’re hemorrhaging so badly. These are real issues. Avoiding Surgery for Fibroids A majority of women who come to me with fibroids are already scheduled for surgery. They come to me for a third opinion. Two or three gynecologists may have already recommended total hysterectomies or other invasive surgical procedures as the only way to deal with their issues. I would say that 80 percent or more of them never have surgery. Their conditions and symptoms seem to clear up to the point where they don’t need surgery; they’re extremely happy; they’re functioning in society again; they’re able to do their work. It’s extremely gratifying. It takes time, but the results are well worthwhile. Dr. Warshowsky’s Book JB: Your book, Healing Fibroids: A Doctor’s Guide to A Natural Cure, a Simon & Schuster publication, is an excellent overview. In the book, you describe what you do and why you do it in a way that’s very understandable. AW: I wanted to get it out to the public. As you probably know, almost 300,000 hysterectomies are done every year in this country for fibroids. I would say the vast majority of them are unnecessary. We could deal with the issue of fibroids from a functional approach. Even the American College of Obstetrics and Gynecology, in its recent Practice Management Bulletin, has said that fibroids as benign tumors do not need to be removed surgically unless symptoms necessitate it. If we could deal with symptoms, it leaves a lot of time to work with the issues that are causing the fibroids to grow. Elizabeth Stewart at Brigham and Women’s Hospital in Boston has been doing a lot of work on growth factors found in fibroid tumors and how they are influenced by inflammatory states. Fibroids and Inflammation I have found that more than 90 percent of women with fibroids have some kind of intestinal inflammation issues. Consider that the intestines are lying on the fibroids right in the pelvic area where estrogens are being produced. (Estrogen is a growth hormone.) There are inflammatory messenger molecules stimulating cellular change within the myometrium of the uterus and the estrogens are causing the fibroids to grow, so inflammatory issues in the gut need to be cleared up. It’s almost a no-brainer to me. These are the issues that need to be cleared up. I use the 4R Program, and thank you so much for it. Patients are thrilled with it. For the first time in years, they don’t have bloating and other digestive problems associated with their irritable bowel syndrome or inflammatory bowel disease. Clearing up these things and then working on the symptoms of the fibroids themselves are extremely beneficial. Fibroids stop growing and start shrinking. Polycystic Ovary Conditions and Insulin Balance Similarly, other conditions of hormone imbalance improve. Polycystic ovary conditions seem to be in the medical news more and more recently because of the connection with insulin. If you can use PPAR agonists and PPAR modulators and diminish insulin resistance, reduce insulin levels, and increase sugar utilization, a lot of these inflammatory issues also seem to clear up. You can clear up polycystic ovary conditions and all the problems associated with it, whether it’s cardiovascular disease, type 2 diabetes, or other chronic conditions of aging that now seem to be associated with inflammatory states. If you can clear up sugar dysregulation issues, you can reduce the incidence of many of the diseases of aging. It’s not just gynecological issues; it’s not just reducing surgical procedures in terms of fibroids. What I’m now doing is dealing with all the conditions of aging, from dementias to arthritides to cancer to cardiovascular disease to diabetes, which you’ve called a pandemic. They all seem to be connected with the major issues that I mentioned. When I see a patient with “hormone imbalance” represented by fibroids, functional cysts, fibrocystic breast problems, or even cervical dysplasia, that to me is just the tip of the iceberg. Finding the “Why” of Chronic Conditions Consider the other conditions, the “why” conditions, why is this happening? Those are the basic conditions—inflammation, immunological conditions, hormone imbalance, sugar dysregulation, GI and detox issues. They need to be cleared up first so that you can reduce the risks of the diseases of aging in later life. That’s what I’ve gotten out of this approach and the journey that I’ve been on. I have moved from the traditional gynecology medical school curriculum—basically fallopian tubes, ovaries, uterus, and vagina—to a total body approach and, ultimately, to increase the optimal health of the individual and reduce the degenerative aging process at the same time. The 4R Program JB: For listeners who may not be familiar with the 4R acronym, those Rs stand for Remove, Replace, Reinoculate, and Repair. That is the gut restoration program. It involves removing allergens, toxins, parasites, and bacterial overgrowth; replacing digestive enzymes where necessary; using pre- and probiotics to reinoculate the gut with friendly bacteria; and last, repairing with nutrients like pantothenic acids, glutamine, and vitamin E to help restore gut mucosal integrity. AW: That’s something I started doing about 10 to 15 years ago, and it’s been a mainstay of therapeutic treatment for these chronic conditions. Bioidentical Progesterone JB: As we all know, we lost a great pioneer and leader in our field with the passing of Dr. John Lee. Perhaps you could tell us a bit about your experience with bioidentical progesterone and where you think it fits into the puzzle. AW: Progesterone gets depleted in a number of different ways in our society. Certainly, there is enough stress in our society with the concomitant elevations in cortisol and alterations in DHEA and progesterone, that I think increased progesterone deficiency states in the reproductive years are common. I suspect numerous nutritional deficiencies also play a role. It’s been estimated that more than 70 percent of the population doesn’t achieve the RDA of things like magnesium and zinc, both of which are extremely important minerals for hormone balance. B vitamins also get depleted very easily in stressful situations, B6 in particular. I have found low levels in some of the testing I’ve done. Progesterone as a Marker of Stress Progesterone, is a very sensitive marker of stress. Certainly, stress also has a major impact on ovulation. We know that when women don’t ovulate, they don’t make any progesterone in the ovaries. My feeling is that whatever progesterone is being produced elsewhere, as in the adrenals, is going more toward production of stress hormones like cortisol. Low progesterone levels or abnormal estrogen/progesterone ratios are extremely common in many of the conditions I see. Replacing or restoring the normal ratio between estrogen and progesterone becomes extremely important. Natural progesterone transdermal creams work very well to restore that ratio. It’s not the only thing we do, but in someone who is premenstrually symptomatic of excess estrogens, natural progesterone can be extremely helpful. I also use the 3 percent progesterone cream that John Lee promoted in menopausal issues. Hormones in Menopause In menopause, I use bioidentical hormones or hormones that are identical to what the human ovary makes. In addition to the estrogens, I also use natural progesterone. The conventional thinking is that once a woman has a hysterectomy and has her uterus removed, she can just use estrogens and doesn’t need progesterone to balance it out in the uterus because there’s not going to be any uterine cancer. I don’t understand the thinking that there are estrogen and progesterone receptors in other parts of the body—in the brain, in bone, in heart, and in blood vessels. If we’re giving estrogen and we’re not replacing any progesterone, we’re going to be stimulating more of an imbalance. In those cases, I also like to use the 3 percent progesterone creams. Transdermal Progesterone Absorption It’s been suggested that the transdermal progesterone creams don’t get into the body. My understanding is that when conventional progesterone serum levels are done, they throw away the red cells, but the red blood cells are, in effect, carrying the progesterone. They’re basically throwing away evidence that progesterone is being absorbed transdermally. However, saliva testing for progesterone will show that progesterone is being absorbed transdermally. I think the transdermal progesterones are very effective. They’re certainly absorbed and can be very helpful in a complete program in restoring estrogen/progesterone balance. Some of Dr. Lee’s work on osteoporosis treatment using the 3 percent progesterone creams has not been borne out in subsequent studies. I think it’s certainly helpful in a total approach, but not by itself. Other interesting work done by Helene Leonetti actually showed that using the 3 percent progesterone cream in menopausal women with a uterus would protect the uterus using a 0.625 Premarin. [22] We know there’s a lot of efficacy in using the 3 percent creams, and it can be very helpful as part of a total program. Soy Isoflavones JB: Another controversial area in which I know you certainly have some experience is the modulation of estrogen-related symptomatologies with soy isoflavones. There has been a recent backlash against soy in the fear that it will stimulate estrogen receptors and cause problems. What is your experience and position on this question? AW: My experience has been that using levels of soy that approach what’s been found in the Asian diet—somewhere between 30 and 100 mg per day—has a modulating effect on estrogen levels. If estradiol has a strength of 1 in terms of its estrogenic effects, soy would have a much lower estrogenic effect, maybe 1/500 to 1/1000. Soy acts more as a tonic. If estrogen levels are very high and soy is added to the mixture, it is going to compete with the stronger estrogens for the receptor sites. That’s going to bring down the total estrogen effect. If the estrogen levels are low, as they can be in menopause, adding the soy isoflavones will help fill up some of the receptor sites that would have been empty, and that would raise the estrogen effect. As with anything else, you can overdo it. You could take very large levels of isoflavones and perhaps get into trouble, perhaps with thyroid conditions, but my feeling is that using soy in moderation only acts as a modulator of estrogen in the body, or a tonic of estrogen in the body, and that it is not harmful. Soy Studies Dr. Messina published a reviewon the safety of soy in breast cancer survivors. [23] After evaluating all of the studies, his take was that soy in moderation is not harmful and is probably helpful, and would not be contraindicated, even in women who are breast cancer survivors. If we’re talking about soy isoflavones as potentially dangerous, then we also have to look at some of the other foods that contain isoflavones. There are fruits, like apples and pomegranates, and several others that contain fairly high levels of isoflavones. Are we also going to restrict all those things from the diet? It doesn’t make much sense to me. Flax and Soy I’m a proponent of using soy in beneficial amounts. As I said, that would approximate the amounts found in the Asian diet. I also use other modulators of estrogen from foods. Flaxseeds are extremely important for modulating estrogen levels. They also have their own isoflavones. Using flaxseeds and soy in combination, which I often do with soy protein powders, seems to be very helpful in reducing some of the symptoms of menopause. Many of my patients are businesswomen in Manhattan; they don’t have time for breakfast. When they run out of the house without eating, they begin the insulin resistance picture. I have them use a soy protein powder shake first thing in the morning, getting them about 20 mg of the isoflavones from the soy, and using flaxseeds along with that, and adding some extra fiber. Most of my patients love it and feel great. It gives them energy for a good part of the day and alleviates a lot of symptoms. I’m a major proponent of using soy in moderate amounts. Cruciferous Vegetables JB: I’d like to ask about one other nutritional modulator and that’s crucifers. People have different opinions about whether the glucosinolates found in cruciferous vegetables and their secondary metabolites like indole-3-carbinol (I3C) and diindolemethane (DIM) are beneficial for modulating hormones. What’s your experience? AW: I certainly use the I3C and DIMfor women who have hormone imbalances. I measure the 2:16 (estrogen) ratio, although right now I’m not sure where we’re going with that. I feel you need to have good levels of the 2-hydroxyestrones in comparison to the 16s. I also feel there is an inverse relationship between the 4-hydroxycatecholestrogens and the 2-catecholestrogens, and the 2s need to be a little bit higher, compared to the 16 catechols. I will be happy to see the day when we can measure the 4s or we can measure the effects of the 4-catechols on DNA, but I have certainly found that in women, using I3C or DIM seems to increase the 2-hydroxyestrones. I believe that the crucifers are extremely important for liver detoxification, and I have a quick personal story to share in that regard. Brussels Sprouts and Health: A Personal Story When I was an intern, I came down with serum hepatitis and for some reason, I couldn’t eat anything. My weight dropped from about 170 to 139; I was just getting ready to be hospitalized. For some reason, I started eating Brussels sprouts. I hadn’t eaten them before, but there was a package of Brussels sprouts in the freezer. I ate those and then started eating them twice a day. Within a short period of time, my enzymes started coming down, my weight started back up, and since that time, which was almost 30 years ago, Brussels sprouts are my favorite vegetable. As a food, Brussels sprouts have a lot of glucosinolates and affect liver detoxification. I think crucifers should be an important part of everyone’s diet, and I certainly recommend one to two servings for everyone every day. The Effects of Dietary Change JB: I saw a paper published recently by Dr. Elizabeth Jeffery and her group at the University of Illinois on the direct influence of broccoli extract on glutathione S-transferase and the detoxifying phase 2 enzyme systems and hepatic cells. They found broccoli extracts protect against oxidative injury and upregulate phase 2 detoxification. This article was published in the journal, Nutraceuticals and Functional Medical Foods. [24] People who increase their consumption of cruciferous vegetables can realize positive benefits. In fact, as you say, you can measure the alteration in 2- to 16-hydroxylated estrogen ratios with an increased crucifer-rich diet. AW: If I had to pick one thing that works best or has the most impact, I would say it’s dietary change. Getting the hormones out of the diet, removing the commercial sources of poultry and meats, getting the acidic foods and dairy products out of the diet, helps reduce inflammation. Gluten grains (wheat, rye, and barley) also seem to have a tremendous impact on increasing hormone imbalance, thyroid imbalance, and immunological and inflammatory imbalance. I started doing celiac panels on anybody who comes in with a hormone problem. I have found that almost 50 percent of women have some elevation of the IgG gliadin antibody. I don’t think anybody is doing that regularly, but just getting these people off the gluten grains for three to six months has a tremendous impact on their energy, their sense of well being, and all the hormonal symptoms. Food Instead of Vitamins: Getting a Foot in the Door You don’t always have to go to a medication or an herb. You don’t even always have to use supplements. There are many people who, for one reason or another, don’t like taking supplements. They don’t like taking vitamins, but if you can get them to change their diet and remove some of the inflammatory foods, the acidic and allergenic foods, they start feeling better. If you can just get a foot in the door you can show them that simple lifestyle changes can help them start feeling better. Then they can start picking up on some of the other things that need to be done, whether it’s gut restoration or supplements for PPAR agonists. Whatever it is, if you can get a foot in the door, and they start to feel better, they can move on and become committed to their own health. Self-Nurturing I think that probably the major thing that I do is to get people committed to self-nurturing. So many of my patients have been nurturers. They nurture everybody else. Whether they’re businesswomen or housewives, they’re nurturers, but they don’t nurture themselves. A major piece of what I do is to get people to understand that they can nurture themselves; they’re entitled to be nurtured. Just getting them to understand that helps them to become committed to a program where they’re going to be optimally healthy. Finding Joy in Life JB: That’s a great message that must play wonderfully with your patients. I’m sure they have not heard that as the standard line from their other physicians. It frames a different type of medicine. I guess that’s why we’ve coined the term “functional medicine,” because it sounds like it has a connection of function between the provider, the practitioner, and the patient. AW: I always ask my patients what it is that gives them joy in life. When I get a patient who tells me that nothing gives him or her joy in life, I know that’s going to be a difficult patient. Whatever the condition is, if there’s nothing that gives them joy in life, that’s a real challenge. They need to find something that is going to give them some joy. Many of these patients are put on Prozac or antidepressants just so they can get out of bed and start seeing that there are roses to smell. It’s not even stop and smell the roses; they don’t know there are roses they can smell because they can’t even get out of bed in the morning. The Holistic Medicine Model JB: We have all learned a tremendous amount from the wisdom you’ve shared with us in the last 30 minutes. It is what holistic medicine was designed to be. You look at the individual as a functioning whole organism in whom the sum of the parts is greater than the whole, and recognize that you’re not treating organs; you’re treating people. Thank you, Dr. Warshowsky, for sharing this with us. I hope it can be a stimulus to produce many more physicians like you across the country. AW: Thank you very much, Jeff. I really appreciate that.  

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1 Connor S. Glaxo chief: our drugs do not work on most patients. Dec 8, 2003. http://news.independent.co.uk/world/science_medical/story.jsp?story=471139 2 American Association of Clinical Endocrinologists medical guidelines for the clinical use of dietary supplements and nutraceuticals. Endocr Pract. 2003;9(5):417-470. 3 Katz PP. Measures of adult general functional status. Arthritis Rheum. 2003;49(5S):S15-S27. 4 Hayes KW, Johnson ME. Measures of adult general performance tests. Arthritis Rheum. 2003;49(5S):S28-S42. 5 Thomas PR. Managing menopause naturally? Nutr Today. 2003;38(5):191-197. 6 Philp HA. Hot flashes-a review of the literature on alternative and complementary treatment approaches. Alt Med Rev. 2003;8(3):284-302. 7 Budhiraja R, Kayyali US, Karamsetty M, et al. Estrogen modulates xanthine dehydrogenase/xanthine oxidase activity by a receptor-independent mechanism. Antioxidants Redox Signaling. 2003;5(6):705-711. 8 Shearman AM, Cupples LA, Demissie S, et al. Association between estrogen receptor a gene variation and cardiovascular disease. JAMA. 2003;290:2263-2270. 9 Krauss RM. Individualized hormone-replacement therapy? New Engl J Med. 2002;346(13):1017-1018. 10 McCarty MF. Estrogen agonists/antagonists may down-regulate growth hormone signaling in hepatocytes. An explanation for their impact on IGF-1, IGFBP-1, and lipoprotein(a). Medical Hypotheses. 2003;61(3):335-339. 11 Garton M. Breast cancer and hormone-replacement therapy: the Million Women Study. Lancet. 2003;362:1328. 12 Rylander-Rudqvist T, Wedren S, Granath F, et al. Cytochrome P450 1B1 gene polymorphisms and postmenopausal breast cancer risk. Carcinogenesis. 2003;24(9):1533-1539. 13 Stern LL, Shane B, Bagley PJ, Nadeau M, Shih V, Selhub J. Combined marginal folate and riboflavin status affect homocysteine methylation in cultured immortalized lymphocytes from persons homozygous for the MTHFR C677T mutation. J Nutr. 2003;133:2716-2720. 14 Bailey LB. Folate, methyl-related nutrients, alcohol, and the MTHFR 677C&#8594;T polymorphism affect cancer risk: intake recommendations. J Nutr. 2003;133:3748S-3753S. 15 Arkbage K, Verwei M, Havenaar R, Witthoft C. Bioaccessibility of folic acid and (6S)-5-methyltetrahydrofolate decreases after the addition of folate-binding protein to yogurt as studied in a dynamic in vitro gastrointestinal model. J Nutr. 2003;133:3678-3683. 16 Setchell KD, Lydeking-Olsen E. Dietary phytoestrogens and their effect on bone: evidence from in vitro and in vivo, human observational, and dietary intervention studies. Am J Clin Nutr. 2003;78(suppl):593S-609S. 17 Iversen MD. Fibromyalgia. The Fibromyalgia Impact Questionnaire (FIQ). Arthritis Rheum. 2003;49(5S):S210-S213. 18 Giesecke T, Williams DA, Harris RE, et al. Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum. 2003;48(10):2916-2922. 19 Logan AC. Dietary modifications and fibromyalgia. Comp Health Prac Rev. 2003;8(3):234-245. 20 Nicolson GL. Lipid replacement as an adjunct to therapy for chronic fatigue, anti-aging and restoration of mitochondrial function. JANA. 2003;6(3):22-28. 21 Garrison RL, Breeding PC. A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone. Medical Hypotheses. 2003;61(2):182-189. 22 Leonetti HB, Wilson KJ, Anasti JN. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Fetility &amp; Sterility. 2003;79(1):221-222. 23 Messina MJ, Loprinzi CL. Soy for breast cancer survivors: a critical review of the literature. J Nutr. 2001;131(11 Suppl):3095S-3108S. 24 Kurilich AC, Jeffery EH, Juvik JA, Wallig MA, Klein BP. Broccoli extracts protect against reactive oxygen species in HepG2 cells. J Nutraceuticals, Functional &amp; Medical Foods. 2003;4(2):5-16.

Welcome to Functional Medicine Update for March 2004. We are in full swing preparing for this year’s symposium, May 11-15, 2004 at the Westin Bayshore Resort in Vancouver, Canada, where we will focus on “The Coming Storm: Reversing the Rising Pandemic of Diabetes & Metabolic Syndrome.” This is going to be a remarkable event. I am excited about our slate of plenary speakers and the workshop sessions with “news to use” formats to help with clinical application of the concepts. I believe we will all gain new insight into how to manage this complex and important disorder, the incidence of which seems to be rising to epidemic proportions. I hope you will plan to be with us. I invite you to call the Institute for Functional Medicine at 1-800-228-0622 if you have any questions about the program. With the symposium in mind, this issue of FMU will focus on aspects of insulin resistance and its relationship to coronary heart disease, diabetes, and inflammatory disorders. These include conditions related to self-proliferative disorders—colon cancer and endocrine-related cancers such as prostate cancer and breast cancer. These conditions may seem at first to be far removed from insulin resistance, but there is a strong, emerging link between insulin resistance and cell-signaling processes related to cellular proliferation of specific tissue types. This link increases the risk and incidence of specific types of cancers and the angiogenic and metastatic processes associated with them. The Homocysteine Theory of Heart Disease Before we begin our discussion, I would like to honor one of our long-term FMU subscribers, Dr. Richard Podell, from the Robert Wood Johnson Medical School in Short Hills, New Jersey. For many years, he has written eloquently about themes in preventive medicine. Recently, Dr. Podell published an article that appeared in the journal, Medical Hypotheses, titled “Understanding the transition from alternative medicine to mainstream science: the homocysteine theory of heart disease and the crucial role of effective mentoring.”[1] I want to compliment Dr. Podell on this article. He used as an example of how science resists change, Kilmer McCully’s hypothesis that hyperhomocysteinemia is associated with increased risk to vascular disease, and not just a digital, but rather a graded increasing risk, depending upon homocysteine plasma concentrations. It is not whether you have it or not; you may be at higher risk with increasing homocysteine plasma levels. That hypothesis faced a lot of resistance by “mainstream medicine” for more than 30 years, but Dr. McCully was committed and quite diligent about pursuing his theory. Even in the face of criticism and adversity, he was able to eventually mount enough persuasive information to get his colleagues to look at the concept more in depth, resulting in a paradigm shift over the last few years. Dr. Podell uses McCully’s homocysteine theory of heart disease to describe the transition from what may have been considered alternative at one point to incorporation into the body politic of mainstream medicine. It is always ironic, because when that transition occurs, it seems that it was initiated in the mainstream and never existed prior to that, even though the theory may have a 30-50 year precedent before it is finally accepted. Dr. Podell uses an interesting format in his article. He asks some questions and then answers them. For instance, why is alternative medicine science so weak? What practical steps might we take to foster a more rigorous research approach? He uses the McCully hypothesis as an example. When McCully first proposed the homocysteine theory of heart disease (HTHD) in 1969, mainstream medical science vigorously rejected both the theory and its author, especially in the US, because it was thought that heart disease was primarily the result of high cholesterol. The cholesterol hypothesis was dominant; it was not politically favorable or fashionable to be speaking against that concept. If research money is sought to investigate something that people do not consider potentially important, the money is usually not forthcoming and science cannot be amassed in support of new concepts. It almost becomes a self-fulfilling circular reinforcement of a preexisting dogma, and it is difficult to break away and support an alternative hypothesis. The problem is that people say there is no research to support the new hypothesis and the cycle continues, like a dog chasing its tail. Dr. Podell asks: “Why was the HTHD first rejected so fervently? What factors, two decades later, resulted in its revival?” He suggests there was a changing philosophy and a changing paradigm slowly emerging as a result of the concept Linus Pauling described in his 1949 landmark article on sickle cell anemia, in which he used the term “molecular medicine.” Dr. Pauling proposed that many disorders that later evolve into various diseases are locked into genetic soil and play out through the interaction of genes and environment to give rise to the diseases. Heart disease is not an infectious disease or a traumatic disease; it is a metabolic disease. This emergence stemmed from the work of Sir Archibald Garrod’s concepts of metabolic genetic inborn errors of metabolism. Pauling then talked about the role that various natural molecules, which he termed “orthomoleculars,” have on the modification of the internal milieu of the body and the promotion of physiological function. From that came the discovery that specific nutrients, which are natural substances in the body, could be used at higher levels to promote specific enzyme function and push sloppy equilibrium and physiological chemistry toward completion. This results in optimization of function in individuals who may have had what we now call genetic polymorphisms that lead to sluggish reactions. Rather than changing genes, promotion or improvement of optimal function is achieved by pushing for equilibrium through a mass action effect with administration of higher levels of a cofactor—the vitamin, mineral, or nutrient factor. This was an interesting new concept in medicine, well described in a landmark article published in Science magazine in 1967 by Dr. Pauling, titled “Orthomolecular Psychiatry.” The article was not well received or understood by those in the traditional medical world because it spoke in physical chemistry terms about enzyme binding, reaction rates, and kinetics. These things were probably not on the minds of most practicing physicians at that time. It did provide a formalism by which one could understand some of the things Dr. McCully was speaking to. A broader body of understanding began to build based upon some fundamental principles: in this case, the Pauling principle of orthomolecular medicine; and later, mega nutrient therapy. Increasing interest began to grow on the part of other investigators to conduct research on homocysteine. Classic papers were published from 1980 through 1985, such as those written by Malinow, Kang, Taylor, et al., which demonstrated that McCully’s hypothesis warranted further research. From the 1980s until the year 2000, there was finally some public acceptance of McCully’s homocysteine hypothesis. This resulted in some public health policy decisions about homocysteine and the B vitamins. There was finally some agreement that the B vitamins could modify function through activating sluggish enzymes involved in the metabolism of homocysteine. That led to a transition of increasing interest in the 1990s. The number of papers and citations in this area increased dramatically as the new concept became more favorable and fashionable. It was finally considered an “OK research project” for an academic or medical researcher to be involved in. It became a new “head of steam” producing its own paradigm shift. The timeline I am talking about—1969 to 2002—is a period in excess of 32 years. That is a pretty remarkable latency period during which people still saw the theory as “alternative” until it finally “clicked over” and became part of the mainstream. Dr. Podell proposes that we need a conference to discuss controversial areas and share broad disciplinary input, and suggests the topic of diabetes, which we will focus on at our 11thInternational Symposium on Functional Medicine. He proposes that the National Institutes of Health, the American Diabetes Association, and other prominent institutions convene a weekend conference of perhaps 20 leading diabetes scientists, including those doing controversial work that is not in the “mainstream.” This would help foster and stimulate new ideas and new research concepts that might lead to faster development of potentially successful therapies. It might also break down barriers and start building bridges across different disciplines. This is a laudatory call for action and certainly has potential for positive outcome if we could suspend our disbelief, work together across disciplines, and look across perceptions about how to solve these problems. I want to thank Dr. Podell. He has helped us to understand some of the barriers we have talked about so many times over the last 20 years in FMU as to why certain of these concepts take so long to finally become absorbed into practice. ny questions about the program. With the symposium in mind, this issue of FMU will focus on aspects of insulin resistance and its relationship to coronary heart disease, diabetes, and inflammatory disorders. These include conditions related to self-proliferative disorders—colon cancer and endocrine-related cancers such as prostate cancer and breast cancer. These conditions may seem at first to be far removed from insulin resistance, but there is a strong, emerging link between insulin resistance and cell-signaling processes related to cellular proliferation of specific tissue types. This link increases the risk and incidence of specific types of cancers and the angiogenic and metastatic processes associated with them. The concept of modifying insulin sensitivity and improving glucose transport is another area that falls under the potential rubric of alternative therapies. There are those who have been arguing for dietary and lifestyle interventions that are not considered within the scope of the American Diabetes Association, but they are starting to accept alternative interventions as possibly being effective and having validity. I am reminded of Robert Atkins’ interesting hypothesis. I met Dr. Atkins in the early 1970s. His concept of weight loss using ketogenic diets (high in protein and fat and low in carbohydrate) was observed to be useful from an empirical standpoint. There was no question that patients who went on the Atkins Diet lost weight rapidly. It was argued against because the loss of weight was principally due to the diuretic effect of the diet (loss of water), and it was felt that you could not lose 10 pounds of fat in a week. Some patients said they lost 10 pounds in a week, but thermodynamically, it was felt that it would not be possible to lose that much weight in a week’s time unless one was training for an athletic endurance performance. People were told they were losing water and electrolytes and increasing ketone and triglyceride levels, which is not good. They were cautioned they might experience metabolic acidosis. Some people who were poorly controlled on this program did have problems. The diet was looked upon as one outside of the mainstream. Yet, it may have had some unique metabolic effects on insulin, cell signaling, adipocyte physiology, and the interrelationship between fat mass and central system function that controls messages related to appetite control and thermogenic response. It was not accepted that a dietary approach with higher protein/higher fat and lower carbohydrate was reasonable. Thirty years later (again, this timeline seems to be interestingly coincident), there were things about the higher protein/lower carbohydrate diet in certain individuals (now called carbohydrate sensitive or dysglycemic), that may account for the remarkable improvement in their body composition. Lowering simple carbohydrate, insulin-mediated responses, and glucose transport difficulties improves cell signaling and has a positive impact on glucose transport and gene expression—things like protein tyrosine kinases that regulate various aspects of cellular function, and lower cellular proliferation and inflammation. These are interesting outcomes from such a simple thing as changing the ratio of carbohydrate to protein to fat. Over the last 30 years, the story has changed as we have learned more. Now, we recognize that the Atkins Diet is not just eating all the fat and protein you want and not eating any carbohydrate. Again, it is eating the right protein and fat, and it is not necessary to rigorously exclude all carbohydrate, but certainly that which has a high glycemic load contribution, leading to increased insulin and impairment of glucose transport. This approach has been refined, but certainly the perception that increasing protein and lowering carbohydrate, particularly the refined simple carbohydrates that have become so predominant in our processed diet, does have a beneficial and salutory effect on insulin dynamics. Insulin activity is much more than controlling blood sugar; that is the interesting part of the story. Insulin activity also has an influence on the regulation of the expression of certain genes, changing the cellular architecture of the way the cells are expressed, which is more than glucose transport alone. Many functions can be altered, such as the expression of inflammatory mediators and various types of peroxisome proliferation and activity that relate to fatty acid metabolism. As a consequence of 30 more years of research, we are now recognizing that there are some extraordinary physiological influences of an altered protein/carbohydrate/fat diet on fundamental processes that affect the human genome and are expressed into the phenotype. This is the “new look” of dietary protein in diabetes. An editorial which appeared recently in the American Journal of Clinical Nutrition, addressed that topic.[2] Dr. Robert Eckel talks about new clinical research being published showing that an increase in dietary protein improves blood sugar response in people with type 2 diabetes. Mechanistically, it occurs through alteration of the cellular signaling process pertaining to insulin mediation and how that interrelates with a variety of other gene response expression patterns having to do with insulin sensitivity and insulin levels. We need to change our view of how protein, fat, and carbohydrate may serve as macronutrients in the modification of gene expression and the regulation of function. Dr. Eckel says that we have to be cautious not to overdo any specific model and assume it is the answer to all problems related to insulin resistance or to diabetes. “Many myths about protein and diabetes control need to be recognized. Although nonessential amino acids may promote glucose production, plasma glucose does not increase after protein ingestion. Moreover, increases in dietary protein do not promote sustained elevations in glucose, slow the absorption of dietary carbohydrate, or accelerate the increase in plasma glucose in response to insulin-induced hypoglycemia.” Dr. Eckel also points out that any diet model can be taken to the extreme. Someone who reads this might wind up thinking protein is great and carbohydrate is bad, and decide to get the majority of calories from protein. That would be considered an extremist position. Why do I say that? Let us assume, for the sake of argument, that a person is on a 2400 calorie-per-day diet, and will get the majority of calories from protein—let’s say 50 percent. Fifty percent of 2400 calories is 1200 calories and there are 4 calories per gram. How many grams of protein would be consumed on a daily basis? It would be 300 grams. Is the average liver and kidneys of an individual capable of processing 300 grams of dietary protein a day, and maintain good functional health over time? The answer for most individuals would be no. That would be considered a very high load of nitrogenous molecules that the body has to deal with through the urea cycle and then through the urogenital system, in order to properly manage and metabolize that level of dietary protein. Clearly, overwhelming the body’s machinery for handling amino acid protein metabolism could take the model of good protein/bad carbohydrate to an extreme. Also, this does not speak to the type of carbohydrate. There is a significant difference in the glycemic load effect of a simple carbohydrate with rapid kinetics of absorption and dramatic effects upon metabolic function, versus a slow-release complex carbohydrate wrapped up in unrefined plant fibers, both soluble and insoluble, with different kinetics and different effects on glucose dynamics. Using the terms “protein” or “carbohydrate” could be misleading. We need to be specific about the type of protein and carbohydrate, and differentiate from things like simple sugars, partially hydrogenated vegetable oils, or saturated fats. Even things in the protein family that might be considered heat-damaged proteins with heterocyclic amines could be toxic and have carcinogenic potential. Sometimes we lose the real specificity by using general terms A paper in the American Journal of Clinical Nutrition discusses an increase in dietary protein resulting in improved blood glucose response in people with type 2 diabetes.[3] This is certainly encouraging. This paper describes a study in which the ratio of protein to carbohydrate to fat was varied in two diets. The ratio of protein to carbohydrate to fat was 30:40:30 in the high-protein diet and 15:55:30 in the control diet. In this washout, crossover study, it was found that the high-protein diet lowered blood glucose postprandially in persons with type 2 diabetes and improved overall glucose control. Glycated hemoglobin decreased 0.8 percent and 0.3 percent after five weeks of the high-protein and control, diets, respectively. Triacylglycerol was significantly lower after the high-protein diet than after the control diet. Insulin, C-peptide, and free fatty acid concentrations were not significantly different after the two diets. The investigators suggest that longer-term studies are necessary to determine the total magnitude of response, potential adverse effects, and the long-term acceptability of the diet. It is encouraging that dietary protein appears to exert a beneficial effect in modifying the glycemic response to diet There has been a longstanding controversy about whether sugars do or do not have adverse effects on glycemic control. It is my strong belief from what has been published over the last few years that in individuals with impaired insulin sensitivity, the higher-sugar diet has a deleterious effect on normalizing blood sugar. It is not total carbohydrate alone, but also the simple carbohydrate that needs to be modified. This topic is discussed in another recent paper in the American Journal of Clinical Nutrition, titled “Sugars, insulin sensitivity, and the postprandial state.”[4] Mark Daly discusses that the pattern of postprandial responses elicited by sucrose and fructose differs substantially from that elicited by starches, and that they may offer a potential explanation for the conflicting results on insulin sensitivity. It is possible that increases in insulin exposure may affect insulin sensitivity through downregulation of insulin action. The concept of normalizing insulin response to the diet might apply to some of our thoughts about vegetarianism. The vegetarian diet has historically been modest in protein, much higher in carbohydrate, and modest in fat, but the fat has generally been that of highly unsaturated vegetable oils, polyunsaturated fats. If protein is really the determinant for lowering insulin response, then why is it that people on an unrefined, complex carbohydrate vegetarian diet appear to experience beneficial effects on the regulation of insulin and glucose? That is why I have been emphasizing that it is not protein alone; it is the full complex of the matrix of the diet. This comes from some work recently published in the American Journal of Clinical Nutrition by David Jenkins on type 2 diabetes and the vegetarian diet.[5] Dr. Jenkins will be a presenter at our 11th International Symposium on Functional Medicine in May, and is one of the world’s most well known investigators on the relationship between insulin sensitivity and carbohydrate nutrition. He is one of the fathers of the concept of the Glycemic Index. He says the vegetarian diet contains a portfolio of natural products that help to regulate insulin sensitivity. It is not just the complex carbohydrate and the fiber; it is also the phytonutrients in a rich, unprocessed, natural, high complex carbohydrate diet that help to regulate insulin sensitivity and cell signaling. White flour and sugar are quite different from colored fruits and vegetables in their natural composition and the way they can contribute to regulating insulin. Protein is important, but the type of carbohydrate and its role in a complex vegetarian diet is important, as well. The takeaway is that both Atkins and Pritikin were right. What Nathan Pritikin and, before him, Dr. Lester Morrison at UCLA talked about, was not wrong. A high complex carbohydrate, unrefined, high fiber diet will help to normalize blood sugar and lower the risk to diabetes and cardiovascular disease. It is not that our physiology has suddenly changed and requires a high protein diet. It is the nature and the form of these ingredients in the context of the highly processed white-type diet that we are consuming today—the diet of convenience—that may feed into dysglycemia and the pandemic of type 2 diabetes. This is also the model that Dr. Dean Ornish has spoken to very effectively from his studies and the discussions we have had with him in FMU (December 1990, May 1992). We need to be cautious not to throw the baby out with the bath water and claim that protein is good, carbohydrate is bad, and the best approach is to eliminate carbohydrate from the diet. There is no evidence to support that. It is the type of dietary protein, carbohydrate, and fat that seems to play the important role. If we examine the contribution of vegetarian diets to health and ask if we are seeing a paradigm shift, I believe it is the type of vegetarian diet. Is it adequate in protein? Is it a diet using unrefined fruits, vegetables, grains, and legumes? Or, is it vegetarian meaning potato chips, Coke, and French fries? That is a high carbohydrate diet, too, but one that contains the wrong kind of carbohydrate. That is what Dr. Joan Sabatè talks about in a recent editorial in the American Journal of Clinical Nutrition on the changing paradigm.[6] She discusses a vegetarian diet that will improve insulin sensitivity and vascular function, reducing the risk to both diabetes and heart disease. You will be hearing much more about this from the experts in the field who will be presenting at our May symposium. It is inappropriate to focus on percentage calories of macronutrients and assume that we now have the perfect diet—the concepts of 40/30/30 or 15/30/45, or whatever the ratios might be. We tend to think that the numbers are the control factors, when it is really what makes up those numbers. What is the type of protein? What is the type of carbohydrate? What is the type of fat? Significant variations in glycemic response and insulin dynamics can occur based upon the composition of each of those macronutrients, as much as the ratio percentage. That does not mean that increasing dietary protein is without benefit in individuals with impaired glucose tolerance or insulin resistance; it is to try to put this argument or perspective into context. It also relates to the presence of various micronutrients in the diet, not just macronutrients. What is the nutrient density of the B vitamins that we know are extraordinarily important for carbohydrate metabolism? We have heard from Dr. Derrick Lonsdale, an eloquent clinician/presenter on FMU many years ago (September 1992, April 1998), who talked about transketolase as an important enzyme for carbohydrate metabolism and the role of vitamin B1 (thiamin). Many people may have a functional thiamin insufficiency that requires much higher levels of thiamin to drive their transketolase and improve their carbohydrate metabolism. They could have a functional vitamin insufficiency that is not recognized that produces carbohydrate craving and a “sweet tooth.” Thiamin does not work by itself; it works as part of the B complex family in balance with riboflavin, pyridoxine, cobalamin, and folic acid. All of these vitamin B family complex members work together to help regulate energy metabolism. What about trace minerals? Chromium also plays an important role in insulin signaling through glucose tolerance factor. This topic is nicely reviewed in a recent paper by Drs. Anne Dattilo and Stanley Miguel, titled “Chromium in Health and Disease,” that appeared in Nutrition Today.[7] They review the work of Dr. James Anderson on the role of increasing dietary chromium in improving insulin sensitivity and glucose transport. Doses or intakes of chromium in the hundreds of micrograms-per-day levels may be beneficial for individuals who have a certain type of insulin resistance or impaired glucose response. Like all nutrients, a little is good; a little more may be better, but a whole lot more may not be better. We should not jump to the conclusion that if an individual does not get a response at a certain level, that the dosage should be increased. Everything has a parabolic dose response curve—coming up the side of the curve to optimal function with increasing concentration, and going down the other side of the curve to reduce function with toxic intake of a substance. With chromium, there is also potential for adverse effects. According to the clinical work on this trace mineral, over 1000 mg per day may be inappropriate unless following a specific uniqueness in a patient in which potentially adverse effects might result. According to the review, a range of 100 to 1000 mg per day is probably in the safe range. Chromium may play an important role in helping to stabilize insulin response. There are also a number of studies showing that vitamins C and E improve insulin sensitivity. The polyunsaturated fatty acids of the omega 3 family also appear to have a beneficial effect on insulin sensitivity. Shifting away from a partially hydrogenated vegetable oil diet to a more fish oil-based or plant unsaturated oil-based diet rich in omega 3s, such as flaxseed oil, may be beneficial in improving insulin sensitivity. The point I am trying to make is that there are many variables and nutritive factors that play a role in helping to send the right message from insulin to the cell to improve and normalize glucose transport. I have not gone into phytochemicals in plants, like flavonoids, glucosinolates, and polyphenolic compounds that can influence insulin sensitivity. We are going to learn much more about those and why they may be important contributors in a complex unrefined diet for improving insulin sensitivity. It is not just the macronutrients or the traditional vitamins and minerals. There are other substances found in plant foods that may help to regulate insulin sensitivity. We have had difficulty in making the transition to the food of commerce, the food of convenience, the food of white sugar, white fat, and white flour, with nominal nutrient fortification to prevent scurvy, beri beri, pellagra, xeropthalmia, and rickets. That diet appears to be associated with increasing prevalence of metabolic syndrome. That diet, coupled with lowered exercise patterns and perhaps other factors such as stress, as discussed in a recent cardiology review, starts the clock ticking. The ticking clock is heading toward increasing atherosclerotic and diabetes risk. This is discussed in an interesting review that appeared in the November 2002 issue of Cardiology Review,[8] talking about what happens physiologically as insulin resistance increases. Microvascular outcomes occur as a consequence of metabolic syndrome, and this increases cardiovascular risk, as well as peripheral vascular injury, neurologic injury, peripheral neuropathies, and ocular injury. Nephropathic problems occur downstream with a loss of kidney function. These are big problems that occur over periods of time. Well before the person may be diagnosed as having diabetes, they may be experiencing these adverse effects. Optimizing insulin sensitivity plays an important role in the prevention of “age-related dysglycemic events.” The thiazolidinedione family of drugs has been used to improve insulin sensitivity through activation of the peroxisome-proliferated activated receptors (PPARs), but there are natural substances in the diet that are PPARg agonists. If diets are consumed consistent with physiological needs, some of the messages for PPAR agonists are sent free of charge. Medications may not be necessary. As the mechanism of insulin resistance is explored, including some of the effects from certain drugs such as metformin, the sulphonylureas, or the thiazolidinediones, it is recognized that dietary factors play roles in the mechanisms the drugs are attempting to treat. They share common pathways. When we eat food that contains the right nutrients, it results in the right physiologic effects. Foods we frequently consume may send altered signals to dysfunctional pathways, for which we sometimes use various medications to modify, block, or alter. As insulin goes up and insulin resistance increases, other secondary endocrine disturbances occur in the metabolism of DHEA through cortisol and into androgens and estrogens. We now know that the steroid dehydrogenase enzymes can be modified in their function by high insulin levels, particularly in theca cells in the ovaries of women. Increasing incidence of polycystic ovary syndrome (PCOS) through hyperandrogenicity is associated with insulin resistance, as well as menstrual dysregulation, menorrhagias, and changing body architecture such as the apple-body shape in women that may occur as a result of a shift in androgen. The insulin resistance/hyperinsulinemia syndrome has a multiple series of effects on endocrine function, thyroid function, sex steroid hormone function, and cortisol function. It is not just blood sugar alone. That is the model that is starting to emerge. There is a good paper in Medical Hypotheses discussing the relationship between postprandial insulin and visceral vs. gynoid adiposity.[9] The apple-body shape (increased waist-to-hip ratio) seen in some women, which may include growth of facial hair and what appears to be male-like shifts in physiognomy, is associated with insulin resistance/hyperinsulinemia and altered postprandial insulin sensitivity. Managing the mechanisms of insulin signaling involves more than just the risk to diabetes. There are microvascular, macrovascular, and endocrinological impacts that cut across many different conditions, diseases, and subspecialties of medicine. Diet and lifestyle play principal roles in establishing the tone of how genes are expressed into these signaling pathways. For instance, they may help to normalize function or create dysfunction that is finally diagnosed as PCOS. PCOS is the last stage of a series of events that promote increasing androgenicityin women, with dysfunctional impact on ovarian function with lowered estrogen and increased androgen concentrations. It is not whether or not you have PCOS. There is a graded effect of increasing relative risk with increasing insulin resistance. This is another important part of the functional medicine model which shows graded effects from complete absence of function, which we call pathology and perhaps death, to the presence of optimal function, and every stage in between. It is a graded series of stages. Diagnosis is often dependent upon crossing a specific threshold that we call the disease threshold. On a functional basis, there is a whole range of different functional states that may precede the onset of disease or diagnosis associated with disability, lowered quality of life, or chronic illness. That is the stage where functional medicine, based on physiological mechanisms, can play its most important role. I hope I have given you some insight into insulin resistance and dietary relationships, and the protein/carbohydrate/ fat connection. We will move to side 2 to continue this discussion.

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INTERVIEW TRANSCRIPT

Clinician of the Month Loren Cordain, PhD, Professor Department of Health and Exercise Science Colorado State University Fort Collins, CO 80523 JB: It’s time for our Clinician/Researcher of the Month. Over the years in FMU, we have been fortunate to listen to some voices of great clarity on complex issues pertaining to lifestyle, health, environmental issues, and chronic disease. This month is no exception. We are privileged to have Dr. Loren Cordain as our guest. Many of you may be familiar with his work. He is the author of the book, The Paleo Diet, which was brought to my attention by one of our physician subscribers. He suggested I read it because it would “fill in a lot of gaps.” That turned out to be a good suggestion. The book is well written from very interesting anthropological and physiological perspectives. Dr. Cordain received his PhD in Health from the University of Utah in 1981. He has been employed as a professor in the Department of Health and Exercise Science at Colorado State University for the past 21 years. His work has been highly publicized. Having looked over your C.V. and observing how many years you have been engaged in exercise science and the relationship of exercise to physiology, my first question is how did The Paleo Diet concept emerge? Emergence of The Paleo Diet Concept LC: Thank you, Jeff, for the kind words regarding my book and our research. By the way, we have a website, www.thepaleodiet.com, and your readers can download all of our scientific papers. We have roughly 30 to 50 papers and abstracts available on this topic. The book itself was written based on our scientific findings in hunter-gatherer societies. About 15 to 20 years ago, I read Boyd Eaton’s seminal paper in The New England Journal of Medicine, titled “Paleolithic Nutrition.”[10] I thought it was just about the best idea I’d ever heard of. I read all the cross references in that article, which generated even more cross references that opened up a gigantic spider web of articles. I began to form files on all the topics and started making connections. In the early 1990s, I finally got up enough courage to call Dr. Eaton at Emory University and had him come to Colorado State University, where he gave a talk. We hit it off and started publishing papers together. Paleolithic nutrition is a passion of mine and whether I get paid to do this work or not, I’d be doing it. It is simply my passion. JB: That rings true very strongly in your work in which there is obviously a strong mission-driven component. For those listeners who might be unfamiliar with the concept of the Paleo Diet, perhaps you could give us a brief overview before I ask you how it interrelates with some other current diet controversies. Overview of The Paleo Diet LC: I think you’ve really hit the nail on the head, Jeff. There are probably as many opinions about what the optimal diet is as there are people on the planet. Initially, when I set out, my original goal was to find the optimal healthful diet for myself. One way of doing that would be to look at every single possible diet to try and find out what would be the best one. But I thought there must be a more powerful and leveraging procedure to do this, and indeed there is. Dr. Eaton’s concept is that our nutritional needs are determined by our genes. I don’t think anybody in your audience would argue that; the fact that we require omega 3 fatty acids or vitamin A is because our cells need them. Why do our cells need them? They need them because our genes are building proteins. The next question that arises is what shapes our genes? Why is an animal a herbivore, another animal a carnivore, and another animal an omnivore? Why have they adapted to different diets? The reason for that is natural selection. It’s the environment the animal evolved in. That is really a biological action that goes without saying, that animals are optimally adapted to their environment and the foods that are found there. Humans are no different than any other animal. What Dr. Eaton proposed was that if we go back to the time when all humans were in their native ecologic niche, the hunter-gatherer niche which was, evolutionarily speaking, very recent. Only 500 generations ago, every human on the planet was a hunter-gatherer and the only foods we could eat were those that were minimally processed wild plant and animal foods. We’ve gone back into the fossil record. We’ve also examined the diets of modern-day hunter-gatherers to determine what they have eaten and what they haven’t eaten. The most enlightening part of all of this is what they don’t eat. What we’re finding now from clinical studies is that increasingly, the foods they don’t eat are those associated with health problems and illnesses. JB: That’s a very interesting model. The concept is that it’s not just the bad stuff we put in food, but also the good stuff we take out. When you look at how these dietary changes over the last 50 or 60 years have impacted health, where do you find the biggest differences between the Paleo Diet and today’s diets of convenience? Differences Between Today’s Diet of Convenience and The Paleo Diet LC: It’s very astute of you to realize that it’s not just what we took out; it’s also what we put in. This process began 10,000 years ago with the domestication of cereal grains. Increasingly, as we ate more cereal grains, something had to give. Something had to be reduced in our diet. We started eating less animal products and less fruits and vegetables. Animals were domesticated at about the same time—10,000 years ago—so we started to include dairy products in our diet. As we include dairy products and cereal grains in our diet, we displace fruits and vegetables, wild lean meats, and seafood. That process accelerated as more and more Neolithic foods came into our diet. For instance, salt was first observed being mined in Europe roughly 6,000 years ago. Prior to that time, very few people had any sort of processed salt in their diet. Except for honey, we ate no processed sugars. Refining sugar didn’t happen until about 1,000 years ago in India, when it was observed for the first time. Since the Industrial Revolution over the course of the last 200 years, we have increased our sugar intake. The same thing can be said about cereal grains. Cereal grains, up until about 200 years ago, were all consumed in their whole form. The procedures to mill cereal grains that produced very fine flour, removed the germ and the bran, were only introduced in steel roller mills in the 1880s. The same thing can be said about high saturated fat meats. Prior to about 1850, all meats that were consumed in this country were basically grass-fed. With the advent of the steam engine, the reaper, and other mechanized industrial tools, we were able to bring cows and corn together and produce feedlot-fed animals. Today, 99.9 percent of the beef, chicken, and pork we consume has been produced in a feedlot. This is very fatty meat compared to that of an animal produced in the wild. Dramatic changes have occurred. Trans fatty acids only came about by the hydrogenation process that was invented in 1897. All of these changes have occurred in our diet, including those resulting from refrigeration. We have come a long way, but way beyond foods that we were genetically adapted to eat. JB: One of the points I have been trying to make in our discussions over the last several months is that these foods you’ve been describing are more than just nutrients; they are also signaling molecules. They impart signals picked up by response systems that alter gene expression patterns. That shapes both our physiology and our physiognomy. That’s why people start looking different. We start seeing more apple-body shaped people with morbid obesity. The reflection at the phenotypic level of what is occurring at the gene response level is a manifestation of how these food changes interface with our gene potential. Is that consistent with the model you’re describing? Research on Diet and Acne LC: That’s absolutely correct. I’m not familiar with the level of sophistication of your audience, but we can go into that kind of detail. For instance, we published a paper in the Archives of Dermatology, probably the finest scientific medical journal on dermatology.[11] The official position of the dermatology community had been that diet and acne were completely unrelated. We traveled to a population of hunter-gatherers, the Ache people in Paraguay in South America, and followed them over a two-year period. It was a small group of about 118 hunter-gatherers. Some of the anthropologists in our group followed them over a two-year period and we had physicians in the field with the anthropologists. We didn’t find one case of acne in any of the adolescents or any of the adults. We went further to a remote island off the coast of Papua New Guinea called Kitava where there are about 3000 people. A member of our research team, Dr. Stefan Lindeberg, examined these folks cross-sectionally over about a four-month period. We examined more than 300 adolescents and didn’t find a single case of acne. If you were to look at a population of 300 adolescents in the United States, roughly 80 to 85 percent of them would have acne. That led us to the idea that there had to be something going on environmentally that was responsible for the vast differences between the acne incidence rate in non-Westernized versus Westernized people. We found that even though the diets between the Ache in Paraguay and the Kitavans on the remote island off the coast of Papua New Guinea were vastly different, they did have similar characteristics, in that the carbohydrates they ate were all low-glycemic-load. Our research group believes, and we set up a mechanism for this, that high-glycemic-load carbohydrates such as refined flours, sugars, potatoes, chips, and processed foods found everywhere in the Western diet, set up a situation where insulin is chronically elevated. When insulin is chronically elevated, other hormones are elevated, as well, and other hormones are reduced. There’s a hormone called IGF-binding protein-3 that is reduced. It turns out that IGF-binding protein-3 is a ligand for an endogenous retinoic acid receptor. Retinoic acid is involved in the proliferation of cells at the gene transcription level. We believe that acne represents unregulated tissue growth, first at the endothelial cells that surround the hair follicle. Acne is a plugging of the hair follicle by excessive endothelial cell growth and it results from excessive sebum production. When insulin is chronically elevated, it also tends to elevate androgens, or the male hormone. The male hormone is responsible for producing more sebum. It actually works at the gene transcription level. Food and genes are intimately related, and they are phenotypically expressed as health and disease. That’s just one small example of how our group has been challenging the status quo and has been on the leading edge with our research. JB: I had a chance to read one of the papers in the Archives of Dermatology on the research you just discussed. I thought it was very well done, and both provocative and substantial in its support. LC: Thank you. I just want to mention to your listeners that we also have empirical intervention data that supports that research. What we had originally done resulted in epidemiologic data. Now, we have dietary interventions. We completed a trial in Australia in which we took 75 adolescents who had acne and put them on a high-protein, low-carbohydrate type diet, similar to what the Paleo Diet is all about. We had a dramatic reduction is acne incidence rates in the group, and complete elimination of acne in many of the subjects. JB: That obviously segues nicely into a companion question. Another of your papers which is equally interesting is titled “Hyperinsulinemic Diseases of Civilization—More Than Just Syndrome X.”[12] One of those diseases we’ve been talking about is acne. Would you tell us a little bit more as to how you see hyperinsulinemia fanning out into other disorders of aged populations? Disease and Elevated Insulin Levels LC: With syndrome X, I think many people think about type 2 diabetes, obesity, hypertension, and dyslipidemia—the characteristic diseases. We determined that diseases of unregulated tissue growth are related to a chronically elevated insulin level. Insulin is a very potent anabolic hormone, meaning that it stimulates growth in all tissues. It does that via a number of hormonal cascades that I described. It tends to elevate androgenic hormones and it tends to influence the IGF-1/IGF-binding protein 3 growth hormone axis, all of which tend to promote growth. Growth is very good during adolescence, and also during the later years, but it also needs to be regulated. We find that perturbation of these hormones after the growth period tends to promote epithelial cell cancers. Epithelial cell cancers are those such as breast, prostate, and colon cancers. We believe that high glycemic load carbohydrates are environmental dietary factors that underlie these diseases. Epithelial cells are those that have very rapid turnover, so the cells in the colon, in the milk ducts in the breast, and in the prostate, have very rapid turnover. Therefore, they are highly responsive to 24-hour changes in hormones. High glycemic-load carbohydrates manifest themselves as epithelial cell cancers because they are so susceptible to changes in IGF-binding protein 3, IGF-1, and insulin. JB: That leads to a common question. Is carbohydrate bad and protein good? Should we shift our diet almost predominantly to protein and leave carbohydrate behind because it’s a bad substance in the diet? From what you’ve said and also indicate in your book, we need to put the type of carbohydrate, protein, and fat in perspective. Perhaps you would comment on that. Ratio of Carbohydrate and Protein in the Diet LC: That’s right. It’s primarily a qualitative rather than a quantitative issue. We believe that by elevating protein in the diet, it can have beneficial effects. In light of the Atkins Diet, some clinicians believe you can consume an unlimited amount of protein in the diet, but that’s not true. We pointed that out in a paper we published in the American Journal of Clinical Nutrition in 2000.[13] All people have a physiologic protein ceiling and that ceiling is based on how much urea is excreted. One of the byproducts of protein metabolism is urea, which is toxic. The body needs to get rid of urea. It does so in the liver and there are enzymes that allow urea to be turned into other products. But those enzymes can’t be infinitely upregulated. It turns out that roughly the maximum amount of protein you can eat in your diet is between 30 and 40 percent of your total energy if you’re in a equicaloric situation, meaning normal calories. There is a limit to protein consumption, and above and beyond that, protein becomes toxic. We believe there is a fine line. The amount of protein one gets in the typical Western diet is about 15 percent of our energy, and we’re eating roughly 50 percent carbohydrate. Increasing protein by 10 to 15 percent, up to 25 to 30 percent of your energy, with a subsequent reduction in carbohydrate and an increase in good carbohydrate (low glycemic-load carbohydrate), will have beneficial effects on the hormonal cascade that I’ve been speaking of. JB: In your book, you describe how one can go about achieving that objective you just described without falling back to the premise that protein comes in high saturated fat forms. Perhaps you can describe how this all gets woven together in a complex agricultural-based society with agri-businesses being the watchword. Diet in a Complex Agricultural-Based Society LC: You have brilliant insight into what’s going on. In the 1950s, we basically threw out the baby with the bath water. We decided that red meat was bad. We should have thrown out two things—the saturated fat that came with the red meat, and the way red meat is produced. We are feeding our cows corn, which is very high in omega 6 fatty acids. We also feed them sorghum. The cereal grains are very high in omega 6 and they produce an obese animal with high saturated fat. The membranes within the meat itself are very low in the healthful omega 3 fatty acids. Inadvertently, we produced big, fat animals resulting in juicy, red steaks that everybody liked, but we produced a very unhealthy product. In the 1950s, when we realized that the LDL receptor was downregulated by certain saturated fats, it became apparent that red meat was a bad thing, but we didn’t look beyond that. As I said, it’s a qualitative rather than a quantitative issue. If we could get healthy, lean meat as we do healthy seafood (providing it doesn’t have heavy metals in it), it’s a very healthful substance, one that we’ve evolved on and one that makes our physiology very correct. It’s a similar situation with grains. Whole grains are clearly much better than refined grains, but fruits and vegetables are better than grains. Evolutionarily, we got our carbohydrate from fruits and vegetables and very little from grains. The agricultural revolution changed that. Most of our carbohydrate came from grains. We ate less and less fresh fruits and vegetables, and more and more fatty meats. JB: I’ve had several recent discussions with Dr. Simin Liu from Harvard, who has been doing quite a bit of work on diet and its relationship to type 2 diabetes. He commented that we often focus a lot of our attention on the altered macronutrient intake associated with insulin resistance and hyperinsulinemia, but that there are also a lot of phytonutrients in fresh fruit and vegetable-rich, minimally-processed, grain-rich diets that probably have beneficial effects on insulin signaling. Is it your sense that these complex constituents also play an advantageous role in the Paleo Diet? Effect of Neolithic Foods in the Diet LC: Yes. Simin Liu is a close colleague of Jenny Brand-Miller, a coauthor on one of our papers on acne vulgaris. She is the author of the International Table of Glycemic Indices. I’ve had numerous conversations with Jenny and David Ludwig at Harvard. I’m absolutely on board with that. I don’t think diseases of insulin resistance have just one cause; they’re multifactorial. Phytochemicals, fiber, minerals, vitamins, omega 3 fatty acids are all involved. High glycemic-load carbohydrates are one of the major factors, but omega 3 fatty acids also play a dominant role. It’s a lot like a symphony orchestra. We need to listen to all of the instruments; we need to listen to the magic of the music rather than picking out single elements. That’s really the beauty of the paleolithic concept; it’s an organizing template that allows us to realize how all of these multiple elements come together. As I pointed out in my book and also in an article that we are preparing right now for the American Journal of Clinical Nutrition, these Neolithic foods that have been increasingly introduced in our diet have altered seven major areas that influence our health and well being. Phytochemicals, vitamins, and minerals comprise one area. The nutrient-density (content) of cereal grains is a joke compared to fresh fruits, vegetables, lean meats and seafood. JB: The pendulum of nutrition swings back and forth. I’ve been in this field for 30 years and I’m in the third cycle of harispendulum swinging as it relates to health, diet, and macronutrients. We can name many personalities associated with different diet approaches. We’ve got Pritikin, Ornish, Atkins, and Sears. There are many different persuasions as to how to prevent degenerative disease. We have everything from the very high complex carbohydrate, unrefined diet, which is modest in protein (about 15 calorie percent) up through suggested amounts as high as 50 percent protein. Each individual claims his diet approach is the one that will create lowered incidence of the major degenerative diseases. What is your take on all of this? Charismatic Individuals and Various Diet Plans LC: In my search for answers, I’ve seen many charismatic individuals who advocated different types of diets come and go, from Paul Bragg in the 1950s to Jack LaLanne, to Frances Moore Lappe (Diet for a Small Planet), on through Atkins, Sears, and Ornish. These diets are dependent on the charisma of a single individual interpreting the data. Rather, the beauty of the Paleo Diet concept is that it requires no charismatic individual; it simply requires an organizing template. The most powerful organizing template in all of biology is evolution through natural selection; it is the governing paradigm for all biological and medical sciences. All medical and biological sciences are determined by evolution through natural selection. We are all organisms that have been created through evolution via natural selection. The trail, or the clues, have been left behind, not by a charismatic individual, not necessarily by dietary interventions, but by examination of who we are and where we came from. Long after I am dead and gone, the concept of applying evolution and natural selection to nutrition, diet, and health will continue, because it is the correct organizing paradigm. Barry Sears doesn’t organize diet and nutrition; genes organize diet and nutrition. By uncovering these elements, we will be able to determine the optimal human diet. JB: That’s a very compelling argument, one I am going to remember in the future. We will be privileged to have you as a keynote speaker at our 11th International Symposium on Functional Medicine in May. Those who have listened to you in this edition of Functional Medicine Update will have a greater opportunity in Vancouver to hear much more. Thank you for your hard work and for sharing it with us today. LC: Thank you, Jeff. I’m looking forward to meeting you and presenting at the May symposium. We thank Dr. Cordain for an informative and eloquent presentation concerning some dietary modifications and their impact on insulin signaling. He made a complex topic easier to understand. At the end of the interview, we talked briefly about the role various phytochemicals and plant foods might have on insulin. I would like to revisit that subject in light of the recent body of research on some of these substances. Hydroxychalcone Derived from Cinnamon Functions as a Mimetic for Insulin in 3T3-L1 Adipocytes One class of substances receiving quite a bit of attention are the hydroxychalcone derivatives from cinnamon. This was first discussed by Dr. Richard Anderson in some preliminary papers looking at cinnamon’s effect on insulin sensitivity. There is an interesting paper that appeared in the Journal of the American College of Nutrition by Dr. Anderson from the Human Nutrition Center in Beltsville, MD and his colleagues, Drs. Karalee Jarvill-Taylor and Donald Graves, from the Department of Biochemistry at Iowa State University.[14] Based upon observational studies and animal work on the role of cinnamon in insulin sensitivity, this group performed experiments with the cinnamon methylhydroxychalcone polymer and insulin with regard to glucose uptake, glycogen synthesis, phosphatidylinositol-3-kinase dependency, glycogen synthase activation, and glycogen synthase kinase-3b activity. It was found that the methylhydroxychalcone fraction appeared to have important insulin mimetic effects in adipocyte cells. Insulin mimetic means insulin-like. It seemed to participate in the same type of influence on gene expression signaling and on glucose transport as insulin itself. These investigators conclude that the results demonstrate that the methylhydroxychalcone derivative from cinnamon is an effective mimetic of insulin and therefore may be useful in the management of insulin resistance and in the study of the pathways leading to glucose utilization in cells. A number of other papers have followed up on this, examining the effect of cinnamon fractions on insulin signaling by certain molecular biological probes—various phosphorylase enzymes and receptor kinase enzymes involved in insulin sensitivity. There is a nice paper in Hormone Research discussing that various cinnamon compounds derived from the hydroxychalcone fraction are involved with insulin-like effects, and the influence they have on specific gene family receptor signaling, indicative of an insulin-like mimetic effect.[15] We are beginning to see some positive influences that various phytochemicals have on insulin-like mediated glucose transport and gene expression. Some studies suggest that 1 gm or 1000 mg of cinnamon containing hydroxychalcone in concentrated form, is capable of greatly improving the areas under the curve after a glucose challenge, demonstrating insulin-stimulating and sensitizing effects. It also appears to bear out in human intervention trials in individuals who have various types of insulin insensitivity or insulin resistance. This is an exciting part of the story showing that there are undoubtedly many different substances found in plants that participate in insulin sensitization. This is discussed in an abstract in the FASEB Journal.[16] A paper in Hormone Research supports these observations and discusses insulin action from cinnamon extract. Green Tea Epigallocatechin Gallate and Insulin Biological Activity In a review in the Journal of Agricultural Food Chemistry, investigators discussed examination of insulin-like biological activity of culinary and medicinal plant extracts and determined that cinnamon was the most bioactive product.[18] Epigallocatechin gallate, in green and black tea, was also high on the list. It is well known that tea enhances insulin activity. This is discussed in an article in the Journal of Agricultural Food Chemistry.[19] We are advancing the understanding of phytochemicals and the physiological mechanisms by which food can influence insulin and insulin reactivity. The cinnamon story is interesting, although it does not argue for consuming cinnamon rolls on a frequent basis. I do not think we can justify the amount of cinnamon in white-flour bakery products to overcome their glycemic load. Regarding green tea epigallocatechin gallate, or EGCG, there are a number of papers that discuss its beneficial effect on insulin sensitivity. One article appeared in the journal, Experimental Molecular Medicine. EGCG was seen to suppress pancreatic b cell injury due to oxidative stress and improve insulin secretion.[20] There are beneficial effects of tea catechins on improving glucose transport and reducing the risk to obesity. This is discussed in an article in the International Journal of Obesity.[21] The point I am trying to make is that are a variety of phytochemicals from different foods and culinary spices that may play favorable roles in helping sensitize the cell signaling process related to insulin. That may also constitute the value of a natural, highly unprocessed plant food-rich diet. These phytochemicals are not found in animal products. I want to emphasize that the complex diet—a mixture of animal and vegetable products of the right type—is undoubtedly what the anthropological history and the emerging physiological story appears to argue for. Lipoic Acid and Insulin Regulation How we view diet and its interrelationship to insulin sensitivity is a fascinating chapter in the emerging understanding of the important role that diet plays in medicine. We began with what Linus Pauling might have called an orthomolecular, a -lipoic acid, as a useful agent for improving insulin sensitivity and perhaps in the treatment of certain forms of diabetic neuropathy, when given in therapeutic doses from 600-1200 mg per day. Everyone jumped on the lipoic acid bandwagon as if it was the universal management tool for insulin resistance. There are many interesting papers on the role of supplemental a -lipoic acid in type 2 diabetes and improvement of the insulin response. One is an article that appeared in Free Radical Biology & Medicine.[22] A clinical intervention, placebo-controlled trial demonstrated that 1200 mg of lipoic acid was capable of improving insulin response and managing glucose response in type 2 diabetics. People started to look at a -lipoid acid as the nutrient to treat diabetes. However, we should be looking at a -lipoic acid, not by itself, but as part of a complex family of nutrients involved in the reduction/oxidation control of beta cell function, insulin sensitivity, and glucose transport. Unfortunately, we often fall into the pharmacological model, thinking that if we can find an effective nutrient, that it is “the drug” for insulin management. Rather, we need to view it as part of a complex milieu of interacting variables from a whole-foods diet, and proper physiology that ultimately regulates cell response at the genotypic level, the so-called nutrigenomic level that controls the phenotype in things such as blood sugar normalization. Certainly, there appears to be a role for a -lipoic acid. It is probably best when included in an overall dietary intervention program, using all the things Dr. Cordain talked about. We still have to eat nutrients; we still have to consume macronutrients and calories. We cannot live on a -lipoic acid alone. We need to put a -lipoic acid in the proper context, the same as vitamins C and E. We know that vitamin E will improve insulin sensitivity. That is not because of vitamin E alone, but as a factor in the presence of other nutrients such as magnesium, vitamin C, calcium, polyunsaturated fatty acids, and other phytonutrients I discussed. All of these work together to give rise to improved insulin response. What seems to be emerging is the concept that the less processed the diet and the more color and texture it has, the more likely it will deliver substances that help to regulate gene expression in a positive way. Dr. Cordain, Boyd Eaton, and others are doing remarkable work, examining the anthropology and history of the human diet and its relationship to function, and there is significant work being done in nutrigenomics and the physiology of glucose control. These seem to converge into a single story—lower processed foods, higher fiber, phytochemicals, less partially hydrogenated vegetable oils and saturated fats, and more of the antioxidant-rich nutrients. All of these are helping to move us in the right direction. Other Foods/Spices and Insulin Regulation I find the cinnamon story to be interesting. If a culinary spice containing a family of substances called hydroxychalcones can positively influence insulin signaling, there may be many other substances derived from different foods and spice products that, as we study them, will demonstrate positive effects on insulin signaling. One of those is bitter melon (Momordica charantia) which has been historically used as a concentrate to help improve insulin regulation.[23] There are plants that have been historically used in equatorial West Africa for normalization of blood sugar. Plants from Amazonia in South America have also been used by indigenous cultures to regulate glucose and treat what we call diabetes.[24] There are hundreds of compounds and medicinal herbs found in various foods and spices now being discovered that undoubtedly play roles in modulating the complex signaling process of insulin, such as the PPARs. We will be learning much more about this as the science unfolds, as well as more about the history of diets, what phytochemicals they contain, and how that relates to some of the ongoing clinical intervention trials. Rather than thinking we need only a single nutrient to treat a disease called diabetes, we should be talking about the complex array of substances from the diet and lifestyle, including exercise. When those factors are combined in the right proportion for that person’s genotype, they result in an outcome called proper glucoregulation. When that occurs, glycosylation decreases, insulin signaling at the gene level decreases, inflammatory mediators decrease, as well as some of the secondary risk factors such as cell proliferation that Dr. Cordain described. It is not just a single problem related to diabetes in and of itself. When we tie this together with the extraordinary Clinician of the Month interview we had last month, in which we talked about insulin and cancer with Dr. Barry Boyd, there is a lot more mileage to be gained as we move into our studies for the symposium. Thanks for being with us. I hope you have received some “news to use” this month about diet and the modification of insulin signaling.  

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Bibliography

1 Podell RN. Understanding the transition from alternative medicine to mainstream science: the homocysteine theory of heart disease and the crucial role of effective mentoring. Med Hypotheses. 2003;61(3):340-345. 2 Eckel RH. A new look at dietary protein in diabetes. Am J Clin Nutr. 2003;78:671-672. 3 Gannon MC, Nuttall FQ, Saeed A, Jordan K, Hoover H. An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes. Am J Clin Nutr. 2003;78:734-741. 4 Daly M. Sugars, insulin sensitivity, and the postprandial state. Am J Clin Nutr. 2003;78(suppl):865S-872S. 5 Jenkins DJ, Kendall CW, Marchie A, et al. Type 2 diabetes and the vegetarian diet. Am J Clin Nutr. 2003;78(suppl):610S-616S. 6 Sabatè J. The contribution of vegetarian diets to health and disease: a paradigm shift? Am J Clin Nutr. 2003;78(suppl):502S-507S. 7 Dattilo AM, Miguel SG. Chromium in health and disease. Nutr Today. 2003;38(4):121-133. 8 Nesto RW, Brunzell JD, Plutzky J. The clock is ticking&ldots;attacking the metabolic syndrome to reduce atherosclerotic risk. Cardiol Rev. 2002;19(13suppl):2-16. 9 McCarty MF. A paradox resolved: the postprandial model of insulin resistance explains why gynoid adiposity appears to be protective. Med Hypotheses. 2003;61(2):173-176. 10 Eaton SB, Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med. 1985;312(5):283-289. 11 Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris: a disease of Western civilization. Arch Dermatol. 2002;138(12):1584-1590. 12 Cordain L, Eades MR, Eades MD. Hyperinsulinemic diseases of civilization: more than just Syndrome X. Comp Biochem Physiol A Mol Integr Physiol. 2003;136(1):95-112. 13 Cordain L, Miller JB, Eaton SB, Mann N, Holt SHA, Speth JD. Plant-animal subsistence ratios and macronutrient energy estimations in worldwide hunter-gatherer diets. Am J Clin Nutr 2000,71(3):682-692. 14 Jarvill-Taylor KJ, Anderson RA, Graves DJ. A hydroxychalcone derived from cinnamon functions as a mimetic for insulin in 3T3-L1 adipocytes. J Am Coll Nutr. 2001;20(4):327-336. 15 Imparl-Radosevich J, Deas S, Polansky MM, et al. Regulation of PTP-1 and insulin receptor kinase by fractions from cinnamon: implications for cinnamon regulation of insulin signalling. Horm Res. 1998;50:177-182. 16 Maber MA, Sokis LM. Cinnamon consumption may enhance insulin action in vivo. FASEB J. 2001;15:A992. 17 Berrio LF, Polansky MM, Anderson RA. Insulin activity: stimulatory effects of cinnamon and Brewer’s Yeast as influenced by albumin. Horm Res. 1992;37:225-229. 18 Broadhurst CL, Polansky MM, Anderson RA. Insulin-like biological activity of culinary and medicinal plant aqueous extracts in vitro. J Agric Food Chem. 2000;48:849-852 19 Anderson RA, Polansky MM. Tea enhances insulin activity. J Agric Food Chem. 2002;50:7182-7186. 20 Han MK. Epigallocatechin gallate, a constituent of green tea, suppresses cytokine-induced pancreatic b -cell damage. Exp Mol Med. 2003;35(2):136-139. 21 Murase T, Nagasawa A. Suzuki J, Hase T, Tokimitsu I. Beneficial effects of tea catechins on diet-induced obesity: stimulation of lipid catabolism in the liver. Int J Obesity. 2002;26:1459-1464. 22 Jacob S, Ruus P, Hermann R, et al. Oral administration of RAC-a -lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Rad Biol Med. 1999;27(3/4):309-314. 23 Chen Q, Chan LL, Li ET. Bitter melon (Momordica charantia) reduces adiposity, lowers serum insulin and normalizes glucose tolerance in rats fed a high fat diet. J Nutr. 2003;133(4):1088-1093. 24 Schwontkowski D. Herbal treasures from the Amazon. Healthy & Natural J. 1994

Welcome to Functional Medicine Update for April 2004. The 11th International Symposium on Functional Medicine will take place next month, May 11-15, 2004, in Vancouver, British Columbia, where we will focus on “The Coming Storm: Reversing the Rising Pandemic of Diabetes & Metabolic Syndrome.” We are excited to have a Clinician of the Month in this issue of FMU who will discuss part of the story we will be talking much more about at the symposium. In order to prepare for that discussion, I would like to talk about the protein connection to insulin, which has certainly received a lot of press recently. As I was driving down the freeway the other day, I noticed a big banner on a 7-11 store that read: “7-11 is Atkins Friendly.” It occurred to me that this issue has come full circle. When 7-11 becomes “Atkins Friendly,” I know the paradigm has shifted. Let us turn to what is happening in the bioscience area related to insulin, dietary protein, and amino acids. I hope through this discussion you will get a somewhat different perspective as to what has been sensationalized, popularized, exaggerated, and marketed for promotional reasons in a way that subliminally seduces many consumers into believing something that may be quite different from what the facts are. It is becoming common knowledge that body composition plays an important role in determining physiology. As body fat percentage increases at the expense of reducing body muscle percentage, there is an altered state of fatty acid metabolism, glucose metabolism, insulin sensitivity, and general mitochondrial oxidative efficiency, because muscle is rich in mitochondria and fat cells are poor in mitochondria. Therefore, oxidative chemistry and oxidative phosphorylation are shifted as body fat is increased, at the expense of body muscle. Many years ago, Dr. Covert Bailey referred to the “thin/fat person” as one who, over the years, remains in the same dress or pants size, but whose internal body composition may have changed considerably due to lack of exercise and poor-quality diet. The “thin/fat person” tries to stay thin with calorie-restriction, but if CT whole-body scanning or examination of musculature is performed, it would likely reveal that his or her body is heavily marbled with fat, much like feedlot-fed beef. There are some good examples in the literature that discuss the relationship of cross sectional CT scanning of various large muscles such as the gastrocnemius with percent body fat and body muscle in active versus sedentary individuals, and the finding that intracellular fat deposition begins to accumulate in those with a sedentary lifestyle. The type of fat of most concern, however, is not that which accumulates in the limbs, but that which accumulates around the abdomen, the so-called visceral adipose tissue, or VAT. We can say that health problems with fat are often present in people who are “over-VAT,” not “over-FAT.” The VAT (inter-abdominal body fat) is that which appears to present the greatest risk to age-related, chronic illness such as heart disease, diabetes, some forms of cancer, and perhaps also to cholelithiasis and gall bladder disease. It is these types of regional fat depositions that seem to be strongly associated with disease related to obesity or adiposity. Determining Body Composition One of the first things one needs to look for clinically is how much body muscle has been replaced by body fat, or the percentage of body fat, and the best way is to determine body composition. Traditionally, the simplest method is to measure height and weight and develop what is called the body mass index (BMI). Using a nomogram scale, the height can be determined in inches versus the weight in pounds to develop a BMI number. BMI>25 is overweight; BMI>30 is obese; BMI>40 is morbidly obese. (The only exception might be for individuals with heavy musculature, such as highly-trained athletes.) For the average individual, the BMI is a pretty good approximation of body composition, or percent body fat. BMI is often coupled together with the waist-to-hip ratio. That ratio is achieved by measuring the circumference of the hips at the widest point and the waist circumference, about an inch or two above the umbilicus. Dividing the waist number by the hip number provides the ratio. If that number is greater than 0.8 for a woman, or greater than 1.0 for a man, it suggests increased incidence of abdominal obesity associated with increased BMI. Increased BMI and increased waist-to-hip ratio represent the VAT. Only a tape measure is needed to gather some inferential information about body composition. CT Scanning and Bioimpedance (BIA) Measuring Techniques There are more accurate methods of determining body composition, such as CT scanning neutron activation (not available to most individuals unless they are in a research situation), and bioelectrical impedance analysis (BIA), which uses resistance and conductivity measurements of the body. BIA is a pretty reasonable technology for evaluating body composition in a person who is properly hydrated and appropriately nourished relative to their normal diet. This would not include people who have consumed five cups of coffee and three drinks of Scotch before having a BIA, which would induce a diuretic effect. Subjects should be normally hydrated. Except for those who have various ponderous physiologies, the BIA regression equations built into the machines that give rise to the percent body fat, percent body muscle, and percent intracellular water calculations, are quite accurate and correlate nicely with other more sophisticated technologies. As a person reaches a very high BMI, this equation tends to break down. In these cases, the BIA calculation from normal bioimpedance analysis tends to be less accurate. For people in the normal or overweight range of body composition (19-30), the BIA machines provide accurate regression calculations compared to those determined by other methods. The simplest in-office technology for evaluating body composition that has the most qualitative inference is height-to-weight ratio and BMI. BIA renders a quantitative calculation that gives more compartmental and regional aspects of body composition and intracellular fluid. A good paper on the comparison of BIA prediction equations for fat-free mass in a population-based sample of 75-year-olds was recently published in the journal Nutrition.[1]The investigators point out that in cases where a person has a lot of sarcopenia and muscle wasting (such as an elderly person), the BIA is not very accurate, and it is not accurate for people who are morbidly obese. In the mid-range of normal body compositions, BIA has a fairly accurate correlation in terms of body fat, body muscle, and body water. Once the body composition is determined, and let us say that person is a man with a percent body fat of 27 percent with increased extracellular fluid and compromised body muscle (low percent body muscle), what is a good clinical approach? Does he need to be on a low-calorie diet, exercise program, some form of anabolic steroid to increase muscle mass, or a nutritional supplementation program? If he is going to be placed on a lower-calorie diet, what type of diet? Should it be a diet high in complex carbohydrates, high in fiber, modest in protein and low in fat, or one that is high in protein, lower in carbohydrate, or any or none of the above? These are controversial and confusing questions as to how we personalize dietary approaches for individuals with altered body composition. Similarly, the patient might be a woman with an initial percent body fat of 34 percent who has increased cellular water levels and who is at risk to obesity-related problems, with an increased waist-to-hip ratio. The same questions would prevail. What type of dietary and lifestyle intervention would be appropriate? Extracellular Fluid and Diet Recommendations In our experience, one of the first things that might be done in the case of a large amount of extracellular fluid, is to put a person on a diet as neutral and low-allergy as possible, without making sweeping changes in calorie intake. Some people call this an oligoantigenic diet; other people might refer to it as a detoxification program. Others might call it just a good, simple, clean diet. Whatever term might be used, the recommended diet is one that would employ foods grown in the ground with lots of color (fresh fruits and vegetables). It would avoid the color white in the diet—white sugar, white fat, white flour, and white alcohol—and include things as organic as possible, staying away from dairy and wheat products, or glutenous grains. We cannot be certain who might have some kind of sensitivity to the food families containing proteins to which many people are sensitive, but the most common allergenic proteins are found in dairy, soy, and wheat. When putting a person on a fairly low-allergy diet, rice protein-based approaches are often used, because rice is well tolerated in western societies and has good-quality protein. Fiber would be increased, and vegetables and fruits would be increased. There are diet plans based on the Mediterranean Diet that avoid gluten grains. When an individual has been on this program for two to three weeks, immune system responses change. A lot of water weight that might have been retained as a consequence of immune system response to a purported offending agent, i.e., an inflammatory-promoting agent, may be lost. The person is now at a baseline physiology and it is easier to examine body composition. Extracellular fluid has decreased; some weight has been lost; the person is feeling better, and energy needs are in clearer focus. One can then move into the next phase, which is to tune up metabolism. The Metabolic Tune-up Dr. Bruce Ames discusses this in an article that appeared in the January 2004 issue of Archives of Biochemistry and Biophysics.[2] He talks about the metabolic tune-up—supplementation and intervention with appropriate nutrients to improve muscle physiology and mitochondrial function. That leads us to diet approaches. There are many different opinions on the ratio of protein, carbohydrate, and fat amount in the diet, as well as type and percentage. We only have to look at the New York Times Best Seller List for the past three years to see the controversy that prevails about what the best diet is—the one with the appropriate ratio of protein, carbohydrate, and fat. My question is (we will be talking about this with our COM on Side 2), what is the best kind of protein, kind of fat, and kind of carbohydrate? That may be more important than the relative ratio. It seems as if we are ruled by numerology. We are so tied up with ratios, we get food-phobic about having exceeded a certain percentage of one nutrient versus another, rather than remembering that it is the type of carbohydrate. Is it complex? Is it whole-grain? Is it unrefined? Is it white starch? Is it sugar? What type of fat? Is it partially hydrogenated? Is it polyunsaturated? Is it monounsaturated? Is it saturated? Is it oxidized? What type of protein? Is it animal or vegetable protein? These questions are exceedingly important in determining the outcome of the body’s hormonal postprandial messaging response to the diet. It is the postprandial period, during which the orchestration of all sorts of hormones that sweep into the blood creates different tunes of genes downstream that ultimately regulates things like body composition. It is not as simple as just thinking about calories in and of themselves. It is the type of calories and typeof nutrients that influence the messaging system of the body—such as the sex steroid hormones, glucoregulatory hormones, neurotransmitters, and the appetite-control hormones, including what are called adipocytokines, the fat-related neurotransmitters, neuroregulators, and immune-regulating substances. ? Fat is now considered an endocrine organ. Isn’t that remarkable? It produces a whole series of messenger molecules. In fact, in very under-lean people, the largest endocrine organ in their body is body fat; it can take over their physiology. It produces its own messenger molecules—TNFa, IL-1, IL-2, adiponectin, resistin, and leptin. These molecules—even sex steroid hormones like estrogen and C-reactive protein—can be manifestations of increased body fat percentage. As body fat percentage increases, physiology changes. There is a functional change. The individual moves from one resting state of physiology to a new resting state, a new homeostasis. We often use the term “homeostasis” implying that it means healthy regulation. But one can be homeostatic with malignancy, cardiovascular dysfunction, diabetes, or inflammation. It is breaking the cycles that give rise to chronic illness that leads a person back to a resting physiology called a healthy homeostasis. The focus of this issue of Functional Medicine Update is on the specific role that protein and possibly carbohydrate play in the regulation of the postprandial messages that alter body composition. Over weeks, months, and years of eating and living, these messages create a body that has altered percent body fat, altered percent body muscle, and altered percent extracellular fluid, as measured by BIA. In order to understand the protein connection, I am going to trace back through some history.[3] The first reported research I could find on this issue was that of Ignatowsky in 1908, when he examined the role of various macronutrients on atherosclerosis. You may recall that Atwater did his landmark work on the calorigenic content of food using human calorimeters at the turn of the 19th century. Ignatowsky’s work follows Atwater’s work on the calorie content of protein, carbohydrate, and fat. Ignatowsky believed there was a toxic metabolite in animal protein that led to atherosclerosis. When he fed high amounts of meat, as well as milk and egg yolk protein, to adult and weanling rabbits, he was able to cause atherosclerosis. About the same time, the Russian physiologist Anitschkov was working with a similar strain of rabbits. He found that feeding the rabbits a soft diet rich in saturated fats and cholesterol could produce arterial sclerosis in the animals. It was a soft, fat, oily, gooey substance, and on necropsy, when he examined the animal’s arteries, he found he could scrape it out on his fingers. It was oily, waxy, and gooey, and that led to the simple explanation that fat does not dissolve in water. If you eat a lot of fat, it clogs up your arteries and eventually results in atherosclerosis. That was the origin of the cholesterol hypothesis. I want to emphasize “hypothesis” as it pertains to the origin of heart disease. About the same time, Ignatowsky was talking about dietary protein as a major contributor to atherosclerosis. There was an interesting battle being conducted between the two camps at that time. For the next two decades, experimental efforts from many laboratories were directed at determining which, if any, animal protein was the most atherogenic. Even in the face of the work by Anitchkov on cholesterol and fats producing heart disease, those in the protein camp continued, over the next 20 to 30 years, to follow-up on the protein hypothesis—that a toxic metabolite of protein caused atherosclerosis. In 1926 Clarkson and Newburgh showed that the amount of cholesterol present in the animal protein they fed animals to make them atherosclerotic was insufficient to be atherogenic by itself, demonstrating that there was some factor other than dietary cholesterol (lipid) that determined atherogenicity of the diet, presumably protein. In 1940, Meeker and Kesten showed that animal protein (casein, the principal milk protein) was more atherogenic than plant protein (soy). The work of Carroll and his coworkers that followed the Meeker and Kesten work, showed that most proteins of animal origin were more cholesterolemic for rabbits than were proteins of vegetable origin, although there was some overlap. The observations made over the last 100 years have been interesting. David Kritchevsky at the Wistar Institute in Philadelphia, has been discussing the dietary protein connection to atherosclerosis for many years. He was the first person I listened to 30 years ago who got me thinking about the subject. We often think that serum lipid abnormalities are a consequence of dietary lipid abnormalities because lipid makes lipid. But dietary protein, the carbon skeletons of the amino acids that make up protein, can also be converted by metabolic/anabolic function into triglycerides and serum lipids, and have effects on de novocholesterol biosynthesis. It is not as simple as saying, “fat makes fat.” Protein can make fat, as well, and it appears from the early work and on up through the work of Carroll et. al., that animal protein may be more atherogenic than vegetable protein. That is an interesting part of the story. Remember I said earlier, it is not just the ratio of protein to carbohydrate and fat; it is also the type of each of these. In the 1970s and 1980s, David Kritchevsky led us to think that perhaps we should be concentrating on the difference between animal and vegetable protein. How do they vary when fat is taken out of the equation? To understand this, we need to go back to 1983 and look at papers like the one titled “Regression of casein and cholesterol-induced hypercholesterolaemia in rabbits.”[4] This is a fascinating study done in the Netherlands in which investigators showed they could develop arteriosclerosis in rabbits by feeding them a low-fat diet, but one that was enriched in casein animal protein. They could cause regression of hypercholesterolemia and arteriosclerosis by transitioning the animals onto an isocaloric amount of vegetable protein, in this case, soy protein. The concept that there is something toxic to the arteries in animal protein appeared to emerge from this research. In 1985, a follow-on paper was done at the Department of Biochemistry, School of Medicine and Health Sciences, George Washington University; the Wistar Institute of Anatomy and Biology in Philadelphia, and the Department of Pathology at the University of Pittsburgh, School of Medicine. The title of the paper was “Effects of Casein and Soy Protein on Hepatic and Serum Lipids and Lipoprotein Lipid Distributions in the Rat.”[5] Again, a similar theme was found (moving from the rabbit to the rat), by feeding the animals an isocaloric diet reasonably low in fat, but containing either casein or soy protein in equal amounts, showing that the casein diet was much more atherogenic. Animal protein increased the de novobiosynthesis of cholesterol and serum lipids, whereas the soy protein diet did not. It also appeared that the animal protein diet had effects on hepatic 7a-hydroxylase, the rate-limiting enzyme for the conversion of cholesterol to bile salts. Supplementation of the soy diet resulted in lowering of total lipids and increased cholesterol 7a-hydroxylase. However (here is the important point), when they took the soy protein diet and supplemented it with the amino acid lysine to make it equivalent in its lysine content to that of beef or casein protein, the diet became atherogenic. It initiated increased concentrations of serum lipids and cholesterol, as well as atherogenicity. That opened the door in 1985 for examination of the fact that there was something about the arginine/lysine ratio in dietary proteins that could influence their atherogenicity and lipid effects. What is that effect? This is where the story becomes quite fascinating. (I will be discussing the arginine/lysine ratio with our Clinician/Researcher of the Month on Side 2.) First of all, animal proteins are much higher in lysine and lower in arginine than vegetable proteins; conversely, vegetable proteins are higher in arginine and lower in lysine. Fortifying a vegetable protein with lysine to make the arginine/lysine ratio equivalent to that of beef protein, results in a similar cholesterol-increasing effect. There appears to be a thermostat of the cholesterol/lysine ratio on cholesterol and lipid biosynthesis, and therefore atherogenicity. What did I say earlier? It is the type of protein as well as the amount. In 1986, work was done at Shizuoka University in Japan, looking at the relationship between amino acid composition of the diet and plasma cholesterol in growing rats fed a high-cholesterol diet.[6] Feeding rats a cholesterol-laden diet, but with soy protein containing a low lysine/high arginine level, resulted in lowered risk to atherosclerosis and injury to the arteries. If the rats were fed a high cholesterol diet with a protein that was high in lysine/low in arginine, it increased atherogenicity. This produced a similar observation to that of Kritchevsky’s published in 1985. In 1992, following the same theme, physiological research out of central Europe showed that casein and soy flour proteins and their amino acid content had a significant influence on liver de novo lipid biosynthesis, including cholesterol synthesis and triglyceride synthesis in experimental animals.[7] Once again, investigators showed that the arginine/lysine ratio appeared to be one of the major determinants. The higher arginine/lower lysine foods (plant-based proteins like soy protein), had a lower cholesterol-stimulating effect and triglyceride-stimulating effect than did the higher lysine/lower arginine foods. This theme seems to have emerged over a period of 10 to 15 years, going all the way back to Ignatowsky’s observations about the vasculotoxic effects of animal protein. In the International Journal of Vitamin and Nutrition Research in 1997, an interesting paper was published from a group out of the Beltsville, Maryland, U.S.D.A Research Labs in collaboration with the Western Region Research Branch of the Agriculture and the Agri-Food Canada research department.[8] In this study, the investigators looked at the influence of casein, soy protein, the ratio of amino acids in those proteins, and the effects on cholesterol and lipoprotein fractions in guinea pigs. The effects of three dietary protein treatments on cholesterol content of plasma, lipoprotein fractions, and oxidation status of liver lipids were compared. This is the LDL oxidation model. All diets were adequate in soluble fiber and well balanced in fatty acids, which provided 30 percent of the total energy. After seven weeks, dietary treatment with casein compared to soy protein increased cholesterol in a subfraction of LDL. Dense LDL, the most atherogenic particle, was increased with the isocaloric animal protein as compared to the soy protein. We are getting even more specific in the potential atherogenicity of animal protein when we begin to look at sub-fractionation. The investigators in this study also found that there were adverse effects on HDL with the animal protein—a lowering of HDL. There were no effects of dietary treatment in the TVA, or the so-called lipid peroxide substances that were extracted from the liver; these diets appeared to principally alter cholesterol synthesis and dense LDL. What does this lead us to? It leads to Ignarro and Murad and their Nobel Prize-winning discovery of the molecule nitric oxide (NO). Historically, pathfinders all the way back to Ignatowsky, and their hypotheses relating to the atherogenicity of animal protein in contrast to saturated fats in the animal protein-rich diet, suggest that the ratio imbalance of arginine to lysine (higher lysine and lower arginine) has something to do with the adverse effects of dietary protein on the arteries. Murad and Ignarro were awarded the Nobel Prize in Physiology and Medicine for their discovery of the production of NO from arginine by an enzyme called nitric oxide synthase (NOS), which is mediated through the cyclic GMP pathway. NO is an essential biomolecule for endothelial health and therefore, it may be possible that the arginine/lysine ratio changes seen with different dietary protein sources have an effect on NO dynamics and the potential atherogenicity and immune effects associated with atherosclerotic disease or atherogenesis. More and more, this is now being seen as “the arteries on fire” related to autoimmunity and the concept that atherosclerosis has an immune origin. This may also tie back to modulation of factors associated with NO chemistry that appear in the artery wall or in the liver itself. Arginine has a powerful immunomodulatory effect. This effect has been demonstrated in many studies, including work in post-surgical patients who have been infused with high doses of arginine to improve wound healing. It has also been demonstrated in lowered levels of arginine administered to animals, demonstrating effects upon immunochemical function of cell-mediated and non-cell-mediated immune defense, and looking at how certain T lymphocytes—natural killer cells—are influenced by arginine, as well. Arginine participates in a variety of immune functions that appear to be related to the various cell types associated with the atherogenic process. We are taking some fairly wide-sweeping brush strokes here. We are trying to tie together the arginine/lysine content at the whole organism level. Increased lipid levels are associated with a high lysine/low arginine diet, and that appears to be related to immune function, arterial health, and proper regulation of NO, which originates from arginine metabolism from NO synthase. There is a nice review on the immunomodulatory effects of arginine in the journal Surgery.[9] If we take that a step further, we might ask what influence the immunomodulatory effect, the NO modulating effect, the serum lipid-modulating effect, or arginine and lysine, have on insulin sensitivity. Insulin is tied to the web of interacting hormones that occur postprandially and regulate downstream function of the individual. Therefore, is there a relationship among atherogenicity, body composition, and adipocyte physiology? Is there something that relates to the type of dietary protein and its potential effect on insulin sensitivity? There is a wonderful article by Sanchez and Hubbard from the Department of Nutrition, School of Public Health, and Department of Pathology, School of Medicine at Loma Linda University that appeared in Medical Hypotheses,[10] titled “Plasma amino acids and the insulin/glucagon ratio as an explanation of the dietary protein modulation of atherosclerosis.” Does that title sound familiar relating to what I have been developing in this story? The authors state: “The amino acid composition of the diet influences the postprandial levels of plasma amino acids along with the hormones insulin and glucagon in humans fed single test meals identical in composition except for protein source. Soy protein (hypocholesterolemic), vs. casein (hypercholesterolemic), contains a higher amount of arginine and glycine and induces an increase in postprandial arginine and glycine. Soy protein induces a low postprandial insulin/glucagon ratio in both hypercholesterolemic and normocholesterolemic subjects. Casein induces a high postprandial insulin/glucagon ratio among hypercholesterolemic subjects. Amino acids such as arginine and glycine are associated with a decrease, while lysine and branched-chain amino acids are associated with increased serum cholesterol levels. Our data are consistent with the hypothesis that the control of cholesterol by insulin and glucagon is regulated by dietary and plasma amino acids. From this hypothesis the insulin/glucagon ratio is proposed as an early metabolic index of the effect of dietary proteins on serum cholesterol levels, a risk factor and a common mechanism through which dietary and lifestyle factors influence cardiovascular disease.” Improved insulin sensitivity is achieved with dietary proteins that are lower in lysine and higher in arginine. Dietary glycemic load may play an important role in determining insulin sensitivity, but it may also be related to the source of dietary protein and amino acid composition. A high dietary glycemic load is associated with risk to colorectal cancer, as suggested by the Women’s Health Study. This information was recently published in the Journal of the National Cancer Institute,[11] showing that high glycemic load diets, those that increase insulin and glucose levels, are associated with increasing incidence of colorectal cancer in women. It is not just carbohydrate. It is not just the amount of protein, but it may be the type of protein. Glycemic load of the diet is not determined by just measuring carbohydrate alone. It is measuring the overall balance of these nutrients that influence postprandial gene response and messenger molecules that signal downstream how cells respond to their environment. As glycemic load comes of age, we should be looking at it not just as a measurement of available carbohydrate, but as one of all the signals coming from the diet that influence the regulatory hormones and alter adipocyte physiology, sarcomeric muscle cell physiology, mitochondria, and changing body composition. It is much more interesting and clinically important information that is emerging from this research. An interesting article, titled “Glycemic load comes of age,” appeared in the Journal of Nutrition last year.[12] Author David Ludwig says we should be looking at glycemic load as a total measurement of all the contributors to the various dietary components—protein, fat, carbohydrate, fiber, minerals, and vitamins—all the things that cause regulation of glucose. This might explain why type 2 diabetes and insulin resistance respond to a vegetarian diet, even though this diet is higher in carbohydrate. It is high in complex, unrefined carbohydrate, and higher in vegetable protein that is higher in arginine and lower in lysine. Type 2 diabetes can, in fact, be favorably influenced by a vegetarian diet. This is the topic of an article in the American Journal of Clinical Nutrition[13] discussing how a diet richer in carbohydrate, but unrefined, proper, and balanced in vegetable protein, will have beneficial effects on insulin sensitivity and help to manage the type 2 diabetic. David Jenkins is the principal author of this article and he will be a presenter at the 11th International Symposium on Functional Medicine. In the Insulin Resistance Atherosclerosis Study, it was shown that high intake of whole grains was associated with increases in insulin sensitivity, not decreases.[14] Carbohydrate, in and of itself, is not dangerous. It is the form in which it is administered to the body and whether it is balanced with the proper amount of vegetable protein. Dietary protein in diabetes, as was described in the article in the American Journal of Clinical Nutrition, requires that we look at it in terms of whether it is properly balanced with regard to vegetable protein and the amino acid ratios that come from proteins. Amino acids play an important role in the regulation of lipid synthesis, insulin sensitivity, and gluconeogenesis. All these factors play a role in the glycemic load of the food and diet, and ultimately its effect on body composition. It is this discussion we will be sharing with our Clinician/Researcher of the Month on Side 2.  

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INTERVIEW TRANSCRIPT

Clinician of the Month Elena Volpi, MD, PhD Associate Professor of Medicine University of Southern California Department of Medicine Division of Endocrinology and Diabetes 1333 San Pablo Street, BMT-B11 Los Angeles, CA 90033 JB: Once again, it’s time for our Clinician/Researcher of the Month. We are pleased to interview a world-renowned investigator, Dr. Elena Volpi, Associate Professor of Medicine at the University of Southern California, Division of Endocrinology and Diabetes. I think most of you are well aware of her work. It was highlighted for many of us in a landmark paper that appeared in the Journal of the American Medical Association, titled “Basal muscle amino acid kinetics and protein synthesis in healthy young and older men.”[15] Dr. Volpi was a principal author of that paper. Some of us have presumed that basal muscle amino acid kinetics are slower in older men and faster in younger men, accounting for the difference in muscle mass. The work of Dr. Volpi and her colleagues dispelled that myth and raised new questions. It is with that in mind that we are going to talk with Dr. Volpi about the protein connection to body composition and how that relates to the insulin sensitivity story. Dr. Volpi, thank you for being with us on FMU. My first question is, what led you to focus on protein-related issues in your research over the last 20 years? Influence of Dietary Protein on Postprandial Insulin Mechanisms EV: Thank you so much, Dr. Bland, for having me on FMU. I’ve always been fascinated with the mechanisms by which the proteins of the body work. Consider that proteins are the major translators of the genetic information in the body. They can be enzymes; they can be structural proteins like muscle proteins or contractile proteins. I find it extremely interesting to look at how the genetic information is translated to the actual function of the body. I became interested because I’m an endocrinologist by trade and I was very curious about looking at metabolism in relation to hormones. My initial studies were done in healthy people in order to understand the physiology of hormone action, especially insulin, and also the physiology of nutrition in relation to the function of proteins. From there, I moved into issues related to aging because it was quite an untouched field at the time. I started doing research on aging in 1996 when I moved to Texas. From that point on, I began studying the potential mechanisms by which muscle is lost with aging. That is my general orientation right now. From endocrinology, I moved into the field of gerontology, geriatrics, and functional medicine. JB: I have been so impressed with your work because it embodies so many of the principles that we here at the Institute for Functional Medicine have been trying to get doctors to understand from a functional perspective. In 1996, you were a principal author of a paper indicating that dietary protein had an influence on postprandial insulin mechanisms.[16] Would you describe how you got into that study and what the results of that first investigation were? EV: That study was done in healthy, young people. We were looking at the mechanisms, the relative contribution of hormonal stimuli and nutrients in the setting of postprandial protein anabolism. Gains in body proteins occur essentially in relationship to nutrition, because at the time of feeding, we are replacing the essential amino acids that have been destroyed by oxidation during the fasting period. Even if we exercise, there is a transient increase in protein anabolism, but overall, we are still missing the essential amino acids that have been lost during the fasting period. Nutrition is a pivotal point of anabolism for the body proteins. It is extremely important to look into that because that’s how we gain and don’t lose proteins during everyday life. The initial studies were on whole-body protein metabolism, the integrated sum of metabolism of all the body proteins—structural proteins, enzymes, plasma proteins, and others. We started with the problems of type 1 diabetes where there is insulin deficiency. The insulin-deficient subject loses protein. Insulin plays an important role in maintaining muscle proteins and whole-body proteins. Initially, we looked at insulin alone and saw that it decreases the breakdown of proteins at the whole-body level. That’s probably one of the mechanisms by which it helps to maintain body proteins. On the other hand, insulin is secreted in large amounts during a meal. We wanted to discern in healthy people how insulin interrelates to protein turnover and protein anabolism during the most anabolic moment for proteins, which is during meal absorption when dietary amino acids are being utilized. We administered a meal containing amino acids, fat, and glucose to one group of subjects. We normally stimulate insulin secretion via ingestion of glucose. Another group of subjects received a meal in which the amino acids were missing; it was a fat/glucose meal. Another group received only a placebo meal. We had a control group essentially drinking water and the other two groups on two meals different for amino acid content. We found that when amino acids are missing in a meal, a net whole-body protein anabolism does not take place. On the other hand, you slow down catabolism to a point where some significant effect is realized by reducing the whole-body protein breakdown. Another interesting thing is that during the absorption of a meal, with or without amino acids, there is an increase in the synthesis rate of albumin, an important protein that can be considered as temporary storage for dietary amino acids. There is no real storage area for amino acids in the body. Every protein in the body has a function. It’s not like fat, where there are triglycerides sitting there waiting to be used if they’re not needed right away. It’s the same for glucose; there is glycogen. What happens when amino acids are consumed is that they need to be used somehow. Albumin is an interesting protein because its synthesis can be doubled by insulin during meal absorption. The uptake of amino acids from the gut that are coming through the liver can be significantly increased. Albumin is synthesized in the liver. There is a kind of conjoined effect. The insulin is coming from the pancreas, the amino acids are coming from the gut, and they increase albumin synthesis. When amino acids are lacking, the albumin synthesis increases as well, meaning that insulin has a stimulatory effect on that. The overall albumin becomes kind of a temporary storage area and it is then taken and broken down everywhere in the body, including in muscle tissue so it can slowly release the amino acids during the fasting period. That’s a very important mechanism because otherwise, amino acids coming in through the gut would be immediately oxidized. You cannot increase the free amino acid pool too much; otherwise, they can become toxic. In fact, this is one of the problems seen in liver disease, for example, when you have liver failure. These were the findings in the paper we published in Diabetes in 1996. It was a matter of physiology and the mechanisms that allow our body to increase the protein content. JB: That’s a wonderful explanation and a good segue into my next question. As far as I remember, albumin as a serum plasma protein is very high in percentage composition of branch-chain amino acids, those of the essential amino acid family—leucine, isoleucine, and valine. You have done some very interesting pioneering work looking at the difference in protein anabolic effects of branch-chain versus mixed amino acids. Would you tell us how the connection between type of amino acids within the protein connects to the story you are emerging? Type of Amino Acids in Protein EV: We don’t really do those kinds of studies, but it is important to know that branch-chain amino acids, especially leucine, can directly stimulate muscle protein synthesis. Actually, they can activate initiation of translation of newly-synthesized proteins. Leucine for sure, but possibly other essential amino acids, may have some direct effect on the stimulation of protein synthesis. Branch chain amino acids alone, although able to stimulate protein synthesis, will probably be unable to sustain a prolonged increase in protein synthesis because to sustain the higher synthetic rate, all the amino acids are required to make those proteins. If the amino acids are not present in sufficient amounts, the synthesis rate slows down because you need to wait for the tRNA to be charged with the specific amino acid that is waiting to be used in protein synthesis. In this case, what I and also others believe is that you can induce stimulation with a single amino acid, but once you have started the increased synthetic process, then all of the amino acids are needed. The essential amino acids are the culprits at this point because you can actually make the non-essential amino acids, whereas the essential amino acids are coming either from protein breakdown or from the diet. Either way, if you have a higher synthetic rate and you don’t have a flux of amino acids coming from the diet, then you must break down more protein. This is one of the potential mechanisms by which acute illness can actually induce severe muscle loss, especially in burn injuries. Bob Wolfe has done a lot of studies on that. In a burn injury, the patient has an extremely high breakdown rate of proteins in the muscle. At the same time, there is a very high synthesis rate of protein in the muscle, so there is a major increase in turnover of proteins in the muscle. The net protein balance in the muscle becomes negative because there is a huge outflow of amino acids from the muscle into the liver. The liver needs these amino acids to build the acute-phase proteins such as fibrinogen and the complement, and all the acute-phase proteins necessary for a response to the acute injury. If you look at the amino acid pattern in the acute-phase proteins on the muscle proteins, the amino acid pattern is different. You break down some muscle, and you need more muscle broken down to be able to make the same amount of acute-phase proteins because the amino acid pattern doesn’t match. The theory is that if you don’t provide large amounts of amino acids in the pattern required to make the acute-phase proteins, you’re going to break down much more muscle and also oxidize the amino acids from the muscle that are not required to make the acute-phase proteins. That could sustain the muscle loss seen in this acute injury. JB: When you, Bob Wolfe and your husband, Dr. Rasmussen, collaborated on the study that appeared in JAMA on basal muscle amino acid kinetics and protein synthesis in healthy young and older men,[17] were the results of your amino acid labeling study a surprise, or did you anticipate seeing those kind of results? Basal Muscle Amino Acid Kinetics and Protein Synthesis in HealthyYoung and Older Men EV: Yes and no. That study followed a series of smaller studies we had done on the physiology of the response of muscle to nutrients in relation to age. Before the JAMA paper we did three studies in which we looked at whether muscle loss with aging was due to alteration in the anabolic response to increased nutrients. Nutrient intake is the most anabolic moment in our lives for muscle proteins and for proteins throughout our body. The major question was, does the muscle respond in older-age as it does at a younger age to the increased amino acid load during feeding? We published a paper in the Journal of Clinical Investigation in 1998 about infusing high doses of amino acids and looking at muscle protein synthesis breakdown in the baseline during the post-absorptive state.[18] We found that the response of muscle protein synthesis and anabolism to the amino acid infusion was normal in healthy older people. There was some data from a French group who had seen in older people that the first-pass splanchnic uptake amino acids, those ingested and then taken up by the splanchnic tissues including the gut and liver, do not appear in the peripheral systemic circulation. They found that it (the uptake) was almost double in older people compared to younger people.The muscle, per se, is working with an IV infusion of amino acids. The question is, when you give amino acids orally, does their uptake decrease their appearance in the systemic circulation so that their actual availability for the muscle tissue is reduced? We did another study in which we compared younger people and healthy older people. We looked at them in the baseline post-absorptive state and then during the ingestion of an amino acid mixture. We confirmed the data from the French researchers who found the increased splanchnic uptake at first-pass. We measured that using stabilized tracers (labeled) of amino acids. The interesting thing was that we didn’t find any alteration in the response of the arterial concentration in the peripheral blood. Younger and older people had the same magnitude of increase in amino acid concentration in the arterial blood that was delivering the amino acids to the muscle tissue. Overall, the muscle response to that specific meal was identical in the young and in the older people. From this data, we concluded that there is an increase in the uptake from the splanchnic tissues, but there is also an increased release of unlabeled amino acids from the splanchnic tissues because otherwise, we couldn’t have seen that same response in the blood amino acid concentrations. The conclusion is that in older people, there is both an increase in splanchnic protein turnover, which is synthesis and breakdown of proteins within the splanchnic bed, but we don’t know where. Is it the gut, the liver? We don’t know. This does not impair their ability to respond to amino acids. When we looked at the baseline data in the studies, we were surprised because we couldn’t find any differences in the baseline muscle protein turnover rates—no difference in synthesis; no difference in breakdown; and no difference in the net protein balance in the baseline. That was quite surprising because other investigators, includingDr. Yarasheski from Washington University, St. Louis, Dr. Welle from Rochester University in NYand Dr. Nair at the Mayo Clinic, had reported in the past that there were significant differences in muscle protein synthesis rates between young and older people. Those differences were in the ballpark of a 30 percent reduction in the protein synthesis rates. We found no differences. At that point, it became a puzzle because the other groups had measured protein synthesis rates using the same methodologies we used. There were no methodological differences that could have explained the differences in the findings. We thought that possibly the differences were due to the population studied, because the subjects were extremely healthy older people; they had no diseases, not even hypertension. They were very healthy. In a way, we had a potentially biased group of people because the subjects were so healthy. Another issue that may have been very important was the fact that in all the studies from the other investigators, there were no measures of muscle protein breakdown. If you want to know exactly what the net balance of muscle proteins is, you must measure not only synthesis, but also breakdown. That gives you the net effect of what is going on in the muscle. When there is only synthesis, it might be that in the earlier studies they had a lower synthesis rate that was accompanied by a lower breakdown rate. That balance would have been normal so they were losing no muscle, but we didn’t know that. What was also done in those studies was to measure the synthesis rate of muscle proteins after the patients had been in a hospital bed for three days. That could have potentially created a difference. It is possible, but we don’t know yet because we have no data from them. If you put an older person in the hospital for three days, their physical activity is significantly decreased. For example, if they had been gardening on a regular basis at home, obviously they couldn’t do that in a hospital setting. They were sedentary for three days. Being sedentary, even for a very short time, can result in significant reduction in muscle protein turnover. There is no stimulation from even very mild exercise, such as walking or simple stair climbing in the home. We decided we wanted to significantly increase the number of subjects because up until the study in the JAMA paper, our numbers were fairly small, usually token groups with less than 10 subjects per group. It is difficult to draw any conclusions from those kinds of numbers. We also decided not to have the subjects come in three days in advance because we wanted to study them under everyday life conditions. We told them to keep doing what they normally did in their homes, eat what they normally ate, and not change anything. We wanted them to come in the night before the study, sleep at the hospital, and we would do the study early in the morning. That way, we saw that there were no significant differences in protein synthesis and breakdown between the two age groups. JB: It’s likely that many of our listeners have had the opportunity to review your JAMA paper and have probably seen your 2003 paper in the American Journal of Clinical Nutrition. They haven’t yet seen the 2004 paper in the American Journal of Physiology Endocrinology Metabolism (due to be published this month), titled “Amino acid ingestion improving muscle protein synthesis in the young and elderly.” Our clinicians might ask, what role does dietary protein play? Should they take a different approach to counseling their patients? There is the current concept of increasing dietary protein, and even popularization of the so-called Atkins Diet. How do you see your work translating into the management of patients who may be at risk to sarcopenia? EV: Referring back to the previous question and the previous explanation of the JAMA paper, we saw no difference in the baseline muscle protein turnover rates in the younger or older people. That might have been biased because those people were extremely healthy. On the other hand, that presents the idea that age, per se, with no complications from disease, does not actually affect muscle protein turnover. Yet, those individuals we studied for the JAMA paper had decreased muscle mass because they had smaller muscles as compared to their younger counterparts. Although their basal protein turnover rates were normal, their muscle mass was smaller. Our general conclusion from that paper was that we were very happy to see no fundamental impairment in the muscle protein synthesis rate in older men. Had it been there, it would have been a serious problem to counteract. We would have to resort to treatments that would actually increase baseline muscle protein turnover, and we don’t even know how to do that—probably with androgens, but that’s for males only and wouldn’t apply to women. When we saw that the baseline was not a problem, we were reassured that it is probably more of a compounded problem of smaller deficits in the anabolic increases in muscle protein synthesis, possibly during the anabolic stimuli that do not adapt over the years and decades, eventually leading to a measurable muscle loss. After having demonstrated that amino acids alone, given orally or by IV were working, we went on to give a more physiological type of chemically-defined meal. We gave amino acids with glucose. We did the same with a large amount of amino acids—40 grams, which is a very large amount. Then we added another 40 grams of glucose to that. We found the gains in muscle protein synthesis that we would have expected due to the presence of amino acids in this meal, were totally lost. Protein synthesis in older people did not increase at all with this kind of meal, whereas in the younger controls, we had a huge increase in protein synthesis, double what we would have seen with amino acids alone. There was a completely different effect of this mixed meal on muscle proteins in young and older people. In both groups, we also saw a decrease in muscle protein breakdown. Overall, there was an increase in net muscle protein balance, but this increase was blunted in the older people because obviously, there was the component that the synthesis rate was missing. The total increase in net balance was entirely due to the decrease in muscle protein breakdown. You need to remember that the net balance of muscle proteins is due to the synthesis rate minus the breakdown rate. If the breakdown rate decreases significantly, the net balance can go up, but it is due to a total suppression, or decrease, in the muscle protein turnover rate. We concluded from that study that in young people when you add carbohydrate (an insulin stimulus which comes with additional carbohydrate in the diet), you see a significant increase of muscle protein anabolism and synthesis above and beyond what you see with amino acids alone. In elderly people, there is no net benefit with additional carbohydrate, but on the other hand, this addition can be detrimental for muscle remodeling because there is a decrease in the total turnover rate of muscle proteins as the breakdown decreases and the synthesis doesn’t increase. There is a reduction in the ability of muscle to exchange the older proteins. That could be one of the reasons why, over time, we see a slow, creeping decrease in muscle mass that could be due to the collection of smaller increases in net balance with mixed meals. I cannot say that the Atkins Diet or the carbohydrate-free diet would work in older people, because there’s no long-term data. We are still in the hypothesis stage on that issue. We don’t know what happens over the long term when you change the diet or add nutritional supplements that do not include carbohydrate and do not stimulate insulin secretion. We don’t know what’s going to happen with that over the long term. We need to do the studies. I turned in a grant proposal just recently so we can see if, with six months of nutritional supplementation with amino acids (essential amino acids in particular, which apparently are the ones most active anabolically for muscle in older people), we can make a difference and regrow muscle mass. Loss of response to the mixture of amino acids and carbohydrate on the other hand indicates a need to focus on the effects of insulin. In fact, when we were writing the paper about the combination of amino acids and glucose, we wondered what would cause this. Obviously, we could not dissect it from the data because we gave one group amino acids and one group amino acids with glucose. We thought that if the glucose we were giving was the culprit, how did it work? We didn’t know that because, if anything, it would have added some calories, some energy, to the meal. Protein synthesis is an energy-consuming process so it should have had a positive effect. The other major variable that changed during the carbohydrate meal with amino acids was insulin. I currently have a grant funded by the National Institutes of Health, to look at the potential for some kind of insulin resistance of muscle proteins which results with age. That might explain the impairments in muscle protein turnover during mixed feeding. I have some preliminary data. We are writing the paper right now, and hope to publish it over the next several months. There is definitely impairment in the response of muscle protein synthesis, once you expose the muscle to postprandial concentrations of insulin in older people. In younger people, there is an increase in muscle protein synthesis at these insulin concentrations, whereas in older people, we see no change in muscle protein synthesis and a decrease in breakdown. That’s one of the potential culprits (I wouldn’t say it’s the only one), that might explain muscle loss with age. JB: That is fascinating work and obviously we are going to be patiently waiting for continued results from your experiments and research. It seems to me that there is some kind of an age-related change that may be related to different signaling molecules focused on muscle physiology in older-age individuals versus younger individuals, and that insulin somehow plays a role. Perhaps diets should change as we grow older. That’s where your research may be taking us. Aging and Diet Changes EV: That’s possible. I can’t give any nutritional advice right now, because we don’t have the long-term data yet. We still need to do the studies, and it can be dangerous if you go on a whole-protein diet, carbohydrate-free diet. Perhaps split diets would be feasible where you eat carbohydrate separately from the meat (protein) . Again, this needs to be confirmed by long-term studies. On the other hand, we do know that if you want to increase muscle mass in older people, they must exercise. That’s the other part of the equation that needs to be stressed. Nutrition is one factor, but exercise is the other. Many people lose muscle just because they cut down on physical activity. Any kind of physical activity is important. Weight-lifting has been repeatedly shown by Drs. Evans, Yarasheski, and Welleto be extremely helpful in stimulating muscle protein synthesis in adults, and also muscle growth over the long term. I understand that weight lifting is not very appealing, so we need to consider aerobic exercise to help the regrowth of muscle—walking, swimming, or cycling. We are only beginning to examine this. There are definitely some dietary components that can be helpful. I do not subscribe to the Atkins Diet from an endocrinologist’s or physician’s perspective because it makes people ketotic and it may actually be dangerous in certain circumstances. A balanced diet is always a good idea to start with, and we can look into whether it needs to be supplemented. It is also important to emphasize, especially in the oldest old—people over 70-75—that they should not strive to lose weight. Weight loss in the elderly is strongly correlated with increased mortality. There are lots of questions still to be answered. The older we get, the higher the risk to become unnourished. We need energy and carbohydrate and fat can help with that. In prescribing diets for older people, one needs to look at body composition, and whether weight has been gained, lost, or is stable. If a patient is losing weight, packing calories is needed. Any cheesecake is good. My patients have always been very happy when I prescribe cheesecake because they feel reborn after years and years of fat-free diets for their heart disease. All the potential problems need to be factored into the equation, including the fact that weight loss is associated with higher mortality in older people. JB: Thank you, Dr. Volpi. You’ve done an eloquent job of covering a very sophisticated topic. It seems so obvious that we should know more about carbohydrate, protein, and fat, and their relationship to endocrine function in aging individuals. As you’ve outlined it, it sounds like a lot of the important, first-level studies are presently being conducted by you and your colleagues. It’s interesting what we’ve taken for granted that we really didn’t know. EV: I agree. It’s a wide-open field right now. JB: Thanks again for being with us today. We look forward to visiting with you at the 11th International Symposium on Functional Medicine. Dr. Volpi’s presentation raised many questions for us and also provided some insight relating to the diet controversy about protein, carbohydrate, and fat. One of the takeaways is that the total environment of the patient determines the way they respond to dietary variables, and that these are messenger molecules, dietary signals, that create the outcome. The outcome is different in different environments. If the patient is in an inflammatory state, is insulin resistant or diabetic, the response to meals may be very different from individuals who do not carry those considerations. Increased Dietary Protein and Blood Glucose Response in Type 2 Diabetics This information helps us to better understand results that were published in the American Journal of Clinical Nutrition, titled “An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes.”[19] In this paper, the investigators used a high-protein diet that was shown to lower blood glucose postprandially in patients with type 2 diabetes, and improve overall glucose control. The authors state that longer-term studies are necessary to determine the total magnitude of response, possible adverse effects, and the long-term acceptability of the diet. A New Look at Dietary Protein in Diabetes The editorial that followed this paper also confirms that there seem to be some interesting results of increasing dietary protein as a consequence of trying to monitor, measure, or modulate type 2 diabetes, insulin resistance, and hyperinsulinemia.[20] Could the state a person is in, with increased inflammatory mediators associated with type 2 diabetes/insulin resistance, affect which protein at an enhanced level has a beneficial effect? As Dr. Volpi said, perhaps uptake, muscle resynthesis, reformation, and remodeling are modified to a greater extent by increased dietary protein in the person with insulin resistance/hyperinsulinemia than in the person in whom inflammatory mediators are absent. That would tend to be consistent with the Volpi et al. paper that appeared in JAMA in 2001 that looked at basal muscle amino acid kinetics and protein synthesis in young and older men, suggesting that the postprandial environment, inflammatory mediators, and the messenger molecules that differ at young age versus older age, might have something to do with muscle protein synthesis, recalling that, in general, older men do not have the same muscle mass as younger men. It may be the total environment. We need to personalize the diet to the environment. As I mentioned earlier about animal versus vegetable protein, the Volpi et al. work indicates that essential amino-acid rich proteins are very desirable for establishing the right postprandial environment for muscle formation integrity. Essential amino acid-rich diets can be delivered withvegetable proteins fortified with specific essential amino acids, as well as with animal protein diets. Although, with soy protein fortified with sulfur amino acids, i.e., methionine, one might worry about soy protein because it contains phytoestrogens, isoflavones that can modify estrogen receptivity. In a recent paper in the American Journal of Clinical Nutrition, titled “Dietary phytoestrogen and breast cancer risk,”[21] the investigators looked at the dietary intake in 15,550 women, age 49 to 70, and constituted a cohort dietary intake looking at isoflavones and breast cancer incidence. They found that a high intake of isoflavones or lignans was not significantly related to breast cancer risk, again dispelling some of the unfounded risk concerns that certain people have about isoflavones. Flaxseed versus Soy Supplementation in Estrogen Metabolism Flaxseed lignans also play a role in estrogen metabolism in postmenopausal women, and may have a more salutary effect than soy itself.[22] Lignans from flax and soy isoflavones appear to be safe in moderate dietary intake. Soy protein has a good arginine/lysine ratio balance to achieve the effects we were talking about earlier. The whole story of protein, carbohydrate, and fat is more complex than it appears on the surface. We should be looking at personalizing individual dietary needs because diet signals create an outcome that leads to muscle preservation. Lignans and Estrogen Modulation When we talk about increasing vegetable protein, most individuals recommend soy-based foods, beans, or legumes, which contain various types of proteins. These are food products that also contain other phytonutrients, other plant-derived chemicals—a whole series of agents in different plant foods that modulate gene expression and function. One of these groups is lignans. Lignans are interesting because they are metabolized by enteric flora in the secondary compounds that have hormone-modulating effects. These secondary compounds from lignans can modulate estrogen metabolism. In a recent paper in the American Journal of Clinical Nutrition, investigators found that the urinary concentrations of the 2-hydroxyestrogens were increased significantly when postmenopausal women consumed a diet higher in flax lignans. The 16-hydroxyestrogens, the more mitogenic estrogens, were lower. Therefore the 2-16 hydroxyestrogen ratio was favorably improved with improved 2-hydroxylation and lowered 16-hydroxylation. This is as a result of consumption of lignan-rich diets, such as those enriched in flax seeds. These plant-based foods may have a whole series of salutary benefits on cell signaling and hormonal messaging beyond that of the protein/carbohydrate ratio or the amino acid ratio. We need to keep a broad perspective, open to all the variables in the diet that influence the complex processes in endocrinology. It is in the unrefined or whole foods diet where one is getting the complex signaling molecules in their natural forms, versus a highly purified diet (giving amino acids and glucose), where one is getting a whole different orchestration of function. As we simplify the diet and refine it more and more, it tends to address only one player in the orchestra, which creates a different symphonic sound than when we have all the players working together. Diets containing natural foods that are minimally processed, rich in color, with proper levels of vegetable protein and complex unrefined carbohydrates rich in phytochemicals, appear to be what would be recommended from much of the research.

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1 Dey DK, Bosaeus I. Comparison of bioelectrical impedance prediction equations for fat-free mass in a population-based sample of 75 y olds: the NORA Study. Nutr. 2003;19:858-864. 2 Ames BN. A role for supplements in optimizing health: the metabolic tune-up. Arch Biochem Biophys. 2004;423:227-234. 3 Kritchevsky D. Dietary protein, cholesterol and atherosclerosis: a review of the early history. J Nutr. 1995;125:589S-593S. 4 Scholz KE, Beynen AC, West CE. Regression of casein and cholesterol-induced hypercholesterolaemia in rabbits. Ernahrungswiss. 1983;22:85-96. 5 Valhouny GV, Adamson I, Chalcarz W, et al. Effects of casein and soy protein on hepatic and serum lipids and lipoprotein lipid distributions in the rat. Atherosclerosis. 1985;56:127-137. 6 Sugiyama K, Ohkawa S, Muramatsu K. Relationship between amino acid composition of diet and plasma cholesterol level in growing rats fed a high cholesterol diet. J Nutr Sci Vitaminol. 1986;32:413-423. 7 Dudasova S, Grancicova E. Influence of casein and soy flour proteins on amino acid content in the liver of experimental animals. Physiol Res. 1992;41:411-416. 8 Atwal AS, Kubow S, Wolynetz MS. Effects of protein source and amino acid supplementation on plasma cholesterol in guinea pigs. Internat J Vit Nutr Res. 1997;67:192-195. 9 Reynolds JV, Daly JM, Zhang S, et al. Immunomodulatory mechanisms of arginine. Surgery. 1988;104:142-151. 10 Sanchez A, Hubbard RW. Plasma amino acids and the insulin/glucagon ration as an explanation of the dietary protein modulation of atherosclerosis. Med Hypotheses. 1991;36:47-32. 11 Higginbotham S, Zhang ZF, Lee IM, et al. Dietary glycemic load and risk of colorectal cancer in the Women’s Health Study. J Natl Cancer Inst. 2004;96(3):229-233. 12 Ludwig DS. Glycemic load comes of age. J Nutr. 2003;133:2695-2696. 13 Jenkins DJ, Kendall CW, Marchie A, et al. Type 2 diabetes and the vegetarian diet. Am J Clin Nutr. 2003;78(suppl):610S-616S. 14 Liese AD, Roach AK, Sparks KC, Marquart L, D’Agostino RB, Mayer-Davis EJ. Whole-grain intake and insulin sensitivity: the Insulin Resistance Atherosclerosis Study. Am J Clin Nutr. 2003;78:965-971. 15 Paddon-Jones D, Sheffield-Moore M, Zhang XJ, et al. Amino acid ingestion improves muscle protein synthesis in the young and elderly. Am J Physiol Endocrinol Metab. 2004;286(3):E321-E328. 16 Volpi E, Lucidi P, Cruciani G, et al. Contribution of amino acids and insulin to protein anabolism during meal absorption. Diabetes. 1996;45(9):1245-1252. 17 Volpi E, Sheffield-Moore M, Rasmussen BB, Wolfe RR. Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA. 2001;286(10):1206-1212. 18 Volpi E, Ferrando AA, Yeckel CW, Tipton KD, Wolfe RR. Exogenous amino acids stimulate net muscle protein synthesis in the elderly. J Clin Invest. 1998;101:2000-2007. 19 Gannon MC, Nuttal FQ, Saeed A, Jordan K, Hoover H. An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes. Am J Clin Nutr. 2003;78:734-741. 20 Eckel RH. A new look at dietary protein in diabetes. Am J Clin Nutr. 2003;78:671-672. 21 Keinan-Boker L, van Der Schouw YT, Grobbee DE, Peeters PH. Dietary phytoestrogens and breast cancer risk. Am J Clin Nutr. 2004;79:282-288. 22 Brooks JD, Ward WE, Lewis JE, et al. Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Am J Clin Nutr. 2004:79:318-325.

Welcome to Functional Medicine Update for May 2004. A number of themes were developed in preparation for the 11th International Symposium on Functional Medicine, held May 11-15 in Vancouver, British Columbia. I would like to summarize those themes in this issue of FMU. I want to talk about where we see medicine going and how it relates to the rising pandemic of metabolic syndrome and type 2 diabetes. We are all hoping for a new medicine to emerge, one that is better able to address chronic, complex health problems. We have a sophisticated healthcare delivery system that, at the crisis care level, is quite adept at handling emergencies and life-threatening events requiring high technology for their successful remediation. It is when we extend some of the procedures that were developed for high-technology intervention and crisis care into the chronic care regime that we start to experience problems. Many of the medications that have been used successfully in the short-term for crisis care, when extended for long-term use, increase health risks and medical costs, drifting away from the benefit side of the equation. Things shift, resulting in adverse drug reactions and other long-term disabilities as a consequence of what have been called the iatrogenic effects of the treatments or procedures, and these begin to appear with greater frequency. There is hope that medicine will deliver therapies to maintain health benefits and decrease risk to complications and adverse effects over decades of use. As Oliver Wendell Holmes said in 1847: “The key to living a long life is to have a chronic disease and take good care of it.” Most of us will probably not develop a disease that will immediately kill us, but we are likely to develop some condition that gets our attention and reminds us that we are mortal and need to work on our health care. We need to practice diligent maintenance of our health. The biology of hope is an interesting topic. It interrelates with the mind/body field of medicine and the concept of complementary medicine. What is the biology of hope? It is an important part of the patient’s healing process. Sometimes it has been spoken of pejoratively as the “placebo effect.” If one has a hopeful and optimistic outlook, there is more likelihood of a positive outcome. From the work of Candace Pert in her book,Molecules of Emotion, we recognize that we can change our neurochemistry by the way we view our world and the sense we have of ourselves. We often want to mobilize the biology of hope in our patients; we want to create a milieu of molecules that will help to normalize the function of their neuroendocrineimmune system and give them optimal defense against disease. I would also suggest that the biology of hope is equally applicable to the practitioner. If, in our work each day, we bring thoughts of despair about the state of medicine and our work within it, we have changed our own molecules of emotion in such a way as to create a different kind of outcome, both in ourselves and in our patients. I think it is important to recognize that concept is being applied every day in our practices—sentient moments spent in the examination room with a patient on a one-to-one basis—that presents an important humanistic therapeutic encounter opportunity. If we ascribe to the biology of hope, it changes the dimension of our own neurochemistry and immune system, versus the biology of despair about the world in which we are working. I am quoting from an interesting article that recently appeared in the journal, ACUMEN,written by Jerome Groopman, MD, titled “The Biology of Hope,” in which he talks about the mind/body connection and the placebo effect.[1] Those of us who have been in this field for a while may recall Norman Cousins’ wonderful paper in The New England Journal of Medicinetitled “Anatomy of an Illness (as perceived by the patient)”.[2] In that paper, he talked about laughter therapy, the biology of hope, and creating a healing opportunity. There have been many papers published in this area since 1976. One of interest looks at catechol-O-methyltransferase (COMT) polymorphisms and how they relate to the production of neurotransmitters through the methylation pathway. We can speculate that the expression of the COMT enzyme can be influenced by an individual’s mood, physical state, and psychological state. With different polymorphisms having different sensitivities to the environment, methylation patterns might be upregulated that would create a different symphonic orchestration of neurochemicals that are converted by methylation—the noradrenaline/adrenaline interconversion. There are some interesting manifestations of the mind/body connection related to biochemistry, neurochemistry, and immunology. There is a significant placebo effect regarding analgesic or hormonal research. In our own clinical work, it has been fascinating to examine the symptoms of perimenopause and menopause. It is interesting to note the placebo effect accounts for upward of 50 percent of the change in hot flushes and night sweats in women. How they believe the outcome of their therapies will affect their physiology represents about 50 percent of the decrease in their symptoms. Similarly, work done on osteoarthritis has shown a significant placebo effect (about 50 percent) on pain. This confounds any kind of pharmacological intervention study. The placebo effect turns out to be a powerful therapeutic tool—the biology of hope, the belief of positive outcome. It extends from the patient to the provider and back again. In a wonderful review article that appeared in Scientific American in 1998 titled, “The Placebo Effect,” Dr. W.A. Brown talks about the extraordinary stratification of different kinds of patients into high-placebo responders versus low-placebo responders.[3] It could be that the high-placebo responders are individuals who can mobilize the biology of hope more effectively. The context of healing, the therapeutic encounter experienced between the practitioner and the patient, is one that is going to be determined, in part, by the definition of what the environment is. Is it one of hope or one of despair? We bring a priori assumptions and belief systems into the moment with the patient, and into our lives. How do we mobilize this positive part of the functional medicine arsenal—the biology of hope? When we look at the state of medicine, which is primarily pharmacologically-based, there are reasons to despair. It appears that we are pushing the model beyond the point of diminishing returns, trying to squeeze out incremental value with the pharmacological model, in which every additional increment of value costs 10 to 100 times more, either in dollar expense, or in expense to potential risk. We have reached the point of diminishing returns. That topic leads to an interesting review paper that recently appeared in The New England Journal of Medicine, titled “The Pharmaceutical Industry versus Medicaid—Limits on State Initiatives to Control Prescription-Drug Costs.”[4] The authors of this paper state that escalating health care costs are closely tied to the escalating cost of medications and their increasing use, and that the healthcare system has not succeeded in controlling expenditures. The cost pressures resulting from technological advances and new drugs for use by an aging population are likely to exacerbate the problem of access and make the system even less cost-effective. Examination of the cost of prescription drugs shows that Medicaid has been hard hit. Its spending on drugs soared from $4.8 billion in 1990 to $21.0 billion in 2000. In a single decade, that is more than a four-fold increase in expenditures for medications. What benefits have been realized as a result of these increases in expenditures? The authors discuss how some states are trying to find ways of reducing the costs of prescription drugs. This is a very complex equation. Much of it is tied to demand management and how patient interest in some of the new drugs is lowered, versus supply management, which is to prevent access to the medications. How is demand for these products reduced? That leads to the hope of a new kind of health care, one that would deliver better health to patients with complex chronic disease who have decades of living ahead during which certain medication regimes will be required. Remember what Oliver Wendell Holmes said about having a chronic disease and taking good care of it as the secret to a long life. How does one take care of it? What is the least expensive way? What is the most cost-effective way? What is the most efficacious way, with the lowest incidence of adverse drug reactions? What conditions are we talking about—vascular insufficiencies, various types of chronic cardiovascular disease, autoimmune diseases, inflammatory disorders, neurodegenerative disorders like Parkinson’s, Alzheimer’s disease, and presenile dementia? What do we do about those? These questions lead to asking whether the epidemic of obesity, insulin resistance, metabolic syndrome, and type 2 diabetes should be included. Shouldn’t we consider treatments for hypertensive disorders and their relationship to cerebral vascular disease and stroke? All of these diseases appear to have complex etiologies, not just a single cause as a result of a single gene that has mutated and can be taken care of with a single drug. These are functional disorders with multiple physiological factors across multiple genes unique to the individual, and interaction with each unique environment and lifestyle. The question is, can we develop, at least theoretically, a preventive cocktail to be taken once per week, after which we instruct patients to call us when they turn 90 years of age? On the basis of the information that has been developed over the last 20 years on the etiology of complex chronic diseases, is there something that could be done that would result in a simple, safe, and effective strategy for reduction of risk to the major age-related chronic, complex diseases? That leads to one of the more provocative papers I have read during the last year, written by Nicholas Wald and Malcolm Law, that appeared in the British Medical Journal, titled “A strategy to reduce cardiovascular disease by more than 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}.”[5] That is a pretty laudable objective. What treatment—surgical, radiochemical, or pharmaceutical—could lower a major disease (in this case, a major cause of death) by 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}? I do not know of a single treatment that could achieve that objective. Yet, these authors are presumptuous enough to suggest that there might be a simple strategy that could be implemented in people 55 years of age and older that would add 11 disease-free years to their life expectancy. That is pretty remarkable. According to statistics, people who have never smoked add 3 &frac12; to 4 years to their life span, on average, but the possibility of adding 11 years to one’s life is a pretty dramatic claim. What is this claim built around? It is built around a preventive cocktail that would contain six different agents addressing the six most dominant contributors to age-related complex chronic diseases. What does the preventive cocktail contain? In a review of the article that appeared in the journal, ACUMEN, the authors talk about a “polypill,” meaning that it contains six ingredients. That is the term Wald and Law used.[6] The authors suggest that this polypill, if implemented by people age 55 or older on a daily basis, could contribute significantly to the reduction of heart attacks and stroke in those with existing cardiovascular disease (statistically, more than an 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} reduction of the overall factors we know contribute to premature death from cardiovascular disease). What are the six different factors? Regarding the mechanism that has emerged from our understanding of cardiovascular disease, cancer, and arthritis, what are the related themes? They are inflammation, oxidative stress, mitochondrial uncoupling, lipid infiltration, and cell signaling relating to proliferative cells. We have talked about those things as unifying mechanisms that underpin the principles and processes of functional medicine. Let me discuss the six agents Wald and Law speak to. First of all, they talk about a statin, which would presumably handle lipid problems and also lower the arterial inflammatory process. Second is a folic acid-containing supplement to manage the homocysteine connection. According to Wald and Law, though vitamins B12 and B6 are significant, folate is by far the most important vitamin for managing the homocysteine connection to chronic health-related problems. Next are three types of blood pressure-modulating agents—a thiazide, a beta blocker, and an ace inhibitor given at half dose. They would be given under the radar screen for therapy, but more prophylactically to modulate the function of different systems (electrolyte management and angiotensin-converting enzymes)—interrelationships with angiotensin and angiotensinogen interconversion with renin and aldosterone. The beta blocker would lower the adrenergic drive in the cardiovascular system. The sixth agent would be an anti-platelet adhesion agent (low-dose aspirin or baby aspirin is suggested). Those are the six agents in the formulation—a statin at normal dose, a thiazide, a beta blocker, an angiotension-converting enzyme inhibitor at half dose, folic acid at a therapeutic dose, and an anti-platelet adhesion agent (aspirin or baby aspirin). Could a lifestyle and diet be designed that would accomplish similar objectives for those six different agents? For instance, could a lifestyle and diet be designed that would lower serum lipids and arterial inflammatory potential; enhance folic acid intake and lower homocysteine; lower blood pressure and create a favorable effect on each of the three mechanisms of the antihypertensives that I described—the thiazide, the beta blocker, and the ace inhibitor? Last, could a lifestyle and diet be designed that would lower platelet adhesiveness and thromboxane production, such as one high in essential fatty acids from the omega 3 family? If you were given that assignment, and had listened to FMU for the past 20 years, by going back and reviewing our summary cards you could probably pull up a strategy that would deliver the six agents in the proposed formulation. As David Deutsch said in his classic book, The Fabric of Reality, the future of medicine is to build on the predictive ability of first principles so that outcomes of therapies never before tried will be successful. That is when medicine becomes scientific and has a predictive, not just a historical, medical taxonomy perspective. That is a powerful example that comes out of the Wald and Law paper. In patients with individual risks in these categories, we might be able to develop a “polypill” or “polyprogram,” personalized to the needs of each individual. Not everyone has the same risk in the six categories that I have just described. That becomes a preventive cocktail, so to speak. If delivered effectively in people 55 years of age and older, statistically it could add 11 disease-free years to their lives and reduce cardiovascular disease by more than 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}. It is in the last 10 years of one’s life that the majority of medical services are needed. That is when morbidity and mortality become much more real and medical service expenditures are extraordinarily increased. Does that represent an alternative to the pharmaceutical model of intervention which leans toward fixing broken systems with increasingly expensive medications? I think the answer is yes. By the way, the six different agents I just mentioned are all generic and would be fairly inexpensive relative to some of the new third-generation drugs. This opens up a different strategic approach based upon understanding the origin of chronic complex age-related diseases. Let us switch from a complex topic to a simple one. That is, what would happen if we simply got people to take a multivitamin and mineral supplement every day as they got older? Would that have any benefit? We should not assume that even a varied and moderate diet delivers all the nutrients needed for optimal function of various organ systems. What would happen if patients took out a nutritional insurance policy or program; for instance, one that included a high-potency multivitamin and multimineral? Results of a study on that issue—the Stockholm Heart Epidemiology Program (SHEEP)—have recently been published, and they are quite fascinating. This study was related to the use of multivitamins and the risk of cardiovascular disease.[7]The investigators examined the association between the self-selected use of a daily multivitamin supplement and the incidence of myocardial infarction (MI) in a group of individuals from 45 to 70 years of age residing in Sweden. The study included 1296 cases, 910 men and 386 women, with a first non-fatal MI and 1685 controls, 1143 men and 542 women, frequency-matched to the cases by sex, age, and hospital catchment area. The odds ratios were calculated from the unconditional logistic regression models. Among controls, 57{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the women and 35{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of the men used dietary supplements; corresponding figures for the cases were 42{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} and 27{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36}, respectively. Of those taking supplements, 80{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} used multivitamin preparations. After adjustment for major cardiovascular risk factors to normalize variables, the odds ratio of MI, comparing regular users of supplements with nonusers, was 0.79 for men and 0.66 for women. This inverse association between increased intake of vitamin supplements and lowered incidence of cardiovascular disease was not modified by such healthy lifestyle habits as consumption of fruits and vegetables, increased intake of dietary fiber, smoking habits, and level of physical activity. The results of the study indicate that the use of low-dose daily multivitamin supplements may aid in the primary prevention of MI. This would be a very inexpensive first step in getting to a “preventive cocktail.” If we look at how this concept cuts across many disorders with differing ICD9 codes, does this strategy also relate to things like reduction of risk to type 2 diabetes, hypertensive disorders, arthritis, inflammatory bowel disease, or certain types of cancer? Is there a connection by way of a mechanism, rather than by a disease type? That is an interesting question that we are going to continue to explore in FMU. Perhaps if we can become masters of mechanisms, diseases will become less important. Let us examine a couple of papers that might illustrate the importance of the mechanism connection, one of which appeared in the Journal of the American Medical Association, titled “C-Reactive Protein and the Risk of Developing Hypertension.”[8] This is an interesting paper, and the authors of an editorial that follows it point out that the material in the paper demonstrates an interconnection between inflammation, hypertension, and metabolic syndrome and its later connection with type 2 diabetes. These are not individual, independent disorders. They are interconnected disorders. Inflammatory disorders are connected to hypertensive disorders, which are connected to the metabolic syndrome, which is connected to type 2 diabetes, which is connected to vascular risk, and ultimately cardiovascular disease risk factors. The original paper in JAMA was written by Dr. Paul Ridker and his colleagues who, for the last several years, have been actively involved with the connection of inflammation to a variety of chronic health problems. In this paper, the authors discuss a prospective cohort study that began in 1992 looking at 20,525 female U.S. health professionals, age 45 years or older, whose blood pressures were examined. They looked at high-sensitivity, C-reactive protein and found it to be significantly associated with an increased risk of developing hypertension in all pre-specified subgroups evaluated, including those with very low levels of baseline blood pressure. This suggests that inflammation has something to do with the etiology, and perhaps even the cause of increased blood pressure. The investigators conclude that C-reactive protein levels are associated with future development of hypertension, suggesting that hypertension is, in part, an inflammatory disorder. As discussed in an editorial that follows this paper by Dr. Scott Grundy, this association with inflammation connects hypertension to metabolic syndrome and atherogenesis, or to the origin of atherosclerosis.[9] Vascular biologists are beginning to help us understand the mechanism that connects inflammation, endothelial dynamics, insulin resistance, metabolic syndrome, and atherogenesis. Therefore, possibly intervening with a program that deals with the reduction of inflammatory potential in a tissue-specific way, will help in the management or even the prevention of many diseases. It goes back to the Wald and Law polypill concept we were discussing earlier. If we hit the right mechanisms, perhaps many positive benefits will play out over decades of living. Certain agents initiate inflammation, contribute to insulin resistance, affect the vascular system, and have adverse effects upon kidney function. This may lead to increased risk of nephropathy and problems with blood pressure control leading to hypertension, or possibly later-stage renal failure. That leads to an interesting series of questions that cut across the environment and the modification of things in that environment that affect function. I want to focus on the concept of glycation. Let us quickly review what I mean by glycation and how it relates to inflammation, insulin resistance, metabolic syndrome, and nephropathic injury leading to renal failure. In following a patient with diabetes, we may measure an analyte in the blood called hemoglobin A1C, or glycosylated hemoglobin. Glycosylated hemoglobin is the heme protein which has undergone a non-enzymatic reaction with glucose in the blood called the Maillard Reaction. This reaction was first described in food chemistry. It is a glycosylation reaction where the aldose form of a reducing sugar, like glucose, reacts with the lysyl amino group of an amino acid and a protein to produce a Schiff’s base that rearranges to form a stable adduct called the Maillard product. That is a glycosylation product. In terms of a mental model, we might think of it as a crust of bread. Glycosylation is to make crusty bread. When dough containing protein and sugar is baked in the oven after it has been yeast fermented in the warm spot of the interface between the oven temperature (the oxygen in the oven and the dough itself), there is an advanced glycosylation reaction. Sugar reacts with the animo groups of the protein to produce the Schiff’s base that becomes the crust of bread. In chemistry, glycosylation is to form crusts, or oxidation ofinjured proteins—a combination of lipids with sugar or protein with sugar. That particular reaction, which makes cosmetically attractive bread and also a different flavor in the crust than the dough of the bread, could also be used analogously to talk about what is going on in the plasma. Glucose reacts with proteins, such as plasma proteins, to induce glycosylation reactions. If they occur randomly and are not controlled by non-enzymatic processes under the agency of the Maillard Reaction, they form crusty proteins floating in the blood. These are called advanced glycation end products, or AGEs. Accumulation of a lot of AGEs is associated with biological aging in all animals that have been studied to date, including humans. We want to prevent the disadvantageous random glycation of our proteins and the formation of AGEs. By the way, it has also been found that there are receptors for AGEs on various cells, such as the immune cells. What does that mean? It means RAGEs. A lot of AGE proteins results in the body becoming “enraged.” RAGEs are activated by AGEs, and many crusty proteins in the body produce an enraged physiology (I am using those terms metaphorically) that upregulates inflammatory potential, oxidative injury, mitochondrial effects, and an immune system that is in a state of alarm. Is there any connection between eating glycated proteins and activation of RAGEs? We assume that the foods we eat are broken down and metabolized by digestive enzymes, and that before they are absorbed across the brush border cells into the blood, they have been suitably detoxified and properly presented so there is no poor information still present in the food molecules that might lead to dysfunction. That is the line of thought in standard gastroenterology. However, in terms of dietary AGEs, the molecules from cooking sugar-rich foods high in protein at high temperature, or carbohydrate/protein connections, AGEs occur when there is glycation of protein that produces a glycotoxin. Glycotoxins have recently been found to be absorbed into the blood to a small extent, which means they could place a burden on the body’s immunological system. That is a whole new “aha” about how individuals might have different responses to cooked foods that are high in protein and high in sugar. Meringue is an interesting example. Egg protein and sugar is cooked to intentionally produce a browning reaction. That represents a huge amount of glycation. When you eat meringue, what does it do to your immune system? It is a new and foreign molecule that may incite the RAGEs to become enraged. That is the model. Let’s talk about an article in the Proceedings of the National Academy of Science, USA in 1997 that came out of the work of Dr. Helen Vlassara and her colleagues at the Laboratory of Diabetes and Aging in Manhasset, New York. It is titled “Orally absorbed reactive glycation products (i.e., glycotoxins): an environmental risk factor in diabetic nephropathy.”[10] Renal excretion of orally absorbed AGEs is markedly suppressed in people with insulin resistance and hyperinsulinemia. It also demonstrates that daily influx of dietary AGEs, or glycotoxins, may constitute an added chronic risk factor for renal vascular injury, and that dietary restriction of AGE food intake may greatly reduce the burden of AGEs in diabetic patients and possibly improve their prognosis. I am quoting directly from the paper. Cooked foods high in sugar and protein may, in fact, enhance the relative age-related reactions associated with AGEs. In animal studies, if exposure to AGE proteins in the diet is restricted, does that have any effect on kidney aging? The answer is yes. I am now quoting from a series of papers, one of which appeared in the Journal of American Society of Nephrology.[11] Investigators showed that restriction of dietary intake of glycation products led to improved retention of kidney function in aged rats versus those intentionally fed certain amounts of AGE protein in their diet. This is very interesting. Using a dose/response relationship, the investigators showed how dietary AGEs could adversely influence kidney function. An interesting example is discussed in another paper from Dr. Vlassara’s group, titled “Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy.”[12] In this paper, it was shown that in diabetes, environmental dietary AGEs promote inflammatory mediators leading to tissue injury, and that restriction of dietary AGEs can suppress their effects. If we look at reviews published in 2001 and 2002 on this topic, it is interesting to see how the field is emerging. One is titled “Advanced glycation end-products: a review.”[13] The authors explain that AGEs are a complex heterogeneous group of compounds that have been implicated in a variety of diabetes-related complications—ocular injury, neurologic injury, and nephropathic injury associated with oxidative upregulation of the immune system. These compounds may also lead to what is called protein carbonylation, another factor associated with immune reactions and oxidative stress that occurs during the upregulation of the immune system caused by exposure to AGEs. It appears that agents used for the treatment of AGEs would be very useful in reducing the injury to tissues in individuals with metabolic syndrome/hyperinsulinemia. What are those agents? One class of substances is the aminoguanadines. They are probably the best studied of the pharmacological agents to reduce glycation. They are the metformin-like compounds. It is possible that one of the benefits of metformin beyond its glucose-regulating effect is its anti-glycation effect. The natural substance carnosine is an anti-glycation agent, as well. Carnosine has been shown in a variety of animal studies to be very helpful when given in supplementary doses for reduction of the combination of glucose with protein that forms AGEs. Clearly, when blood sugar is inappropriately controlled, and when insulin regulation is disturbed, there is a strong increasing risk to the formation of AGEs. That relates to increased inflammatory potential, which ties together with increased cardiovascular risk, nephropathic risk, neurological injury, and ocular injury. It is part of an accumulative process of degenerative disease. Rather than putting people on medications once they get to the endpoint of damage, perhaps they should be put on an early-stage protector against AGEs, meaning a diet and lifestyle that could reduce glycation. From a clinical management perspective, this might mean lowering a patient’s glycosylated hemoglobin and not allowing it to reach the upper limits of normal. It might be well to manage their glycosylated hemoglobins in the low-normal range, not in the high-normal range, and use this as a marker over the life of the red cell (about 120 days). Any change made today may not result in significant changes in glycosylated hemoglobin for another three months, but it can be used as a marker for tracking some of the variables that associate diet and lifestyle with glycosylation and subsequently, with inflammation, hypertension, and metabolic syndrome. Again, it is a web of interacting variables. We are looking for a way to lower the incidence of later-stage, chronic, complex diseases which require cost-ineffective pharmacological intervention. What other age-related problems might be approached from a similar strategy? That leads into a discussion about how AGEs and other factors initiate brain injury. We will talk about dementia, Alzheimer’s, Parkinson’s, and neuroprotective therapy on Side 2. Let us move from the mind/body association to some of the other principles emerging from neuroscience that, from a functional medicine perspective, might deliver on the objective of protecting the reserve of our cognitive and emotional function over time. In order to do that, I want to mobilize a nutritional component. There may be factors in our diet that play important roles in the neuroprotection pathway I have been describing. That brings back a term you have heard me use several times—nutrigenomics—the role that nutrition plays in gene expression. What I am referring to is that no two people respond identically to the constituents of their diets. Based on genomic uniqueness, one may have differing sensitivities to environmental stimuli, different inflammatory potential, different oxidative stress potential, and different risk to neuronal injury. Nutrigenomics not only examines inflammatory disorders; it also looks at the role nutrition can play in inflammation. Nutrigenomics implies both the role of macronutrients (fat, protein, carbohydrate and their forms), micronutrients (vitamins, minerals, and essential fatty acids), and conditionally essential phytonutrients. These could be plant-derived phenols or bioflavonoids, or nucleic acids. They could also include glucosinolates from cruciferous vegetables and their effects on detoxifying enzyme systems, as well as substances that activate synthesis of coenzyme Q10, taurine, carnitine, or intra-mitochondrial glutathione in the body, all of which have positive impact on neurological function. There may be a whole array of nutrients, both macro- and micronutrients, that may be important in modulating gene expression and proteomic outcome, and later metabolomic function, in a tissue-specific way that might be harnessed to deliver neuroprotection. That is the strategy the nutrigenomics model is focused on. It is a long way from suggesting a nutrigenomic approach to delivering it in the clinic because of a wide variety of differences from person to person, assessment methods, and how programs would be personalized to the individual’s need. But for the first time I can recall in my 30 years in this field, tools are becoming available to answer those questions. In the next few years, We may see multi-panel gene screens that will allow us to evaluate inflammatory genes that are most tracked against neurodegeneration. We may be able to mark their influence by different dietary effects on expression and how to “cool them off” so as to quench the flames of neurodegenerative fire (the “brain on fire,” as it has been described). I want to go over nutrigenomic goals and strategies. We have reviewed this in the past, but I want to revisit the wonderful paper that appeared in Nature Reviews, titled “Nutrigenomics: goals and strategies.”[20] In this article, the authors specifically describe the use of various nutrients to modulate inflammatory signals in neurological function and brain aging. Let me cut to the clinical takeway. That is discussed in a wonderful paper recently published in the Journal of the American Medical Association, titled “Neuroprotection in Parkinson Disease. Mysteries, Myths, and Misconceptions”[21] I want to focus on some of the features in this article because of their important clinical relevance. The authors state that Parkinson’s disease is an age-related neurodegenerative disease that affects approximately 1 million persons in the United States, and that its incidence is increasing as we become an older-aged society. Current therapies, such as L-dopa Sinemet, provide effective control of symptoms, particularly in the early stages of the disease, but most patients develop motor complications with long-term treatment. Negative features develop, such as postural instability, falling, and dementia that are not adequately controlled with existing medications. This opens up an opportunity for a different augmented or accessory approach. Neuroprotective therapy might slow, stop, or even reverse disease progression, and we urgently need to find a way of both understanding what neuroprotective therapy for Parkinson’s is and then delivering it more effectively. In this paper about neuroprotection trials, there is a figure that represents a landmark. It is everything we have spoken to in the foundation of the philosophy of functional medicine for the past 20 years. The figure ties together genes and environment into a modification program focused, in this case, on the prevention of neurodegenerative disorders, i.e., Parkinson’s disease. Let us go through the model that appears in Figure 1 on page 359 of this paper. What is the emerging etiology for the neurodegeneration associated with Parkinson’s disease? First, there are the genetic factors. These have been identified as specific genes that may be associated with poor detoxification, like single nucleotide polymorphisms (SNPs) of glutathione-S-transferase, catechol-methyltransferase, N-methyl-transferase, or the sulfation enzymes involved with detoxification of exogenous xenobiotics—foreign compounds capable of inducing neurological injury. Historical and epidemiological research has shown that Parkinson’s disease is more common in individuals in workplace environments associated with exposure to toxins, such as farmers and agricultural workers, and those in the tanning, paint, and glue industries. Individuals in work environments that may be the most susceptible are those with genetic susceptibilities to the inability to effectively detoxify toxins. We have reviewed many papers on this topic, including Rosemary Waring’s classic studies in England at Birmingham University Medical School in the Department of Neurology, showing that lower detoxification of sulfation, glucuronidation, and glutathione conjugation are associated with increased risk to neuronal injury. Those are the genetic factors. Next are the environmental factors. What xenobiotics and endogenous chemicals are the genes exposed to that lead to a gene/environment interaction that presents as the etiology of Parkinson’s disease? The answers to that question would be sought in the field of environmental medicine, e.g., in papers discussed above. If one has genes of high susceptibility, he or she should not be put into a high-risk environment. The environment needs to be tailored to the individual. That is what environmental medicine is all about—cleaning up the environment, pollution control, local eco-environmental control, the home, air, water, mold, toxins, etc. Now, let’s move from etiology to pathogenesis. What are the four mechanisms that have been postulated as being the causative agents for the cellular injury and death of the nigra striatum associated with Parkinson’s disease? You have heard about all of them in FMU. They include oxidative stress, mitochondrial dysfunction, excitotoxicity (NMDA receptor activations and the hypothesis of endogenous excitotoxicity), and inflammation. If you have been a student in this field for some time, I am sure you would agree that all four of those mechanisms are interrelated. They are not independent etiological processes. Oxidative stress is interrelated with mitochondrial dysfunction, which is interrelated with inflammation, which is interrelated to excitotoxicity. These do not stand as independent contributors, but rather engage in crosstalk and messenger molecules that share pathways throughout the process. How do we approach oxidative stress? What would we do to implement neuroprotective therapy to lower oxidative stress? The authors of the January 2004 JAMA article talk about antioxidant intervention with vitamin E, vitamin C, various antioxidants, and iron chelators to prevent free iron from becoming available in the nervous system that induces free radical oxidative injury through dismutation of superoxide. We want to enhance the redox potential of the brain (reduction/oxidation potential) by building power or reducing buffering capacity, a term often used with blood buffer and pH. We can consider redox buffering by enhancing these antioxidants. Next is the area of mitochondrial dysfunction. What can be done to improve that? The authors talk about bioenergetic agents. What examples do they give? They discuss coenzyme Q10, lipoic acid, N-acetyl-carnitine, agents that enhance the control of electron transport and mitochondrial function, and lower oxidative leakage out of the mitochondria by mitochondrial uncoupling. These are some interesting examples of intervention with antioxidants. The intervention might also include things like N-acetylcysteine to enhance glutathione synthesis, and bioenergetic agents such coenzyme Q10 and lipoic acid. Next is excitotoxicity. The authors talk about lowering activation of the NMDA receptors. Some new drugs are being explored that will be available on the market soon. They are anti-glutaminergic agents which will lower NMDA activity and stimulation of the receptors. There are dietary variables that will lower neuroexocitotoxicity, such as a clean diet, one that is lower in food chemicals, more basic in hypoallergenicity, and which may have a salutary effect on lowering neuroexocitotoxicity. Less exposure to mercury, lead, or cadmium may play a positive role, as well. These are environmental and dietary factors that may lead to lower excitotoxicity. Last is inflammation. How do we lower that? First, we use antiinflammatories. We have talked about downregulating NFkB expression, managing and controlling cyclooxygenase and lipoxygenase activities, and trying to restore proper Th1 and Th2 balance in the immune system. Antiinflammatories might have important roles to play in regulating the expression of NFkB; in other words, liberating it from its inhibitor kB and the cytosol so it becomes available to the nuclear genome, resulting in a change in expression patterns. This is another important potential approach—stabilizing the NFkB complex and lowering its activity. There are important things that relate to diet and lifestyle. We have talked about natural substances that modulate inflammation potential. There is a whole range of different dietary spices and phytochemicals that have antiinflammatory capability. What about the omega 3 fatty acids, DHA and EPA, and the role they play in some of the cyclooxygenase pathways? What is emerging from the discussion in the JAMA article about neuroprotection in Parkinson’s is a model that sounds very much like a functional medicine approach—evaluating antecedents, which they call genetic factors; looking at triggers, which they call environmental factors; and the interaction of triggers with antecedents resulting in a gene/environment interaction. Next, looking at the mediators that result from oxidative stress, mitochondrial dysfunction, excitotoxicity, and inflammation, and modulating those using differential approaches based on diet, lifestyle and, where necessary, pharmaceutical intervention. That ultimately results in improved protein handling, lowered loss of neuronal reserve, and lowered apoptotic cell death, which leads to what Dr. James Fries talked about—the loss of organ reserve and ultimately, increased dysfunction. The article in JAMA on neuroprotection in Parkinson’s disease is a model for so many things that we have talked about in functional medicine. It also addresses, in part, the “polypill concept” of reducing age-related, complex chronic diseases by the modulation of various pathways. To take this to the next level, one might ask if there are any papers that have been published documenting the role that nutritional factors play in mitochondrial disorders or neurodegeneration, or is this all speculation? There is quite a large bibliography in that area, and I want to touch upon a couple of interesting papers. Recently, in the Journal of the American Dietetic Association, a paper was published, titled “Nutritional Co-factor Treatment in Mitochondrial Disorders.”[22] In this paper, it is shown that one of the most accepted ways of approaching the management of mitochondrial disorders is by augmentation of specific nutrients to restore proper mitochondrial oxidative function.The authors identify metabolic therapies have been reported to produce positive effects on mitochondrial degenerative disorders, including coenzyme Q10, ascorbic acid, vitamin E, lipoic acid, increased levels of riboflavin (vitamin B2), niacin and thiamin, vitamin K, creatine, and carnitine. A review of these supplements in mitochondrial disorders unfolds quite a large bibliography of supporting documents. In this article alone, there are over 80 citations on the use of various nutrients in the treatment of mitochondrial disorders. Generally, they are talking about inborn errors of mitochondrial dysfunction, but there are induced injuries to mitochondria in the somatic cells through oxidative stress, inflammatory upregulation, and mitochondrial uncoupling. It is not just inborn errors, but perhaps the mild, induced mitochondrial injuries where these particular interventions might prove useful. Coenzyme Q10, riboflavin, vitamin E, lipoic acid, N-acetylcarnitine, N-acetylcysteine, vitamin K, and creatine are all interesting nutrients in this emerging story. Coenzyme Q10 intake elevates mitochondrial and tissue levels of coenzyme Q10 and vitamin E in animals. This has recently been shown by Dr. Sohal and his colleagues at the University of Southern California.[23] If there is mitochondrial injury due to oxidative stress reactions, it can modify cognition and increase age-related dementia. This has been shown in a variety of control studies in animals. A good paper was recently published in Nature Genetics looking at how mitochondrial DNA injuries can modify cognition and produce dysfunction at what is called the “intelligence level” in animals.[24] To take this to the next level, one might ask if there are any papers that have been published documenting the role that nutritional factors play in mitochondrial disorders or neurodegeneration, or is this all speculation? There is quite a large bibliography in that area, and I want to touch upon a couple of interesting papers. Recently, in the Journal of the American Dietetic Association, a paper was published, titled “Nutritional Co-factor Treatment in Mitochondrial Disorders.”[22] In this paper, it is shown that one of the most accepted ways of approaching the management of mitochondrial disorders is by augmentation of specific nutrients to restore proper mitochondrial oxidative function.The authors identify metabolic therapies have been reported to produce positive effects on mitochondrial degenerative disorders, including coenzyme Q10, ascorbic acid, vitamin E, lipoic acid, increased levels of riboflavin (vitamin B2), niacin and thiamin, vitamin K, creatine, and carnitine. A review of these supplements in mitochondrial disorders unfolds quite a large bibliography of supporting documents. In this article alone, there are over 80 citations on the use of various nutrients in the treatment of mitochondrial disorders. Generally, they are talking about inborn errors of mitochondrial dysfunction, but there are induced injuries to mitochondria in the somatic cells through oxidative stress, inflammatory upregulation, and mitochondrial uncoupling. It is not just inborn errors, but perhaps the mild, induced mitochondrial injuries where these particular interventions might prove useful. Coenzyme Q10, riboflavin, vitamin E, lipoic acid, N-acetylcarnitine, N-acetylcysteine, vitamin K, and creatine are all interesting nutrients in this emerging story. Coenzyme Q10 intake elevates mitochondrial and tissue levels of coenzyme Q10 and vitamin E in animals. This has recently been shown by Dr. Sohal and his colleagues at the University of Southern California.[23] If there is mitochondrial injury due to oxidative stress reactions, it can modify cognition and increase age-related dementia. This has been shown in a variety of control studies in animals. A good paper was recently published in Nature Genetics looking at how mitochondrial DNA injuries can modify cognition and produce dysfunction at what is called the “intelligence level” in animals.[24] What nutrient has been found to be most useful for the protection of the mitochondrial processes that are so important for the maintenance of neuronal energy production and neuronal function, may ultimately control the production of neurotransmitters and neuromodulators, and may have significant effects on mood, mind, memory, and behavior? That is a question still being vigorously debated at both the laboratory and clinical levels. The nutrient I want to focus on (beyond the obvious coenzyme Q10) is vitamin E. The emerging vitamin E story is quite fascinating. It is a useful story as to how our understanding is evolving in the area of neuroprotective and other health-protective agents. Vitamin E was first discovered in 1922. It was found to be a family of substances derived from vegetable oil and given the name “tocopherol” (Greek for “to give birth”). Research has shown that a lack of vitamin E results in fetal death in animals. Rats have a very convenient way of managing this; they resorb their fetuses. They do not miscarry; instead, the fetus is resorbed. In the absence of including this unusual fat-soluble factor of substances in the diet, the animals would become infertile, resulting in fetal resorption. Putting the substances back in the diet resulted in normal fertility and offspring. Because of that research, vitamin E gained the reputation of being a “fertility vitamin.” Early lore about vitamin E described it as an aphrodisiac good for sexual vitality. That was a result of the research on its ability to prevent fetal resorption in animals and produce proper fertility and litters. Since then, vitamin E has been the subject of much more research and discussion. It is now recognized as a member of different molecules in the family of tocopherols. It can be broken down into several different types of tocopherols based on the methylation patterns of the chroman ring, which is part of the structure of the vitamin E molecule. It can be an a, b, g, or dtocopherol. There are some derivatives of vitamin E that have unsaturated linkages in what are called the phytyl side chain of the vitamin E molecule, which makes them into what are called tocotrienols. There are a, b, g, or d tocotrienols, a family of different members that share similar chemical structure, but which may have different functions at the physiological level. Different plant oils from which vitamin E is derived have different dispositions or ratios of a, b, g, or d tocopherols and tocotrienols. Depending upon what plant oil the vitamin E is extracted from, there may be differing amounts of the various family members. What has been considered the most active form of vitamin E? The literature over the past 50 years tells us that the natural form of vitamin E in the d-a form is the most active. It has 1.39 IU of activity per milligram, as contrasted to the synthetic vitamin E, the dl-a-tocopherol that has one unit per milligram. The natural form of d-a-tocopherol is about 30 to 40 percent more active per milligram. How was that activity analyzed? What was the biomarker used for determining its higher activity? Why is the a form more active than the b, g, or d forms? That is a fascinating part of the story. In developing the bioassay, the best way of determining its activity in animals was to look at its ability to prevent rat fetal resorption. It was found that the most active form of vitamin E to prevent rat fetal resorption was the a form. Therefore, it was given the highest potency—1.39 IU per milligram. How many people take vitamin E to prevent rat fetal resorption? The obvious answer is that no one does. They take it for other reasons—cardioprotection, immunological effects, mitochondrial defense, and neuroprotection. Does that relate directly to vitamin E’s effect on the prevention of rat fetal resorption? That has been a big controversy. For years, we have assumed that the a form, the most active form for the prevention of rat fetal resorption, was also the most active form for the prevention of many other conditions in humans. What research on vitamin E has emerged over the last few years? First, it has been found that the most common form of vitamin E in plant food oils is not the a form, but the g form. Therefore, the manufacturers of vitamin E often intentionally converted g to a to convert it into a “more active formulation,” meaning higher IUs per milligram, or better in preventing rat fetal resorption. The a form is the most common form in human tissues as well, but is not the most “natural” in the diet. Gamma forms were intentionally moved to become a forms, but in a natural diet the major form is g-tocopherol. Vegetarians have been eating mostly the g form, but we have been supplementing mostly with the a forms. This is discussed in a paper published in the American Journal of Clinical Nutrition[25] that talks about g-tocopherol being the major form of vitamin E in the US diet. Let us examine the role that g-tocopherol has, as contrasted to a-tocopherol, in the range of physiological function beyond rat fetal resorption. Gamma tocopherol produces a dramatic series of effects that do not appear to be as well shared with the a form, meaning there may be some benefits of g-tocopherol in human physiology that we have been missing for the last 10 years. In 1978, I spoke at an international conference on vitamin E and raised a parenthetical question, not realizing what I was asking at the time, only that we had been doing research on vitamin E since 1971. I asked whether it might be possible that the major food form of vitamin E, g-tocopherol, had hitherto unexplained physiological effects, and that perhaps we were putting our eggs in the wrong basket, always focusing on a-tocopherol. That question ended up in an article on the proceedings of that conference presented in England in the late 1970s. Since then, many others have become interested in the g-tocopherol story, and research began to demonstrate that it has a profound influence on cytoprotection against certain free radical oxidants greater than that of a-tocopherol. This is described in a book on vitamin E that contains a chapter, titled “Beyond a-tocopherol: the role of the other tocopherols and tocotrienols,”[26] that includes its effect on signal transduction, platelet adhesion, and other processes. Is g-tocopherol the new vitamin E? asks Maret Traber and Sridevi Devaraj in a recent paper in the American Journal of Clinical Nutrition.[27] The answer is no; it is not the new tocopherol; it has been around since time immemorial, but we are now reviewing its activity in a different way than before. It may be the preferable form of vitamin E to prevent nitrosation reactions and protect against peroxynitrite, the result of immune upregulation and inflammation. It may be preferable to defend against endothelial arterial injury. Perhaps g-tocopherol deserves a lot more attention than the a form in terms of its potency, as it relates to physiological protection against age-related chronic disease. This is discussed in a number of research papers. For instance, recently in the FASEBJournal, a paper was published by Bruce Ames and his colleague, Qing Jhiang at the Division of Biochemistry and Molecular Biology, University of California, Berkeley and Children’s Hospital Oakland Research Institute, Oakland, California. [28]In this paper, they discuss g-tocopherol (but not a-tocopherol), decreasing proinflammatory eicosanoids in animals—the cyclooxygenase and lipoxygenase-derived eicosanoids. They used a-tocopherol-supplemented corn oil and g-tocopherol-supplemented oil and showed that the g form had a much better ability to lower leukotriene B4 and cyclooxygenase-mediated eicosanoids. In this study, g-tocopherol appeared to be preferable in these functions. I want to emphasize that this was a study done in animals. In another paper written by Bruce Ames and his colleagues that appeared in Free Radical Biology and Medicine, they talk about g-tocopherol supplementation inhibiting both protein nitration and ascorbate oxidation in animals in which inflammation had been promoted.[29]This suggests that g-tocopherol has preferable antiinflammatory effects. Gamma tocopherol, as contrasted to a-tocopherol, may directly inhibit cyclooxygenase activity in macrophages, one of the most important cell types involved in the production of inflammatory mediators. This work appeared in the Proceedings of the National Academy of Science.[30] Supplementation of a, b, g, and d tocopherols, when studied in humans, showed enhanced function on endothelial NO synthase, and regulation of superoxide dismutase and protein kinase C activities in leukocytes of human subjects. These were 64 subjects randomized into three groups given either a-tocopherol, mixed tocopherols, or controls. A more salutary effect on endothelial constitutive NO synthase was observed with the use of the mixed tocopherols. This is work published in Nutrition Research.[31] Mixed tocopherol preparations have been found to be superior to a-tocopherol against hypoxia-reoxygenation injury. This work was published in a paper in Biochemical and Biophysical Research Communications.[32] There is a fairly broad body of literature indicating that the vitamin E family (e.g., g-tocopherol), with coenzyme Q10, and lipoic acid, appears to have beneficial effects in helping to lower oxidative injury, NO inflammatory effects, and peroxynitrite nitrosation reactions, and offer neuroprotection, as well. Obviously, there is much more to learn about the vitamin E story. The Wald and Law article on the reduction of age-related chronic cardiovascular disease by way of a “polypill” has opened the door from a functional medicine perspective for more cost-effective medicine and delivering a biology of hope to our patients. We will see you in June.  

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Bibliography

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INTERVIEW TRANSCRIPT

CLINICIAN OF THE MONTH Catherine Willner, MD Neurology and Pain Medicine (Board Certified) 130 Rock Point Drive Durango Tech Center Durango, Colorado 81301 JB: It’s time for our Clinician/Researcher of the Month. This month, we are very pleased to have not only a primary clinician in the area of neurology, but an individual who has been a consummate educator in this field pertaining to our Applying Functional Medicine in Clinical Practice training program (AFMCP). She is a faculty member of AFMCP and is actively involved at the Institute for Functional Medicine (IFM) in helping to develop the concept of functional neurology. I am talking about Dr. Catherine Willner, a Board-certified neurologist and specialist in pain management. Dr. Willner is a graduate of the University of Kansas College of Health Sciences and Medicine. She was a Fellow at Mayo Clinic for a number of years before going into her own private practice in Durango, Colorado. We have all been very fortunate to have Dr. Willner as our mentor in helping us to understand what is happening at the cutting edge of neurology and how functional medicine might make contributions to some of the complex neurological disorders. Dr. Willner will be heading up a new module to be offered by IFM—a two-day intensive course on functional neurology starting in the fall of 2004. It is with great pleasure, Catherine, that we welcome you to Functional Medicine Update. For those of us who are not neurology specialists, let’s begin by having you give us an overview of how you see neurology as a discipline, how it has changed in the past ten years, and the most significant problems you deal with. Neurology as a Discipline CW: Thank you for those kind words, Jeff. I really appreciate the opportunity to discuss these issues. This is a very exciting time for neurologists. It is also a very frustrating time because of the amount of research evolving as we begin to understand a lot of the basic science about many of the diseases that have haunted us over the course of our treatments of patients. These treatments have typically been designed to consider neurological diagnoses as the primary problem, even among the neurodegenerative disorders. In general, neurologists are practitioners who are essentially assessing things that typically have been considered to be episodic disorders like stroke or migraine, but disorders that are also degenerative in nature. Some of the disorders are genetic (present from birth onward) and some may be genetically mediated and develop during a lifetime, but they are usually considered multi-factorial and include environmental conditions in their evolution and progression. Historically, neurologists were considered to be those who could name things, diagnose disease, and localize pathology in the nervous system, but that did not necessarily mean they could improve the outcome from those conditions. We were quite good, but had a limited armamentarium to impact the course of patients with problems traditionally diagnosed as neurological—things like Huntington’s disease, various dementias, and Parkinson’s disease—the system disorders. Those are very frustrating. In the late 1980s and early 1990s, things started to change quite a bit, partially because as a profession, we identified things on the horizon that looked very promising in terms of being able to modify some of the things that neurologists did. The 1990s were identified as the Decade of the Brain, but I think this new century has brought even more insight and availability of tools to alter the course of these diseases. As a neurologist, I am frustrated because I can’t keep up with all the literature that’s in the basic sciences these days. At the same time, some incredibly important clinical studies have been done, and it’s our job to make people in the field aware of them. That’s one of the most important roles I see clinicians playing—divulging information about what neurologists can offer to patients now. JB: As a full-service practicing neurologist, do you see patients with non-specific types of symptoms—individuals in a pretty severe state of pathology—or does it cover the whole gamut? CW: It runs the gamut. Neurology is one of those specialties where, when practitioners can’t identify what might be wrong, if there’s something that sounds like it might be mediated by the nervous system, we investigate all sorts of things. They range from trying to identify the etiology of spells, unusual sensory symptoms, and changes in cognition, all the way to people who come in with full-blown diagnoses which may or may not be neurologically correct. I used to joke that I saw more people who were diagnosed with Parkinson’s disease but really only had minor tremor. It was because tremor was always the first symptom presented to the primary care physician. It was assumed that it might be Parkinson’s because they saw a little early tone change or a little slowing in some movement factor. In reality, these people only had tremor. The exciting aspect is that only some of those patients would, indeed, go on to develop Parkinsonism. Neurology practice runs the gamut all the way from seeing people who do not carry a diagnosis. That’s the most exciting part. In terms of the range of things that neurologists see, there is such breadth. It keeps you on your toes because there are so many areas that can involve the role of a neurologist. You don’t see just one population of patients (with the exception of those clinicians who are in centers of excellence where they only see patients with Parkinson’s disease or movement disorders). One of the nicest things about being in training at Mayo was seeing grass roots neurology at the earliest stages of diagnosis or investigation. We also saw some intriguing and different presentations of a variety of syndromes that some people might spend a lifetime waiting to see one or two cases of. It was a very rewarding experience. As I stayed on staff there, I became more involved in sub-specializing because that’s the nature of Mayo, but I still saw a huge variety of patients. The most exciting thing for me now in private practice is that people come in with their relatives. I can identify a problem that may be well beyond my ability to make much impact in terms of the pathophysiology, but we know that their relatives may be at risk. A big part of my practice is trying to educate these patients and their primary caregivers about things that might impact their natural risk for a potential problem as they age. Mitochondrial Connection to Neurodegeneration JB: That leads to an interesting question which probably relates to the thinking of most of our listeners. If the nervous system is principally composed of cells called “post-mitotic” (not likely to divide and replicate), we have memory of all the things those cells have been exposed to since their initiation in the nervous system. We start looking at the nervous system as a highly active metabolic part of our body in terms of energy production and ATP generation from the mitochondria. Last, we look at genetic inborn errors of mitochondrial DNA, the so-called mitochondrial encephalopathies. Perhaps it leads us to recognize that there is something about the mitochondrial connection to neurodegeneration. Is that partly how you see the evolution of thinking in your field? CW: Absolutely. In fact, one of the highlights of focus in our field was when people started to realize that some diagnoses were considered ineffective in terms of therapy. When we realized there were some people who had mitochondrial encephalopathies who could actually respond to certain treatments, we began to ask what else might be involved in terms of mitochondrial dysfunction. It gave us a great basis in pathophysiology for other disorders which might not be so severely impacted in terms of respiratory chain function, but had relevance to the model of certain diseases that were neurodegenerative in nature. Up until as late as 2000 in our literature, you’ll see statements such as “Alzheimer’s disease is a neurodegenerative disease, but the underlying pathophysiology is not really understood.” That’s in our textbooks; it’s in our literature; it’s in our current articles. That has all made a transition. Paramount is understanding some of the unique features of the nervous system. Among those is being highly dependent upon the availability of glucose, and upon the productive ability of the mitochondria to maintain an energy gradient. That’s because the nervous system is an electrochemical system in and of itself. It is highly energy-dependent. Disorders associated with mitochondrial dysfunction gave us great insight as to how the mitochondria, in several ways, may impact neurodegenerative processes. That has been the beginning of so many attempts at research arms of treatment—trying to ascertain if improvement of mitochondrial function could be achieved, and whether or not the cell can be protected from a course of death in terms of any of the neurodegenerative diseases. We used to say these disorders were very different. It is now clear that they share certain things related to the pathophysiology of a post-mitotic tissue. There is a beautiful discussion in one of the recent Lancet Neurology journals (a relative newcomer to our list of resources) written by people who are involved in the field of genetics. They have studied the issue of whether or not post-mitotic tissue differentiates in such a way that it might actually be able to revert and try to divide. If a post-mitotic tissue like the nervous system starts to divide, it may produce a problem, because it cannot go back through the cell cycle other than impending its own death. It may be one of the triggers for apoptosis. The requirement for energy in the presence of mitochondrial dysfunction may put a cell at risk because of oxidative stress. People who have attended the AFMCP course have heard that time and again from me during my presentations, but it bears repeating. Because of the risk factors related to mitochondrial dysfunction imposing secondary risk of oxidative stress, both at the level of membrane function as well as energy production, those cells are at risk for certain degenerative properties, among which the most obvious is apoptosis. There’s an entire cascade now being discussed in terms of genetic risk for disability to de-differentiate and then incur apoptosis, as to whether or not healthy mitochondrial function can protect the cells from that particular demise. That’s where a lot of basic research is being directed—trying to identify genetic risks for that outcome, including mitochondrial dysfunction, but also other inborn errors that may put a cell at risk. Over a lifetime, a cell may not die right away, but it sets itself up for apoptosis because of those risks. There are several good discussions in an article by Zhu et al. in the April issue of Lancet Neurology.[1] They talk about the “two hit hypothesis” of neurodegenerative diseases. Among those intricate to that discussion is the role of the mitochondria and oxidative stress that may arise out of dysfunction. Neurology and the Blood/Brain Barrier JB: You have raised some very important points that impinge on our clinical assumptions. One of those assumptions has been the long-held belief that the brain is isolated from the rest of the body by the blood/brain barrier and things cannot cross it. Therefore, the brain is insulated or protected. That model is starting to change pertaining to the blood/brain barrier being a signaling medium. Would you tell us a little bit about how the blood/brain barrier is viewed in the field of neurology? CW: We see it as a selective barrier. Even as recently as when I trained, it was considered to be an absolute barrier; there is no immune connection; there is no signaling across the membrane. Breaking down of the blood/brain barrier was a clinical concept. That has completely changed. I don’t consider myself an expert in that area, but we now understand that there are certain aspects of the blood/brain barrier that make our attempts to treat these mechanisms frustrating because we want to get neurotrophic factors across the barrier and we struggle with that. Or, we want to get chelators across the blood/brain barrier and we struggle with that. We don’t know whether or not the ineffectiveness of certain protocols is related to the blood/brain barrier. We also recognize that a lot of signaling occurs at that area and that it is regulated in the normal brain. It begins to become dysregulated in brains that are affected by neurodegenerative processes such as chronic inflammation and the changes that occur at the level of the blood/brain barrier. There are beautiful review essays related to those changes and how our concepts are evolving, as we begin to understand that. Sometimes, the question comes down to something you and I have discussed in the past. That has to do with whether or not diseases that are considered neurodegenerative, or those that have a component of loss of neurological tissue over the course of time, have a common set of mechanisms or whether there is more than one set involved. Is there something going on systemically that might be involved in this process? If so, the blood/brain barrier is not protecting itself. There is also the question about the underlying pathophysiology of all neurodegenerative disorders. I think the blood/brain barrier concept is shifting, but I don’t think any neurologists would say they completely understand it yet. That’s an evolving concept that will begin to fade in the same way all other concepts have been modified, as we begin to understand more of molecular genetics and the effect of interaction by cell signaling. That remains to be seen. I think we will understand a whole lot more about that in the next decade. Microglia and Neuronal Function JB: That relates to another changing concept you know much more about, that being the role of the microglia in neurological function. I recall learning about it some 30 years ago as being pretty much a structural component, the glia being a kind of glue-like substance that ties the neurons together in some kind of a three-dimensional structure. Now, suddenly, it seems that the microglia have a functional aspect that reinforces neuronal function. Would you tell us a little bit about that? CW: There is an entire literature on that, as well, that is demonstrating beautifully the functional capacity of the microglia, both to regulate cleanup around the brain, as well as immune protection. There is also the intricate role of microglia in the modification of some things that can become chronically problematic to the nervous system. Once the microglia are turned on, that is, they think something is wrong, they have a habit of maintaining a low level of inflammation that can damage neurons. In every single disease that neurologists see where there is a process in which neurons are lost, we originally made the assumption that the microglia did their job—they would come in and clean up. They were called “sleeping giants” to some extent because they were capable of being very dormant cells. When there was an immunological attack, or some sort of toxic attack on the nervous system, they would turn on and act like immune-based cells that would clean things up. We then started to realize that in some of the neurodegenerative diseases, these cells are actually on all the time at a low level, not to the point where they’ll kill you, but to the point that they will maintain a low level of inflammation. Now, one of the ongoing hypotheses about some of the types of dementia, including Alzheimer’s, is that the A-b protein (amyloid beta protein) may be aggregating partially because the glial cells cannot accommodate this protein and they can’t break it down. All sorts of efforts are being made to try to figure out ways of dissolving the protein at the same time the glia are turned off. They may be the main reason the neurons are being damaged, more so than just the aggregation of the A-b proteins, and the aggregation itself may not be the problem. The problem is that the microglia cells are trying to break the protein down and, as a consequence, they are turning on an inflammatory process. That also applies in other disorders that are much too complicated to talk about in our short time together here, but things like multiple sclerosis and various types of chronic ongoing inflammatory processes that can be turned on intermittently to create attacks. The glial cells play an incredible role. It’s not only the microglia; it’s the other supporting structural glial cells that can inhibit certain activities and can also remain “on fire,” to use Dr. Perlmutter’s analogy when he presented “The Brain on Fire.” It is one of those things thought to be the basics of the pathophysiology involved with cell degeneration in that situation. There is a very intricate connection between neuronal cell health and the actual functioning of the glial cells, supposedly the support structure, which do, in fact, a lot more than support. JB: That leads to a segue among these factors—the post-mitotic tissue, the blood/brain barrier, and the glial cells. I recall a number of years ago—I think it was at our 3rd International Symposium on Functional Medicine—when Dr. Flint Beal presented his work. At that time, he was at Massachusetts General Hospital; I think he is now at Dartmouth working in the neurology area. He talked about the role that upregulation of the microglia had in the production of high amounts of nitric oxide, conversion to peroxynitrite, and how that related to the production of oxidative stress factors in nervous tissue such as he could measure with 8-hydroxydeoxyguanosine (8-OHDG). 8-OHDG is a breakdown product of nucleic acids that can be seen in the blood as a consequence of neurodegenerative oxidative processes. Has this theme continued to evolve since the early 1990s? Are neurologists generally agreeing with this? CW: Those who are reading the current literature are agreeing with that. I have seen three separate articles in the last year and a half where those very specifics were talked about. Before, if you looked up things like 8-OHDG, you would be looking in basic science reviews and there would be no clinical applicability. In several recent review articles discussing neuroprotection (an exciting new concept for all of us in neurology), those topics are discussed specifically. It warms my heart because I know those things were talked about early on in functional medicine circles and they are now appearing in our literature. It’s a rewarding sense of a full circle process to show that those things have been determined to play a role. Neurologists are very cautious. We are very obsessive/compulsive types to some extent. We are very cautious in terms of our conclusions. Right now, if you ask the average neurologist in practice whether he/she is measuring those levels or not, I think you’d find that functional neurologists are doing that (those few who call ourselves that), but you don’t necessarily find that to be the case. There are precautions about measuring those things until we can deliver absolute clinical criteria for their management. The pathology originally presented as playing a potential role is bearing out in article after article in review of the concepts of neurodegeneration, or the concept of neuroprotection to try to slow the course of these diseases. The disease courses are considered to be an unrelenting progression of neurological dysfunction. Indeed, we are seeing things related to the issue of measuring oxidative stress levels, as well as the role of free radicals. That has been quite controversial in our literature, as well, but it is leaning toward the other side of the pendulum in acknowledging that those things do play a role. It is imperative that we identify ways of trying to modify those risks early in life before the natural course of apoptosis has been set in motion. Neuroprotection and Parkinson’s Disease JB: Let’s take all of what we have been describing and possibly apply it to conditions some of our listeners are more familiar with, such as Parkinson’s disease and loss of nigral striatal neuron function. In the January 2004 issue of JAMA, there was a nice review that discussed neuroprotection in Parkinson’s.[2] I first recall reading about the concept of “neuroprotective therapy” in a review article written by Clough in 1991 on the management of Parkinson’s disease.[3] In the JAMA paper, I was fascinated with what the authors said about oxidative stress, mitochondrial dysfunction, excitotoxicity, and inflammation being the four etiological contributors to Parkinson’s. You and your colleagues in functional medicine have been speaking to that for the better part of ten years. Would you tell us how you see this article contributing to the general understanding, and its place in the history of the development of neurology? CW: I wouldn’t go so far as to say that article is a culmination of everything. There have been several articles that have appeared since then that are a culmination, in terms of looking at all the factors. But it brings it to the general physician’s practice. When something that basic gets into JAMA, heads go up, and eyebrows lift to some extent, but it generates a lot of debate. That article contains some beautiful expression of the controversies in our field, and how we can interpret information from our basic science and clinical research. It also contains numerous caveats of caution about interpretations related to whether L-dopa, in the form of Sinemet®, is a toxic product or whether dopamine agonists are a protective product in Parkinson’s disease. In making their conclusions, the authors are cautionary in the sense that they don’t want to say they have identified that these things are neuroprotective, but they are outlining a course for where research should be going. Indeed, I’m pleased to report that it is going in that direction because they are summarizing some of things that have to do with how we will approach interpretation of our literature. I don’t know how many of your listeners know about the study that was done initially in the 1990s that suggested there was a protective role for the MAO-B inhibitor (monoamine oxidase inhibitor type B). I spend quite a bit of time in AFMCP classes talking about the imperative of these basic and clinical research studies that evolved our thinking about this. There is now a lot of effort going toward trying to identify whether blocking MAO-B as an enzyme involved in excitotoxicity is something that could prove to be protective. That concept has received more attention related to the controversies about what the original drug we tested actually involved. People were given vitamin E or selegiline and vitamin E, at that time called L-Deprenyl. It was clearly shown that vitamin E in isolation really didn’t help people very much. However, there was another smaller study somewhat later that showed that vitamin C and vitamin E may actually play a role. I remember in the mid- 1990s, our movement disorders expert at Mayo told us that when we saw Parkinson’s patients, we should put them on seligiline, 5 mg twice a day, along with vitamins C and E. We gave vitamin C in a gram and vitamin E in 1200 IUs. Obviously, it was a-tocopherol and you could ask all the questions you want about whether those are the most appropriate antioxidant-type treatments, but at least the concept was being studied. L-Deprenyl, or selegiline, had somewhat of an agonist or dopamine protective effect. It might not have been the MAO-B inhibitor effect that actually created the response. These types of controversies are well discussed in the January 2004 JAMA article. These things might be protective, but there are no large, definitive, long-lasting, placebo, double-blind studies to advise what to do when a patient comes in with early Parkinson’s disease, or is showing the earliest signs of any of the neurodegenerative disorders. In this situation, that article takes us straight to the facts—here are potential things that could impact these mechanisms. The mechanisms are potentially modifiable with evolving drug therapy, but also with other things. The most rewarding part of the JAMA article is that when the four basic pathophysiological mechanisms are discussed, the authors mention a role for drug therapy and also vitamin E or other types of antioxidant therapy. Other things are mentioned that may be more natural in terms of the ability to modify oxidative stress or mitochondrial dysfunction, like coenzyme Q10. I found it interesting that the authors of the JAMA article refer to coenzyme Q10 as a “drug.” The idea that these basic pathophysiological processes are being investigated from all possible aspects of intervention is rewarding to those of us who have been saying there are other ways to modify these things besides drug therapy. If you start early enough, you can make a significant difference in the course of a patient who has been diagnosed with Parkinson’s disease. A lot of the things being studied about Parkinson’s also seem to have effect on some of the other neurodegenerative disorders like amyotrophic lateral sclerosis (ALS), Alzheimer’s, and other types of storage diseases. This particular focus enables us to have the ability to modify some symptoms. It remains to be seen where the best place to start is. Does one start everywhere? As a functional medicine practitioner, I think of things in terms of the matrix, and I want to know that I am trying to look at all aspects of a condition. First, look at all aspects that may affect an individual patient, and then make a test to measure it. That article falls short in guiding practitioners in what to do. One of the forerunners in terms of our clinical research has been Clifford Shults, who I think is still at the University of California/San Diego. He did phase 2 of the primary pilot study on the beneficial effect of coenzyme Q10 that was published in the Archives of Neurology in October of 2002.[4] That is always cited as a pilot study in our literature and everyone agrees with what Shults stated at the conclusion of the article—that a larger study is needed to confirm the results. Even though we know that coenzyme Q10 is probably not harmful for people, a lot of physicians don’t know whether to advise their patients to take it as a supplement or not. But they can show their patients the data from this study and tell them that if they can afford it, perhaps they should take it. All of us are excited about the idea that these things are being looked at in our practice. These are the forerunners to a complete transformation in the practice of neurology. That’s why I’m excited about this. There were other things that weren’t discussed in that article that Shults points out in a recent issue of the Archives of Neurology. He wrote an article, titled “Treatments of Parkinsons: circa 2003,” and added to the list mentioned in the JAMA article beyond excitotoxicity, impaired protein degradation, abnormal protein aggregation, the concept of neuroinflammation, and the role of the glia.[5] It talks about apoptosis as an early and late phenomenon. If readers are interested in what was started and discussed so thoroughly in the January 2004 JAMA article, they should read the Shults article. Though it is aimed toward neurologists and carries a lot of jargon related to some of our studies, it does very clearly define some of the issues that may also be included in that pathophysiology. JB: There was another interesting paper on the same theme written by Dr. Bruce Ames from the University of California/Berkeley. Though not a neurologist, he has certainly made some startling and important discoveries about the biochemistry of the nervous system. The paper appeared in the Archives of Biochemistry and Biophysics and in it, Dr. Ames talks about a metabolic tuneup to prevent neurodegenerative disorders, which includes the use of lipoate, N-acetylcarnitine, and N-acetylcysteine.[6] What seems to be emerging is a collection of different antioxidant manipulators that may have an effect on redox of neuronal cells. Is that how you’ve watched the literature evolve into clinical practice? CW: Yes, and all avid readers of the primary neurological literature are waiting for things like Dr. Ames’ views to get into it. Editorial comments discuss those things, but the primary papers are not yet making it into our literature. I apologize for not mentioning that article earlier. It is a beautiful step forward in terms of opportunities to modify things in ways that we already understand are efficacious. As I said, neurologists are cautious. Until we have a very large, randomized, placebo-controlled, double-blind study on a treatment, with every explanation possible explored as to the efficacy and the reason for it, we tend to be cautious. At the same time, it is so exciting to see. From my own patient population, I know these things work. I do these things on a regular basis and I have some very happy patients who could be a lot worse by now but are not. Taking that full circle, if we look again in a decade, we’re going to see those things in our literature. I think the rest of the practice of medicine will make a tremendous impact on these patients. That’s the most rewarding thing, along with looking at those things from the perspective of our concepts about what antioxidants are. I don’t remember specifically which conference it was where you discussed mitochondrial function, but there were some beautiful concepts presented at that meeting about what a safe antioxidant really is. There were some beautiful questions posed that are sorting themselves out. Environmental Effects on Neurological Function JB: Regarding the management of a complex patient with a set of neurological symptoms, we often go back to what we call our “matrix,” looking at various confounding contributors that might relate to the outcome seen in signs and symptoms. One part of the matrix for neurological conditions which the authors partially allude to in the January 2004 JAMA article on Parkinson’s, is the genes/environment connection. In this case, it’s the genes and uniqueness related to the xenobiotic detoxifying enzymes and how various environmental toxins might be interrelated with Parkinson’s. That brings into play the toxicity argument and unique detoxification capability. Would that suggest that neurologists are going to be looking beyond the brain at other things that have to do with systemic detoxification? CW: Absolutely. That’s one of the most important concepts. That does not get a lot of attention, but I remember your comments earlier about the blood/brain barrier. I believe those things are all issues being looked at. Neurologists tend to be neurocentric, but we do have models for toxicity that come from the systemic aspect of things. Hopefully, most of your listeners know about the MPTP model of Parkinsonism, which was a Demerol analog. Street use by people who took it as drug abusers caused them to develop Parkinsonism very quickly. That model has gone on to serve us well in terms of primate research related to identifying animal studies that can be done on Parkinsonism. That took us back to an “aha”—this is a systemic toxin that comes environmentally by exposure. There are some patients who didn’t get it and some who did, which took us back to the differences in their ability to detoxify things. That took us to the liver. We are reluctant to admit that any other organ in the body might be doing anything other than serving the brain, but we do understand that now. That’s one of the things that will evolve along with the concepts about protecting from environmental risks versus modifying genetic risk. If you can control either one of those things, but also at the downstream end, protect from the pathophysiology that those two conditions may engender, you have a treatment plan that allows for a lot of areas of entry. I think that’s what’s going to be coming forward in the next decade or so. I’m really excited about the module we’re putting together. It goes way beyond neuroprotection and neurodegenerative diseases. As a neurologist, the matrix that we use at AFMCP applies to just about every single diagnosis. I’m not a diagnosis-based person in that sense, but as a neurologist, obviously trained to name things, I think about diagnoses. Even in those conditions where you suspect something might be neurological, but you’re not yet ready to diagnose it, that matrix works. The beauty of it is that looking at the environmental risks, the genetic risks, issues related to ability to detoxify, and all of the other aspects of the matrix, it applies beautifully to anything neurological. I’m biased, but I suspect it applies to every other discipline traditionally considered allopathic medicine. I’m extremely excited by the marriage of those two concepts—basic science and neurology coming so far with the pathogenesis of things that are now bearing out to have established abilities to modify genetic risk as well as environmental exposure. Just to cite something else about Parkinson’s disease, there was another interesting article in the same journal that included Dr. Shults’ update on Parkinsonism. In it, a pilot study was briefly presented in which investigators used an old antibiotic (discarded quite some time ago) that has chelating effects.[7] Neurologists are not strangers to chelation. We have been taught how to chelate related to certain neurological disorders associated with heavy metal toxicity because, as most people know, they are disorders that are easily identified. The fascinating thing was that the investigators looked at the levels of copper and zinc in association with chelation, using a quinone-type antibiotic, clioquinol. They saw a lowering of the levels of the aggregation of A-b, the beta amyloid plaque that we were talking about earlier. The comment was made at the end of the article that it would be interesting if this applied to the genetic risk for Parkinson’s disease from accumulation of beta synuclein (one of the proteins that aggregates in Parkinson’s disease), and its affiliation with iron. We think our practitioners should be assessing these things. It’s fascinating that things which may be toxic to the nervous system may come from the environment. We have ways of manipulating those things, and clinical articles are beginning to come to the forefront which suggest we take them into consideration. I thought it was incredible that this is making it into our literature. The beauty of that is to identify things that we can modify, and the matrix is a beautiful place to start for any disorder. It helps one to come to grips about asking questions relevant to genetic and/or environmental risks. That’s the teaching that remains to be taken into our primary neurological practices. We don’t typically ask about those things until it’s too late. I’m excited by that concept, the application of the matrix, and the module we’re planning for this fall. JB: You’ve reminded me of an interesting sidebar relating to an environmental effect on neurological function. A number of years ago, I recall reading about some neurodegenerative clustering that occurred in a geographical area where people were eating sugar cane. A mold was found in the sugar cane that was producing a metabolite (3-nitropropane), a small contaminant of the sugar cane being consumed. 3-nitropropane was found to be a very strong uncoupler of neuronal mitochondrial function and which basically caused peroxynitrite formation and neuronal death. Here is a connection between the environment and lifestyle, and probably some genetic-related effects, that translates into neurodegenerative disease. CW: Absolutely. The isolated cases where people have been exposed to something that turns out to be toxic and produces neurodegeneration, have been the early, preliminary eye openers for our practice. Our profession has been inundated by such things. It took us a decade or so to figure out what it was. Once we figured it out, we could apply it to mechanisms, and those things are well established in our literature now as being the forerunners of the interaction between genes and the environment and the role that might be modified by changing environmental risk in terms of neurodegenerative disease. Those examples are exciting, but threatening in a sense because it makes us aware of the fragility of the nervous system. People who have looked at those things environmentally and who then went on to look at them from the standpoint of the pathophysiology, added legions to our experience in terms of being able to understand these mechanisms. Early Warning Signs of Neurological Disease JB: Dr. Willner, we only have a couple of minutes left. Would you tell our clinicians what early warning signs and symptoms they should look for in their patients where neuroprotection might be of some benefit? You talked about motor system dysfunctions, but are there other hallmark signs and symptoms? CW: The hardest part about answering that question is that neurologists are trained to pick up things having to do with dysfunction long before people express a disease. We are always examining whether someone has a tone change. From the standpoint of symptoms, it’s sometimes difficult. I personally think that anyone who has a tremor or a change in balance ought to be examined by a neurologist, or someone who has neurological skills that can ascertain that there may be an early problem. But symptoms are sometimes difficult. Any of the early warning signs of any neurological disease should be investigated, and immediately these prophesies that we’ve been discussing should be thought about. There’s a corollary to that. Often, by the time a patient gets to a neurologist, the diagnosis is a little bit in question, but it’s mostly obvious. Often, patients are sent to neurologists that are far along in treatment. The neurologist may not have chosen that primary treatment for the disorder. The primary example is Parkinsonism, which we were discussing earlier. Patients are often started on Sinemet, or they’re immediately started on the newer medications, the dopamine agonists, because there’s been some early literature to suggest they may be protective. That has not at all been decided among those people who look at our literature with a critical eye. When such patients come in, the corollary is to ask about their relatives and children, in order to make sure they are aware of things they can be doing now to prevent the possible progression of a condition because of their genetic risk. Oftentimes, they also share environmental risks related to the development of a neurodegenerative disorder. It’s a question of asking a patient whether or not they have relatives who are older than they are who have neurodegenerative diseases. Neurologists are asking their younger patients if there is Alzheimer’s, Parkinsonism, or ALS in their families. What would we do differently in a young person who may have that familial genetic risk? That’s the turning point. I think that’s what going to be done in the next few years, in addition to looking at biochemical individuality and genetic individuality. We’re going to be looking at risks where we may not be able to halt the disease in the patients who are diagnosed, but if someone comes in, even for a migraine, we want to know whether or not they have Parkinsonism in their family. We want to know if even just one relative has it. We want to know if they’ve been exposed to things. The functional approach to that is beautiful in terms of its ability to identify those things. JB: I want to thank you, Dr. Willner. This has been a most enlightening discussion, though just touching upon the tip of the iceberg in terms of what you’ll be covering in your two-day, intensive module on functional neurology this fall. Thank you again, and we will be keeping close tabs on your work. Side 2 It is hard to believe that in just 40 minutes, Dr. Willner presented such a panoramic review of the current state of affairs pertaining to neurodegenerative disorders. I would call that a “tour de force”—a remarkable job on her part. It leaves us with a lot of important questions, many of which will be addressed in much greater detail during Dr. Willner’s two-day course on functional neurology, which will be offered this fall. Let me give you a sense of where I believe the concepts that Dr. Willner discussed are going. I want to focus specifically on the four areas of the etiology of neurodegenerative disease that were described in the article in the January 2004 issue of the Journal of the American Medical Association—oxidative stress, mitochondrial dysfunction, excitotoxicity, and inflammation. I believe I can add a few thoughts about each of those in the context of the contemporary literature and how they might relate to the management of early warning signs of neurodegeneration—gait disturbances or specific types of functional neurological imbalances. It is also important to remember, as Dr. Willner so eloquently pointed out, that the matrix—the fundamental lens through which the functional medicine model is focused—tells us that there are many different contributing components of organ-specific or tissue-specific pathologies. In general, a condition of a specific tissue is related to a functional change in the body, not just solely what is going on in that tissue. We are obligated to take a broader look. In functional medicine assessment, we start with antecedents, which include the genetic factors that underpin the relative susceptibilities and strengths of an individual that are modified in their expression by triggering factors—environmental and endogenous factors that can trigger the expression of mediators. The mediators are the signaling molecules that may work locally, but act globally. Last are the specific signs and symptoms of different duration, intensity, and frequency. It is that model versus the traditional differential diagnosis model that characterizes functional medicine and leads to the matrix, a series of interlocking physiological functions that may contribute to a dysfunction. Let us talk about specific neurodegeneration. We will go back and re-explore the brief discussion we had with Dr. Willner concerning the glia, and the emerging role of importance it appears to play in functional neurology. There is mounting evidence, as described by Dr. Willner, that glial cells, overlooked for nearly half a century, may be nearly as critical to thinking and learning as neurons are. In an article in Scientific American, titled “The Other Half of the Brain,”[8] Dr. Douglas Fields points out that the mental picture most people have of our nervous system resembles a tangle of wires that connect neurons. Each neuron is thought to have a long, outstretched branch (the axon) that carries electrical signals to buds at its end (the synapse). Each bud emits its own family of neurotransmitters through the synapse—chemical messenger molecules that act across a short synaptic gap to a twig-like receptor, or dendrite, on the adjacent neuron. Packed around the neurons and axons is a diverse population of glial cells—glial from the Greek word for “glue.” They were assumed to be structural and glue-like, attaching the neurons into a three-dimensional space, but research on glial cells faded into the background of science for a long time. Neuroscientists failed to detect signaling among glia, partly because they had insufficient analytical technology, but primarily because they were looking in the wrong place. They incorrectly assumed that if the glia could chatter, they would use the same electrical mode of communication seen in neurons. They would generate electrical impulses called action potentials that would ultimately cause the cells to release neurotransmitters across synapses, igniting more impulses in other neurons Over the past 10 years, it has been determined that the glia have their own unique messenger system. This system is not related to the traditional neurotransmitters, but to unusual molecules (not so unusual now, but unusual 10 years ago) like nitric oxide (NO). NO and other neurochemicals are neuromodulators that act like cytokines/chemokines, the messenger molecules produced by the immune system. That is what led neurologists to recognize that the microglia are, in fact, a subtype of the immune system. The brain has its own immune system. In fact, the glial cells are derived embryologically from the same progenitor cells as the Kupffer cells in the liver, the embedded lymphocytes, the circulating white cells, and the mucosal-associated lymphoid tissue (MALT) found in our gut. The gut, liver, systemic circulation, and glia are all communicating one to the other through similar messenger systems. Once it was known that the glia had their own chemical messenger system (reminiscent of the body’s immune system), it was recognized that it was possibly a part of immunological vigilance and could be activated by the same precipitating agents that activate the immune system at large. These would be things like antigenic stimulants and foreign cells. Viral infections of the brain can upregulate inflammatory reactions through the immune-like process found in the brain, not necessarily occurring only systemically, but regionally in the brain itself, and this could interface with the messenger system of the immune system at large. It is an interesting evolution of our understanding about the other half of the brain, the glia, and how they relate to function and control of immune defense in the brain. One of the principal agents released by the glia through activation is NO, through upregulation of neuronal NO synthase. Neuronal NO synthase, when undergoing a rapid immunological upregulation or activation, can induce an uncoupling of this enzyme to some extent, producing superoxide. Superoxide chemically reacts rapidly with NO to produce a caustic chemical called peroxynitrite. Peroxynitrite, in turn, can degrade into a nitrosating substance that can injure proteins—nucleic acids—and it is a promiscuous molecule when released into tissues. It does not need an introduction; it does not have a calling card; it basically “nails” anything that is near it. When peroxynitrite is produced in the nervous system, there is potential for injury to neurons, which can uncouple their mitochondrial oxidative phosphorylation, resulting in neuronal oxidative stress that produces a shift of the neuron toward an oxidative chemistry leading to its own apoptotic death, or cell suicide. Neuronal reserve is lost. Over time, this accelerates the loss of post-mitotic tissues, increasing the loss of cellular reserve, and ultimately decreasing the function of that portion of the brain, leading to decline. This is another example of Dr. James Fries’ concept of organ reserve and losing reserve over time (in this case neuronal reserve), as a consequence of an upregulation of the apoptotic process that was initially triggered through glial cell activation and peroxynitrite production. One of the interesting things that is emerging related to the control of mitochondrial function, is insulin signaling and insulin resistance, which tends to creat mitochondrial dysfunction. A number of papers have been published on this topic, including one in Science magazine, titled “Mitochondrial Dysfunction in the Elderly: Possible Role in Insulin Resistance.”[10] The investigators show that there is an interrelationship between alteration in mitochondrial function, insulin resistance, and lowered energy production, as in mitochondrial uncoupling. As much as a 40 percent reduction can be observed in mitochondrial oxidative and phosphorylation activity when assessed by 13C/31P NMR spectroscopy. The data support the hypothesis that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly. Whether it is insulin insensitivity or hyperinsulinism causing mitochondrial dysfunction, or mitochondrial dysfunction causing insulin sensitivity, appears to still be somewhat controversial. It may be a component of both. In the paper I am citing, it appears that insulin resistance is caused by mitochondrial dysfunction that occurs with age. Is it the chicken or the egg? In the functional medicine model, that is always an important question. It is caused either through the mitochondria, or through insulin signaling. The takeaway is that it is possible insulin regulation and mitochondrial support are interrelated in terms of the regulation of cell signaling, and how that influences oxidative chemistry and ultimately inflammation. One of the hallmarks of neurodegenerative disorders is the inflammatory response. The neurons are “chock-full” (to use the vernacular) of mitochondria. It is interesting to note that the cell type that probably contains the highest percentage composition of mitochondria in its volume, is the cardiocyte (75 percent mitochondria). This heart cell would be visualized as being absolutely chock-full of mitochondria doing all the energy metabolism work required to keep the heart beating for all of our lives. Similarly, the neurons, which are engaged in oxidative chemistry, are also very dense in mitochondria, not quite to the same extent as the cardiocyte, but still very prevalent. As mitochondrial oxidative phosphorylation decreases, or there is a mitochondrial phase transition leading to increased oxidative release, it leads to neuronal injury and apoptotic death of the neurons, as well as increased inflammatory response in the nervous system. There are now several links between mitochondrial metabolism and hyperinsulinemia/insulin resistance metabolic syndrome, and even to how that relates to neurodegenerative disorders. There may be a relationship between dysglycemia/dysinsulinism, and neurodegeneration. Examining this from a web-like perspective using the matrix of the functional medicine model, there is a way to connect together what might appear to be processes outside the nervous system with things going on within the nervous system—a shift to inflammation and oxidative chemistry. There is a good review paper on the topic of mitochondrial metabolism and type 2 diabetes that appeared in Diabetes and Metabolism.[11] One of the other things that increases neuronal oxidative injury, oxidative stress, and the associated inflammation of neurodegenerative disease, is oxygen itself. Oxygen plays a paradoxical role. There is a parabolic dose response relationship between oxygen and tissue function. At too low a level of oxygen the cells die, and at too high a level of oxygen the cells die. In the middle is the zone of optimal oxygen regulation. The brain is very dependent on oxygen. Obviously, we can go for weeks without eating. We can certainly go for days without drinking fluids, but we can only go for minutes without breathing. Oxygen is a critically important nutrient to stabilize mitochondrial oxidative phosphorylation and energy production. The paradox is that as oxygen decreases in tissues resulting in ischemia, there are ever-increasing degrees of oxidative stress. That is paradoxical, because it would appear that the time of lowest oxidative stress would be when there is no oxygen. Just as is seen in reprofusion ischemia, where there has been an interruption of the oxygen supply to the heart associated with increased oxidative stress and injury, so it is similarly in the brain in times of low oxygen delivery or any kind of ischemic event. One can sustain vascular toxic injury to the arteries, creating atheroma that results in lower oxygen to the brain. That is a possible cause of cerebral ischemia leading to increased oxidative injury to the brain and to early-stage dementia or neurodegenerative disease. Oxidative control is very important, and delivery of oxygen is also very important . As I have often mentioned, medicine in every culture, going back to the dawn of early Ayurvedic medicine, has a way of delivering oxygen to tissues through dance, deep breathing, or exercise such as yoga. There are many ways of delivering oxygen non-technologically to try to improve tissue specificity and function. How do cells endure low oxygen? That is an interesting question that is now being explored. Cells can respond to hypoxia or ischemia, but in so doing, the production of various oxidant species is increased. As was recently pointed out in a nice review in Science magazine, it is now recognized that cells cannot exactly gasp for breath when they are deprived of oxygen.[12] They must have a way of coping. The method of coping is to turn on a host of genes at low oxygen levels that help the cell survive through times of low oxygen. This is not necessarily the primary way a cell would like to work, however. In turning on those genes, different response elements related to inflammation and oxidative injury are also turned on. The genes controlled by the so-called hypoxia-inducible factors (which are gene response elements), are those that code for such things as red blood cell production and angiogenesis (formation of new blood cells through the angiogenic process), as well as for glycolytic enzymes that produce energy from glucose without the aid of oxygen. This is the pyruvate/lactate shuttle. These hypoxic inducible factors are like master switches that allow cells to respond to falling oxygen. In so doing, it turns on a series of secondary factors related to the production of oxidants—like superoxide and hydroxyl radical—through a series of processes. These are very strong oxidants which can cause injury to tissues. There is a price to be paid when working in an oxygen-deprived environment. This is seen in a whole series of different types of tissue pathology. Probably most interesting is the one in rheumatoid arthritis and how it relates to the pathogenesis of that condition. A nice review was published on this topic in the journal, Arthritis and Rheumatism, which discusses physiological responses to hypoxia and implications for the hypoxia-inducible factor in the pathogenesis of rheumatoid arthritis.[13] The authors point out that there is close control of oxygen tension in tissues that leads to proper healing and proper immune response. Too low or too high an oxygen level can increase adverse oxidative reactions and lead to conditions that might precipitate or aggravate different types of injurious processes. In terms of the arthritis process, a wide variety of genes is turned on again by the hypoxia-inducible factor, the gene-response element, that leads to activation of specific types of processes. One of those is angiogenesis, which may be desirable or useful in certain types of protection against low oxygen tension in tissues. The other is the activation of angiogenic-promoting factors that induce oxidative injury. It is, again, how the balance factors play out. In general, increasing activation of processes involved with protection against low oxygen tension will increase the risk to oxidative injury. But, proper delivery of oxygen to the brain is essential. Why might the brain not be getting adequate oxygen? Is it because of coronary artery atheroma? Is it because of anemia? Is it because of a constriction in some kind of blood supply in a tissue? Is it because of a cardiac abnormality? These are important considerations in assessing proper delivery of oxygen to tissues. Next, Dr. Willner talked about the excitotoxic relationship to neurodegenerative diseases. The activation of excitotoxicity can occur through various types of receptors on the neuron. These receptor sites may have influence on upregulating the response elements associated with oxidative injury and ultimately apoptosis of the cell. Dr. Willner alluded to the MPTP work associated with neuroexcitotoxicity and Parkinsonism in young street males taking the Demerol analog. This work suggests that there may be a relationship between toxicity and neuronal excitotoxicity. This may have to do with the activation of specific receptor sites, like the glutamate receptor site that overstimulates the neuronal cell, by upregulating its oxidative function. One of the things that can cause initiation of this process is the lack of control of glutamate/glutamine interconversion in nervous system function. Glutamine production from glutamate is very important. Initiation of excitotoxic reactions could result from poor conversion of glutamate into glutamine due to a defect in glutamine synthetase, the enzyme responsible for glutamine’s production from glutamate. There is now evidence from the neurology literature showing that the loss of glutamine synthetase activity is associated with epileptogenic effects seen in the hippocampus. One might ask how activation of glutamine synthetase is accomplished and what it is that might lower the activation of the glutamate receptor site. This is the so-called methyl-D-aspartate receptor site, or NMDA. On examination, we find there is a certain family of cofactors that could activate glutamine synthetase and also lower NMDA stimulation. The article that discusses the loss of glutamate synthetase activity in human epileptogenic responses is found in the Lancet.[14] This is another part of the excitotoxic model for neuronal degenerative disease. The cofactor for the glutamine synthetase enzyme is the pyridoxal phosphate family, which is also involved with the folate cycle. Are there any relationships between inflammation, mitochondrial uncoupling, excitotoxicity, and poor B vitamin nutriture? There is evidence in the literature from animal studies and certain human epidemiological studies that suggests there is an increased incidence of neurodegenerative disease with B vitamin insufficiencies, particularly those B vitamins related to the control and regulation of the steps in neurochemistry. Certain B vitamins play a role in modulating inflammatory response, such as through the modulation of acute phase reactants involved in inflammation and how they interrelate with mitochondrial uncoupling and oxidative stress. Investigators have reported that patients with active IBD are more likely to have low vitamin B6 plasma levels. In this study, a strong correlation between markers of thrombosis risk and alteration in inflammation signaling and low vitamin B6 status was also observed.[15] Again, we come to the web of these interrelated variables and why the matrix is so important when examining vascular effects, gastrointestinal effects, and effects on neurological tissue. Then we begin to search for Occam’s Razor. What is the central theme that might tie these effects together? Could vitamin B insufficiency be a factor that contributes to the progression or etiology of this condition? When we talk about B vitamins, inflammation, mitochondrial uncoupling, and the connection between the gut, liver, vasculature, and the brain, we need to ask about homocysteine because it is one of the precursor markers related to the process of CVD . Does homocysteine have any relationship to these inflammatory mediators? The answer that is emerging to that question is yes. However, it does not mean that homocysteine is the be-all-and-end-all for evaluation of the relative risk to inflammation. There are other markers being developed, but homocysteine is certainly one of the variables we want to look at. Homocysteine engages in neurodegenerative reactions through two mechanisms. One is its oxidation to homocysteic acid, an NMDA receptor activator associated with exocitotoxicity and neuronal apoptosis. The second mechanism, as I mentioned earlier, is that homocysteine may be associated with vasculotoxic injury to the endothelium, which leads to an atheroma that leads to vasculotoxic stress due to oxygen deprivation to the brain. The outcome is cell apoptosis through oxidative injury. As we look at these two mechanisms, we might ask if homocysteine is connected to B vitamin nutriture. Those of us who have been in this field for a while are well informed of that particular association. What about B6, B12, folic acid, betaine as a methyl donor, and riboflavin as part of the MTHFR reductase complex? Riboflavin stimulates the production of flavin-adenine-dinucleotide, or FAD, the cofactor responsible for the activity of MTHFR. There are cases where individuals have single nucleotide polymorphisms (SNPs) or polymorphisms of MTHFR that require much higher intake of vitamin B2 in order to properly regulate the activity of MTHFR. B vitamin nutrients are responsible for the regulation of homocysteine. Elevated homocysteine can induce oxidative injury, inflammation, and is involved with endothelial injury and NMDA receptor activation and exocitotoxicity. This connects the heart to the brain to the immune system to the liver to the vasculature to the gut. It is a central theme that unites all those organs and resulting pathologies together. To give you an interesting example from the recent literature, there is a paper published in the Journal of Thrombosis and Haemostasis, titled “Homocysteine and markers of coagulation and endothelial cell activation.”[16] In this paper, the authors discuss the in vitrofindings that have shown a procoagulant effect of homocysteine and present findings from their in vivo study, in which they did not see a relationship between hyperhomocysteinemia and markers of prothrombin activation. However, they used patients with mild homocysteinemia. I am speculating, but conditions of inflammation and systemic cell stickiness that occur through the activation of adhesion molecules could influence blood/brain barrier permeability in such a way as to increase the uptake of various molecules previously excluded from the brain, initiating increased potential excitotoxicity. Evidence is starting to emerge that indicates this is not just wild speculation, but may have some clinical importance. That also raises the question about how to maintain proper membrane and endothelial cell activity, which comes back to essential fatty acid nutriture. Is there a potential role in the diet for the proper composition of omega 3 fatty acids such as EPA and DHA, respectively? These fatty acids are known to be important for the proper regulation of the phospholipid composition found in membranes, and in the actual structure/function of membranes. If one is deprived of adequate levels of omega 3 fatty acids, it may have adverse effects on endothelial integrity and on permeability factors that relate to leakiness of those tissues. One of the things currently being discussed is that within the folate cycle that controls methylation, there are many enzymes dependent upon specific cofactors that are nutrient-derived for their function. Each of those enzymes may be potentially polymorphic, with different SNPs that have differing sensitivities upon specific nutrients. Therefore, we might see a significant variation from individual to individual with regard to how each folate cycle, or methylation cycle, works in different tissues based upon a unique dependency on specific nutrients that is part of that pathway for activation of its function. This model was recently discussed in a fascinating review paper in the journal, Regulatory Research Perspectives, that talks about the Food & Drug Administration’s ongoing work in the area of methyl deficiency and how that interrelates to environmental exposures and to nutritional imbalances.[17] This came out of a workshop that took place in 2001 and subsequent followup, that talked about the “Trans-HHS Workshop: Diet, DNA Methylation Processes and Health,” held at the National Institutes of Health. There are many individuals now involved in different laboratories and from different prospective clinical research studies looking at the folate cycle, how it interfaces with homocysteine, and how it interrelates with clinical conditions. Interest in this has increased as a consequence of using disease-modifying agents in rheumatoid arthritis that are anti-folates. I am speaking about low-dose methotrexate that blocks the production of SAM. There is now concern about patients with RA who are on low-dose methotrexate for some period of time. What effects does it have on their folate cycle and ultimately on the tissues, organs, and organ systems that depend upon SAM for their activity (virtually every tissue of the body)? When we look at that, we look at potential neurological risks, as well as potential cardiovascular risks that could come from things that might interfere with the SAM pathway. There are a variety of exogenous substances that can cause this, other than the use of an anti-folate medication. We can have what is called a “total load effect.” That gets into looking at polynuclear aromatic hydrocarbons and polyhalogenated compounds like DDT and dioxins. All of these have adverse effects upon the production of SAM. We look at toxic metals, including arsenic, lead, and cadmium, which can have adverse effects on the SAM biosynthetic pathways. Even zinc deficiency has an adverse effect on SAM synthesis. B12, folate, B6, betaine, 5-MTHF, zinc, riboflavin, and the absence of exposure to various toxins are all considerations, again coming back to the web-like approach toward reducing relative risk to tissue toxicity. Last is detoxification. Dr. Rosemary Waring at the Birmingham University Medical School in the Neurology Department, has been studying the relationship of toxicity to neurodegenerative disease for decades. Her work is legendary and has been published about Parkinson’s being associated with certain toxic exposures in the workplace environment—agriculture workers, paint and dye workers. In a recent paper in the Journal of Nutrition and Environmental Medicine, she talks about the plasma cysteine-to-sulphate ratio being a potential marker for individuals undergoing exposure to toxicity and who have endogenous or exogenous toxicity.[18] Low sulphate-to-creatine ratios are associated with poor detoxification. Alterations of the cysteine-to-sulphate ratio may also be an assessment/prognostic indicator of alteration and detoxification that tracks back to potential risk to neurodegeneration. It is a fascinating story that is emerging and certainly we owe Dr. Willner a tremendous debt of thanks for giving us such a panoramic review to work from in this issue of FMU. Thank you for being with us. We will see you in July.

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Welcome to Functional Medicine Update for July 2004. We are still reliving the extraordinary emotional experience we had at the 11th International Symposium on Functional Medicine. It is always such a pleasure when 400 of our colleagues get together to celebrate the evolution of this model of medicine, and to observe the incipient paradigm shift as it starts to occur. It was rewarding to share our clinical experiences and to hear from top researchers and medical clinic directors about how functional medicine concepts are emerging to be fundamental tools in managing complex, chronic, age-related diseases. There were many topics that came out of this year’s symposium that will help us focus on inquiry during the 2004/2005 year. The 12th International Symposium on Functional Medicine will be held in Palm Springs, California during the third week of May 2005. You may want to add those dates to your calendars. The topic of the 2005 symposium will be decided based on the evaluations and the outcome of the survey filled out by this year’s attendees. This information will help guide our Curriculum Committee toward making decisions about the content of the 2005 symposium. The evidence indicates that we may be focusing on the area of immune function/dysfunction related to infection and autoimmunity. I wanted to give you a little glimpse as to where we might be headed in the year 2005. Let’s focus on some of the clinical applications that came out of the 11th International Symposium on Functional Medicine, the first of which relates to the regulation of neuroendocrine-immune system function through fatty acid nutrition. For most of us, this is not a new topic, but it appears to be a fascinating chapter in the history of nutrition. We are beginning to recognize that certain fats in our diet are not just calorie-rich energy sources, either processed by our energy machinery or stored in the contractile tissues called adipocytes for a rainy day that never comes. They are also important regulators of neuroendocrine-immune system function. Fatty acids can either promote increased inflammation and alter immunological function (an adverse affect), or they can act as anti-inflammatory agents that downregulate and normalize certain aspects of immune system function. This effect of fats on immunological function between the Th1 and the Th2 type cells, the cell-mediated and the antibody-secreting cells, is a fascinating chapter of discovery concerning what were considered for so long only calorigenic portions of the diet. In fact, we went through a period where it was thought that the more fat we could take out of the diet, the healthier we would be. That is, until we saw people with all sorts of immunological problems as a result of being fat-deprived because of a lack of essential fatty acids and of the omega 3 fats. Originally, we were told that the only essential fatty acid was linoleic acid, the 18-carbon omega 6 fatty acid, meaning its first double bond was six carbons in from the methyl end of the 18-carbon chain and that it had two double bonds. It was considered a C18:6 with two double bonds. We now recognize that omega 6 is only one of the essential fatty acids. One of the others is the omega 3 fatty acid, alpha-linolenic acid, sometimes abbreviated ALA. ALA is also an 18-carbon atom fatty acid, but it has three double bonds, and the first double bond is three carbons in from the methyl end of the chain; hence it is called an omega 3 fatty acid. Each of these has different metabolic properties and different physiological principles. We are learning much more about the omega 3, omega 6, and omega 9 families–the monounsaturated fatty acids. Long-chain saturated fatty acids and medium-chain fatty acids have different effects than long-chain unsaturated fatty acids. As we begin to learn more about the biochemistry of fats, we also learn more about their physiology. We should not just lump them all together and call them fats. That probably is a pretty good admonition for all of the categories of macronutrients. We probably should not talk about “just carbohydrates,” either. We need to talk about the kinds of carbohydrates. Are we talking about long-chain amylostarch molecules, amylopectin molecules, shorter-chain oligosaccharides, or di- and monosaccharides, the so-called sugars? Are we talking about refined bleached white flour carbohydrates or complex, fiber-rich, flavonoid-rich, unrefined carbohydrate? All of these have different effects on physiology. It is the same with protein. Although protein is generically called “protein,” suggesting that all proteins provide four calories per gram and have equal opportunities for function in the body, we now know there is a vast difference between different kinds of proteins. Certainly, we can differentiate the effects of vegetable-based proteins from those of animal-based proteins. And, within the family of animal-based proteins, there are different physiological effects based on their amino acid composition, their digestibility, and how they deliver the amino acids to the blood. Again, the takeaway from this discussion is that we should be cautious about using generic terms—“protein,” “carbohydrate,” and “fat.” Rather, we should talk about the individual constituents or characteristics of those macronutrient families. That is one of the dominant themes that came out of the 11th International Symposium on Functional Medicine related to the modification of insulin sensitivity, triglyceride synthesis, lipoprotein synthesis, cardiovascular risk, and endothelial function. We should not just be looking at ratios of protein, carbohydrate and fat, one to the other, but at the individual constitution of each of those families and how they signal different changes in cellular physiology. There is now an emerging view of diet that involves more than just calories and micronutrients. It is a diet that provides dietary signals that modify gene transduction and signal transduction, and how that translates into ultimate cellular physiological function. The theme that is emerging about how nutrients influence cellular physiology takes us beyond simply the concepts of the calorie. Going back to fatty acids as a clinical theme, let’s review some of the basic concepts. Dietary fatty acids are related to hemostasis and cardiovascular disease risk. This has been a long-standing role of fats. “The cause of many myocardial infarctions is occlusive thrombosis, or a blood clot that stops blood flow in a coronary artery. Hemostasis involves a complex system of factors, which normally form and degrade blood clots that work within a delicate balance.[1]” If there is anything we can say in functional medicine, it is that the balance points in physiological function are where we should be spending most of our time. When we have imbalance at those points, we begin to see certain disease states. As Lefevre[1] points out: “Emerging evidence suggests that some hemostatic factors, including factor VII, fibrinogen, and plasminogen activator inhibitor-1, are associated with increased risk for cardiovascular disease (CVD). Accumulating evidence suggests a relationship between dietary fatty acids and emerging hemostatic CVD risk factors, although much of this evidence is incomplete or conflicting. Dietary supplementation with marine n-3 fatty acids prolongs bleeding time and may decrease risk for thrombosis. Factor VII coagulant activity modestly decreases with reductions in saturated fatty acid (SFA) intake and thereby may contribute to the beneficial effects of low SFA diets. Large triglyceride-rich particles formed during postprandial lipemia can support the assembly and function of coagulation complexes and seem to play a role in the activation of factor VII, and thus may partially explain increased CVD risk associated with increased postprandial triglyceridemia. As our understanding of the role of dietary fatty acids and hemostasis evolves, it is likely that we will be able to make specific dietary recommendations to further decrease CVD risk.”[1] It may not be just taking out fat; it may be taking out the bad fats and adding the good fats. I am saying this euphemistically because I do not think biochemicals are necessarily either “bad” or “good.” It is how we use them and to what magnitude we consume them that gives rise to the balance. “At this juncture, however, increasing marine n-3 fatty acids and decreasing certain SFAs are leading strategies to reduce hemostatic CVD risk factors.”[1] Dietary fat goes beyond becoming incorporated into serum triglycerides and into membrane phospholipids. Dietary fats of the appropriate family may also serve as gene signaling agents having to do with gene activation, and are actually messenger molecules that create different genomic, proteomic, and metabolomic outcomes. This is a large breakthrough in our understanding of the role that certain essential fats play in modifying physiology. Therefore, we cannot necessarily account for all the clinical benefits seen from the substitution of a small amount of omega 3 fatty acids for other fats, such as displacement of arachidonic acid or other long-chain fatty acids from membrane lipids. The effects are more than just the incorporation into lipids; they also have to do with the regulation of gene expression resulting from the intake of specific families of fatty acids. Let me give you a couple of examples that are representative of many papers published over the last several years. Last year, a paper appeared in the Journal of Nutrition, titled “Dietary Fat Interacts with the –514C>T Polymorphism in the Hepatic Lipase Gene Promoter on Plasma Lipid Profiles in a Multiethnic Asian Population: The 1998 Singapore National Health Survey.”[2] The investigators demonstrated that there is an interaction between a specific polymorphism in the hepatic lipase gene and dietary fat because of its ability to regulate high-density lipoprotein cholesterol metabolism. This means that HDL levels may be related to the signals that specific dietary fats have on specific genotypes that give rise to the lipoprotein cascade, ultimately regulating HDL versus TG levels. Based on different genotypes, no two people respond in the same way, but fatty acids could be regulating gene expression that helps in the development of certain lipoprotein particles, particularly the anti-atherogenic HDL, in this particular case. That is one example of literally hundreds that have been published recently indicating that polyunsaturated fatty acids are, in fact, gene expression regulators. This is a fairly remarkable discovery that emphasizes how important the particular types of fat are in promoting health or disease. The complement DNA microarray studies published to date clearly show that omega 3 fatty acids, usually provided as fish oil, modulate expression of a number of genes with such broad functions as DNA binding, transcriptional regulation, transport cell adhesion, cell proliferation, and membrane localization.[3] These effects, in turn, may significantly modify cell function development and/or maturation. N-3 fatty acids influence more than one disease. They may modify functions that relate to mechanisms associated with many diseases that we will be describing here from subsequent research. a-Linolenic Metabolism in Adult Humans The first member of thefamily of omega 3 fatty acids is a-linolenic acid, or ALA. It has been studied extensively over the last 30 years. There is a wonderful review of ALA’s activity that was recently published in Current Opinion in Clinical Nutrition and Metabolic Care.[4] This review evaluated current knowledge of ALA metabolism in adult humans, based on findings of studies using stable isotope tracers and increased dietary ALA intake. The relative roles of ALA and of longer-chain polyunsaturated fatty acids in cell structure and function have been found to be very important in modifying the overall personalities of that cell type. Overall, ALA appears to be a limited source of longer-chain, n-3 fatty acids in man. Adequate intake of preformed n-3 polyunsaturated fatty acids, in particular docosahexaenoic acid (DHA), may be important for maintaining optimal tissue function. ALA is not easily converted into either eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). Therefore, people who take flax oil or flax seeds as a source of n-3 fatty acids are certainly getting reasonable quantities of ALA, but they may not be converting it very effectively into either EPA or DHA. It is the action of EPA and DHA that results in the most profound influence on gene signaling and cellular function. This is an important characteristic to keep in mind. It does not mean that there is no benefit from ALA as a substitute for saturated fats or partially hydrogenated vegetable oils. What it does indicate is that different people may not see the same clinical benefit from an ALA-supplemented diet. Flax oil contains one of the highest concentrations of ALA, over 50 percent of the fatty acid present. One may achieve a much better clinical response by giving EPA and DHA. Dietary ALA—Decreases Risk to Fatal Coronary Heart Disease, but Increases Prostate Cancer Risk Dietary ALA is associated with reduced risk of fatal coronary heart disease, but there is also some evidence that it is associated with increased incidence of prostate cancer risk. It appears there may be some kind of a tradeoff. A recent paper in the Journal of Nutritioncontains a meta-analysis looking at these particular variables.[5] The objective of the meta-analysis was to quantitatively establish the association between intake of ALA and mortality from heart disease, and the occurrence of prostate cancer in observational studies. The authors of the paper identified five prospective cohort studies that reported intake of ALA and mortality from heart disease—the Lyon Diet Heart Study being one of the most profound in this area, showing a strong inverse relationship between ALA intake and the incidence of coronary heart disease. Also reviewed were data from three clinical trials of ALA intake and heart disease. In addition, nine cohort and case-control studies were identified that reported on the association between ALA and/or blood levels of ALA, and the incidence and/or prevalence of prostate cancer. Risk estimates were combined across studies using a random effects model. It was found that high ALA intake was associated with reduced risk of fatal heart disease in prospective cohort studies, with a combined relative risk of about 0.79, or a little less than 80 percent of the risk against the control group. Three open-label trials also indicated that ALA implementation or intervention may protect against heart disease. However, epidemiologic studies also showed an increased risk of prostate cancer in men with a high intake or blood level of ALA. The meta-analysis suggests that consumption of ALA might reduce heart disease mortality. The authors point out that the association between high intake of ALA in prostate cancer continues to be a concern and warrants further study. As I looked at these studies, I found them quite interesting, because in some of them, blood levels of ALA were assessed and found to be elevated. In my opinion, this may indicate a block in the conversion of ALA into EPA and DHA. The association with prostate cancer may be more than just increased ALA. It may be that this is a stress marker for defects in n-3 fatty acid metabolism and the gene regulation that occurs with downstream chain elongated desaturated n-3 fatty acids, EPA and DHA. I do not necessarily jump to the conclusion that ALA produces prostate cancer. I think that if one were to do an ALA stress or challenge test, and proper elimination of ALA is not seen (conversion into EPA and DHA), it means the blood levels of ALA remain high. That may indicate there is some downstream problem with regulating cell communication, and intracellular function and signal transduction that would occur from the appropriate metabolism into DHA and EPA. We need to keep our eyes on this story as it evolves, but I would not necessarily jump to the conclusion that ALA is toxic. What I would suggest is that its metabolism and control into the longer-chain, desaturated n-3 fatty acids is quite important. The clinical takeaway from these studies is that EPA and DHA supplements may be better in terms of providing the appropriate balance that one might be trying to achieve clinically, rather than giving ALA. Effect of CLA on Body Composition and Plasma Lipids in Humans Similarly, ALA has been shown to lower the release of eicosanoids and nitric oxide (NO) from human aortic endothelial cells in culture, as has conjugated linoleic acid (CLA).[6] We have heard much about that. CLA is a fatty acid derived from the omega 6 family. CLA, as well as ALA and EPA, will lower the adverse effects that occur on endothelium associated with insulin resistance. Again, we see some basic mechanisms by which these fatty acids regulate cellular function that may be associated with major disease families, such as atherogenesis. CLA, which is a derivative of the omega 6 linoleic acid, and ALA, which gets converted into EPA and DHA, both have interesting regulatory effects on gene expression. Lessons from DHA Status Regulation, Diet and Epidemiology The DHA and EPA story is starting to look as if each of them is essential in its own right. That question has been raised in a series of interesting papers. One is titled “Is Docosahexaenoic Acid (DHA) Essential? Lessons from DHA Status Regulation, Our Ancient Diet, Epidemiology and Randomized Controlled Trials.”[7] This is an interesting review paper. Michael Crawford is one of the authors and he has been involved in the fatty acid research area for more than three decades. According to details in this paper, the evidence appears to indicate that consumption of EPA and DHA directly from the diet may be critically important for brain function, ocular development in the fetus, brain development in the infant, and, ultimately, for controlling neurobiochemical function in adults. It may have a lot to do with regulation of neuroendocrine-immune system function. This is a fascinating part of the emerging story about fatty acids indicating that we should not anticipate that diets supplying only the homologues of these chain-elongated fatty acids of the n-3 family are sufficient. Perhaps we need to give DHA and EPA in the diet directly. They come from fish or marine lipid-containing foods. Fish actually concentrate DHA in their bodies from marine algae. Algae are the organisms that biosynthesize long-chain, unsaturated n-3 fatty acids, and they are concentrated at high levels in specific types of fish oils. There are ways of extracting intercellular algae rich in DHA directly in some of the non-fish-derived fish oils. It seems paradoxical that one can give a non-fish-derived fish oil, but that is because these specific fatty acids in the fish oil did not originally came from the fish; they came from algae. Effect of EPA and DHA on Oxidative Stress and Inflammatory Markers in Type 2 Diabetic Patients EPA and DHA are important modulators of insulin signaling and cellular function, and they have been found to lower blood pressure in type 2 diabetes patients. This is discussed in a paper in Free Radical Biology and Medicine, in which the authors looked at the supplementation effects of n-3 fatty acids in type 2 diabetes patients.[8] They evaluated the effect they had on oxidative stress by measuring F2-isoprostanes, C-reactive protein, interleukin-6, and tumor necrosis factora (TNF-a) before and after intervention with EPA/DHA supplementation. Doses used in this study were about 4 grams per day of purified EPA, DHA, or olive oil. Thirty-nine diabetic men and 12 diabetic women, averaging 61.2 years of age participated in the trial. Their baseline urinary F2-isoprostances were positively associated with the level of hemoglobin A1c (HbA1c) and fasting glucose, meaning more glycosylation, poor glucose control, and increased oxidative stress. The elevation in fasting glucose with increased F2-isoprostanes also meant dysglycemia, increased glucotoxicity, and increased oxidative stress. You might think giving a highly oxidizable fatty acid would stimulate free radical oxidation and possibly increase isoprostane levels, but the reverse occurred. The isoprostane levels decreased significantly with the DHA and EPA. The investigators report that this is the first study demonstrating that EPA/DHA supplementation reduces in vivooxidative stress in individuals with type 2 diabetes, hyperinsulinemia, and elevated fasting glucose. This is a fascinating, almost counter-intuitive study showing that regulating proper cell signaling of the molecule insulin and glucose signaling processes ultimately produces an antioxidative effect, even though we might think of these fatty acids as being prooxidants. We sometimes have to discard a previous bias and remember systems biology and how these agents work together. EPA and DHA are also actively involved in support of immune function. A good review on the immune effects of EPA and DHA appeared in the American Journal ofClinical Nutrition.[9] In a placebo-controlled, double-blind, parallel study, 42 healthy subjects were randomly allocated to receive supplementation with either placebo (olive oil), EPA (4.7 g/d), or DHA (4.9 g/d) for 4 weeks. It was found that supplementation with DHA suppressed T lymphocyte activation, as assessed by expression of CD69, whereas EPA did not appear to have that same effect. Therefore, EPA alone does not influence CD69 expression. No other marker of immune function assessed in this study was significantly affected by either EPA or DHA. There are differential effects on the immunological system of EPA versus DHA, which means we might expect different clinical outcomes with different immunologically-related disorders. There is now emerging evidence from a variety of studies that supplementation with fish oils can have positive benefit on lowering renal inflammation, and slowing of renal function and lowering progression to renal failure. One of the papers published on this topic appeared in the Journal of the American Dietetic Association.[10] Fish oil supplementation in a population undergoing chronic hemodialysis therapy may be beneficial for various challenges to the progress in this population group. Pruritus symptoms were improved in individuals who were supplemented with fish oils. As we learn more about the roles these fatty acid families play in various immunological, cardiovascular, and endocrine function, we are seeing that the regulation of intake can have positive therapeutic benefit. If there is anything we know about what n-3 fatty acids apparently do, it is that they assist in establishing gene expression signaling that helps to maintain immune balance. This is discussed in a report titled “N-3 polyunsaturated fatty acids and allergic disease.”[12] This is a review of evidence that ties together n-3 fatty acids and the reduction of allergic disorders. The authors state that n-3 fatty acids are now recognized as important, but that we still do not know about all the mechanisms by which they seem to effect a lowered incidence of atopic and allergic disorders, at least in population-based studies. There is a need for ongoing, further research into the role of how n-3 fatty acids participate in the reduction and incidence of allergic disease, particularly in early life before atopy is established. N-3 fatty acids appear to play an important role as cell regulators of immune function. Recall that I previously mentioned proper nourishment of mothers with regard to n-3 fatty acids during pregnancy.[13] Docosahexaenoic Acid and Nerve Membrane Phospholipids: Bridging the Gap between Animals and Cultured Cells DHA is incorporated into nerve membrane phospholipids. This may help bridge the gap between some of the studies we have seen from a clinical observational perspective related to the improvement in neurological function that occurs in people who increase their n-3 fatty acids, and that which we see in cell culture studies. A good review paper on this topic appeared in the American Journal of Clinical Nutrition that talks about the dose-dependent responses of cells and the brain to DHA supplements that can be compared by looking at the DHA incorporation rate in neuronal phospholipids.[14] Clearly, there is turnover in brain phospholipids, or neurological phospholipids, and there is a re-incorporation based on the availability of the n-3 fatty acids Even conditions like cystic fibrosis may be modified in their phenotype by the role that fatty acids play in the diet. The gene locus for cystic fibrosis was first identified in 1989. There were great expectations for rapid progress in the understanding and effective treatment of the disease. It was generally believed that cystic fibrosis was a monogenic disease that would soon be treatable with gene therapy. Now, 15 years later, we have not been able to do that. What has been identified is a wide variety of mutations (1200) in the so-called cystic fibrosis transmembrane conductance regulator (CFTR) gene that have to do with the transport of substances across the GI mucosa.[15] We now know that transport of fatty acids is altered in the cystic fibrosis patient, and that n-3 fatty acids become more important. The western diet, which has a high level of n-6 fatty acids and a fairly low level of n-3 fatty acids, may further aggravate some of the imbalances apparent in the cystic fibrosis patient with n-3 fatty acid transport difficulties. The studies tend to indicate that improved intake of n-3 fatty acids can help modify inflammatory conditions for a better outcome prognosis. It is not just fatty acids that modulate immunological function. There are many micronutrients which do so—folate, vitamin B6, vitamin B12, selenium, magnesium, vitamin A, and vitamin E—micronutrients that modulate natural killer cell and immunological function. Add zinc, copper, and iron to that list as trace minerals important for immunological function. There is a good review of the influence of micronutrients on natural killer cell immune function in healthy living subjects, age 90 years or older, indicating that improving their micronutrient status helped to improve their NK cell activity and cell-mediated defense. This review appeared in the American Journal of Clinical Nutrition.[16] The relationship between micronutrients, n-3 fatty acids, and immune function is further complicated, or at least amplified, by the role that gut microflora play in immune function. More than 50 percent of our immune function is clustered around the gut. If we have imbalanced enteric bacteria, we may have altered immunological function. It is interesting to look at antibiotic use, a condition that may sterilize the gut and cause alterations in enteric bacteria, in relationship to the risk of breast cancer. This is discussed in a paper that appeared in the Journal of the American Medical Association.[17] The authors report that the use of antibiotics may be associated with increased risk of incident and fatal breast cancer. The specific mechanism has not been determined, but one possibility the authors postulate could be alteration in the enteric bacteria and the altered effect their metabolites have on normalizing the immune system. We might look at the intestine and the microflora as partners in the protection of the immunological condition of the host. We might even think of this as “the intelligent intestine” that has cross communication with enteric bacteria. There is a wonderful review on “The Intelligent Intestine” in the American Journal of Clinical Nutrition, which talks about immune system activity by interaction between the gut-associated immunological system, the lymphoid tissue in the gut, and the effects that diet has on enteric bacteria and their function. Wheat Gliadin Promotes Interleukin-4-Induced IgE Production As has been pointed out in many papers, food may contain dysinformation. Gluten in wheat may be sensitizing in certain people and promote upregulation of specific Th-2 cytokines, such as IL-4 that may have peripheral or non-local effects on altering the immune system. This is discussed in an article in the journal, Cytokine.[19] Altered gut flora may be dysbiotic and produce adverse effects on the immunological system. There is a wonderful review on this subject in the Journal of Clinical Nutrition.[20] The point I am trying to make is that a combination of fatty acids, micronutrients, proper diet, and the regulation of enteric bacteria using prebiotics and probiotics, may frame an interesting way of approaching the imbalance associated with inflammatory and atopic disorders. This is interesting “food for thought” that we will be exploring further in future issues of FMU.  

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INTERVIEW TRANSCRIPT

CLINICIAN OF THE MONTH Mark Hyman, MD Medical Director Canyon Ranch in the Berkshires 165 Kemble Street Lenox, MA 01240 JB: It’s time for our Clinician of the Month. We are pleased to have Dr. Mark Hyman as our guest. Many of you know him very well. For those of you who don’t, you are in for a real treat. Dr. Hyman completed his BA in Asian Studies at Cornell University and his medical degree at the University of Ottawa in Canada. He completed his postgraduate training at a Family Medicine Program of the University of California at San Francisco. He is Board Certified in Family Medicine. He has a broad-based background, which includes study of the Chinese language and traditional Chinese Medicine in China. He has had a wide-range of experience in medicine, from private practice to group practice. Currently, he is Medical Director at Canyon Ranch in the Berkshires in Lenox, Massachusetts. Recently, he took over as editor of a major journal in our field—Alternative Therapies in Medicine—and he is doing a tremendous job heading up that editorial board and setting the direction of that periodical. Dr. Hyman is also active in collaborative work with medical schools involved with integrative medical curriculum. He is a true clinician’s clinician. He understands patient psychology, motivation, and the mechanisms that relate to complex, chronic disease. He uses a wide diversity of tools available to the practitioner to ameliorate medical problems. I’ve asked Dr. Hyman if he would be willing to speak to us about the implementation of functional medicine in clinical practice through his own experience. Mark, it’s a real pleasure to welcome you to Functional Medicine Update. My first question is, what type of patients do you see in your practice? I’d like to get a sense of the array of different problems and patient types that are part of the spectrum of your clinical intervention. MH: Thanks, Jeff. I’m really happy to be on Functional Medicine Update. It’s been an inspiration to me for many years and I’m happy to be sharing my experiences with you, which have been very broad at Canyon Ranch. Canyon Ranch is an interesting place because it’s a health resort. People come here for many reasons, from just trying to de-stress and relax, to dealing with complex and difficult health problems that have been resistant to treatment. I often joke and say I’m a “resort doctor” (the doctor of last resort), particularly since my book —Ultraprevention, The Six Week Plan that Will Make You Healthy for Life—has been published. Subsequently, there has been a real influx of people who are looking for an alternative to conventional practice. They are not necessarily looking for alternative benefit, per se, but for a new approach to medicine. I think that’s really what we’ve evolved here at Canyon Ranch—an ability to work with people in an in-depth way over long periods of time to find the route of their illnesses. And we’ve had remarkable success. We’ve put together a team of practitioners—physicians, nutritionists, behavorial therapists, exercise physiologists, and so on. They all work together to help engage the patients, and to teach them what they need to know to take care of their bodies to help navigate them through the potential for healing that lies in functional medicine. Type of Patients Who Seek Integrative Care JB: What type of patients seek out that remarkable type of integrative care? MH: Young women who are going through menopausal problems from PMS to menopause to bone density. Today I saw a woman who has had severe ulcerative colitis for many years. She’s tried almost every alternative therapy. She’s on Imuran (azathioprine) and prednisone. Her sister has rheumatoid arthritis which is resistant to treatment. I see people with chronic fatigue syndrome, fibromyalgia, chronic arthritis, migraine headaches, weight issues, those who are interested in preventing cardiovascular disease, and a lot of people with insulin resistance. We treat a tremendous number of people with insulin resistance, and diagnose them here. We see people who are trying to deal with mental health and mood issues, and people who are trying to deal with preventing Alzheimer’s and maintaining optimal brain function. We deal with a whole spectrum of disorders. I see myself as a super generalist. There’s almost nothing I don’t take care of. JB: You talked about a team that obviously includes individuals in the health community with divergent skills and backgrounds. How do they work together? How do you consult on patients across these different areas of expertise? MH: We have different mechanisms for doing that. We share notes in the charts. We share phone calls and communicate with each other via phone calls. We have a health package coordinator who controls the flow of patients through the system. When people are in our package, their background data is communicated to all our practitioners, and we all know who’s seeing whom. For example, if I know someone needs a particular treatment, such as an elimination diet, I’ll work with them and call the nutritionist to talk to him/her about the patient. Then we follow them on the phone, and we communicate pretty vigorously together to try to figure out the best approach from a behavioral point of view, nutritional point of view, and functional medicine point of view. JB: When you first brought it to Canyon Ranch, the concept of functional medicine was considered pretty new. Anything new always has a communication barrier. How have you integrated functional medicine into what you do and communicated it to your colleagues? How An Integrative Health Team Works Together MH: It’s been an interesting experience. Basically, when I came across functional medicine, I told myself that if there was anything true about it, then I owe it to my patients to find out about it and try it. I began very quietly to “try it on,” to experiment with the concepts, methods, and the therapies, and began to have amazing success. I am still often amazed at how people get better, just applying the principles of the matrix in functional medicine. The results spoke for themselves. I didn’t really need to do a lot of convincing, other than just seeing the results that happened in people over time, and the letters that got written, the positive feedback from patients. We call it “the Jacuzzi effect”—people talking about their experiences—and it sort of filtered out through there. At the same time, I had the job of discussing and educating my colleagues about the value of this approach to medicine. Part of it was through encouraging them to take the Applying Functional Medicine in Clinical Practice (AFMCP) course, attending the functional medicine symposia, and your seminars. All those things help to fill in the blanks and give people the tools to understand the matrix. Now, it’s become second nature. It’s our practice. I can’t imagine doing anything else. In my view, there’s no other way to practice medicine. JB: You speak with positive affirmation, but clearly, you’ve had to cross some bridges and introduce some concepts that had barriers in front of them. What was the biggest barrier you experienced in introducing these concepts to your patients and your colleagues? MH: I think the comprehensive diagnostic stool assessment (CDSA) was probably the biggest barrier. I began to break down some of those barriers by shifting over to look at these functional processes. By bringing it down to that level, people really got it. The best way I found to break the barriers was to discuss things like inflammation, detoxification, nutritional status, and to really understand the signs behind it and be able to communicate those concepts in an effective way that was scientific, literature-based, and that it was really irrefutable. Then, I suggested that we might try to apply therapeutic methods that allowed us to take advantage of these new concepts, and see what happened. Of course, we always trying to start with the principle, “First, do no harm.” Obviously the tools we’re using are relatively free of significant risk. Diet, nutrition, exercise, mind/body therapies, vitamins/minerals, herbs, for the most part are very safe and have a large margin of error in terms of harm you could do to somebody. By doing that, by being systematic, and by really knowing my stuff, so to speak, I was able to help convince a lot of people around here that this is a valuable model of health care. JB: For a person who may be just starting in functional medicine, what would be your affirmation as to how they would gain a certain level of competence to make them feel comfortable with implementing functional medicine with their patients? MH: It’s such a huge field. I always say that the science of medicine is very complex. Learning about the concepts involved in functional medicine is like learning a new language. It takes time and study, and it takes experience. But the practice of functional medicine is relatively easy. You can learn some of the therapeutic principles and apply them without having a huge understanding of biochemistry or physiology. Tackling the big problems that have a high reward and a good outcome in functional medicine is probably the easiest way to get into it; for example, insulin resistance. That’s a slam dunk. Helping people with irritable bowel syndrome, for the most part, is a slam dunk. Helping people with chronic migraine headaches and food allergies—another slam dunk. There are some really easy entry points for people. They don’t have to do everything all at once. It can be a slow accumulation of experience and knowledge. If one starts with just one thing to focus on, let’s say helping people deal with insulin resistance, and learn about the issues surrounding inflammation, mitochondrial dysfunction, oxidative stress, and nutritional imbalances, with one particular condition, like insulin resistance. Those principles really apply to everything in medicine. That’s the beauty of functional medicine. It gives one a filter to understand the function of the human body and apply those same principles to multiple conditions across a wide array of problems. When you learn about one problem, you’ve really learned about all of them, because they all come down to the same basic core of dysfunctions in the body—metabolic dysfunction, inflammation, detoxification, oxidative stress and nutritional imbalances. These things are common themes throughout every illness, whether it’s ulcerative colitis or insulin resistance. It’s the same approach. The therapies might be a little different, the treatment might be a little different, but the thinking process is very much the same. JB: In listening to you, I am reminded of what Pasteur said: “Chance favors a prepared mind to make a discovery.” Your mind was certainly prepared, it seems, for this model because of your background in Asian Studies, and your examination of eastern medical models, which are more weblike and less analytical/ reductionistic. In the absence of having that kind of background and perhaps preparing your mind to make these associations, do you feel you still could have arrived at mastery with functional medicine? MH: Oh, absolutely. I definitely had a “fertile field” for growing the practice of functional medicine, but I don’t think it’s a prerequisite. This thinking is really pervasive across society. “Systems thinking” is infiltrating all fields of social and scientific endeavor, and this is just another manifestation of that. It’s the only way things operate in the universe, which is as an interconnected web of relationships. Once you begin to understand that, whether it’s in social or scientific systems, the rest falls into place. It’s intuitive. I think our patients understand it. I think that’s why they’re willing to connect with this. When I’m able to explain to them the way their body works, it’s like giving them insight into the owner’s manual for their bodies and they say, “Wow! This is how my body works; this is how I can take care of it. This is not some sort of a restrictive thing; this is actually learning how to live in harmony with my own biology.” You teach them, basically, how their bodies work. Then they make the choice, and they feel good. That’s the immediate payoff. Yes, you can control inflammation, oxidative stress, and improve detoxification, but the bottom line is, people feel better, and that’s what’s motivating for them. JB: You say that so beautifully in your book, Ultraprevention, The Six Week Plan That Will Make You Healthy For Life. I think that was eloquently described in the book. You also talk in the book about how you use various tools for assisting the patient to make these observations about their health along their journey; for instance, the laboratory. Would you tell us a little bit about how you use the laboratory and what tests you might find most useful in getting people to connect to themselves perhaps in a different way. The Role of Laboratory Tests in Functional Medicine MH: Absolutely. I think there are two main roles for laboratory tests. One is to help the doctor, and the other is to help the patient. As I’ve gotten more experienced in the practice of functional medicine, I’m usually able to predict the results of the tests without ever seeing them. After doing hundreds of thousands of tests, there are certain similar patterns that emerge that you can pretty much predict. My need for testing has decreased, but from the patient’s point of view, I think there’s real value in showing them their biology on paper and telling them that something isn’t working. For instance, when they have a sugar drink, their sugar goes up 200 points. This is a problem. Or, to get them to look at inflammation in their body and to tell them it isn’t normal and that it’s going to lead to significant illness later on. Or, explaining that a subtle imbalance in their hormones is making them feel bad, and advising them what they need to do about it. Or, explaining their digestive tract, what food allergies they may be reacting to; even though we all know that food allergy testing is imperfect, it still can be a motivating tool. I’ve found them very helpful over the years. There are a lot of tests within conventional laboratory testing that we don’t use that we should be using that tell us a lot about biology without even getting into more esoteric things like metabolic analysis with amino acids, mineral levels, antioxidant status, organic acids, toxic elements, and so forth. These are obviously more complex. But even just basic stuff we’re missing; I see that over and over again. We look at lipids in a careful way; at C-reactive protein; at homocysteine; at sugar metabolism, in particular; at hemoglobin A1C levels in normal patients; at a 2-hour glucose tolerance test with insulin; at a broader thyroid panel; and free T3 levels and thyroid antibodies in more people. We’re going to be able to tell a lot about what’s going on with their biology just by looking at some of these basic things that are overlooked in conventional testing. JB: Let me pose a challenge to you. Let’s say we just gave you three tests that you could use beyond that of the standard pathology-focused blood screen and hematological pattern. What would you choose? MH: My favorite functional medicine test is the organic acid profile. It’s also the most confusing, but once you learn it, it contains a lot of information about mitochondrial function, nutritional status, B vitamins, neurotransmitter function, oxidative stress, detoxification parameters, and digestive function. In one sweep, you can get a huge idea of what’s happening. Clinically, it’s been one of the most helpful tests because it seems to correlate the best with people who are sick. The worse the test, the sicker they are. As they get better, the test gets better. That’s been a very useful and helpful test for me in terms of the functional medicine profile. The other thing I would say is the celiac test, something I wouldn’t want to be without, although it’s available in conventional labs. I think that’s way under-diagnosed and very important. The third thing that I don’t think I can guess at very well is toxic element analysis. That’s usually accomplished with a challenge test, looking at heavy metal status. I think that’s very key. With the organic acid test, the celiac profile, and the toxic element analysis, I think I can probably take care of most problems. The rest I can probably guess at. JB: From what you’ve seen, do you feel that the problem of toxic element body burden is as real as has been implied in some of the more recent studies? MH: I have a lot of experience, both personally with my own mercury toxicity, and also in patients. There’s a wide array of manifestations from the asymptomatic patient with potential risks. For example, someone who has a high body burden of metals and has a risk, for example, for neurodegenerative disease because of APO E4 or family history. I worry about those patients, even though they may not feel sick. There’s another subset of people who are very sick and who have significant problems. I see dramatic changes in those people. I’ll give you a couple of examples. One is a patient who had severe intractable muscle cramping. She couldn’t open a jar; she couldn’t sleep at night. She couldn’t drive her car because her foot would cramp up on the gas pedal. It was quite serious. She was about 40 years old, and had gone to many physicians. Her husband was a physician, and she had extensive workups by neurologists, nephrologists, endocrinologists, and so forth. From a functional medicine point of view, anything that cramps is magnesium deficiency and the diagnosis is usually pretty easy. I told her she was pretty magnesium-deficient. Let’s give you some magnesium. That helped her symptoms a little bit. But then I told her there had to be a reason that her magnesium was so low; that it wasn’t normal to be leaking that much magnesium, and that she must have a problem with her cellular ATP-dependent, calcium/magnesium pump. I told her the most common toxin I knew of that screws that up is mercury. We checked, and she had an extraordinarily high level, up to 220 after a challenge with DMPS (for chelation therapy). Over the course of nine months with DMSA orally, with saunas, with nutrient supplementation, with IV glutathione from her husband who was an anesthesiologist, we were able to dramatically reduce her mercury, and her symptoms completely disappeared. That was a fairly clear-cut case. I had a number of other cases, one with early onset Parkinson’s who was diagnosed with a benign tremor, who had an extraordinarily high level of mercury ( 350). She had a mouth full of amalgams. She had the amalgams out and her level came down to 50. Again, her symptoms improved. Her tremor improved, and she was much better. I think there are clinical cases where there is, in my mind, clear-cut evidence of there being benefit by reducing the mercury. In other cases, I think it’s more preventive. Just the whole idea that you can have this toxic substance in your body over time and that it’s a known mitochondrial toxin and immunologically active substance, is not a good thing. JB: Those are very dramatic case histories. One of the things you have described is communicating things to the patient that he/she may never have thought of before. As you said, you’re a “doctor of last resort.” Often they’ve been seen by other physicians and had many other tests done. The question is, how do you motivate a change in the patient or communicate these new tools so that patients will accept them as something that is of value? Motivating Change in Patients MH: I feel very fortunate, because I’m in a situation where people come to me who are ready and willing to change, or they wouldn’t have even walked into my office. I’m in a little bit of an artificial situation because I know many practitioners out there are facing people who are just barely struggling to make it to life, who are economically challenged, who are not eating in a way that supports their biology, and who are not able to exercise. There are a lot of obstacles that I honestly don’t face with people, because I’m lucky that I get to spend a lot of time with people and I get people who come in to see me who are ready to change. I think some people need to be coached in a way that we’re not used to in medicine. Part of it is developing the skill to match the treatment to the patient. Some patients are willing to take 60 supplements a day; other patients are not willing to take anything but a multivitamin. Some people hate to exercise; some people love to exercise. Some people have certain addictions and emotional stresses that make it difficult for them to overcome their behavior. The key is to truly listen to their story and find out what their key goal in life is that would motivate them to make changes and alter their behavior. If you can’t connect with them on an emotional level to find out what their problems are—things that are not working in their life, and how they want to change them—then you’re not going to be successful. You have to start there. You have to figure out what’s the most important thing for them. That’s always what I ask. “What do you want? What are you looking for? How can I help you?” I think those are questions we don’t often ask. We tend to start out with a preset idea of OK, you’ve got this problem so I’m going to give you this treatment. We really need to take a step back and say, OK who is the person sitting in front of me? What is the situation is his/her life right now? What are their physical and emotional obstacles, and how can I connect with them at a place where they can get emotionally connected to the opportunity and the possibility for transformation in their health and in their life. JB: One of the things you’ve said so beautifully in your book, Ultraprevention, and you also voiced this before your peers, I think, in your closing address at the 11th International Symposium on Functional Medicine. It appears that this kind of medicine is good medicine; whatever you call it, it’s good medicine. You also exhorted the audience to become ambassadors in this change of producing a good medicine. What do you feel the barriers are to this becoming whatever it is called, and the way that patients are generally managed in this more comprehensive ultraprevention form? MH: Part of my personality is that I’m a terminal optimist. I see change happening in a dramatic way across many sectors of society. Obviously, the consumer sector is seeking out this kind of care, as are physicians. In fact, this week, we have two residents from Brigham and Women’s Hospital who are looking for something different in medicine and who found functional medicine on the web and sought us out. They have come here for a week to study functional medicine with us. If top cardiology Fellows and endocrinology Fellows from Harvard are coming and seeking this out, I think that’s a very hopeful sign. When academicians at the top universities in this country are seeking us out and trying to understand this model, and are helping us to put it forward in academic centers throughout the country, I think we’re moving in the right direction. I believe the obstacles at this point are less than the opportunities. The real opportunity is because the system we have now is crumbling and is so harmful to us as a society. It carries such an emotional and economic burden in terms of lives lost and economic cost, that it’s going to destroy itself. We’re going to be there to help create a new model. How Functional Medicine Works—Patient Histories JB: One of the things you do so brilliantly is to integrate this kind of vision of the future with the reality of the rich array of experiences with patients that you’ve had. Perhaps you would close by giving us one or two noteworthy examples from your experience about how functional medicine works. You gave us a couple having to do with heavy metal toxicity. Do you have another couple you might share with us? MH: Absolutely. I always love to tell the story about this one gentleman because he’s such a classic example of the functional medicine matrix, and how we need to think in that way in order to treat our patients successfully. He was a gentleman about 57 years old. He had multiple diseases, and he came into my office looking for sort of a wellness checkup. I asked him how he was feeling. He said he felt great. I told him I was surprised because he was taking about 15 different medications and had five or six different diseases. He said that he felt good, and that the medications seem to control everything. I noted that he had asthma, ulcerative colitis, alopecia areata (an autoimmune disease of the hair follicles), hypertension (which we now know is an inflammatory disease), and a little extra weight around the middle, which is probably an inflammatory condition called insulin resistance. I told him he was just “on fire.” He had a pulmonologist for his lungs, a gastroenterologist for his gut, a dermatologist for his hair, an internist for his high blood pressure, and everybody was treating him as a separate disease, with separate treatments. I asked him if anybody had ever asked him why he might be so inflamed, and he said no one had ever asked him that. I suggested we look. Basically, this is the process I go through with everybody. I ask what the major condition is and how it’s related to the matrix. In this case, inflammation was a big factor and I asked him what the triggers for inflammation are. We know they’re generally infections, toxins, or allergens, for the most part. Obviously, stress and diet play a huge role. I suggested we look for some of these things. Based on my experience, the first place I looked was for a gluten allergy. Sure enough, he had celiac disease. Six months later, he came back after getting off gluten. He was on almost no medications. His asthma was gone; he had normal bowel movements for the first time in 40 years; his hair was growing back; and he had lost 25 pounds. It was a very simple intervention, but it required asking the right questions. I think that’s really the opportunity of functional medicine. It allows us to ask the right questions. JB: That’s an absolutely brilliant case history because it really demonstrates the power of the web, filtering things through the matrix, and the whole model you’ve described in your book, Ultraprevention. You’ve described the fundamental part of our curriculum in functional medicine—looking for the mechanisms more than looking for what we call the outcome of those mechanisms in diseases. Any other thing you’d like to share with your colleagues about where you see the application of functional medicine or the field going over the next year or two? MH: I am really excited about the opportunities in this field, because more than ever before, I see these concepts emerging and popping up everywhere. It’s permeating the medical literature now. Yesterday, I pulled up the New England Journal of Medicine and there were two articles on homocysteine and osteoporosis. It’s all over the place. If it’s in the medical literature, and if our colleagues are reading this, and if the universities are turning out students who are interested in this, I think medicine is poised for a huge change. As practitioners of functional medicine who are curious and visionary leaders, we have to be ambassadors for this field and help bring this information to our patients and to our colleagues, and do it in a steady and deliberate fashion. I believe that within the next five to ten years, all of medicine will be radically different. JB: I want to thank you. You’ve given us the kind of affirmation that comes out of our 11th International Symposium on Functional Medicine, which says we need to keep to task, keep our focus, and keep our vision alive. This paradigm shift that we’ve been talking about is imminent, the so-called “tipping point.” You are a leader in the field, and we look to you as a lighting rod or a barometer of where we’re going. Dr. Hyman, I want to thank you very much. Keep up the tremendous work. You’re applying the principles of functional medicine that result in making a real difference in people’s lives. MH: Thank you, Jeff. It’s my pleasure. I want to thank Dr. Hyman for a wonderful, and very positive, affirming discussion about the role of functional medicine and management of patients with complex, chronic problems. Clinical Applications of Fish Oil Going back to some of the things I discussed on Side 1 on the regulation of immune function with fatty acids and micronutrients, I would like to talk again about fish oils. What amount are talking about? Often, patients think of fish oil as cod liver oil, a ghastly substance that is hard to swallow. Actually, the therapeutic amount of oil is remarkably small for most applications. We are talking about somewhere on the order of 3 to 6 grams of n-3 fatty acids for general modulation of function in the immune, endocrine, and neurological systems. There may be cases where one might need to go to higher levels for autoimmune disorders like rheumatoid arthritis, but for general applications, 3 to 6 grams should suffice. I want to emphasize to clinicians that I am talking about 3 to 6 grams of a combination of EPA and DHA. Depending on the fish oil formulation, there may be different percentages of EPA/DHA. One needs to look at the labeling to see if it is a high percentage EPA/DHA. It could be as much as 50 to 70 percent of the oil and even higher in some cases. Or, it may be fairly low—30 percent EPA/DHA in some lower-potency formulations. The algae-derived product, such as DHA from algae, can be 90 percent plus DHA therapeutically. A smaller number of capsules would be required to deliver a higher level of DHA or EPA. Make sure you examine the relative formulation. When I say 3 to 6 grams, I am speaking of a high-content oil with more than 60{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} EPA/DHA specifically. It may require total grams to be greater, depending on the potency of the oil. Second, I talked about the differential effects between EPA and DHA. There may be some cases where one would want to use DHA by itself at the level of 1 to 3 grams. There may be other, probably more common cases, where one would want to use an EPA-dominant formula with a smaller amount of DHA. This would be for endothelial modification, insulin resistance, and poor cardiovascular modification. In these cases, probably a balanced EPA/DHA—perhaps 50/50—would be considered good, or even a higher EPA-containing formula. Based on the clinical outcome one is looking for, gram levels in the 3 to 6 range can be used, and the ratio of EPA/DHA can be varied for different outcomes you are trying to support in a patient. Let me go back to the discussion about enteric bacteria and its relationship to immunological function. I spoke about feeding the friendly bacteria, which we consider the symbiotic bacteria. This has to do with what is often called “prebiotics.” Prebiotics are specific types of carbohydrates that are non-digestible but fermentable by the symbiotic bacteria that selectively feed them without feeding the unfriendly bacteria. Hopefully, they lead to selective starvation of the parasitic bacteria. Inulin, for instance, is one of the oligofructose-containing substances that serves as a prebiotic. This comes from Jerusalem artichoke or chicory. There are a variety of substances containing arabinogalactans, another form of prebiotic that stimulates growth of the friendly bacteria, such as Lactobacillus acidophillus or species of Bifidobacteria. Prebiotics versus Probiotics There is an interesting paper that was recently published in the Journal of Nutrition (an animal study) that talks about enriching the diet with a combination of oligofructose and probiotics and looking at effects on immune system markers.[21] Prebiotics have very marked effects on lowering the inflammatory response of the gut. They may have positive benefit in conditions like inflammatory bowel disease (IBD), and even systemic disorders associated with increased inflammatory potential and imbalances between Th-1 and Th-2 lymphocytes. There is a paper on this topic that appeared in Current Opinion in Clinical Nutrition and Metabolic Care, that discusses the effects of prebiotics in lowering inflammatory potential and other colonic inflammatory disorders.[22] Beyond prebiotics and probiotics, the friendly bacteria that ferment the non-digestible carbohydrates into secondary byproducts helpful in modulating immune function of the gut and which have positive effects on immune function of the whole organism, there are other things in the diet that can serve as signals for immune function. This is where the story becomes quite interesting. Often, we fail to recognize the important role that specific food proteins might have when partially digested. Oligopeptides liberated from partial digestion may have specific effects on cell signaling and modulating function of the neuroendocrineimmune system. This is quite a remarkable chapter, because it is not just the story of the food itself, but of the breakdown products of the food through partial digestion, and then the fermentation products of the food that result as a consequence of the fermentation of specific bacteria. For instance, the fermentation of lignans by specific bacteria gives rise to compounds like equol that modulate hormone action. This is a very exciting chapter in the story that explains that our diet is much more than what we put in our mouths; it is also how foods are converted by digestion and microbiological effects in the gut that may have effects on cell signaling. Effects of Milk-Derived Bioactives Let’s look at milk-derived protein as an interesting example. In the British Journal of Nutrition, there is a paper that talks about effects of milk-derived bioactives on rat jejunum.[23] These are peptide fragments from specific protein found in milk, members of the lactoglobulin family which go on to be partially hydrolyzed into bioactive substances,a– and b-lactorphins and another compound called albutensin, that go on to influence cellular function in remarkable ways. It is not just the stuff we put in our diet, but how it is broken down and the influence it has on cell receptor systems. These milk bioactive peptides induce mucus release and immunological function in the gut, modulating immune function. This was discussed in the Journal of Nutrition.[24] The influence of these bioactive peptides and certain dairy proteins may have remarkable influence on things as far ranging as blood pressure. For instance, there is angiotensin-I-converting enzyme inhibitory activity found in the gastric and pancreatic proteinase digests of whey proteins that may lower blood pressure. It has been shown to do so in animals, and there is some recent clinical evidence in humans that these bioactive peptides lower blood pressure. I cite from an article in the International Dairy Journal as just one of several papers in this area.[25] There is even now testing of peptides that may help inhibit b-amyloid aggregation.[26] This is a pretty remarkable chapter that deserves considerably more research. b-amyloid aggregation is associated with conditions such as Alzheimer’s disease. There are now a variety of targeted pharmacological interventions attempting to deplete serum amyloid bcomponents for the treatment of human amyloidosis and Alzheimer’s disease, by blocking the formation of amyloid aggregates.[27] It appears that certain peptide inhibitors may, at least in vitro, prohibit amyloid aggregation. I am speculating but, could it be that specific dietary proteins, when digested in specific ways, serve as anti-amyloid agents? The accumulation of amyloid protein in cells is associated with all sorts of aspects of biological aging. In closing, I hope I have given you some sense that functional medicine intervention is more than just a simple story, because it is complex. But, as Dr. Hyman so brilliantly pointed out, the complexity of the story does not mean that the application is complex. The application is simple; the mechanism is complex. I hope you will stay tuned, because we will be talking about many more strategies to put into our tool kit for evaluating and ultimately managing complex chronic disease based on functional medicine principles, sometimes using the neuroendocrineimmune system as signaling tools for complex diseases. Thanks so much. We look forward to being with you in August.

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Bibliography

1 Lefevre M, Kris-Etherton PM, Zhao G, Tracy RP. Dietary fatty acids, hemostasis, and cardiovascular disease risk. J Am Diet Assoc. 2004;104:410-419. 2 Tai ES, Corella D, Deurenberg-Yap M, et al. Dietary fat interacts with the –514C>T polymorphism in the hepatic lipase gene promoter on plasma lipid profiles in a multiethnic Asian population: the 1998 Singapore National Health Survey. J Nutr. 2003;133:3399-3408. 3 Lapillonne A, Clarke SD, Heird WC. Polyunsaturated fatty acids and gene expression. Curr Opin Clin Nutr Metab Care. 2004;7:151-156. 4 Burdge G.a-Linolenic acid metabolism in men and women: nutritional and biological implications. Curr Opin Clin Nutr Metab Care. 2004;7:137-144. 5 Brouwer IA, Katan MB, Zock PL. Dietarya-linolenic acid is associated with reduced risk of fatal coronary heart disease, but increased prostate cancer risk: a meta-analysis. J Nutr. 2004;134:919-922. 6 Eder K, Schleser S, Becker K, Körting R. Conjugated linoleic acids lower the release of eicosanoids and nitric oxide from human aortic endothelial cells. J Nutr. 2003;133:4083-4089. 7 Muskiet FA, Fokkema MR, Schaafsma A, Boersma ER, Crawford MA. Is docosahexaenoic acid (DHA) essential? Lessons from DHA status regulation, our ancient diet, epidemiology and randomized controlled trials. J Nutr. 2004;134:183-186. 8 Mori TA, Woodman RJ, Burke V, Puddey IB, Croft KD, Beilin LJ. Effect of eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and inflammatory markers in treated-hypertensive type 2 diabetic subjects. Free Rad Biol Med. 2003;35:772-781. 9 Kew S, Mesa MD, Tricon S, Buckley R, Minihane AM, Yaqoob P. Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Am J Clin Nutr. 2004;79:674-681. 10 Vergili-Nelsen JM. Benefits of fish oil supplementation for hemodialysis patients. J Am Diet Assoc. 2003;103:1174-1177. 11 Holgate ST. The epidemic of asthma and allergy. J R Soc Med. 2004;97:103-110. 12 Prescott SL, Calder PC. N-3 polyunsaturated fatty acids and allergic disease. Curr Opinion Clin Nutr Metab Care. 2004;7:123-129. 13 de Groot RH, Hornstra G, van Houwelingen AC, Roumen F. Effect ofa-linolenic acid supplementation during pregnancy on maternal and neonatal polyunsaturated fatty acid status and pregnancy outcome. Am J Clin Nutr. 2004;79:251-260. 14 Alessandri JM, Poumès-Ballihaut C, Langelier B, et al .Incorporation of docosahexaenoic acid into nerve membrane phospholipids: bridging the gap between animals and cultured cells. Am J Clin Nutr. 2003;78:702-710. 15 Strandvik B. Fatty acid metabolism in cystic fibrosis. N Engl J Med. 2004;350:605-607. 16 Ravaglia G, Forti P, Maioli F, et al. Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged >=90 y. Am J Clin Nutr. 2000;71:590-598. 17 Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA, Taplin SH. Antibiotic use in relation to the risk of breast cancer. JAMA. 2004;291:827-835. 18 Bourlioux P, Koletzko B, Guarner F, Braesco V. The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium “The Intelligent Intestine,” held in Paris, June 14, 2002. Am J Clin Nutr. 2003;78:675-683. 19 Dugas B, Dugas N, Conti M, et al. Wheat gliadin promotes the interleukin-4-induced IgE production by normal human peripheral mononuclear cells through a redox-dependent mechanism. Cytokine. 2003;21:270-280. 20 Mai V, Morris JG. Colonic bacterial flora: changing understandings in the molecular age. J Nutr. 2004;134:459-464. 21 Roller M, Rechkemmer G, Watzl B. Prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis modulates intestinal immune functions in rats. J Nutr. 2004;134:153-156. 22 Delzenne N, Cherbut C, Neyrinck A. Prebiotics: actual and potential effects in inflammatory and malignant colonic diseases. Curr Opin Clin Nutr Metab Care. 2003;6:581-586. 23 Shah NP. Effects of milk-derived bioactives: an overview. British J Nutr. 2000;84(suppl 1):S3-S10. 24 Trompette A, Claustre J, Caillon F, Jourdan G, Chayvialle JA, Plaisanciè P. Milk bioactive peptides and b-casomorphins induce mucus release in rat jejunum. J Nutr. 2003;133:3499-3503. 25 Mullally MM, Meisel H, FitzGerald RJ. Angiotensin-I-converting enzyme inhibitory activities of gastric and pancreatic proteinase digests of whey proteins. Int Dairy J. 1997:7:299-303. 26 Findeis MA. Peptide inhibitors of beta amyloid aggregation. Curr Topics Medicinal Chem. 2002;2:417-423. 27 Pepys MB, Herbert J, Hutchinson WL, et al. Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature. 2002;417:254-259

Welcome to Functional Medicine Update for August 2004. We were privileged last month to have Dr. Mark Hyman as our Clinician of the Month. He gave us a lens to see through as to how functional medicine applies to the management of complex patients with chronic conditions. Dr. Hyman is to be complimented for the way he articulates the vision. I was impressed when I saw the most recent issue of the Alternative Therapies journal (May/June 2004), and read the editorial by Dr. Hyman titled “Integrative Health and Medicine: An Opportunity for Leadership and Collaboration.”[1] Dr. Hyman has recently been appointed Editor-in-Chief of this journal, and his introductory theme was very prescient. It is certainly consistent with our view at The Institute for Functional Medicine about where medicine is going. I would like to quote some of the interesting features of Dr. Hyman’s editorial. “Emerging and traditional models of alternative and integrative care have long fostered the understanding of the relationships between biological, psychological, social and spiritual forces that lead to the disequilibrium we call illness. Emerging from the very heart of conventional medical science is a call for action to discard antiquated concepts and build a science of health that is founded on understanding these relationships. “The nature of practice must shift in the way we acquire information, in the structure of our days, in the tools we use to acquire history, in the tests we use to identify patterns that connect myriad symptoms into one story, in the way we educate our patients and discover with them the instruction manual for their bodies and minds, and in the way we engage, motivate and inspire our patients to change. Herein lies the opportunity for integrative health and medicine to lead the transformation of our disease care system into a healthcare system. “The good medicine of the future will move beyond the tools of pharmacology and surgery to the modification of the infinite variables that create health or disease. The new medicine, based on a sound theoretical framework, will allow us to formulate with our patients sensitive instructions to modify gene expression through entry points in the new biological landscape and speak through the new biological language. We can communicate to our cells with precision and balance using new therapeutic tools that include nutrition, exercise, mind-body medicine, nutraceuticals, and traditional healing systems, as well as more refined pharmacogenomic and surgical interventions. “Our tools of instrumentation are becoming more refined, peering not only into our anatomical structure, or the structure of cells, but into the very heart of dynamic functioning, into the very story of our life, and the potential held within our genetic code. “The field of integrative health and medicine is at the center of this new vision; it is the compass along the new road we are traveling in medicine. As a community we need to stand together, build bridges and consensus, guide research, shape public policy, create new opportunities in medical education, and lead the way with a cohesive voice that both welcomes rigorously and examines all perspectives.” Dr. Hyman is to be complimented for that insight. It is the theme we should hold onto as we move into this month’s Functional Medicine Update, to talk about the extraordinary understanding that is evolving about vitamin D.  

INTERVIEW TRANSCRIPT

Colleen Hayes, PhD Department of Biochemistry University of Wisconsin-Madison 433 Babcock Drive Madison, WI 53706 JB: Once again, it’s time for our Clinician/Researcher of the Month. This month, we are pleased and privileged to have Dr. Colleen Hayes as one of our guests. Colleen Elizabeth Hayes is a professor of biochemistry at the University of Wisconsin-Madison. She has an extraordinary background, which includes a series of important contributions from her nearly 30 years of research experience. Dr. Hayes received a Chemistry BA at DePauw University, and a PhD in biological chemistry at the University of Michigan. She was the Helen Hay Whitney Postdoctoral Fellow at Harvard Medical School, Department of Pathology, and the Helen Hay Whitney Postdoctoral Research Fellow at the University of Wisconsin-Madison, Immunobiology Research Center. She has been engaged in research having to do with nutritional interrelationships and the function of the immune system through work on retinoids and, more recently, in the area of vitamin D. Her bibliography is quite remarkable, and I would like to cite a couple of noteworthy papers that relate to the discussion we are going to have today. In 1986, Dr. Hayes coauthored a paper with Hector DeLuca at the University of Wisconsin on monoclonal antibodies and their relationship to the receptor for 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) in the pig model.[2] This might signal a change in thinking about the vitamin D connection and its relationship to the immune system, which she will be talking to us about today. Ten years later, in 1996, she coauthored another paper with Dr. DeLuca that started down the fascinating road of looking at vitamin D and its relationship to multiple sclerosis (MS).[3] Just to show you where this work has gone as she has continued it, in 2004 she published a paper titled “Gene expression analysis suggests that 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by stimulating inflammatory cell apoptosis.”[4] Here, we interface with what I have called “nutrigenomics,” the interrelationship between various nutrients and gene expression—proteomic and metabolomic outcomes. I hope that gives our listeners an overview as to where we are going in this interview. It is with great privilege that I would like to introduce Dr. Hayes to FMU. Thank you so much for being with us. CH: It’s a great pleasure to be here, and thank you for inviting me. Biochemistry of Vitamin D JB: As background for our listeners, would you quickly review the biochemistry of vitamin D as a prohormone? I want to make sure everyone is on the same page. CH: Yes. This is a so-called vitamin that isn’t really a vitamin at all. It’s a compound that derives from 70-hydrocholesterol in the skin when ultraviolet B radiation penetrates the epidermal layer. The photons cleave to one of the bonds in 70-hydrocholesterol and form previtamin D3, which then isomerizes to vitamin D3. It is transported on a vitamin D-binding protein out of the skin to the liver, where a 25-hydroxyl group is put on that compound. Now, we have the circulating form—25-hydroxyvitamin D3, the form that a clinician should measure to determine a patient’s vitamin D status. It is not the biologically active form, however. The final activation step occurs in the kidney, but also in many other tissues. One a-hydroxyl group is placed on the molecule to generate 1a,25-dihydroxyvitamin D3. Another name for that is calcitriol, a hormone in the steroid hormone family. Although we call it a vitamin for historic reasons, it really is a hormone. We can talk more about how you get your vitamin D requirement and what that hormone does. JB: Dr. Hayes, we were fortunate some months ago to have Dr. Michael Holick from Boston University Medical School talk to us about some of the work he has been doing on vitamin D physiology. He made the comment that from his experience in measuring 25-hydroxyvitamin D3 levels in patients that it is commonly below what he considers important in maintaining proper function. He felt there was a lot of nascent insufficiency of this important prohormone. Have you experienced the same thing, and do you share some of those views? How Latitude Affects Vitamin D Levels and Pervasiveness of Vitamin D Deficiency CH: I share his view. I have read Michael Holick’s work and it is excellent. There are other scientists who have made similar measurements and I’ve read their publications, as well. One of them was MK Thomas who surveyed patients in a hospital.[5] Vitamin D deficiency is very common. It’s common in infants who are entirely breastfed. It’s common in elderly people who have a slightly lower capacity for forming vitamin D in their skin. It’s common in people of color because the pigment in their skin effectively absorbs the photons and prevents them from generating vitamin D. Another group of people that have deficiency are those who use sunscreen heavily, or who practice sun avoidance. We have a lot of groups of people that are at risk for vitamin D deficiency. Also, those of us who work a little too much indoors are at risk for vitamin D deficiency. The winter is a particularly difficult time of the year for those of us who live where I live (Wisconsin), or at latitudes similar to that. Above 35 degrees latitude, the photons don’t have enough energy during the winter to break that bond and generate vitamin D. The ozone absorbs those photons and the sun angle is so low that there isn’t enough energy. People who live in the northern United States or equivalent parts of Europe and around the world experience about a five-month period of time where they don’t get high-energy photons, so they don’t make any vitamin D. By the end of the winter term, they can fall well into the vitamin D-deficient range, unless they’re supplementing their diets with vitamin D. JB: If you were to go to the average practicing physician and ask her/him to do a quick association test with vitamin D, the response would probably be, “calcium and bone.” Yet, you and others are starting to identify that vitamin D has a much broader series of effects on physiological function beyond that of the relationship to calcium, through its immunological effects. Would you describe how we’ve emerged that view? CH: Classically, vitamin D is known as the vitamin that’s important for forming and maintaining the skeleton, and controlling the calcium that is used in forming that skeleton. There has been a realization over the last 20 years that this is just the tip of the iceberg. The hormone binds to a receptor protein called the vitamin D receptor. You referred to one of my publications where we were actually measuring that receptor. But it turns out that receptor is in almost all cell types. In fact, I don’t know of a cell type that doesn’t express that receptor. That tells us that there are many, many cell types that use the hormone for some biological purpose other than skeletal maintenance and the mineral ion homeostasis. A Possible Protective Role of Vitamin D in Diabetes, Arthritis, Inflammatory Bowel Disease, Systemic Lupus Erythematosus, Thyroiditis, and Psoriasis To give you some examples from my area, we have been investigating the vitamin D receptor expression in lymphocytes and cells of the immune system. We have seen it function there, and we have good evidence from our own work in animal models that this hormone has a protective role in MS, diabetes, arthritis, and inflammatory bowel disease (IBD), to name just four autoimmune diseases. Others have shown an effect in systemic lupus erythematosus, thyroiditis, and psoriasis, as well. We are seeing a very broad spectrum of autoimmune diseases in animal models that can be prevented using the hormone 1,25-dihydroxyvitamin D3. There is some evidence that our animal data is also applicable to humans. Vitamin D may be very critical in helping the immune system to maintain tolerance to prevent a broad spectrum of autoimmune diseases. JB: I have heard that the 1,25-dihydroxyvitamin D3 binds to a receptor that has been lumped into the family of orphan nuclear receptors. Would you tell us a little bit about what they are? I think that would be of interest. CH: There is a family of proteins that has been called the steroid hormone receptor family. All of these family members have some common features. One is that they have a DNA-binding domain and they are found in the nucleus of a cell. Another common feature is that they have a ligand-binding domain, which binds to a ligand and then the receptor can stick to the DNA. Each member of the family has as its function the control of gene expression in a ligand-responsive manner. To use the vitamin D receptor as an example, when this protein binds the ligand 1,25-dihydroxyvitamin D3, and also binds DNA, it turns on the transcription of a nearby gene. It recognizes a particular site on DNA to bind, and that gives us a spectrum of genes that are responsive to the hormone. You mentioned the orphan receptors in that family. There are proteins that, by looking at their structure and sequence, we can tell they must belong to this family. They have a DNA-binding domain, but for some of them, we don’t know the ligand, and so they have been called orphan receptors because we’re searching for a ligand that will trigger their transcriptional control activity. The vitamin D receptor is not an orphan because we know its ligand. The important take-home point is that it functions in the nucleus to regulate gene expression, so it gives us a spectrum of genes that respond to this hormone, and the hormone, of course, is responding to light. It is a tool that our cells can use to tune certain cellular processes to light availability. Again, that gives us a sense that there are many more biological processes tuned to sunlight than just the maintenance of our skeleton. JB: I’ve been told that some of these are heterodimeric, meaning they have multiple ligands; for example, triiodothyronine, or T3, the thyroid hormone metabolite. Even fatty acids like eicosapentaenoic acid (EPA) or the vitamin A derivative, retinoic acid, seem to have binding affinity for some of these receptors. Are there interactions that occur among 1,25-dihydroxyvitamin D3 and some of the other agonists? CH: Yes. The vitamin D receptor is a single protein, but it can’t function as a single protein; it needs a partner. Its partner is the retinoid X receptor. That retinoid X receptor does partner with a number of the hormone receptors, and it does bind retinoic acid. There are interactions between these ligands in controlling gene expression. The retinoid receptor family is very interesting because it’s a big family of receptors. There are retinoic acid receptors a, b, and g, and these are controlled in a tissue-specific manner, so you may see the retinoid receptor g expressed only in a limited spectrum of tissues, whereas the a form is expressed in nearly all cells. That large family of receptors can mediate gene expression control in a very tissue-specific way. The vitamin D receptor is an ancient molecule, we think, and there is only one form of it, unlike the retinoid receptors which have multiple isoforms. Again, it does partner with the retinoid X receptor, forming a heterodimeric protein. There are lots of possibilities for interactions between the retinoid family of compounds and the vitamin D hormone, in terms of tuning gene expression to achieve a certain biological outcome for the cell. JB: About a year ago, I remember reading a paper coauthored by Dr. Walter Willett about vitamin A excess and bone fracture.[6] Is there a molecular association between overstimulation with vitamin A of these RXR receptors, or is that another mechanism? CH: That’s work I don’t know, so I would hesitate to comment about it. I haven’t read that paper, and I’m not familiar with retinoic control of bone metabolism. JB: Let’s move on to your extraordinary evolution of the model between vitamin D and MS. I remember in one of the talks I was privileged to hear you present, that you spoke of the history of how this whole association emerged. Suggested Link Between Vitamin D and Multiple Sclerosis CH: It’s a very exciting history. The story begins with a very old observation that was made by an astute World War I Army physician in the United States. He noticed, in examining recruits, that those who had symptoms of MS came from the northern states, such as Maine, Vermont, New Hampshire, Michigan, Wisconsin, Minnesota, and Oregon. He never saw a recruit from the southern states, such as Florida, New Mexico, or Georgia, with symptoms of MS, so he began to collect data and wrote up a description of a latitude gradient in the incidence of this disease. That triggered four decades of epidemiological research around the world, attempting to find out if the latitude gradient that had been described in the United States was also a feature of other places. In fact, it was a very robust finding. MS does show a gradient of prevalence with latitude. The disease is almost unknown at the equator; it is very, very rare at the equatorial part of the world. As you move away from the equator, either to the north or to the south, the disease becomes increasingly prevalent. It reaches its peak of prevalence in northern Scotland and northern Canada, as you might expect. The same gradient applies in the Southern hemisphere, although there are not as many data about that. The next piece of the puzzle came in 1960. A man named Donald Acheson was trying to sort out all the variables that might be associated with latitude and determine which one of the many variables might best explain the prevalence of MS. After a long and intense study, he determined that winter sunlight showed the best correlation. It was an inverse correlation. The more the winter sunlight, the lower the disease prevalence; the less the winter sunlight, the higher the disease prevalence. The chairman of my department, Dr. Hector DeLuca, discovered the active hormone 1,25-dihydroxyvitamin D3 when he was a graduate student. He has researched that hormone ever since. We are steeped in the biology of vitamin D here and I knew, as did Hector, that sunlight catalyzes the first step in vitamin D biosynthesis. He and I were also interested in why the vitamin D receptor was in lymphocytes. We had been talking for some time about trying to figure out why lymphocytes had a receptor for this hormone, which was known at the time for its skeletal maintenance function. We put 2 and 2 together and formed a hypothesis that sunlight might protect people from getting MS because it might be catalyzing vitamin D synthesis, and the vitamin D might be essential for lymphocytes for some functions that would protect a person from MS. We went about testing that idea in an animal model of the disease called experimental autoimmune encephalomyelitis. In that mouse model, we can induce a disease that looks very much like MS if we force a mouse to make an immune response against myelin basic protein, which is a component of the axonal sheath allowing axons to transmit an electrical pulse. We treated some mice with the hormone 1,25-dihydroxyvitamin D3, and other mice were given a placebo. I should also mention that Dr. Marguerita Cantorna worked with us on this project and was a key person in doing experiments. Then, we attempted to induce the disease and, to our astonishment, we found that when mice were given the hormone, we could not induce it. Furthermore, if we first induced the disease and then treated the mice with the hormone 1,25-dihydroxyvitamin D3, the disease symptoms went into remission and didn’t come back. We were very excited. That was back in 1996. We thought we had some evidence that it was, in fact, correct that sunlight protects against MS through the activity of sunlight generating vitamin D, and that was a starting point for my last decade of work, trying to figure out why that’s the case. JB: That is an unbelievably exciting story, which emphasizes taking advantage of the chance observation that leads to great progress and discovery. Let’s fast-forward to 2004 and the most recent paper you submitted on gene expression analysis and 1,25-dihydroxyvitamin D3 reversing the experimental autoimmune encephalomyelitis, and how it relates to the stimulation of inflammatory cell apoptosis.4 There’s a lot of importance in that paper that is underneath the water line. Would you bring us up to speed? CH: We are very excited that paper was finally published. It was a labor of love. It took us a long time to do that piece of work because, as you know, DNA microarray technology is relatively new. It’s a technique that allows you to ask about control of gene expression on a genomic wide scale. I mentioned earlier that the vitamin D receptor controls gene expression in a ligand-responsive manner. We finally realized that what we needed to know was the range of genes that are controlled by this hormone in the central nervous system, where the pathology of MS is going on. We established the encephalomyelitis disease in mice, and when the mice were severely ill (they were actually paralyzed from this disease), we treated half of them with 1,25-dihydroxyvitamin D3 and the other half with a placebo. Within a few hours, we collected the central nervous system tissue, isolated the RNA, and applied the RNA to DNA microarray chips (which interrogate all the genes known to be expressed in any tissue, at any time) so we could see the spectrum of genes that were expressed in a placebo-treated diseased animal. We could also see the spectrum of genes that were changing within hours after hormone treatment. In that experimental design, we applied the hormone treatment to start this process in a synchronous manner so we could actually define those genes. If we think about it in terms of a person who has adequate supplies of vitamin D, these processes would be going on all the time; it wouldn’t be a matter of turning them on synchronously. We did that experimentally so we could learn what they were. We looked at 12,488 genes in nine different samples—a massive amount of analytical work. I must tell you that without the help of our collaborators, that wouldn’t have been possible. We had wonderful assistance from Dr. Tom Prolla in our Genetics Department here. He’s an established expert in DNA microarray analysis and interpretation. We also had wonderful help from Dr. Brian Yandell, a mathematician and statistician. As you can imagine, wading through 12,488 genes in nine samples to determine what’s statistically significant, was a challenge beyond me. At the end of the day, we saw a small number of genes change. The family was certainly less than 100 in that timeframe. What we found remarkable was that in the types of gene changes we observed we saw some themes. One theme was protection of the central nervous system (CNS) cells like the neurons, the astrocytes, and the oligodendrocytes. We saw them turn on genes that we know to be protective in terms of signaling their survival. Certainly, this hormone has some effects protecting the CNS. Another family of gene changes that occurred, which we found very exciting, were those that signaled cells that were becoming sensitive to apoptotic signals. An apoptotic signal is something that can trigger a cell death program. Of course, when you think about an inflammation, you have a stimulus for the inflammation. It might be a virus; it might be a bacterial infection. In any case, you call in all the white blood cells and they do the work of eradicating the stimulus. And then, what happens to them? Somehow, you have to resolve this inflammation. An inflammation that is allowed to persist can do a lot of tissue damage. That is, in fact, the underlying pathology in MS. There’s ongoing inflammation that damages the oligodendrocytes and the neurons. What we saw was that in the presence of the hormone 1,25-dihydroxyvitamin D3, the inflammatory cells were becoming sensitive to apoptotic signals. They were turning on pro-apoptotic genes and they were turning off genes that could signal survival. We think what it did was reset the threshold for apoptosis and allow us to ask those cells to die, now that their job was done, and return the CNS to its homeostatic set point without inflamed cells being present. We were able to take that genetic information from the genomics research and go in and look with a method that would actually keep a feature of a cell undergoing apoptosis; that feature is the fragmenting of the DNA. It’s one of the late steps in the apoptotic program. We used a method to label them (“mixed ends”), and visualized it with an antibody to the label that we used, and we could see apoptotic cells appear in the portion that has infiltrating inflammatory cells. We could see those cells beginning to undergo apoptosis. What we think this hormone helps the immune system do, at least in part (this is probably one mechanism of many), is that it resets the apoptotic threshold so these inflammatory cells are more sensitive to apoptotic signals and they will die at the end of the inflammatory process. With that knowledge, what would it look like if a person was vitamin D deficient and didn’t have that hormone available? The outcome might be that these inflammatory cells are not going through apoptosis when the inflammation needs to be resolved. The inflammation would be going on much longer than is necessary, and long enough to do some tissue damage. We think this may be one explanation as to why so many autoimmune diseases are showing sensitivity to sunlight, and possibly to vitamin D, because they all involve an inflammation. In diabetes, it’s an inflammatory infiltration of the pancreatic islets. In rheumatoid arthritis, it’s an inflammatory infiltration of the synovium of the joint. In thyroiditis, it’s the thyroid. The common theme of all these autoimmune diseases is an inflammation that is not resolved and goes on long enough to damage tissues. We think we may have a handle on one of the underlying mechanisms for all of these processes, and an explanation that sunlight is required to help resolve inflammatory lesions before they do damage. That paper, although it took several years to bring it all together, has opened a floodgate for us in terms of understanding mechanisms, and we’re very excited about it. Now, we’re going after the mechanism in a cell to see if we can prove that hypothesis, or test it. JB: I want to compliment you and your group. I think this is stunning work. It combines so many different tools and techniques in a synthesis to uncover very complex mechanisms and give insight into qualitative observations that have been made, as you said, for over 40 years. This is one of those threshold breakthroughs. I have a great appreciation for the quality of the work that went into this paper. On behalf of all of us, thank you for this work; it’s wonderful. CH: You’re entirely welcome. May I just take a minute and say that the National Multiple Sclerosis Society has been funding our work, and we’re very grateful to them for the opportunity to do it. Without them, it wouldn’t have been done. The Suggested Link Between Vitamin D and Multiple Sclerosis JB: That’s a great team. Are you aware of any experimental clinical work that has gone on in applying some of these observations about 1,25-dihydroxyvitamin D3 with human MS? CH: That’s a very important question and there isn’t yet very much data in the literature. There is an important paper that came from Kassandra Munger (a graduate student) and her mentor, Alberto Ascherio at the Harvard School of Public Health.[7] We had a conversation some years ago about how one can test the idea that vitamin D might be protective in terms of lowering the risk of MS. Donald Atcheson pointed out that there was one database in the world that might shed some light on this, and that was the Nurses Health Study Database out of Harvard. Walter Willett is using that database to look at cardiovascular disease and various nutritional questions. This database contains work with a group of 200,000 nurses who have voluntarily allowed their health to be monitored over a period of 30 years. They’ve collected nutritional information from these nurses and they have a massive database. We realize that you could go to that database, if it had adequate nutritional information in it, and ask if those nurses that took vitamin D supplements had a lower risk of MS. Alberto and Kassandra have done that work and published it in January of this year. What they found was very exciting, that being that those nurses who took a multiple vitamin tablet of 400 IUs of vitamin D, plus other vitamins, had a 41 percent lower risk of MS than the nurses who didn’t take a multiple vitamin supplement. We don’t have any information on the vitamin D levels in their serum. That’s something Alberto is looking for now. We also don’t know which component of the multiple vitamin may have performed the protective function. That’s why we need the serum data to see if we can get a closer look at how they achieved that protection. But the suggestion is there that vitamin D supplementation early on can reduce the risk of MS later. There is also a beautiful study by Elina Hipponen in Finland.[8] She didn’t study MS; she studied diabetes. She also had access to a national health database and was able to show that infants—children who received 2000 IUs of vitamin D daily in their childhood—had an 80 percent lower risk of diabetes as adults. That is also a very exciting outcome, suggesting that vitamin D supplementation reduces the risk of diabetes. In terms of what we can do for individuals who are already affected with MS, there is a study going on now in Canada that is addressing that question, but I’m not part of it and I don’t know how far it has progressed. I think they will probably be announcing results soon. Reinhold Veith is the principal investigator of the study and they’re trying to see if supplementary vitamin D might be able to lessen the symptoms of MS. There’s a suggestive report that that’s possible, something I found very exciting. It’s well known that the severity of the disease varies during the year, so the most severe symptoms typically occur in the late winter and early spring. The disease lessens in severity by the end of the summer and the early autumn. As you know from my earlier comments about vitamin D biosynthesis and sunlight, by the end of the winter, most of us are vitamin D deficient. The severe symptoms were correlating with vitamin D deficiency, and the abatement of symptoms was correlating with the synthesis of vitamin D in the summer. That periodic variation in MS severity gives me some hope that we’re going to be able to at least affect the severity of the disease. Even if by this time it’s not possible to completely rid an individual of these difficult symptoms, we may be able to make it better. That’s what the Toronto study under Reinhold Veith is trying to accomplish. JB: As I listen to you talk of all the various potential implications of this extraordinary work, I’m reminded of your 1998 paper, looking at the effect of 1,25-dihydroxycholecalciferol on inhibition of the progression of arthritis in murine models of human arthritis. Even this suggests that what people say about their arthritis being worse in the winter and better in the summer may be true.[9] There are lots of interesting implications here. CH: I hear from people all the time that they’ve been using a tanning booth, or they’ve been flying to Arizona or Florida during the winter months and feeling better. There’s probably a very good reason they’re feeling better. Many people have discovered their arthritis symptoms improve when they’re exposed to the sun in the summer. I’m hopeful that we’re going to be able to help people afflicted with that painful disease. JB: When I look at the list that you provided—diabetes, MS, IBD, atherosclerosis, systemic lupus erythematosus, thyroiditis, and rheumatoid arthritis—I note that’s a lot of age-related chronic illness. CH: I haven’t said that there is work by other people showing a protective effect of vitamin D on cardiovascular disease, breast cancer, colon cancer, and prostate cancer. JB: I think this shows the implications of your work. CH: It’s a tremendous spectrum of biological activities that is just now opening up, so it’s a very exciting time in translational medicine for this system that’s classically been thought of in the context of bone, to be opening up in so many other areas. JB: I want to thank you. We’ve taken more time than we probably deserve, but it’s a great privilege to have you go through this story. We wish you continued success with your work. It’s pioneering and it will make a difference at the clinical level. CH: Thank you so much, Jeff, for inviting me. I’ve enjoyed this immensely and hope that you’re correct and we’re on the track to better health. JB: You’re speaking to the right group. They will be very receptive to your message. Thank you, Dr. Hayes.  

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Clinician Of the Month Norton L. Fishman, MD, FACP, CNS 15235 Shady Grove Road, #102 Rockville, MD 20850 JB: I hope you have been as stimulated with Dr. Hayes’ presentation as I have been, as it relates to the implications of vitamin D chemistry and physiology and its impact on health and medicine. I thought it would be useful to move from the biochemical realm into the clinical realm by talking to an expert clinician who understands nutritional medicine, and who incorporates it into his practice. Dr. Norton Fishman is a graduate of the Applying Functional Medicine in Clinical Practice (AFMCP) training program and is a functional medicine doctor of great distinction. He has been in practice for many years and is currently located in Rockville, Maryland. His practice bears the title, “Optimal Health Physicians,” which certainly conveys the focus of his work. At a meeting of the American College of Nutrition that Dr. Fishman and I both attended, I was privileged to hear him talk about his clinical experiences with the vitamin D connection to health problems. I thought it would make a wonderful segue for our listeners to hear how such information gets woven into real practice. It is a great privilege to introduce you to Dr. Fishman. Norton, it’s wonderful to have you with us today, and thanks so much for giving us some time. NF: Indeed, Jeff, it’s an honor to be on FMU. JB: Would you tell us a little bit about how your experience led you to the AFMCP course and defining your practice as “Optimal Health Physicians?” NF: I was a pretty regular primary care physician in Internal Medicine back in Chicago, where I had a practice for almost 27 years. It evolved into doing a lot of work in geriatric medicine, which included treating clients in nursing homes. Things began to change around 1993/1994. I always use the image of being on the Titanic, walking up to the ship’s purser and asking why my ankles are wet, and getting the following answer: “Don’t worry about it; go up to the deck; they’re playing the violins.” What I did instead was to get into a lifeboat. I saw this great big ship of medicine that I had been part of for several decades starting to sink. Getting into functional medicine is like getting into a lifeboat, and it’s floating. The big ship is having a problem dealing with the chronic health conditions that we’re seeing more and more of. Regular medicine is wonderful for delivering acute illness needs, but I stepped off the big boat. To get into functional medicine, you need to be open minded, curious, and in my case, I had a personal experience that led me into it. I think a lot of doctors have had a personal experience that leads them into functional medicine. Sometimes, it’s fortunate or unfortunate, but getting exposed to things that functional medicine has to deliver opened me up. Your programs, training with the American College for Advancement in Medicine (ACAM), and training in environmental medicine, have been like taking a new residency. Over a couple of years here in Rockville, Maryland, and with several valuable mentors, I have been able to change the way I looked at medicine and recreate the joy I once had. JB: That’s a marvelous story. Have you found that patients have traveled with you on your journey? Do you have a new kind of patient population? How has this transition been for you in practice? Vitamin D and Seasonal Affective Disorder NF: Interestingly, some of it is because I changed cities. We went from the Midwest to the east coast, via the Olympic Peninsula for a short while, and I’ll get back to that. Of course, I have a whole new cadre of patients who have stayed with me the past 10 years since I’ve been here. What I’m finding is that there is a different between the word “patient” and “client.” In medicine, we love the word “patient.” When I looked it up in the Oxford Dictionary, I found it meant “somebody who lets you do something to them.” So, my idea of a patient became someone who is on a gurney. When you’re going into surgery or into the emergency room, you’re a patient, but someone who sits across from you at your desk is a client. I found that my clients here wanted a consultant; they wanted advice and guidance. This has been a great area here in DC. People are very medically sophisticated. Many of them want to take good care of themselves. In many ways, it’s been like preaching to the choir, which I enjoy. My clients are very grateful to have somebody listen to them, to be open minded to their ideas about nutrition, to give them guidance, and not to laugh at them. JB: Being here in Gig Harbor, Washington, you’ve piqued my curiosity. Tell us a little bit about your travels from Chicago through the Olympic Peninsula to Washington, DC. That sounds like a very interesting, non-linear path. NF: We actually moved to Port Townsend on the Olympic Peninsula, figuring that would be an ideal place to live, once we left the city. In many ways it was, but something came up. There’s an area at Port Townsend that I’m sure you’re aware of called the “rain shadow from Mt. Olympus,” so we didn’t get the rain you get in Seattle, and it was lovely. There was sunshine often. We moved in around January and my wife found out that she suffered from major seasonal affective disorder (SAD). When we looked on the map, because the weather is relatively warm, we realized we were further north than Montreal or Toronto. Although the sun was coming down, it was coming down at the wrong angle; it was very low. We spent six months there; it was beautiful, but we realized it wasn’t going to work out and we became attracted to the Mid-Atlantic States. That leads me to vitamin D because in October of 2000, I attended a symposium on osteoporosis. I think it was sponsored by John Hopkins. I had a takeaway that really changed my life and the life of my wife. It was one of those “by the ways.” Dr. Michael Gloth was talking about using large doses of vitamin D—100,000 units a month for ladies with osteoporosis. The “by the way” was that the ladies taking vitamin D who had SAD got better. I don’t remember much about the osteoporosis, but I came home, talked to my wife, and told her we had the “magic.” I put her on a dosage of 100,000 units of vitamin D a month (a very large dose), and magic occurred. After a short while, Kathy noticed that her normal “dip” into SAD wasn’t happening. I told her we needed to describe this. I began to realize, as I went over the symptoms, that SAD is not depression. I think we have depression/depression, and SAD is a separate disease. But the things that work for depression don’t work for SAD. When Kathy described to me what was happening, and as I’ve talked to clients since, I got a very similar story. They all say that as October and November approach (in the northern latitudes), they start feeling like they’re going into a bed of molasses. There’s inertia—physical, mental, and emotional. Everything is an effort; it’s hard to get up. They start slowing down. They have a sense of social isolation; they tell people to go away and not bother them. Libido decreases. They’re in a mental fog. Some people even say they’re fattening up on sweets. They want more sleep. I’ve talked to some who say they feel confined, as if they’re in a cave. They’re just getting isolated. After a while, I realized that these people were describing a pattern, which I’ll call mammalian hibernation, and that it was occurring inappropriately in cognitively advanced primates called humans. I realized that SAD symptoms were indicative of someone who is inappropriately going into hibernation. My wife, Kathy had tried special lights designed for those with SAD, but they had a very minimal effect. The magic was the vitamin D, which gave her a new winter. I’ve talked to many people who find that lights help a little bit, but they’re not the answer. The reason we moved away from the Olympic Peninsula no longer existed, but we love it in Maryland and plan to stay here. JB: This is one of those extraordinary discoveries. Out of this comes some clinical replication, so an observation of one becomes the value for many. Have you had occasion to measure 25-hydroxyvitamin D3 levels in the serum? Do you follow serum calcium levels, or parathyroid hormone levels when you’re giving that high a dose of vitamin D? NF: What happened initially is that I started doing this enterically, and luckily I came across evidence, as you pointed out, from several people who had done some work at the University of Wisconsin, and there are several people who have been writing about these things. Actually, there’s a certified nutritionist by the name of Krispin Sullivan whose website I came across, which has some very good material. I believe Dr. Michael Holick has written some books on this. I suddenly realized I’d better be checking this out, because it’s nice to get a clinical response, but we need to make sure we’re being safe. One can get into vitamin toxicity. I began measuring 25-hydroxyvitamin D3, and it’s been well pointed out that’s the test to get, not the 1,25. I’ve found that many people with SAD have low levels of vitamin D. I also learned that the lab values I was getting back were not correct in terms of what “normal” is. We’ve been working with lab values (what I’ll call normal) of 30 to 60 nanograms, with the optimal probably being 40 to 45 nanograms of what I want to shoot for when I’m giving vitamin D. I’ve cut back the dosage for many people. I test after three months and I find that some people come back into a normal range in that length of time, so then I go to lower doses. For other people taking large doses, it might take a year before we see an improvement. JB: That is fascinating. There’s a general view, because we’ve all read in the textbooks that vitamin D is a toxic vitamin in excessive doses, that 100,000 units would immediately produce a toxic plasma level in all people. It’s very interesting to hear of your clients’ responses. NF: I write a prescription for a 50,000-unit capsule of vitamin D. I caution clients that they are to take only one capsule every two weeks. I know people who have used higher doses, but I would be very cautious about that. I’ve noticed, interestingly, way before vitamin levels even rise, that there’s a change in those with the SAD condition. There may be a particular UV band that is important regarding vitamin D and SAD. I know people have tried light boxes, but I think the key is vitamin D. It does something even beyond what we know it does for immunity and other factors. It must be affecting brain receptors in some way because we’ll often see a very quick response, way before levels improve. JB: Do you see any elevation in serum calcium when your clients are on this higher dose of vitamin D? Importance of Periodic Testing of 25-hydroxyvitamin D Blood Levels NF: No. I check 25-hydroxyvitamin D levels every three or four months initially, including a chemistry screen along with it to make sure we are checking calcium and phosphorus. I have found that it has no effect on serum calcium. If you have a client who’s getting levels above 45 and you’re supplementing, you’ll want to go very easy. Then, a value to look at would be to use an over-the-counter form of vitamin D3 from a fish oil extract, perhaps in a dosage of 1000-2000 units a day. I don’t see getting into any problem with that. You’d want to hold off getting past 60 nanograms because then you’re moving toward toxic levels, but I personally have not seen any problems with getting the levels too high, or certainly the calcium rising. JB: This is a very interesting observation. I’m doing a little speculation with you here, but let’s assume that one of the reasons individuals have vitamin D-related SAD is because they have an inability to properly convert vitamin D into the 25-hydroxy or the 1,25-dihydroxy hormonal form. The block is at some level in perhaps gene uniqueness or some other metabolic effects that prevent the appropriate conversion. That is similar to the classic example Linus Pauling talked about in molecular medicine, or that Bruce Ames has recently talked about. By mass action effect—by increasing the concentration of the substrate—we push the reaction, in this case conversion of vitamin D into its active form, the 1,25-dihydroxyvitamin D3. When you don’t see a significant elevation in the 25-hydroxy with very high doses of vitamin D, it raises the question about whether there is a metabolic block preceding the 25-hydroxy formation. NF: That’s exactly true. And it’s because there’s such variation between individuals. It does pay (this has been emphasized), to do frequent testing. I do testing on everybody coming in for an initial exam and for followup, not just for SAD. You may have looked into all the issues that are arising indicating that we probably have an epidemic of under-utilization of vitamin D that people are totally unaware of, which is very subtle. SAD stands out. People get better and they know it. It’s real and it’s great because it’s very rapid and very specific. The general underlying low vitamin D that many people have no knowledge of is probably a factor affecting immunity. They’re showing that it affects the potential for epithelial cancers like breast, prostate, and colon cancer, by helping to resist getting into that problem. Certainly, people have shown that it’s affecting autoimmunity and multiple sclerosis specifically, and we’re going to be looking at osteoporosis. This is a pretty important substance. In my testing, using the new standards, I’ve found a lot of people have lower levels than I ever would have expected. In people with SAD whom I’m not treating dramatically, I may use smaller doses, such as 2000 units of an over-the-counter vitamin D as a base, (60,000 units a month instead of 100,000), and then monitor them. JB: I want to compliment you. This is doing both good observational and clinical medicine, coupling together the science that has emerged around this interesting hormone, vitamin D and its 1,25-dihydroxy form, and how it relates to clinical observation. This is historically how medicine has evolved. I really want to compliment you on the way you’ve assembled this information. NF: Thank you, Jeff. JB: Do you feel the observation you’ve made regarding vitamin D and your wife’s SAD has been replicated in other clients? Is this something you think may be a cornerstone in SAD that all doctors should be looking at? NF: I definitely think so. Obviously, I took my case of one and expanded it. In the old days of medicine, treating chronic illness was an interesting experience because sometimes it takes a long while to see results. I used to love treating strep throats—give them penicillin and they call you up two days later and tell you you’re a hero. What I’ve found in treating SAD is the same response. We take on a problem that is a severe disability for people. Many of them are knocked out of function for three or four months of the year. And the further north in latitude, the worse it shows up. Being able to ameliorate it in rapid fashion has been great. I’m finding clients responding who have true SAD. What’s interesting is that we may even have a diagnostic test. If somebody doesn’t respond to a good vitamin D dosage, they may not have SAD; they may have depression. I’ve found that people who have SAD don’t respond to antidepressants unless they also have depression. I think we’re dealing with two diseases that have different treatment protocols. JB: That’s tremendous insight. As you’re talking, I’m sitting here with my colleague, Jay Johnson, in the studio we have shared for the last 25+ years. In the middle to late 1970s, when Jay and I were involved at the Northwest Academy of Preventive Medicine, we had a physician from Canada who spoke about the use of Aquasol (containing vitamin A and vitamin D) for the management of MS and autoimmune dysfunctions, and for what he called depression. I think he was practicing in Manitoba, and had experienced some big problems with the medical licensure board about the fact that he was audacious enough to use a vitamin A, vitamin D-containing nutritional supplement for the management of something on which the vitamins were not thought to have any impact at all. As I recall, he was an older-age physician and he retired rather than have to live with the insults of the medical licensure board. Sometimes, being a pioneer can have its price. NF: Being a pathfinder is not an easy job. I’m not necessarily recommending it unless you have a real predilection for it. It’s too bad, but I guess that’s human nature. That reminds me of two points I want to make about dosing and vitamin D. First, make sure people are taking calcium. Vitamin D’s job is to bring calcium up in the blood level and if there’s not enough nutritional calcium available, it may rob the bones. Calcium supplementation is important. Also, people have pointed out that being on vitamin A in sufficient amounts with vitamin D is valuable. It makes an interesting point. We’ve talked about the fact that MS seems to be tied into the vitamin D story. One of the suggested treatments for MS is supplementation with fish oils. I suspect what may have been a factor is related not as much to the omega 3s as to the vitamin D they were getting. JB: That is interesting. It goes back to the old cod-liver-oil-for-breakfast recommendation. We’re learning old things in new ways and now calling it “modern.” It’s pretty fascinating. Importance of Regular Exposure to Sunlight for Short Period in Maintaining Normal Vitamin D Levels NF: There’s one other point I’d like to make about people being confined and therefore cut off from light. Dermatologists are now telling everybody to stay out of sunlight and use sun block, but I think they’re wrong. I’m a clinician so I can be audacious; I don’t have to have my research. I think we need sunlight in proper amounts to help with vitamin D levels. We’re looking at cancer protection, and perhaps even for melanoma. The UV band gives us vitamin D, and that only comes from direct sunlight. That’s why the sun needs to be overhead. One needs to be out in the noonday sun for perhaps a short time if light-skinned, and perhaps a longer time if dark-skinned. Light is a nutrient, just like water and all our foods are. I don’t think locking people out of it is the right approach. Chronic, long-term exposure to ultraviolet light is what gets people into problems, and perhaps acute sunburns. I was thinking about people in nursing homes who are locked up in bed, away from the sun. We might even look at people in prisons who are locked away. I’m willing to bet a great number of those people are going to be found to be vitamin D deficient. We see a lot of lethargy and inertia in our nursing home patients. I wonder if we checked them and then gave them vitamin D whether we might find more active people. I think we’re opening a door at a nutritional level, to a whole new concept that we had no knowledge of before. JB: Thank you for such extraordinary insight. What a great “1-2 punch,” having Dr. Hayes talk about the fundamental science around vitamin D as a hormone, and for you to add clinical applications. I want to encourage you to continue on this great path. We see you as a pathfinder in the future of functional medicine. Thank you again, Dr. Fishman, for your extraordinary work and for your contribution to FMU. NF: Thank you, Jeff. We have been privileged to hear wonderful presentations by Dr. Hayes and Dr. Fishman concerning the underpinning of the bioscience in the emerging story of vitamin D and its clinical implications. This is a fascinating, evolving chapter in nutrigenomic-based functional medicine. I would like to amplify some of those thoughts about the emerging vitamin D connection, to better understand its application in the prevention, and perhaps even treatment, of chronic, age-related disorders. Vitamin D and Prevention of Falls Let us not forget about the role of vitamin D and bone in the prevention of osteoporosis. A recent paper appeared in the Journal of the American Medical Association titled “Effect of Vitamin D on Falls.”[10] This is a meta-analysis of a series of published papers from 1960 to February 2004 related to vitamin D and bone fracture. Falls reportedly occur in 30 percent per year of those 65 years of age or older and 40-50 percent of those are 80 years or older. Falls are a big contributor to morbidity and ultimately to mortality, because many of these individuals go into the hospital and never come out after sustaining a fall with injury. Falls constitute the largest single cause of injury mortality in elderly individuals, and are an independent determinant of functional decline, leading to 40 percent of all nursing home admissions and substantial societal costs. It is certainly something we need to be more attentive to in geriatric medicine. Any way we can help prevent falls would not only be important for the individual, but would be significant in terms of public health and use of medical services. Because of the increasing proportion of older individuals, annual costs from all fall-related injuries in the United States in people 65 years or older have been projected to increase from $20.3 billion dollars in 1994 to $32.4 billion dollars in 2020. Previously, the moderate protective effect of vitamin D on fracture risk has been attributed primarily to bone mineral density changes. However, vitamin D may also directly improve muscle strength thereby reducing fracture risk through fall prevention. It was found in a number of randomized controlled trials that vitamin D reduced fractures within eight to 12 weeks, a finding consistent with muscle strength benefits. Now that we recognize that the hormonal form of vitamin D (the 1,25- dihydroxyvitamin D3 you have heard so much about) has receptor sites on virtually every cell, and that it is related to gene expression patterns and outcome associated with both the proteomic and metabolomic function of the cell and tissue in that organ, it would not be too far-ranging to speculate that vitamin D might have an effect on sarcomere function or muscle cell function. The potential effect of vitamin D on falls, however, has not been well established. Several randomized controlled trials have addressed this, but results have been mixed, including several trials that reported non-significant results. In the JAMA paper on the effect of vitamin D on falls, the authors looked at the cumulative literature published from 1960 through February 2004 to see how the vitamin D story has evolved relating to prevention of the frequency of falls. Based on five randomized controlled trials involving 1237 participants, vitamin D reduced the corrected odds ratio of falling by 22 percent, compared with patients receiving calcium or placebo. From the pooled risk difference, the number needed to treat was 15, or equivalently 15 patients would need to be treated with vitamin D to prevent one person from falling. The inclusion of five additional studies involving 10,001 participants in a sensitivity analysis, resulted in a smaller, but still significant effect size. Subgroup analyses suggested that the effect size was independent of calcium supplementation, type of vitamin D, duration of therapy, and gender, but reduced sample sizes made the results statistically nonsignificant for calcium supplementation. It is concluded from the meta-analysis that vitamin D supplementation appears to reduce the risk of falls among ambulatory or institutionalized older individuals with stable health by more than 20 percent. This may be due to its effect not just on bone but also on muscle strength. Therefore, there may be other values of vitamin D beyond that which we have traditionally thought of in terms of the calcium connection to osteoporosis and bone fracture. As we so eloquently heard from Dr. Hayes, the conversion of vitamin D to its hormonal form (first the 25-hydroxylation in the liver and then the 1-hydroxylation in the kidney to produce the 1,25-dihydroxyvitamin D3, or calcitriol) is dependent upon a series of hydroxylating enzymes which are members of the cytochrome P450 family. These cytochrome P450 hepatic mono-oxidases and the renal mono-oxidase enzymes are those that deliver the hydroxyl groups that make the vitamin D into the hormonal form. You might ask what the specific oxidases are that engage in the process of vitamin D hydroxylation. That is now fairly well understood. CYP27A1 and CYP27B1 are the two cytochromes that appear to be engaged in the hydroxylation patterns of vitamin D. Therefore, one might speculate that lowered activities of these hydroxylating enzyme systems, or mono-oxygenases, would lead to underconversion, or slower conversion of vitamin D into its hormonal form, the rate-limiting step being the 25 hydroxylation of vitamin D itself. How could one upregulate the hydroxylation in individuals who have sluggish or impaired hydroxylation; in other words, upregulate the specific cytochrome P450s involved in the production of the hormonal form of vitamin D? That goes back to the discussion we had with Dr. Fishman about why some people may have seasonal affective disorder (SAD) as a consequence of impaired vitamin D metabolism into the active 1,25 dihydroxy hormonal form. It turns out that recent work has suggested at least one pair of phytonutrients that can upregulate CYP27B1, thereby increasing the hormonal form from the vitamin D in cell culture systems. These are the soy isoflavones that we have heard so much about—genistein and diadzein—from soy concentrate. Phytoestrogens and Vitamin D Metabolism—Prevention and Therapy of Colorectal, Prostate, and Mammary Carcinomas In a recent paper published in the Journal of Nutrition, work from James Armbrecht and his collaborators at the Department of Pathophysiology, University of Vienna Medical School, Austria; the Institute for Preventive Medicine, Nutrition and Cancer, and Division of Clinical Chemistry, University of Helsinki, Finland; and the Geriatric Research, Education, and Clinical Center at the St. Louis Veterans Administration Medical Center found that soy isoflavones increased levels of CYP27B1.[11] They suggest this may result in increased 1,25 dihydroxyvitamin D, which many be one of the reasons why soy consumption has been associated with reduced incidence of colorectal, prostate, and mammary carcinomas. By increasing the active hormonal form of vitamin D, which has an effect on epithelial cell regulation and differentiation through the processes Dr. Hayes talked about, through the immune system and favorable effects on apoptosis, there may be an indirect effect on reducing the incidence of these three forms of mucosal cell carcinoma—colorectal, prostate, and mammary. There may be an interrelationship of interest between consuming soy products and increasing vitamin D metabolism in individuals who have low levels of 25-hydroxyvitamin D3, a very important potential observation coming out of the recent primary research literature. If a person is increasing dietary vitamin D level intake and does not see a concomitant increase in plasma 25-hydroxyvitamin D3 level, he/she may want to increase soy isoflavone intake to see if that amplifies the conversion of the vitamin D into the active hormonal form. Vitamin D, Bone Loss, and Inflammation We have also started to look at the loss of bone from the bone remodeling unit and the production of osteoporosis from a slightly different perspective. In the past, it was a fairly simple model of calcium-in versus calcium-out, principally controlled by a dynamic relationship between parathyroid hormone, calcitonin, and dietary calcium, and how that influenced the osteoclast and the osteoblast. Now, we are starting to see a new component emerge that is important in bone loss, and that is inflammation. “Inflammation and bone resorption often go hand in hand, a fact evident in conditions such as joint destruction in rheumatoid arthritis or periodontal disease.”[12] The most common loss of teeth in the adult is that of alveolar bone associated with periodontal disease. Even in people with reasonably good oral hygiene, there can often be loss of alveolar bone. How does this work? Arming the Osteoclast Osteoclasts, the bone-resorbing cells of the organism, also share several features with macrophages and dendritic cells. Osteoclasts are derived from hematopoietic stem cells within the macrophage lineage, and they respond to several interleukins produced by activated T cells involved with the inflammation pathways. These include the receptor activator of nuclear factor kappa B (NFkB), the so-called RANKL. RANKL and tumor necrosis factor (TNF) stimulate osteoclast differentiation and bone resorption. In the case of high TNF levels or high RANKL levels, the osteoblast is converted to the osteoclast cell more rapidly, increasing the number of bone resorbing units, at the expense of lowering the number of bone formation units. The equilibrium is shifted in the bone-remodeling unit toward bone loss. In the April 15, 2004 issue of Nature, work by Koga and Inui et al. tightens the link between bone resorption and the immune system.[13] The authors show that cells of the immune system and osteoclasts share requirements for costimulatory signals that are mediated by immunoreceptor tyrosine-based activation in osteoclasts, and this costimulation is needed for RANKL-induced differentiation and bone resorption. Therefore, high levels of inflammation or inflammatory mediators increase the relative risk of bone loss, or osteoclastic osteolysis. We might also ask about the role of the hormonal form of vitamin D. We learned from Dr. Hayes’ work that it is engaged in influencing macrophage apoptosis and attenuating an upregulated immunological system associated with inflammation. There may be another role that vitamin D plays other than the calcium connection in maintenance of bone integrity. It may serve as an antiinflammatory or an inflammation-balancing substance that has to do with the ability to reset the balance between the thymus-dependent 1 (Th1) and thymus-dependent 2 (Th2) lymphocytes. Dr. Hayes has made active contributions in this area over the last 20 years in our understanding of that relationship. What I am describing is an interesting relationship between inflammation, bone loss, vitamin D in its hormonal form, immune cell activity, and the interrelationship between Th1 and Th2, or systemic inflammation versus tissue-specific inflammation. The vitamin D hormonal form, calcitriol, may have a central role in establishing the proper equilibrium or the cell system responsiveness to stimuli, so it is not shifted too much in terms of Th1 or Th2 predominance, but is able to maintain the proper equilibrium so it does not tip over into extended systemic inflammation or into extended or amplified tissue-specific inflammation that is often associated with disorders such as atopy, asthma, allergy, or eczema. The Parathyroid Gland and Calcium and Phosphorus Dynamics Let us not forget the relationship with the parathyroid gland, as well. The parathyroid gland plays an important role in the secretion of parathyroid hormone on the little tufts of tissue that sit embedded within the thyroid gland that produce parathyroid hormone, or PTH, and interrelate and counter-balance the release of calcitonin from the thyroid gland. The combination of those two establishes another equilibrium pertaining to calcium and phosphorus dynamics. A number of individuals over many years have talked about the fact that as our diets became lower in calcium and higher in phosphorus; we started “tipping the thermostat” of the parathyroid hormone/calcitonin connection to more bone loss. High phosphorus intake and low calcium intake turns up PTH activity. There is a nutritionally-induced, secondary hyperparathyroid-like condition which causes more calcium to be pulled from bone as a source of maintaining plasma serum calcium levels. Phosphorus stimulates this process. The high soft drink-containing diets or lifestyles of many children may contribute to this nutritionally-induced, borderline or secondary hyperparathyroidism. Increasing calcium and lowering phosphorus in the diet helps to maintain the proper balance, one with the proper dietary signals that influence the proper regulation of calcitonin and parathyroid hormone. I do not want to exaggerate this connection. This is not the major source of bone loss, but it is another factor that can contribute to altered hormonal messages that interrelate with the dynamics of calcium and ultimately, soft tissue calcium deposition or hard tissue calcium loss; in other words, bone calcium loss. The parathyroid gland takes its signals from many sources. For instance, when there is chronic renal failure, there are often alterations in hormonal messages from the kidneys, which alter parathyroid function so chronic glomerulonephritis can have adverse effects on parathyroid function that influences the calcium/phosphorus dynamic. I do not want to make the story so simplistic as to say that only dietary calcium/phosphorus ratios control these hormones and ultimately, their impact on bone. I want to put that into the mix because when dietary recall studies with food-frequency questionnaires or diet diaries are done in many individuals, it is found that dietary calcium levels are fairly low (below 800 mg per day), and dietary phosphorus levels may be up in the several grams-per-day level, particularly if they are taking phosphate-containing foods and eating a lot of high-protein meals. Phosphorus in diets is generally associated with the nucleo-proteins or nucleic acids; the phosphorus in them is part of the triphosphate residues. Therefore, when we look at high protein diets, we often see high phosphorus, as well. A high protein diet is generally a low-calcium diet because calcium comes from vegetable products, whole grains, and things of that nature (along with dairy products, obviously). As a consequence, that can shift dietary calcium/phosphorus intake to a higher phosphorus/lower calcium basis, which then increases the parathyroid output of PTH and decreases calcitonin, leading to bone loss. Fooling the Parathyroid Gland There are several researchers now working on secondary hyperparathyroidism, particularly in individuals who have renal failure and who are on hemodialysis. There are some new medications now being released that “fool” the parathyroid gland and prevent secondary hyperparathyroidism. Certainly, the pharmacological world is working on how to manipulate parathyroid function in the pathophysiology of renal failure. Those among what I call “vertically diseased” individuals suffering from the blues, lack of energy, some muscle weakness and fatigue, sleep disturbances, modest bone loss, and tissue calcification—the complex of what we call the trajectory-toward-ill-health type of person, may be the candidates for whom dietary calcium/phosphorus ratios play an important role. Vitamin D and its conversion into its hormonal form are very important in “putting them back on the trail,” so to speak. If you are interested in the parathyroid connection to renal failure, there are a couple of recent papers in The New England Journal of Medicine you might want to look at. There is a nice editorial titled “Fooling the Parathyroid Gland—Will There Be Health Benefits?”[14] Another paper discusses the management of secondary hyperparathyroidism in patients receiving hemodialysis titled “Cinacalcet for Secondary Hyperparathyroidism in Patients Receiving Hemodialysis.”[15] There is also a paper on a good case history of a patient with asymptomatic primary hyperparathyroidism, if you would like to review the role of the parathyroid in controlling a variety of different functions beyond bone.[16] I hope we have given you some “news to use” in this edition of FMU relating to the exciting, emerging story around vitamin D in its hormonal form and its effect on the immune system. We look forward to visiting with you in September.

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Bibliography

1 Hyman MA. Integrative health and medicine: an opportunity for leadership and collaboration. Alt Therapies. 2004;10:10-11. 2 Dame MC, Pierce EA, Prahl JM, et al. Monoclonal antibodies to the porcine intestinal receptor for 1,25-dihydroxyvitamin D3: interaction with distinct receptor domains. Biochem. 1986;25:4523-4534. 3 Cantorna MT, Hayes CE, DeLuca HF. 1,25-dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci USA. 1996;93:7861-7864. 4 Spach KM, Pedersen LB, Nashold FE, et al. Gene expression analysis suggests that 1a,25-dehydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by stimulating inflammatory cell apoptosis. Physiological Genomics. 2004: In Press. 5 Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-783. 6 Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA. 2002;287:47-54. 7 Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62:60-65. 8 Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358:1500-1503. 9 Cantorna MT, Hayes CE, DeLuca HF. 1,25-dihydroxycholecaliferol inhibits the progression of arthritis in murine models of human arthritis. J Nutr. 1998;128:68-72. 10 Bischoff-Ferrari HA, Dawson-Hughes B, Willett, WA, et al. Effect of vitamin D on falls: a meta-analysis. JAMA. 2004;291:1999-2006. 11 Cross HS, Kallay E, Lechner D, Gerdenitsch W, Adlercreutz H, Armbrecht HJ. Phytoestrogens and vitamin D metabolism: a new concept for the prevention and therapy of colorectal, prostate, and mammary carcinomas. J Nutr. 2004;134:1207S-1212S. 12 Baron R. Arming the osteoclast. Nature Med. 2004;5:458-460. 13 Koga T, Inui M, Inoue K, et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 2004;428:758-763. 14 Curhan G. Fooling the parathyroid gland—will there be health benefits? N Engl J Med. 2004;350:1565-1567. 15 Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med. 2004;350:1516-1525. 16 Bilezikian JP, Silverberg SJ. Asymptomatic primary hyperparathyroidism. N Engl J Med. 2004;350:1746-1751.

Welcome to Functional Medicine Update for September 2004. We have a wonderful session in store in this issue—an interview with Dr. Robert Heaney, our Clinician/Researcher of the month. I am sure many of you have heard of his work. He has been a founding father and researcher in the area of osteoporosis/bone mineral metabolism for five decades. I think you will find the insight and contributions he makes in his interview fascinating. As well, it is very usable information from a clinical perspective. Diclofenac Devastates South Asian Vulture Population I would like to begin this month by talking about an interesting observation that is quite far afield from clinical medicine and nutrition topics traditionally addressed in FMU—the side effects of the increasing use of non-steroidal antiinflammatory drugs (NSAIDS) in veterinary medicine. This is one of those “aha” experiences because often we do not understand the global implications of what we do. We think in very myopic terms about localized effects of various decisions in the health sciences. We do not consider the broader contextual framework. This topic will broaden our perspective and open our minds to some of the ecological and biosphere influences that the decisions we make in medicine might have. This information comes from a report three years ago on a mysterious ailment that was causing massive die-offs in the Asian subcontinent of three species of vultures, birds of prey.[1] At that time, the populations of two vulture species had dropped by 90 percent in India alone, in a period of less than 10 years. Large numbers of these stricken birds were seen with their heads and necks drooping down, later to drop from their perches and die, apparently of kidney failure. Since then, the situation has gotten worse. According to Peregrine Fund researchers, the Oriental White-backed Vulture, the Long-billed Vulture, and the Slender-billed Vulture have declined by 92 to 99 percent over the last decade. Less than a decade ago, these vultures numbered in the tens of thousands across India, Pakistan, and Nepal. The crash in their populations is a human as well as an environmental disaster, according to research that has been accomplished over the past year. What role do these large birds play in the ecosystem? They are a free waste disposal system, quickly devouring dead cattle and other animals in the countryside, as well as in cities. For instance, a flock of vultures can reduce a full-grown cow to a pile of bones in an hour. They play an important role in managing waste in an agrarian society. What is the cause of the rapid decline in the population of these birds of prey? It has been thought by the countries involved that it was some kind of infectious disease. They looked at specific types of viruses and bacteria that might induce disease. This year, the mystery seems to be solved, and it is not a consequence of a disease, but rather of chemical poisoning. It has to do with the recent use of the NSAID, diclofenac. In terms of human medications, its trade name is Voltaren. It is now being used in veterinary practices on large animals, particularly cows, for treatment of inflammation, fever, and lameness, because it is a very powerful antiinflammatory medication. Concern about the three declining species of birds led a variety of groups to investigate the source of their decline by doing autopsy and tissue sample research. In the journal Nature in 2004, a fairly wide body of research was published which identified the veterinary use of diclofenac as the responsible agent for the devastating declines in the South Asian vulture populations.[2] This was a three-year study by The Peregrine Fund and Ornithological Society of Pakistan that found that 85 percent of 259 vultures examined had died of visceral gout, a condition caused by renal failure. Having eliminated the classic causes of renal failure, which includes viral or bacterial infectious disease, pesticides, poisons, heavy metals, or nutritional deficiency, the investigators tested the theory that vultures were encountering a toxin while feeding on livestock carcasses (their main food source). They found that just in the last few years diclofenac has been used as an NSAID in India, and that most of the animals found to be lame were being treated with it. This use was increasing the tissue levels of the drug in the animal carcasses. Diclofenac is known to be toxic to kidneys in mammals, but in vultures, it appears to be extraordinarily toxic, and therefore a biomarker organism. Further investigation showed that diclofenac was fatal to vultures at 10 percent of the recommended mammal dose. Tissue residues in livestock treated at the labeled dose rate were sufficient to cause gout and death in vultures. This, coupled with the high incidence of visceral gout in wild vultures found dead in Pakistan, India, and Nepal, confirms that diclofenac is the primary cause of the Asian vulture decline. This is interesting because diclofenac is widely used in human medicine, but was only introduced to the veterinary market in the Indian subcontinent in the early 1990s. In that period of time, we have seen the rapid decline in the vulture population. The drug is very inexpensive—less than $1 for a course of treatment in an animal—and it is widely used in the treatment of inflammation, pain, and fever in livestock. This is a very interesting bit of second-tier information about how certain pharmaceutical agents, when they are introduced into the environment, may have broader implications than we think. That poses the question, if a vulture is a very sensitive organism, what about other living things that are less sensitive, but habitually exposed? Could this have other effects we have not yet looked at? Could this be the yellow canary, so to speak, as it relates to this issue? We often think that when medications travel through our chain that they somehow end up being detoxified and eliminated and that their residues are never revisited. Now, there is more and more evidence to indicate that, starting with aquatic biota and going all the way up through, in this case, higher mammals, these medications may sometimes be commonly found in the biosphere where they can have deleterious effects. After talking about NSAIDS, I would like to move to human medicine and discuss the evolving story of the benefit-to-risk ratio of the use of selective cyclooxygenase 2 inhibitors (COX-2) and non-specific NSAIDS in the management of chronic pain. These are some of the most commonly-employed medications, such as over-the-counter ibuprofen, and also include higher-potency prescription derivatives and the new selective COX-2 inhibitors. People have been looking with greater intensity at the role of COX-2 and COX-1 in various tissue functions. There is differential function relating to these two enzymes that control the regulation of conversion of arachidonic acid into various 2-series prostanoids, based upon tissue activity. One cannot assume that the conversion of arachidonic acid into proinflammatory prostaglandins like PGE-2 occurs at the same rate in all tissues. In fact, there is differentiation between a platelet, a GI mucosal cell, a coronary artery cell, or a myocyte in the effects of selective COX-2 inhibitors. COX-1 and COX-2 have different activities. One is inducible (COX-2) and the other constitutive (COX-1). We call COX-1 a housekeeping enzyme, but COX-2 can play an important role, as well; for instance, in the endothelium, it appears to have a partly housekeeping function. Excessive suppression of its activity may have deleterious effects because its function is necessary for the health of the endothelium. In the endothelium, COX-2 produces the conversion of arachidonic acid into prostacyclin. Prostacyclin, when secreted by the endothelium, is an anti-platelet adhesion agent that balances against thromboxane A-2, which is produced by the platelet as a consequence of COX-2 conversion of arachidonic acid. There is a pro-platelet aggregation effect from the production of thromboxane A-2, and there is an anti-aggregation effect by the production of prostacyclin by the vascular endothelium. The balance of those two gives rise to proper clotting control. If there is a reduction in endothelial COX-2 production by excessive blocking, it has potential for shifting the equilibrium between clotting and non-clotting in an untoward way. That leads to a risk of thrombosis because thromboxane production precedes or exceeds that of prostacyclin. That has been the emerging model about some of the potential risks of excessively suppressing COX-2 in a non-specific way. That leads us to a recent article in the Journal of the American Medical Association titled “A Polymorphism in the Cyclooxygenase 2 Gene as an Inherited Protective Factor Against Myocardial Infarction and Stroke.”[3] This is an interesting paper that picks up on the theme of endothelial COX-2 activity. In this study, investigators looked at myocardial infarction (MI) and ischemic stroke, thought to be caused by matrix degradation by metalloproteinases, leading to rupture of the atherosclerotic plaque, the so-called unstable plaque. Production of macrophage metalloproteinase is induced by prostaglandin E-2, which is due to COX-2 activity. The authors investigated the relationship between COX-2 polymorphisms and the risk of MI and stroke, specifically the 765G®C polymorphism of the COX-2 gene, and whether it had any relationship to clinically evident plaque rupture. The study took place between 2002 and 2003 with 864 patients having a first MI or atherothrombotic ischemic stroke, and 864 hospitalized control patients matched for age, sex, body mass index, smoking, hypertension, hypercholesterolemia, and diabetes. The 765G®C variant of the COX gene was genotyped. In this study, markers such as COX-2, MMP-2, and MMP-9 expression and activity in plaques and peripheral monocytes; urinary 6-keto PGF1a(marker of endothelial prostacyclin); and endothelium-dependent and -independent forearm blood flow vasodilation were also monitored. That would mean looking at some of the nitric oxide endothelial interrelationships. What did they find? They found that the prevalence of this COX-2 polymorphism was 2.41 times higher among controls than among cases. These are individuals that had a decreased risk to MI and stroke apparently as a consequence of the COX-2 genotype. Although we are looking at a genetic variant, a polymorphism, some individuals may have higher sensitivity and higher risk than others. However, we should not make the assumption that because a person has elevated COX-2 activity we want to suppress it in a way that is not specific throughout the whole of the body. This is what often happens with non-specific NSAIDS. If a person has difficulty with inflammation and pain, they may be taking a COX-inhibiting NSAID, only to find some untoward secondary side effect because of COX-2 activity in another tissue. There are many further questions about the increasing prevalence of NSAID drug use, and even the selective COX-2 inhibitors that can be raised. Granted, there are differences among different selective COX-2 inhibitors in their influence on endothelium. I believe this is still an evolving story and that we should not yet jump to any conclusions. Let me move from that to the evolving story of cardiovascular risk associated with metabolic syndrome (syndrome X), which is characterized by glucose intolerance, insulin resistance, and hyperinsulinemia. Metabolic syndrome is another extraordinarily interesting, evolving story that Dr. Gerald Reaven brought to our attention some 15 or 20 years ago, but it has picked up steam and yielded greater understanding over the past five years. In looking at glucose metabolism and its relationship to coronary heart disease (CHD), we find that the glucose tolerance test (used as the sine quo non for determining difficulties in glucose removal and transport), may have some difficulties in its specificity of determining individuals who have dysinsulinism and increasing risk to CHD. Why do I say that? This is discussed in a recent paper in the Journal of the American Medical Association titled “Glucose Metabolism and Coronary Heart Disease in Patients With Normal Glucose Tolerance.”[4] There are several prospective studies that have shown a significant correlation between glucose metabolism and atherosclerosis in patients without diabetes, but differences in parameters of glucose metabolism among the various degrees of coronary artery disease (CAD) have not been specifically evaluated. In this paper, investigators were trying to find a marker that could clinically evaluate those individuals who had normal blood sugar levels, but who were at increasing risk to CHD as a consequence of dysinsulinism. A cross sectional study was conducted in 234 men, mean age of about 56 years, with normal glucose tolerance and suspected CHD, who were admitted to a medical center for coronary angiography from Jan 1 through June 30, 2001. Glucose and metabolic factors were determined, as well as the extent of atherosclerosis by coronary angiography. The blood chemical factors to evaluate glucose metabolism included fasting and postload (postprandial) glucose and insulin (the glucose tolerance and insulin tolerance tests), glycosylated hemoglobin (HbA1c), and lipids, as well as insulin resistance measured by homeostasis model assessment method (HOMA). Patients were divided into four groups based on coronary angiography—no significant stenosis, 1-vessel disease, 2-vessel disease, and 3-vessel disease. Simple correlation analysis showed that the factors correlated with the extent of atherosclerosis were levels of postload glucose, postload insulin, and fasting insulin, as well as HOMA. Multiple stepwise regression analysis suggested that the factors independently associated with the number of stenosed coronary arteries were levels of postload plasma glucose, postload insulin, and fasting insulin, as well as HOMA. For patients with normal glucose tolerance and different extents of atherosclerotic disease, postload glycemia and HbA1C levels were not equally distributed but were significantly higher in those with more severe disease, suggesting that the glycemic milieu correlates with the cardiovascular disease risk according to a linear model, with increasing dysinsulinism associated with increasing cardiovascular disease risk. It was graded in its effect. There was not only a grading effect of insulin and glucose as it relates to diabetes risk, but there was a gradient risk of insulin and glucose correlated to CHD and stroke risk. These are very important variables when we are clinically evaluating patients, looking at their fasting blood sugar or even their two-hour postprandial blood glucose after an oral glucose load. We may be better off looking at postprandial insulin levels, as well as HbA1C. Recall that we used to feel that HbA1C was only useful for monitoring diabetics to follow their level of control, and anything above 8 or 9 percent of total hemoglobin as A1C would be clinically concerning. Now, we start to see a gradient effect of HbA1C, starting at about 5.5 percent and on up into the abnormal range (above 9 percent), with increasing relative risk to CAD and to glucose dysfunction and insulin signaling problems. The ways we have been assessing glucose tolerance historically have been limited in their specificity and sensitivity to determining risks to CAD that have to do with altered insulin signaling. What does one do from a clinical perspective, once these conditions have been identified? In the early stages, with modest elevations of HbA1C, for instance in the 6.5 percent range, and there is some modest postprandial elevation of insulin after a 50 gram glucose load, that patient is at risk. He/she has a fasting triglycerides-to-HDL ratio that is, say 5.5 to 6, so that is also elevated—another indicator of metabolic syndrome. And let us say the patient has some degree of visceral adiposity—the waist-to-hip ratio is elevated; perhaps they have an increased waist measurement, which is another indicator of insulin resistance and hyperinsulinemia. Now, what do we do? The patient is probably not yet a candidate for medication, so we might first try diet and lifestyle intervention. One of the principal ways for modifying that individual’s diet is with a low-glycemic-index diet to try to lower the overall glycemic response of the diet, and time-release their carbohydrate and glucose to the bloodstream to better regulate the release and activity of insulin in peripheral cell stimulation of glucose uptake. The glycemic index remains a very promising indicator. We were fortunate at the 11thInternational Symposium on Functional Medicine to have one of the co-discoverers of the glycemic index, Dr. David Jenkins, from the University of Toronto School of Medicine. Dr. Jenkins provided an eloquent presentation on the historical development and application of the glycemic index and its relationship to the high-complex carbohydrate/high-fiber diet for improving insulin sensitivity and glucose transport. In some quarters, the glycemic index and the glycemic load are still quite controversial. Controversy regarding application of the glycemic index in the management of diabetes was recently re-ignited with the publication of a positive meta-analysis on low glycemic index interventions in diabetics in the journal, Diabetes Care, by Brand-Miller and co-workers, and the negative editorial it received from Franz, the past co-chair of the American Diabetes Association working group on nutrition recommendations.[5] The controversy continues regarding the implications and integration of glycemic index and glycemic load concept into clinical nutrition and medicine. It has been heavily debated since 1981 when Dr. Jenkins and his co-workers first discussed it. The debate centers on the importance of carbohydrate quality versus quantity in medical nutrition therapy. Often, we go astray by talking just generically about carbohydrate, protein, and fat, rather than talking about each type. Carbohydrate can either be high glycemic index or low glycemic index, depending upon its composition, form, and physical characteristics. If it is a component of highly unrefined roughage, including grains, it is generally low glycemic index. If it is very highly purified starch, it can be higher glycemic index. For instance, a potato, once mashed or fried, becomes a source of higher glycemic index than a baked potato. Rather than just talking about carbohydrate, we need to talk about the glycemic index of specific foods, and the total glycemic load that carbohydrate contributes to the daily diet. In a recent issue of the Journal of the American College of Nutrition, there was an interesting commentary on the clinical application of glycemic index.[6] This commentary examined various recommendations from different groups on the management of diabetes, glucose intolerance, and hyperinsulinemia, with regard to carbohydrate, fat, protein, and sugar intake. In none of the recommendations did they talk about glycemic index. The American Diabetes Association, for instance, has no recommendations about the glycemic index. Some other groups, such as the Canadian Diabetes Association, do recommend a lower glycemic index diet, although they do not specify how that is to be achieved. The European Association for the Study of Diabetes has a fairly strong position on the low glycemic index component, and they define it more rigorously as it relates to its inclusion in the dietary management of diabetics. What are the arguments for and against the inclusion of the glycemic index? It seems to be a cut-and-dried thing to most of us, but then controversies can be continued for decades. What are the arguments for it? Glycemic index is a robust measurement. There is some variability in how food pertains to overall glycemic contribution to the diet versus its stand-alone glycemic index. That is why we often talk about the glycemic load of the total diet, not just the glycemic index of a food. Glycemic index is a physiological measurement. It therefore has some important values to correlate with the area under the curve of blood sugar after eating. Glycemic index of single foods has been shown to apply to mixed meals, and pooled glycemic index values of single foods are strongly correlated with the relative glycemic responses to mixed meals and can accurately predict the effects of mixed diets on glycemic control. Glycemic index is an easy concept to use, and can be employed by people who are not nutritional professionals. It has clinical utility because it correlates with HbA1C, fructosamine, fasting blood sugar, and fasting postprandial insulin levels. Those are all arguments for the glycemic index. What are the arguments against the glycemic index? People might say there is too much variability in the glycemic index. They might say that its calculation ignores glucose values below the fasting baseline, which is based on measurement of postprandial glucose over only two to three hours. They might say there are interactions among carbohydrate and other food factors, such as protein, fat, fiber, and the food form processing and preparation that complicate the accurate predictions of the glycemic response because of the way the food has been consumed in conjunction with the total meal. Last, criticisms of the glycemic index have shown that people feel there have not been enough randomized, clinical control data to make definitive clinical recommendations about how to apply the glycemic index of a food and appropriate cut-offs for what is high and what is low. My position, in light of all the literature, is in support of the glycemic load concept as being a good clinical indicator for doing diet evaluation and ultimate diet prescriptions for individuals with dysglycemia and dysinsulinism, and increasing relative risk to CAD and diabetes. From many papers published over the past few years, it is now recognized that this may be the best clinical tool to apply to the construction of diets that will lower glycemic load and for the reduction of HbA1C, reduction of postprandial insulin, and improved insulin signaling. If we look at how carbohydrate connects to other factors in the diet—protein and fat, for instance—we talk about monounsaturates like oleic acid and polyunsaturates, and the oil component of the diet being much more favorable than long-chain fatty acids that are saturated in nature. We talk about the effects of vegetable proteins, particularly soy protein, on improvement of insulin sensitivity and insulin signaling. There is some obvious difference among different types of protein and how they influence insulin. We should not say that protein is non-insulinogenic. We have seen a number of papers published over the past few years that clearly identify that certain dietary protein sources, including even beef protein, at higher levels, will increase plasma glucose and plasma insulin levels. Therefore, we cannot say carbohydrate is uniquely glucogenic and protein is not. Again, it depends on the relative amount and type of protein, and the physiology of the individual. We can say generally, however, that soy protein has a salutary or be neficial effect on stabilizing insulin. It is possible that the isoflavones present in soy are participants in the signaling process through the effect they have on gene expression and protein tyrosine kinase activities, which may be interrelated with insulin signaling and the phosphatidylinositide pathway that modulates glucose transport. In a recent paper published in the Journal of the American College of Nutrition, it was indicated that dietary intake of soy protein and isoflavones was demonstrated to be associated with lowered CVD risk factors in high-risk, middle-age men in Scotland.[7] When the glycohemoglobin levels were examined for the men on the soy protein-enriched diets, they had lower glucose versus the baseline dietary run-in. I think we ought to be examining the type, as well as the magnitude of protein, the type and the magnitude of fat, and the type and magnitude of carbohydrate when doing dietary prescriptions, to establish total glycemic load for individuals with dysinsulinism. Mild Hyperhomocysteinemia Induced by Diets Rich in Methionine or Deficient in Folate Promotes Early Atherosclerotic Inflammatory Processes Let us not forget about the hyperhomocysteinemia that may result from high protein diets rich in the sulfur amino acids. That is something often overlooked as another potential indicator of vascular risk. When one is eating a very high protein diet, particularly an animal protein diet, which is rich in sulfur-containing amino acids, cysteine and methionine, one is activating the transsulfuration pathway which then engages the metabolism through homocysteine, leading to a need for proper homocysteine control. If one has certain types of polymorphisms or nutrient insufficiencies with B6, B12, or folic acid, it might result in poor metabolism of homocysteine. Increased homocysteine could be associated with increased vascular risk. In animal studies, even mild hyperhomocysteinemia induced by feeding diets rich in methionine, or concomitantly, insufficient in folate, has been found to promote early atherosclerotic inflammatory processes. I am now citing from a recent paper published in the Journal of Nutrition.[8] That is obviously another variable that we need to take into account when looking at dietary prescriptions. Often, people are advised to increase their protein and decrease their carbohydrate. In fact, they may be told that carbohydrate is bad, to eliminate it, and fill in the gap with more protein. If that person is consuming more protein than the homocysteine cycle can manage, their homocysteine levels can go up and lead to an increased risk to heart disease by a non-lipid mechanism. It is a homocysteine mechanism. I want to make sure we are all on the same page. We have a lipid hypothesis that relates to coronary atherosclerosis. We have a homocysteine hypothesis that relates to coronary atherosclerosis and its association with high protein diets and low folic acid status. We have a carbohydrate association that we have talked about with regard to hyperinsulinemia and the difficulties that it promotes in endothelial function—ADMA increases, alteration in endothelium nitric oxide production, and coronary injury through oxidative stress mechanisms. All of those are at play, and to try to take a simple-minded approach by suggesting that one increase protein and cut out carbohydrate, belies the range of important information that has been developed in the research and clinical field over the past decade. Again, it is a matter of balance—moderation, variety, color in food, minimally processed food, proper nutrient density with regard to vitamins and minerals, and not swinging the pendulum so far as to become a carnivore, not even looking at the source of the protein which may also have some secondary effects through high saturated fat intake. Dietary Omega 3 Fatty Acids We are talking about fats and I mentioned the monounsaturated oleic acid component. There is also the omega 3 polyunsaturated fatty acid component. There are many benefits of omega 3 fatty acids with regard to vascular function beyond those originally described in the literature. The first reports in the 1980s outlined the paradoxical situation of supplemental eicosapentaenoic acid (EPA) or fish oil supplements, resulting in lowered blood triglycerides. How does giving a triglyceride, a fat, lower a fat in the blood? It seems paradoxical. But over the ensuing 20 years, considerable research has identified the mechanism by which this can occur. It is now recognized that the omega 3 fatty acids have a remarkable nutrigenomic effect on modulating gene response elements associated with fatty acid metabolism, insulin sensitivity, and glucose transport. These are principally through things such as the peroxisome-proliferated activated receptor (PPAR) family where there are agonists for PPARgactivity. We have begun to understand that these fats have cell signaling capabilities. When we eat more omega 3 fatty acids, we are delivering dietary signals that modify gene expression patterns and cell physiological function. Some of the other things now being observed for omega 3 fatty acids have to do with the stability of plaque. A study was published in the Lancet two years ago that we reviewed in a previous issue of FMU, indicating that individuals who supplement their diets with omega 3 fatty acids, even if they had plaque, were stable rather than unstable, which is associated with high saturated fat intake diets. That is another benefit. A more recent report appeared in the Lancet titled “Immediate effects of n-3 fatty acid infusion on the induction of sustained ventricular tachycardia.”[9] This is an interesting paper. The investigators showed that increased consumption of omega 3 fatty acids reduced mortality from sudden coronary death, indicating that these fatty acids have antiarrhythmic effects. In this study, researchers did electrophysiological testing in 10 patients with implanted cardioverter defibrillators who were at high risk to sudden cardiac death. To assess their immediate effects on the induction of sustained ventricular tachycardia, n-3 fatty acids were infused. Such tachycardia was not induced in five of seven patients. The findings show that infusion of n-3 polyunsaturated fatty acids does not induce arrhythmia, but did result in a reduction of sustained ventricular tachycardia in some patients. That would suggest that n-3 fatty acids have some effect on cell pacing in the cardiocyte. In the editorial that follows this paper, the investigators state: “Observational and trial data have accumulated to support the hypothesis that increased consumption of the long-chain n-3 polyunsaturated fatty acids found in fish, especially EPA and DPA acids, lower the risk of dying from coronary heart disease, and interest has focused on the antiarrhythmic properties of these fatty acids. In the late 1980s, McClennan et al. were the first to show anti-arrhythmic properties associated with these fatty acids in animal models. Billman et al. confirmed and expanded on these experiments in a dog model. Further experiments reported plausible cellular mechanisms for the anti-arrhythmic effects, including modulating of sodium, potassium, and calcium channels. N-3 fatty acids might also have favorable actions on heart rate variability, and therefore could be exerting anti-arrhythmic actions through effects on the autonomic nervous system.”[10] In the DART Study, the Diet and Reinfarction Trial, published by Burr et al., just over 2000 men with a history of myocardial infarction (MI) were randomized to three dietary strategies (lowering saturated fat, increasing fiber, and increasing fatty-fish intake). There was a 29 percent reduction in total mortality in the participants who received advice to eat at least two portions of fatty fish a week, but no difference in total events for coronary heart disease because more non-fatal MIs occurred in the fish-advice group. Burr et al. suggested that fish consumption might reduce the risk of fatal arrhythmias, and therefore preferentially affect mortality after myocardial infarction. “What are the implication of these findings? As has been shown with traditional anti-arrhythmic drugs, suppression of ventricular tachycardia during electrophysiological testing does not directly translate into a survival benefit when the same drugs are administered chronically. Therefore, the implications of these data on their own are limited.”10 However, this study, in conjunction with previous experimental data provide a possible mechanism to explain the preferential benefit seen with dietary intake of n-3 fatty acids on sudden cardiac death. Currently, there are three randomized trials on the effect of fish oil supplements on recurrent episodes of ventricular tachycardia and/or fibrillation in patients with implantable cardioverter defibrillators. Results of these trials will help us to understand more about the anti-arrhythmic properties of n-3 fatty acids. Differential EPA Elevations and Altered Cardiovascular Disease Risk Factor Responses After Supplementation With DHA in Postmenopausal Women Receiving and Not Receiving Hormone Replacement Therapy DHA has triacylglycerol-lowering potential, but it appears that it is less important than EPA in cardiac rhythm function. Differential EPA is associated with reduced cardiovascular disease risk and sudden coronary death. This was recently studied in postmenopausal women receiving and not receiving hormone replacement therapy (HRT).[11] Investigators studied the effects of supplementation with DHA (free of EPA) on the resulting elevation in EPA and on selected cardiovascular disease risk factors. In all women, DHA supplementation was associated with significant changes. DHA supplementation resulted in a 45 percent lower net increase in EPA and a 42 percent lower estimated percentage retroconversion of DHA to EPA in women receiving than in those not receiving HRT. It may be that giving combinations of EPA and DHA in a highly purified state, to get the benefits of both of these long-chain, omega 3 fatty acids, would be desirable. The doses we are talking about are in the range of 3 to 6 grams per days of the EPA/DHA combination, EPA appearing to have more of an antiarrhythmic effect. The story continues and we have a lot more to learn about the omega 3 fatty acids. As we move toward glycemic diets and toward cardiovascular risk reduction, we need to make sure we are getting adequate levels of pure EPA/DHA through either dietary cold-water fish or dietary supplements. It is time for our Clinician/Researcher of the Month interview.

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INTERVIEW TRANSCRIPT

RESEARCHER OF THE MONTH Robert P. Heaney, MD John A. Creighton University Professor Creighton University Omaha, NE 68178 JB: It’s time for our Clinician/Researcher of the Month. We are privileged this month to interview a professional whose work I have admired for the 30 years I have been in this field-Dr. Robert Heaney from Creighton University in Omaha, Nebraska. Dr. Heaney was Chairman of the Department of Medicine at Creighton University, as well as Head, Section of Endocrinology & Metabolism, and Vice President for Health Sciences. He is currently the John A. Creighton University Professor, a position he has held since 1984. His publication record is extraordinary. He has covered an entire horizon in his research, and has been one of the premier leaders in the area of bone mineral metabolism in helping us to understand the complicated interrelationship of diet, lifestyle, vitamin nutriture, and osteoporosis and bone status. It is with great privilege that we welcome you to FMU, Dr. Heaney. Because your work has spanned so many years and so many different areas, I would like to ask what got you started down your path as a medical doctor in the area of clinical nutrition? RH: I started studying the problem of osteoporosis. As I looked at the cases we had, I saw that I was studying the barn after the horse had gone. It dawned on me that we needed to look at what was going on in the physiology of women before they became osteoporotic, rather than after they were already in that condition. I cast my net broadly. I was fortunate enough to get long-running support from the National Institutes of Health (NIH), and looked at all kinds of things that were happening to women in mid-life, starting before menopause, and following them longitudinally for what has turned out to be 30+ years. What I saw was that calcium intake made a difference. I hadn’t originally believed that, but my own data convinced me that if you had a high calcium intake, you were more likely to be in bone balance, not losing bone. If you had a low calcium intake, you were more likely to be losing bone, and that you could change one into the other simply by improving people’s calcium intake. I came into clinical nutrition through the back door. I started my medical life as an endocrinology researcher, looking at the issues surrounding bone metabolism and bone turnover, and why bone mass might go up or down. Most of the early bone research in medicine, from Fuller Albright on was done by endocrinologists, so it was a natural entry point into the topic area. Subsequently, I focused much more on clinical nutrition than I have on formal endocrinology in the past few years. JB: Going back to some of your earlier work in the late 1950s and early 1960s, did you have any idea at that point how this field would evolve? Did you have a sense of the vitamin D metabolism connection and the thyroid/parathyroid, hepatic hydroxylation, and all the things that would open up in this field? Measurement of 25-hydroxyvitamin D Levels As a Functional Status Indicator RH: 25-hydroxyvitamin D hadn’t even been discovered then. That didn’t come on board until the late 1960s and early 1970s, if I recall correctly. Vitamin D was a great sleeper. Nobody knew anything about vitamin D. I had the privilege of serving on the Calcium and Related Nutrients Panel of the Food &amp; Nutrition Board that released the DRIs for calcium and related nutrients in 1997. When we did the chapter on vitamin D in 1997, we knew almost nothing more than we had known in 1936. The one thing we could be certain of was that blood 25-hydroxyvitamin D, at that point, was the functional status indicator. This was how you could tell whether a patient had enough vitamin D, or not. We didn’t know in 1997, however, how much was enough. We just knew that if you had a higher blood 25-hydroxyvitamin D level, you would be more likely to be vitamin D replete, but we didn’t have a number that we could assign to where the cutoff level is between adequacy and deficiency. There has been a tremendous amount of vitamin D work that has come on the scene in the last nine or ten years. For all practical purposes, we’ve learned more about vitamin D in the past few years than in all the rest of vitamin D’s history, going all the way back to the 19th century. We now have good reason to believe that at least three fourths, and maybe 90 percent, of the vitamin D our body uses every day has nothing to do with calcium metabolism whatsoever, or bone, for that matter. Vitamin D is involved in so many other tissues, so many other systems, and probably in many other diseases. We have simply been unaware of it because it took so long for the effects to become manifest that we couldn’t connect cause with effect. Long- Versus Short-Latency Nutritional Deficiencies JB: One of the more eloquent and important citations I have recently read, is your article in the American Journal of Clinical Nutrition, which discusses long-latency deficiency disease versus short-latency deficiency disease.[12] It’s an interesting concept for many clinicians that we probably haven’t fully explored, that being things that may show up soon as a consequence of insufficiency of a specific nutrient, and things that may take some period of time clinically to appear. Would you help us to understand your concepts of long- versus short-latency deficiencies? RH: It’s useful, I think, to remember back about 100 years. Obviously, we can’t do this on personal memory, but at least we have history, so we know what’s going on. About 100 years ago, nutritional science was born. At that time, the prevailing conception in medicine was that all disease was caused by external invaders, either germs or toxins of some sort. The idea that not eating something could make you sick was absolutely foreign to medicine and to medical science. The early work with nutritional science really had to swim upstream, because it didn’t make sense to anybody that not eating something could make you sick. Eating something could make you sick if it poisoned you somehow, but not eating something? How could that be? The whole idea of essential nutrients didn’t exist 100 years ago. Some of the earliest work was done by Christian Eijkman, at that time a young physician in the Dutch East India company in the Indies, confronting the problem of beri-beri in tropical workers. He noted that when he fed chickens the same rice that was fed to the plantation workers, they got a syndrome that was very much like human beri-beri. He also noted that if he fed rice polishings to the chickens, it seemed to heal or prevent the problem, and he fed that to the workers and they got over the beri-beri, too. That was really the first proper nutritional experiment where a food was associated with a disease, or the absence thereof. The paradigm of external invader was so powerful that when he published that work, he explained the finding, not in nutritional terms, but said that he figured the rice must carry a microbe with it, and that the rice polishings had a natural antidote to the microbe. If you just fed the polished rice to people, you were feeding them a germ that made them sick. And if you fed the rice polishings back with the polished rice, then you fed a natural antidote and they didn’t get sick anymore. And even that first nutritional experiment was misinterpreted. It was interpreted in view of the prevailing paradigm of disease caused by external invaders. Because of EV McCollum and a number of other workers, particularly in this country, it was soon understood that there were essential constituents of food that were vital for health and for life. By the first decades of the 20th entury, we had begun to move into an era that saw the birth of nutrition. But the connection between cause (taking something out of the diet) and the development of illness, or symptoms, had to be short. We couldn’t have seen the connection otherwise. If it took 20 years to develop beri-beri, Eijkman never could have seen the effect, and we couldn’t have done it in humans. We didn’t have the conceptual models to work with that kind of a problem. History of Vitamin D Research Nutrition has been working for the last 100 years with the short-latency deficiency disease model. This is how it is with nutrition. The short-latency deficiency disease for vitamin D was rickets, or osteomalacia. The RDA for vitamin D is pegged to the amount you have to take in order to ensure that you’re not going to get rickets or osteomalacia. The field considered the deficiency disease for vitamin D was, as I say, rickets or osteomalacia. But, because of the implicit and unspoken assumption that there was one disease per nutrient, what happened if you didn’t get quite enough vitamin D, but didn’t have rickets? We coined a funny term for that one. We called it insufficiency. It was as if we said to ourselves, well you can’t be deficient because you don’t have rickets, but you obviously are not getting enough vitamin D to absorb all the calcium your body needs, so we’ll call it something else. We’ll call that insufficiency. The literature over the last 10 or 15 years in the vitamin D field is filled with the term “insufficiency,” as contrasted with normalcy, which would be a blood vitamin D at a higher level. That’s the background to the short- and long-latency deficiency problem. The long-latency deficiency disease related to bone and calcium for vitamin D would be osteoporosis. I have to confess that when I was teaching this to medical students back in the 1960s and 1970s, I made a clear distinction. I said that vitamin D has to do with rickets; it has nothing to do with osteoporosis. And I’m sure I graded some papers wrong which said to the contrary, but it turns out I was the one who was wrong; the whole field was wrong. The milder degrees of vitamin D deficiency actually produce osteoporosis; they don’t produce osteomalacia. Osteomalacia is a manifestation of the most severe degree of vitamin D deficiency, but before you get there, you go through a stage of osteoporosis-at least, most people do. The problem with the long-latency deficiency diseases is there is not a single cause for them. There are a lot of ways to get osteoporosis. There are a lot of ways to get cardiovascular disease. There are a lot of ways to get brain degeneration. Nutrition figures into some of those ways, and the real challenge confronting nutritional science in its second century of existence, is to try to figure out the right kinds of scientific approaches to unravel the role of nutrition in these chronic diseases. We run the risk of a pendulum swing, with too much enthusiasm and people thinking they can prevent all chronic disease, or that they can cure all chronic disease with megavitamin therapy. That’s clearly not right, and it leads to all kinds of mistakes and terrible problems. At the same time, we don’t want to err on the side of such extreme caution that we deprive people of some probably correct insights. For instance, in our osteoporosis clinic here at Creighton, we give everybody 1000 IUs of vitamin D per day. We used to test them individually, but they were all low, and so we ended up supplementing everybody anyhow. We find that many of them may require 2000 IUs per day. That’s above the RDA figure for vitamin D, but we’ve been able to show that the RDA barely budges the blood 25-hydroxyvitamin D level. That’s just not enough for us to meet our respective needs. I’m not suggesting that all of our patients with osteoporosis are in that state because they haven’t had enough vitamin D. It’s just that we can’t treat them adequately if we don’t insure that they have adequate vitamin D. JB: This is obviously a fascinating paradigm, meaning it’s a fundamental thought process shift. I know you have some thoughts about how one would go about experimentally answering some of these questions of the long-latency deficiencies, or insufficiencies. These are obviously methodologically more complicated and often, in the development of any field (as David Deusch talks about the evolution of medicine in his book, The Fabric of Reality), it is still pretty much in its early stages as a true science. It’s more of a medi-science, an observational science. How do we go about asking methodological questions about the longer-latency deficiency disorders? RH: I’ll take a page from E.V. McCollum’s book. I mean “book” metaphorically; he didn’t actually write one. One hundred years ago, or less, when he was working as a young PhD scientist at the University of Wisconsin, he was concerned with the health of dairy cows, which is obviously a matter that Wisconsin would be interested in. He realized that dairy cows had a relatively long life span, and that he’d never find things out quickly enough if it took a while for them to develop, so he moved to laboratory rats. Laboratory rats didn’t exist back then; they had to be created, and he didn’t have access to any at the University of Wisconsin, so he set traps in barns and caught wild rats and started to work with them. But they were not sufficiently docile, and he ultimately found a pet supplier in Chicago who could give him some laboratory rats that were much easier to work with. And, of course, now we know that rats and mice have much shorter life spans. A surprising amount of what we know about nutrition has actually been learned in these laboratory animals, simply because you can compress so much of a lifespan within a reasonable period of the experimental life of the investigator. I’m not suggesting that is the full answer, but I think we have to think in those kinds of terms. How can we find models that play out their effects in a period of weeks or months, rather than years and decades? That’s step number one. Individually, it’s going to depend upon the nutrients. For instance, in the paper that you referred to in the American Journal of Clinical Nutrition last fall, I speak specifically about calcium, phosphorus, and folic acid. But I could have chosen vitamin K; I could have chosen vitamin E. There are quite a number of other nutrients that have effects on multiple systems, where nutritional science has, nevertheless, tended to focus on a single one. What do we think of with vitamin K? We think of blood clotting. What do we think of with respect to folic acid? Well, the classical issue was megaloblastic anemia. Subsequently, we’ve learned that it’s very important for neural tube defects in early stages of embryonic development. But even then, nutritional science had trouble absorbing that. They figured that was a unique pharmacologic effect that didn’t really have anything to do with the regular role of folic acid in ordinary, everyday nutrition. We now know that’s wrong, but this is an example of how we had trouble assimilating this new information that didn’t fit in this one disease/one nutrient model system that had so trapped our thought processes. JB: Let’s go back to an area in which you are a world expert, that being osteoporosis, and take a look at it as a disease, and as something that can be clinically defined. It’s related somehow to osteogenesis/osteolysis equilibrium such that one is sustaining a net loss of calcium and a net loss of protein in the framework of bone. What has been the changing thought about the dynamics that relate to that condition, given the long- versus short-latency concept? There is now data saying that loss of calcium from bone is not directly related to fracture rate, so there may be other mitigating factors that we need to pay very important attention to. Excessive Bone Remodeling RH: That’s exactly right. We now recognize that the vigorousness of the turnover, or remodeling, of bone may be a more important fragility factor than the amount of bone you have. Obviously, if you have very little bone, you’re going to have a flimsy skeleton, no matter what. Bone mass remains important, but a high rate of turnover also creates fragility in its own right. This is a very nice example of the fact that we have to reconceptualize this disease, in which decreased bone mass is actually a part of the name of the disorder itself. Osteoporosis, of course, means porous bones. The clear idea there was that you have moth-eaten, or inadequately mineralized, or incomplete bone. That was so intuitively obvious that it made very good sense and has had a century-long existence. Now that we’re able to measure bone mass with some precision, we find that it does, in fact, predict fracture with some degree of accuracy. If you have low bone mass, you are much more likely to fracture than if you have high bone mass. But within any given mass category, some people are fracturing and some aren’t. We now recognize that the difference there is due to the fact that some have high remodeling rates, and others low remodeling rates. Probably the major reason the new drugs, the new bone-active agents work, is that they slow down excessive remodeling. When you go on a bisphosphonate drug, such as alendronate or risedronate, for example, you begin to get a reduction in your fracture risk that begins essentially at day one of your taking the medication. And by three to six months, you’ve probably achieved the maximum benefit. Now, that doesn’t mean you shouldn’t keep taking the drug, because if you stop, then your fracture risk will go back up. But you haven’t changed bone mass very much in that short period of time, probably trivially, as a matter of fact. What’s really happened is that you’ve shifted the basic relationship between bone mass and fragility by cutting out the weak points where you’ve been constantly remodeling. Think about it as if you were remodeling the side of your house. You tend to do it a piece at a time. If you were to take the whole side out, the house might fall down, because you’d be taking out some essential structural supports. Well, too much remodeling in the skeleton is a source of great fragility for it. It’s important that we hold remodeling in check. Treatment of Bone Loss We now have reason to believe that the primitive human skeleton remodeling rate, under the conditions in which we evolved (high calcium intake, high vitamin D status, and a lot of exercise/physical activity), would have been one third or less of what we typically take for granted. We think it’s normal, but we’re probably all living on the precipice of osteoporotic fragility, simply because we all have such high remodeling rates. One of the challenges in terms of this long-latency deficiency disease is to try to figure out why the remodeling rate is so high, because that is relatively easy to fix. Bisphosphonates will reduce a postmenopausal woman’s remodeling rate down into a healthy premenopausal normal rate. We didn’t realize that was what it was doing. We invented the bisphosphonates to slow down bone loss, and they do that. But they do a lot more than that; we just didn’t know it at the outset. JB: I’d like to propose a thought for your response. We are starting to see an increasing body of literature discussing remodeling rates as a manifestation, in part, of activation by signaling molecules like TNFa and other inflammatory mediators, suggesting that perhaps part of this problem is inflammatory-mediated. Then we get to the 1,25-hydroxyvitamin D question as an immune-modulating hormone. From your position of understanding, do you feel there is something about inflammation at the bone remodeling unit that participates in the high remodeling rate? 1-25-Dihydroxyvitamin D as An Immune Modulator RH: Circumstantial evidence demonstrates that there is something there, but we don’t yet have proof of the concept that we’d like to have. It’s a hypothesis that’s worth testing. Yes, it needs to be looked at. With respect to the 1,25-hydroxyvitamin D as an immune modulator, the key point that we are just now beginning to understand, and that many people haven’t probably adequately grasped, is that the 1,25-hydroxyvitamin D that circulates in our blood is as a result of a high level of parathyroid hormone secretion. That’s necessary for calcium absorption and for bone health. That’s the classical vitamin D function that we’ve known about for years, although we continue to work out the details. But it’s the basic vitamin D/calcium bone health function. Widespread Variation in the Absorption Rate of Different Calcium Supplements What’s important with respect to immune modulation, multiple sclerosis (MS), and so many other disorders, is not the circulating level of 1,25-dihydroxyvitamin D, but the circulating level of 25-hydroxyvitamin D, the thing that the Food & Nutrition Board recognizes as the functional status indicator for vitamin D. How this plays a role is the following. If there is a high blood level of 25-hydroxyvitamin D, then the immune cells in the central nervous system-the epithelium of the prostate, breast, colon, and a whole host of other tissues that have vitamin D receptors-are able to see and work with a high blood level of 25-hydroxyvitamin D, which they use internally to make their own 1,25-hydroxyvitamin D. They make their own 1,25-dihydroxyvitamin D. They don’t depend on what’s circulating in the serum. And they probably make a lot more than they could get out of the serum under any circumstances. That’s why I say that probably three fourths to 90 percent of the vitamin D we use every day, is being used for other functions. But it’s being used through the mediation of 25-hydroxyvitamin D, which is the critical basis for all vitamin D function. That’s where vitamin D may be important, for instance, in the prevention of MS. There’s a very clear association between MS and serum 25-hydroxyvitamin D. If you have a high 25-hydroxyvitamin D level, you have less MS and vice versa. The same thing is true with prostate cancer. JB: Once again, that certainly is a beautiful example of what you’re discussing-that it isn’t just a one nutrient/one disease connection. These are very important biomolecules that have pleotrophic effects, I guess we would say. I’d like to go back to a couple of simple questions that come out of your extensive research. A lot of clinicians are interested in the work as it pertains to nutrition and the prevention of osteoporosis. Can we get into the amount of calcium, the form of calcium, the amount of vitamin D, and the form of vitamin D? There is a whole range of different calcium sources, with the highest percentage calcium being that of calcium carbonate (though it’s fairly insoluble), up to more soluble forms like calcium citrate. I know you’ve researched the different forms of calcium. Would you give us some insight as to the calcium/vitamin D composition and amount question? Foods as the Primary Source of Calcium RH: I’ve looked fairly extensively at various calcium sources. I’ve not done it exhaustively, simply because there isn’t any way to get financial support for a really exhaustive survey of the field. And I do think something of that sort needs to be done, because the FDA regulates calcium supplements as foods, and there aren’t any efficacy standards for foods. How do you tell how efficacious broccoli would be, for instance? The consumer naturally thinks that two calcium sources are going to be the same, but I can tell you they are not. Solubility, it turns out, doesn’t make all that much difference. The absorption of calcium is typically from a neutral, or slightly alkaline, medium in the small intestine, anyway. Acid solubility is really not particularly important, and we’ve shown this. Different substances varying over seven orders of magnitude (10 million times more soluble than others), are not absorbed any better than one or another. The intestine is smart enough to know how to do something that we haven’t figured out how to do in a chemistry laboratory yet. Absorption is OK from calcium carbonate. Calcium phosphate has nearly the same calcium content as does calcium carbonate. That’s also a good source. But really, the best source is food. I have to stress this over and over again. Dairy calcium, for instance, is much more preferred over supplements. I realize that not everybody is going to get all the calcium they need from food sources, but they really have to start there. Why do I say that? It’s not just a question of bioavailability. It’s that we need more nutrients than just calcium. We’ve shown, in three different cohorts of women, that people who have low calcium intakes, that is, less than two thirds of the recommended amount, which is a kind of working definition of “low,” tend to be low (less than two thirds of the recommended amount) in at least four other nutrients on top of calcium. If you take nine key nutrients in an ordinary diet, people who are low in calcium tend to be low in more than half of all the key nutrients. It’s hard to fix that with a pill. We really have to stress proper diet counseling with our patients, or get them connected with a nutrition professional who can knowledgeably help them find ways that work for them in their lives to do a better job of getting the food sources of calcium they ought to have. Having said that, what supplements are best? We need to be savvy consumers, and that’s professional consumers, as well as patient consumers. We need to ask of the calcium suppliers that they have demonstrated bioavailability of their product. If they have, you can use it with confidence. If they haven’t, I’d steer clear of it. You can’t tell from looking at them whether they’re going to be well absorbed or not, and you can’t tell from their composition. I’ve studied probably a dozen different preparations of calcium carbonate. They all look pretty much the same on the outside. Some are absorbed twice as well as others; some 2 1/2 times as well as others. The consumer is naturally thinking that if it says 500 mg per tablet, that he/she is getting 500 mg. That’s not true. We just have to hold the manufacturers to a higher standard. I’m currently working with some people at the National Osteoporosis Foundation (NOF) to see if, in view of not being able to get the FDA to create some standards, if perhaps voluntary health agencies such as NOF could do something about that, as well. Vitamin D2 versus Vitamin D3 JB: How about the vitamin D question? Is there a difference clinically between ergosterol and cholecalciferol-vitamin D2 versus D3? RH: We didn’t used to think so in humans. That’s why the units are the same. One hundred IUs of D2 is the same chemical quantity as 100 IUs of D3. But we’ve known that’s not true in experimental animals; they’re not equivalent. And for many reasons that I don’t fully understand, we just assumed that the two were equivalent in humans. We now know, when we measure the serum 25-hydroxyvitamin D response, that they’re not. I have a paper in press right now which shows that D3 may actually be up to 10 times more active than D2. The pharmaceutical preparation that’s out there, 50,000 IUs of D2, may be the equivalent of only 5 or 6,000 IUs of D3, so it’s nowhere near as much as it sounds in terms of what it will do for your body. JB: We’ve made some interesting clinical observations over the years. When therapeutic doses of up to 50,000 IUs of D2 were given to some individuals with low 25-hydroxyvitamin D3 levels in their serum, it took some time for their 25-hydroxyvitamin D3 level to come up into normal range, suggesting that there’s either an absorption problem or a biotransformation problem. Has this been something you’ve seen clinically; that these repletions don’t occur rapidly? RH: We see two things. One, even if you use pure D3 by mouth, and for experimental purposes, you can get it in essentially any size dose, but it’s not available pharmaceutically above 1000 IUs. If you use pure D3, it takes about five months to bring a normal person up to a new level where it becomes a steady state. Much of that is accomplished within the first couple of months, but you’re still rising, and it takes about five months to reach a new plateau. It’s a slow process, inherently. And that reflects the fact that the human body evolved in an equatorial environment where we got D all the time through the skin, and we were always having huge inputs. The rapidity of conversion of D3 made in the skin to 25-hydroxyvitamin D, which is what the tissues need to work with, didn’t really make any difference because it was always up there where it ought to be. But now, when we’re treating our patients with oral preparations of vitamin D, we need to understand that we won’t know what the new level is until we wait for several months. There’s a second problem, however, with D2 and that is, some of the lab assays don’t pick up 25-D2. You may be giving your patient enough D in the form of D2 to change the basic physiology that you’re trying to fix, but you won’t see any change in the blood level because the lab assay misses it. What would you see that might be indicative? Let’s say you’re treating a patient with malabsorption syndrome, with clear signs of osteomalacia, symptoms/lab changes-low serum calcium, low serum phosphorus, high PTH, high alkaline phosphatase, those things. You give the vitamin D2, the ergosterol. The PTH will drop; the alkaline phosphatase will drop; the serum phosphorus will come up, but, depending on the lab that your hospital may be using, you may see no change at all in the serum 25-D level. That’s not very helpful for the clinician. That’s a lab analysis problem, and the clinical pathologists simply need to get their act together. They need to understand that clinicians now want to know vitamin D status. Let’s get a single method that works in all hospitals that produces a number that our patients can take with them when they go from provider to provider, or from system to system, that means the same thing, the same way that serum potassium, serum sodium, or a blood glucose would. We ought to have something we can rely on and not have to worry about what lab did on this one. JB: I want to thank you very much. For our listeners, I wanted to make a parenthetical comment. You were very kind in going back historically and talking about some of the founding fathers of clinical nutrition including, obviously, Dr. E.V. McCollum. For those listeners who are not aware of this, Dr. Heaney was just granted what I think is the most prestigious award from the American Society of Clinical Nutrition in 2003-the E.V. McCollum Award. His award address was the one published in the American Journal of Clinical Nutrition that we have mentioned. Dr. Heaney, congratulations on the acknowledgment of all your years of extraordinary contributions, and thank you so much for sharing this wisdom with the listeners of FMU. RH: Thanks for your comment, and I’m pleased to be able to discuss these matters that I think are of great importance. As Dr. Heaney mentioned in his discussion, the long and short-term latency disease concept can be applied to many conditions and many different substances, or nutrients. Low intakes of both calcium and vitamin D produce not only an index of disease, but also long-latency diseases that were previously unrecognized, such as osteoporosis. Similarly, with folic acid, we are starting to see that same theme develop. Recall that a number of years ago, we interviewed Dr. John Lindenbaum, a professor of neurology, now unfortunately deceased. He talked about the long-latency disorders of sub-clinical deficiencies of vitamin B12 and folate and their relationship to dementia and cognitive impairment in the elderly, even in the absence of pernicious anemia, megaloblastic anemia, or any other hematological sign. He recommended that the only way to determine that was with metabolite studies, looking at either homocysteine or methylmalonic acid. Mechanisms of Homocysteine Toxicity on Connective Tissues: Implications for the Morbidity of Aging Implications of the folic acid story have extended into the area of osteoporosis. Plasma homocysteine is associated with decreased folate and B12 status, and it has repeatedly been identified as a strong independent risk factor for cardiovascular disease. And more and more, we are starting to see it related to osteoporosis. For example, Krumdieck and Prince have called attention to the close parallels between the hallmark manifestations of homocystinuria, with serum homocysteine concentrations typically elevated in occlusive vascular disease, osteoporosis, mental deterioration, and counterpart manifestations of normal aging, with homocysteine concentrations between 10 and 100 mm/L.[13] That is also associated with increasing incidence of occlusive vascular disease, osteoporosis, dementia, and changes in vision in the aged population. To that extent, it appears that folate and B12 insufficiency might also be long-latency disorders that might present in mid- to late-age, as well. For those of you who are long-time subscribers to FMU, you will recall that the interview with Dr. John Lindenbaum was in April 1995, some nine years ago. We discussed the concept of long-latency B12 and folate insufficiency and dementia, although he did not actually call it long latency. Dr. Heaney’s theme brings a nice definition to it. Let us begin to look at these long-latency conditions and how they relate to clinical medicine. Nutritional scientists are becoming increasingly aware of the role of nutrients in reducing disease burden of several chronic diseases. However, I think we need to start looking at more than just the short-term deficiencies, but at the long-term deficiencies, as well. How has this been regulated and ultimately codified into dietary recommendations? It is, as Dr. Heaney points out in his article in the American Journal of Clinical Nutrition, difficult to understand or justify the resistance of regulatory authorities to changes in current practices that is typified by not taking these long-latency discoveries into account. Regulatory bodies obviously cannot respond to every shift in the winds of public opinion, so caution is recommended. Nevertheless, as Dr. Heaney points out, a middle ground should be found. The manifestation and appearance of these disorders present some difficulty because of the nature of conservancy in change. Yet, another aspect of the problem is the position of nutritional policy makers that “we won’t change without proof.” This is the old burden of the double-blind, placebo-controlled, randomized trial and adequate, irrefutable scientific justification for change. The irony of that position, which seems unassailable, was captured by Walter Willett in a recent interview with Gary Taubes. Dr. Willett stated: “They say, ‘You really need a high level of proof to change the recommendations,’ which is ironic, because they never had a high level of proof to set them.”[12] What is the standard in the burden of proof when we’re already dealing on shaky science from which the recommendations were originally established? Dr. Heaney points out: “The most difficult part of the challenge, I suspect, is finding the will to settle on nutrient intake recommendations that are biologically defensible while we wait for evidence that lower intakes may be safe or higher intakes more beneficial. In many instances, because the current recommendations are based on the prevention of the index of disease only, they can no longer be said to be biologically defensible. The preagricultural human diet, insofar as it can be reconstructed, may well be a better starting point for policy. Such a diet cannot be known in detail, but as several investigators have shown, the diet probably would have had at least the following features: high protein intake, low glycemic index, high calcium intake, high folic acid intake, an alkaline ash residue, and (for reasons of latitude and skin exposure) high vitamin D input. It is in this nutritional context that human physiology evolved, and it is to this context that human physiology is adapted. The burden of proof should fall on those who say that these more natural conditions are not needed and that lower intakes are safe.”[12]

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Welcome to Functional Medicine Update for October 2004. I have the privilege of announcing the topic and dates for our 12th International Symposium on Functional Medicine, which will take place on May 24-28, 2005 at the five-star Westin Mission Hills Resort in Palm Springs, California. I have visited this facility and it is a lovely place to hold a meeting. The topic of the 2005 symposium will be, The Immune System Under Siege: New Clinical Approaches to Immunological Imbalances in the 21st Century. This topic is at the forefront of our interest because we are all concerned about infectious disease. Atherosclerosis is now being seen as an autoimmune inflammatory disease and metastatic events in cancer are related to immunological imbalances and inflammatory mediators. We are also interested in type 2 diabetes and osteoporosis and their relationship to immunological changes, and the list goes on and on. The 2005 symposium will focus on what we know about the immune system under siege from a 21st century perspective, and how we can harness new discoveries to ameliorate, manage, and prevent specific types of disorders that cut across the spectrum of immune imbalance. The program, as designed by the Curriculum Committee, and the plenary lectures and concurrent sessions associated with this topic, will give us a whole new way of looking at immune system function. It will result in more tailored evaluation tools for designing specific therapeutic intervention programs for patients based on their immunological status. You will be hearing much more about the program soon. For those of you preparing for the symposium, we will be introducing some concepts in FMU regarding immune system balance in the months before the symposium. We will also have some clinicians and researchers who will help us to better understand these topics. This month, I would like to focus on a discussion that sets the stage for much of what we will be speaking about in subsequent months regarding immune system function. It has to do with the methodology of developing evaluations and designing programs, so-called research methodology. How do we arrive at making decisions based upon the research? What is the type of research being done, knowing that the immune system is complex and that it interfaces with the outside and inside world? It is our internal defense mechanism, a translator system, taking outside information and converting it into physiological functional changes for defense of the organism. We need to know something about the complex orchestration of events occurring in the outside world and how that translates into internal physiological information, which is more than just one function occurring at a time. In fact, the more we study the immune system, the more we recognize that it is a little bit like studying particle physics. Early on, we learned that there are electrons, neutrons, and protons. We also learned that energy can travel in discrete units called photons. As particle physicists became more involved in research, they determined that there are actually subatomic particles as well, particles from which the neutrons and protons are composed. They are called bosons and fermions, the daughters and brothers of the bigger atomic particles. These are the fundamental particles that make up the nature of the universe. We have heard about these particles by other specific names, such as neutrinos and quarks, as well as other types of subatomic particles. Understanding how these particles interact helps us to better understand the physics of our universe. Let me use some examples of how complex these interactions can be. Cholesterol gallstone disease, cholelithiasis, is a condition seen with certain epidemiological relationships. In particular, overweight women frequently have this disorder, resulting in a need for surgery. The supersaturation of bile with cholesterol results in the crystallization of cholesterol into gallstones. The bile is a mixture of three components—cholesterol and its esters, bile salts, and lecithin. The lecithin and bile salts are solubilizing agents; they are amphoteric; they have detergent-like properties because they are both water-soluble and fat-soluble to some extent. They tend to emulsify fats. When bile is made up of more of these emulsifying materials—more lecithin, more bile salts, and less cholesterol—there is a soluble matrix. If, however, the ternary phase diagram shifts and there are higher levels of cholesterol and its esters and a lower level of bile salts, even with the same amount of lecithin, a zone of crystallization may result. Cholesterol starts to crystallize out of solution and there is risk to gallstones. What factors contribute to crystallization? Is there a single factor? Obviously, the answer is no. When the physiology of gallstone formation is examined, we find that there are literally tens of differing factors that contribute to the condition, many of which are connected to lifestyle, as well as genetics. Let us take one of those factors, the conversion of cholesterol into 7-a-hydroxycholesterol, the rate-limiting step for the formation of the bile salts chenodeoxycholic and cholic acid. There is a specific enzyme involved in that particular step, the 7-a-hydroxylase enzyme, which is genetically unique to the individual. Therefore, there is variegation and different frequency of conversion, or the facility of conversion of cholesterol into bile salts. Some people may be at higher risk to forming cholesterol stones because they cannot hydroxylate cholesterol into solubilized bile salts as effectively as others. Therefore, their ternary phase diagram of bile becomes more supersaturated with cholesterol because of a lower amount of bile salts. However, there are substances known to promote the conversion of cholesterol to bile salts by activating the 7-a-hydroxylase enzyme. One of them is vitamin C, or ascorbic acid. Historically, there has been lore that one can lower the risk to cholelithiasis and gall bladder stones by increasing vitamin C intake. Individuals with the 7-a-hydroxylase insufficiency due to a genetic polymorphism may be more susceptible or more sensitive to vitamin C intake; therefore, not everyone can reduce gallstone risk by taking vitamin C. We are stratifying now for an individual genetic type. In a group study of vitamin C and gallstones, there might not be a high frequency of individuals with that specific polymorphism. If 100 patients are treated with vitamin C, a statistically significant decrease in gallstone formation might not be demonstrated because most people do not have that unique sensitivity. However, the study cohort with the sensitivity may have a positive result, although it would be washed out as a consequence of not having a high enough percentage frequency to shift the average data into the positive. This has always been part of the difficulty in doing nutritional intervention trials with a poly-genomic population. Let’s use another example. Ultimate solubility resulting from the conjugation of bile salts has to do with conjugation of various secondary moieties, one of which is the amino acid, taurine. Taurine is a sulfated molecule that helps form a solubilized, detergent-like bile salt. Inappropriate taurine conjugation might also lower the effectiveness of bile to solubilized cholesterol and lead to cholesterol stone formation. In some individuals, risk to gallstone formation has been reduced by increasing dietary taurine supplementation, but not everyone responds in a positive manner. Who are the individuals most likely to respond? They are likely to be those who have the conjugation insufficiency, which is another cohort. What about individuals who may have decreased production of lecithin, another important solubilizing component of bile? This may comprise another subtype which might respond to choline or phosphatidylcholine supplementation to lower the risk of cholesterol deposition in bile. The point I am trying to make is that diet as a risk factor for cholesterol gallstone disease may have many variables that are very specific to the individual genotype. Therefore, a study that only examined diet and gallstones may lose some of the discrimination in the “noise,” which we call regression to the mean, or the average response. However, there are certain epidemiological associations between gallstone disease and diet that seem to stand out. For instance, the consumption of simple sugars and saturated fat is correlated with a higher risk to gallstone disease. Fiber intake and moderate consumption of alcohol are also associated with a decreased risk to gallstone disease, but high levels of alcohol intake are associated with increased risk to gallstone disease. There are certain things that pop out of the literature as gross epidemiological markers, but when it comes to individual nutritional associations, a different type of study methodology is required, a different type of stratification. I have been quoting from an interesting review paper that appeared in the Journal of the American College of Nutrition, titled “Diet as a Risk Factor for Cholesterol Gallstone Disease.”[2] Another important issue in research relates to whether research risks are reasonable in relationship to anticipated benefits. That is the title of a recent paper in Nature Medicine,[1] in which the authors raise the question about some of the clinical research using the placebo-controlled model. Even well-designed controlled trials may be marginal regarding the relative risk to which the participants are subjected. These trials often do not address the broader questions such as how we stratify uniqueness in the cohorts that might lead to differences in the way they respond, i.e., accounting for biochemical individuality. How do we recognize that there is more than one thing going on, when only one endpoint is being studied? How do we deal with the possibility, and often occurrence, of atypical adverse effects, which are probably not atypical, but reproducible in the people who have them? We call them atypical because they occur at low frequency, but the question is, when are research risks reasonable in relationship to anticipated benefits? When we begin to examine the ethics of clinical trials, we get into how institutional review boards (IRBs) function. IRBs review various experimental protocols and determine the ethics and the risk-to-benefit of a trial proposal. An IRB might ask whether a trial puts people at undue risk. What are the ethical questions related to placebo controls, knowing that sometimes the placebo is a very powerful force in medicine and may play an important role in outcome that is not to be dismissed as trivial? IRBs play an important role in research as to how we eventually answer more complex questions—real-world questions about what a person should eat, or think, or believe, or drink, how they should exercise, what environment they should be exposed to, or what type of nutritional intervention program they should be involved in. How does the information obtained from trials relate to how a trial is performed? These are important ethical issues being brought to the foreground in the research literature, and discussions may ultimately result in a new decision-making process based on multidimensional or multifactorial questions. The placebo-controlled clinical trial may remain as the “gold standard” if one is looking at a single molecule against a single endpoint; for example, a drug for a condition that can be directly measured, such as blood pressure. But it may not be the methodology of choice if one is trying to examine other more complex questions related to an individualized response to a complex environment. What about multivitamin supplements? That topic is still considered fairly controversial in some quarters as to whether it is cost effective to take a nultivitamin supplement or whether it results in expensive urine. Some feel nutrients get flushed out of the body through yellow urine, indicating that supplements clearly are not useful. I think there is a flaw in that logic: If the supplements were not flushed out of the body, but were retained, then in eating diets that contain vitamins, we would eventually accumulate so many that we would turn into a crystallized vitamin. One has to get rid of supplements; we do not hold onto vitamins throughout the course of our lives. In particular, the water-soluble nutrients are always turned over. The concept that they are just spilled into the urine does not address the question as to whether they were absorbed and did something on their way through the body. Perhaps they have some positive impact on promoting proper cellular function. Cost Effects of Daily Multivitamins for Older Adults In January of this year, the Lewin Group, Inc. published a report on a study it was enlisted to carry out on the cost effects of daily multivitamins for older adults.[3] This was an extensive review and assessment of the cost effectiveness of multivitamins that resulted in some extraordinary conclusions. In order to evaluate whether taking a daily vitamin and/or mineral supplement has value, one cannot simply look at the course of one day. A timeframe of a month or a year would be better, as well as reviewing data over a broad range of individuals. Appropriate endpoints and markers are needed that can be carefully evaluated to determine whether there is any cost effectiveness. This particular study looked at a population group 65 years of age or older and certain high-prevalence conditions in that population to see if the incidence of several conditions was mediated or modified by multivitamin/multimineral intake. These conditions included coronary artery disease (CAD), colorectal cancer, diabetes, osteoporosis, prostate cancer, and dementia. Over the years in FMU, we have discussed many studies on nutrient intake related to those clinical areas. When this study was done, the investigators felt that the potential savings resulting from the reduction in the relative risk of CAD and improved immune function, and subsequent reduction in infection through providing older adults with a daily multivitamin supplement, is approximately 1.6 billion dollars. (The five-year estimate of gross cost of providing the Medicare beneficiary population with a daily multivitamin, if it was to be employed across the board, would be about 2.3 billion dollars, and the overall cost reduction in total for all the major age-related diseases, including CAD is 3.9 billion, making the net cost of potential savings approximately 1.6 billion dollars.) We are looking at gross numbers in this study. We are not looking at individual lives. We are not looking at individual responses. We are not looking at functional changes that might have improved quality of life, things like range of motion, soreness, sleep patterns, prevention of colds and infection, and even things like memory, recall, and cognitive function. We all know from the studies done by Dr. Lindenbaum over 25 years ago that cognition is improved in older-age individuals who take vitamin B12 and folate-containing nutritional supplements. The cost effectiveness study done by The Lewin Group is very interesting, again trying to address how we state whether there is value. How do we come to decision making? How do we tell a patient he will get benefit from taking a daily multivitamin/multimineral. How do we convince a patient that the return on his investment will be greater than the cost if he just stays with the program? Again, we often have to use inferential information for decision making because we do not have the value of a prospective trial on that person over time against a placebo. That would be like observing a person’s identical twin living an identical lifestyle to see what the outcome is. We have to make the best estimates based upon this type of patterned information. Cooling Off Hot Flashes Let’s take another example, which I think is a fascinating one—hot flashes. We have seen a lot in the news recently about the use of equine estrogens and synthetic progestins for the management of menopausal symptoms. It was not long ago that this was considered the preventive medicine of its time. Conditions associated with postmenopausal health problems in women, such as bone loss, loss of cognitive function, cardiovascular disease, as well as sexual dysfunction, and a reduced sense of vitality, would all be neutralized, or would be managed by the combination of equine estrogens and synthetic progestins. Then, the Women’s Health Initiative began to give us information about this association, or this hypothesis, and it was found that not only was the hypothesis somewhat overstated, but on further inspection with multiple studies, it was found to be incorrect. Some women had increased risk to conditions for which they were supposedly being protected by equine estrogens and synthetic progestins. One of the conditions for which synthetic progestins and equine estrogens are used is hot flashes. Over the last five years, the question has been raised about where hot flashes come from. What is the physiological mechanism by which women suffer from hot flashes? Is it an estrogen deficiency, for which the use of estrogen replacement therapy (ERT) is the treatment, the simple model of estrogen deficiency/flashing, and estrogen administration/no flashing? That leads to an interesting revelation. When one looks in the literature for information about the mechanism for hot flashes and night sweats in perimenopausal women, one expects to find a definitive answer because of the wide use of equine estrogens (at one time the number one prescribed medication in the U.S.). One would believe there must be a definitive understanding of what is going on, but that is not the case. Even today, we do not understand the mechanism that results in hot flashes and night sweats. Therefore, the treatment with equine estrogens was a symptom treatment alone, based upon empirical evidence that 70 percent of women who take an ERT product will achieve remediation of symptoms. But this was not built on any known mechanism of action. In a paper in the Journal of Clinical Oncology, titled “Cooling Off Hot Flashes,”[4] the author states that vasomotor symptoms represent the most common complaint among perimenopausal women. It is estimated that up to 60 percent of postmenopausal women experience these symptoms, up to 20 percent of women find them intolerable, and a similar proportion of women suffer symptoms up to 15 years after menopause. In 2001, up to 4,000,000 women complained of severe symptoms for which they sought intervention in 2002. There are probably more today because of a greater number of women going through menopause. Women who suffer hot flashes may complain of associated symptoms such as depression, anxiety, and difficulty with sleep patterns and sexual function. Women who undergo premature menopause often suffer symptoms of longer duration. Where do these hot flashes come from? The pathophysiology of the phenomenon is not well understood. Estrogen action in the central nervous system (CNS) is complex and it may not be just estrogen alone. It may be estrogen metabolites like hydroxylated estrogens that are also exerting influence on the CNS, the so-called hypothalamus/pituitary signaling. Estrogen exerts its function not only through an interaction with its receptors, but also through an interaction with other receptors importanty in the regulation of sleep, mood, and cognition. We have moved beyond 17-b estradiol to looking at the other estrogen metabolites and how they influence these hypothalamic pituitary functions. Non-Hormonal Agents and Hot Flashes Some non-hormonal agents have shown promise for the management of hot flushes, which suggests that more than just estrogen is involved. Dr. Charles Loprinzi at the Mayo Clinic Center in Rochester, MN, has talked about the use of venlafaxine in managing symptoms of hot flushes in women who have had hysterectomies.[5] A half dose of the antidepressant (75 mg versus 150 mg) results in a 60 percent reduction in the hot flush score in women. We are beginning to see that there may be some interesting interrelationships among agents that modify hypothalamus/pituitary function and hot flashes. Frequency of Menopausal Hot Flashes and Blood Glucose Levels If hot flashes result from more complex hormonal signaling than just estrogen alone, what about other things that modify HPA axis function, such as stress, or blood sugar and insulin? In a recent paper in Nursing Research, investigators reported that frequency of hot flashes was correlated with alterations in blood sugar.[6] When women had low blood sugar followed by rapid increases in blood sugar, an increased frequency of hot flashes was observed. What is called reactive hypoglycemia and dysglycemia/dysinsulinism may also have associations with hot flashes and night sweat conditions seen in perimenopause. It appears that stress, diet variables, and hormonal imbalances play a role in this complex web, not just estrogen alone. We still do not know exactly how estrogen plays a role in modifying the frequency of hot flashes, or how the mechanism works. The complex interactions of a program developed for a woman with menopausal symptoms would be more than just a simple intervention with mixed conjugated equine estrogens. It might include diet alterations, stress reduction, lifestyle modification, and a regular exercise program. All of these have been found to modify and ameliorate hormonal imbalances associated with the onset of menopausal symptoms. This is much more complicated than just giving a pill against a single endpoint. Once again, we are talking about polyfunctional or multifactorial agents and their relationship to multiple symptomatologies. It is more than just hot flashes. A woman may have a lowered quality of life as a consequence of hot flashes and night sweats, but what about her other health risks, such as cardiovascular disease, cognitive decline, and bone loss? In these areas, we need to be looking at more complex intervention programs that deal with all of these variables. Dr. Allan Warshowsky talked about this topic eloquently in his interview as an FMU clinician in February of this year. Estrogen for Treatment of Hot Flashes in Postmenopausal Women The literature is beginning to support this concept. If you have been reading the Journal of the American Medical Association recently, you probably saw a series of papers published in 2004, titled “Postmenopausal Estrogen for Treatment of Hot Flashes.”[7],[8] The author says that evidence supports estrogen for the reduction of hot flashes as a clinical endpoint, but that it does not appear to have any other significant benefit beyond modification of that endpoint. The other risk factors may still be present. A woman may actually be “persuaded” into thinking she is OK because her symptoms are decreasing while on estrogen therapy, yet her relative risk to cognitive decline, CVD, and bone loss may still be increasing. These are very interesting parts of the story. Sometimes, interrupting the symptoms is like taking the smoke detector out of your children’s upstairs bedroom. You do not hear it go off so you think everything is fine, but you still have the fire to worry about. In a paper in JAMA,titled “Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy,”[9] the authors state in the last sentence of the conclusion: “Thus, CEE (conjugated equine estrogen) should not be recommended for chronic disease prevention in postmenopausal women.” That is a very different type of conclusion than we were presented with just a few years ago. In fact, in the editorial that follows these papers titled “The WHI Estrogen-Alone Trial—Do Things Look Any Better?”[10], the answer was no, they did not look any better. In moving away from CEEs to estradiol itself, there still did not appear to be a significant benefit on other health risks by estrogen intervention alone. The authors state: “In the absence of evidence for an overall net benefit of postmenopausal treatment with estrogen alone, and with the evidence that estrogen plus progestin is harmful, neither therapy should be used for preventing disease. Although it is possible that other forms or doses of hormones could be more beneficial, this must be demonstrated in disease-end point trials before any hormone regimen can be recommended for disease prevention. Fortunately, there are other good approaches to preventing CHD and fractures for which trials have found benefits to outweigh harms.” We are talking about lifestyle multifactorial intervention trials, not single agents against single endpoints. Sometimes, one needs to question the double-blind, placebo-controlled trial as to whether it leads us down the wrong path and actually mis-affiliates a benefit against a treatment, rather than looking at the total complex situation with respect to relative risk and benefits. Weight Loss/Diabetes Connection Let’s look at another interesting example of this complexity that has to do with the weight loss/diabetes connection. Most of us have heard through lectures and through the body politic and the scientific literature that excessive adipose tissue weight gain, particularly visceral adipose tissue, will, in fact, cause diabetes, and that there is a direct association between body fat and diabetes. If you have been listening to FMU for the last few years, you have probably heard me challenge that hypothesis. There is no question that there is a strong association between body fat and type 2 diabetes. The question we have raised is whether body fat necessarily causes diabetes or whether it is one of the covariables associated with a metabolic disturbance that produces type 2 diabetes, hyperinsulinemia, hypertension, CVD risk, increased inflammatory mediators, increased adhesion molecules, and increased obesity as a consequence of a change in the physiology of adipocyte cells. The real question is one of the chicken and egg, and we have always assumed that the chicken (i.e., diabetes), came from the egg (i.e., body fat). Now, it is reasonable to ask whether this is, in fact, correct. We are not being told that trying to achieve proper or ideal body mass index (BMI) or proper body composition is ill founded. We are still talking about the importance of maintaining leanness, but the real question is, what should be the major focus in our intervention? Should it be just taking off pounds of fat, or should it be trying to build pounds of muscle that create an opportunity for altered cell signaling and a differential effect on insulin sensitivity? I am again getting away from the single endpoint concept of body-fat produces-diabetes. The endpoint would be diabetes and the indicator would be body fat. I am looking at a multifactorial model of how diabetes develops through interactions between genes and environment, of which body fat is a component. Effect of Liposuction on Insulin Action and Risk Factors for Coronary Heart Disease A paper was published recently in The New England Journal of Medicine that bears in part on this question, and which is quite fascinating. It is titled “Absence of an Effect of Liposuction on Insulin Action and Risk Factors for Coronary Heart Disease.”[11] This paper is probably counter-intuitive to those of you who have believed that body fatness, in and of itself, causes diabetes. In this remarkable study, the investigators evaluated the insulin sensitivity of liver, skeletal muscle, and adipose tissue with a euglycemic-hyperinsulinemic clamp procedure and isotope-tracer infusions, as well as levels of inflammatory mediators and other risk factors for CHD in 15 obese women before and 10 to 12 weeks after abdominal liposuction. Eight of the women had normal glucose tolerance, although their BMI was certainly showing obesity at 35+, and seven had type 2 diabetes with a BMI nearly 40 (39.9 on average). Liposuction was found to decrease the volume of subcutaneous abdominal adipose tissue by 44 percent. This was a gross liposuction with tremendous loss of subcutaneous body fat via the liposuction technique. It was 44 percent reduced in patients with normal glucose and 28 percent reduced in those with diabetes. The authors of this study found that there was no significant reduction or change in the concentrations of C-reactive protein, interleukin-6, TNFa, or adiponectin. There was also no significant change in blood pressure, plasma glucose, insulin, or lipid concentrations in either group. Therefore, they came to the conclusion that abdominal liposuction, although it did remove tremendous amounts of body fat, did not significantly improve obesity-associated metabolic abnormalities, and that decreasing adipose tissue mass alone will not achieve the metabolic benefits of weight loss. This is to be contrasted to gastric bypass surgery. In that case, individuals that are type 2 diabetics do experience, at least in the short term, improved insulin sensitivity. In the long term, it appears as if they return to insulin resistance some years after recovery from the surgery. There is something much more complex going on than just the issue of body fat. That is the important takeaway from these studies. In the editorial that follows this study in The New England Journal of Medicine, titled “Thermodynamics, Liposuction, and Metabolism,”[12] David E. Kelley points out that we cannot draw unequivocal conclusions from this liposuction study because subcutaneous fat rather than visceral adiposity was removed. Visceral adiposity is that which delivers lots of blood fats directly into the major hepatic artery, and therefore may be a much higher risk in terms of the relative effects on insulin and diabetes. However, given the history I talked about with gastric bypass surgery, it appears as if there may be other factors going on besides the thermodynamics of calories alone in signaling for insulin resistance, and ultimately type 2 diabetes, CVD risk, and inflammatory mediators. It is something related to the physiology of the adipocyte. When we start looking at single agents against single diseases and simple-minded studies, which have been the gold standard, we are often led to conclusions that are not accurate. They are not realistic and they lead to clinical decision making that in some patients may be good, but in many others may not be good because they did not meet specific needs. It is the revolution occurring in medicine that is going to teach us how to get better in achieving higher outcomes from specific tailored programs, moving away from the medicine of the average to the medicine of the individual. This has been the theme of functional medicine since its inception. Frequent Intentional Weight Loss and Lowered Natural Killer Cell Cytotoxicity in Postmenopausal Women For instance, in weight loss alone, if a person goes on weight cycling by repetitive weight loss/weight regain, he/she can develop immunocompetence over time. This was recently discussed in an article in the Journal of the American Dietetic Association.[13] By focusing on just calorie restriction alone, weight recycling may actually lower natural killer cell cytotoxicity and alter immunological vigilance over time, putting that individual at higher risk to conditions associated with lowered immune potential. The editorial that preceded this article is titled “Weight Cycling and Immunocompetence.”[14] One needs to be cautious about making simple-minded decisions from complex data sets that are cohort-variable based upon genetic diversity. It is from that kind of standard that we will be seeing the emergence of a new form of medicine built upon a different decision-making strategy that will take these multiparameter, multifactorial components into account. Then we can start looking at cohort analysis and individualizing treatment from specific characteristics of the group. Let’s move to our Clinician of the Month, who will carry this theme to a much higher level.

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INTERVIEW TRANSCRIPT

Clinician of the Month Joseph E. Pizzorno, Jr., ND P.O. Box 25801 Seattle, WA 98165-1301 JB: It’s time for our Clinician/Researcher of the Month. This month, we are fortunate to have an individual who falls under both categories of researcher and clinician. He is an institutional leader and an icon in our field. I’m speaking about Dr. Joseph Pizzorno. His name is synonymous to many of you with the worldwide development of the science of natural medicine and naturopathic medicine. Dr. Pizzorno and I have been friends and colleagues for the better part of 25 years and it’s been a great privilege to watch the impact of his work on the field of health care. He is a past FMU Clinician of the Month and we are revisiting him now, some ten years later. Let me give you a quick vignette on Dr. Pizzorno’s background for those of you who are not familiar with his work. He has effectively created policy change in many, many areas. I can only scratch the surface here. It began when he worked with a group of physicians to improve and renew Washington State licensure for naturopathic doctors. In the late 1970s/ early 1980s, he was involved in the formation of Bastyr University, the first fully accredited university in the area of natural medicine and naturopathic medicine. He has been involved as a leader in education and is the author of the Textbook of Natural Medicine, which is probably the premier publication that people use in the field worldwide for gaining skill in the area of natural medicine. It is the text used in many institutions of post-graduate education. He was also appointed to the White House Commission on Complementary and Alternative Medicine (CAM) Policy, where he was a member for several years. He was active in the culmination of their final “white paper,” a mandate as to what needed to happen in health education and healthcare delivery, which incorporated some of the CAM concepts. He was recently appointed to the Medicare Coverage Advisory Committee regarding issues related to financing and brings a natural medicine perspective to that group. This is a remarkable chapter in his book and in the field. Last, but not least, he was awarded the Linus Pauling Functional Medicine Award this year, and joined an esteemed group of his colleagues that have previously won the award over the last 11 years. We at the Institute for Functional Medicine felt very privileged to have Dr. Pizzorno join the ranks of the Linus Pauling Award winners. With that short biographical sketch, I’d like to welcome you to FMU, Joe. Perhaps for those individuals who are not that familiar with naturopathic medicine, you would tell us about what characteristics differentiate naturopathy from other branches of health care. JP: Thank you, Jeff, for your kind introduction, but more importantly, thank you for being such a teacher to me and to so many for the last 25 years. It’s very clear that the advancements I’ve been privileged to be a part of would not have happened without your wise counsel and your brilliant education. JB: Thank you so much. We’ve had an extraordinary group of people over the last 25 years that have been both our teachers and our colleagues. It’s amazing how we learn from one another when the right people get together. Naturopathic Medicine versus Other Branches of Medicine JP: It’s been a wonderful journey together. You asked about naturopathic medicine. In general, people would first think about that as a profession. I think about it more as a way of life and a way of thinking about health care. What characterizes naturopathic medicine is not what we use, which is how many people tend to think of us. They see us as people who use herbs, vitamins, and things of that nature. I prefer to view it as a fundamentally different way of thinking about health care than what has been seen in conventional medicine for most of the last century. What characterizes naturopathic medicine is a very strong philosophical basis in how we think about patients. We try not to think about them as diseases to diagnose, or as therapies to relieve symptoms, but rather as understanding why people are sick and how they can become healthy. We’re far more interested in understanding what the characteristics of that person’s own unique genetics are, what environment they’re in regarding toxic exposure, what nutritional deficiencies they may have, and what lifestyle behaviors they may be engaging in that are setting up physiological dysfunction in their bodies that leads to disease. For example, as a naturopathic doctor, when a patient comes to see me with a condition like migraine headache, I could use a conventional drug approach like Sumatriptan, which relieves the symptoms, but it does not address the underlying causes of the disease. Or, you could take what I would call a “green drug approach,” one which concerns me a lot, and one I see a lot of people who use natural therapies doing. They will use an herb like feverfew, for example, to treat the migraine. How effective that will be in relieving the symptoms does not address the underlying cause of why that patient has migraine headache. The kind of approach I like to take, and one which I think is consistent with what you’ve been doing in the world of functional medicine, is to look at the underlying physiology that has led the person to the endstage symptomatology of migraine headache. When we look into it, we find a lot of reasons why that person is having migraine headache and those reasons, those physiological dysfunctions, lead not just to migraine headache, but also to many other healthcare problems they are experiencing. For example, about 40 percent of people with migraine headache have mitochondrial dysfunction. About 40 percent of those with mitochondrial dysfunction have it because they don’t have enough magnesium in their body. Forty percent of 40 percent means that 1 out of 6 people with migraine headache should be given extra magnesium, either a dietary supplement, changing the diet, or looking at what may be causing lack of proper magnesium absorption or magnesium leaving the body too quickly. One out of six people will respond to magnesium; yet, five out of six will not. The way a lot of people approach the use of natural therapy is to do a “grab-bag approach” of using a wide range of therapies they hope will work, but they don’t actually understand the physiology. I know I got a little far afield from naturopathic medicine in terms of specific detail, but the idea here is to understand why the person is sick and how to help him become healthy by correcting underlying causes of his illness. JB: There are a number of very important concepts embedded in your thoughts that I would like to explore. In the area of differential diagnosis, when a physician looks in the book for an international diagnostic code, an ICD9, he is often led to the belief that something like migraine headache (because it may have a specific singular number), is a singular disease and that we can put a ring around it and just call it a disease. The example you just used, which is one of many, suggests that there are subtypes or subcategories of diseases, so disease may be misleading if we start thinking of it as a singular entity. Is that an implication of what you’re saying? JP: It is. As you know, I am Founding Editor of the journal, Integrative Medicine: A Clinician’s Journal, and there was an editorial on this about a year ago titled, “Is Disease Real?” I meant to be provocative. If you look at a condition like juvenile onset diabetes, for example, where it’s clear that the pancreas has been seriously damaged and is not producing insulin, the disease name, IDDM, actually describes the physiological dysfunction. However, if you look at adult onset diabetes, or type 2 diabetes, there are wide ranges of different physiological effects, only one of which might be low insulin. Most often, there’s plenty of insulin, but the body is not responding to it. The use of the term diabetes in that condition, while it actually describes elevated blood sugar, obscures the physiological dysfunction that the patient is experiencing. It leads conventional medicine to use therapies and agents which, while they may reduce the blood sugar, don’t deal with the actual problem the patient is experiencing, so you continue to get the sequelae of the disease. JB: That begs another question. I may be misstating this, so please correct me if I’m wrong. In my years of experience of observing naturopathic medicine, it appears that there may be two separate camps. One camp is a group that would be characterized as believing that the understanding of physiology and even aspects of cellular physiology might be of value in developing a specific clinical treatment program for the patient. There appears to be another group that might say that those are just artifacts. We know more about less and less, and eventually we know everything about nothing, so it’s better to deal with the natural history of the disease and to look at it in the context of the historical record and ethnography. By digging deeper, we obscure how to properly manage the patient. Is that an accurate characterization of some of the polarization that appears in the field? JP: I think that’s a good observation. The field of naturopathic medicine is quite eclectic in many ways. I think we all share the core belief of patient focus rather than disease focus, as well as a strong belief in the body to heal itself, if given a chance. Many of us approach that differently. My own background and orientation is much more biomedical and much more in the hard sciences. There are those who would prefer to take a more constitutional, whole-body, or other kind of approach. For example, people who use homeopathy will not get into biochemistry the way I would. There are those who lean more toward the more nature cure side, and they don’t really look at the biochemistry, but at fundamental changes in how the person lives, what they eat, how they rest, and how they detoxify their bodies. There are many aspects of how this profession is practiced. JB: When I was first associated with you and your colleagues, the better part of 25 years ago, as I recall, there were only two states in which naturopathic physicians were licensed—Oregon and Washington. There has been a great extension of that now. In how many states are naturopathic physicians presently licensed? JP: Actually, it was seven back then, and it is now 13. JB: Does that 13 include the recent addition of California? JP: It does. JB: It seems like a big step forward for the profession with licensure in California. JP: It is. When we look at the population of California, the licensing there doubled the percentage of the U.S. population that now has access to licensed naturopathic doctors. JB: You have done a tremendous service to the profession by helping develop and incorporate a successful comprehensive curriculum at Bastyr University that takes students from their first year right up to graduation. Have you seen the development of that curriculum, the increased activity of the American Association of Naturopathic Professionals, and the textbook all leading to a concept that can be transferred so that you can actually teach it better and introduce it to new students? Extent of Naturopathic Education JP: I think that’s an accurate statement. One thing I think most people don’t realize is the intensity of the education that the naturopathic doctor receives. To become a licensed naturopathic doctor, a student has to complete premed and a four-year graduate school education. During the four years, they study all the conventional basic medical sciences and all the standard diagnostic procedures, but they also study the natural diagnoses and therapies. During that period, they are also engaged in clinical training in teaching clinics. At that point, there are residencies available, but they are optional in most states for licensure. One of the changes I’d like to see in the future in naturopathic medicine is a required residency for all licensed people. But unfortunately, the resources aren’t there for that right now. One of the things that’s happened, in the last 10 years especially, has been bringing professional educators into the profession. These are people that have doctorates in areas in which they teach and are developing a more consistent body of knowledge. By having a more consistent body of knowledge, I think it’s easier for the concepts of this medicine to be taught. Equally important, it’s easier for the concepts of this medicine to be researched. One of my greatest prides in creating Bastyr University was our strong commitment to a science-based approach to natural medicine. We have quite a large research department. What I want to tell people about the research is that we do it not to prove ourselves to the world, but we do it to get better. There is a rich body of concepts and therapies in the field of natural medicine, and yet I don’t think they are applied as well as they could be because they don’t have a strong research basis from which to function. I see that rapidly changing and improving at this time. JB: That leads to an interesting question that has been debated by scholars in the field of the health sciences and that is, how do you prove a hypothesis in a complex world where people are doing all sorts of things? They’re not lab rats in an experiment. In terms of naturopathy and natural medicine, many of the therapeutic interventions require complex multifactorial changes, which is different than taking a single pill for a single endpoint. As we know, the double-blind, placebo-controlled trial is very amenable to proving hypotheses related to a single agent against a single endpoint against placebo. But when getting into multifactorial types of therapies, it becomes a much more complicated issue to prove efficacy. Would you tell us a little bit about methodologies and how these complex information sets might be handled so critics will understand that there is some substance to these associations? Multifactorial Intervention JP: That’s an excellent question, Jeff. And it’s been a huge challenge because so many of our interventions are multifactorial and not single agents. I had a good experience with this. I was brought in to consult with a conventional medical university that wanted to do a study on a chronic, degenerative disease. We went through with this group of experts and we came up with monthly algorithms for treatment of the disease. In other words, we had a diagnosis, but we would not give every patient exactly the same intervention because they’ve all got different pathways. We came up with a very complex, pretty sophisticated, and well-referenced algorithm that basically developed about 12 different potential interventions that could be used for patients with this disease, but each would get a different group of interventions based on their own unique presentation. It was rejected by the International Review Board. They said that only one protocol could be used and to try that protocol on the patient. Of course, that’s what’s being utilized right now. What has happened is that they’ve gotten a fundamentally poor outcome because they’re not actually looking at the research that we’re doing. Actually, I should say that differently. They’re not actually looking at how we clinically think about patients and treat them. It is a challenge, but I think it’s doable. I think it’s doable by being very consistent with what the selection criteria are for the differentiation of the interventions and then doing appropriate outcomes to see if indeed, the interventions, as a comprehensive approach, are effective. Looking at just single interventions or protocols that are blindly applied to all people does not utilize the understanding that this medicine has to offer. JB: That’s well said. It reminds me, from a biochemistry perspective, of the evolving story about folic acid. If you look at just the gross population with respect to homocysteine and folate, you might not be able to find high levels of significance relating to various diseases and folate status. But if you start stratifying for the MTHFR polymorphism, the slow methylator polymorphism, then the significance of your data starts to get richer and more robust because you’ve looked at the individuals that are most susceptible to folate insufficiency. The problem we’ve had in the history of our research in the past is that we have lumped everybody together, assuming that they’re all similar, and sometimes you end up getting no data of significance at all. Embedded in that are tremendously interesting cohorts that either respond very well or have an adverse response to a specific therapy. But they all get washed out in the averages. JP: Exactly. Going back to the example of magnesium and migraine headache, if you do a Pub Med search on magnesium and migraine headache, you’ll see a fair number of studies and they’re all over the board. Some show effects; some don’t show effects. The problem is that when only one out of six people is going to respond to your therapy, unless the study is large enough and carefully enough designed, it won’t show efficacy. But for that one out of six, it is extremely efficacious. JB: That leads to an area in which I know you’ve had personal interest and expertise for the better part of the 25 years I’ve know you, and that’s how you gather information in this more complex, multifactorial world and analyze that data. In the past, this may have been one of those theoretical questions that could have engaged long discussion without resolution because we didn’t have the technology available on the desktop to be able to handle large data sets. Over the last 25 years, that’s changed entirely with the advent of the high-powered, super computer that we can now buy for $1000 from our local computer supply store and with which we can crunch data that previously only the super computers could have done 20 years ago. I know you’ve been an expert in following the transition we call biomedical informatics. Would you tell us how that may help in harnessing answers to’ some of these questions? Biomedical Informatics JP: Thank you, Jeff, for an opportunity to speak about this. This is work I’ve been doing since I left Bastyr University in 2000. I’ve had a long-term interest in the use of artificial intelligence as a tool to assist clinicians in dealing with complex situations. The example of migraine is a very good one. My thinking was that if indeed this approach to healthcare makes sense (understanding the patient’s unique physiology), how would we go about understanding that physiology and then determining what the most optimal approaches are to restore normal physiology? I came up with the idea of mapping the body into about 5000 distinct physiological functions. For example, how well the stomach secretes hydrochloric acid, or how well one of the cytochrome P450 isoforms in the liver detoxifies chemicals a person is being exposed to, and whether those chemicals are natural chemicals from the diet or drugs that are given to the patient. When you think about it, 5000 distinct physiological functions is a tremendous number. How can anybody keep all those in mind? Not only that, but how can anybody keep in mind what all the signs and symptoms of those physiological dysfunctions might be? Once you recognize what the physiological dysfunction is, then how do you know what intervention is most appropriate for an individual that would most likely restore normal function? Going back to the example of migraine headache, my research team has now determined 21 distinct different physiological pathways that may be imbalanced in a person with migraine headache. But of course, it’s different in every person. Those 21 different physiological dysfunctions have over 50 possible different interventions to normalize one or more of those physiological dysfunction pathways. As you start to look at this, it gets very complex. That’s one of the wonders of the age of technology where we now have very powerful computers easily available to everybody. By utilizing an artificial intelligence system that keeps all these physiological dysfunctions in memory (it can also keep in memory all the reasons why they may become dysfunctional and what to do about them), we can develop a tool for clinicians that they can use to understand which physiological dysfunctions exist and what the causes and best potential interventions are. JB: That obviously begs a series of other questions. If we saw that a condition we previously thought was one condition, or one disease, is broken down into more than 20 subtypes, then the question is, how do we differentiate the patient? Assessment becomes a very important part of differentiation. Beyond just labeling somebody with a disease like migraine headache, we need more exact knowledge about the differentiation of their condition into subtypes. That goes back to how we establish these diagnoses, or prognoses, or differential assessments, but you get into the signs and the symptoms, the history, the environment, and the biochemistry as different buckets of information that you need. Would you tell us a little bit about how the clinician would make these assessments to go about making the differentiation? JP: It takes time for the clinician. The standard right now is to spend 10 minutes or so with a patient. I don’t think it’s possible for a clinician to do anything other than make a disease diagnosis and suggest a drug therapy that’s more symptom oriented than curative in nature. It takes time. It requires understanding the patient at a deep level, assessing the person’s diet, assessing their environmental toxin exposure, looking at their lifestyle, and then carefully listening to and eliciting the signs and symptoms the patient is experiencing so you can start to develop a physiological map of the patient. I also think it will require a lot of study of biochemistry and physiology. That’s one reason why I enjoy Functional Medicine Update so much, as well as the conferences you put on every year, because it gives the clinician an opportunity to delve deeply into understanding these complex physiological issues and how to recognize when they apply to a patient that the clinician is trying to help. JB: This model sounds like what would be called a paradigm shift in thinking, because we have seen the primacy of diagnosis as the sine quo non for medical training over the last 50 or 60 years. Now, we are beginning to acknowledge that is a good place to start, but not where to stop. We need to look at precipitating factors, underlying causes, and the interconnection of those signs and symptoms to things other than the first-level diagnosis. Do you see this as a shift of that magnitude in medicine and if so, do you see some signs that we’re moving toward a tipping point? JP: Good question, Jeff. That is where I think medicine has to go, and it requires a lot more of the clinician. That’s one reason we’ve been working so hard on this artificial intelligence system—to give people tools with which they can do this. I think it’s going to take a fundamental change in thinking at the level of medical school education before we can start applying the body of knowledge that’s available to assist people and give them a lot more help than we do right now. Looking at the incidence of chronic, degenerative diseases in our society, most of them have risen in every age group every decade for the last 50 years. It’s clear that the current healthcare system is not working very well. And we can no longer afford it. We need to change to a system which is much more similar to the functional medical model that you’ve been teaching for so long and which also incorporates many of the concepts of natural medicine that so many of us have been working on for the last few decades. Until we do that, we’re going to continue to have the problems we have with the healthcare system. I think it’s great that we have excellent clinicians who can make a disease diagnosis. That’s useful to know, but that’s only the starting point in understanding the patient, not the endpoint. JB: We could go on with this discussion for hours and, in fact, over the years we probably have. My image is that perhaps we’re at a bifurcation point in the development of medical technology. We will always need medical intervention technology for people who have sustained traumatic injury or who have a crisis experience. It requires a certain set of skills and a certain set of tools to do that well—a kind of emergency room medicine to keep the patient functioning. Then we’ve got this other philosophy about trying to improve function that would stave off age-related dysfunctions that later become diseases of specific diagnosis that require a high-cost intervention type of medicine. Maybe you can’t wrap both of them into a singular four-year medical curriculum. Maybe we’re seeing a bifurcation in the system that will produce two types of doctors with different skills that live in harmony. Is that a possibility, or do you think I’m off the mark? JP: Oh, I agree with you fully. We clearly need the almost miraculous intervention technology and diagnostic procedures typical of conventional medicine, but that’s the second choice, not the first choice for the majority of healthcare problems people are experiencing today. We shouldn’t have the healthcare problems we’re experiencing. I don’t think it’s an issue of information; I think it’s an issue of getting well. You mentioned that I’m the editor of the Textbook of Natural Medicine. That textbook has over 10,000 citations, peer-reviewed scientific literature, showing that many of these natural therapies are indeed effective for a wide range of healthcare problems people experience. But that body of knowledge is not being used. A very sophisticated body of knowledge is being developed in the functional medicine arena. It’s at a point now where it’s usable and reproducible. The research exists to support its use, but until there’s a philosophical change at the medical school level, it will not penetrate into the healthcare system and result in the necessary kinds of changes. JB: That’s a very good watchful note for all of us. I believe, as you’re indicating, that philosophy often results in action rather than action resulting in philosophy. It seems as if we’ve pushed a model to a point of diminishing returns and it’s time to start looking very seriously at the types of philosophical underpinning that naturopathic/natural medicine has to offer. I want to thank you personally, once again, for the extraordinary contributions you’ve made over the last two and a half decades as the rational voice of this movement. I also want to honor you as the 11th International Linus Pauling Functional Medicine Award winner. Thank you for sharing your concepts with us today. JP: Thank you again for the honor of the Linus Pauling Award. I was surprised and deeply honored. Dr. Pizzorno’s discussion stimulates so many thoughts and followup questions. One of the many that come to mind is the concept that the therapies we often use, based upon a single-agent mentality, do not address the full complement of things necessary to get outcome from the cause rather than just treating the symptoms. I would like to go back to the insulin resistance beta cell dysfunction association that Dr. Pizzorno alluded to. Over the last several months, we have been discussing vitamin D physiology, starting with Dr. Michael Holick from Boston University Medical School, moving to a wonderful discussion with Dr. Colleen Hayes at the University of Wisconsin Department of Biochemistry and, more recently, an exchange with Dr. Robert Heaney of Creighton University. All of these researchers have given us extraordinary new insight into the role and physiological importance of vitamin D as a prohormone being converted into its hormonal form, 1-25-dihydroxy-cholecalciferol. How does this relate to our discussion with Dr. Pizzorno regarding insulin resistance and insulin sensitivity? There is a connection. The paths are all in a web, interwoven one with the other. Let’s talk about hypovitaminosis D and its association with insulin resistance and beta cell dysfunction.   Hypovitaminosis D, Insulin Resistance, and b Cell Dysfunction Although the role of vitamin D in type 2 diabetes is well recognized, its relationship to glucose metabolism has not been well studied until recently. A paper appeared on this topic in theAmerican Journal of Clinical Nutrition.[15] These investigators were from the Division of Clinical Endocrinology and Preventive Medicine and the Center for Clinical Nutrition at the Department of Medicine, University of California, Los Angeles. Their work demonstrates that we need to look at second- and third-level questions when we start to develop individualized patient treatment programs for complex, chronic diseases. There is not one cause for these diseases—for instance, type 2 diabetes. In this study, the researchers investigated the relationship of 25-hydroxyvitamin D (which you have all heard about in previous interviews), to insulin sensitivity in b cell function. This study included 126 healthy glucose- tolerant subjects living in California. Insulin sensitivity index and first- and second-phase insulin responses were assessed by using a hyperglycemic clamp methodology. Regression analysis showed that 25-hydroxyvitamin D concentrations were positively correlated with the insulin sensitivity index and negatively correlated with insulin resistance, both the first- and second-phase insulin responses, which means higher 25-hydroxy vitamin D, higher insulin sensitivity, or lower insulin resistance. How could this be? Once again, it shows a strong potential endocrinological effect on b cell function, insulin sensitivity, and insulin reactions and glucose transport in type 2 diabetics, undoubtedly as a consequence of the pleiotropic effects of the hormonal form of vitamin D, the 1-25 dihydroxyvitamin D3. We are starting to look at a molecule that we thought of as only being involved with the prevention of bone loss. This was included in Dr. Heaney’s eloquent discussion in last month’s interview. We are now looking at its pleiotrophic effects as a hormonal initiator across cell signaling in many different cell types. The authors of this study state that although only glucose tolerant subjects were enrolled in this study, they are not sure whether this could be used to treat type 2 diabetes. It certainly appears to illustrate the importance of vitamin D in improving insulin sensitivity, and perhaps in helping to prevent type 2 diabetes. The observations suggest that hypovitaminosis D is associated with increased risk of metabolic syndrome. Vitamin D and Metabolic Syndrome Why would this be? What could be the role of the hormonal form of vitamin D in the prevention of metabolic syndrome? The role of vitamin D in metabolic syndrome was suggested by a recent report from the Coronary Artery Risk Development in Young Adults Study, a population-based prospective study in 3157 black and white adults, age 18 to 30 years of age, from four U.S. metropolitan areas.[16] It was observed that dairy consumption was inversely associated with the incidence of insulin resistance syndrome among overweight adults. Therefore, dairy consumption may reduce the risk of type 2 diabetes and CVD. Overweight subjects with the highest dairy consumption had a 72 percent lower incidence of the metabolic syndrome than did those with the lowest dairy intake. We could hypothesize that this may relate to vitamin D since individuals who drink vitamin D fortified milk likely ingest larger amounts. Therefore, it now appears that some studies are suggesting a relationship between vitamin D and insulin sensitivity. These studies do not yet prove that type 2 diabetes or insulin resistance will be ameliorated by intervention with vitamin D, but they broaden the web of understanding of the role that vitamin D plays as an immunological modifier and antiinflammatory in various cell types. We have already heard from Dr. Colleen Hayes that it helps to set the balance between the thymus dependent-1 (Th1) and thymus dependent-2 (Th2) lymphocytes, the part of the immune system that has to do with proinflammatory and antiinflammatory balance. Aging, Th1 and Th2 Balance, and Immunological Function One of the things we will be discussing at length at the 12th International Symposium on Functional Medicine is Th1 and Th2 balance and how it regulates immunological function. A recent interesting paper appeared in Clinical and Experimental Immunology, titled “Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans?”[17]In this paper, the authors talk about the increasing incidence of infectious diseases in older-age people, which they suggest may relate to a shift toward Th2 cytokine expression profile. As Dr. Hayes told us, vitamin D and its metabolite, 1-25-dihydroxyvitamin D, play a role in setting the balance of the Th1 and Th2 system. Connecting these ideas leads us logically to wonder whether this is part of the explanation as to how vitamin D could play a role in the reduction of incidence of type 2 diabetes, metabolic syndrome, insulin resistance, and CVD relative risk. We begin to look at the balance between TH1 and TH2 as an important factor in the outcome of several immune-related disorders. In elderly humans, it shows increased morbidity and mortality from infectious diseases, and we begin to see a shift toward Th2 dominance with a lowered level of Th1. In inflammatory conditions in individuals with CHD or arthritis, we often see the shift the other way, moving toward dominance of the Th1 type. By understanding some of these differentiations in immunological function and balance, and what agents help set the balance, we might be able to develop programs that would modulate not just the disease, but the underlying cause of the disease that relates to the immunological functional disturbance. Hypovitaminosis D in Burn Patients Patients with injuries, wounds, and burns have been shown to have low levels of vitamin D. It is proposed that the damage to the epithelial cells decreases their ability to produce active vitamin D. In an interesting paper published in the Journal of the American Dietetic Association,[18] a very high incidence of low serum 25-hydroxyvitamin D was demonstrated in individuals who (in this case, children), had burn trauma. The authors state that it is unclear why there is a deficiency of 25-hydroxyvitamin D; however, it appears that the reasons are related to a metabolic etiology. This has an implication on immunological function and the turnover of these active, signaling molecules. We are witnessing an extension and expansion of our vision. The simple mindedness that there is one agent that controls one endpoint is starting to wane. The primacy of the differential diagnosis is starting to be replaced by the concept of understanding the function of the system. A model of what people call personalized medicine is emerging built around the principles of multifactorial interrelationships between genes and environment to give rise to the outcome called function. One of the important takeaways in this discussion, and Dr. Pizzorno said it very eloquently, is that as we start to understand how to harness this information, we need to keep it at a level that can be delivered in clinical practice. Unfortunately, we will probably never have all the time we would like with each patient, which would mean hours of information-gathering and discussion. It has to be codified into a procedure and a system that will allow for cost-effective application and be non-discriminatory for those who may be less advantaged. We do not want to end up with a medicine for the elite. We find that some of the people who need these kinds of interventions are those who are the least capable of being able to afford the necessary high technology. The challenge for us is to find simpler ways of analyzing complex information sets and delivering more prudent information to the patient related to the management of the cause (not just the signs and symptoms) of the disease, based upon increasing understanding of function. That wraps up this issue of FMU and sets the stage for November, with increasing interest in immunological disorders associated with chronic diseases of aging.

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Bibliography

1 Weijer C, Miller PB. When are research risks reasonable in relation to anticipated benefits? Nature Med. 2004;10(6):570-573. 2 Cuevas A, Miquel JF, Reyes MS, Zanlungo S, Nervi F. Diet as a risk factor for cholesterol gallstone disease. J Am Coll Nutr. 2004;23(3):187-196. 3 The Lewin Group Inc. Prepared for Wyeth Consumer Healthcare. A study of the cost effects of daily multivitamins for older adults. 2004;1-30. 4 Stearns V, Hayes DF. Cooling off hot flashes. J Clin Oncol. 2002;20(6):1436-1438. 5 Gottlieb N. Nonhormonal agents show promise against hot flashes. J Natl Cancer Inst. 2000;92(14):1118-1120 6 Dormire SL, Reame NK. Menopausal hot flash frequency changes in response to experimental manipulation of blood glucose. Nurs Res. 2003;52(5):338-343. 7 Nelson HD. Postmenopausal estrogen for treatment of hot flashes. JAMA. 2004;291(13):1621-1625. 8 Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes. JAMA. 2004;291(13):1610-1620. 9 The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative Randomized Controlled Trial. JAMA. 2004;291(14):1701-1712. 10 Hulley SB, Grady D. The WHI Estrogen-Alone Trial—do things look any better? JAMA. 2004;291(14):1769-1771. 11 Klein S, Fontana L, Young VL, et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med. 2004;350(25):2549-2557. 12 Kelley DE. Thermodynamics, liposuction, and metabolism. N Engl J Med. 2004;350(25):2542-2543. 13 Shade ED, Ulrich CM, Wener MH, et al. Frequent intentional weight loss is associated with lower natural killer cell cytotoxicity in postmenopausal women: possible long-term immune effects. J Am Diet Assoc. 2004;104:903-912, 14 Nebeling L, Rogers CJ, Berrigan D, Hursting S, Ballard-Barbash R. Weight cycling and immunocompetence. J Am Diet Assoc. 2004;2004;104(6):892-894. 15 Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and b cell dysfunction. Am J Clin Nutr. 2004;79:820-825. 16 Pereira MA, Jacobs DR Jr, Van Horn L, Slattery ML, Kartashov AI, Lu DS. Dairy consumption, obesity, and the insulin resistance syndrome in young adults. JAMA. 2002;287(16):2081-2089. 17 Sandmand M, Bruunsgaard H, Kemp K, et al. Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans? Clin Exp Immunol. 2002;127:107-114. 18 Gottschlich MM, Mayes T, Khoury J, Warden GD. Hypovitaminosis D in acutely injured pediatric burn patients. J Am Diet Assoc. 2004;104:931-941.

Welcome to Functional Medicine Update for November 2004. What is one of the most significant, prevalent disorders that functional medicine professionals see in their practices? That is the theme we will be discussing in this edition of FMU. Our listeners may agree that this condition ranks high on their lists of the most prevalent clinical conditions seen in the rapid-paced world in which we live. I am speaking about functional, or borderline hypothyroidism. According to epidemiological evidence, hypothyroidism is increasing in our culture, particularly in women as they age. It is potentially serious, often clinically overlooked, readily diagnosed by laboratory testing, and eminently treatable. Given that the majority of patients seen by general practitioners are females, and that we are an aging baby boomer population, it is not unexpected that virtually every practitioner in the field has had to deal with conditions related to functional, borderline hypothyroidism. There is a large amount of information, both formal and informal, about the assessment and intervention in this condition. We felt it would be useful to focus the whole first section of FMU this month on the story of borderline hypothyroidism. As part of that, our Clinician of the Month has had extensive experience in this area, and he will share some of his own clinical takeaways from seeing several thousand patients with different aspects of thyroid dysfunction. Before we get to his interview, it is important to set the stage and define borderline functional hypothyroidism. How does it present and what clinical intervention protocols might be most useful for its management? Fortunately, there is a review paper that appeared in The Lancet this year that contains some good “news to use” about the thyroid gland and the state of hypothyroidism.[1] I am going to cite some of the information from that review paper. History of Hypothyroidism First, I want to talk about the history of hypothyroidism. When we look at the history of thyroid-related dysfunction, we see that knowledge about the condition is fairly recent. It goes along with the emerging theme of our understanding of the endocrine system. Only since the establishment of organic chemistry as a discipline, and application of that discipline to physiology, have the concepts of endocrinology advanced. “In 1874, Gull described several previously healthy women who acquired clinical features similar to those in cretinism. 4 years later, Ord coined the term myxoedema to describe a syndrome in five women with coarse features, mental dullness, dry skin, hypothermia, and oedema. At much the same time, two Swiss thyroid surgeons, Kocher and Reverdin, independently described cachexia strumipriva, a cretin-like state developing after thyroidectomy. In 1883, the Clinical Society of London formed a committee to investigate the connection between myxoedema, cretinism, and cachexia strumipriva; and 5 years later, the committee issued its landmark report linking the three conditions. In 1912, Hashimoto described autoimmune thyroiditis in four women with goitres that seemed to have turned into lymphoid tissue (struma lymphomatosa); and in 1956, Roitt and colleagues reported the presence of circulating thyroid autoantibodies in this disorder.” This suggested that the thyroid gland was being attacked as if the body was allergic to it. “Treatment for hypothyroidism with sheep thyroid extract was first reported by Murray in 1891. Thyroid hormone was crystallized in 1914 by Kendall.” This treatment ultimately won the Nobel Prize in Medicine for Murray and his group. “Reports of thyroxine’s synthesis by Harington and Barger, and of its initial physiological testing both appeared in 1927. Triiodothyronine was discovered by Pitt-Rivers and Gross in 1952; and its endogenous generation from thyroxine was described by Ingbar, Sterling, and Braverman in 1970. “In 1963, Condliffe purified thyrotropin (thyroid stimulating hormone), and soon thereafter Odell and Utiger both reported the first immunoassays for human thyrotropin. In 1971, Mayberry and Hershman simultaneously described use of thyrotropin immunoassays for diagnosis of hypothyroidism.” The field, as we are now describing it—the immunochemistry, physiology, and function of the thyroid gland, and the activity of the thyroid hormone components—is fairly recent (within the last 30 to 40 years), as it has contemporarily been developed. Through that period of time, the first discoveries were made about frank thyroid disease. This resulted in the naming of conditions like Graves’ disease and Hashimoto’s thyroiditis. Over the last decade or two, however, concerns about borderline hypothyroidism have become more prevalent. It appears there is a much wider range of thyroid dysfunction in the absence of overt pathology than was previously recognized. This can be connected to many signs and symptoms related to thyroid hormone function at the cellular or tissue level. If we look at the prevalence of subclinical hypothyroidism in the United States population, the data suggest, based upon interpretations of thyroid stimulating hormone (TSH) levels, that five percent or more of the population probably presents with functional borderline hypothyroidism, or so-called subclinical hypothyroidism. The controversy that exists is whether the presence of borderline or subclinical hypothyroidism demonstrates the need for treatment, or whether it is just a marker for later-stage, more serious clinical conditions indicating further treatment. Would we be under-treating if we did not intervene in subclinical hypothyroidism or, if we did, would that constitute over-treatment? Those are interesting questions that have been discussed in both academic and intellectual circles, and that have now filtered down to the ground level. Some practitioners and certain medical and disciplinary boards have examined physicians who have intervened in borderline or subclinical hypothyroidism and determined that they were over-treating. I want to address that issue, because it is important for the patient and the practitioner from the standpoint of clinical and medical/legal issues. Causes of Hypothyroidism The most common cause of acquired hypothyroidism, either subclinical or overt, is autoimmune thyroiditis, commonly called Hashimoto’s disease. This condition is seven-fold more common in women than in men, and increases in incidence during middle life.1 The role of autoimmunity in its pathogenesis is lent support by a histological finding of diffuse lymphocytic infiltration of the thyroid gland, presence of circulating thyroid autoantibodies in almost all patients, and in animal models created by immunization with thyroid antigens, suggesting that there is an immunological component. The finding that affected thyrocytes express the MHC class II proteins needed for antigen presentation to CD4 (helper) T lymphocytes, and evidence of activated CD4 T cells specific for thyroid antigens, appear to support the etiology of Hashimoto’s thyroiditis. The questions are: Why are people, as they age, more susceptible to the production of antithyroidal antibodies? Why do they become allergic, in part, to their own thyroid gland? These questions are open to much controversy and discussion because, to date, there are no definitive, clinical answers. Symptoms of Hypothyroidism In patients with autoimmune thyroiditis, the thyroid gland can be nonpalpable, or diffusely enlarged (150-300{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of normal size). In patients with the fibrous variant, the thyroid gland is hard and markedly enlarged, but that is not necessarily a prerequisite or a clinical finding in individuals with borderline, subclinical hypothyroidism. Antimicrosomal or anti-thyroid peroxidase antibodies are present in 95{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of affected individuals, and this has often been used as a biochemical or laboratory marker. Anti-thyroglobulin antibodies, however, are present in only about 60{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of patients, and therefore appear to be less clinically specific or sensitive. Obviously, indications for hypothyroidism tests depend on the clinical indications and presentation in the patient. Many physicians are very skilled at evaluating and understanding the connection of symptoms to thyroid-adrenal-pituitary- hypothalamic function. Clinical signs include fatigue, cold intolerance, constipation, impaired memory, slowed mental processing, depression, ataxia, muscle weakness, muscle cramps, menstrual disturbances such as alteration of the cycle producing dysmenorrhea, infertility, goiter, hoarseness, and weight gain. All these symptoms are classic examples associated with hypothyroidism, and can be seen in different degrees and prevalence relative to borderline subclinical hypothyroidism. Radiological and Laboratory Test Abnormalities of Hyperthyroidism Radiological abnormalities often show pericardial and pleural effusions and pituitary gland enlargement in frank cases of hypothyroidism, but these are not necessarily to be seen in borderline cases. Laboratory test abnormalities often show elevated cholesterol as LDL cholesterol, lowered HDL cholesterol levels showing an elevated LDL-to-HDL ratio, low levels of plasma or serum sodium, and often hyperhomocysteinemia. This implicates some influence on the modulation of important amino acid metabolism, which is associated with vascular disease, dementia, Alzheimer’s disease, certain forms of cancer, bone loss, and arthritis. Apparently, there is an interconnection between hypothyroidism and the folate cycle, renal function, and homocysteine metabolism and excretion. Risk Factors for Hypothyroidism When we look at the risk factors for hypothyroidism, we see conditions that would initiate autoimmunity, particularly focused on the thyroid gland, such as any type of precipitating event that might upregulate MHC class II antibodies against the thyroid. These could be allergens, stress factors, or toxins. Some environmental factors have been clearly implicated that may be associated with the appearance of autoimmune thyroiditis and borderline hypothyroidism. I want to emphasize that there are genetic underpinnings of risk. Therefore, we cannot say that all people respond identically. Genomic concepts indicate that there is wide variation in the ways people respond to the environment through their neuroendocrine and immune systems and that these variations might translate into potential risk to hypothyroidism. Treatment for Hypothyroidism Once the condition has been diagnosed, how is it managed? The most common treatment is intervention with synthetic thyroxine (T4). In the literature, it is generally considered that the optimal dose of T4 for hypothyroid patients is related to body weight, trying to achieve about a 1.8 mg-per-kg dose in adults. I will speak more to that in a few moments. Generally, when physicians initiate thyroxine therapy, they start with a dose around 125 mg per day in the 70-kg individual, and laboratory monitoring for TSH is repeated some four to six weeks after initiation. That is the standard approach for frank hypothyroidism, but the question might be raised as to whether this is the best approach for managing a patient with borderline subclinical hypothyroidism. There are many potential causes of TSH elevation related to things such as drugs and other covariant illnesses that may create alteration in thyroid function, sensitivity, and metabolism. I will be speaking about those in a moment because it is important to clinically evaluate other factors that may contribute to what appears to be a thyroid-related dysfunction. Adverse Reactions to T4 Treatment What are the adverse reactions to T4 treatment? The most common reaction is called subclinical thyrotoxicosis, with increasing risk to bone loss, and atrial tachyarrhythmias. These symptoms appear to be the most common in over-treatment with T4. It is also important to note that if the patient has borderline adrenal cortical insufficiency (often called hypoadrenocorticism), and ischaemic heart disease, over-treatment with T4 intervention can induce cardiac-related dysrhythmias. One has to be mindful of the fact that there is close communication between the adrenal glands through the hormones they secrete, particularly cortisol, and the thyroid hormone-modulated effects on cellular function, particularly the cardiocyte. Managing a patient with borderline hypothyroidism patient with T4 intervention needs to be accomplished skillfully and carefully. Neuropsychological Deficits Associated with Hypothyroidism The big advantage of using T4 is lowering the potential risk to either primary or secondary diseases. Often, the rationale for treatment in borderline subclinical hypothyroidism is reduction of later-stage problems. Then, the question is whether a combination of T4 and T3 needs to be used in primary prevention. That has been a long-standing debate, and there has been considerable controversy about it. We have discussed this in previous issues of FMU. We cited from a paper in The New England Journal of Medicine several years ago, indicating that neuropsychological deficits associated with hypothyroidism appear to be better managed by using a combination intervention with T3 and T4.[2] However, since that paper appeared, two others have evaluated that intervention in similar patients and, in both cases, investigators came to the conclusion that there was no advantage to using a combination of T3 and T4. These papers included studies by Walsh et al. and Sawka et al. that noted no improvements in well being, cognitive function, or quality of life with a combined treatment of T3.[3],[4] There is still some controversy about the use of T4 by itself versus a combination of T3 and T4. I should point out that in the Bunevicius study, a ratio of T3 to T4 that was physiologically unnatural was used (a very high level of T3 relative to T4). That may not duplicate the rhythmic effect these hormones have when secreted from the thyroid gland at normal ratios—90{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} T4 and 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} T3. It may have been a better trial if those ratios had been used, as they appear to be more compatible with normal physiology. Notwithstanding that controversy, patients with mild hypothyroidism (borderline or subclinical hypothyroidism) may receive an advantage from primary or secondary prevention of things like cardiovascular disease (CVD), as well as dysphoria. First of all, the potential benefit is to prevent the progression to overt hypothyroidism with all the attendant risks. Second would be intervention for reducing future risk of CVD by improving lipid profiles, reducing inflammatory markers, and improving insulin sensitivity and glucose tolerance, all of which are interrelated with thyroid hormones through the web of the neuroendocrineimmune system. The general strategy in managing a patient with borderline subclinical hypothyroidism is not solely to reduce the symptoms associated with the condition, but also as secondary prevention for the improvement of cardiovascular and endocrine function, in general. I would like to talk about some of the conundrums associated with subclinical borderline hypothyroidism. It is important to talk about what is said in the traditional endocrinological literature about the assessment of this condition. I am going to cite some of the treatment guidelines from the National Academy of Clinical Biochemistry and the Laboratory Support for the Diagnosis of Thyroid Disease, first published in 2003.[5] In this monograph, the authors discuss the kinds of discordances in the FT4/TSH blood chemical analysis that assesses thyroid function that lead us to see that there may be conditions where there are normal levels in the blood panel, but still some concern about abnormal levels in the individual. Let me cite some examples. What happens if a person has a modestly elevated TSH, but a normal T4? For example, a TSH not high enough to be pathologic, but one which is just above the reference range, and a T4 level that is within the reference range. What should the practitioner do in this case? This is a classic example of mild borderline subclinical hypothyroidism. Clinical symptoms in the patient should be examined very carefully to see if any of them are associated with what would classically be called a thyroid-related function. In that case, anti-thyroidal antibodies to thyroid peroxidase should be measured, with confirmation of TSH levels after six weeks of intervention. These symptoms may carry the strongest connection between borderline hypothyroidism and later-stage concerns. What about a normal T4 and a depressed TSH? Some people might call this mild hyperthyroidism. This would require looking for some kind of thyroid toxic effect that is inducing hyperthyroidism. It is clinically uncommon to see a TSH less than 0.5 with a normal T4, but in the scheme of looking at the range of thyroid function, this would be the other side of the coin—a hyperthyroid condition which might later become a hypothyroid condition based upon reserve and exhaustion of the gland and the system. What about individuals with a normal TSH, but either a slightly elevated or slightly depressed T4? They are not driving the thyroid gland very hard with pituitary TSH, but they have either a low or slightly elevated T4 level. In those cases, we would look at the same symptom cluster. Is there evidence of thyroid-related dysfunction? Is there evidence of glucose intolerance? Is there evidence of lipid abnormalities in the plasma profile? We would need to try and pull together a web of understanding about the complex. Perhaps rather than being a cause, it is the effect of other disturbances in the endocrinological system that need to be brought into balance. It could be estrogen, testosterone, or progesterone imbalances, cortisol imbalances, or insulin imbalances, all of which are interrelated in the communication with thyroid hormone. Recall that the principal way T3 is produced is by extra-thyroidal conversion of T4 to T3 by a deiodinase enzyme that is selenium-dependent. Selenium deficiency can produce secondary symptoms of hypothyroidism. Sometimes, by increasing selenium intake, thyroid function can be improved by the enhanced extra-thyroidal conversion of T4 to T3. I am not talking about toxic doses of selenium; I am talking about 50 to 400 mg per day of an organoselenium source to see if it would influence the conversion of T4 to T3. The intracellular activity of thyroid hormone comes through T3 cellular communication to the T3 receptor site. Therefore, the interconversion of T4 to T3 is very important in establishing tissue-specific activity of thyroid function. When the data from laboratory analysis is ambiguous for TSH and T4, and even T3, and one thing looks normal and another looks slightly abnormal, symptoms need to be correlated and nutritional and environmental factors need to be examined. Then, one can start to develop a whole picture of how these things may interconnect, giving rise to what appears to be only a slight imbalance in thyroid hormone function as it pertains to laboratory analysis. What about TSH levels? TSH can be slightly elevated or slightly depressed, with normal levels of T4. In that case, pituitary level dysfunction is somehow regulated by compensation of the thyroid gland production level of T4. I would start looking at things like feedback processes from the adrenal glands. I would also look at cortisol and stress. These may be playing on organ reserve, where the web of interaction has been stressed, yet there is enough resiliency or reserve in that web to compensate by mobilizing the reserve. We may only be seeing the shadows of dysfunction by slight elevations or depressions of TSH, but the thyroid gland is still regulating itself adequately with reasonably normal levels of T4. There can also be normal levels of TSH and elevated levels of T4 in the pathological range. There could be very high levels of T4. In that case, one would be getting into the concept of endocrinopathy, and should be looking at TSH-secreting pituitary adenomas, or something like that. In the case of marginal alterations in TSH, T4, or T3 levels, if they do not appear to make sense, I would start looking at imbalance and reserve situations, and the tissue specificity when tied with clinical symptoms. Relationship of Serum TSH to T4 What about the serum TSH-to-T4 relationship? When the hypothalamic pituitary function is normal, there is a log linear inverse relationship between TSH and free T4. This means the log of the TSH levels is associated with a reduced level of free T4 because of negative feedback inhibition by pituitary TSH secretion by thyroid hormones. Thus, thyroid function can be determined either directly by measuring the primary thyroid gland product (T4), or indirectly by assessing the TSH level, which inversely reflects the thyroid tissue concentrations sensed by the pituitary gland. It follows that high TSH and low T4 is characteristic of hypothyroidism. That would be the general way it has been historically diagnosed as primary hypothyroidism. However, as I just mentioned, there are many conditions that reflect a borderline subclinical imbalance state that do not appear to be clear. In those cases, looking at other variables necessary to assess the state of the patient is important. Variations in Hormone Levels There are variations in thyroid hormone levels over age and over conditions. I have already talked about anti-thyroidal antibody conditions leading to hypothyroidism that increase with age, more commonly seen in women than men. There are hormonal effects from cortisol and from estrogen and testosterone that influence thyroid-binding hormones and thyroid metabolism. It would be safe to say that one needs to be very cautious in assessing thyroid hormone blood analyses by making sure all of the other variables are examined—age and gender of the patient, medications, and the presence of other illnesses. We know about the euthyroid sick syndrome that is sometimes seen in hospital patients. It is less common in ambulatory patients, but there are modifications based upon other illnesses that affect the way thyroid hormones are secreted, metabolized, and excreted. All of these variables need to be taken into account as we start evaluating whether the patient needs thyroid hormone replacement therapy. Coefficient of Variation in Test Results I want to say something about the tests. We often think when we get a number from a biochemical test from a clinical lab that the same number would be reproduced if we were to do it repetitive times. But every test has an interindividual variability, so-called coefficient of variation, or CV. T4 and T3 have fairly tight CVs in the range of 10-15{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} inter-sample variation. But with TSH or thyroglobulin, we see a lot more potential variation, a higher CV, meaning there is more scatter in the test. It is important to recognize that the same number may not be reproduced every time, and one needs to look at both the laboratory variation, as well as the patient physiological variation, in applying a meaning and interpretation to that number. The reason I mention this is because I often hear individuals talk about very small changes in TSH and placing considerable amount of clinical importance on them. This is probably uncalled for, based on the variation in the test and the percent CV. Indications of High T3 and T4 Levels I want to discuss things that might influence T3 and T4. Many individuals have moved away from T4 and rely more on T3 levels. A high serum T3 level is often an early sign of recurrence of Graves’ hyperthyroidism. High serum T3 usually precedes iodine-induced thyroid toxicosis. Serum T3 measurements are useful for distinguishing mild subclinical hyperthyroidism from T3 toxicosis. Looking at T3 levels to determine thyroid toxic effects may be better than looking at T4 levels. TSH and T4 measurements have historically been found to be most useful for picking up borderline functional hypothyroidism. T3 levels may be better for evaluating at the higher end of the normal range for potential thyroid toxicosis. The reason for that is because most of the T3 that is working at the cell physiological level is intracellular and not available for analysis, and we can be misled as to how much T3 is really functioning in the body. A high level of free T3 in the blood suggests thyroid toxicosis, and it normally occurs as a consequence of a drive from iodine or an increased conversion of T3, with drugs or disease being the principal reasons. Drugs that Compete for Thyroid Hormone Binding There are many drugs that compete with thyroid hormone binding and therefore displace thyroid hormone off the binding globulin, thereby liberating as free hormone into the plasma, making it more active. This can induce thyroid toxicosis by increasing availability to free hormone. The most common interactions occur from drugs such as Phenytoin, Furosemide, and some anti-psychotic and antidepressant medications. These can displace thyroid hormone from the binding globulin, increasing its availability and potential for activity, and also increasing the level in the plasma. One might be led to a false sense as to where that hormone is coming from if these medications are not taken into account. By the way, blood-thinning medications like heparin may also increase potential for thyroid dysfunction. Serum from patients treated with heparin, including the low molecular weight heparin preparations, variously exhibits high free T4 levels secondary to heparin’s effect on inducing lipase activity that increases free fatty acids, thereby altering the binding of T4 to the thyroid hormone globulin, and increasing its level. This is just a reminder to make sure that the patient’s medications are evaluated when interpreting a thyroid hormone blood chemical analysis. We have talked a little bit about T4 and T3 hormone replacement for assessment. In patients with mild subclinical hypothyroidism, starting at lower-dose interventions of either T4 or a combination of T4 and T3 is what has been called for. Elevated Thyroid Hormone-Binding Globulin Autoantibodies or Thyroid Peroxidase Autoantibodies What about patients with elevated thyroid hormone-binding globulin autoantibodies or those with thyroid peroxidase autoantibodies? This is an important part of the story because there are patients with borderline hypothyroidism for whom the etiology is not well recognized. Once antithyroidal peroxidase autoantibodies are assessed and an elevated level is observed, one begins to think of immune system dysfunction or autoantibody production against the thyroid gland as the etiological agent. When this is the case, one wants to lower the load of antigenic precipitators. These could be allergens, toxins, or various agents that induce upregulation of expression of the antibodies from B cells, the so-called Th2 component of the system, that try to reestablish a balance between Th1 and Th2 lymphocyte activity. Omega 3 fatty acids, various flavonoids, vitamin C, and vitamin E are immune-modulating substances that help restore balance to the Th1 and Th2 system. Lowering the load of various antigens, such as gluten from grain-based products, may be very important. Upon continued consumption of gluten, individuals with gluten sensitivity can suffer adverse effects in their immune systems that increase anti-thyroidal antibodies and produce what might look like Hashimoto’s thyroiditis and altered thyroid hormone metabolism and function. I would urge evaluation of the potential of food-based antigens That brings up the important role that insulin and insulin resistance may play, and their association with endothelial dysfunction, lipid abnormalities, and thyroid dysfunction. There is an interesting article in the Journal of Internal Medicine which examined associations among leptin from adipocyte fat cells, insulin resistance, and thyroid function in patients placed on a long-term weight-loss program. The investigators found an interesting correlation between insulin, leptin, body composition, and thyroid hormone metabolism.[6] Often, patients with hypothyroidism also present with cholelithiasis and gallstones. The cholesterol gallstone is also often found in individuals with metabolic syndrome. Increasing saturation of the bile with cholesterol and its esters produces cholesterol gallstones. If insulin sensitivity is regulated, blood lipids managed, and thyroid function improved, the risk to gallstone formation may be significantly reduced. We see this most often in the postmenopausal woman, as well as a high prevalence of cardiac disorders, hypothyroidism, and Hashimoto’s autoimmune thyroiditis. Again, looking at the web, these things tend to track together. If you want to know more about the metabolic syndrome and cholesterol gallstones, there is an editorial about their association in the American Journal of Clinical Nutrition.[7] When putting a person into an insulin improvement program, stress management program, or a thyroid management program, one is starting to develop a comprehensive strategy toward the management of what might be considered borderline subclinical hypothyroidism. Even patients with excess body fat who go into an appropriate weight-loss program—which lowers inflammatory biomarkers such as tumor necrosis alpha (TNFa) and C-reactive protein (CRP), improves serum lipid patterns, and improves insulin sensitivity—are those in whom improved thyroid function should also be observed.  

INTERVIEW TRANSCRIPT

Clinician of the Month Raphael Kellman, MD 250 West 90th Street Apt 17C New York, NY 10024 JB: It’s time for our Clinician of the Month. This month, we are fortunate to have a clinician who is actively involved in the area of functional and nutritional medicine. He has gained a wide and well-deserved reputation for understanding the interconnectedness, what we call the functional medicine matrix, and applying it successfully in clinical practice. Dr. Raphael Kellman is a medical doctor who completed his training at Albert Einstein College of Medicine in New York City. He has been involved in the development of what I call a “frontier level clinic” in New York City, one I hear a lot about from people as I travel on the East Coast. It is a great privilege to have Dr. Kellman with us this month. Raphael, welcome to Functional Medicine Update. Perhaps you would tell us about how you made the transition from your training to functional and nutritional medicine. The Thyrotropin-Releasing-Hormone (TRH) Stimulation Test RK: Thank you, Jeff. It’s a pleasure to be here. I’ll tell you how it all started. When I first finished my residency in internal medicine, I was working for other doctors and noticed that many of the patients I was seeing had typical symptoms of low thyroid, yet their blood tests turned out to be in the normal range. I knew something was off. Other doctors had placed many of these people on antidepressants. They were told they needed to lose weight and they needed a vacation. Yet, they all had the textbook symptoms of hypothyroidism. I knew there was another thyroid test called the TRH Stimulation Test, which was recommended in the medical textbooks, and that when one was in doubt, meaning when the blood tests were borderline, one should do this test. Even though the blood tests were in the normal range, the patients seemed borderline in terms of their symptoms, so I thought we should do the TRH test. The doctor I was working with agreed to let me do it, and we didn’t charge the first 100 patients. I began conducting the TRH Stimulation Test on patients who had typical symptoms of hypothyroidism, and they failed the test significantly. I started these people on thyroid hormone and saw that they got better, beyond the placebo response. This all happened in 1989, and it got me thinking in terms of functionality, that there isn’t a sharp demarcation between sickness and health; that in fact, there must be some gradient. I was taught in medical school that you’re either healthy or you’re sick. You have a disease and, if you don’t, you’re totally healthy. Immediately, I got to see firsthand that the black-and-white type of thinking is not really up to date. I started seeing the same principle with diabetes. There was a gray area where people actually didn’t have diabetes, but they seemed to have all the symptoms of a diabetic. I also believe they probably had all the risk factors for diabetes. Of course, ten years later, most doctors know that to be true. The thyroid is just lagging behind, but eventually they’ll get it in that domain, as well. We have to think in terms of functionality and if the tests are not revealing functionality, then they are inadequate, not the patients. That’s basically how I came to understand the human body in terms of functional medicine. JB: That’s a fascinating story. You have also done a nice job in describing that in your book, Total Renewal, which I found to be a very well-described premise about functional medicine and the difference between pathology and reduced function. You’re to be complimented on the way you contextualized that. Let me ask you a question about the specifics of the TRH Stimulation Test. We have all studied that test in school in endocrinology classes, but most people who are not endocrinologists probably have not brought it into practice because they think it’s only applicable to frank, primary, severe hypothyroidism. The concept of using it as a challenge test to evaluate organ reserve is a fascinating concept that you’ve developed. How do you do the test, and what would you consider to be an abnormal result? Interpreting TRH Test Results RK: I’ve probably done at least 7000 TRH tests. By now, I can tell you what the abnormal graph should look like. Part of it is experience. I’ve learned that even if it’s something written in a textbook, you may have to take it with a grain of salt. You have to understand what you see in clinical practice. Frequently, it’s not the same as what you might read in a textbook. You need to have self-confidence in what you’re doing in your own practice. After you’ve done enough of these tests, you know what’s normal and what’s abnormal. Let me explain the test. We inject TRH (a hormone which comes from the hypothalamus), into the vein and take blood 25 minutes later. We check for levels of TSH. If one’s thyroid is low, the pituitary is going to be producing a lot of TSH in an attempt to wake up the thyroid to produce more thyroid hormone. Theoretically, that increase of TSH in the pituitary should be reflected in the blood on what I call a static blood test, a regular blood test. However, we’re finding that’s not always the case. Even though sometimes there’s a lot of TSH in the pituitary, it might not actually show up in the blood for a number of reasons which unfortunately, we don’t have time to get into. However, if you inject TRH, which challenges the pituitary, it has no choice but to reveal how much TSH it is building up in its system, in the gland. It will then spill out into the blood. You give the blood test, after which you get an inner view of what’s happening in the pituitary, which is a reflection of what’s going on in the thyroid. If you do this test and see that the pituitary secretes a TSH of, let’s say 25, it’s pretty conclusive (in a woman especially, but also in a man) that the thyroid is low. Anything in a woman above around 15, 17, or certainly 20, reflects hypothyroidism. In a man, it would be anything above a 12. That, in my opinion, after doing so many of these tests, is very suspicious of a hypothyroid. However, there are some cases where people don’t have a brisk TRH response because the pituitary is malfunctioning, as well—the pituitary’s level of functionality is declining and it can’t produce a lot of TSH. That also has to be taken into account. For example, if someone has heavy metal poisoning, it will frequently not only affect the thyroid, but in some situations, it can also affect the pituitary. This type of test requires not only the science of medicine, but a hefty dose of the art of medicine, as well. Pituitary versus Thyroid Problems JB: You’ve raised some very interesting questions. Given that you are stimulating with TRH, which then stimulates the release of thyroid stimulating hormone from the pituitary, which subsequently influences the release of thyroxine from the thyroid gland, how do you differentiate clinically between a pituitary level problem versus a thyroid problem? Or, do you treat them both together? RK: If the thyroid is very low, then the pituitary, under ordinary circumstances, would be producing a lot of TSH. Then you know that the thyroid is low. That’s what we’re finding in the vast majority of patients. There are a small percentage of patients that still have hypothyroidism, but the problem is coming from the pituitary. In that situation, you are not going to get a high TSH response when you inject TRH. Then, you are going to have to use more clinical judgment. In that type of situation, I find that the baseline TSH tends to be over 2.5, or maybe even 3.0. In that case, it tends to be higher than in people who have low thyroid from a thyroid abnormality, not a pituitary abnormality. What happens is that the difference between the pre- and post- tends to shrink. In my experience, in people who have only a pituitary abnormality, they’re not going to secrete much TSH. Sometimes, it’s a combination problem, meaning that the thyroid is slightly dysfunctional and the pituitary is slightly dysfunctional. Then you will see an effect where the pre- and the post- of the TSH will not be very different. JB: Do you find there’s any evidence of differential clinical signs or symptoms that are markers, or are the symptoms diffuse and don’t give specificity? RK: Unfortunately, the latter is true. It’s difficult to differentiate. Symptom Clusters in Hypothyroidism JB: In your experience, over the 7000 people you’ve tested, some of whom have shown abnormal tests, what kind of symptom clusters are indicative of subclinical hypothyroidism? RK: Frequently, they’re going to complain of fatigue and weight gain. Not everyone has weight gain, and sometimes this can be misleading. Sometimes, you can have weight loss, even in hypothyroidism. The common complaint is that they wake up more tired in the morning than when they went to sleep or, after they wake up, they feel they need another night’s sleep. Brain fog is common; constipation is frequent. People do not have bowel movements on a daily basis. Women tend to have irregular periods. There is muscle and joint pain. Unfortunately, a lot of people who are only in their 40s or 50s just assume that it’s due to aging, which is absurd. Where they’re getting this notion from is beyond me. I think it’s coming from some doctors and our culture, but that needs to be changed. If someone in their 50s has joint pain, it’s not due to aging. I always tell these patients that if they were 95 years old and they told me their joint pain was due to aging, I might accept it, but not at the age of 55. We find there is some functional problem based on the TRH test. When you start treating the thyroid, all of a sudden, the fatigue goes away, the brain fog goes away, and the joint pain goes away. The Dysphoria Component JB: How about dysphoria? Do you find there’s a depressive component? RK: Absolutely. A significant percentage of people with low thyroid have depression. They don’t know why they’re depressed. Their lives could be great, and yet they’re depressed. Recently, I had a woman who said she just got married a year ago. She has a wonderful husband and a wonderful life. Money is not a problem, but she’s depressed. She had a low thyroid proven on the TRH test. She started on thyroid hormone and all of a sudden, she’s not depressed any more. Dysphoria, depression, anxiety, and mood swings are all quite common signs and symptoms of hypothyroidism. JB: It’s interesting, because these observations you’ve made beg the question of origin. Why the thyroid as a problem organ in the late 20th, early 21st century? Is it stress? Is it environmental factors? What relationships have you seen between the ways a patient might present and the appearance of a thyroid problem? Environmental Toxins RK: These are good questions. There is a virtual epidemic of dysfunctionality, and it comes significantly from the thyroid, although that’s not the only culprit. I believe that we’re environmentally poisoned. It’s not like we’re in Bangladesh and it becomes quite obvious that we’re being poisoned by arsenic because we’re developing severe neurological symptoms. It’s a lot more insidious; it’s a lot more chronic; it’s a lot more slippery here. It’s not that the levels of these heavy metals, like arsenic, aluminum, and mercury, cadmium, and titanium are so high that it becomes obvious. It’s more in the range where we don’t really believe it could play a role. Why we don’t believe it could play a role has to do with the way we were taught in medical school with the paradigm that was used to understand health and disease. The most important thing that I’ve accomplished is finding a way to uproot that way of thinking. That paradigm was instilled in us in medical school only ten years ago, and that is the non-functional perspective, a very limited way of understanding health. Now, I’m coming from a different paradigm and seeing health with a different pair of glasses. If I see a level of arsenic, or mercury, or aluminum that’s even slightly elevated, it’s shocking to me and red lights go off. Ten years ago, I probably would have just dismissed it as nothing. I would hesitate even bothering to do the test. But that paradigm has shifted. Now, I believe that when someone has even low, low levels of these heavy metals, it’s a significant problem. It’s going to affect our health in ways that will not lead to a specific diagnosis, but might lead to debilitating problems that will consistently elude the typical medical doctor. Intervention for Toxicity and Thyroid Dysfunction JB: If you have identified in a patient’s history that there may be an underlying toxicity relationship with their thyroid dysfunction, what type of intervention do you use? Obviously, you’re going to support the thyroid, but there may be other mitigating triggers. RK: It can be approached on two levels. First, you can treat the symptoms. If they have low thyroid, I always use a combination of T4 and T3, meaning I would use Armour thyroid frequently, or any preparation that has a combination of the two. There were some small studies and reports in The New England Journal of Medicine showing that adding T3 does make a difference, especially with cognitive/emotional/psychological issues. Clinically, I find that to be true—it’s necessary to add T3. If the thyroid gland makes 10{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} T3, why not try to mimic what the body is doing? That’s what I do, so we use a combination of T4 and T3. It’s also necessary to look into the underlying causes. Why did this happen in the first place? In addition to understanding the psychological/emotional/stress components, you can evaluate with neurotransmitter testing. You can evaluate it, of course, through the patient’s history; and you can evaluate using adrenal saliva testing that we frequently do. You can evaluate the person’s response to the stress. There are definitely ways of modulating that with supplements, nutrients, and herbs, even on a purely physical level. However, we also look into other potential causes like heavy metal toxicity. I frequently look into that, certainly with urinalyses. Of course, some people feel that hair analysis should be done. In New York, it‘s a little more difficult to do hair analysis. You also want to look into gastrointestinal (GI) function. Even if someone doesn’t have GI complaints, when you look at the body from a holistic perspective, you need to look into what’s happening in the gut. Gut toxicity could certainly cause thyroid problems. I have many stories about that, so I know it to be true. You may want to clean up the gut with a number of different programs. You always want to look for the causes. However, it could take time until the condition is cured. In the meantime, placing patients on thyroid hormone helps. They see significant improvement. Then, over time, you can get them off of it. I tell them they don’t have to be on it for life. They go on it for a week, a month, perhaps six months, and then we can try to get to the underlying causes. Psychological/Psychogenic-Related Stress Factors JB: As you’re talking, it reminds me of the web of interconnectedness. We have the hypothalamus/pituitary, the adrenal, and the thyroid axis all speaking to each other and communicating with the outside environment. There is a big receptor system taking in information by way of sight, sound, touch, feel, and taste, and then translating it into hormonal messages that regulate cellular function. It sounds to me like what you do is functional endocrinology. You’ve moved way beyond just trying to find the disease, to trying to find the nature of the dysfunction in that web. When you do that, do you find that the psychological/psychogenic-related stress factors are a major component? How would you weigh that in your experience? RK: It certainly plays a role. Sometimes it’s the cause; sometimes it’s the effect. It’s difficult to be completely emotionally and psychologically stable when you have so many physical symptoms. Again, I think it forms a web. I think it’s even beyond what we imagine, that it is such a complete web that you have to begin everywhere. The whole idea of cause and effect actually begins to get rather blurry. It all happens simultaneously. Any way you can intervene, you can make a difference. That’s why sometimes you find people get completely better when you intervene on just a psychological/emotional level. That doesn’t mean there isn’t something going on physically, as well, but it seems to be such an interconnected web that I look at it as a simultaneous happening. The way you intervene can make a difference. I like to intervene on a few levels. I look at it more from a systems theory perspective, in that you never know what’s going to cause the body to make that quantum leap to a healthier state. That one new variable you might throw in today that you didn’t throw in yesterday gives the body additional incentive or push to make that quantum leap. A Case History JB: Maybe the best way to get this across to our listeners would be for you to give us a case history, one that you think exemplifies how this looks from the assessment through the treatment program and the outcome, just to give us a reality check. RK: Of course . A few weeks ago, I showed this case history to someone to illustrate functional medicine in practice. I had a lady who came in complaining of fatigue. She was in her mid 50s, and this had been going on for over ten years. She had a strong family history for diabetes, and had numbness and tingling in her hands and legs. She also had gained 25 pounds over the last two or three years. She had experienced brain fog, impaired memory, decreased libido, and irregular periods for a number of years, along with decreased mood. She had gone to a few doctors and all her blood tests were normal. Her PFT thyroid function tests were in the normal range. The TSH tests (she did three of them) reflected 2.3, 2.8, and 1.4. I could see that they widely differed. These were done in one year on the same patient. Her glucose was in the normal range. Her liver function test was slightly abnormal. There was no treatment done. One doctor put her on Paxil and, of course, her libido got worse, so she was switched to Effexor®. At that point, she came to see me. Her blood pressure was 130/84; pulse 60. She was obese. Her thyroid was not enlarged. There was a little bit of fluid retention in her extremities, but that was about it. In terms of routine testing, her cardiogram was sinus bradycardia. The R waves were somewhat diminished on the cardiogram, but it was nothing significant. In terms of the workup, we did a TRH Stimulation Test. The pre-TSH, the first TSH, was around 2.4, similar to what she had in the past. The second one we did 25 minutes later after injecting TRH went up to a 33, which is very low. We also did an adrenal test. It’s very important to do both, not just treat the thyroid and ignore the adrenals. Sometimes you can actually make people worse if you’re not looking at things holistically. We did an adrenal saliva test and her adrenals were very, very low in the morning, in the afternoon, and at night. Her DHEA level was very low, both in the blood and in the saliva. We also did an ACTH stimulation test, which I do in certain cases with someone who has had chronic fatigue for a number of years. That test also revealed a blunted response, which is another discussion. I also did a glucose tolerance test and even though her glucoses were in the normal range, her fasting insulin was around 16 or 17. It spiked up to almost 100 in the first and second hour. In the third hour, it still remained elevated, even though her sugars were in the normal range on all the tests. We started her on Armour thyroid. I also did a little bit of work on her adrenals with pregnenolone, a little bit of DHEA, and licorice root at low dose because she had a little bit of borderline hypertension. She came back two weeks later saying that it was the first time in ten years she was able to think clearly. That was after only two weeks. In a month, her energy was significantly better. It wasn’t even close to anything that she had done in the past. Her body spoke to her about her low thyroid. She was convinced that she felt it in her bones. We did a followup TRH a month later. We had to tweak it a little bit; we had to raise the dose a bit. She started feeling even better. I addressed her glucose tolerance test, as well; to me, it’s abnormal when you have a high insulin level. Plus, I discussed diet and told her she was at risk to diabetes. I told her that pre-diabetes is a disease, too. That was one of the causes of her tingling and numbness. Actually, both low thyroid and glucose intolerance can cause numbness and tingling. I started her on things that could help that directly—B12, folate, glutathione, or N-acetylcysteine as a precursor. Those are some of the things we did to try to alleviate that, but just improvement in the glucose tolerance test will help with numbness and tingling. And I started her on some supplements that can improve insulin sensitivity. When you put people on a comprehensive program, their lives turn around. This is what happened to this person. She lost weight. I tell people that thyroid hormone is not going to be a magic pill, that they have to work at it. They have to change their diets and they have to exercise. But the point is that this woman’s TRH normalized, her tests normalized, and her energy improved. Now, a few months later, she’s completely better. Also, when we retested, her insulin was down to less than 10 and her TRH test was within the normal range. Her blood pressure also began to drop. We now know that 130/84 or 85 is abnormal, too, and we saw hers come down to 118/74. That’s the blood pressure we like to see. Hypothyroidism can elevate blood pressure, as well, and certainly insulin resistance. That’s a typical story, not that uncommon. We see it over and over and over again. That’s why this information needs to be widely disseminated across America. JB: That’s a brilliant clinical case example. What you have done so eloquently is describe many of the components we touch upon in Functional Medicine Update. What we might call borderline hypertension based on the new guidelines is probably related to some endothelial dysfunction. The endothelial dysfunction is related to insulin resistance. The insulin resistance is related to cortisol imbalance. The cortisol imbalance is related to thyroid imbalance, and those are related to the fact that your patient is in her 50s and probably starting into perimenopause. She may very well have an estrogen/progesterone imbalance. When you deal with all these issues, as you’ve done in a weblike sense, it’s amazing how all of what may appear to be disparate clinical signs start to come in line and improve. RK: It’s fascinating, and it’s just looking beneath the tip of the iceberg. It’s amazing. People come in and everything’s fine, the doctor said. All of a sudden, you’re looking at it from a different angle and you may find 10 or 15 variables that are abnormal, and they’re all interconnected, as you said. Even glucose intolerance and insulin resistance are not only related to cortisol abnormalities, but also to hypothyroidism. If the thyroid is low, just a slight dysfunctionality, it will also cause one to be more susceptible to insulin resistance. JB: I want to thank you, Dr. Kellman, for sharing this with us. This is extraordinary and it’s a magnificent application of functional medicine as we have thought of it over the last 15 or so years. And I really liked your books, Gut Reactions and Matrix Healing. For people who want to follow up and get more information about these books, I presume they can contact you at your office. RK: Of course. JB: Thank you for being such a tremendous clinician and for sharing this important information with us. RK: I want to thank you, too, Jeff, for working in the same way. JB: We’ll talk to you soon. Dysphoria and Dementia in Postmenopausal Women I would like to follow up on Dr. Kellman’s clinical comments about borderline subclinical hypothyroidism and its importance in health care, and talk about dysphoria and later dementia in postmenopausal women. The thoughts Dr. Kellman shared with us about the role thyroid metabolism plays in central nervous system (CNS) function is germane to the increasing number of women in the current postmenopausal age group who have historically been candidates for taking conjugated equine estrogens (CEEs) and synthetic progestins—also called hormone replacement therapy, or HRT—for the management of postmenopausal health risks. Women were told that CEEs would reduce risk to bone loss, lower the risk to cardiac disease, improve cognitive function, and lower the risk to dementia. It was a clinical approach that appeared to be the “be-all and end-all” for managing problems associated with postmenopause. Now that the data from the Women’s Health Initiative (WHI) studies have been published, we know that panacea was not realized. There is now a more cautious view of the role of mixed CEEs. It is not that they have no value; it is that the kind of excessive support for their application has diminished considerably in light of some of the more recent evidence. That also holds true as it relates to estrogen and dementia. Recently, in the Journal of the American Medical Association, two back-to-back papers were published that discussed the issue of HRT and dementia or mild cognitive impairment in postmenopausal women.[9],[10]The editorial that followed those two articles sums it all up. The author states that there is no evidence from the WHI data that the implementation of mixed CEE intervention did, in fact, help protect against the loss of cognitive function. The author further states that there may be some evidence that CEE intervention increased the loss of cognitive function.[11] That was not good news. The final message appears to be—do not use CEEs to try to improve cognitive function in postmenopausal women, whether alone or as part of HRT. Nutritional Intervention in Postmenopause What are the alternatives? How do we keep mood, mind, memory, and behavior intact? Some individuals have suggested that nutritional intervention with soy proteins containing phytoestrogens that function as selective estrogen response modulators (SERMs) may be an alternative. There is a paper in the Journal of the American Medical Association, titled “Effect of Soy Protein Containing Isoflavones on Cognitive Function, Bone Mineral Density, and Plasma Lipids in Postmenopausal Women.”[12] In this trial, 25.6 grams of soy protein containing 99 mg of isoflavones were taken daily versus milk protein as an alternative. The authors conclude that this double-blind randomized trial does not support the hypothesis that the use of soy protein supplements containing isoflavones improves cognitive function, bone mineral density, or plasma lipids in healthy postmenopausal women, when started at the age of 60 years or later. I do not want to throw out the baby with the bath water with this study. Clearly, there is a considerable body of literature that indicates there are many benefits in terms of improved endocrinological function, using diets that include soy protein and isoflavones at normal dietary cultural levels. But soy isoflavones, at least at that level, are not a panacea to help protect against the loss of function that occurs postmenopausally. What other nutritional associations are linked to bone loss, cardiac function, lipid panels, and CNS function? Once we ask that question, it comes back to looking at thyroid function. Therefore, intact thyroid function is very important. There is an estrogen/thyroid connection, a connection of calcitonin and thyroid function, and a connection of T3 to CNS function. The story begins to evolve as a functional web to support continued high-level CNS function in postmenopausal women. We should look at things that might lower thyroid activity—food allergies, and gluten and its association with autoantibodies against the thyroid gland. We should look at selenium in the diet to make sure there is adequate conversion of T4 to T3. We should look at zinc, another important mineral for the proper sensitivity and metabolism of thyroid hormone. We should look at iodine to make sure it is adequate but not excessive in the diet to support proper thyroid hormone formation. We should look at things in the diet related to support of proper adrenal function. We should look at exercise, stress management, and things that help lower excessiveadrenal output of cortisol. We should look at things that help to stimulate insulin sensitivity because that will have a salutary benefit on thyroid hormone metabolism and sensitivity. We have discussed some of those things in previous issues of FMU, such as a diet with a lower glycemic load; cinnamon for improving insulin sensitivity; and lipoic acid, another insulin-sensitizing or supportive nutrient. What I am speaking to here is, as Dr. Kellman pointed out, broadening our perspective—moving from a slit to a window of opportunity. Often in medicine, we go from big and are trained to think small, rather than starting with small and going to big, and connecting the issues that may control the outcome of the variable we are analyzing in a patient. There are many nutritional associations we should be attending to in conditions of bone loss, dyslipidemia, and CNS dysfunction in postmenopausal women that go beyond estrogen. Thyroid function, metabolism, and activity, and its interrelationship with insulin, cortisol, calcitonin, and things relating to parathyroid function, are all extraordinarily important. Parathyroid function takes its message, in part, from the calcium and phosphorus ratio of the diets. Women who drink a lot of soda pop and other synthetically sweetened beverages, may be getting a fairly high dose of phosphorus as the phosphates in cola drinks, but fairly low levels of calcium. They have an interrupted calcium-to-phosphorus dietary ratio that may induce secondary hyperparathyroidism, having an adverse effect upon thyroid hormone balance and calcitonin. All of these things are interwoven. That is the excitement of functional medicine—putting the system into a context for clinical management so the whole person is being treated, not just the disease. The challenge is that it requires making a lot of thoughtful connections that may be more complicated than simply jumping to the conclusion of a diagnosis. I hope that Dr. Kellman’s message came across strongly—that the payoff for that cerebral process for developing those relationships, is better patient outcome and solutions to complex, chronic age-related dysfunctions that are not amenable to polypharmacy. There is an interesting paper in the American Journal of Clinical Nutrition which examines nutritional associations beyond soy isoflavones, having to do with bone loss, serum lipids, and CNS functioning in the postmenopausal transition.[13] These are things like calcium, flavonoids from fruits and vegetables, and various vitamins and minerals, as I have previously described. Asking the Right Questions A lot can be done once we ask the right questions. There is a common theme that comes through in every discussion we have had to date in FMU and that is, the questions you ask determine the answers you receive. If you do not ask the question, it is unlikely you will receive the answer. In functional medicine, one of the principal components of our teachings involved in gaining competency is learning how to ask the right questions. Once you ask the right questions, there are a multitude of places where you can find the answers. With the advent of the worldwide web, and accessibility of Medline and PubMed to virtually anybody with a computer, we can now find answers if we know what questions to ask. The difficulty in medicine has historically been to distill down the number of questions to a very few so that one will get “the right answer.” That lowers reinforcement for asking questions and begins to make it a disadvantageous part of a daily practice. The fewer questions one asks, the better off and more efficient and effective one should be. That is antithetical to the functional medicine model, which basically states that the more questions one can ask to help connect important strategies for the management of complex symptoms in the patient, the more successful one will be in the outcome. That is what Dr. Kellman was referring to regarding how he approaches thyroid-related dysfunctions. Thyroid function is an example of both the complexity and simplicity of functional medicine. There is a tremendous amount of information about the thyroid. We have only scratched the surface. We could discuss the topic for tens of hours. But through drilling deeper into the understanding of the thyroid, we start to explore and understand other connections as well, such as those of insulin, cortisol, testosterone and progesterone, and estrogen, which help us to understand how the body functions to improve the efficacy of patient outcome. I hope I have provided you with some good takeaway information about using the thyroid panel and how to evaluate patients with subclinical borderline hypothyroidism. We will see you in December.  

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Bibliography

1 Roberts CG, Ladenson PW. Hypothyroidism. Lancet. 2004;363:793-803. 2 Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340(6):424-429. 3 Walsh JP, Shiels L, Lim EM, et al. Combined thyroxine/liothyronine treatment does not improve well being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab. 2003;88(10):4543-4550. 4 Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3’-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003;88(10):4551-4555. 5 Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13(1):3-126. 6 Naslund E, Andersson I, Degerblad M, et al. Associations of leptin, insulin resistance and thyroid function with long-term weight loss in dieting obese men. J Int Med. 2000;248:299-308. 7 Grundy SM. Cholesterol gallstones: a fellow traveler with metabolic syndrome? Am J Clin Nutr. 2004;80:1-2. 8 Deibert P, Konig D, Schmidt-Trucksaess A, et al. Weight loss without losing muscle mass in pre-obese and obese subjects induced by a high-soy-protein diet. Int J Obesity. 2004;28:1349-1352. 9 Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women. JAMA. 2004;291:2947-2958. 10 Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women. JAMA. 2004;291:2959-2968. 11 Schneider LS. Estrogen and dementia. Insights from the Women’s Health Initiative Memory Study. JAMA. 2004;291:3005-3007. 12 Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women. JAMA. 2004;292:65-74. 13 Macdonald HM, New SA, Golden MH, Campbell MK, Reid DM. Nutritional associations with bone loss during the menopausal transition: evidence of a beneficial effect of calcium, alcohol, and fruit and vegetable nutrients and of a detrimental effect of fatty acids. Am J Clin Nutr. 2004;79:155-165.

Welcome to Functional Medicine Update for December 2004. It is hard to believe we have arrived at the last month of this year. It seems that 2004 was beginning only last month. That is an indication of the time warp, the compression, the pico-second society in which we live, where time is our most precious commodity. More than anything else, time seems to be the most compressed thing in the world in which we live. That certainly is the case with developments in the field of functional medicine. It has been quite a year. We are beginning to understand the connection between type 2 diabetes, insulin resistance, hyperinsulinemia, cardiovascular disease, and other inflammation-related disorders. The circle draws tighter. Functionality becomes more important in understanding the mechanisms, rather than simply naming diseases. This is the future of medicine. The Need for Clinical Education in Managing Chronic Disease In October of this year, I saw a wonderful editorial in the Journal of the American Medical Association,written by Dr. Halsted Holman from Stanford University, School of Medicine in Palo Alto, California. He made the following comment in somewhat apologetic tones: “It is axiomatic that medical education should prepare students well for the clinical problems they will face in their future practice. However, that is not happening for the most prevalent problem in health care today: chronic disease.”[1] Dr. Holman’s apologetic tone stems from the fact that chronic illness, which requires a different management strategy than acute illness, represents the most dominant health problem. “Chronic disease is now the principal cause of disability and use of health services and consumes 78{56bf393340a09bbcd8c5d79756c8cbc94d8742c1127c19152f4230341a67fc36} of health expenditures.” As pointed out by Dr. Holman, we do not have a chronic illness management system today, and it is a tremendous waste of dollars to use an acute care management system to manage chronic illness. Chronic illness management requires a different strategy, a different implementation, a different set of tools, and a different level of communication with the patient than an acute illness from which, presumably, with proper treatment, the patient gets well. In an age-related chronic illness, the patient may have a chronic susceptibility or impairment in functionality througho Let us look at the concept of chronic illness, what tissues are involved, and whether it is initiated or potentiated. It is related to imbalance in the immunological system. In this issue of FMU, I thought it would be appropriate, perhaps even propitious, to talk about the center of the immune system and how it regulates, or at least influences, the broad array of dysfunctions associated with chronic illness. I am talking specifically about the gastrointestinal immune (GI) system. There are extraordinary messages sent out through the GALT and the MALT that are received systemically as well as regionally. They influence, at a distant site, how a tissue or organ responds to its environment and can potentiate or modulate inflammatory response. This understanding, the roots of which go back to the turn of the last century at the Pasteur Institute and the work of Elie Metchnikoff, has taken on a new meaning and implication pertaining to the management of chronic illness. A functional medicine provider who does not understand the role of the GALT in modulating immunological function may be missing one of the most important things in his or her tool kit for being more successful in the management of chronic illness. This will be the focus of the December 2004 FMU. And, as we talk to our Clinician/Researcher of the Month, we will learn a lot about how to modulate GALT relationships through pre- and probiotic intervention. Role of the GALT in Immunological Status First, let us discuss the role of the GALT in overall immunological status and in the balance of inflammation. The GALT is responsible for secreting about three-quarters of the body’s antibodies through the B cells. It is also involved with the secretion of various types of lymphokines and cytokines. It is actively involved in phagocytosis mucous secretion, and secretory IgA, the immunoglobulin that coats the interior lining of the gastrointestinal mucosa. The GALT plays an active role in translating friend to foe, or foe to friend at the GI barrier level. One might think of the GI mucosal cells as being loaded with antennae or membrane receptors on their external membranes which pick up messages from the internal milieu of the GI tract. These are messenger molecules that come from the digestion of food, biological organisms, contaminants, and xenobiotics. These messages are picked up by the GI mucosal information system and translated through the immune system into regulatory modulators such as cytokines, lymphokines, leukotrienes, and prostanoids. Downstream, these messages ultimately influence the Kupffer cells in the liver (the embedded white blood cells), the circulating white cells, and even the embedded white cells in the brain called the microglia, all of which receive some of their messages from the process that was initiated at the gut level. Foreign Molecules in the Diet The gut mucosal tissue represents over 50 percent of the overall immune tissue of the body clustered around the gut. Over the course of life, a person eats at least 50 tons of food. Because those foods are partly composed of molecules foreign to the body, they need to be translated into friendly molecules. That is partially accomplished by digestion, during which they are changed into small nondescript nutrients like amino acids, monosaccharides, and free fatty acids. There are also some residual information molecules present in the diet that have to be further identified as friends or foes, and this is done through the agency of the gut immune system. There are antigen-presenting cells, dendritic cell activity, mucus secretion, and IgAs, all there to defend the body from foreign information coming from the diet. Some people have food allergies due to a breakdown in the translation process of what is food/friend and what is a foe/toxin. Classic examples of food constituents that produce adverse immunological responses are peanuts, cod, and wheat, each of which can produce fairly severe anaphylactic or life-threatening responses based upon activation of the immune system during an alarm reaction. Not only is the gut/immune system inhabited by many interesting immune cells, but almost a kilogram of foreign cells resides in the colons of most people. These are called the commensal bacteria. We hope they are commensal and symbiotic, and not parasitic. On a simple arithmetic basis, in any gram of stool, there are hundreds of species of bacteria. The gut is a highly populated area, and the GI bacteria turn over very rapidly. Rather than turning over in a matter of weeks, months, or years, they turn over in a matter of hours. The composition of the gut microflora (e.g., its “personality”) can change based upon what it is fed and the environment that is provided for the 1011 to 1013 bacteria found within it. Witness the rapid onset of gastroenteritis that occurs in many people after exposure to something pleasant, such as stress. We are starting to understand that there is a dynamic interrelationship between commensal bacteria in the gut, their metabolic activity, and how that influences the GALT, which subsequently influences the immunological system of the host at large and sets up a balance or imbalance of regulatory mediators. This is an important part of the overall story of how the dynamic interplay occurs between the body’s external environment and internal immunological signaling, as translated through the GALT. Etiological Role of Commensal Bacteria I want to talk about the role of commensal bacteria in a variety of conditions. Balfour Sartor is one of the very knowledgeable researchers in investigating such issues.[2],[3],[4] Let us focus for a moment on inflammatory bowel disease (IBD). This is an interesting model from which we can understand the more general principle about how regulation of gut immune function can influence systemic health through various environmental agents. Gastrointestinal Bacteria in Normal Humans The stomach has a fairly small number of microorganisms, which may include Lactobacillus, Candida, Streptococcus,and Helicobacter pylori. The duodenum has more bacteria, primarily Lactobacillus and Streptococcus. The jejunum also has Streptococcus and Lactobacillus. In the distal ileum, there are many more bacterium, including Clostridium, Bacteroides, and coliforms. In the colon, there are 1011 of various strains of Bacteroides, Bifidobacterium, and various strains of Clostridium. This is where most of the bacteria reside. It is important to point out that the distal ileum also has quite a few bacteria, as well. In fact, one can get small intestinal bacterial overgrowth which may be able to influence IBD and which has been shown to influence irritable bowel syndrome (IBS). There is interesting research on these topics currently going on in the field of gastroenterology.[5],[6],[7] Etiologic Hypotheses The hypothesis that relates commensal bacteria to IBD suggests that a person may have either persistent infection with mycobacteria or H. pylori. One can even have things like embedded viral infections from measles, mumps, listeria, or adherent/invasive E. coli(enterotoxigenic E. coli like H0157). All of these can create persistent infection. One can also have defective mucosal defense due to “funny” or altered bacteria in the gut that change gut immunological defense. Altered mucus formation and increased intestinal permeability (the so-called “leaky gut syndrome”) may cause cellular starvation, impaired resuscitation, and lead to defective bacterial clearance. The contribution of both persistent infection and defective mucosal defense may result in dysbiosis where productive bacteria counts are decreased and aggressive, and harmful bacteria counts increased, leading to a dysregulated immune response with loss of tolerance, aggressive cellular activation, and defective apoptosis of the gut mucosal cells, leading to IBD. No two people are identical in the susceptibility of their gut mucosa to the types of imbalances just described. IBD in a susceptible individual depends somewhat on how actively regulated the inflammatory cytokines are through messages from the gut mucosa and the contents of the gut. Relative to flora and digested food, how do the contents trigger a gut/immune response? Individuals with hypersensitive or highly sensitive upregulated inflammatory systems experience a loss of tolerance by alteration in both the thymus-dependent 1 (Th1) and thymus-dependent 2 (Th2) components of the gut immune system, resulting in increased IgG formation, increased formation of tumor necrosis factor alpha (TNF-a), IL-1, and interferon gamma (IFNg). As a consequence, there is much greater inflammatory potential that occurs at the interface between the luminal adjuvants, the leaky mucosal barrier, and the brush border cells. The IBD-susceptible individual is one in whom specific triggers produce a heightened response in the inflammatory area. They experience elevated Th1 production with increases in TNF-a and IL-1b, leading to tissue destruction and inflammation, and ultimately, to the bleeding observed in IBD. The Role of Commensal Enteric Bacteria What is the role of commensal enteric bacteria? In studies using gnobiotic animals, that is, animals who have had their guts sterilized and, therefore, contain no bacteria, it has been shown that stimulation with an agent known to initiate IBD-like conditions in normal (bacteria-containing) animals does not induce colitis. However, if certain resident bacteria are reintroduced to the gnobiotic animal when the adjuvant is given, there is significant activation of macrophages and the Th1 immune response. Within a week, it produces serious colitis and an inflammatory condition of the colon. Many different model systems have been used in an attempt to identify how resident bacteria become triggers for inflammation. It is not just one factor at work, such as bad bacteria. It is a combination of altered gut flora with a genetic susceptibility, and other adjuvant agents that trigger immune hypersensitivity and inflammation. There is a strong correlation between the degree of microbial stimulation and aggressiveness of the GI inflammation. This is even seen in genetically-engineered animals in which transfection studies are done that basically produce animals with well-defined bacteria composition and show activation with specific bacteria. The mechanism of these actions is starting to become much better understood. It is not just descriptive, but understood more at the cell physiological and molecular genetic level. Results of Germ-Free Studies The lessons learned from germ-free studies include the following: normal luminal bacteria can induce and perpetuate chronic colitis, duodenitis, arthritis, and gastritis in genetically susceptible hosts. There is the gene connection toward susceptibility. Both luminal bacteria and genetic factors are essential, but neither is sufficient for chronic inflammation alone. There is a need for both of them simultaneously. An interaction of both genes and microbial factors results in chronic diseases. We know that from food allergy and the fact that no two people have identical responses to their diet. Sinusitis and rhinitis may occur in one person from eating peanut butter, but in another person, it may result from eating something containing wheat protein. There are differing responses of the immune system to different antigenic determinants. When the luminal contents of Crohn’s disease patients are examined, different types of bacteria are found. We might ask whether the altered flora is a consequence of the disease, or does the flora cause the disease? It is the old push/pull, cause-and-effect argument. A paper appeared in Gastroenterology that talks about fluorescent probes detecting increased mucosal-associated bacteria in an IBD biopsy.[8] Some good genotyping has been done relating to polymorphisms in people who are more susceptible to these types of interactions, with an upregulation of gut/immune function producing an NFkB-mediated process that activates nearly 100 genes associated with inflammation of the gut. There is immune-dysregulation with antigen-presenting cells at the gut mucosal level that is triggered through the personality of specific types of bacteria. From both animal and human studies, there is an emerging connection with loss of tolerance as a consequence of altered enteric bacteria, which is ultimately associated with a clinical diagnosis of IBD. The question is, what is the strategy for treatment? Should selective antibiotics active against specific bacterial subsets be used, or should there be intervention trying to modify the GI environment of the host, using pre- and probiotics and altering the diet? Research on both strategies is being conducted. For instance, in experimental colitis and enteritis, a series of different antibiotics has been studied-metronidazole, Cipro, and various types of tetracyclines-to see if they have different influences on different bacteria in animal models relative to the outcome of IBD. The implications of this research are that a combination or broad-spectrum of antibiotics is needed to manage what would be considered the animal model of Crohn’s disease and ulcerative colitis. We do not yet know what selective antibiotics might work on specific biota to eliminate or alleviate the inflammatory-initiated process. Antibiotics can work, but we still do not know everything we need to know. If we look at various things that have been used clinically, like metronidazole, there does not appear to be any real difference in treatment versus placebo in conditions such as Crohn’s disease. Possibly altering the GI environment would be equal to, or even more successful than, antibiotic therapy in patients with chronic IBD. Those cases lead us into looking at different kinds of bacteria and modifying the gut mucosal environment to try to rebalance Th1 and Th2 immune function, and to decrease chronic conditions leading to acute inflammation associated with IBD, its progression, and its serious interrelationship with colon cancer risk. If we look at the luminal microbe biological environment trying to find the right balance, the injurious organisms associated with proinflammatory effects that could lead to IBD include the Bacteroides species, Enterococcus faecalis, and the enteroadherent/invasive forms of E. coli. Those are the injurious proinflammatory organisms, or what we call invasive or aggressive commensals. On the other side, protective probiotics are emerging, such as specific species of Lactobacillus, Bifidobacterium and non-pathogenic E. coli. That opens the door for an intervention for IBD, one that would change the GI environment to a less proinflammatory state by modifying the function of enteric bacteria, and trying to reduce the activity of the aggressive commensals, while increasing the activity of the symbiotic bacteria. We are talking about building an intestine through an appropriate relationship of commensal bacteria. I find this a fascinating topic. There is an article published in a recent issue of The New England Journal of Medicine, titled “Building an Intestine-Architectural Contributions of Commensal Bacteria.[9] The author discusses what we have been talking about. “Bacterial cells within the intestine (commensal microflora) vastly outnumber the epithelial cells lining this organ. Like all bacteria, they release chemical signals with conserved patterns recognized by specific receptors-called toll-like receptors (TLRs)-of the innate immune system. It is therefore assumed that the healthy intestinal surface somehow defuses the threat of commensal bacteria to the lumen, where they thus reside undetected.” In a recent study in the journal Cell, Rakoff-Nahoum and colleagues provide insight into the fact that the commensal bacteria interact with the intestinal surface and, to some degree, trigger TLR signaling.[9] This interaction is required to maintain the architectural integrity of the intestinal surface. Thus, it seems that the epithelium and resident immune cells do not simply tolerate commensal bacteria, but are dependent on them-a very strong relationship. The authors used mice deficient in a necessary downstream component of the TLR pathway, therefore preventing all TLR signaling. Such mice have a profoundly exaggerated response to intestinal injury. When introduced to something like an NSAID, for instance, they were much more likely to have NSAID-induced enteropathy and injury through inflammation of their GI mucosa. “Bacteria have proved to be a rich source of information on the function of our own mammalian cells…. The recognition that TLR signaling is activated by common bacterial products has also helped to shift the focus of study from how the intestinal mucosa becomes inflamed in disease to why surface inflammation is the exception rather than the rule…. The study by Rakoff-Nahoum et al. helps to refine the new focus because, in addition to the previously known fact that commensals may quench as well as elicit inflammatory responses, it teaches us that basal commensal-dependent signaling is also critical to intestinal health and the ability of the luminal surface to respond to injury.” The interaction we are talking about between bacteria and the GI mucosal epithelium, and translated through the GALT, becomes a key feature in better understanding the dynamics of the immune system and the balance of Th1-dependent and Th2-dependent activity. “The importance of context has also emerged from models of spontaneous intestinal injury and inflammation in mice deficient in various signaling molecules. A deficiency in any of numerous signaling molecules can induce intestinal inflammation-a precursor of inflammatory bowel disease-indicating that dysregulation of any one of multiple pathways involved in inflammation or repair disrupts the normal homeostatic mechanisms (which include microflora) and thereby results in disease. Thus, although microflora are required for homeostasis, they are also required for the full manifestations of inflammatory bowel disease induced in most genetic models.” As we understand how to shift this, using friendly bacteria and pre- and probiotics to optimize the intestinal environment, it will help us to better manage the genetically susceptible individual who is at risk to IBD. Bacteria in the gut can either be friend or foe. We can alter the balance by what we eat, what we drink, how we think, the medications we take, and the environmental toxins we are exposed to. All these things can influence the gut environment. There is a link between the barrier function of colonic microflora and susceptibility to disease. This becomes of great importance in both reducing the risk of and managing age-related chronic disease. Most of our knowledge of gut microflora comes from studies in humans. Microbiologically, the gut can be thought of in terms of three principal regions: the stomach, small intestine, and colon. We have talked about the different types of bacteria that live in each region and the contribution they make to alteration in gut immune function. Most often, people have focused their interest on understanding colonic bacteria, but the small bowel bacteria can also play a role in modulating immune function, opening portals of entry through small mucosal barrier function breakdown (“leaky gut”), and delivering molecules of greater weight to the immune system that can perpetuate its upregulation. It is now like a dog chasing its tail-leaky gut leading to more entry of these molecules that further initiate and upregulate the inflammatory components of the immune system. These molecules further break down the integrity of the gut mucosa, leading to more entry and so on down the line, leading to a spiraling effect of influence on immune function. Food Allergy and Dementia These effects can be either acute or chronic. I am always reminded of the interesting statistical relationship between chronic gluten sensitivity (and people who continue to eat wheat in their diet) and early-stage dementia. How would the brain be connected to the gut and the diet? The model we are describing, through the gut/immune system and imbalances and upregulation of Th1 and Th2 activity, may help us to better understand that. If a person eats a food to which he or she is sensitive, it alters the gut environment, alters the bacterial population, alters the antiinflammatory balance in the gut mucosa, and leads to upregulation of proinflammatory mediators. These mediators communicate and translate their messages through the portal blood to the Kupffer cells in the liver, which send out messenger molecules to the circulating white cells in the blood. The white cells send out their message or molecules to the blood-brain barrier, which influences the activity of the microglia, the brain’s immune system, upregulating inflammation in the brain, and ultimately leading to neuronal apoptotic death, which leads to dementia. That is the emerging model connecting food allergy to dementia, or food allergy to neurological symptomatology, through activation of imbalance in the GALT and its interrelationship with altered gut flora. This is an important emerging part of the story. The particular model I have just described was discussed during a recent presentation at the WALTHAM International Science Symposium, titled “Nature, Nurture, and the Case for Nutrition.” The title of the paper is “Bacteria in the Gut: Friends and Foes and How to Alter the Balance,”[10] published in the Journal of Nutrition. It offers a good indication of how differing substrates influence different bacteria, and how different bacteria can influence gut immune function. In this article, the authors talk about probiotics, as well as prebiotics. I want to differentiate a prebiotic from a probiotic. Prebiotics versus Probiotics Prebiotics are substrates that specific bacteria can ferment or live upon. An example of prebiotics would be fructooligosaccharides (FOS) or arabinogalactans. These are specific types of carbohydrates unique for the fermentation support of specific bacteria. The key with a prebiotic is to feed the food useful for the bacteria that one wants to promote at the expense of starving the bacteria one does not want to promote. The combination of pre- and probiotics has been used to create enhanced GI proliferation of friendly bacteria, altering or lowering the pH and increasing short-chain fatty acid production. These would be things like butyrate, a gut fuel used by the colonocyte for its metabolism. Increasing butyrate production by stimulating probiotic organisms through the use of effective prebiotics enhances physiological outcome. Substrates for Gut Colonic Bacteria In the Journal of Nutrition article, the authors talk about the different kinds of substrates used for gut colonic bacteria, or enteric bacteria. They talk about FOS versus high-maltose corn syrup versus cellobiose, isomalto-oligosaccharides, lactose or maltose, and high fructose-containing corn syrups, raffinose, stachyose, and sucrose. When looking at different microorganisms, one can see that some proliferate when fed the appropriate substrate. For instance, Lactobacillus reuteri had virtually no growth on sucrose, but had very high growth on oligosaccharides. One would want to feed the appropriate type of substrate as a prebiotic, along with a probiotic to improve the function of the specific family of bacteria. That becomes part of what we have often called in functional medicine parlance, the “4R Program.” Recall the four Rs: remove the unfriendly bacteria, parasites, and food allergens; replacedigestive enzymes and acid, where necessary, to acidify the chyme; reinoculate with friendly pre- and probiotic organisms; and repair using nutrients such as glutamine, vitamin E, zinc, magnesium, and pantothenic acid, all of which are helpful for repairing gut mucosal integrity. Small Intestinal Bacterial Overgrowth What about small intestinal bacterial overgrowth? That is another interesting part of the story. IBS is highly prevalent in our society. Eleven to 14 percent of our population suffers with IBS. It is a diagnosis made principally on the basis of meeting clinical criteria. The symptom-based approach has been used because no consistent biological marker or unifying framework has been available to explain the different symptoms. Constipation, diarrhea, pain-diarrhea-constipation are predominant symptoms in IBS. It is basically more a symptom definition than a pathognomonic diagnostic marker in defining IBS. Another way to look at IBS symptomatology may be to emphasize the differences rather than the similarities in patients. There is a close correlation between IBS and other conditions like chronic fatigue syndrome (CFS) and fibromyalgia (FM). We reported this over ten years ago and it seems to be well characterized in subsequent studies that the chronic problem of gut function appears to be tied to other types of energy/fatigue-related disorders and alterations in the hypothalamus-pituitary-thyroid-adrenal axis (HPA). It is now well recognized that the GI and immune effects of small intestinal bacterial overgrowth provide a possible unifying framework for understanding frequent observations seen in IBS. These include postprandial bloating and distension, altered motility, visceral hypersensitivity, and abnormal brain/gut interaction that produce fatigue- related and sleep disorders, autonomic dysfunction, and immune activation. One might say that what I just discussed sounds like something out of a functional medicine textbook. When I talk about small intestinal bacterial overgrowth being associated with that wide a range of symptomatology, including postprandial bloating and distension, it is fairly evident it is a GI-related function. What about visceral hypersensitivity or abnormal brain/gut interactions leading to sleep disturbances and what has often been called “foggy brain syndrome” and fatigue-related syndromes? What about systemic immune dysfunction? Those conditions sound less likely to be commonly associated with an IBS diagnosis, and probably do not fit into a traditional medical model. Yet, that particular collection of symptoms I just described is actually a list I quoted out of a recent paper in the Journal of the American Medical Association, titled “Small Intestinal Bacterial Overgrowth. A Framework for Understanding Irritable Bowel Syndrome.”[11] It contains an interesting recapitulation of what has been talked about in functional medicine for over ten years relating to the interrelationship between bacterial overgrowth, altered flora, and alterations in gut immune system, which also has effects on cell signaling to neurotransmitters. This particular association takes us across a wide range of function. Dr. Mary Ellen Sanders, our Clinician/Researcher of the month, will share with us later that various types of probiotics can ameliorate arthritis in animal models and can have systemic antiinflammatory effects through signaling in the gut. I am quoting from a paper that appeared in the Journal of Nutrition.[12] Alteration of gut signaling through flora can alter glucose tolerance. Increasingly, we are realizing that insulin resistance may be associated with altered gut flora, as well. I am now quoting from two papers that appeared in Current Opinion in Clinical Nutrition and Metabolic Care on glucose tolerance and the gastrointestinal tract.[13],[14] The authors talk about the proper maintenance of gut flora and proper GI tract immune system function for improving glucose tolerance. Arthritis and its relationship to gut inflammatory disorders, the relationship of glucose tolerance and insulin sensitivity to such wide-ranging dysfunctions as the gut/brain connection that relates to “foggy brain” or dysphoria or fatigue-related symptoms, and perhaps even activities related to energy production in myocytes associated with FM-all of these have been implicated as having a gut immune-related functional connection. There is an interesting model emerging for immune system modulation, using the gut immune system as the triggering or signaling device. By focusing therapies on this organ through adjustment of the environment, implementing the appropriate “4R Program,” and using the appropriate pre- and probiotic intervention tools, we may see remarkable species-specific alteration in immune function leading to the remediation of many age-related chronic disorders. We are ready to move into a discussion with our Clinician/Researcher of the Month, who will take this platform to a whole new level of application using the gut and probiotics as a tool for modulating systemic function

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INTERVIEW TRANSCRIPT

Clinician/Researcher of the Month Mary Ellen Sanders, PhD Consultant Dairy and Food Culture Technologies 7119 South Glencoe Court Centennial, CO 80122 JB: There is one therapeutic area of intervention in medicine that has been getting more and more attention recently, and that is the area of probiotics. For years, I have been thinking that we need to do an issue of FMU on this topic with a leader in the field of probiotics who can help us to understand what this category is all about. What is a probiotic, how is it defined, what are its standards, how does it work, and what does it do? We are fortunate to have a colleague with that knowledge in her experience base-Dr. Mary Ellen Sanders, a consultant at Dairy and Food Culture Technologies in Centennial, Colorado. I’ve had the privilege of meeting Dr. Sanders on several occasions. She has a broad-based background in probiotics, going back more than 20 years. Her experience brings to bear the techniques and tools that define probiotics as an important category in therapeutics. With that brief history in mind, I would like to introduce Dr. Sanders to our FMU audience. Thank you for being with us, Mary Ellen. For those who might not be familiar with probiotics, I would like to begin by asking you to define the category, and discuss its origin and history. MS: Thank you for having me on FMU. I appreciate this opportunity to share some information on probiotics. The concept of probiotics probably originated with Elie Metchnikoff, a Russian Nobel Prize-winning scientist at the Institute Pasteur in Paris. At the turn of the last century, he published a book titled The Prolongation of Life. In it, he presented a theory that the reason people in certain cultures in Russian society lived such long and healthy lives was because they consumed quite a few live Lactobacilli in the fermented milk common in their diet. Dr. Metchnikoff was a strong proponent of supplementing the diet with these types of bacteria. The concept of probiotics was really born at that time, although the term probiotics was not coined until about the mid 1970s. Now, it refers to the fact that live microorganisms, when consumed in adequate amounts, can confer a health benefit on the host. JB: In the human GI tract, there are hundreds of different species of live organisms, and in our food, there are hundreds more species. This leads to a potential cornucopia of things that could be of benefit or of harm. How did one seek out those that were considered favorable probiotics, and what are those species? Favorable Species of Probiotics MS: As you mentioned, there is a wide range of microbes. Some that inhabit our intestinal tract are pathogens that are clearly bad for us. There are other microorganisms, those that constitute the majority in the GI tract, that probably have neither harmful nor necessarily beneficial effects. There are microorganisms on the other end of the spectrum that seem to show very positive effects. Through studies by a variety of microbiologists and clinicians, we have found that certain microorganisms, especially the Lactobacillus and Bifidobacterium, appear to be associated with healthy intestinal tracts. The results of those studies, and the observations of Metchnikoff highlighting the value of Lactobacillus, turned the probiotics industry in the direction of that particular genre-Bifidobacterium and Lactobacillus. Having said that, the type of research we have seen going on in recent decades has focused on trying to specifically delineate the advantages of particular strains of those groups of bacteria. JB: There is a wide range of taxonomic varieties of microbiological organisms. You have defined two families that appear to be quite important. How do we know what we have? What is the mechanism used to define what we have? Microbiological Techniques for Identifying Components of Microbiota MS: Microbiological techniques have been in the process of development for over 100 years. Microbiologists now have tools to sort out and select for different microbiological components of the GI tract that help them identify specific components of microbiota. There is also a variety of culture techniques. For example, growth on culture medium, and then plating on agar-coated plates specifically designed to be selective for particular groups of microorganisms, have helped microbiologists identify the presence of different components. Over the past 10 or 15 years, we have also seen an explosion in techniques based on the genetic complement of particular organisms. Now, we can use DNA-based techniques to probe for particular organisms that we are looking for as part of the group of microbes that inhabit the GI tract. JB: Not too long ago, I recall reading an editorial in which the authors discussed a molecularly-engineered or genetically-engineered bacterium that had specific favorable characteristics in the GI tract. Is there a trend toward genetic modification of these organisms, or are we still looking for the most favorable organisms through the natural selection process? Genetically Altered Microbes MS: Natural selection is the backbone of most procedures, but specifically designed, genetically altered microbes are being considered, probably more for specific therapeutic applications than, for example, applications through dietary supplements or in food products. Another area of research includes studies targeting delivery of certain antiinflammatory cytokines through probiotic bacteria, and delivery of certain vaccine epitopes through bacteria that are orally fed. I think we will see genetic development of very targeted probiotic bacteria, but those will likely come out in a range of therapeutic products, initially at least. JB: Is there a dividing line between products considered as drugs in the area of probiotics versus those considered as dietary supplements or food, and labeled GRAS (generally recognized as safe)? MS: Yes and no. A genetically engineered probiotic bacterium would not be considered a GRAS organism that could be used as part of the food supply without required review by the FDA. I’m not a regulatory specialist. However, my understanding of regulatory issues is this: whether a probiotic is considered a food, a dietary supplement, or a drug, has a lot to do with how it’s labeled and presented to the public. It also has to do with what types of claims are made for its use, where the organism is isolated, and what types of natural selection screening processes were conducted to select it. For example, certain types of intervention would preclude an organism from being used in food without evaluation, such as genetic modification. The same microorganism might be considered as a food, a dietary supplement, or for therapeutic use, depending on how it is labeled and what types of studies were done to support its use. JB: Is it safe to say that the probiotics now commercially available are non-GMO (genetically modified organisms), based on what you just said? Or, are there GMO-products that have found their way into the market place? MS: I don’t know of any GMO probiotics currently being sold. I would say that’s very likely. They are all non-GMO at this point. JB: Let’s move to physiology. Presumably, each of these species of organisms has its own unique biochemical machinery, as determined by its genetic lineage. Each produces different primary and secondary metabolites, which has something to do with their influence on physiological function. Would you tell us about the influence of some of these organisms on physiological function? MS: Probiotics cover a range of bacteria. I mentioned two different genres-Lactobacillus and Bifidobacterium. These are commonly used as probiotics. They have different metabolic capabilities. All Lactobacilli have a certain number of traits in common, but within the genus Lactobacillus, there are dozens of different species, each of which can be distinguished based on other types of traits. Sometimes, those are certain physiological or metabolic characteristics. And sometimes, it has to do with variation in the way they evolved and the genetic complement that allows them to be split into different taxonomic groups. We are at a phase in molecular taxonomy where people who like to split up groups into different ones based on homology are ruling the day, and more and more species are being identified. This is sometimes based on genetic complement and homology, more so than clearly identifiable, specific functional metabolic or physiological traits of the organism. But, clearly, there are many species and they all have different characteristics. Interestingly, there is a tendency in the field to try to attribute certain capabilities on physiological effects in the human, or in the host, and tie that to a specific species. We’ve found that the different species are almost as important as the different strains, each of which may have its own individual characteristics. The analogy I like to use is that of different breeds of dogs. All dogs are the same species, but different breeds of dogs have very different characteristics. The German Shepherd might be a good watchdog, and the Golden Retriever might be a good hunting dog. They are all the same species, but they have individual unique traits that better suit them for different characteristics. That’s the same type of thing that can go on within strains of particular species of particular genres of probiotic bacteria. JB: That’s very helpful. Metchnikoff undoubtedly was using Lactobacillus vulgaris, or some genre species of that type. Now, we have become much more precise in how we define some of the individual strains within those species. What do we currently understand about the strains’ specific activities? Evolution of Research on Probiotics MS: Research over the past 10 or 15 years has grown by leaps and bounds compared to that done in the 1980s or early 1990s. One big step forward was the advent of the double-blind, randomized, placebo-controlled trial now being more and more commonly used to determine the health effects of these organisms. There is also better definition of the products being used as interventions in these studies. You might see a paper that was published back in 1985 in which the investigators said they used yogurt to try and observe its effects. There was almost no microbiological characterization of the yogurt, and no identification of the particular species or particular strains that were used. Therefore, it was very difficult to know exactly what was being tested in those studies. Today, very defined strains of probiotic bacteria are used in studies. They are defined based on standard microbiological and physiological traits, such as their enzymatic capabilities, their carbohydrate fermentation capabilities, and different physiological structures of the cell. They are also defined using modern DNA-based techniques that allow for patterns; for example, through an electrophoretic gel, that show specific fragments characteristic of a particular strain. We can get DNA-based patterns or reactions to DNA-based probes that will very specifically identify strains. Additionally, strains are often deposited in international culture collections so that work can be repeated in different labs. We have come a long way with research in this area and have applied the modern, molecular techniques to identify what strains are being used and what is being documented for those particular strains. JB: Before we discuss the clinical effects of probiotics, I’d like to talk briefly about potency and quality assurance/standards-related issues. In 2002, you were elected by your peers to be the first president and chairperson of the Board of The International Scientific Association for Probiotics and Prebiotics, a group that is working hard to understand what constitutes the standards for these products, these organisms. Would you tell us where we are in that process and whether we agree or don’t agree about what the definitions are? Standardization of Probiotics MS: We are closer to a fairly agreed-upon definition of probiotics. There was an international consultation assembled by the Food and Agriculture Organization (FAO) branch of the World Health Organization (WHO) back, I believe, in 2002, which put forward a definition for probiotics which I alluded to earlier. “Live microorganisms, when consumed in adequate amounts, confer health benefits on the host.” It doesn’t seem like a very difficult thing to do, but there have probably been nine or ten or more published definitions of probiotics, all of which all varied slightly in terms of the requirements. That definition was put forward by expert consultation and it has received fairly good acceptance worldwide, although there will always be dissension among certain people in the scientific community. In terms of standards, at least on an international basis, they do not exist. I think anyone in the probiotics industry understands what it takes to market a responsible product, but in terms of having standards imposed by government agencies or other types of watchdog groups, they don’t occur, at least to my knowledge. For example, in the United States, you can buy a probiotic product and there really isn’t anyone watching. There aren’t any standards you have to meet that require what levels or what specific types of bacteria are contained in your product. However, there are very general recommendations for standards. In the United States, you have to label your product in a truthful and not misleading fashion. Exactly what that has meant for the dietary supplement industry in the United States has been open to interpretation by the manufacturers. The FDA has not taken action against supplement manufacturers unless their products are labeled as drugs or are deemed to be unsafe. For example, a company is not held accountable for meeting claims of particular potencies in their products, or to meet standards requiring that the types of organisms in their products match what is claimed on the label. We have a long way to go, domestically as well as internationally, to get enforceable standards in place. There are guidelines, however. There was an FAO action that did publish some guidelines for the production of probiotic products that are available. JB: We have talked about potency (the number of organisms per gram), that the organisms have to be bile-acid resistant, adhere to the GI mucosa, and be able to proliferate within a medium consistent with the GI environment, i.e., be viable. Are these reasonable standards for evaluating how they are going to work clinically, or are none of those four standards that closely tied to the clinical arena? Clinical Evaluation of Probiotics MS: In terms of doing a clinical evaluation, you have to know, as I mentioned earlier, what organism or blend of organisms you are looking at. You have to know the genus, the species. You have to have some handle on strain-specific patterns that you can identify and what organism you’re testing. Those are the minimum criteria. One of the things that’s confusing in the area of probiotics is what many people have asserted are “requirements for a probiotic.” In the published literature, you’ll see many papers describing what a probiotic “must be,” followed by a list of things. Common to those lists are phrases like “of human origin,” “must be bile-resistant” (for survival in the small intestine); “must be acid resistant,” (for survival in the stomach); “resistant to pancreatic enzymes” (for survival in the small intestine); “must be able to survive transit and be isolated from human feces”; and “must be able to adhere to intestinal epithelial cells.” I take a much more pragmatic approach. There are many well-documented probiotic strains, for example, from species that are not normally thought to be indigenously associated with the human GI tract. Therefore, saying that a strain needs to be of human origin and, by that, I assume what they mean is that it is a normal inhabitant of the intestinal flora of humans, is not necessarily a prerequisite for probiotic function. Sometimes, these organisms traveling through the intestinal tract are able to exert influence on the physiology of the host. Regarding other attributes I mentioned, such as surviving stomach acid or resistant to bile, if the physiological effect you are looking for as an endpoint is the ability for them (probiotics) to replicate in the colon, then that would be true. They would have to be resistant to acid and resistant to bile. But there are certain characteristics, for example, of probiotics that have been found to help decrease Helicobacter pylori colonization of the stomach. Bile resistance would not be a trait important to a probiotic targeted to the stomach. There are probiotics that have been tested and shown to decrease the incidence of dental caries in children. Again, bile resistance is not going to be an important trait for a probiotic organism used in the mouth or oral cavity. From my point of view, the list of required probiotic traits is a pretty small one. My list would include that the organism has to be alive; it has to be safe for human consumption; and it has to be able to be technologically produced in a manner that can deliver the viable organisms in the final product at high enough levels to be effective. Short of that, the rest of the list becomes very host target-site specific, if that makes sense. JB: That was a helpful differentiation. That leads me back to the question of relative potencies-the number of organisms per gram. Is this a pretty good standard to use for the evaluation of potency or, is that also subject to question? MS: I think it’s the best we can do right now. A probiotic organism, by definition, is a live microorganism that is delivered to the host. Therefore, we need a handle on standardizing the organisms in terms of numbers delivered. That will always be part of the story. Another issue to consider, however, is that potency, in terms of how many are required, can be different for different applications and for different microorganisms. When I’m asked how many are needed, I always tie it back to how many were used in the scientific publication that documented the effect. Then I can tell you how many you need to use in your product. The number used always has to be tied to the scientific study documenting efficacy. That may be different for different strains. You may be able to deliver 100 million of some strains and achieve an effect, but for other strains, you may need to deliver 100 billion in a day to achieve an effect. That needs to be tied to the specific studies that show the impact. Therefore, I would not necessarily be a supporter of broad scale recommendations or standards that state one needs to have a minimum number in a product. More important is that the product has to labeled accurately and has to deliver an efficacious dose, regardless of what that dose is. JB: That’s also very helpful. It appears there are at least two broad mechanistic approaches to physiological activity of probiotics in the host. One could be the release of secondary or primary substances from their metabolism that influence physiological function of the host in some way. Another could be an interaction between cell wall constituents and, as they travel through, they interact with receptor sites on the GI mucosal surface, which has an intracellular signaling process. It doesn’t require any release of substances; it’s more the environment of whatever the messages are on the cell wall of that specific strain. Can we make sense of how probiotics work mechanistically? Mechanisms of Action MS: Both of the mechanisms you just described are exactly what people are focused on. It’s the ability of the organism to interact with cells as it’s traveling through the intestinal tract. That’s a general description, because there are many, many different types of cells. Therefore, there are many different types of potential interactions that can occur. Very clearly, these organisms have been shown to have the ability to influence immune cells, and there are many different types of immune cells. The gut is the largest immune organ in the body. Therefore, the types of interactions you mentioned very clearly take place. Interactions with different types of intestinal cells have also been shown. In cell culture work, an interaction has shown enhancement of mucus secretion ability of intestinal epithelial cells. These organisms have the ability to decrease pathogen colonization and growth at different sites. That may be a function of competitive exclusion using, as you mentioned, metabolites and end products of growth by these organisms. They produce quite a few organic acids and other types of short-chain fatty acids that can interfere with pathogen growth. Or, it may be steric hindrance in terms of interfering with binding sites on the cell surfaces. It could be an enzymatic interaction where toxins or toxin receptors are degraded by these organisms. There are a variety of mechanisms that have been suggested in terms of how they might interact and ultimately exhibit their effects. You gave an excellent summary of the two possibilities. JB: We have discussed the isolation, the history, the characterization, the standardization, and the potential mechanisms of probiotics. It’s time for the payoff. Tell us about the clinical effects-the range of things these organisms may be useful for as therapies. Health Promotion Capabilities of Probiotics MS: Before I begin this discussion, I want to say that when you talk about probiotics, a general discussion can be very misleading. Oftentimes, generalizations are made to the category as a whole. If I start listing attributes or health-promotion capabilities of particular strains of probiotics, there may be a tendency to think that all probiotics can do all of these things. Of course, they can’t. Even if they could, we haven’t done the studies to show that they can. As I go through a discussion of the types of very exciting research that’s been done to document physiological effects on humans, the listener has to keep in mind that any one of these effects has probably been documented with only one or a handful of different probiotic organisms. It’s not a function of taking any probiotic available today and seeing these benefits. That’s the underlying thinking that has to go into a discussion about effects. However, I will try to delineate some of the areas of research that have been the most promising with probiotics. It’s up to people to make sure that any product is scrutinized for its documentation. Some of the most exciting research that’s been done in the past ten years has been in the area of immune interactions. A variety of probiotic bacteria have been shown to upregulate immune response, enhance macrophage activity, or enhance certain cytokine or tumor cell killing activities that help a person to better resist infections, either by bacteria or viruses or improvement in their ability to decrease proliferation of certain types of tumor cells. That type of upregulation has been studied for a while and has been shown in different strains of probiotics. In the past five or six years, probiotics have also been shown to downregulate certain immune functions, including allergic and inflammatory responses involved in varied diseases that are on the rise, such as IBD diseases such as Crohn’s disease, and different types of other allergic responses. Certain probiotic bacteria appear to have the ability to either upregulate or downregulate negative responses so as to achieve more optimal or normal functioning of the immune system. Another large area of research has to do with the ability of probiotics to decrease the incidence or duration of certain diarrheal illnesses. The most extensive studies have been done on anti-viral effects and the ability of probiotics to decrease diarrhea in infants, especially in the realm of rotavirus diarrhea. There have also been studies on probiotics and antibiotic-associated diarrhea. Not all of those studies have been positive, however. It depends on what organisms are being examined and at what dose they’re administered. Another area of research is investigating the ability of certain probiotic organisms to deliver lactose to the small intestine, thereby helping its digestion in people who are lactose-intolerant. Dairy products can be better tolerated by people who are consuming certain live microorganisms, either as part of yogurt or a probiotic supplement. That can be important from a nutritional point of view. There are some interesting studies, many of them done in animal models, on the ability of probiotics to decrease pathogen colonization, such as Helicobacter pylori in the stomach and certain intestinal pathogens in the small and large intestines. There are some very interesting areas of research on the horizon, one in the area of IBD. There have only been a few publications, but some of them show some positive effects with probiotic bacteria. There have only been one or two published papers on probiotics and dental caries. Other areas include control of halitosis and control of kidney stone formation. There are a variety of very interesting areas of research being documented right now. What they have in common is that they are all physiological situations contributed to by normal flora. It’s the modulation of the flora to some extent that can help control many of the different problems. JB: I think I’ve seen a paper or two recently discussing the role of probiotics in atopy and allergy in children. Is that another area of research? MS: Yes, and I meant to mention that. I put that in the category of regulation of immune function. There have been some excellent studies done in children showing the downregulation of the allergic response. One study published in Finland showed a dramatic decrease in the incidence of atopic dermatitis in infants whose mothers, when they were pregnant, had been administered a probiotic, and the children received it up through the first six months of life.[15],[16] It was a randomized, double-blind, placebo-controlled trial. The control group had twice the level of atopy at two years of age as the intervention group did. It showed a dramatic ability of the flora and the particular probiotic intervention, to downregulate the allergic response and to appropriately gear the immune system for normal responses. JB: Let me ask you about the up- and downregulation of the immune system. For instance, if the wrong strain is used, one that upregulates the immune system in an inflammatory patient, it might exacerbate the problem and result in a negative outcome. MS: That’s a very fair comment. I think we’re going to learn a lot more in upcoming years about how particular bacteria interact with each other. In animal studies, there does seem to be some evidence that one particular component of a blend may either modulate the ability of another probiotic component to engage in certain functions with the immune system. I don’t think the story has been told yet about how those are going to interact. In dealing with people within a reasonably normal range of capabilities, there doesn’t seem to be any evidence of hyperstimulation of immune function, or downregulation of inflammatory activity to the point of not being able to appropriately respond to some type of a pathogen infection. There seems to be more of a modulation effect. If you’re considering taking these products for specific therapeutic benefit, you want to make sure that the product has been tested for that benefit, and that there is a basis on which to expect an effect. One wouldn’t want to throw any probiotic at someone with Crohn’s disease. One would want to look for a probiotic that has been documented to show a downregulation of inflammatory effect. With someone with an immune-suppressed condition, one would want to choose a probiotic that has been shown to have the ability to enhance immune function. If you’re looking at probiotics that are just coming through in the food supply, such as yogurt products, they are being targeted for a more healthy population and I don’t think we have to be too concerned about an effect going too far in one direction or the other.[17] JB: That’s very helpful information. For the clinician, that’s probably the best guidance. They are obviously not able to spend the time you would spend understanding all the research subtleties in the literature. A question they might ask is, what is the published work for this strain against the condition of my interest? It seems that everything we’ve talked about distills down to that question. Thank you very much, Dr. Sanders. This has been most interesting and it’s been a good synopsis that many of our listeners have been looking for related to this category of therapeutic agents. For many people, it might have sounded strange to consider administering a live bacterial culture orally to someone when they were trying to treat bacterial diseases with antibiotics. This offers a different approach, using the appropriate symbiotic personality of these organisms to do something favorable. You’ve given everybody the foundation they need to gain more confidence as they move ahead with this category. MS: It’s been my pleasure. JB: We wish you the very best and we’ll check in with you in the future.   Yogurt and Gut Function Once again, we want to thank Dr. Sanders for a superb description of this complex category and her help in raising our level of understanding. She mentioned something I thought would be worthwhile closing on, and that is the relationship of probiotics to the yogurt connection. As she mentioned, Dr. Metchnikoff was probably responsible for first introducing these cultured milk products. In recent years, numerous studies have been published on the health benefits of yogurt and bacterial cultures used in the production of yogurt. In the United States, these lactic acid-producing bacteria include species of Lactobacillus and Streptococcus, and they have been discussed in a variety of publications. Yogurt is one of the best known of the foods containing probiotics and it is defined by the Codex Alimentarius of 1992 as a coagulated milk product that results from the fermentation of lactic acid in milk by Lactobacillus bulgaricus and Streptococcus thermophilus. It has this characterization, a history of safe use, and a standard identity. Therefore, is giving yogurt the way to do probiotic therapy? Other lactic acid bacteria species are now frequently used to give the final product unique characteristics. We have talked about Lactobacillus bulgaricus and Streptococcus thermophilus, but there may be other organisms that have been used, depending upon the manufacturer and what they have spelled out on their labels. A carefully selected mixture of these Lactobacilli species is known to complement one another. We are beginning to see yogurts that have mixtures of species to optimize the low pH and high acidity of the GI environment. One might ask if probiotic therapy, giving yogurt, is the same as giving concentrated organisms as a therapeutic agent. It depends somewhat on whether we are talking about the prophylaxis and prevention versus the therapeutics, as Dr. Sanders and I discussed earlier. If we are talking about a high-potency product going to a dewatered viable concentrate of organisms, that will result in a much higher potency per dose than yogurt. However, if the organisms are viable and have not been pasteurized and killed, yogurt can have some positive benefit as a prophylactic with general immunological-balancing properties pertaining to GI function. Numerous studies suggest beneficial effects of yogurt consumption on GI health. However, results have been inconsistent, which may be due to differences in the strains of lactic acid-producing bacteria, routes of administration, and investigational procedures used in these studies. If we were to examine the clinical applications, it would appear that the more highly defined concentrates that have published research with specific dosages is preferable to that of using yogurt in clinical therapy, but it does not suggest that yogurt is of no value at all. Yogurt does have value, certainly in the general area of gut health. If you would like to read a good review paper on this topic, Drs. Simin Meydani, Robert Russell, and Oskar Adolfsson-investigators at Tufts University Medical School, USDA Human Nutrition Center on Ageing-have published a paper in the American Journal of Clinical Nutrition, titled “Yogurt and gut function.”[18] This article contains a good overview of the effect yogurt consumption has on fecal flora. The authors also talk about some of the clinical applications of yogurt in diarrheal disorders; reducing the risk to colon cancer; helping with milk sugar digestion by supplementing lactase, the milk sugar digesting enzyme in individuals with lactase deficiency; and helping patients with IBD so they have less susceptibility to relapse. All of these are interesting discussions of differing strains of bacteria that have been recently been employed in yogurt, and how they might also play a role in the functional food approach toward improved GI health. Thank you for being with us this month. We will see you in 2005. I would like to follow up on Dr. Kellman’s clinical comments about borderline subclinical hypothyroidism and its importance in health care, and talk about dysphoria and later dementia in postmenopausal women. The thoughts Dr. Kellman shared with us about the role thyroid metabolism plays in central nervous system (CNS) function is germane to the increasing number of women in the current postmenopausal age group who have historically been candidates for taking conjugated equine estrogens (CEEs) and synthetic progestins—also called hormone replacement therapy, or HRT—for the management of postmenopausal health risks. Women were told that CEEs would reduce risk to bone loss, lower the risk to cardiac disease, improve cognitive function, and lower the risk to dementia. It was a clinical approach that appeared to be the “be-all and end-all” for managing problems associated with postmenopause. Now that the data from the Women’s Health Initiative (WHI) studies have been published, we know that panacea was not realized. There is now a more cautious view of the role of mixed CEEs. It is not that they have no value; it is that the kind of excessive support for their application has diminished considerably in light of some of the more recent evidence. That also holds true as it relates to estrogen and dementia. Recently, in the Journal of the American Medical Association, two back-to-back papers were published that discussed the issue of HRT and dementia or mild cognitive impairment in postmenopausal women.[9],[10]The editorial that followed those two articles sums it all up. The author states that there is no evidence from the WHI data that the implementation of mixed CEE intervention did, in fact, help protect against the loss of cognitive function. The author further states that there may be some evidence that CEE intervention increased the loss of cognitive function.[11] That was not good news. The final message appears to be—do not use CEEs to try to improve cognitive function in postmenopausal women, whether alone or as part of HRT. Nutritional Intervention in Postmenopause What are the alternatives? How do we keep mood, mind, memory, and behavior intact? Some individuals have suggested that nutritional intervention with soy proteins containing phytoestrogens that function as selective estrogen response modulators (SERMs) may be an alternative. There is a paper in the Journal of the American Medical Association, titled “Effect of Soy Protein Containing Isoflavones on Cognitive Function, Bone Mineral Density, and Plasma Lipids in Postmenopausal Women.”[12] In this trial, 25.6 grams of soy protein containing 99 mg of isoflavones were taken daily versus milk protein as an alternative. The authors conclude that this double-blind randomized trial does not support the hypothesis that the use of soy protein supplements containing isoflavones improves cognitive function, bone mineral density, or plasma lipids in healthy postmenopausal women, when started at the age of 60 years or later. I do not want to throw out the baby with the bath water with this study. Clearly, there is a considerable body of literature that indicates there are many benefits in terms of improved endocrinological function, using diets that include soy protein and isoflavones at normal dietary cultural levels. But soy isoflavones, at least at that level, are not a panacea to help protect against the loss of function that occurs postmenopausally. What other nutritional associations are linked to bone loss, cardiac function, lipid panels, and CNS function? Once we ask that question, it comes back to looking at thyroid function. Therefore, intact thyroid function is very important. There is an estrogen/thyroid connection, a connection of calcitonin and thyroid function, and a connection of T3 to CNS function. The story begins to evolve as a functional web to support continued high-level CNS function in postmenopausal women. We should look at things that might lower thyroid activity—food allergies, and gluten and its association with autoantibodies against the thyroid gland. We should look at selenium in the diet to make sure there is adequate conversion of T4 to T3. We should look at zinc, another important mineral for the proper sensitivity and metabolism of thyroid hormone. We should look at iodine to make sure it is adequate but not excessive in the diet to support proper thyroid hormone formation. We should look at things in the diet related to support of proper adrenal function. We should look at exercise, stress management, and things that help lower excessiveadrenal output of cortisol. We should look at things that help to stimulate insulin sensitivity because that will have a salutary benefit on thyroid hormone metabolism and sensitivity. We have discussed some of those things in previous issues of FMU, such as a diet with a lower glycemic load; cinnamon for improving insulin sensitivity; and lipoic acid, another insulin-sensitizing or supportive nutrient. What I am speaking to here is, as Dr. Kellman pointed out, broadening our perspective—moving from a slit to a window of opportunity. Often in medicine, we go from big and are trained to think small, rather than starting with small and going to big, and connecting the issues that may control the outcome of the variable we are analyzing in a patient. There are many nutritional associations we should be attending to in conditions of bone loss, dyslipidemia, and CNS dysfunction in postmenopausal women that go beyond estrogen. Thyroid function, metabolism, and activity, and its interrelationship with insulin, cortisol, calcitonin, and things relating to parathyroid function, are all extraordinarily important. Parathyroid function takes its message, in part, from the calcium and phosphorus ratio of the diets. Women who drink a lot of soda pop and other synthetically sweetened beverages, may be getting a fairly high dose of phosphorus as the phosphates in cola drinks, but fairly low levels of calcium. They have an interrupted calcium-to-phosphorus dietary ratio that may induce secondary hyperparathyroidism, having an adverse effect upon thyroid hormone balance and calcitonin. All of these things are interwoven. That is the excitement of functional medicine—putting the system into a context for clinical management so the whole person is being treated, not just the disease. The challenge is that it requires making a lot of thoughtful connections that may be more complicated than simply jumping to the conclusion of a diagnosis. I hope that Dr. Kellman’s message came across strongly—that the payoff for that cerebral process for developing those relationships, is better patient outcome and solutions to complex, chronic age-related dysfunctions that are not amenable to polypharmacy. There is an interesting paper in the American Journal of Clinical Nutrition which examines nutritional associations beyond soy isoflavones, having to do with bone loss, serum lipids, and CNS functioning in the postmenopausal transition.[13] These are things like calcium, flavonoids from fruits and vegetables, and various vitamins and minerals, as I have previously described. Asking the Right Questions A lot can be done once we ask the right questions. There is a common theme that comes through in every discussion we have had to date in FMU and that is, the questions you ask determine the answers you receive. If you do not ask the question, it is unlikely you will receive the answer. In functional medicine, one of the principal components of our teachings involved in gaining competency is learning how to ask the right questions. Once you ask the right questions, there are a multitude of places where you can find the answers. With the advent of the worldwide web, and accessibility of Medline and PubMed to virtually anybody with a computer, we can now find answers if we know what questions to ask. The difficulty in medicine has historically been to distill down the number of questions to a very few so that one will get “the right answer.” That lowers reinforcement for asking questions and begins to make it a disadvantageous part of a daily practice. The fewer questions one asks, the better off and more efficient and effective one should be. That is antithetical to the functional medicine model, which basically states that the more questions one can ask to help connect important strategies for the management of complex symptoms in the patient, the more successful one will be in the outcome. That is what Dr. Kellman was referring to regarding how he approaches thyroid-related dysfunctions. Thyroid function is an example of both the complexity and simplicity of functional medicine. There is a tremendous amount of information about the thyroid. We have only scratched the surface. We could discuss the topic for tens of hours. But through drilling deeper into the understanding of the thyroid, we start to explore and understand other connections as well, such as those of insulin, cortisol, testosterone and progesterone, and estrogen, which help us to understand how the body functions to improve the efficacy of patient outcome. I hope I have provided you with some good takeaway information about using the thyroid panel and how to evaluate patients with subclinical borderline hypothyroidism. We will see you in December.

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Bibliography

1 Holman H. Chronic disease-the need for a new clinical education. JAMA. 2004;292(9):1057-1059. 2 Isaacs KL, Sartor RB. Treatment of inflammatory bowel disease with antibiotics. Gastroenterol Clin North Am. 2004;33(2):335-345. 3 Schultz M, Timmer A, Herfarth HH, Sartor RB, Vanderhoof JA, Rath HC. Lactobaccilus GG in inducing and maintaining remission of Crohn’s disease. BMC Gastroenterol. 2004;4(1):5. 4 Rath HC, Schultz M, Freitag R, Dieleman LA, Li F, Linde HJ, Sartor RB. Different subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice. Infect Immun. 2001;69(4):2277-2285. 5 Guarner F. Microecology as a target for therapeutic intervention in inflammatory bowel disease. IDrugs. 2003;6(9):868-873. 6 Guarner F, Casellas F, Borruel N, et al. Role of microecology in chronic inflammatory bowel diseases. Eur J Clin Nutr. 2002;56(Suppl 4): S34-S38. 7 Lin HC. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA. 2004;292(7):852-858. 8 Swidsinski A, Ladhoff A, Pernthaler A, et al. Mucosal flora in inflammatory bowel disease. Gastroenterol. 2002;122:44-54. 9 Madara J. Building an intestine-architectural contributions of commensal bacteria. N Engl J Med. 2004;351(16):1685-1686. 10 Rastall RA. Bacteria in the gut: friends and foes and how to alter the balance. J Nutr. 2004;134:2022S-2026S. 11 Lin HC. Small intestinal bacterial overgrowth. JAMA. 2004;292:852-858. 12 Baharav E, Mor F, Halpern M, Weinberger A. Lactobacillus GG bacteria ameliorate arthritis in Lew rats. J Nutr. 2004;134(8):1964-1969. 13 Vella A, Camilleri M, Rizza RA. The gastrointestinal tract and glucose tolerance. Curr Opin Clin Nutr Metab Care. 2004;7:479-484. 14 Thorens B, Larsen PJ. Gut-derived signaling molecules and vagal afferents in the control of glucose and energy homeostasis. Curr Opin Clin Nutr Metab Care. 2004;7:471-478. 15 Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet. 2001;357(9262):1076-1079 16 Kalliomaki M, Saliminen S, Poussa T, Arvilommi H. Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of randomised placebo-controlled trial. Lancet. 2003;361(9372):1869-1871. 17 Sanders ME, Heimbach JT. Functional foods in the USA-emphasis on probiotic foods. Food Sci Technol Bulletin; Oct 18, 2004:1-9. 18 Adolfsson O, Meydani SN, Russell RM. Yogurt and gut function. Am J Clin Nutr. I2004;80:245-256.

Welcome to Functional Medicine Update for January 2003. Last year was a year of change, and I expect that change will continue as we move into 2003. We are involved in a biomedical revolution that encompasses dynamic social and economic changes in the modeling of the healthcare system. The revolution will change the way clinicians provide services to individuals, as well as the services those individuals select. As Dr. Regina Herzlinger from the Harvard School of Business suggests in her consumer-driven healthcare proposition, this will be a decade in which we will see a shift away from provider-controlled services to consumer-controlled services.1 This shift will obviously have a bearing on the way functional medicine, as we define it, is presented and utilized. In the supply/demand curve, if there is more demand, there will be more supply, and that will lead to a paradigm shift. We are heading toward a convergence of biomedical transitions and new discoveries based on genome and post-genome knowledge. This will connect with consumer and economic shifts in the healthcare system and growing disillusionment on the part of many healthcare providers. When all these forces converge, the age of functional medicine will emerge. What is functional medicine?  A recent article in the New England Journal of Medicinedefines what I consider the more traditional meaning of functional medicine. The article is titled “A Program to Prevent Functional Decline in Physically Frail, Elderly Persons Who Live at Home.”2 Investigators randomly assigned 188 individuals, age 75 or older, who were physically frail and living at home, and put them through a six-month, home-based intervention program that included physical therapy and focused on improving impairments in physical abilities. Individuals in the intervention who had moderate frailty showed significantly less functional decline 12 months after the start of the intervention when compared with similarly impaired control individuals. The study discussed above demonstrates functional medicine focused on older individuals with impairments; however,  functional medicine goes far beyond this concept. Certainly, physical function throughout all of one’s life is very important, but a number of other variables are also important. We talk about physiological function and cell biological function — function that encompasses gene transcription and gene translation, as well as  proteomics and the metabolome – that is, control of all metabolic function. A recent paper in the Journal of Clinical Endocrinology and Metabolism illustrates another way of looking at function, in this case thyroid function.3  Investigators reported that selenium supplementation in patients with autoimmune thyroiditis resulted in normalized thyroid peroxidase antibody concentrations. These investigators administered 200 mg of selenium or a placebo in conjunction with L-T(4) orally for  three months. This research, of course, does not mean thyroiditis is always a selenium-insufficiency condition. It does, however, suggest that selenium status is one variable affecting thyroid function. A number of factors may affect a single outcome we are able to examine, such as a thyroid panel or an autoantibody against thyroid gland. In the broader definition of functionality, we examine the effect of selenium administration on physiological and physical function downstream. It may be possible to prevent the physical dysfunctions that emerge some years later from autoimmune thyroiditis by an upstream evaluation of cellular, biological, and physiological functional aspects of an individual. It is a different way of looking at the same concept, but at an earlier, preventive stage. This study of autoimmune thyroiditis and selenium supplementation demonstrates even individuals who do not have frank selenium deficiency may be suffering from selenium insufficiency. It shows that the thyroid peroxidase enzyme and its relationship to deiodinization of T4 to T3 appear to be related to selenium status. It may be an early warning marker for selenium insufficiency, well before the appearance of reduced glutathione peroxidase levels or other more traditional selenium-deficiency pathology. The answers you find depend on where you look. If you do not look in the right place, you do not get those answers. In functional medicine we have been attempting to broaden the definition beyond physical frailty and dysfunction to a range of dysfunction One might ask how to deduce these relationships.  How do you come to conclusions?  What kind of standards do you use in moving to judgment and taking action? I will cite one extraordinary paper on the topic, by Sir Richard Doll, a world-renowned epidemiologist. He was the first to bring scientific focus to the concept of smoking and lung cancer, and he was knighted for his contributions. His recent paper, published in Perspectives in Biology and Medicine, is titled “Proof of Causality. Deduction from Epidemiological Observation.”4 The paper eloquently describes how one deduces answers and ultimately arrives at an understanding of cause and effect. Dr. Doll begins by asking what causality means if you do not fulfill Koch’s postulates directly. It is not as simple as looking at an infectious disease that fulfills the traditional early 20th-century definition. How do you determine whether something like selenium could, in fact, be related to thyroid function? The Questions to Ask and Answer Dr. Doll explains there are certain questions that guide a determination of causality between observed associations:

• What is the strength of that association? ·      How consistent is the association from one observation to another? ·      Does a dose/response relationship exist? ·      Is there evidence of a relationship between time of exposure to symptoms/outcome? ·      Has a plausible biological mechanism been proposed? ·      Does the observed relationship show specificity? ·      What is the coherence of the evidence? ·      Have different investigators expressed disparate opinions? ·      Has it been experimentally evaluated? ·      Can it be viewed in terms of an analogous situation with something else?

All of those questions are guides to causality. No one answer by itself determines causality, but when more and more answers begin to point in the same direction, it more and more closely approaches what we would call “proof.” If you use that series of criteria to evaluate observations to see if there is a causal relationship with a specific observation, then it may lead to deductions about things like lung carcinoma and smoking. Smoking and Lung Cancer In this paper, Dr. Doll explains that initially there was a lot of resistance to the concept that smoking caused lung cancer. Many people pointed out that many variables could be involved, including air pollution. In fact, air pollution was believed to be the dominant cause at the time, not smoking. This particular model of epidemiological association, according to Dr. Doll, eventually led to recognition of the causal link between smoking and lung cancer. During this period of time, which lasted about 15 years, critics offered every possible objection to the suggested association between smoking and lung cancer. Finally, however, on the strength of the continued associations I described above, there was epidemiological strength and consistency in the data. There appeared to be a dose/response relationship based on smoking studies in animals, and a biological plausibility emerged as we began to understand more about carcinogens. The evidence appeared to be coherent, and animal experiments showing that smoking increased lung cancer incidence finally nailed down the causality. Eosinophilia Myalgia Syndrome (EMS) Dr. Doll uses another model, the toxic oil syndrome that produced eosinophilia myalgia syndrome (EMS). This syndrome was very similar to a problem that occurred in the United States with tainted tryptophan several years ago. The toxic oil syndrome, which occurred in Spain, involved tainted olive oil. In this case, the manufacturers had imported commercial, non-food-grade rapeseed oil that contained aniline into Spain. The oil was refined to remove the aniline; however, traces of this toxic substance were still present. This contaminated oil was mixed with olive oil and sold on the street as food-grade olive oil. Consumption of this oil with the aniline residues led to very serious EMS, including autoimmune dysfunction and some deaths. In tracing through this syndrome, it was once again difficult to get a distinct causality from the epidemiological record, and a number of explanations were offered. Causality was determined by going through the questions in the above list and asking how many of these criteria were fulfilled in the association between EMS and the consumption of this black market olive oil. Evidence-Based Medicine That’s what we try to do in functional medicine. We use all types of data: epidemiological data; cell culture work; animal studies; historical (retrospective) studies; short-term trials; individual case management studies; and even, obviously, the double-blind, randomized, placebo-controlled trial. All of these types of data are combined to help define causality. Is functional medicine evidence-based?  In a recent article titled “Evidence-Based Medicine, Opinion-Based Medicine, and Real-World Medicine,” Dr. John Hampton states the following: “The freedom of a doctor to treat an individual patient in the way he believes best has been markedly limited by the concept of evidence-based medicine. Clearly all would wish to practice according to the best available evidence, but it has become accepted that ‘evidence-based’ means that which is derived from randomized, and preferably double-blind, clinical trials. The history of clinical trial development, which can be traced to the use of oranges and lemons for the treatment of scurvy in 1747, has reflected a progressive need to establish whether smaller and smaller effects of treatment are real. It has led to difficult concepts such as ‘equivalence’ and aberrations such as ‘meta-analysis.’  An examination of evidence-based practice shows that it has usually been filtered through the opinions of experts and journal editors, and ‘opinion-based medicine’ would be a more appropriate term. In the real world of individual patients with multiple diseases who are receiving a number of different drugs, the practice of evidence-based (or even opinion-based) medicine is extremely difficult. For each patient a judgment has to be made by the clinician of the likely balance of risks and benefits of any therapy.  Good practice still requires clinical freedom for doctors.” 5 This is a powerful statement as we move from evidence-based to what Dr. Hampton calls “opinion-based medicine” to real-world medicine, seeing real patients, not experimental animals in a study, and how we come to judgment in managing their individual conditions. When we start asking the questions presented by Dr. Doll, new data become available along with observations that take us into new areas. We as a society are consuming an increasing number and quantity of pharmaceutical compounds. A speaker at a seminar I once attended pointed out that, after those drugs are metabolized and excreted, they go into our waste effluent stream and end up in rivers, lakes, and oceans. We must, therefore, be medicating these water sources. I had not considered that concept before, so I was particularly interested in a recent editorial in the Lancet, titled “Environmental Stewardship and Drugs as Pollutants.”6 The author states: “It is early morning—do you know where your drugs are?  More than likely, some are on their way to local streams, rivers, and perhaps even farms, as sewage biosolids used as fertilizer. The public’s inseparable connection to the environment is illustrated by an emerging understanding of drugs as environmental pollutants. That any chemical introduced commercially has the potential to find its way into the environment is not surprising, but pharmaceuticals and personal-care products as environmental pollutants have captured the attention of the public and the mass media because such pollutants result not primarily from manufacturing but from widespread and continual use in human and veterinary clinical practice. “Beginning in the 1970s, an escalation of research and monitoring, mostly by analytical chemists, has revealed the propensity for drugs and metabolites to enter the environment—usually by treated and untreated sewage. Many drugs from a wide array of therapeutic classes have been established as ever-present trace environmental pollutants in surface and ground waters, generally occurring at concentrations (eg, ng/L-mcg/L) far below human therapeutic levels.” Medicating the Food Chain Drugs may be bioconcentrated by various organisms, and that might lead to medicating biota and even the food chain. These processes, in addition to oxidizing our waste with ozonization, can create secondary products of these molecules that may create an even higher toxic risk. The author points out that with the increasing use of synthetic substances — such as estrogen compounds (eg, ethinylestradiol) used for the management of menopause — we are seeing increasing levels of hormonal materials going directly into our waste water and effluent from the metabolism and excretion of these synthetic steroid molecules. We should not discount any data or observations. They are all part of evaluating the web of understanding and specific aspects of functionality at the cell/tissue/organ/organ system and whole organism level.   I want to spend the rest of our time together in this issue of FMU reviewing some of the clinical takeaways we learned about in 2002 that will help us, as pathfinders, in 2003. Glycemic Control and Healthcare Expenditures Insulin resistance/hyperinsulinemia, or what Dr. Gerald Reaven termed “syndrome X,” is a condition in which there are high levels of insulin with insulin receptor refractory response, and an insufficient insulin-signaling process that occurs in the cell. Improved glycemic control would result in considerable reduction of healthcare utilization. In 2002, a number of studies were published on this topic. One study, published in the Journal of the American Medical Association,concluded that a sustained reduction in hemoglobin A1C (HbA1C) levels in adults with type-2 diabetes is associated with a significant reduction in healthcare expenditures.7 Hemoglobin A1C (HbA1C) When I first learned of HbA1C in the late 1970s, most people believed there was a step function; that is, HbA1c levels below a specific point indicated a non-diabetic state, whereas levels above a certain amount meant diabetes. The number at which this transition to diabetes occurred started off at around 7.5 percent of total hemoglobin as HbA1c, and went up to as high as 9 percent. Now, HbA1C levels are not considered on the basis of a step function, but rather from the standpoint of a curvilinear relationship between HbA1C levels and glycemic control. We can’t necessarily say that at a particular level you are safe from diabetesand at another level you are at risk. Instead, there is a continuous, increasing relationship between the level of HbA1C and relative risk of vascular complications. Lowering HbA1c below 5 percent would be considered desirable since many individuals who are nondiabetic actually have some relative risk to insulin difficulties and poor glycemic control. Syndrome X Metabolic syndrome, or syndrome X, is associated with hyperinsulinemia, dense LDL particles, elevated triglycerides, low HDL, increased blood pressure, and abdominal obesity. Waist circumference, a means of determining abdominal obesity, is a big risk factor. Many individuals have asked if visceral adipose tissue (VAT) precedes diabetes or if there is a metabolic transition that actually precedes and encourages the weight gain. This is a chicken-and-egg argument. Does insulin resistance/hyperinsulinemia, coupled with other factors, encourage the accumulation of VAT, or does VAT cause insulin resistance and later-stage type 2 diabetes?  There is evidence to indicate it is attributable to both factors. A review in Nutrition Reviews describes the push/pull association between serum lipids, body composition, and insulin/insulin resistance.8 Diet Control and the Glycemic Index How do you control the diet to lower HbA1C to regulate insulin more effectively and reduce some of the insulin signaling processes associated with metabolic syndrome?  Could the glycemic index of the diet be a factor?  We have heard a lot about the glycemic index of the diet in the past 10 years, which was defined by Wolever and Jenkins. A good review about the glycemic index at its 20-year anniversary appeared in the American Journal of Clinical Nutrition.9  Clearly, individuals who regularly consume a high glycemic index diet, a diet that causes great surgesof blood glucose and postprandial insulin, are more at risk to cardiovascular disease, diabetes, and other chronic health-related problems.10The glycemic index of an individual food or even a collective group of foods does not necessarily indicate the overall glycemic index of that diet, however. It is only a direction finder. Individuals who eat more legumes, unrefined whole grains, and fresh fruits and vegetables historically have better glycemic control than those whose diet primarily features the color white. White flour, white sugar, and white fat generally have higher glycemic indices, and induce higher postprandial glucose and insulin. Over time, the practice of consuming a diet of foods with a high glycemic index appears to be associated with increased risk of insulin resistance, hyperinsulinemia, and later-stage type 2 diabetes. This is also discussed in the American Journal of Clinical Nutrition. Medical Therapy for Syndrome X What do we do for a patient who has begun to shift toward increased HbA1C, increased triglyceride/HDL ratio, increased waist circumference area, increased waist-to-hip ratio, and increased percentage of body fat? All of these things are associated with insulin resistance. Medical nutritional therapy for syndrome X was the topic of an article in Nutrition Reviews.12The authors of this article indicate that a diet containing unrefined, complex carbohydrates, high in fiber and vegetable protein, more unsaturated fats within a limited total amount of fat is desirable. Individuals may respond differently to carbohydrates based upon their own physiological personality, and no single diet is perfect for every type of person. Therefore, the concept of a number or a zone for which everyone should strive is unrealistic based upon what we have learned about biological heterogeneity in the human population. Micronutrients and Glucose Control We need to construct a diet to meet the needs of the individual and also look at the micronutrient levels of specific foods known to help stabilize insulin, glucose, and glucose transport. These include nutrients like a-lipoic acid, which is used as a drug at higher levels for type 2 diabetes in Europe. These levels may be from 600 mg per day to as high as 1200 mg per day. The amino acid arginine has been used to help normalize blood sugar, and chromium has been used as glucose tolerance factor or a chromium mineral supplement. Coenzyme Q10 is important in glucose control. Magnesium is a mineral whose importance in regulating blood sugar levels is often overlooked. The omega-3 fatty acids are also recommended, including a-linolenic acid (ALA) from flaxseed oil and eicosapentaenoic acid (EPA) from fish oils. We need to get away from saturated fat-rich or partially hydrogenated vegetable oil-rich diets from fast foods, and into more unrefined omega-3 oil-rich diets. (We may be asked for references on some of these. For example, magnesium and CoQ10. I am not sure how direct the evidence is here.) Selenium, which we mentioned above, is also an important nutrient for management of glucose and insulin. Vanadium, given therapeutically as vanadyl sulfate, is more part of a therapeutic rather than a prophylactic approach. One should use vanadium at high doses only for short periods of time. There is no evidence that one should be on high levels of vanadium for an extended period of time. Last, higher levels of intake of both vitamin C and vitamin E are associated with improved glycemic control.11 Chromium Supplementation In Animals Several papers appeared in the literature in 2002 on chromium supplementation in animals. Supplementation with oral chromium picolinate improved carbohydrate and lipid metabolism in obese, hyperinsulinemic animals. This study appeared in the Journal of Nutrition.13A human dose equivalent is probably in the range of 300–600 mcg per day of chromium as chromium picolinate or glucose tolerance factor chromium. A meta-analysis study of human trials on chromium supplementation looking at glucose and insulin responses to dietary chromium supplements appeared in the American Journal of Clinical Nutrition.14 When the investigators conducted a meta-analysis, chromium appeared to have no effect on glucose or insulin concentrations in non-diabetic subjects. In those who had type 2 diabetes, however, the effect seemed to vary from very positive to no effect. My clinical experience, and that of colleagues I’ve spoken to over the years, indicates significant improvement of insulin regulation and glucose control may occur in individuals with hyperinsulinemia or metabolic syndrome by supplementation with chromium as chromium picolinate, chromium chelate, or the glucose tolerance factor chromium. I would not want to say chromium is of no value in the non-diabetic subject. Clinical experience may prove otherwise when individualized to the patient. Lipoic Acid Lipoic acid, from as little as 100 mg per day to as high as 600 mg per day, can have a dramatic effect on improving insulin regulation a A discussion of the use of lipoic acid in the treatment of insulin resistance/hyperinsulinemia appeared in Diabetes Care. At fairly high doses—600 mg twice daily for four weeks—in both obese and lean individuals with type 2 diabetes, lipoic acid helped improve glucose transport and insulin stimulation.16 The role of lipoic acid in improving insulin and glucose control in GLUT-1 and GLUT-4 was discussed in an article in Diabetes.17A number of publications describe the role of lipoic acid in protecting against oxidative stress, glucose transport defects, and hyperinsulinemia. These studies all describe its important role in the insulin-mediated pathway.18 The next important area of discussion for 2002 is hormone replacement therapy (HRT), focusing in particular on therapy for peri- and post-menopausal women. We saw a storm of controversy surrounding HRT in 2002 and we have discussed this controversy in FMU. A recent article in the Lancet, titled “Evidence from Randomised Trials on the Long-Term Effects of Hormone Replacement Therapy,” highlights the issue.19The authors of this paper stated exactly what we have all learned: substantial new data indicate that, compared to placebo, HRT does not show the purported value for protection from cardiovascular disease and it appears to be best in managing one symptom: flushing. With flushing as the principal presenting symptom, we know that HRT will, in fact, lower the symptoms. The question is, at what risk?  That question has led to discussions about the relative role of HRT. What are its effects on other cellular physiological processes?  What is the relation to other relative risks?  Earlier this year, I cited an editorial that appeared in the Journal of the American Medical Association,titled “Postmenopausal Hormone Therapy and Quality of Life—No Cause for Celebration.”20is article followed up on the quality of life and depressive symptom study that appeared in the same issue. That article indicated that women whose principal menopausal symptom is flushing did get positive benefit from HRT, but for all other women the adverse effect of HRT appeared to be greater than its benefit.21 HRT, Breast Cancer and Cardiovascular Risk Then we looked at HRT in relation to breast cancer risk. Information on that topic was presented in 2002 in the Journal of the American Medical Association.22The data reported in that paper added to the growing evidence that long-term use of HRT is associated with increased breast cancer risk and may be particularly related to lobular tumors. We also examined the risks and benefits of estrogen plus progestin in healthy postmenopausal women from the HERS Trial data.23That trial did not show the anticipated cardioprotective effects from HRT. In fact, it demonstrated that HRT might even pose a cardiovascular risk for some women. This information also appeared in the Journal of the American Medical Association. There are many papers on this topic, including an editorial titled “Failure of Estrogen plus Progestin Therapy for Prevention.”24 We are witnessing a tremendous change with regard to HRT and an evaluation of alternatives. That leads to a discussion of soy and soy products and the relationship to lignans from flax in the diet. Many papers are now discussing the role of isoflavones that inhibit cell proliferation and have both estrogen receptor-dependent and -independent pathways. A paper in Nutrition and Cancer describes how isoflavones inhibit these processes.25We tend to overreact to this type of news. We may think that if a little isoflavone is good (40-60 mg per day from a couple of portions of soy food), then 200 mg per day in a purified pharmacological dose form would be a whole lot better. The data do not appear to support that assumption. The data indicate that the traditional equivalent to what people get in their diet may be the safe and effective range. We consider soy isoflavones in combination with lignans from plant foods, particularly flax, because flax contains some of the highest level of lignans. We now know that lignans also serve as modifiers of relative risk to hormone-related dysfunction in women. Therefore, the lignan combination of flaxseed meal with soy foods a couple of times a day may be a prudent way to approach some of these difficulties. How do we improve the metabolism of estrogen so that the friendly estrogens are excreted without a buildup of the mitogenic estrogens in the body?  This relates to substances in the diet that stimulate the production of the 2-hydroxy and subsequent 2-methoxylated estrogens, reducing the production of the 16-hydroxy and 4-hydroxyestrogens. That leads to a discussion of the Brassica vegetables and the Crucifers. We heard a lot about these vegetables last year, and the glucosinolates present in cabbage, broccoli, Brussels sprouts, and cauliflower. A series of papers have discussed the use of indole-3-carbinol, a glucosinolate byproduct that comes from eating cruciferous vegetables. Indole-3-carbinol appears to be efficacious as a chemopreventive agent when consumed at normal levels of intake. That topic is discussed in a paper in Carcinogenesis.26Another paper, which appeared in Nutrition and Cancer, is titled “Abrogation of Estrogen-Mediated Cellular and Biochemical Effects by Indole-3-Carbinol.”27Another paper describes the determination of urine levels of the metabolic byproducts of indole-3-carbinol in women who have consumed oligomers of indole-3-carbinol, one of which is diindolylmethane, a breakdown product polymer of I3C. Individuals who consume I3C will excrete various of these oligomeric I3C derivatives in their urine, one of which is diindolylmethane.28 Indole-3-carbinol and diindolylmethane appear to induce apoptosis in cervical cancer cells in culture and preneoplastic cervical epithelium, causing reversion back to normal cell architecture.29In the acidic stomach environment, I3C is converted to a variety of its oligomers, which have varying effects on gene response and cellular physiology. When broccoli, Brussels sprouts, or cauliflower is consumed, the body converts I3C into oligomers that have a variety of effects on the body. The upstream I3C precursors serve the downstream control of these regulating phytonutrient substances. These substances may be considered secondary or even tertiary metabolites, because when the glucosinolate is consumed, it is converted into I3C by myrosinase and subsequently in an acid stomach into oligomers of I3C, which have effects on gene expression and cellular physiology. We are seeing some interesting changes in our view of the way diet can regulate estrogen metabolism and a woman’s risks in relation to her own estrogen. Men’s Estrogen Issues             We also learned in 2002 that women are not alone in having estrogen issues. Men may also be at risk. The 16- and 4-hydroxyestrogens may induce prostatic dysfunction. Most men do not think of estrogen in the prostate, but it plays an important role, although in small amounts, in the regulation of aspects of prostate function. Estrogen metabolism is as important in men as it is in women, and diet plays a role in estrogen metabolism, cell sensitivity, transport through sex hormone-binding globulin, and its relative excretion as the biotransformed substances. Early Detection and Functional Medicine We have learned about the importance of diet, genes, and environment on hormone normalization. This relationship provides a fine example of the functional medical concept. We do not wait for a proliferative mass to develop before we take action. Even breast examination is a late-stage evaluation for what may be occurring at the cellular level. We want to back up in our prevention toward the cellular perspective — the functional aspect — from the physiological perspective. This process is described in an article titled “Development of a Multi-Organ Model for Evaluating Chemopreventive Agents: Efficacy of Indole-3-Carbinol.”30 While we want cellular-specific activities, we would like to get a beneficial effect, in the breast for example, without having an adverse effect on the liver or on the kidneys when we begin to supplement with specific agents that help to normalize function. Seeking Balance             There are no substances, including air and water, that are not toxic at some level.  Therefore, we should balance levels of intake. We want to adhere to Dr. Richard Doll’s concept of looking at causality and efficacy, putting all the pieces of the puzzle together. That is the logic tree we try to use in functional medicine to promote or describe specific approaches toward prevention or management of conditions.

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INTERVIEW TRANSCRIPT

  Clinician of the Month David Jones, MD, President Institute for Functional Medicine P.O. Box 1697 Gig Harbor, WA 98335 Phone: 253-858-4724 Fax: 253-853-6766 www.functionalmedicine.org JB: Welcome to our Clinician of the Month interview. We begin the New Year with a special guest—my long-time colleague and friend David Jones, MD, president of the Institute for Functional Medicine (IFM). You have listened to Dr. Jones in previous FMU interviews, but today we will focus on his view of the future of medicine in 2003. We will discuss medical education, trends and changes that are taking place, and how the IFM maintains a leading edge in the face of such change. David, welcome to Functional Medicine Update. In May of 2002, IFM conducted its most successful meeting—the Ninth International Symposium on Functional Medicine—in Ft. Lauderdale, Florida. After reviewing the course evaluations and being a major contributor to that meeting, what are your impressions? What we have learned? DJ: First of all, thank you for inviting me to be Clinician of the Month. I am still a clinician. I still run a practice and have two very good associates who come from a background in nutritional medicine and are graduates of our Applying Functional Medicine in Clinical Practice course. Here in Ashland, Oregon, our clinic is very busy because of the education we have all received through the IFM. Your specific question about what we learned and what we experienced in Ft. Lauderdale brings me to two issues that I think about all the time as president of the IFM and about its origin nine years ago. It’s been quite a journey, and Ft. Lauderdale was a two-pronged experience for me. High Quality of IFM Practitioners The first issue is the quality of people who, over the years, have embraced the notion of functional medicine. We are looking at the scientific basis for evaluating and developing treatment plans for complex chronic illness and for primary prevention, examining the underlying biological processes that lead to chronic illnesses. The high quality of practitioners who have been drawn to our particular matrix of biological processes is humbling to me. These practitioners are highly motivated. Many of them are FMU listeners, so I’m speaking directly to them now in appreciation. When we took the Hippocratic Oath, or the oath specific to our particular kind of healthcare practice, we took that commitment very seriously. We wanted to work as partners with our patients and their health problems to help them see the underlying causes of those problems. That’s very humbling for me. A number of very high-quality practitioners look to us to help form the intellectual matrix that organizes a huge amount of information so it can be applied in real time in a one-to-one relationship with patients. Balancing Research Information with Clinical Application The second issue is balancing what we know at the IFM because of the leadership you give, Jeff, in terms of organizing information, and the connection we have, through the IFM, with leading scientific institutions, universities, and organizations around the United States. We know where this is going and, at the same time, we listen very carefully to our attendees and our members as to how they want us to present that information. The experience at Ft. Lauderdale was like being at the forefront of clinical practice, where you combine leading-edge information with clinical application. That’s the constant conundrum for us. We always strive to find the point of intersection between good, reliable information and its application in clinical practice in a way that does no harm. We strive, in fact, to find ways to improve patient care as early as possible by applying leading-edge interventions, based on emerging evidence and scientifically sound thinking. Folic Acid as Example Fifteen years ago, for example, well before the role of folic acid supplementation in preventing spinal defects in children was accepted, you and I were talking about it in our study groups. That same information might have prevented thousands of spinal defects had it been released and placed in a matrix that could be used clinically in everyday patient encounters. That’s what humbles me. We have access to that information; we have providers who are excited about applying that information; and we have to be circumspect in finding where that edge is that makes it possible to apply it in a safe and efficacious way. Presenting the Research That’s what happened for me in Ft. Lauderdale. And that’s what’s going to happen in Tucson in May of 2003. In Tucson we are bringing together world-renowned researchers who have transformed the field of cardiology, including Dr. Paul Barton Duell, the expert in using homocysteine in clinical practice, from the Oregon Health Sciences Center; Dr. Walter Willett from Harvard; Dr. Mark Houston from the Vanderbilt University Medical Center; Dr. John Cooke from Stanford University; and Dr. Serge Renaud from France, the leading researcher in the Lyon Study. Around the topic, The Heart on Fire—Modifiable Factors beyond Cholesterol, we will have world leaders in cardiology giving us their take on inflammation as an underlying process that causes complex illness. It is involved far more extensively than in the cardiovascular system, although that will be the focus this year. We also have a host of clinicians with a functional medicine orientation for our afternoon workshops. We have never before put together the number of workshops with the variety of people we’re going to have this year. We will conduct eight workshops each afternoon. Making Functional Medicine Practical I am humbled and excited about where we have taken the concept of functional medicine so that it can be applied in real time on Monday morning after people leave our educational activities. At the same time, we constantly go through reevaluation of how to make it more practical; how to take it from a theoretical view right down to what happens between two people — a healthcare provider and a patient — to change patients’ lives. We are finding the educational tools to make that possible. For me, toward what I thought was going to be the end of my career, it is very exciting to begin in such a large way to execute something you said to me many years ago, Jeff. I’ll never forget it and I’ve mentioned it a number of times to you and to audiences. You said: “David, there’s nothing short of changing the world that’s worth doing.” There’s no question in my mind that through the IFM we will change the way patients are taken care of, not only in the United States but around the world. Applying Functional Medicine in Clinical Practice JB: That’s a wonderful answer covering a huge expanse. I want to follow up on one of the things you mentioned. The symposium in Tucson on May 21-25, 2003, will be the 10th International Symposium on Functional Medicine. A lot of things are being planned. Three AFMCP training programs will have taken place between the Ft. Lauderdale symposium and the one in Tucson, so we ought to have good momentum going into Tucson with regard to the enthusiasm you describe. DJ: The other thing that has happened for the IFM is that the word is out. Graduates of the Applying Functional Medicine in Clinical Practice courses are talking to their peers and colleagues, saying this is the premier course. It is a week-long course where they rub shoulders with functional medicine experts and clinicians throughout the United States. It is set up so that from the day they arrive to the day they leave graduates can anticipate being able to apply that information. They can get to their offices the following Monday morning knowing how to take a vast array of information and apply it in a consistent way to the clinical problems their patients bring to them. This is most exciting for me because it is the premier way of changing the organization of information. It’s taking a vast amount of information and knowing there are clear underlying processes that you can organize around the patient story. Then you know how to organize their story in such a way that you understand the antecedents that indicate how they got where they are, what triggered the problem, and what things can be done to those modifiers that continue the disorder. In March, we will have the AFMCP program in Gig Harbor, and in October we will be going back to Boston. Then in December, we will be opening up a new territory in the Los Angeles area for the doctors in the Southwest. There’s a tremendous commitment on our part to get the information to a point where it can be used by providers and try to make it as comfortable for them as possible. AFMCP in the Southwest JB: In my travels, a number of people have asked me if we would ever have an AFMCP training program in the Southwest. I’m sure that information will come as a nice surprise. When is it scheduled to occur? DJ: That will be the first week of December 2003 in the Los Angeles area. AFMCP in Boston JB: And the Boston meeting will be in the fall? DJ: That will be around the first week in October when the trees are beautiful and the threat of snowstorms hasn’t quite hit. AFMCP in Gig Harbor JB: And then in Gig Harbor in the spring of 2003? DJ: Yes. That’s the next course we’re conducting. That will be in March of 2003. We are now accepting registrations for participants in that program. Seattle is an easy airport to get into from around the United States. There are many direct flights, and we often get very good attendance in the Seattle region. We usually get a number of participants from Asia, as well. Some folks are uncomfortable about flying since the September 11 debacle, so we are trying to respond by providing this educational activity in three areas. Taking IFM out of the Commercial Environment I would like to talk for just a minute about taking the IFM out of the commercial environment. When HealthComm and Metagenics merged, you and your wife Susan accepted the assets for IFM out of that environment. You immediately put them into the corporate context we now call IFM, which is now recognized by the IRS as a tax-exempt 501(c)(3) organization. We have just started our first fundraising drive. A lot of FMU listeners, as well as former AFMCP and symposium participants, will be getting our brochure. This is exciting for us because we have created a real community and there’s a real sense of responsibility within that community. Now that people know a contribution to IFM is tax-deductible, it is not unusual for us to get checks from people who spontaneously send money to make sure the Institute continues. You can’t imagine what an affirmation that is for me and for our staff. As we were launched, there were certainly some financial limitations. The biggest limiting factors to our postgraduate fellowship and diplomate programs are financial, and we’ve put together a grant for large amounts of money from foundations. If we weren’t operating in the world of the stock market crash and the 9/11 experience, we would probably have that funding at this point, because we have on the drawing board all the plans to go forward with a fellowship in functional medicine. The Functional Medicine Community We have great plans for IFM. The key is a sense of community. Providers all over the world look to us for reliable science-based information that is integrated from all specialties and all healthcare provider niches. They want science behind what they do. It’s a huge responsibility, but at the same time, it’s the most exciting thing I’ve ever done I thought becoming a doctor was exciting, and it continues to be so. To be involved with the growing of this paradigm is way beyond my expectations. You said many years ago that nothing short of changing the world is worth doing. I understand now why you said that. I used to be in awe that you felt that way. I no longer am in awe because I know it’s possible. IFM Staff JB: I want to stress the importance of the IFM staff. Although small in number, they are an incredible group. I applaud the excellence they achieve, their dedication and perseverance. They are champions. That’s what it takes to create this type of change in the world—people who are warriors. We are very fortunate at IFM to have that type of staff. DJ: One of the foundations is going to give us a grant toward the revision of our website, a place where we feel it is important to have a sense of community. We will have a case forum content and clinical consultant so people can put their difficult case studies up and receive an organized response. That foundation is going to grant part of the resources. They believe we do have a paradigm that needs to be leveraged out into the world. Second, they’ve looked at our staff and what they have been able to accomplish with the resources we’ve had and have been astounded by the competence. They can give us money and be assured that it will be leveraged strongly toward the mission, which is making a difference in patient outcome. I second your observation that the IFM staff is absolutely remarkable. Functional Medicine and Third-Party Reimbursement JB: Can functional medicine be incorporated effectively into a third-party payer reimbursement system, or is it just a tool in search of codification within the business community we now see in the health sciences? DJ: This is the biggest logistical question for our AFMCP graduates—how to configure their practices in such a way that they make a living equal to the kind of effort they put in. At the symposium in Tucson, the first pre-course will be on office management. We have chiropractors, naturopaths, MDs, and DOs who have been very successful applying this paradigm. That will be a full-day pre-course on how to make this possible. Not only am I the president of IFM, but I have also been president of the regional Independent Physician Association (IPA) in Southern Oregon area for 10 years, so I have some experience in this area. Making a living within managed care in the conventional world is a big issue right now. There’s a question of whether internists can make a living, with Medicare just about to cut back. Internists who are dedicated to their Medicare patients are wondering if it will be financially viable to continue. The world as we know it, in terms of reimbursement, is in chaos right now. Health Resources Account Program The biggest issue on the floor, in my opinion, is the federal qualifying of what’s called the HRA, Health Resource Account program. Together with major medical, it will put a whole different spin on patient empowerment in selecting healthcare providers. This has been very quiet on the horizon because insurance companies are not happy about this transition. Basically, health insurance will become major medical health insurance, which is what it was originally intended to be. It wasn’t an entitlement for all medical care. The marriage of that will be an employer benefit that’s called a Health Resource Account that builds up over time and goes with the employee like an IRA account. That account can be used for any medical care that would qualify under IRS regulations. The valley I work in consists mainly of small employers, but contrary to some of the information the insurance companies have published, large and small employers both qualify for this new and novel approach to getting patients into the healthcare equation. Patient Choices With this program, patients will be able to decide where to spend the money they have for medical care up to that deductible. They’re going to go to doctors and healthcare providers within their community who have a reputation for making changes that work. I’m very excited about this. It is exciting within the conventional medical community as well, because it puts accountability back on the shoulders of the patient/provider interaction. If that’s not working, patients aren’t going to take money out of their account to go see that healthcare provider. It’s not going to be controlled by the insurance company. No longer will there be panels of providers, none of whom you may want to select but you have to go there because that’s the only place your insurance company allows you to go. This is a very exciting concept, but it is poorly known. Some of the big companies are moving their Human Resource Insurance Plan Benefits into this environment because they know the studies are very clear. When patients have control of the money, they are more empowered to take care of themselves. And that will open doors for functional medicine providers that have never been open before. Functional Medicine in the HRA Environment Patients currently feel they have to go to where their insurance has a panel, but there will be many more discretionary resources for patients to pursue for their healthcare answers. Of course, we feel that functional medicine providers will be a major force in this arena. That is why, as we revise our website, we will include a consumer side so our providers can be located. We will list AFMCP graduates and where they are located. We need to be able to integrate providers who understand the underlying functional processes of illness with patients who are looking for that kind of care. I get chills when I see the way the world in which we are working right now is moving toward a very favorable environment compared to that which existed 10 years ago at the beginning of the IFM. 2003:An Auspicious Year JB: It is wonderful to see all these things converging at the 10th anniversary of our international symposia. Ten years is not significant in geological time, but in the context of the changes you’ve described, I think 2003 is going to be a very auspicious year for the IFM and its participants. Dr. Jones, thank you for serving so ably as president of IFM and for generating such excitement for us all as we start 2003. DJ: This 10th symposium is going to be a party. It’s going to be a celebration of where we’ve been and where we are. I can’t think of a better celebration of what the conventional medical world is beginning to understand. I showed our program to one of the cardiologists in my IPA who has never been to a functional medicine meeting of any kind, for example, and he said he had to be there. He said he had been looking for such a conference for the last five years, because he knew cardiology was going in this direction. What a celebration! We bring a program that bridges all healthcare providers with the very best science and speakers for our 10th-year anniversary. I can’t wait! Pharmacogenomics and Nutrition I would like to continue by highlighting three other important areas we described in 2002 that will be further explored in 2003—aspects of nutritional pharmacology, the pharmacogenetic detoxification concept, and the TH-1/TH-2 autoimmune and hypersensitivity/inflammation connection. I have been discussing the role of glucosinolates, derived from the cruciferous vegetables, on estrogen detoxification and metabolism. Two daily portions of cruciferous vegetables provide between 150 mg and 300 mg of I3C. This phytochemical plays a role in the expression of specific types of detoxification enzymes, the biotransformation enzymes that are part of the phase I and phase II detoxification system. These enzymes include the mixed-function cytochrome P450 enzymes in phase I detoxification and the conjugation enzymes in the phase II system. The Many Roles of Cytochromes P450 The genetic control of metabolism and biotransformation of substances has been called “pharmacogenetics” or “pharmacogenomics.” It began as a discussion of drug metabolism, but it has been generalized to cover all substances undergoing phase I and phase II types of biotransformation processes. The authors of a review article titled “Clinical Importance of the Cytochromes P450,” which appeared in the Lancet, explain that this super-family of enzymes is comprised of 57 genes.31These genes code for enzymes that play a role in the metabolism of drugs and foreign chemicals. They also play a role in arachidonic acid metabolism and formation of eicosanoids, cholesterol metabolism, bile acid synthesis, steroid metabolism, vitamin D and vitamin A metabolism. A number of other functions for cytochromes P450 will no doubt be discovered in the next few years. Cytochrome P450 was once believed to be mainly a hepatic drug detoxification system, but we now understand it includes a myriad of enzymatic reactions implicated in tissues other than the liver. In the breast, for example, cytochromes P450 can be involved in the production of hydroxylated estrogens in the absence of liver metabolism. Inducible Forms of CYP450 There is significant clinical importance in understanding what regulates the inducible forms of CYP 450s. The expression of the inducible forms of these enzymes can be modified by environmental factors. The constitutive forms, on the other hand, are not easily modifiable by environmental factors. The overall family of enzymes numbers over 100, and they control specific functional aspects of resistance to xenobiotic chemicals or endogenous substances. Any one of the CYP 450s may compete with another one for metabolism of drugs, alcohol, environmental chemicals, or endogenous molecules. Various single nucleotide polymorphisms (SNPs) occur within these families resulting in a variety of different detoxification profiles. Slow Metabolizers and Toxicity Risk The genes of some individuals predetermine that they are slow metabolizers. When such individuals begin loading substrates onto that particular pathway, they might overload that step in the detoxification process and begin to develop toxicity, a drug overdose, or an environmental toxicity. In a person who is a normal detoxifier this would not be a problem, but the slow detoxifiers may be considered metabolic “yellow canaries.” They are at first risk to exposure to a given substance. As we learn more about the CYP 450s and phase II conjugation, we learn what dietary and environmental factors regulate and modulate their function. That leads to a better understanding of the pharmacogenetics related to adverse drug reactions and adverse environmental responses. A review titled “Pharmacogenetics and Adverse Drug Reactions,” which appeared in the Lancet, caused us to think more about atypical drug reactions and realize they are not atypical at all.32These drug reactions are typical and reproducible in an individual as a consequence of that individual’s unique genetics. Various substances can modulate and improve detoxification. One that comes to mind is N-acetylcysteine (NAC). NAC, traditionally used in emergency medicine for the treatment of paracetamol or acetaminophen overdose, is now recognized as having a positive effect on many detoxification pathways. A paper that appeared in the Lancet explains that NAC can help prevent hepatocellular injury and improve detoxification in individuals who may be slow sulfators or have poor glutathione conjugation ability.33 Bifunctional Modulators A variety of phytochemicals from various foods enhance detoxification by normalizing both phase I and phase II. These phytochemicals are called bifunctional modulators, and they may modulate the ratio of phase I to phase II activity. We do not want phase I activity to be too high while phase II is low. The result would be the production of more biotransformed intermediates, which may be more toxic than the substances we are trying to detoxify. We are seeking regulation and balance between phase I and phase II, which occurs through these bifunctional modulators. Constituents in curcumin have been shown to be bifunctional modulators, as have substances in the glucosinlate family of Brassica vegetables, including the watercress family.34  Watercress contains glucosinolates that serve as bifunctional modulators. For example, a paper in Cancer Epidemiology titled “Effects of Watercress Consumption on Metabolism of a Tobacco-specific Lung Carcinogen in Smokers” reported watercress consumption helped improve metabolism of potential procarcinogens in smokers. 35 Certain molecules found in specific types of food help normalize phase I and phase II activity at intake levels that are equivalent to what people would consume in a traditional diet. Two portions a day of cruciferous vegetables, for example, would provide approximately 300 mg of I3C. We talked about doses of NAC or glutathione in the range of 200 mg to 400 mg per day. There is the relationship of curcuminoids in fairly small doses, perhaps 50 mg to 100 mg. All of these molecules have been found to have positive impact on normalizing phase I and phase II detoxification pathways. S-adenosylmethionine Another molecule in the news in 2002 is a therapeutic molecule derived out of the folate cycle, the N-methyltetrahydrofolate-mediated conversion of homocysteine into S-adenosylmethionine (SAM). SAM is a universal methylator. 36 It is involved in hormone detoxification, phospholipid formation, and metabolism of neurotransmitters. It affects DNA integrity and nucleoside base formation. It also plays an important clinical role in the management of depression.37It has been used for the management of inflammatory disorders and joint arthritides as well. SAM has been shown to produce similar changes to that of a classic antidepressant on electroencephalograms.38It may play a role in the management of liver disorders and disease. 39,40 SAM’s Role as a Conditionally Essential Nutrient SAM might be considered a conditionally essential nutrient, meaning it is a therapeutic or pharmacological agent that may be used in certain individuals at doses beyond that which their body can synthesize. It is not an essential nutrient for all individuals because our bodies do make it. In individuals who have defects in the folate cycle, however, or who have increased need beyond what their folate cycle can produce, SAM may be a conditionally essential therapeutic substance. Charles Lieber and Lester Packer wrote a review that appeared in the American Journal of Clinical Nutrition, on the role of SAM in the prevention of liver toxicity and also as a therapeutic agent for brain function.41It is a pleotrophic molecule, having potential effects on depression, dementia, vascular myopathy, liver disorders, and osteoarthritis. The doses we are talking about are not extraordinary. When taken with vitamin B12 and folic acid or 5-methyltetrahydrofolate, oral doses in the hundreds of milligrams can be efficacious. More than 2000 publications have been written on SAM. Many of them describe double-blind, placebo-controlled trials. SAM plays a powerful role as a methylating substance in the folate cycle. It is another example of a functional approach toward medicine, rather than just waiting for the pathology to exist. Th-1/Th-2 Balance and Atopic Disorders We will be hearing more about the Th-1/Th2 relationships to inflammation and immune function. This balance is important in the management of various conditions, including atopic disorders in children, allergic rhinitis, allergy, and inflammatory bowel disease, as contrasted to rheumatoid arthritis and other traditional joint space inflammatory conditions. The balance between thymus-dependent-1 (Th-1) and thymus-dependent-2 (Th-2) cytokines plays a role in determining the clinical outcome of our immune defense system. Individuals who are Th-2 predominant have allergic-like symptoms with IgE-mediated function and increased mucosal immunity producing more inflammatory response. A review on Th-1 and Th-2 appeared in Nature Medicine.42 Perilla Seed Extract We look at nutritional agents that can modulate the balance of Th1 and Th2 in the individuals who have excessive expression of Th-2. One that has emerged from Japanese pharmacological literature is the extract and concentrated derivatives of perilla seed, Perilla frutescens. Concentrates of this plant food are rich in a variety of substances, particularly flavonoid and phenolic substances. These substances may modify the Th-2 hypersensitivity and can lower the IgE-mediated response. They include powerful superoxide scavenging substances, as well. This information was published in the Journal of Agriculture and Food Chemistry.43 Studies of the IgE-mediated response indicate perilla seed extract also  may exert an influence on allergic disorders. The perilla seed concentrates, extracts that are standardized to specific flavonoids, have proven to be powerful functional nutrition agents in allergic and atopic disorders, Th-2-predominant disorders. The doses reported in the Japanese pharmacological literature are in the range of 100 mg to 200 mg of the standardized perilla seed concentrates per day.44 We are learning a great deal about the complex array of substances found in our foods, literally tens of thousands of different chemical compounds. When taken together as combinations, these substances have remarkable effects in modulating gene expression, proteomic outcome, and metabolic influences that occur at the functional level before you get into physical dysfunction and more serious pathologies. The same theme holds true with regard to the 2002 literature on Alzheimer’s disease and its relationship to antioxidant intake. A paper and an editorial in the Journal of the American Medical Association looked at dietary intake of antioxidants and the relative risk of Alzheimer’s disease. These papers showed that higher intake of vitamins C and E and flavonoids can have important implications in lowering  risk to Alzheimer’s disease, which leads to questions about the mechanism(s) involved.45,46,47 Folate, B12, B6 and Cognitive Function Individuals who have impaired vitamin B12 intake may have impaired cognitive function, and we should consider folate, B12, vitamins C and E, and the flavonoids for improvement of function.48,49 A short-term memory performance study examined women on folate, B12, and B6. It showed that intellectual performance, memory and cognitive function can be improved by supplementation with folate, B12, and B6.50 This is a new view of functional nutrition, functional medicine, and nutritional pharmacology. Looking back, 2002 was a year of great excitement in this area,  That excitement will continue in 2003 in subsequent issues of FMU. Thanks for being with us. We look forward to seeing you in February.

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Bibliography

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Arzneim-Forsch/Drug Res. 45(II):872-874. 19 Beral V. Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet. 2002;360:942-944. 20 Rexrode KM, Manson JE. Postmenopausal hormone therapy and quality of life. No cause for celebration. JAMA. 2002;287(5):641-642. 21 Hlatky MA, Boothroyd D, Vittinghoff E, Sharp P, Whooley MA. Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy. JAMA. 2002;287(5):591-597. 22 Chen CL, Weiss NS, Newcomb P, Barlow W, White E. Hormone replacement therapy in relation to breast cancer. JAMA. 2002;287(6):734-741. 23 Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288(3):321-333. 24 Fletcher SW, Colditz GA. Failure of estrogen plus progestin therapy for prevention. JAMA. I2002;288(3):366-368. 25 Chen X, Anderson JJ. Isoflavones inhibit proliferation of ovarian cancer cells in vitro via an estrogen receptor-dependent pathway. Nutr Cancer. 2001;41(1&2):165-171. 26 Stoner G, Casto B, Ralston S, Roebuck B, Pereira C, Bailey G. Response to Letter to the Editor. Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Carcinogenesis. 2002;23(10):1769. 27 Ashok BT, Chen Y, Liu X, Bradlow HL, Mittelman A, Tiwari RK. Abrogation of estrogen-mediated cellular and biochemical effects by indole-3-carbinol. Nutr Cancer. 2001;41(1&2):180-187. 28 Sepkovic DW, Bradlow HL, Bell M. Quantitative determination of 3,3’-diindolylmethane in urine or individuals receiving indole-3-carbinol. Nutr Cancer. 2001;41(1&2):57-63. 29 Chen DZ, Qi, M, Auborn KJ, Carter TH. Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr. 2001;131:3294-3302. 30 Johnson F, Huff J. Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Carcinogenesis. 2002;23(10):1767-1768. 31 Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet. 2002;360:1155-1162. 32 Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet. 2000;356:1667-1671. 33 Schmidt LE, Knudsen TT, Dalhoff K, Bendtsen F. Effect of acetylcysteine on prothrombin index in paracetamol poisoning without hepatocellular injury. Lancet. 2002;360:1151-1152. 34 Dinkova-Kostova A, Talalay P. Relation of structure of curcumin analogs to their potencies as inducers of phase 2 detoxification enzymes. Carcinogenesis. 1999; 20(5):911-914. 35 Hecht SS, Chung FL, Richie JP, et al. Effects of watercress consumption on metabolism of a tobacco-specific lung carcinogen in smokers. Cancer, Epidemiol Biomarkers Prev. 1995;4:875-884. 36 Bottiglieri T. S-adenosyl-L-methionine (SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule. Am J Clin Nutr. 2002;76(suppl)1151S-1157S. 37 Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. 2002;76(suppl):1158S-1161S. 38 Saletu B, Anderer P, Di Padova C, Assandri A, Saletu-Zyhlarz GM. Electrophysiological neuroimaging of the central effects of S-adenosyl-L-methionine by mapping of electroencephalograms and event-related potentials and low-resolution brain electromagnetic tomography. Am J Clin Nutr. 2002;76(suppl):1162-1171S. 39 Martinez-Chantar ML, Garcia-Trevijano ER, Latasa MU, et al. Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury. Am J Clin Nutr. 2002;1177S-1182S. 40 Lieber CS. S-adenosyl-L-methionine: its role in the treatment of liver disorders. Am J Clin Nutr. 2002:76(suppl):1183A-1187S. 41 Lieber CS, Packer L. S-adenosylmethionine: molecular, biological, and clinical aspects—an introduction. Am J Clin Nutr. 2002;76(suppl):1148S-1150S. 42 Neurath MF, Finotto S, Glimcher LH. The role of Th1/Th2 polarization in mucosal immunity. Nature Med. 2002;8(6):567-573. 43 Nakamura Y, Ohto Y, Murakami A, Ohigashi H. Superoxide scavenging activity of rosmarinic acid from Perilla frutescens britton var. acuta f. viridis. J Agriculture Food Chem. 1998;46:4545-4550. 44 Oryza Oil & Fat Chemical Co., Ltd. Perilla seed extract. Perilla seed extract catalogue Ver. 4.2SO. 45 Morris MC, Evans DA, Bienias JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA. 2002;287(24):3230-3237. 46 Foley DJ, White LR. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002;287(24):3261-3263. 47 Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002;287:3223-3229. 48 Louwman MW, van Dusseldorp M, van de Vijver JR, et al. Signs of impaired cognitive function in adolescents with marginal cobalamin status. Am J Clin Nutr. 2000;72:762-769. 49 Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr. 132:1345-1356. 50 Martin A, Youdim K, Szprengiel A, Shukitt-Hale B, Joseph J. Roles of vitamins E and C on neurodegenerative diseases and cognitive performance. Nutr Rev. 2002;60(11):308-334

Welcome to Functional Medicine Update for February 2003. We are focusing our attention on functional cardiology as a prelude to the 10th International Symposium on Functional Medicine, to be held at the Westin La Paloma Resort in Tucson, Arizona, May 21-25, 2003. We have had principal investigators in cardiology as our FMU guests, at both the research and clinical levels. Those guests have included Dr. Louis Ignarro, 1998 Nobel Prize winner in Medicine and Physiology; Dr. John Cooke from Stanford; Dr. Mark Houston from Vanderbilt University Medical Center; and this month’s Clinician of the Month, Dr. Richard Delany.

Cardiovascular disease remains the single highest cause of mortality in the United States. When an individual experiences a sudden coronary event, he or she is robbed of many productive years of life. Many such individuals do not get a second chance. The first coronary event is often the last event of their lives. Many who are fortunate enough to survive experience some limitation in their functional ability for the rest of their lives. Clearly, this major health problem looms as significant as ever. Cardiovascular Disease and Gender Cardiovascular disease has increased in visibility as a consequence of the discovery that women on hormone replacement therapy (HRT) continue to be at risk. In fact, as the HERS Trial revealed, equine estrogens plus synthetic progestins may slightly increase the relative risk of vascular events in some women. Cardiovascular disease is revealing itself to be a non-gender-specific condition. It is not only the major cause of mortality but it also makes a significant contribution to morbidity. Statin Drugs Cardiovascular disease has fueled the development of an extraordinarily successful new component of the pharmacology industry. I refer to lipid-lowering drugs, particularly those born out of the statin family of drugs, as well as the fibrates. These fungal metabolites called monocolins, which were discovered in Japan, have influence on lowering LDL cholesterol. They also have far greater effects on cellular physiology and pathophysiology than simply blocking an enzyme called hydroxymethylglutaryl coenzyme A reductase (HMG CoA), which is the rate-limiting step in cholesterol biosynthesis. Researchers are now finding the statin drugs influence a number of other functions related to vascular outcome. We will be speaking more about that over the course of this month’s FMU.

A review of functional cardiology reinforces the view most of us have long held, that the cardiovascular system is connected to the legs, arms, and trunk of the body. Therefore, what we do in terms of activity plays a role in our cardiovascular function. It is the old “use-it-or-lose-it” adage.

Manson et al. last year published an insightful paper in the New England Journal of Medicine,titled “Walking Compared with Vigorous Exercise for the Prevention of Cardiovascular Events in Women.”1,2 This paper reinforced some things we already knew, but it also provided compelling new research support. Investigators in this study used questionnaires to measure recreational physical activity levels in 73,743 postmenopausal women in the Women’s Health Initiative Observational Study. The study excluded women who had coronary heart disease or other selected medical conditions. The researchers were looking at individuals who were presumably healthy. Measuring Metabolic Equivalent Hours (METs) Participants were followed for an average of three years, during which 1551 participants had cardiovascular events. The subjects were divided into quintiles of physical activity according to their weekly energy expenditure in what are called metabolic equivalent hours (METs). Exercise evaluations reflect MET capability. One MET equals a level of oxygen consumption of 3.5 ml per kg of body weight per minute, as defined by exercise physiologists. This approximates the average energy expenditure during rest. One MET is about the amount of oxygen a person would be consuming at rest. Let’s look at the energy expenditure of walking three miles per hour. Those of you who use pedometers would agree that is a vigorous walking rate on level ground. It is equivalent to about 3.3 METs, or 3.3 times the resting energy expenditure compared to sitting and thinking about walking. You might think that if you walk three times as long, you would get the same benefit, but that is not how it works. Raising the activity of your vascular system has a neuroendocrine cardiovascular impact that has positive benefit in maintaining health of the vasculature. Exercise and Cardiovascular Events In the Women’s Health Initiative Observational Study, the women in the highest quintile of physical activity had 23.4 MET hours per week, which is roughly equivalent to walking three miles per hour for an hour each day. These women were compared to all other subjects with lower levels of activity. After adjustments for possible confounding factors, the researchers found that as women became progressively more active, they had progressively fewer cardiovascular events. The women at the highest level of activity (three miles per day, seven days a week) had about 28 percent fewer cardiovascular events than those at the lowest level. According to the unadjusted data from this trial, women who spent a total of between 45 minutes and 7 hours each week exercising had between 3.6 and 7.8 fewer cardiovascular events for every 1000 participants during the three years of the study. A 3.6 reduction in a life-threatening condition is quite good. That was the reduction in cardiovascular events achieved by the modest walking group, the group that walked only 45 minutes per week. More Exercise, More Risk Reduction Many people complain they don’t have time for such activity, but we are only talking about 10 minutes per day. Perhaps it is poor use of one’s time if one cannot find time for 10 minutes per day of exercise. Even at the low levels of activity in the study (45 minutes per week), there was a significant advantage. At the high level (seven hours per week, or one hour per day), participants experienced 7.8  fewer cardiovascular events per 1000 participants. Exercise Compared to Statin Drugs How do those results compare to drug therapy?  The reduction in cardiovascular events that was observed in this study compares to the result when healthy women were treated with lipid-lowering agents over five years, which is a reduction by four for every 1000 women. That means modest exercise is equivalent to the results one would achieve with statins. Statins involve some potential untoward side effects (neuromuscular or hepatotoxic). I know of very few people who experience toxic side effects from walking 45 minutes a week, or even seven hours a week. This study indicates it is not necessary to participate in extraordinarily vigorous exercise to achieve marked benefit for the cardiovascular system. As our society evolves, it sometimes appears that our major evolutionary objective is to exercise less and less. The more we sit around and allow ourselves to be transported by mechanical means, the better off we suppose we are. In fact, according to the New England Journal of Medicine, the U.S. Postal Service is currently evaluating a human transporter, a self-balancing personal transportation device that will permit letter carriers to make their appointed rounds without walking. If the U.S. Postal Service adopts that device, very few occupations will continue to involve any kind of activity. We are becoming a more and more sedentary population, and cardiology is becoming a more and more important subspecialty in medicine.

Another part of the evolution of understanding functional cardiology is the role of insulin resistance and hyperinsulinemia as a cholesterol-independent risk factor to cardiovascular disease. We increasingly recognize that type 2 diabetes, syndrome X, and the precursor condition—hyperinsulinemia or insulin resistance—track against the relative risk to cardiovascular disease. This connection was described in an article in the Lancet, titled “Diet and Risk of Coronary Heart Disease and Type 2 Diabetes.”3

The author of this paper discussed the epidemiology of cardiovascular disease and showed that populations whose diet is high in simple sugars, saturated fats, and alcohol have a much higher incidence of both diabetes and cardiovascular disease. These two disorders do not correspond exactly with one another, however. This diet contributes to the etiology of diabetes in a slightly different way from its contribution to heart disease, in a traditional sense of heart disease coming from cholesterol elevations. The Role of Diet and Lifestyle in Insulin Resistance and Hyperinsulinemia Diet and lifestyle play significant roles in modulating relative risk to cardiovascular disease associated with insulin resistance and hyperinsulinemia. We have discussed this role in previous issues of FMU. We pointed out that the first step that should be taken with a patient who has insulin resistance or hypercholesterolemia, before we intervene with insulin-stabilizing or glucose-normalizing drugs, is to introduce lifestyle therapy. (An exception, of course, would be a patient in a fulminating state of diabetes.) In the precursor marker stages of diabetes, such as syndrome X or insulin resistance, intervening with diet and lifestyle may be preferable. The recent National Institutes of Health guidelines, the Therapeutic Lifestyle Choices Program (TLC), advocated intervention first with diet and lifestyle before intervening with a medication. This important component is often overlooked in the traditional practice of medicine, because it is assumed that the patient won’t change his lifestyle, so he is never given the option to make that choice. Most doctors’ first resort is to the prescription pad, and from then on the patient is recruited into a pharmacological management program. It may turn out that some patients, if given the option, would choose not to make therapeutic lifestyle changes and would opt for the prescription pad. But there may be others whose first preference would be to retain a locus of control and choose to manage their own lives. Rather than have their condition managed by something out of a bottle, they would prefer to be counseled in regard to controlling both sugar and blood lipids through diet and lifestyle

One of the principal features, from a physiology perspective, that seems to contribute to the insulin resistance/ hyperinsulinemia, decreased HDL, increased triglyceride profile associated with cardiovascular risk, is central adiposity, or the accumulation of visceral adipose tissue (VAT). Many people who do not necessarily look “fat” may actually have a problem with VAT rather than fat. VAT accumulates in the inter-abdominal region, around the organs. It appears to have the greatest correlation with relative risk to vascular disorders and diabetes, and it is associated with increased waist-to-hip ratio if you are doing physiognomy and anthropometric measurements.

The concept that allows patients to retain locus of control is the Albert Bandura approach.  Bandura, a professor at Stanford University and a social theorist, is author of the book, Self-Efficacy: The Exercise of Control.4  Using this approach, the clinician would introduce the concept that the individual patient has the ability to create a different shape by making diet and lifestyle changes. The physiological impact of increased visceral adipose tissue is that this tissue has the differentiation of pre-adipocytes into mature fat cell components. These components then elaborate from their genes the specific messenger molecules that create a different physiology. The Active Role of Adipocytes Fat is not benign, at-rest, tissue, as we have traditionally thought it was. It is not just the stored result of all those abusive meals we may have consumed. That concept of body fat is changing. We now recognize that fat cells, adipocytes, are metabolically active and elaborate their own messenger molecules. These messenger molecules include a family of proinflammatory cytokines, like tumor necrosis factor-a and interleukin-2 and -6. Therefore, the visceral adipose tissue in our bodies may be releasing into systemic circulation, or into adjacent regions, messenger molecules that change physiology and function of cells, tissues, and organs. We end up with a biological response that shifts the body into a state of alarm or inflammation. Scientists have recently found that adipocytes can also elaborate angiotensinogen and can influence blood pressure and electrolyte regulation in the body.5 This is a fascinating new chapter in the emerging story that body fat secretes its own messenger molecules and creates a different systemic physiology. Angiotensin Recent findings indicate there is a mechanism by which transient or chronic overexpression of angiotensinogen in adipose tissue favors the synthesis of lipids and the accumulation of triglyceride in the adipocyte. This process sets up a vicious cycle. It stimulates production of angiotensinogen and accumulates more light lipids in the fat, and the cycle continues. Once it starts, the problem is self-replicating. You may frequently have observed patients who never had weight problems until a particular point in their lives. Then it seemed that just thinking about food resulted in weight gain, and nothing could reverse it. That’s a changed state of physiology. Homeostasis of Dysfunction We often think of homeostasis as the regulation of physiological function around health, like good glucose, good oxygen, CO2 levels, good electrolyte balance, and good redox potential. We can actually be in a homeostasis of dysfunction, however, in which there is a balanced equilibrium of inflammatory mediators or other molecules of alarm that are creating a long-term, chronic problem. That state was often associated with the accumulation of visceral adipose tissue. VAT is interrelated with hyperinsulinemia/insulin resistance, inflammation, and coronary heart disease. It is involved with the recruitment of monocytes that start to become foam cells, and all the things that are associated with atherogenesis, as well as increased blood pressure, decreased HDL, and increased triglycerides. When we look at functional cardiology, we are looking at the heart and vascular system in the context of the whole body, interconnected with all of the other tissues and organs

One of the principal features, from a physiology perspective, that seems to contribute to the insulin resistance/ hyperinsulinemia, decreased HDL, increased triglyceride profile associated with cardiovascular risk, is central adiposity, or the accumulation of visceral adipose tissue (VAT). Many people who do not necessarily look “fat” may actually have a problem with VAT rather than fat. VAT accumulates in the inter-abdominal region, around the organs. It appears to have the greatest correlation with relative risk to vascular disorders and diabetes, and it is associated with increased waist-to-hip ratio if you are doing physiognomy and anthropometric measurements.

The concept that allows patients to retain locus of control is the Albert Bandura approach.  Bandura, a professor at Stanford University and a social theorist, is author of the book, Self-Efficacy: The Exercise of Control.4  Using this approach, the clinician would introduce the concept that the individual patient has the ability to create a different shape by making diet and lifestyle changes. The physiological impact of increased visceral adipose tissue is that this tissue has the differentiation of pre-adipocytes into mature fat cell components. These components then elaborate from their genes the specific messenger molecules that create a different physiology. The Active Role of Adipocytes Fat is not benign, at-rest, tissue, as we have traditionally thought it was. It is not just the stored result of all those abusive meals we may have consumed. That concept of body fat is changing. We now recognize that fat cells, adipocytes, are metabolically active and elaborate their own messenger molecules. These messenger molecules include a family of proinflammatory cytokines, like tumor necrosis factor-a and interleukin-2 and -6. Therefore, the visceral adipose tissue in our bodies may be releasing into systemic circulation, or into adjacent regions, messenger molecules that change physiology and function of cells, tissues, and organs. We end up with a biological response that shifts the body into a state of alarm or inflammation. Scientists have recently found that adipocytes can also elaborate angiotensinogen and can influence blood pressure and electrolyte regulation in the body.5 This is a fascinating new chapter in the emerging story that body fat secretes its own messenger molecules and creates a different systemic physiology. Angiotensin Recent findings indicate there is a mechanism by which transient or chronic overexpression of angiotensinogen in adipose tissue favors the synthesis of lipids and the accumulation of triglyceride in the adipocyte. This process sets up a vicious cycle. It stimulates production of angiotensinogen and accumulates more light lipids in the fat, and the cycle continues. Once it starts, the problem is self-replicating. You may frequently have observed patients who never had weight problems until a particular point in their lives. Then it seemed that just thinking about food resulted in weight gain, and nothing could reverse it. That’s a changed state of physiology. Homeostasis of Dysfunction We often think of homeostasis as the regulation of physiological function around health, like good glucose, good oxygen, CO2 levels, good electrolyte balance, and good redox potential. We can actually be in a homeostasis of dysfunction, however, in which there is a balanced equilibrium of inflammatory mediators or other molecules of alarm that are creating a long-term, chronic problem. That state was often associated with the accumulation of visceral adipose tissue. VAT is interrelated with hyperinsulinemia/insulin resistance, inflammation, and coronary heart disease. It is involved with the recruitment of monocytes that start to become foam cells, and all the things that are associated with atherogenesis, as well as increased blood pressure, decreased HDL, and increased triglycerides. When we look at functional cardiology, we are looking at the heart and vascular system in the context of the whole body, interconnected with all of the other tissues and organs

Another component of this relationship is the folate cycle and the interrelationship of inflammatory mediators to increased homocysteine levels. There seems to be a clinical correlation between elevated homocysteine and elevated inflammatory mediators and between homocysteine and homocysteine thiolactone. These elements all seem to be related to the triggering of inflammation signals. Patients with elevated homocysteine often also have elevated high sensitivity C-reactive protein (CRP) in their blood, suggesting a relationship between the two.

The metabolic state that results in elevated homocysteine is tied to some type of insufficiency in the folate cycle. Therefore, we have often jumped to conclude this must mean that a particularly patient has a folic acid insufficiency. The first-line treatment choice for hyperhomocysteinemia would be elevated intake of folic acid at 400 mg, 1000 mg, even up to as high as 5000 mg, or its vitamer called 5-methyltetrahydrofolate. This is the methylated derivative of folic acid that has already been processed through the methylenetetrahydrofolate reductase pathway. Considerable genetic polymorphism exists in this pathway, which may involve a slow methylating step. By giving 5-methyltetrahydrofolate as a supplement, you may bypass that particular blocking step in the folate cycle. High doses of folic acid or 5-methyltetrahydrofolate have resulted in reduced homocysteine levels in many patients.

On the other hand, some patients seem to be refractory to folic acid supplementation alone, and their homocysteine levels remain elevated with this supplementation. This was the topic of a recent Lancet paper titled “Effect of Supplementation with Folic-Acid on Relation between Plasma Homocysteine, Folate, and Vitamin B12.”7 Here the story becomes more important clinically.

In another Lancet paper last year, Quinlivan et al. reported that both folic acid and vitamin B12 are important in reducing the risk of vascular disease, and that as one supplemented with higher doses of folic acid, the need for vitamin B12 became more important.8 Therefore, you could have fulfilled the need for folic acid only to have B12 insufficiency exert a limiting effect on homocysteine reduction. In this recent Lancet paper, the authors say to make sure you are giving B12 because you may not be getting the kind of benefit in homocysteine reduction by giving folate alone. The B12 may have to be given at fairly large doses, depending upon the genetic polymorphisms of that individual and how he or she handles vitamin B12

The authors of a recent paper in Clinical Chemistry talked about some of the genetic polymorphisms found surrounding vitamin B12 metabolism. The more individuals examine this issue, the more they find different types of SNPs that relate to vitamin B12 metabolic uniqueness, such as polymorphisms in what is called the transcobalamin gene that relates to vitamin B12 metabolism9.

In this paper, the investigators reported that, of the individuals in the highest quartile of vitamin B12 distribution (blood levels greater than 299 pmol/L), those with the unique nucleotide polymorphism of the transcobalamin gene called the 259PP polymorphism (the homozygous form) had a much lower total homocysteine than those without this polymorphism, indicating that these individuals may be more likely to respond to B12 by lowering homocysteine. These individuals may, thus benefit more from supplemental B12. Individualizing Folic Acid and B-Vitamin Supplementation Other SNPs of this particular transcobalamin gene were less efficient in utilizing vitamin B12. At the same level of vitamin B12 intake, they would have higher levels of homocysteine. Again, this shows there is genetic variation in homocysteine related both to folic acid and vitamin B12. This study indicates there is a genetic variation both in how vitamin B12 is metabolized, stored, transported, and utilized in methylation reactions, as well as genetic variation in how folic acid is metabolized. One could, therefore, see a potential for adjusting doses of these individual vitamins in order to create the right outcome in that patient based on his own genotype. This same argument applies to vitamins B6 and B2. They also play roles in the folate cycle, along with the methylating cofactor betaine, or trimethylglycine. All these substances work together to regulate the management of methyl groups in the folate cycle to reduce the level of homocysteine. A recent paper in Clinical Chemistry revisits the question of expensive urine. If you supplement with vitamins and your urine suddenly turns a bright yellow color, many individuals suggest you are wasting those vitamins because they are passing right on through the body and spilling out in the urine. What’s wrong with that model?  It assumes that as the vitamin passes through the body, it does nothing along the way, that it is eliminated directly without any kind of molecular exchange or events at the cell physiology level. If that were true, we could also say that drinking water is a waste of time because it just gets urinated away. As a vitamin passes through the body, it does something along the way. In the same way, we ultimately get rid of the food we consume, but it has done something on the way through the body. Riboflavin, FMN, and FAD Another article in Clinical Chemistry is titled “Riboflavin, Flavin Mononucleotide, and Flavin Adenine Dinucleotide in Human Plasma and Erythrocytes at Baseline and after Low-Dose Riboflavin Supplementation.”10 Riboflavin, or vitamin B2, is a precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These compounds serve as cofactors for many reduction/oxidation biochemical reactions related to energy production or energy management in the body. We would consider them energy-stimulating or -supporting nutrients, and their relationship to the folate cycle is very important. FMN and FAD are involved in the metabolism of folate, vitamin B12, vitamin B6, and other vitamins. This probably explains why plasma riboflavin is a determinant of plasma homocysteine, which is associated with risk to cardiovascular disease, neurological disease, and inflammatory disorders. Challenging the Expensive Urine Model Pregnancy complications such as neural tube defects, spina bifida, and cognitive impairment related to dementia are all associated with riboflavin sufficiency. Considering all of its important roles, riboflavin appears to be a very important nutrient. According to the expensive urine model, however, those who eat a well-balanced diet of variety and moderation containing RDA levels of riboflavin need not worry. They must be producing, in their plasma and in their cells, adequate levels of the enzymes that convert the riboflavin into its respective cofactors, FMN and FAD. Therefore, additional supplementation of that nutrient would only cause expensive urine because we are already near or at saturation of those enzymes related to that function. The Stimulation Test Subjects in the study described in Clinical Chemistry, who were apparently healthy individuals with a mean age of 69 years, participated in what is called the stimulation test. Investigators removed red blood cells from the subjects and stimulated them with additional riboflavin in the test tube. (Red blood cells provide a good measure of intracellular FMN, FAD, and riboflavin levels.) They found an activation of the effectiveness of that cell function that depended on riboflavin. The degree of activation indicates how deficient the cell is or how far it is from saturation of that vitamin. The more activation you get when you add the vitamin to the test tube, the further away it is from saturation. What did they find in these apparently healthy individuals? An activation number above 1.2 reflects a marginal vitamin insufficiency. The average of these people was 1.18; the range was from 1.07 to 1.29, and almost half of the subjects had values of 1.2 or greater. Based on a fairly conservative intracellular measurement of functional vitamin utilization, this means that people who were presumed to be healthy at the age of 69 had a functional vitamin insufficiency. Effects of Riboflavin Supplementation These individuals were then supplemented with riboflavin, i.e., they created expensive urine. The investigators once again studied their red cell levels of FMN and FAD and their activation levels. As we might expect, their activation levels went down, meaning they were closer to saturation. The levels of erythrocyte FAD and, in particular FMN, went up considerably higher than the elevations in the plasma of FMN, FAD, or riboflavin. If we only used plasma analysis to determine blood vitamin sufficiency, it seems we would be led to misunderstand the relative status of those vitamin levels in tissues and cells. By increasingly supplementing with those vitamins, we drive them into the coenzyme form that can function within the cells. This is independent of polymorphisms. I haven’t even mentioned the additional complicating factor of people who have specific polymorphisms related to difficulty in metabolism of these nutrients. Individualizing Supplementation to Support Methylation When you are dealing with a cardiovascular risk pertaining to the folate cycle, make sure you personalize your vitamin recipe with regard to riboflavin, pyridoxine, vitamin B2, vitamin B6, folic acid, and 5-methyltetrahydrofolate or 5-formyltetrahydrofolate, vitamin B12, and betaine or trimethylglycine. All of these nutrients play roles in covering the range of polymorphisms and individual needs. One size does not fit all. What we are dealing with here is methylation. Methylation is related to cardiovascular disease, neural tube development, insulin management, inflammation management, neurodegenerative disease, and also cancer. All of those disorders are related to the methylation pathway. If you want to follow up on this topic, I urge you to look at a series of papers that emerged from a symposium on diet, DNA methylation, and health. They appeared in the Journal of Nutrition.11,12,13,14,15,16 Gene/Nutrient Interactions and DNA Methylation These papers discuss gene/nutrient interactions and DNA methylation. They explain the important role methylation can play as an epigenetic variable that controls cell differentiation and cell cycling. Our genome may carry information that can only be properly expressed by methylation. Folic acid insufficiency has an adverse effect on DNA stability. DNA methylation-related processes are involved with atherosclerosis, diabetes, cancer, and neurodegeneration. All of these topics are discussed in these papers. Last month we also discussed S-adenosylmethionine (SAM) and its relationship to folic acid. This is a very powerful emerging story.  

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INTERVIEW TRANSCRIPT

  Clinician of the Month Richard Delany, MD Medical Specialty Group Two Reedsdale Road Milton, MA 02186 JB: Continuing with our theme of functional cardiology, we are pleased to have as this month’s Clinician of the Month Dr. Richard Delany, a board-certified internist and cardiologist who has been in practice in the Boston, Massachusetts, area for about 23 years. His practice is focused on personalized functional cardiology. Dr. Delany is a leader in his field, having organized an Independent Physicians Association. He is familiar with all the eccentricities of the managed care system and how to deliver quality care within the constructs of the present financial medical establishment. He has been a leader and an innovator, always pushing the envelope of new knowledge and information, which includes his commitment to attend a science and nutrition course at the Harvard School of Public Health in the late 1990s. We are pleased to have Dr. Delany as our guest this month. Evolution of Dr. Delany’s Career Rich, I’d like to start off by asking how your evolution through your academic medical training and the development of your practice helped you arrive at this point in your career? RD: Thank you for inviting me to be your guest today. My evolution as a physician is ongoing; it never stops. In recent years my approach to medicine has become more and more personalized, down to the individual level. Attending your lectures on functional medicine over the past 10 years taught me to think about each patient, link his or her illnesses, and look at each patient as an individual. The focus in cardiology has always been a single cholesterol measurement, but the risks are much more global than that. There are many other individual risks that affect a person, and my treatment over the last few years has been with a global, personalized approach to the risk factors. A Personalized Approach After taking a history, doing a physical exam, and getting the results of various blood tests, I tabulate to find out what that patient’s individual risks are that we can identify now, because there are going to be new ones coming along. Then, in a very methodical way, I try to correct those abnormalities, starting with diet and exercise and appropriate pharmaceutical medications, always trying to think about what the patient’s response is, if the individual can afford it, and whether his or her health plan allows it to happen. I collect each patient’s uniqueness in a methodical way. I think the future is with genome analysis, and proteomics is going to provide even further definition of those who are at risk and how we can modify what they need to do in their lives to prevent atherosclerosis. Assessment Tools JB: Most doctors use a triad approach—assessment, diagnosis, and treatment. When a patient comes to you, how do you use the presently available noninvasive, invasive, chemistry, and genomic assessment tools? Have you constructed a panel of tests that allows you to assess aspects of personalized risk? RD: People always ask me that. What tests do I order on patients? Do I have a panel? Yes, I do. I have a basic panel, and then it spreads it out depending upon the patient’s individuality. The first thing I do is to take a family history; that is so significant. That’s not any test you do; you just sit down and think about the patient and his or her family. That begins defining how risky the patient is. Then I do an examination. I look for cutaneous evidence about the sclerosis; I look at blood pressure; I look for funduscopic changes in the eyes, like every traditional doctor does, to get a sense of whether this patient is healthy, very unhealthy, or in between. Where is he in his cycle of life down this path of atherosclerosis if he’s atherosclerotically prone? Blood Tests The blood tests I do include a standard lipid panel and then a specialized lipid panel. I try to break the patient’s LDL molecule into subfractions, the HDL into subfractions, and the triglyceride into subfractions. That involves sending the test to a lab that does that type of subfraction analysis. For patients who have clear risk of atherosclerosis based on a family history or who have already had the disease, I find the specialized analysis of the subfractions very helpful. It guides me, not only in terms of how to raise HDL cholesterol, but how to raise the good fraction of the HDL, not only lowering the LDL, but lowering the small dense LDL. What part of the triglyceride is abnormal? Is it the risky one that is elevated, or is it the non-risky one? I try to individualize my assessment in that patient to bring it down. Specific Panels First of all, I order a lipid panel, and then sometimes a lipid panel that’s more specific. The next test I run is a homocysteine, LpA, a fasting blood sugar, a serum insulin level if I think the patient has insulin resistance, and a CRP. I think we’re going to move into some of these atherosclerotic-prone genome analyses, especially when we find the single nucleotide polymorphism, the SNP. We will need to know if that information is going to change what we do in the patient. It is going to allow us to tell the patient that he or she really needs to go on a low-fat diet, that the patient really needs to exercise and enhance his or her compliance. We’re going to find that out in the next few years as they begin running these tests. Up until recently, the tests for a procoagulant patient, someone who tends to clot more, would allow us to check to see if he or she had too many platelets or if the patient had protein C or protein S deficiency. Now, with these genome tests, we are going to begin separating out those patients who have individual protein polymorphisms. That’s my basic initial panel. Assessing Syndrome X JB: Let me pick up a couple of components in a little more detail. According to Dr. Gerald Reaven, the father of syndrome X, the hyperinsulinemic predecessor to type 2 diabetes, one of the hallmarks of syndrome X is elevated dense LDLs. Do you use lipoprotein fractionation of LDL as a marker that ties to insulin resistance/hyperinsulinemia? RD: Yes I do. When I receive the profile on my patients, it’s subfractioned into the dense and non-dense LDLs. I find an order of treatment; I determine what I’m going to treat first. The most important thing is to get the LDL cholesterol level down. Once that is down, sometimes it normalizes and sometimes it stays in the dense fraction. Usually, the person who has that mixed insulin resistance pattern that Dr. Reaven talks about has a depressed HDL triglyceride. If you focus treatment on normalizing the triglycerides and getting the HDL up by exercise, diet, and possibly the addition of combined treatments to treat the hyperlipidemia, the dense HDL takes care of itself. That’s like a red flag, and I know I need to be aggressive about it. It tells me that I’m probably going to have to use two medications; some traditional statin or a fibrate to lower the LDL if diet doesn’t work, and the addition of something like niacin to boost up their HDL and lower their triglyceride. When you do that combined approach of treating the hyperlipidemia, the dense LDL normalizes itself. I look at it and know that when I treat everything else, that’s going to normalize, and it usually does. The key is that all those patients have truncal obesity. They all have highfasting serum insulin levels. None of them exercise. They all skip breakfast or they eat a lot of carbohydrate at breakfast. I spend a lot of my time looking them in the eye and asking them to please modify their diet and do the exercise as we go ahead and correct the rest of the risk factors. Measuring C-Reactive Protein JB: Another analyte that’s very much in the news right now is C-reactive protein (CRP) as an inflammatory marker. According to Dr. Ridker at Harvard, we ought to be measuring high-sensitivity CRP, because normal CRP measurement is not sensitive enough to pick up the differentiation. Others maintain there is no justification for CRP testing; it is overutilization and doesn’t provide enough additional diagnostic value. What’s your opinion? Is there justification for measuring high-sensitivity CRP? RD: Good question. I think it’s so sad when some blue ribbon panel says a test is not cost-effective or justified. We need to treat people as individuals, and there’s no doubt in my mind that high-sensitive CRP is justified. I was always taught that if you do a test and the result of the test changes what you do, then you should do the test. That doesn’t mean you do a test for which one out of a million people has an abnormality, however. In a recent article in the New England Journal of Medicine, published in November, Dr. Paul Ridker discusses CRP as an independent risk factor. He points out that when a group of women modified their CRP it was more predictive than LDL. That brings to bear the independent risk factor nature of CRP.17That article pointed out that LDL was a risk factor and CRP was a risk factor, and synergistically that added to a person’s risk. The Inflammatory Element of Atherosclerosis When I was in training to be a cardiologist, we talked about lipids and then we talked about clotting. We devised all sorts of methods to stop the thrombotic element of atherosclerosis by aspirin and giving people thrombolytic therapy and lowering lipids by diet and medications. Now this inflammatory element of atherosclerosis has been identified and it’s very key. In answer to your question, I think it is important. I routinely do it. When I have a patient who has atherosclerosis or who is at high risk of it, I first treat his or her LDL, HDL, and triglycerides. If I have done that adequately and the patient still has an elevated CRP, I look around the body to make sure there’s no secondary inflammatory process that invalidates the interpretation of that test. If the person has chronic arthritis of his right knee, that mitigates the interpretation again. You can’t really interpret it. Lowering CRP In the absence of any obvious inflammatory process, I conclude that the patient is upregulated. I don’t do an interleukin-6 value, but if I did, it would be elevated. I then try to add in something that would lower the CRP. The question is, what do you do then? Medications that can lower CRP are statins, aspirin, very high dose vitamin E, getting rid of the visceral obesity. That is the key because I’m not sure we know exactly where the CRP comes from. It comes from interleukin-6, but it’s probably produced by the fat cells that you see on a CT scan of someone’s abdomen. Again, we’re back to that old metabolic profile that Dr. Reaven talks about. If we can get the person to lose weight and they lose the weight in the trunk area, it reduces insulin resistance, improves HDL, lowers triglycerides, makes the small dense particles become large, and lowers the CRP. I think measuring CRP is important. Once you see it again elevated, it tells you to focus on that patient. Get him to lose weight, give him aspirin. If he’s not on a statin and that’s what you need to do to bring it down, we probably should bring it down. Homocysteine Testing JB: You discussed another area that I know is considered controversial, and that is homocysteine and whether testing for it is cost-effective. If it is, at what levels do we start to have risk; is it 11 or 12 nanograms per ml, or it is 8? What’s your opinion on the homocysteine connection? RD: This is interesting. About 12 or 13 years ago the Lancet contained a simple article on homocysteine, and a group of doctors in England who were giving patients a supplement of vitamin E, B6, and folic acid. They simply reduced homocysteine. This was well before homocysteine as a risk factor was common news. Since then, I’ve been treating homocysteine for over 12 years with some form of a compound that has that mixture. If you go into the literature, you’ll read that homocysteine thiolactone is clearly irritating to the endothelium. We know it’s a risk factor. Interestingly, Time magazine, which certainly more people read than they do our medical journals, contains a summary of homocysteine. The article said it really doesn’t help that much. It only reduces your risk (as I recall the article’s stating) about 12 percent. Well, 12 percent is a lot. We now give statins, production of which is a billion dollar industry, to lower LDL cholesterol. Statin drugs reduce the risk of heart disease between 24 and 30 percent; that’s the maximum. If you raise the HDL, you can get another 30 to 40 percent decrease in risk. Reducing Risk by Lowering Homocysteine We’re left with people who have an elevated homocysteine, and each of those individuals is probably at a higher risk. If I can lower that person’s risk another 12 to 15 percent by giving him or her a pill that costs about 6 cents a day, it’s just intuitive to synergistically treat that patient’s risk factors. In summary, I check homocysteine all the time. I make sure the patients don’t have B12 deficiencies, so I check their B12 level. I also check methylmalonic acid level, because I find that a serum B12 level is not a good excluder of B12 deficiency. If the methylmalonic acid level is elevated, I look for and treat B12 deficiency. Once I correct that, then I treat them with folic acid, in increasing doses, in combination with oral B6 and B12. If that doesn’t work, I move on to the methyltetrahydrofolate acid that you’ve talked about so much, Jeff. That has also been helpful. In summary, in my experience, when I give somebody a combination of B6, B12, and folic acid, I have about 85 percent response in my patients. The objective is to get the homocysteine down to less than 8. Each year the recommended level keeps coming down, but the most recent recommendation is less than 8. If that fails, I add in methyltetrahydrofolate acid. I find another 50 to 60 percent of the remaining people drop their homocysteine into the normal range. People who still don’t respond are patients who have chronic renal failure and then a few others we are probably going to ferret out in the next few years. I also think it’s important that when you give someone methyltetrahydrofolate acid, you also give him or her folic acid so you don’t just isolate one part of that pathway. Medicine for the Average Patient JB: Your point about homocysteine’s ability to reduce risk an average of only about 12 percent brings up another important part of this story. The concept of medicine for the average patient, within two standard deviations of the mean, versus medicine for the real person may be one of the biggest challenges in medicine. It may explain why certain things have not worked and why certain things have been excluded in therapy because they didn’t work in the average. RD: Jeff, the point you just made is so important. We treat people by the mean. I have a slide when I give lectures, of response to a therapy. I have the arrows going up the graph, straight across, neutral, and then down. The next slide has a mean showing slightly positive change. I ask people in the audience how they would like to be this person, and I point to people for whom the arrow went down, and then the person over here who went way up. Everybody is an individual. An example of this phenomenon is in the HERS Trial with estrogen. They showed that when patients who had atherosclerosis were put on PremPro, the nonbiologically identical estrogen and progestin, that they increased their risk of heart disease for the first 15 months and then over time, got no net benefit. If you look at the subclassifications, those women who had an elevated LpA, markedly improved. In other words, you have to look at subgroups. Medicine for the Individual I agree with you completely. If you took groups of people who have a slightly elevated homocysteine and you treated all of them, you get a 15 percent improvement in this group of people. If, on the other hand, you looked at the individual person, the results might be entirely different. An example is the person who comes to my office following a heart attack. His lipids are normal, his blood pressure is normal, and yet his brother had a heart attack and his sister had a heart attack. The only abnormality was homocysteine. For that patient the improvement has got to be more than 15 percent. That’s why I think the approach must be on an individual basis. Find out what characteristics that patient has, what his lipids are, whether he has insulin resistance, if he is obese, and what his homocysteine level is. Then you treat. And you see that evidence-based medicine shows only a 12 percent decrease. Well, if 12 percent adds to that benefit, it’s just great. Synergism in a single individual is the way to go. Genomic Analysis and the Future of Medicine JB: You also talked about genomic analysis and what that might mean in the future for pinpointing some of these personalized relative susceptibility factors. You asked if genomic analysis will change the way we practice medicine. What’s your feeling about that? RD: To give you an example, in the December 11, 2002 issue of JAMA (Volume 288[2813]) there was a brief mention of a recently published study in the Journal of the National Cancer Institute18hat pointed out that the presence in certain patients of H. pylori together with predisposing SNPs involving the interleukin 1 receptor antagonist and interleukin 1B were associated with a markedly increased risk of stomach cancer—up to 90 times greater risk! Thus, if you happen to have H. pylori (the environmental stress) and the predisposing SNPs, then your risk is much higher. Tailoring therapy specifically to eradicate H. pylori and to carefully monitor these patients, is an example of bringing medicine down to the individual, i.e., personalized preventive medicine. I think that it’s also going to happen with the genomic analysis of patients who are at risk to atherosclerosis. I expect we will find individual abnormalities of a host of biologically plausible links to atherosclerosis, such as abnormalities of lipoprotein lipase or SNPs, that relate to the individual handling of HDL. This beneficial lipoprotein has great promise in reducing the risk of atherosclerosis if we can learn what environmental elements in the individual can enhance or worsen HDL’s function. Then we’re going to devise ways that the individual person can live a lifestyle, or consume a dietary nutrient that will modify his/her risk by modifying the function of HDL. Lastly we will find some medication that will modify the risk. The key concept is to bring treatment down to the individual level based on a knowledge of his/her genetic predisposition and a knowledge of the environmental influences and/or medications that can promote a desired biological effect. This is the way I feel that genomic analysis will be used by clinicians for their individual patients. I am just beginning to perform gene testing on my cardiac patients and will have more first-hand experience in the practical application of these principles in the individual patient over the next year. Statin Drugs JB: Statin drugs have created a revolution in cardiology. We now have, in a sense, a preventive pharmacology with the statins being used to lower LDL cholesterol. Recent evidence indicates the role of statins is more than just as an HMG CoA reductase inhibitor. They actually can do things like recruit macrophages to the edges of atherosclerotic plaque leading to healing, and they may have a variety of other influences on cell recognition and gene expression. As a cardiologist, what’s your view of the evolving statin story? RD: I think we are just touching the tip of the iceberg of how the statins reduce risk. Traditional thought was that they work by lowering LDL cholesterol inside the cell, which makes more receptors by competitive inhibition of the enzyme, increasing the likelihood of a cell’s making more receptors so it can pull more cholesterol out of the bloodstream and therefore reduce risk. We also know there’s another pathway off that through G protein isoprenylation and that’s probably how it becomes antiinflammatory. It blocks that side pathway that comes off if you looked at the pathway before it gets down to cholesterol. And that same pathway is the way those biphosphonates work to stop osteoclasts from chewing up bone. Statins and Risk Reduction Fosamax™ works in the same pathway, blocking an enzyme right off that pathway, but specific for the bone. That’s why some statins that can get into the bone also reduce osteoporosis. They also reduce Alzheimer’s disease by some other mechanism yet to be determined, but it’s probably antiinflammatory because we know that nonsteroidals also reduce risk of Alzheimer’s disease or the progression of it. I think we’re beginning to find, when we give someone a statin, that besides lowering LDL cholesterol, it does something to macrophage function. It does something to the inflammatory aspect of this disease for which our only surrogate marker now is CRP. It’s quiet. It’s happening in the body quietly, so we give the person a drug that goes into this body that’s clinically quiet and yet inflamed, and it dampens it. It dampens it at the brain and prevents or delays Alzheimer’s; it dampens at the bone and prevents osteoporosis; it dampens at the vascular level and prevents activation of unstable plaques. It does so by mechanisms we still have not defined, probably the macrophages, probably the G protein isoprenylations so they can’t create some inflammatory cytokines. Individualizing Therapy with Statins It’s very exciting. It’s difficult, though. When doctors are taught to look at just LDL cholesterol, and the LDL comes down to where they want it, since it’s a different pathway, it’s not dose-related. When you look at the studies, CRP reduction is not dose-related, so you have to do something difficult. You have to individualize it. You have to determine what the CRP is. It is interesting when we see a patient as a total. It always excites me to see someone who has a risk for Alzheimer’s disease, has a risk for osteoporosis or already has it, has atherosclerosis, and has elevated CRP. That is a person who should have a drug that hits all forms of those pathways. That would be an appropriate use of statins. Application of Functional Medicine JB: It is interesting to hear you talk about cell biology, cellular mechanisms, and applied biochemistry. It warms the heart of a functional medicine advocate to hear this strategy and the logic that goes into the way you construct these personalized therapies. This is the kind of medicine that as a student you thought you were ultimately going to practice. RD: I attended your Applying Functional Medicine in Clinical Practice course in Gig Harbor a couple of years ago. I learned about the concept of thinking about a patient and linking it to all his or her bodily processes, trying to understand that individual person at that point in time. I learned the importance of understanding the history that came before and using it to prevent a pathogenic history in the future. That’s what functional medicine is. It’s thinking and linking and using alternative medicines, diet, pathophysiology, appropriate pharmacological agents. If you can kill two or three illnesses with one stone, all the more power to you, but you have to understand and think about these things. Thinking and Linking JB: I think you just created a sound byte we will have to capture and attribute to you. “Functional medicine is thinking and linking.” I like that. It’s a very interesting concept. RD: As opposed to naming and blaming? Red Rice Yeast for Cholesterol Management JB: Well said. I recently had a discussion with Dr. David Heber at UCLA. He is doing some work on red rice yeast monocolins, which is a mixture of statin-like molecules. Statins were originally natural products. They isolated one of the monocolins that came to be known as lovastatin. Dr. Heber has been studying this mixture of the monocolins and finds that, as a mixture, they have lower hepatotoxicity than when you use a single molecule as a drug. Have you had any experience in looking at some of the natural products for cholesterol management? RD: I have done a few gene analyses, and included in the recommendations from the panel was rice yeast. I started looking that up, and I put myself on red rice yeast about two weeks ago to lower the LDL naturally. I haven’t had much experience with it yet, but I think it’s biologically plausible. It’s probably very safe for the liver, and so I think that plays a role. The question I would want someone to answer in the future is what does it do to the subfractions of LDL, HDL, and triglyceride, and what does it do to CRP, the inflammatory surrogate marker? In addition to lowering LDL naturally, I want to know what it does to the subfractions. I want to know what it does to the inflammatory element like the statins, because then I’ll know where to put that into the decision tree analysis and treatment that I use for an individual patient. Nutritional Support Products JB: We will be sure to ask Dr. Heber those questions. He has been actively exploring this over the last several years. As a final question, I know you use a variety of tools based upon what you feel is best for the patient, from pharmacology to nutrition and lifestyle intervention and even nutritional pharmacology. Do you have a list of nutritional substances that you find most effective in the patients you’ve been treating? If a doctor new to this field asked you what’s on the short list of things that really prove to be useful as adjunctive nutritional support products, what would you tell him or her? RD: In terms of nutritional products, I try to have my patients take a soy protein shake in the morning and in the afternoon to try to get rid of the high glycemic carbohydrates and give them a healthy form of protein. I have them take a synergistic antioxidant, notwithstanding all the studies that show that if you give someone with well-established coronary disease vitamin E for four years, it doesn’t do anything. Again, it’s looking at the wrong patient at the wrong time in their natural history. Looking at vitamin E alone, you need a synergistic antioxidant, so I give my patients a combination of mixed tocopherols, coenzyme Q10, lipoic acid, vitamin C, and tocotrienols, which is that subclass of vitamin E. It also works in a post-translational way to lower HMG CoA reductase inhibitors. I have patients who can’t take any statins on high-dose tocotrienols, trying to get g-tocotrienol, which lowers LDL in a post-translational way, blocking the effect of that enzyme. To answer your question, in terms of antioxidants, I use a synergistic antioxidant. I always use folic acid now because it not only helps lower homocysteine, but it helps DNA methylation that patients need to prevent cancer and all the other ravages of age and free radicals. I try to focus on their diet and get rid of that truncal obesity and insulin resistance. Simplifying the Complex JB: That’s an extraordinary summary of a vast amount of information, and something a person could put down on a note card and paste up in their exam room and practice with their patients. Thank you very much for taking the complex, rapidly evolving field of cardiology and distilling it down so we can all understand and take away some very practical and useable information. RD: Thank you, Jeff. I would like to add some comments to Dr. Delaney’s eloquent discussion of personalized functional cardiology. Beginning with the current issue, we will be adding a new section to each issue of FMU. That section, which will be titled “From the Lab to the Clinic,” will provide how-to information for clinicians who want to apply the concepts that are presented. Agents that increase inflammatory mediators, the inflammatory cytokines, are those elements of our environment that initiate chronic inflammatory response. We think of chronic infection, for instance, in terms of the relationship of H. pylori to cardiovascular disease, or Pneumocystis carinii and its relationship to chronic inflammatory mediation. Another is allergy and the relationship of allergens to alteration of the ratios and balance between the thymus dependent-1 (Th-1) and thymus dependent-2 (Th-2) cytokines. We generally think of allergy as shifting the balance toward the Th-2-dependent cytokines and increasing inflammatory load based upon an imbalance between Th-1 and Th-2. Perilla Frutescens and Th-1/Th-2 Imbalance For several years I have been following Japanese literature that has discussed the development of a food concentrate that can be used to assist in Th-2 imbalance situations, the allergic profile, the IgE-mediated profile, either the pulmonary allergen or the food-related gastrointestinal allergen. This concentrate is a mixture of flavonoids derived from the concentrate of Perilla frutescens. This interesting fruit has berries that contain a rich array of flavonoid-like molecules unique to this particular fruit. The perilla seed, when concentrated, has very high levels of luteolin and other unique flavonoids, which have been found to be IgE modulators. They influence IgE modulation in such a way as to lower allergy potential. They help stabilize mast cells; they help prevent degranulation; they help prevent the release of the Th-2 proinflammatory cytokines; and they help restore balance of Th-1 and Th-2 function. Perilla Seed Concentrate and Liver Inflammation A number of papers have described the effects of Perilla frutescens concentrates in cell culture systems, in animal models, and in human trials. In one such paper, researchers examined a major polyphenolic component of perilla for its ability to reduce lipopolysaccharide (LPS)-induced liver inflammation. Supplementation with this substance had some profound stabilizing effects in an animal model.19 In clinical trials the level of standardized perilla seed concentrate used to manage allergic-type IgE-mediated disorders is in the range of 100-200 mg per day. This level proved to be a great help in stabilizing mast cells against degranulation. It is interesting to note that it has an effect at a lower level than chromolyn sodium, which is also a mast cell-stabilizing substance that helps to block IgE-mediated effects. The perilla concentrate, in doses of 100-200 mg, may be a clinically useful product for those individuals who have inflammatory shifts as a consequence of allergic potential. Estrogen and Catechol Ortho-Quinones One other area that we know increases inflammatory potential is the production of the so-called 4-hydroxyestrogens. We have talked at length in previous issues of FMU about the “flame-dancing estrogens.” Those are the estrogens of the hydroxylation pattern of the 4-position on the estradiol or estrogen molecule, the carbon No. 4 of the A ring of the estrogen, which produces catechol estrogen that then undergoes auto-oxidation to produce a quinone estrogen. This quinone estrogen can chemically react very rapidly with DNA in the adjacent tissue, causing chromosomal injury and becoming potentially carcinogenic. This approach talks about the role of a metabolite of estrogen as an endogenous toxic molecule, and how that interrelates with proinflammatory potential of estrogen and carcinogenic implications of estrogen. Auto-Oxidation These are called the catechol ortho-quinones of estrogen. Estrogens are not the only molecules that undergo auto-oxidation to form quinones. The catecholamines do this as well, and that may be why increased catecholamine in a specific tissue with increased oxidation can be associated with neurodegeneration. I am talking about Parkinson’s disease. I have connected what appear to be dissimilar facts, one of estrogen and breast cancer, and the other of dopamine and Parkinson’s disease into a singular model related to auto-oxidation to form these quinone molecules, these catechol ortho-quinones. High production of dopamine oxidation products or high production of 4-hydroxyestrogens can interrelate to these risk factors. Redox Potential An interesting discussion of catechol ortho-quinones was published in Carcinogenesis.20 It indicates that redox potential in the cells, i.e. the brain or the breast, may be important in protecting against the formation of quinones that can cause injury. Redox potential means specific antioxidants like lipoic acid, green tea catechins like epigallocatechin gallate compounds (EGCG), and limonene from citrus. All of these substances have important roles as food-derived, redox potential agents that help protect against the formation of these quinone-like molecules. If you are producing an excessive level of these oxidation products, you are at risk to DNA injury and inflammatory insult. In the case of estrogen in animal studies, one study found that the 4-hydroxylation pattern is generally a low-activity pathway.21There is not much 4-hydroxylation. But in some cases there may be upregulation due to exposure to various potentiating agents like dioxins or other petrochemical hydrocarbons. When the body’s detoxification machinery has been upregulated by certain of the P450 cytochromes, production of 4-hydroxyestrogens is increased. Therefore, as we look at protecting a woman against her own estrogens, we would want to achieve balance by increasing the production of the 2-hydroxyestrogens and their methylation to form the 2-methoxyestrogens, and reducing the production of the 4-hydroxy compounds. Managing Estrogen Risk Research has shown that diindolylmethane (DIM) and indole-3-carbinol (I3C) help potentiate the production of the favorable 2-hydroxyestr If a woman is at risk to her own estrogens, she needs to get higher levels of the B complex vitamins, consistent with what we discussed on side I of this month’s issue of FMU. She needs to lower her exposure to the toxic substances that are upregulating the production of quinone estrogens, and she needs to increase her cruciferous vegetable intake to two or three portions a day (150-200/day equivalent of I3C). We have talked about the web that Dr. Delany described, the connection of various functions that make cardiology a functional cardiology. Thanks for being with us. We look forward to talking with you in March.

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